Food and Drug Administration Advisory Committees

title: FoodandDrugAdministrationAdvisoryCommittees

author: Rettig,RichardA.publisher: NationalAcademiesPress

isbn10|asin: 0309048370printisbn13: 9780309048378ebookisbn13: 9780585085500

language: English

subject

InstituteofMedicine(U.S.).--CommitteetoStudytheUseofAdvisoryCommitteesbytheFoodandDrugAdministration,Publichealthadvisorygroups--UnitedStates--Evaluation.

publicationdate: 1992lcc: RA395.A3I561992ebddc: 353.0077/8

subject:

InstituteofMedicine(U.S.).--CommitteetoStudytheUseofAdvisoryCommitteesbytheFoodandDrugAdministration,Publichealthadvisorygroups--UnitedStates--Evaluation.

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FoodandDrugAdministrationAdvisoryCommittees

CommitteeToStudytheUseofAdvisoryCommitteesbytheFoodandDrugAdministration

RichardA.Rettig,LaurenceE.Earley,andRichardA.Merrill,Editors

DivisionofHealthCarePolicy

InstituteofMedicine

NATIONALACADEMYPRESSWashington,D.C.1992

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NATIONALACADEMYPRESS2101ConstitutionAvenue,N.W.,Washington,DC20418NOTICE:TheprojectthatisthesubjectofthisreportwasapprovedbythegoverningboardoftheNationalResearchCouncil,whosemembersaredrawnfromthecouncilsoftheNationalAcademyofSciences,theNationalAcademyofEngineering,andtheInstituteofMedicine.Themembersofthecommitteeresponsibleforthereportwerechosenfortheirspecialcompetenciesandwithregardtoappropriatebalance.

ThisreporthasbeenreviewedbyagroupotherthantheauthorsaccordingtoproceduresapprovedbyareportreviewcommitteeconsistingofmembersoftheNationalAcademyofSciences,theNationalAcademyofEngineering,andtheInstituteofMedicine.

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SupportforthisprojectwasprovidedbytheFoodandDrugAdministrationpursuanttoContractNo.223-91-8050.

LibraryofCongressCatalogCardNo.92-62633ISBN0-309-04837-0

Copyright1992bytheNationalAcademyofSciences.Allrightsreserved.

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Theserpenthasbeenasymboloflonglife,healing,andknowledgeamongalmostallculturesandreligionssincethebeginningofrecordedhistory.TheimageadoptedasalogotypebytheInstituteofMedicineisbasedonareliefcarvingfromancientGreece,nowheldattheStaatlichemuseeninBerlin.

FirstPrinting,October1992SecondPrinting,March1993

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CommitteetoStudytheUseofAdvisoryCommitteesbytheFoodandDrugAdministration

LAURENCEE.EARLEY,*Chair,FrancisC.WoodProfessorofMedicine,DepartmentofMedicine,HospitaloftheUniversityofPennsylvania,Philadelphia,Pennsylvania

ROBERTS.ADLER,AssociateProfessorofLegalStudies,GraduateSchoolofBusinessAdministration,UniversityofNorthCarolina,ChapelHill,NorthCarolina

RICHARDA.BERMAN,*President,HoweLewisInternational,NewYork,NewYork

RICHARDE.CLARK,ProfessorofSurgery,AlleghenyGeneralHospital,Pittsburgh,Pennsylvania

DEBORAHCOTTON,HarvardUniversitySchoolofPublicHealth,Boston,Massachusetts

J.RICHARDCROUT,President,BoehringerMannheimPharmaceuticals,Rockville,Maryland

CAROLYNEK.DAVIS,*NationalandInternationalHealthCareAdvisor,Ernst&Young,Washington,D.C.

JORDANU.GUTTERMAN,ProfessorandChairman,DepartmentofClinicalImmunologyandBiologicalTherapy,M.D.AndersonCancerCenter,Houston,Texas

SHEILAJASANOFF,ProfessorandChair,DepartmentofScienceandTechnologyStudies,CornellUniversity,Ithaca,NewYork

PAULMEIER,*ProfessorofStatistics,UniversityofChicago,Chicago,Illinois

THOMASC.MERIGAN,JR.,*BeckerProfessorofMedicineand

Head,DivisionofInfectiousDisease,StanfordUniversitySchoolofMedicine,Stanford,California

RICHARDA.MERRILL,*DanielCaplinProfessorofLaw,UniversityofVirginiaSchoolofLaw,Charlottesville,Virginia

HARRYM.MEYER,JR.,President,MedicalResearchDivision,AmericanCyanamidCompany,PearlRiver,NewYork

FRANKE.SAMUEL,JR.,GovernmentStrategyAssociates,Washington,D.C.

LOUISE.UNDERWOOD,ProfessorofPediatrics,UniversityofNorthCarolina,ChapelHill,NorthCarolina

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ALBERTP.WILLIAMS,TheRANDCorporation,SantaMonica,California

JAMESB.WYNGAARDEN,*AssociateViceChancellorforHealthAffairs,DukeUniversity,andForeignSecretary,NationalAcademyofSciencesandInstituteofMedicine,Washington,D.C.

StudyStaff

RICHARDA.RETTIG,StudyDirector

STANLEYW.AMMONS,JR.ProgramOfficer

HOLLYDAWKINS,ResearchAssistant

THELMAL.COX,ProjectAssistant

NANCYDIENER,FinancialAssociate

RUTHELLENBULGER,Director,DivisionofHealthSciencesPolicy

*Member,InstituteofMedicine

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PrefaceThedepartmentsandagenciesofthefederalgovernment,especiallythosedeeplyengagedinscientificandtechnologicalmatters,havemadeextensiveuseofexternaladvisorycommitteesasameanstoacquireindependentscientificandtechnicaladvice.Thisuseofadvisorycommitteeshasreceivedattentionovertimefromanumberofsources,includingtheCongress,andinrecentyearshasbeenthesubjectofmoregeneralanalytictreatment.

1,2

TheFoodandDrugAdministration(FDA)oftheDepartmentofHealthandHumanServicesmakesextensiveuseoftechnicaladvisorycommittees.Itdoessoprimarilyinthesupportofitsevaluationandregulationofdrugs,biologics,andmedicaldevicesforhumanuse.In1991,promptedbytheCommissionerofFoodandDrugs,Dr.DavidA.Kessler,theFDArequestedthattheInstituteofMedicine(IOM)examinetheoptimaluseofFDA'sadvisorycommitteesinproductevaluationandinrelationtoagencymanagementandagencyaccountability.ThisreportresultsfromthedeliberationsofacommitteeconvenedbytheIOMtoconductthisstudy.

Ingeneral,advisorycommitteesarethemajorwaybywhichtheFDAobtainsindependenttechnicalandscientificadvice,althoughworkshops,symposia,consultants,andextensive,ofteninformal,contactsbetweenagencyprofessionalsandthescientificandmedicalcommunitiesareotherimportantmeansfordoingso.Althoughthisreportfocusesonadvisorycommittees,theIOMcommitteerecognizesandendorsestheuseoftheseothermeansofobtainingindependentexpertadvice.

TheFDAadvisorycommitteesystemwasestablishedattheagency'sinitiativetoprovideitwithtechnicalassistancerelatedtothedevelopmentandevaluationofdrugs,biologics,andmedicaldevices,tolendcredibilitytoitsdecisionsanddecision-makingprocesses,andtoprovideaforumforpublicdiscussionofcertaincontroversialissues.

TheIOMcommitteebelievesthattheprimaryroleofFDAtechnicaladvisorycommitteesisandshouldbetoprovideindependentexpert

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scientificadvicetotheagency.ItalsobelievesthattheexistingFDAadvisorycommitteesystemisfundamentallysound,hasservedtheagencywell,anddoesnotneedwholesalereorganization.Itshouldberetainedandstrengthened.However,theIOMcommitteerecommendsanumberofadministrativeandproceduralchangesthataredesignedtoimprovetheperformanceandusefulnessoftheadvisorycommitteesystem,tostrengthenitsmanagement,andtoincreaseitsaccountability.

Inresponsetotheagency'srequest,thereportseekstoprovideFDAwithoperationalguidanceontheuseofitsadvisorycommittees.Indoingso,itexaminesandmakesrecommendationsontherecruitmentandacquisitionofcommitteemembership,theagency'smanagementofthefinancialconflictofinterestandintellectualbiasofcommitteemembers,andtheoperationsandmanagementoftheadvisorycommitteesystem.

ThecontroloffinancialconflictofinterestreceivedmoreoftheIOMcommittee'sattentionthananyothertopic.Thispriority,whichwastheforemostconcernoftheCommissioner,stemmedinlargemeasurefromthefactthattherapidchangeinthecriteriaandproceduresbywhichconflictofinterestcontrolswereadministeredappearedtobeimpairingtheFDA'sabilitytouseadvisorycommittees.

Theissuesoffinancialconflictofinterestandofintellectualbiasaregreatconcerntothescientificcommunityatthepresenttime.Theypervademanyrealmsofscienceandmedicineandhavehighlycomplexmanifestationsinspecificinstitutionalcontexts.TheIOMcommitteeconsideredtheseissues,however,inrelationtoFDA'sregulatoryresponsibilitiesfortheevaluationofdrugs,biologics,andmedicaldevices.Consequently,thisreportgivesgreatweighttothelegalandadministrativeaspectsofthesematters,astheseweretheimmediatesourceofFDA'sproblems.Althoughthereport

acknowledgestheimportanceofbroaderconcernsforconflictofinterestandintellectualbias,itdoesnotexaminethematanylength.

TheIOMcommitteefoundgreatvariationinthewayadvisorycommitteeswereusedbythethreecentersresponsiblefordrugs,biologics,andmedicaldevicestheCentersforDrugEvaluationandResearch,BiologicEvaluationandResearch,andDevicesandRadiologicalHealth.Onethemethatrunsthroughoutthisreport,therefore,callsforthedevelopmentofuniformguidelinesapplicabletoadvisorycommitteesacrossthethreecentersandfortheeliminationofunnecessarydifferences.

AnotherthemeembeddedintheIOMcommittee'srecommendationsistheneedforFDAtoensuretheindependenceofitsadvisorycommittees.Inthehighly-chargedenvironmentsurroundingproductevaluationbytheFDA,chargesthatitseekstoinfluencetheoutcomeofcommitteedeliberationsmayormaynothavemeritbutareoftenmadebyinterestedparties.Asaresult,ascertainingthevalidityofsuchchargescanbeverydifficult.

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appeartobe,abletoprovideindependentexpertadvice,andpointtotheuniformpoliciesandproceduresneededtoensurecommitteeindependence.

Finally,thecommitteefocusesonanumberofstepsthattheFDAshouldtaketostrengthenitsmanagementoftheadvisorycommitteesystem,fromtheOfficeoftheCommissionertotheprofessionalswhostaffadvisorycommitteeoperations.TheIOMcommitteesrecommendationsinthisareastrikeabalancebetweenthosewhourgeahighdegreeofcentralizationofcommitteemanagementintheOfficeoftheCommissionerandthosewhoarguethatnochangeiswarranted.

Insum,theIOMcommitteehasattemptedinthisreporttoprovidetheagencywiththeguidanceitsoughtinordertoenhancetheuseofadvisorycommitteesintheevaluationofdrugs,biologics,andmedicaldevices,toimprovetheagency'smanagementoftheadvisorycommitteesystem,andtoincreasetheaccountabilityofthatsystemtothegeneralpublic.

Notes

1.SheilaJasanoff,TheFifthBranch.ScienceAdvisersasPolicymakers(Cambridge,Mass.,HarvardUniversityPress,1990).

2.BruceL.R.Smith,TheAdvisers:ScientistinthePolicyProcess(Washington,D.C.,TheBrookingsInstitution,1992).

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AcknowledgmentsThisreportresultsfromthedeliberationsoftheInstituteofMedicineCommitteetoStudytheUseofAdvisoryCommitteesbytheFoodandDrugAdministration.Therecommendationsofthereportreflectthejudgmentsofthecommittee.

Theactualpreparationofthereportunderthedirectionofthecommitteehasbeenaccomplishedbythecollectiveeffortsofcommitteemembers,projectstaff,andothercontributors.Thecommitteegratefullyacknowledgesthesecontributions.

Thecommitteethankstheauthorsofthebackgroundpapersthatitcommissioned,whichprovidedvaluableinputtoitsdeliberations.Theseauthorsinclude:WendyE.Anderson,ScottDavidson,LaurieM.C.Faro,GokurajuK.Raju,andPaulK.Stockman.RebeccaWallacewasaconsultanttotheprojectandpreparedtheanalysisonwhichAppendixAwasbased.

ThecommitteeexpressesitsappreciationtotheIndustryLiaisonPanelthatitconvenedtoadviseit,especiallytoMarionJ.Finkel,itschair.Theothermemberswere:N.KirbyAlton,ScottA.Hensley,BruceMerchant,GeorgeOhye,MartinRose,EveRoss,andR.WilliamSoller.

SupportforthestudywasprovidedbytheDepartmentofHealthandHumanServices,FoodandDrugAdministration(ContractNo.223-91-8050).EquallyimportanttothesuccessfulconductofthestudywasthecooperationoftheFoodandDrugAdministrationstaff.ThecommitteethanksDavidA.Kessler,MaryK.Pendergast,CarolR.Scheman,JaneE.Henney,MaryJoVeverka,AmandaB.Pedersen,PatriciaM.Kuntze,DoloresD.Willis,CarlC.Peck,D.BruceBurlington,GeraldF.Meyer,RobertJ.Temple,JamesM.Bilstad,

MaryDougTyson,JohnTreacy,IssacRoubein,KathrynC.Zoon,GeraldV.Quinnan,JackGertzog,JamesS.Benson,HalynaBreslawec,andNancyPluhowski.Italsothanksthemanydivisiondirectorsandexecutivesecretarieswhogavegenerouslyoftheirtimeininterviewsbytheprojectstaff.OurspecialthanksgotoJamesWeixel,projectofficer,andStuartL.Nightingale,whooversawthestudy.

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ininterviewsbytheprojectstaff.OurspecialthanksgotoJamesWeixel,projectofficer,andStuartL.Nightingale,whooversawthestudy.

InhercapacityasDirectoroftheDivisionofHealthSciencesPolicy,RuthEllenBulgerprovidedvaluableguidanceoverthedurationoftheproject.StanleyW.AmmonsandHollyDawkinsprovidedablesupportasmembersoftheprojectstaff.ThelmaCox,projectassistant,sawthestudythroughfromstarttofinishwithunflappablegrace.

Contents

Preface v

Acknowledgments ix

ListofAbbreviations xii

Summary 1

1Introduction 33

2HistoricalEvolutionofFDAAdvisoryCommittees 46

3TheFDAAdvisoryCommitteeSystem 70

4RecurringIssues 100

5CommitteeMembership 116

6

EnsuringCommitteeIntegrity 127

7CommitteeOperations 173

8OrganizationandManagement 196

Appendixes

AResourceImplications 215

BGlossary 222

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ListofAbbreviations

CBER CenterforBiologicsEvaluationandResearch

CDER CenterforDrugEvaluationandResearch

CDRH CenterforDevicesandRadiologicalHealth

CFR CodeofFederalRegulationsCGMP CurrentGoodManufacturing

Practice(s)DHHS DepartmentofHealthandHuman

ServicesFACA FederalAdvisoryCommitteeActFDA FoodandDrugAdministrationFFDCAFederalFood,Drug,andCosmeticActFR FederalRegisterFOIA FreedomofInformationActGAO GeneralAccountingOfficeGSA GeneralServicesAdministrationIDE InvestigationalDeviceExemptionIND InvestigationalNewDrugNDA NewDrugApplicationNIH NationalInstitutesofHealthOGC OfficeoftheGeneralCounselOGE OfficeofGovernmentEthicsOSCE OfficeoftheSpecialCounselfor

Ethics,DHHSPHS PublicHealthServicePMA PremarketApproval(application)

SGE SpecialGovernmentEmployeesSMDA SafeMedicalDevicesAct(of1990)USP UnitedStatesPharmacopeia

SummaryTheFoodandDrugAdministration(FDA),inmid-1992,had41standingtechnicaladvisorycommitteesorpanelsthatsupportedtheworkofitsthreecentersresponsiblefortheevaluationandregulationofhumandrugs,biologics,andmedicaldevices.WereferinthisreporttothesecommitteesandtheiradministrativesupportastheFDA's''advisorycommitteesystem.''

Inlate1991,theInstituteofMedicine(IOM),inresponsetoarequestfromtheFDA,undertookastudyoftheagency'sadvisorycommitteesystem.ThisrequestwasinitiatedbyCommissionerDavidA.Kessler.HeaskedthattheIOMexaminetheoptimaluseofFDAadvisorycommitteesintheevaluationofdrugs,biologics,andmedicaldevicesandalsoconsidersuchcommitteesinrelationtoagencymanagementandagencyaccountability.TheCommissionerhimselfemphasizedhisdesiretoreceiveareportthatprovidedoperationalguidancefortheagency.Inaddition,hesingledoutasthemostimportantissuethecommittee'sexaminationoffinancial"conflictofinterest"controlsastheyaffectedadvisorycommittees.

TheIOMconvenedacommitteetoconductthisstudy.Itsmembersbroughtexpertiseinmedicalresearch;developmentofdrugs,biologics,andmedicaldevices;designandconductofclinicaltrials;medicine,surgery,andnursing;regulationofdrugs,biologics,devices,consumerproducts,andhealthcareservices;administrationofmedicalresearch,healthcarefinancing,andthedeliveryofhealthcareservices;andhealthandsciencepolicyresearch.ThreemembersoftheIOMcommitteecurrentlyserveonFDAadvisorycommittees,othershaveservedinthepast,andseveralwerepreviouslyinvolvedasFDAofficialsinthedesignofthecurrentsystem.

Ingeneral,advisorycommitteesarethemajorwaybywhichtheFDAobtainsindependenttechnicalandscientificadvice.Othermeansforobtainingsuchadviceincludeworkshops,symposia,consultants,andextensive,ofteninformal,contactsbetweenagencyprofessionalsandthescientificandmedicalcommunities.Althoughthisreportfocusesonadvisory

committees,theIOMcommitteerecognizesandendorsestheuseoftheseothermeansofobtainingindependentexpertadvice.

TheFDAadvisorycommitteesystemwasestablishedattheagency'sinitiativetoprovideitwithtechnicalassistancerelatedtothedevelopmentandevaluationofdrugs,biologics,andmedicaldevices,tolendcredibilitytoitsdecisionsanddecision-makingprocesses,andtoprovideaforumforpublicdiscussionofcertaincontroversialissues.Ingeneral,theIOMcommitteebelievesthattheexistingsystemisfundamentallysound,hasservedtheagencywell,anddoesnotneedwholesalereorganization.Itshouldberetainedandstrengthened.However,theIOMcommitteerecommendsanumberofadministrativeandproceduralchangesthataredesignedtoimprovetheperformanceandusefulnessoftheadvisorycommitteesystem.

TheRolesofFDAAdvisoryCommittees

TheIOMcommitteebelievesthattheprimaryroleofFDAtechnicaladvisorycommitteesisandshouldbetoprovideindependentexpertscientificadvicetotheagencyinitsevaluationofspecificdrugs,biologics,ormedicaldevicesatanystageofconsiderationbytheagency.Arelatedroleistoadvisetheagencyongeneralcriteriaforevaluationandonbroadregulatoryissuesthatarenotrelatedtoaspecificproduct.(ArolespecifictoCBER,whichtheIOMcommitteerecognizes,isthereviewofintramuralresearchprogramsandpersonnel.)Severalkeytermsandassumptionswarrantfurthercomment.

First,"independence"referstofreedomfrominfluencebythesponsoroftheproductunderconsideration,byanyotherentitiesorpersonsthatcouldgainorloseasaresultoftheoutcomeoftheprocess,andbytheFDAitself.Asapracticalmatter,theissueofindependenceofadvisorycommitteesisusuallyraisedwithrespecttotheirrelationtotheFDA.

ThehighstakesassociatedwithFDAdecisionsmeanthatpartiesdisappointedbyitsactionshavestrongincentivestochargethattheindependenceofadvisorycommitteesiscompromisedbyundueFDAinfluence.However,theissuesofindependenceandundueinfluencemayariseasaresultofsubtlefacetsoftheprocess;forexample,therecruitmentofcommitteemembers;delaysindistributionofadvancematerials;thecontentandtoneofagendaquestions;andevenseatingarrangementsatcommitteemeetings.TheIOMcommitteemakesrecommendationsonalltheseissues,whichcollectivelypointtogreatersafeguardsoftheindependenceofcommittees.

Second,"expertscientificadvice"impliesthatmemberswillbeacknowledgedexpertsinsomeareaofsciencethatisrelevanttothepurviewofthespecificadvisorycommittee.

Third,advisorycommitteesadvisetheFDAanddonotthemselveshaveauthoritytomakedecisionsthatobligatetheagencyoranyprivatepartytoacourseofaction.

Fourth,advisorycommitteesrespondtospecificquestionsthathavebeenidentifiedbytheprofessionalstaffoftheagency.Thesequestionsmaydealwithstudydesignormethodology,adequacyofdata,andassessmentandinterpretationofrisksandeffectiveness.

Finally,althoughadvisorycommitteeshaveaprominentroleintheproductapprovalstage,theyaresometimesusedearlierintheproductdevelopmentcycleandsometimesinvitedtoconsiderpostmarketingissues.TheIOMcommitteebelievesthatitisproperfortheFDAtousecommitteesatanystageofreviewwhenscientificadviceisneeded,whetherornotregulatoryactiononaspecificproductisunderconsideration.

PracticalLimitsonAdvisoryCommittees

ItisimportanttoacknowledgethattherearesignificantpracticallimitsontheFDA'suseofadvisorycommittees.Themostimportantlimitisthetimecommitteemembersareabletocommittotheactivity.Anotherlimitationisthenecessitythattheagencybeselectiveinchoosingquestionsforcommitteesfromanenormousamountofmaterialandwiderangeofissuesunderreview.Stillanotherlimitisthedifficultyofexercisingtightcontroloveragendatime,withtheconsequencethatcommitteediscussiontimeisoftenseverelytruncated.Finally,theuseofadvisorycommitteesislimitedbytheresourcesthattheFDAhasavailabletosupportthem.

CommitteeMembership

NominationCriteria

TheabilityoftheFDAtoattractandretainqualifiedindividualswhopossess"expertiseinthesubjectmatterwithwhichthe[advisory]committeeisconcerned"iscriticaltothesuccessfuloperationoftheadvisorycommitteesystem.The"subjectmatter"ofadvisorycommitteespertainsto(a)theevaluationofdrugs,biologics,andmedicaldevicesregardingtheirsafetyandeffectiveness,includingindicationsandcontraindicationsforuseandrelatedissuesoflabeling,and(b)tobroadertechnicalissuesrelatedtoproductevaluation,suchasspecificmethodologiesforassessingaparticularclassoftherapeuticagents.GiventhepurposesofFDAadvisorycommittees,

TheIOMcommitteestronglyendorsesthecriterionofscientificortechnicalcompetenceasarequirementforselectingallvotingmembersofFDAtechnicaladvisorycommittees.

Inthiscontext,"diversity"goalsofgender,raceandethnicity,andgeographyalsoguidetheselectionofcommitteemembers.TheIOMcommitteebelievesthatthesegoalsarenotincompatiblewiththecriterionofscientificandtechnicalcompetencebutreflectlegitimatepolicyobjectivesofapluralisticsocietythataredesignedtoensurearangeofviewpointsonwhatareseldompurelytechnicalissues.However,meetingthesediversitygoalsmaynecessitatespecialeffortsbytheFDAtoidentifywomenandminoritygroupmemberswhopossessthenecessaryexpertise.

TheIOMcommitteerecommendsthattheFDAcontinueitspolicyofactivelyseekingqualifiedwomenandmembersofminoritygroupsaspotentialcandidatesforadvisorycommitteemembership.

SomeconstraintsmaylimittheaccessoftheDepartmentofHealthandHumanServices(DHHS)toscientificandtechnicalexpertiseasitseekstomeetitsdiversitygoals.CurrentpolicyoftheDepartmentofHealthandHumanServicespreventsanindividualfromservingconcurrentlyonmorethanonePublicHealthServiceadvisorycommitteewithoutaspecialdepartmentalwaiver.Thispolicylimitstheexpertisethatcanbetappedforaparticularcommitteeandimpedesmeetingdiversityobjectives.

TheIOMcommitteerecommendsthattheDepartmentofHealthandHumanServiceseliminateitspolicyprohibitingdualcommitteemembershipandthatqualifiedcandidatesforFDAadvisorycommitteesbeallowedtodecidewhethertheywishtoserveonmorethanonePublicHealthServicecommittee.However,italsorecommendsthattheDepartmentexhaustothermeansofrecruitmentbeforeitresortstoselectingindividualswhoserveonotheradvisorycommittees.

AlthoughtheFederalAdvisoryCommitteeAct(FACA)requiresthat

advisorycommitteemembershipbe"fairlybalancedin...thepointsofviewrepresentedandthefunctionstobeperformed,"thiscriterionprovideslittleoperationalguidancetoagencyheadsinthenominationandselectionoftechnicaladvisorycommitteememberswhoadviseonawideandunpredictablerangeofissues.TheIOMcommitteebelievesthat"balance"fortheFDA'stechnicaladvisorycommitteesshouldbeinterpretedasamixofrelevantscientificdisciplinesandadiversityofscientificviews.TheIOMcommitteealsobelieves,andcourtdecisionsnowsupport,thatitis

ultimatelytheCommissioner'sresponsibilitytoseethatsuchbalanceisachieved.

TheIOMcommitteeconsideredthewisdomofrecommendingthat'balance"beinterpretedascommitteemembershipthatincludedrepresentatives(oradvocates)ofspecificconstituencies,irrespectiveofscientificcompetence.Thecommitteerejectedthispremiseonthegroundsthattheprimaryroleofadvisorycommitteesistoprovidetheagencywiththebestscientificinterpretationsandadviceandnottorepresentspecificconstituencies.*

RecruitmentProcedures

TheFDAusesanumberofprocedurestogeneratenomineesforadvisorycommittees.Theonlyagency-wideformalmechanismistheannualFederalRegisterannouncementofadvisorycommitteevacanciesrequiredbytheFACA.Informalnomination-seekingpracticesvaryacrosscenters,withincenters,andovertime.

TheIOMcommitteerecommendsthattheFDAadoptanagency-widerecruitmentpolicyanddevelopamoresystematicapproachtoseekingnominationsonacontinuingbasisforpotentialadvisorycommitteemembership.Theagencyshouldactivelyseeknomineesfrommanysourcesacademicmedicine,professionalsocieties,othergovernmentagencies,industry,andconsumerandpatientorganizations.Itshouldnotrelysolelyonitsownstaffforsuchnominations.Eachcentershoulddevelopandperiodicallyupdateapoolofqualifiedcandidates,ratherthansimplyseeknominationstofillvacancies.

TheIOMcommitteeconsiderstheresponsibilityofnominatingqualifiedindividualsforFDAadvisorycommitteestobesharedbymedicalandscientificsocieties,medicalschooldeansanddepartmentchairs,consumerandpatientorganizations,andotherinterestedparties.

TheIOMcommittee,addressingitselftothesegroups,urgesthemto

acceptasacontinuingobligationtheidentificationandnominationofindividualstothepoolofpotentialFDAadvisorycommitteemembers.

*TheIOMcommitteerecognizedtheimportanceofinputtoadvisorycommitteedeliberationsfromnon-scientificsourcessuchaspatients,industry,andconsumergroupsandconcludedthatsuchinputcanbebestachievedbytestimonythatrelatesdirectlytothespecificagendaofacommittee.

ConsumerMembers

TheIOMcommitteeregardstheexpressionofconsumerviewsonFDAtechnicaladvisorycommitteesasbothvaluableandnecessary.Formedicaldeviceadvisorypanels,theseviewsareprovidedbynonvotingconsumerrepresentatives,asrequiredbystatute.Foralldrugandtwobiologicsadvisorycommittees,theyaresupplied,notbynonvotingconsumerrepresentatives,butbyconsumer-nominated,technicallyqualifiedvotingmembers.

ThecommitteeattachesgreatimportancetothecriterionoftechnicalexpertiseforthenominationandselectionofvotingmembersofFDAadvisorycommitteesandopposesgrantingvotingmemberstatusbasedonrepresentationofspecificconstituencies.Itconsideredandrejectedtheextensiontodrugandbiologicsadvisorycommitteesofthelegally-requiredCDRHapproachofnonvotingconsumerandindustryrepresentativesbutchosenottorecommendmoficationofthelaw.

TheIOMcommitteebelievesthattheconceptof"consumer"bothforconsumer-nominatedmembersandconsumerrepresentativesshouldbeexpandedtoincludepatientsorpatient-nominatedindividuals,whoseviewpointscanbevaluableintheproductevaluationprocess.TheFDAshouldactivelysolicitnominationsfromconsumerandpatientorganizationsfortechnicallyqualifiedindividualstoserveasvotingmembersonallofitsadvisorycommittees.Theagencyshouldcontinuetosolicitnominationsfromtheconsortiumofconsumerorganizations,butitshouldalsoreachouttootherinterestedparties.InthejudgmentoftheIOMcommittee,thepracticeofallowinganyoutsideorganizationtoscreen(andthustoscreenout)nomineesforFDAadvisorycommitteesisunsound.

TheIOMcommitteerecommendsthattheFDAseektechnicallyqualifiednomineesfromconsumerorganizationsandotherinterestedpartiesto

serveasvotingmembersonallofitstechnicaladvisorycommitteesandpanels.Appointmentshouldrequirethebasicqualificationofscientificortechnicalcompetence.Thecommitteealsorecommendsthattheconceptof"consumer"beexpandedtoincludepatientandpatient-orientedorganizations.Furthermore,noprivateindividualororganizationshouldbegiventherighttoscreennominationsfromothersourcesonbehalfoftheagency.

AppointmentAuthority

Untilearly1991,theSecretaryofHealthandHumanServicesappointedmembersofFDAtechnicaladvisorycommittees.Thissometimesresultedin

nomineeswhomaynothavebeenscientificallyqualifiedorwhowereselectedtobringapoliticallypreferredviewonscientificandregulatorymattersbeforetheFDA.FollowingenactmentoftheFoodandDrugAdministrationRevitalizationActof1990,theCommissionerhasappointedtechnicaladvisorycommitteemembers,butheremainsunderanobligationtosendnominationpackagestotheOfficeoftheSecretary10daysinadvanceofanyappointment.TheIOMcommitteebelievesthatvestingpowertoappointcommitteemembersintheCommissionerconstitutesasubstantialstepforwardinbothexpeditingtheappointmentprocessandensuringthatsuchappointmentsareresponsivetothespecificscientificandtechnicalneedsoftheagency.

TheIOMcommitteecommendstheOfficeoftheSecretaryforitsconcurrencethattheRevitalizationActvestsformalauthoritytoappointadvisorycommitteemembersintheCommissionerofFoodandDrugs.

AdministrativeResponsibilityforAppointments

TheCommissioner,underhisauthoritytoappointadvisorycommitteemembers,shouldclearlyindicatetoallFDAstaffthatcenterdirectors,officeanddivisiondirectors,andexecutivesecretariesshareresponsibilityforrecruitingqualifiedadvisorycommitteemembers.NominationsshouldcometotheCommissionerfromthecenterdirectors.

TheIOMcommitteerecommendsthatthejobdescriptionsoftheFDAcenter,office,anddivisiondirectors,andexecutivesecretariesbeexpandedtoreflecttheirresponsibilitiesforrecruiting,nominating,andrecommendingadvisorycommitteemembers.

CommitteeIntegrity

TheIOMcommitteebelievesthatitisessentialthatmembersofFDA'sadvisorycommitteebeimpartialandobjectiveandnot

compromisedbyfinancialconflictsofinterest.Itisalsocriticalthattheybefreeofdemonstratedintellectualbias.Thesegoalsarebothpracticalconditionsfortheeffectiveperformanceofadvisorycommitteesandanexpressionofdeeplyhelddemocraticvalues.Toachievetheseends,theIOMcommitteehasaddressedtheFDA'sstandardsandproceduresforcontrollingfinancialconflictofinterestandintellectualbias.

Attheoutsetofthisstudy,CommissionerKessleraskedthattheIOMcommitteeprovidetheFDAwithspecificguidanceonthehandlingof

potentialfinancialconflictsofinterestinvolvingadvisorycommitteemembers.ControversiesoverthisissuewerethreateningtheFDA'sabilitytouseadvisorycommittees.Thestudyrevealedthatthe"problem"identifiedbytheCommissionerinvolvedtheinteractionofnewconflictofintereststatutesandexecutiveorders,thelegalinterpretationofwhattheselawsrequired,theiradministrativeimplementation,andseveralhighlyvisiblecommitteemeetings.Moreover,thisinteractionwasoccurringinahighlypoliticizedenvironmentandinacompressedperiodoftime.

Thefinancialconflictofinterestlawsthatapplytofull-timefederalemployeesalsoapplytoadvisorycommitteememberswhoareappointed,asthoseattheFDAare,asspecialgovernmentemployees(SGEs).Asappliedtoadvisorycommitteemembers,theselawsexisttoensurethattheirimpartialityisnotcompromisedbytheirpersonalfinancialinterests,orthoseoftheirspousesandimmediatefamilies,oroftheiremployers.

Advisorycommitteemembersarescreenedforpotentialconflictofinterestattwodifferenttimes.First,candidatesformembershipareevaluatedatthetimeofnominationand,ifappointed,fileastatementdisclosingtheirfinancialinterests.Thisinitialscreenprovidesthebasisforasetofso-called"exclusions,"namely,specificcompanies,products,orissuesthatmightcomebeforeacommitteeandthattheindividualmaynotconsider.

Althoughthisstageofreviewisimportant,byfarthegreaternumber,andmoredifficult,conflictofinterestissuesarisewhenamember'sfinancialinterestsarefoundtointersectwithparticularmeetingagendaitems.Foreachcommitteemeeting,theFDAreviewseachcommitteemember'sinterestsandaffiliationsinrelationtotheagendatodeterminewhetherapotentialfinancialconflictortheappearanceofsuchconflictexists.Thediscoveryofapotentialconflict

disqualifiesamemberfromparticipatingintheparticulardiscussionofaspecificagendaitemunlessawaiverisgranted.Thelawallowsawaiverif(1)themember'sinterestisnotsubstantial,(2)ifitistooremoteorinconsequentialtoaffecthisorherimpartialjudgment,or(3)ifthemember'sparticipationissoimportantthatitoutweighsthepotentialconflict.Anywaivermustbesoughtandapprovedbeforetheindividualmembermayparticipateinthecommittee'sdiscussionofthespecificmatterinquestion.

Eventsin1989and1991raisedquestionsaboutfinancialconflictofinteresttoanewprominence.In1989,inthewakeofseveralwell-publicizedinstancesofhigh-levelgovernmentofficialsengaginginunlawfulfinancialtransactionsforpersonalbenefit,includingthegenericdrugscandalsthataffectedtheFDA(althoughnotwithrespecttoanyadvisorycommittee),theexecutivebranchtookaction.ThePresident'sCommissiononFederalEthicsLawReformrecommendedthatstandardsofconductbeupdatedandthat

theOfficeofGovernmentEthics(OGE)begivenauthoritytoissueuniformregulationsforallexecutivebranchagencies.ExecutiveOrder12674,issuedbyPresidentGeorgeBushonApril12,1989,revokedthedecentralizedregulatoryschemethathadbeenestablishedin1965anddirectedtheOGEtodevelop"asingle,comprehensive,andclearsetofexecutivebranchstandardsofconductthatshallbeobjective,reasonable,andenforceable"(56FR33778,July23,1991).TheOGE,whichhadbeenpartoftheOfficeofPersonnelManagement,wasestablishedasaseparateagencyoftheexecutivebranchonOctober1,1989.

Congress,unwillingtocedeleadershipinthisarenatotheexecutivebranch,enactedtheEthicsReformActof1989(PublicLaw101194)onNovember30,1989.Thisactincludedaprovision[Section208(b)(3)discussedbelow]intendedtofacilitatetheuseofexpertadvisorycommitteesbyempoweringagencyheadstograntwaiversfromthelaw'sbasicprohibitionwhentheneedforanindividualmemberoutweighedanypotentialconflict.

ResponsibilityforimplementingtheexecutiveorderandthenewstatutefellprimarilyontheOGEand,withinDHHS,onanewunitintheOfficeoftheGeneralCounsel.Thatunit,theOfficeoftheSpecialCounselforEthics(OSCE),isresponsibleforDHHS-widepoliciesandproceduressafeguardingtheethicsofgovernmentemployeesandforcoordinatingdepartmentalpolicywithOGE.WithintheFDA,anexistingunit,theDivisionofEthicsandProgramIntegrity(DEPI),retainedresponsibilityforapprovingwaiverrequestsfromthecentersonbehalfoftheCommissioner.

In1991,severalFDAadvisorycommitteesconvenedtoreviewhigh-profileproductsthatpresentedparticularlycontroversialproblemsofpotentialconflictofinterest.ThetopicsonwhichtheagencysoughtadviceincludedthecontroversyoverthereviewofTHAasadrugfor

thetreatmentofAlzheimer'sdisease;thedisputeoverthepossiblepropensityofProZactoinducesuicideinSeptember1991;thesafetyofsiliconegelbreastimplantsinNovember1991andagaininFebruary1992;andacontroversyovertheuseofphotopheresisinthetreatmentofscleroderma.Althougheachofthesecommitteemeetingsoriginatedinuniquecircumstances,alldrewunprecedentedattentiontoFDA'sproceduresforcontrollingpotentialconflictsofinterest,andtheyarrivedatFDA'sdoorstepinthesameperiodoftime.

Whatdidthesecasesreveal?First,theagencyhadbeenprocessingwaiversunderoutdatedstandardsthathadnotbeenupdatedtoaccordwiththe1989statute.Second,althoughwaiverprovisionsarepartofthefederalcriminalcode,governmentlawyerswerenotinvolvedinreviewingwaivers.Consequently,theFDA'sChiefCounsel,inthefallof1991,assignedtwolawyerstoreviewwaivers,andtheybegantoquestiontheagency'sexisting

procedures.Soonthereafter,OSCEbecameinvolvedonbehalfofthedepartmentandeventuallyreplacedtheagency'slawyers.Third,OSCEandtheOGEintroducednewandexpansivewaiverstandardsandprocedures.Fourth,theunitsintheFDAstillresponsibleforconflictofinterestcompliancecontinuedtoperformtheirroleswithoutanyhigh-levelpolicyguidance.Fifth,boththeagency'slawyersandthosefromOSCE,whofeltcompelledtochangetherulestoaccordwiththelawandexecutiveorder,dealtwithwaiverissuesonacase-by-casebasis,andprovidedlittlegeneralguidancetothoseadministratorsresponsibleformanagingtheadvisorycommitteesystem.Tomakemattersworse,allofthesechangeswereoccurringwithinaveryshortspanoftime.

Notsurprisingly,theconflictofinterestproblemwasfarmorevisibleinsideFDAthanoutside.Andwithintheagencynoonefullygraspedthatnatureofthechangesthatweretakingplace.However,tosomeitappearedasthoughconflictofinterestrestrictionsmightcausetheadvisorycommitteesystemtogrindtoahaltbecausenewstandardshadnotbeenoperationallyclarifiedandtheprocesshadbeengreatlycomplicated.

Anyattempttoaddresstheproblemmustdealwithissuesoflaw,ofbureaucraticprocedure,andofadministration.TheIOMcommitteeconsideredreformsthatwouldrequirenewlegislationandthosethatcouldbeimplementedwithinexistingstatutoryauthority.

OptionsRequiringLegislation

TheIOMcommitteeconsideredseveraloptionsthatwouldrequirenewlegislation.Thefirstwouldsubstituteforthepresentdisqualificationsystemonethatrequiredcommitteememberstopubliclydisclosealloftheirinterestsandaffiliations,andthenreliedonpublicscrutinytoassesstheobjectivityoftheiradvice.TheIOMcommitteefoundthisapproachunacceptable,asitwouldallow

participationofmemberswithsignificant,directfinancialintereststhatshouldbedisqualifyingandwouldunderminetheappearanceofobjectivity.

Asecondoptionwouldbeasystemthatcoupledfulldisclosureofallinterestswithageneralrulebarringparticipationbymemberswithsignificantfinancialinterests.Althoughthisproposalmaycontainthecoreofapromisingreformofthesystemforregulatingconflictofinterest,theIOMcommitteedidnotexplorefullyitsramifications.Thecommittee'sjudgmentandthatofmanywespoketowasthatamajorlegislativeoverhaulofthismagnitudewassimplyunlikely.GivenFDA'sexpressedneeds,ourcharge,andourtimetable,thecommitteeturnedtosolutionsthatwerefeasiblewithintheexistingstatutoryframework.However,thisapproachisclearlyacandidateforfurtherstudy.

OptionsAvailablewithinExistingAuthority

Whatcanbedoneunderexistingauthority?Potentially,agooddeal,asthefollowingoptionssuggest.AlthoughthefirstoptionbelowcouldbeimplementedbyFDAitself,thesuccessfulimplementationoftheotherrecommendationswouldrequiretheactiveinvolvementoftheCommissionerandhisoffice,thesupportivecollaborationoftheOSCE,andatleastthetoleranceoftheOGE.

OnetheoreticaloptionforFDAwouldbetoavoidappointingadvisorycommitteemembersasspecialgovernmentemployees,thuscircumventingtherestrictionsofthefederalconflictofinterestlaw.Thissolutionhasthenotabledisadvantageofattemptingtodefinetheproblemaway,whichishardlyawaytoinstillconfidenceinthesystem.Moreover,newlegislationwouldpossiblybeneededtoallowpaymentofmembersandsharingoftradesecretinformation.

Second,theFDAitselfcouldexercisegreatercareintheinitialappointmentofadvisorycommitteemembers.Itcoulddemandevenmoreinformationthaniscurrentlyrequiredtoenableittoidentifyinadvancepotentialmemberswhosefinancialinterestswouldclearlydisqualifythemforsomecommitteemeetings.Yetbecausetheinterpretationofaprohibitedinterestisalreadyextremelybroad,andpotentialconflictcannotbeidentifiedbeforemeetingagendasareset,seriouspursuitofthisproblematicapproachmightdisqualifyvaluablemembersandproducenogaininintegrity.Moreover,theconflictsofinterestthatmightariseoverthedurationofacommitteemembershipareunpredictableatthetimeofappointment.

Third,theFDA,workingwithOSCE,couldformulateandcodifycriteriaforgranting208(b)(3)waivers.TheIOMcommitteebelievesthatthisisessential.Codificationwouldbealengthyprocess,butsomemutualunderstandingofthegroundsforjustifyingawaiverisbadlyneeded.Achecklistofvariablesmustbeformulatedthat

includes:thesizeoftheinterest;thecharacteroftheinterest;thelikelihoodthananinterestwillbeaffectedbyagencyactionbasedonthecommittee'sadvice;andtheactualimportanceofthemembertothecommittee'sdeliberations.Regardingthelatterpoint,membershipaloneshouldnotbetakenautomaticallyasadecisivemeasureofamember'simportance.

Ofimmediateimportanceistheneedtoclarifythecriteriafordealingwithpotentialconflictsarisingfrominstitutionaloremployerfinancialinterests,researchgrantsandcontractstocommitteemembers,andmemberinvolvementwithcompetingproductsandtechnologies.Regardinginstitutionalfinancialinterests,mostadvisorycommitteemembersareuniversityemployees;mostoftheiremployersoperatemedicalschools,

hospitals,andhospitalpharmacies.OCSE,withtheFDA,shoulddevelopclearcriteriafordealingwithwaiverrequeststhatarisebecauseacommitteememberisaffiliatedwithaninstitution,someofwhosefinancialinterestsflowfromsuchsubordinateentities(e.g.,revenuesderivedfromprescribingdrugs).Inaddition,mostuniversitiesholddiversifiedendowmentfunds;itisoftenthecasethatsomeofthesefundsareinvestedinpharmaceutical,biotechnology,ormedicaldevicesecurities.OCSE,withtheFDA,shouldclarifythecriteriafordealingwiththese''employerinterests.''

TheIOMcommitteerecommendsthattheFDAandtheOSCEbeginimmediatelytheprocessofcodifyingthecriteriaforgranting208(b)(3)waivers,especiallywithrespecttoinstitutionalconflicts,researchgrantsandcontracts,andcompetingproductsandtechnologies.

Fourth,theagencyhastheauthoritytostreamlineitsowninternalpoliciesandproceduresfordecidingwhentoseekwaiversandhowtopreparetheirjustifications.TheIOMcommitteebelievesthatthisactionisalsoessential.Responsibilityforpreparingtheinitialwaiverrequestshouldresidewiththedivision.Thedecisiontorequestawaivershouldbemadebythecenterdirector.TheIOMcommitteeseesnoneedforreviewbytheDEPIorbyFDA'sChiefCounsel,aslongasOSCEhasareviewingrole.Centralagencyreviewofwaiverrequestsshouldbebyahigh-levelpolicyofficialintheOfficeoftheCommissioner.

TheIOMcommitteerecommendsthatFDAstreamlineitspoliciesandproceduresforrequestingandprocessingwaivers.Thisclarificationshouldfixtheprimaryadministrativeresponsibilityforimplementingthesechangesattheleveloftherespectivecenters.TheauthoritytograntwaiversshouldberetainedatleveloftheCommissioner(i.e,atthatoftheappointingauthority).

Fifth,theFDAshoulddevelopandadheretostrictschedulesforprocessingwaivers.ItshouldpresentwaiverrequeststoOSCEno

laterthanthreeweeksinadvanceofameeting.*TheCommissionershouldseekagreementfromtheOSCEthatitwillreviewanyproposedwaiverwithinthreedays.TheCommissionermayevenwishtoestablishdefaultrulesthatpenalizecentersforlatesubmissions(e.g.,thememberisdisqualifiedortheagendaitemispostponed).

*TheIOMcommitteenotesthatiftheFDAadoptstherecommendationforadvanceschedulingofadvisorycommitteemeetingsproposedbelowandinChapter7,itmaybepossibletoincreasethisperiodoftime.

TheIOMcommitteerecommendsthattheFDA,withthecooperationofOSCE,adoptapolicyofstrictschedulingforprocessingwaiversandthatsuchapolicyincludedefaultrulesforlatesubmissionsofwaivers.

Sixth,theFDAmustupdatethetrainingprogramsofitsofficialswithresponsibilityforimplementingconflictofinterestpoliciesinvolvingadvisorycommitteemembers.Thesetrainingprogramsshouldbuildaroundthesubstantiveandproceduralchangessuggestedabove.ParticipationshouldberequiredofallFDAprofessionalstaffwhodealwithadvisorycommitteemembers.

TheIOMcommitteerecommendsthattheFDAdevelopatrainingprogramregardingconflictofinterestforallofitsprofessionalstaffwhodealwithadvisorycommittees.Thisprogramshouldbebasedonthepolicyandproceduralchangessuggestedinthisreport.

Seventh,theFDAmustalsoinitiateandmaintainorientationprogramsforadvisorycommitteemembers.Individualmembersshouldclearlyunderstandthecriminallawsthatgovernfinancialconflictofinterestandthejustificationsforgrantingwaivers.However,theIOMcommitteebelievesthatguidanceonconflictofinterestshouldbelinkedtoabroaderorientationprogram(discussedbelowandatlengthinChapter8).Thislinkageisimportantbecauseanexclusivefocusonconflictofinterestwillnecessarilyemphasizetheriskofcriminalprosecutionandtheneedforintensiveinquiryintopersonalfinancialmattersanemphasisthatwouldsurelyobscurethepublicservicedimensionofadvisorycommitteemembership.

TheIOMcommitteerecommendsthattheFDAdevelopanorientationprogramforitsadvisorycommitteemembersandthatthisprogramincludeexplicitattentiontoconflictofinterestinthecontextofabroaderorientationtothepublicserviceaspectsofadvisorycommitteemembership.

Eighth,theFDAandOSCE,onbehalfofDHHS,shouldseekthe

issuancebyOGEofagovernment-widegeneral208(b)(2)waiverregulationsassoonaspossible.Thisstatutoryauthorityhasyettobeexercisedbutisintendedtoremovecertainconflictsfromacase-by-casedetermination.Institutionalfinancialinterestsandholdingscouldbedealtwithbysucharule.

TheIOMcommitteerecommendsthattheOfficeofGovernmentEthicsdevelopandissueagovernment-wide208(b)(2)waiverrulesassoonas

possible.ItfurtherrecommendsthattheFDAprovideinputtothescopeofthesewaiversruleandthattheFDAandOSCEcontinuetoimpressonOGEtheurgentneedforsuchrules.

Finally,theFDA,andDHHS,shouldseektherevisionofExecutiveOrder12674requiringcase-by-caseconsultationwithOGEonallwaiverrequests.

TheIOMcommitteerecommendstothePresidentthatExecutiveOrder12674beamendedtoremovefromOGEtheresponsibilityforcase-by-casereviewofadvisorycommitteememberwaiverrequests.Thecommitteerecommendsthatsuchcase-by-casereviewauthoritybedelegatedtothedepartmentsandthatOGEauthoritybelimitedtogovernment-wideoversightofagencies'policiesandprocedures.

TheforegoingdiscussionhasdealtwithfinancialconflictofinterestasregulatedbySection208ofTitle18oftheU.S.Code.Ithasnotaddressedtheissueofintellectualbias,whichrefersheretothepotentialeffect,subtleorovert,ofascientist'spriorresearchorpublicstatementsonhisorherobjectivity.Advisorycommitteememberswhobringstrongopinionsaboutspecificmatterstotheirassessmentofdataarenotnecessarilyandautomaticallybiased.Ajudgmentofbiasturnsontheirwillingnesstoholdtheirpersonalviewsinabeyancewhileexaminingthepertinentdatainacarefulandimpartialway.

Althoughthelegalrestrictionsthatmightgovernthetreatmentofintellectualbiasonthepartofadvisorycommitteemembersmaybequiteuncertain,themattershouldneverthelessbeofconcerntotheFDA.Onereasonforsuchconcernisthatacommitteewhoseadviceisnotimpartialdefeatsthepurposeofseekingindependentexpertadvice.AsecondisthatcommitteememberswhowerenotopentopersuasionbyevidencewoulderodepublicconfidenceinamechanismthatFDAhasdevisedtogeneratesuchconfidence.

TheIOMcommitteeholdstheviewthattheFDAshouldbesensitivetothepossibilitythananadvisorycommitteemembermightbesocommittedtoapointofviewonapotentialmatter,orsopubliclyidentifiedwiththatview,thathisorherobjectivitycannotbeassumed.Undersuchcircumstances,whichthecommitteehasnoevidencewilloccuroften,theFDAshouldexcludethatmemberfromparticipatinginthediscussionsofthematter.Ifthedeterminationofbiasrestsonpubliclystatedpositions,fullexclusionmaybewarranted.However,ifexclusionstemsfromthemember'spriorresearch,especiallyasaprincipalinvestigator,theFDAshouldnotbedeprivedofthatindividual'sexpertise.Thiscanbesolvedby

invitingthepersontoaddressthecommitteeasawitness(orasa"guest").Asensibleapproachmightrecognizejustthreerolesforcommitteemembersinthecaseofintellectualbias:(a)fullvotingparticipation;(b)fullexclusionfromameetingoranagendaitem;or(c)appearanceas"witness"or''guest''oftheagency.

Issuesofintellectualbiasdonotinvolvelegalquestionsoffinancialconflictofinterest.Therefore,remediesshouldbedeterminedbytheCommissioner,onadviceoftherelevantcenterdirector.Anylegalramificationsshouldbedealtwithbytheagency'sChiefCounsel.Theentireissue,clearly,isonedeservingfurtherattentionbytheagency.

TheIOMcommitteerecommendsthattheFDAdevelopcriteriaandproceduresforidentifyingpotentialintellectualbiasoradvisorycommitteemembersandprotectingtheobjectivityandimpartialityofadvisorycommittees.Thecommitteerecommendsthattheagencyroutinelyrequestinformationaboutresearchinterestsandpubliclystatedpositionsonscientificissuesfromadvisorycommitteemembers.Itrecognizesthattheagencymustrelytoalargeextentoncommitteemembersthemselvestoprovidesuchinformation.

Whentheagencyconcludesthatacommitteememberhasdemonstratedalackofobjectivityonamatter,themembershouldbeexcludedfromparticipationinthecommitteedeliberationsconcerningthatissue.Ifinformationrevealsonlythepossibilityofbias,theagencyshoulddeterminewhethertopermitthemembertoparticipate.Amemberwhoisexcludedfromparticipationinthecommitteedeliberationsmightneverthelessbeinvitedtoofferviewsasaguestorwitnesscalledbythecommittee.IndividualcasesshouldberuledonbytheCommissioner,afterconsultationwiththeappropriatecenterdirector.

CommitteeOperations

FewwrittenpoliciesexisttoguideFDAadvisorycommitteeoperations.Notsurprisingly,substantialvariationoccursintheactualuseofcommitteesbothamongandwithincenters.Someofthis

variationisjustifiedbytheheterogeneityofthesubjectmatter,andtheIOMcommitteewishestoavoidrecommendingrigidstandardizationinsuchcases.Asageneralproposition,however,substantialuniformityinpoliciesandproceduresforadvisorycommitteeoperationsisbothdesirableandfeasible.

TheIOMcommitteerecommendsthattheFDAdevelopuniformmanagementguidelinesforadvisorycommitteesapplicableacrossall

threecentersandthatiteliminateunnecessarydifferencesinthemanagementofcommittees.

SchedulingMeetings

FDAadvisorycommitteemeetingsareseldomscheduledmorethanafewmonthsinadvance,andspecificagendasareusuallyaresultofthedecisiontoholdameeting.Thesepracticescomplicateadvanceschedulingbycommitteemembersoftheirparticipationinmeetingsandadvanceplanningbysponsorsofproductsbeingevaluatedbytheadvisorycommittee.

TheIOMcommitteebelievesthatadvancescheduling(andaccompanyingdeadlinesforsuchactionsassponsorsubmissionsofdata,agencyreviewofanapplication,andadvancedistributionofmaterialstothecommittee)wouldallowmoreeffectiveplanningbybusyadvisorycommitteemembersfortheirparticipationinmeetingsandimposegreaterdisciplineontheproductevaluationprocess.Thecommitteeisawarethatsuchaproposalisnotwithoutits"costs";someoftheseincludethedifficultiesthatwouldbefacedbyFDAinadvanceschedulingofagendas,theheavydemandsmadeonreviewertime,andthepotentialforcompromisingthereviewofthedata.Nevertheless,althoughtheIOMcommitteehasnotexaminedingreatdetailtheimpactofthisproposalonFDAreviewertimeoritsbudgetaryimplications,itregardsthebenefitsofadvanceschedulingofmeetingsandagendaitemsasoutweighingmostpotentialdisadvantages.

TheIOMcommitteerecommendsthatFDAadoptapolicyofannualadvanceschedulingofadvisorycommitteemeetingsandofmeetingagendas,withreviewcycleshavingdeadlinesforsponsorsubmissionofdata,FDAcompletionofreviews,andadvancedistributionofmaterialstocommitteemembers.

MeetingPreparation

GeneralCriteriaforSettingtheAgenda

Thegeneralcriteriafordeterminingadvisorycommitteeagendasvaryfromcentertocenterandtendtoderivefromhistoricalpracticeasmuchasexplicitpolicy.

The1976MedicalDeviceAmendmentsrequiredtheCenterforDevicesandRadiologicalHealth(CDRH)tobringallpremarketapprovalapplications(PMAs)toanadvisorycommittee;thecenternowhassomediscretiononthatissueundertheSafeMedicalDevicesActof1990.Based

onitsinterpretationofwhatthelawrequires,CDRHasksadvisorycommitteeswhetheragivenPMAshouldbeapproved;itdoesnotgobeyondthisquestion.

TheCenterforBiologicsEvaluationandResearch(CBER)bringsspecificproductlicenseapplications(PLAs)andestablishmentlicenseapplications(ELAs)toitsadvisorycommittees,aswellasgeneralmattersofbiologicsdevelopment.ItformulatesandasksquestionsofthecommitteeinmuchthesamewayasdoestheCenterforDrugEvaluationandResearch.Unliketheothercenters,however,CBERalsoasksitsadvisorycommitteestoreviewitsintramuralresearchprogramsandevaluateintramuralresearchpersonnel.

TheCenterforDrugEvaluationandDevelopment(CDER),inSeptember1991,clarifiedtherangeofissuesthatitmightbringtoanadvisorycommittee:theapprovabilityofspecificdrugs;generaldrugdevelopment;issuespertainingtomarketeddrugs;andthemanagementofthenewdrugevaluation(NDE)program.

1Adviceontheapprovabilityofspecificdrugsmaybesoughtonclinicaltrialdesign;thedatasupportingsafety,effectiveness,overallrisk-benefit,anddosingandscheduling;appropriatesurrogateendpoints;otherneededstudies;postmarketingsurveillance;indicationsforspecificpopulations;andshiftsofprescriptiondrugstoover-the-counterstatus.Generaladvicemaybesoughtonthedevelopmentofguidelinesforclassesofdrugs,clinicalstudydesignissues,andspecificsafetyissuesforparticulardrugs.

TheIOMcommitteecommendsCDERforthisclarificationandrecommendsthatCBERandCDRHdevelopsimilarstatements.

Inaddressingthemanagementofthenewdrugevaluationprogram,theCDERdocumentexpandsseveralimportantaspectsofthe

advisorycommittee'stasks.Committeesmaybeaskedtoreviewperiodically(usuallyannually),first,thependingnewdrugapplications(NDAs)andthemajornewindicationsofotherdrugsintheCDERpipeline;second,the"importantproductsunderdevelopment,"thatis,investigationalnewdrugs(INDs);andthird,theprioritiesandresourceallocationsofCDER'sreviewingdivisionsforthemanagementofINDs,NDAs,abbreviatedNDA(ANDA)applications,andsupplementstoapprovedapplications.

TheIOMcommitteerecommendsthateachcenterscheduleanannualreviewbyeachadvisorycommitteeofthemajorNDAsandINDs(ortheirequivalents)inthepipelineoftherespectivereviewingdivision.

SettingSpecificAgendas

TheIOMcommitteeconsideredanumberofaspectsregardingsettingcommitteeagendas.Forexample,thenoticeofanFDAadvisorycommitteemeetingmustbepublishedintheFederalRegisteratleasttwoweeksinadvanceofthemeeting;thismayrequiresubmissionforpublicationbythecenteratleastsixweeksbeforeameeting.Anannouncementincludesageneraldescriptionoftheagenda,forexample,thespecificNDAofagivensponsor,andthegeneraltopicsofthemeeting;however,thisdescriptionvariesinitsspecificity.

TheIOMcommitteerecommendsthattheFederalRegisterannouncementsofscheduledadvisorycommitteemeetingsroutinelyincludethemostdetailedstatementoftheagendathatisfeasiblewithinexistingtimeconstraints.TheIOMcommitteealsorecommendsthattheseannouncementsbesentroutinelytoadvisorycommitteememberswhensubmittedforpublication.

ThegeneralquestionsthattheFDAmustconsiderinevaluatingdrugsandbiologicsarewhether,inthedeterminationofsafety,therisksofacompoundareoutweighedbyitsbenefitsandwhether"substantialevidence"fromwell-controlledtrialsexiststosupporttheclaimsofeffectiveness.Itwouldhelpthereviewprocessifadvisorycommitteememberswereregularlyremindedofthesedecisioncriteriaastheyreviewasponsor'sdata.

TheIOMcommitteerecommendsthattheFDAroutinelysendthegeneralstatementoftheregulatorycriteriagoverningproductevaluationtoeachadvisorycommitteememberinadvanceofameetingtoassistmembersinframingtheirreviewofthedata.

SettingthedetailedagendaofanadvisorycommitteemeetingandpreparingspecificquestionsforitareprimarilytheresponsibilityofFDAstaff.Theyarenotfeasibletasksforcommitteemembersthemselvestoundertake.Yet,theexerciseofthisresponsibilityby

FDAsometimesresultsincriticismregardingitsapparenteffortstomanipulateorinfluencecommitteedeliberations.

TheIOMcommitteerecommendsthatintheformulationofmeetingagendasandofquestions,theadvisorycommitteechairberoutinelyconsultedasastandardprocedure.ItfurtherrecommendsthatcommitteemembersberoutinelyinformedthattheymaymodifyFDA-

preparedquestions,basedontheirreviewofthedata,andintroducequestionsoftheirownbeforeoratanadvisorycommitteemeeting.

AnissuebroughttotheattentionoftheIOMcommitteewaswhetherFDAquestionstoanadvisorycommitteeshouldberestrictedtoscientificandclinicalmattersorwhethertheyshouldincludetherelevantregulatoryquestions.TheIOMcommitteebelievesthatthescientificandregulatoryquestionspertainingtoanissueareinterrelatedandthatanyattempttopresumeadistinctionbetweenthemisartificial.

TheIOMcommitteebelievesthatFDAreviewingunitsshouldbefreetoaskadviceonbothscientificquestionsandrelatedregulatoryimplications,astheydeemimportant.

TheFDAissometimeschargedwithasking"loaded"orleadingquestions.Thecommitteehasmadenodeterminationwhetherthishasoccurred.Itbelieves,however,thatitisnecessarytodistinguishbetweenthetoneandobjectivityofFDAquestionsandthefactthatparticularquestionsmayattimesindicatetheproblemsthattheagencyperceivesinanapplication.Thecommitteeisnottroubledbythefactthatprecisequestionsoftenwillrevealtheagency'sconcernsaboutanapplication.

TheIOMcommitteerecommendsthatquestionsaskedofadvisorycommitteesbefairandobjectiveintoneandavoidlanguagethatmightbeconsideredbiasedorinflammatory.

TimelyDistributionofMaterials

AmajorcomplaintofFDAadvisorycommitteemembersthathasbeenheardformanyyearsisthattheagencyoftenfailstodistributematerialssufficientlyinadvanceofameetingtopermittheircarefulreviewbycommitteemembers.Somedelaysareattributedtolimitedpersonnelandadministrativeresourcesoftheagency,toitsnaturaltendencytocompletereviewsatthelastminute,andtoitslong

toleranceofsuchpractices.Whateverthereasons,theeffectiveandefficientuseofadvisorycommitteesrequiresthatmembersreceivereviewmaterialsareasonableperiodoftimebeforeameeting.

TheIOMcommitteerecommendsthattheagencyadoptandfollowastrictscheduleforadvancedistributionofmaterials.Themeetingagenda,sponsor'sdataandanalyses,andagencyreviewsshouldbedeliveredtomembersatleastthreeweeksinadvanceofameeting.The

specificquestionsforthemeetingshouldbedeliverednolaterthan10daysbeforeameeting.

Inthecommittee'sview,theresponsibilityforfulfillingthisrecommendationrestsnotonlywithcommitteeexecutivesecretaries,butalsowiththedirectorsandtheapplicationreviewersoftheappropriatedivision.Thecommitteealsobelievesthatschedulingcommitteemeetingsandagendasinadvanceshouldfacilitatecompliancewiththisrecommendation.

SummariesofMaterialsSenttoAdvisoryCommittees

TheformatofmaterialssenttoadvisorycommitteemembersvariesaccordingtohowmuchofanapplicationtheFDAdecidestosend.Thematerialstypicallyincludethesponsor'sdata,theagencyreviews,andthequestionstobediscussedatthemeeting.AlthoughadvisorycommitteemembershavesuggestedthattheFDApreparesuchmaterialinaformatthatwouldfacilitateitsreview,theagencyunderstandablyresistssuch"packaging."Thismajordeficiencycouldbeeasilyremedied,however,bythepreparationofconcise(2025page),complete,andintegratedsummariesofthesponsor'sapplicationandtheagency'sreview.

TheIOMcommitteerecommendsthattheFDAdevelopastandardformatforsponsorstosummarizetheirapplicationbrieflyyetcomprehensively,aswellasacomparableformatforasummaryoftheagency'sreview.Thesesummariesshouldbeprovidedinadditiontothematerialsnormallysenttoadvisorycommitteemembers.

UseofPrimaryReviewers

TheCDRHassignsprimaryreviewresponsibilityforaparticularPMAtooneadvisorycommitteemember,mainlytoobtainaclinicalevaluationoftheapplication.TheIOMcommitteebelievesthatthispracticecanalsoensureamorethoughtfulcommitteediscussionand

thatitdistributestheworkloadmoreevenlyamongcommitteemembers.Inaddition,thepracticehasgreatutilityinthosesituationsinwhichthematchbetweencommitteeexpertiseandaparticularagendaitemmaybeweak.(Seethediscussionon"customtailoring"below.)

TheIOMcommitteerecommendsthatthethreecentersconsidertheroutineassignmentofprimaryreviewersforeachapplication.

CommunicationsIssues

Fivetypesofcommunicationbeforeanadvisorycommitteemeetingdeserveattention:FDAcommunicationtoadvisorycommitteemembers;communicationamongcommitteemembers;communicationbetweensponsorsandmembers;FDAcommunicationtosponsors;andFDAcommunicationtothepublic.

First,advancecommunicationbyFDAofficialswithadvisorycommitteemembersbeforeameetinghasgenerallybeenlimitedtoonememberatatime,basedonaninterpretationofthestricturesoftheFederalAdvisoryCommitteeAct(FACA).However,theChiefCounseltotheFDAindicatedinalettertotheIOMcommitteethat"suchpreliminaryissuesasagendatopics,materials,andquestions"couldbediscussedsimultaneouslywithsomeorevenallmembersofacommittee.

TheIOMcommitteenotesthisdiscrepancybetweenwhatguidesagencypracticeandtheviewsoftheChiefCounsel,endorsestheopinionofthelatter,andrecommendsthattheFDAclarifyitsguidancetoFDAstaffandtoadvisorycommitteemembers.

Second,FDAguidance,basedalsoonaninterpretationoftheFACA,toadvisorycommitteemembershasgenerallybeenthatcommunicationamongindividualmembersbeforeameetingisprecluded.Again,theFDAChiefCounselhaswrittenthat"preliminarydiscussions"amongcommitteemembersdonotviolatethelaw.

TheIOMcommitteenotesadiscrepancybetweenpracticeinsomepartsoftheagencyandtheviewsoftheChiefCounsel,endorsestheopinionofthelatter,andrecommendsthattheagencyclarifythelegalbasesgoverningcommunicationamongadvisorycommitteemembers.If,asexpected,theChiefCounsel'sopinionisadheredtoasagencypolicy,thisshouldbeclearlycommunicatedinwritingtoallFDApersonnelwhodealwith

advisorycommittees,tocommitteemembersthemselves,andtootherinterestedparties.Preliminarydiscussionsamongmembersforinformationpurposesandtoclarifytechnicalissuesonlyshouldnotbediscouraged;thelimitsonsuchconsultationsshouldbeclearlydefined;committeemembersshouldbeinstructedtodocumentsuchconsultationsbyalogorother,similarmeans;andtheseconsultationsshouldbedisclosedateachcommitteemeeting.

Third,asamatterofFDApolicy,sponsorsarediscouragedfromcommunicatingwithadvisorycommitteemembersbeforeameeting.The

agencyinformssponsorsandcommitteemembersofthisstricture.Thispolicyisdesigned,ingeneral,toprotecttheindependenceofthecommitteefromlobbyingbysponsors.

TheIOMcommitteeaffirmsthesoundnessofthispolicy.

Fourth,theFDAtakestheviewthatitisnotobligatedtosharewithsponsors,orthegeneralpublic,itscommunicationstoadvisorycommitteemembersbeforeameeting.TheIOMcommittee,however,believesthatitisappropriatefortheFDAtoprovidesponsorswithcopiesofallinformationthatitsendstoadvisorycommittees.Thispracticewouldfacilitatethepreparationbythesponsorofitsresponsetoagencyquestions.

TheIOMcommitteerecommendsthattheFDAprovidesponsorsofapplicationswiththesamematerialsthatitsendstoadvisorycommittees.Questionsshouldbesenttocommitteesandsponsorsonthesameschedule.

Fifth,asageneralpractice,theFDAreleasestothepublicthequestionsthatithaspreparedfortheadvisorycommitteeonthemorningofameeting.TheIOMcommitteeagreeswiththispracticeanddoesnotrecommendearlierreleasetothepublic.

ArecentreportbyKutak,Rock&Campbell,whichdealtwithFDA'shandlingoffinanciallysensitiveinformation,basicallyconcurredthatFDAreleaseofthequestionstothepubliconthemorningofacommitteemeetingwassoundpractice.

2TheFDAhasbeforeittheKutakRock&CampbellreportandthisIOMreportonadvisorycommittees;itmustaddresstheimplicationsofwherethetwointersectandmakeanyappropriatepolicydeterminations.

ConductinganAdvisoryCommitteeMeeting

Thesuccessfulconductofanadvisorycommitteemeetinginvolvestheconscientiouseffortsofthecommitteechair,themembers,FDAofficials,andthesponsors.ToimprovethedeliberationsofadvisorycommitteesandthequalityoftheiradvicetotheFDA,thissectionrecommendsanumberofstepstobetakenregardingtheinteractionsamongtheseparties.

AllocationandControlofAgendaTime

Oneofthekeystoaneffectiveadvisorycommitteemeetingistheallocationandcontrolofagendatime.Typically,theinitialassignmentof

timetoagendaitemsisdonebyFDAprofessionals,sometimesinconsultationwithcommitteechairs.Oncetimeisallocated,ofcourse,itisimportantthatcommitteemeetingsadheretotheestablishedschedule.Forthistooccur,itisnecessarythatthechairexercisecontroloveragendatime.

Theprotectionofopportunitiesforcommitteediscussionisperhapstheprimaryreasonforthechairtoexercisestrictadherencetotheagendaschedule.Discussiontimeoftengetssqueezedbecauseitisthelastscheduleditemonanagenda,sponsorandagencypresentationsfrequentlygolongerthanscheduled,andsomecommitteemembersmayleavetoreturnhome.

TheIOMcommitteerecommendsthattheFDAroutinelyconsultcommitteechairsintheallocationoftimetoagendaitemsandthatthisallocationtrytoanticipatepointsthroughoutthemeetingatwhichcommitteequestioningwillbenecessary.Itfurtherrecommendsthatcommitteechairsbeinstructedthatthecontrolofagendatimeisoneoftheirprimaryresponsibilities,andthattheymustworktoprotectcommitteediscussiontime,includingexercisingstrictcontrolonthepresentationsofsponsorsandtheFDAbeforethecommitteeaswellasattendantquestionsanddiscussionsbycommitteemembers.

ElectronicCoverageofMeetings

FDAadvisorycommitteemeetingsoftenreceivetelevisioncoverage,whichcanbeintrusiveincommitteedeliberations.FDAregulationsgoverningtelevisionor"electronicrecordingequipment"(21CFR10.200206)vestauthorityintheadvisorycommitteechairtocontrolsuchcoverageasnecessary.

TheIOMcommitteerecommendsthatadvisorycommitteechairsberoutinelyorientedtotheirauthoritiesandresponsibilitiesinregardtothecontrolofelectroniccoverageofadvisorycommitteemeetings,forthepurposeoffacilitatingcommitteedeliberationswithoutcompromisingthepublic'srighttoknow.

Voting

VotingbyCDERandCBERadvisorycommitteesoccursatthediscretionofthecommitteechairoraccordingtothetraditionofthereviewingdivision.Dependingonthecommittee,novotesmaybetaken,votesmaybetakenonlyonscientificquestions,orvotesmaybetakenonlyonregulatoryquestions.AllCDRHcommitteesvoteontheregulatoryquestiononly,i.e.,theapprovabilityofadevice.

TheIOMcommitteerecommendsthatFDAadoptapolicy,consistentacrossalladvisorycommittees,bywhichcommitteesareaskedforavoteonimportantquestionsbeforethecommittee.Totheextentfeasible,thechairshouldidentifyinadvancetheissuesonwhichvotesaretobetaken.

AgencyNeutrality

Asageneralproposition,theIOMcommitteebelievesthatFDAstaffmembersshouldconductthemselvesatadvisorycommitteemeetingsinwaysthatavoidtheappearanceofexertingundueinfluenceoverthecommittee.Agencypresentationstoacommitteeshouldfocusonthecriticalevaluationofdatabutshouldnotwithholdordisguiseexpressionsofagencyconcernswithanapplication.Thetoneofagencypresentationsshouldbeprofessional,thorough,anddispassionate,andagencystaffshouldnotdominateorappeartodominatecommitteediscussions.

Seatingarrangementsatadvisorycommitteemeetingsshouldfacilitatecommitteediscussionsratherthantheconvenienceoftheaudience.Asageneralrule,theIOMcommitteebelievesthatthedivisiondirectorshouldnotsitnexttothecommitteechair.NorshouldotherFDApersonnelsitamongthecommitteemembers.

CustomTailoringofCommitteeMembership

TheFDAhasrechartered,orsoonwillrecharter,allofitsadvisorycommittees.ThiswillpermitagencyofficialswhoareorganizingagivenmeetingtodrawvotingmembersfromanyotherFDAadvisorypanelorcommittee,orfromapoolofconsultants,onanas-neededbasis.Althoughthis"customtailoring"authorityiswelcomeinprinciple,ithasnotyetbeenusedwithanyfrequency,anditposesseveralchallengestotheagency.

Ingeneral,theIOMcommitteebelievesthatthecontinuityofthestandingadvisorycommitteeshouldbemaintainedandthatcustom

tailoringshouldbeusedsparinglytoaugmentacommittee'sexpertiserelativetoaspecificagendaitem.Ontheonehand,theIOMcommitteerecognizesthatitmaybenecessarytoaddvotingmembersinsomecasesinwhichthescientificorclinicalscopeofacommitteemaynotbeadequateforconsideringaparticularclassofdrugs,biologics,ordevices.Ontheotherhand,thefrequentuseofthisflexibleauthoritybytheFDAmaymakeitvulnerabletochargesof"stackingthedeck"withcommitteememberslikelytofavoritsviews.

TheIOMcommitteerecommendsthatincasesinwhichFDAmustmodifythecompositionofanadvisorycommitteeby''customtailoring,''itdosojudiciouslyandsparingly,augmentingthecorecommitteebyaddingtheneededexpertise.ThecommitteealsorecommendsthatFDAactivelyconsultthecommitteechairintheprocess.Italsorecommendsthatthedirectoroftheappropriatecenterapproveallsuchdecisions.

MeetingFollow-up

SomeFDAcentersordivisionsprovidelittleornofollow-uptoadvisorycommitteemembersregardingtheresultsoftheirdeliberations.Failuretodosoisasourceofcomplaints.Asystematicefforttoprovidefollow-upwouldconveyastrongpositivemessagetoadvisorycommitteemembersthattheagencyattachesgreatvaluetotheirservice.

TheIOMcommitteerecommendsthattheFDAfollowupeachadvisorycommitteemeetingbyroutinelyandimmediatelyprovidingcommitteememberswithacopyofallpressreleasesissuedafterameeting;informingmembersbyFAXatthetimeofapprovalordisapprovalofanyapplicationthatthecommitteehasconsidered;routinelyreportingthestatusofmatterspreviouslyconsideredbythecommitteeatthebeginningofeachmeeting;andreportingannuallythedispositionofcommittee-relatedmatters.

OrganizationandManagement

SeveralpriorreportsonFDAthatdealwithadvisorycommitteescallforvaryingdegreesofcentralizationofcommitteemanagementfunctions.Thesereportsalsohighlighttheneedtoaddressissuesoforganizationandmanagement.

SystemManagement

FDA'stechnicaladvisorycommitteesarecharteredbytheCommissionerofFoodandDrugsforthepurposeofadvisinghimonthesafetyandeffectivenessofdrugs,biologics,andmedicaldevices.

Inaddition,committeemembersareappointedbyhimandrequestsforwaiversofconflictofinterestaregrantedbyhim.Legally,advisorycommitteesreporttotheCommissioner.

Inactualoperation,however,thecurrentFDAadvisorycommitteesystemishighlydecentralizedandsubstantialvariationsexistsbothacrossandwithincenters.Thesevariationshavearisenasaresultofhistorical,

organizational,andidiosyncraticinfluencesthatarenotalwaysrootedingenuinescientificorfunctionaldifferencesamongcommittees.TheIOMcommitteebelievesthatunjustifiedvariationintheuseofadvisorycommitteesshouldbeminimizedintheinterestofstrengtheningtheirroleasindependentadvisorstotheFDA.

Thishighlydecentralizedsystemlacksanyagency-wideadministrativepolicyandmanagementguidance.Itthusappearsvulnerabletocontroversiesthatmightbeavoidedormoreeffectivelymanaged,givenagreateragency-widemanagementcapability.

TheIOMcommitteerecommendsthatahigh-levelofficialintheOfficeoftheCommissionerofFoodandDrugsbeassignedprimaryresponsibilityfordeveloping,disseminating,andenforcingadministrativepolicyandmanagementguidancetotheadvisorycommitteesofthethreecenters.

Thedirectorsofthethreecentersshouldhaveexplicitresponsibilitiesformanagingtheadvisorycommitteesystem.Centerdirectorsshouldimplementagency-widepolicyforadvisorycommittees;monitortherecruitmentofmembersfortechnicalexpertise,sourceofnomination,andidentificationofqualifiedwomenandminoritycandidates;personallyapproveany"customtailoring"ofcommitteestoavertchargesthatFDAstaffareseekingtoinfluencetheoutcomebytheselectionofmembersknowntofavoraparticularview;helpdesignanorientationandtrainingprogramforcommitteemembers;examineissuesthatariseinaparticularcommitteethatmaycutacrossseveralcommittees;andsupportinnovationintheuseofadvisorycommittees.

Officeanddivisiondirectorsoftheproductreviewunitsshouldalsohaveexplicitresponsibilitiesformanagingtheadvisorycommitteesystem.Theyshouldbeactivelyinvolvedinrecruitingadvisorycommitteemembers,preparingcommitteeagendas,anddevelopingspecificquestions.

Executivesecretariesshouldreporttoacentralunitwithineachcenter.Theirresponsibilitiesareprimarilytoprovideadministrativesupporttocommitteeoperations.Executivesecretariesshouldalsoreporttotheappropriatedivisiondirectortoassistthatindividualintheprogram-relatedworkofthecommittees.TheIOMcommitteerecognizesthatCDRHexecutivesecretariesdifferfromthoseinCDERandCBERinthattheyarealsoengagedinthetechnicalreviewofapplications;thus,somecommentsmaynotapplytothem.

TheIOMcommitteerecommendsthattheexecutivesecretariesreporttoacentralunitintheirrespectivecentersforthepurposeofproviding

administrativesupporttothatcenter'sadvisorycommittees.Italsorecommendsthattheyreporttotheappropriatedivisiondirectorstoprovideprogramsupporttothecommittees.

Ingeneral,theIOMcommitteebelievesthataclarificationoftherolesofallFDAofficialsresponsiblefortheadvisorycommitteesystemislongoverdue.Theobjectiveofthisroleclarificationshouldbetoensurethatadvisorycommitteesprovidetheindependentexpertadvicethattheagencyrequestsandneeds.

TheIOMcommitteerecommendsthattherolesandresponsibilitiesofallFDAofficialsinvolvedintheadvisorycommitteesystembeclearlyarticulatedinagencypolicythatiswidelydistributedtoFDAprofessionalstaff,advisorycommitteemembers,andotherinterestedparties.Thecommitteefurtherrecommendsthatthejobdescriptionsofallofficialsbechangedtoreflecttheirrespectiveresponsibilities.

Compensation

TheauthoritytosetthedailyrateofcompensationforFDAadvisorycommitteesresideswiththeCommissionerofFoodandDrugs.Heissubjecttofourconstraintstwolegal,onebudgetary,andoneadministrative.ThestatutorylimitoncompensationforallfederalgovernmentadvisorycommitteemembersisthedailyrateforaSeniorExecutiveServiceIVposition,currently$429.50perday.RegulationsoftheGeneralServicesAdministrationfurtherlimitthedailyratetothatofaGS-15intheGeneralSchedule,currently$320perday,unlesstheagencyheadpersonallydeterminesthatahigherrate"isjustifiedandnecessary."Thebudgetarylimitistheobviousrequirementthatanagencyheadmusthavefundstocoverthecostsofwhateverrateisadopted.

Althoughagencyheadshaveauthoritytosetratesforthemembersofthecommitteesthatadvisethem,FDA'sstatusasaPublicHealthServiceagencyalsolimitstheexerciseofthatauthority.Asapractical

matter,nosinglePHSagencycanpayadvisorycommitteemembersatratesmuchhigherthanthoseoftheotheragencies.Currently,theCentersforDiseaseControlpayscommitteemembers$188perday,whiletheNationalInstitutesofHealthandtheFDApays$150perday.

FDAadvisorycommitteemembersarepaidonlyforthosedaysonwhichtheyattendameeting.Theagencyisbarredbyregulationfrompayingthemforhomeworkfornormalmeetingpreparation,eventhoughamembermayspendfivedaysormoreinpreparation.However,CDRHdoescompensateindividualadvisorycommitteemembersforhomeworkiftheyconductan

"agency-directedassignment"thatresultsinatangibleendproduct,usuallyareport,thatisnottheendproductoftheadvisorycommittee.Typically,thisinvolvesusingmembersasprimaryreviewersofapplications.NeitherCDERnorCBERcompensatescommitteemembersforhomeworkinthisway.

FDAregulationsalsopermitpaymenttoadvisorycommitteemembersatthedailyratefortraveltimethatinvolves50percentofanadditionaldaybeyondthemeetingtimeandthatresultsinthelossofsomeregularcompensation.However,nouseismadeofthisauthority.

TheIOMcommitteebelievesthatallPublicHealthServiceadvisorycommitteemembersareunderpaid,includingthosewhoadvisetheFDA.ThisistruebothwithrespecttothemaximumdailyrateallowedbylawandGSAregulationsandwithrespecttotheopportunitycosttomembersofforegoneconsultingfeesfromdrugordevicefirmsof$1,000adayormore.Moreover,youngermembersinacademicmedicineoftenconfronttheperceptionthatserviceonanFDAcommitteecarrieslessacademicrewardthanthatofanNIHstudysection.

TheIOMcommitteebelievesthatpublicserviceshouldbeadequatelycompensated,althoughobviouslynotattheratesoftheprivatesector.ItisconcernedthatthecurrentmeagerrateofcompensationmaydissuadesomeindividualsfromservingasFDAadvisorycommitteemembersandmaydiminishtheincentivetootherstoprepareadequatelyformeetings.Ingeneral,theIOMcommitteeisconcernedthattheseratesdonotaccuratelyreflectthevaluethatFDAandthegeneralpublicattachtotheimportantworkperformedbyadvisorycommitteemembers.

TheIOMcommitteerecommendsthattheCommissioner,withtheSecretaryofHealthandHumanServices,reviewtheadequacyof

compensationforPublicHealthServiceadvisorycommitteemembers,includingFDAadvisorycommitteemembers,andtakeappropriatestepstomaintaindailyratesinrelationtoincreasesinthefederalsalaryschedule.ItfurtherrecommendsthatCDERandCBER,totheextentthattheyuseprimaryreviewersforapplicationspresentedtoadvisorycommittees,compensatethesereviewers,asCDRHcurrentlydoes,for"agency-directed"homework.

TheIOMcommitteenotesthatlegislationenactedinOctober1992authorizestheFDAtochargeuserfeesforproductevaluation.Underthisnewauthority,itmaybeappropriatefortheFDAtoreviewthecompensationofadvisorycommitteemembersinrelationtotheircontributiontoproductevaluation.

OrientationandTraining

Arecurringcomplaintfromadvisorycommitteemembershasbeentheabsenceofanadequateorientationandtrainingprogram.Althoughthecentersandmostdivisionshavemadeanumberofefforts,nosystematicagency-wideorcenter-wideorientationprogramhasbeenorganized.TheIOMcommitteebelievesthattheneedforsuchaprogramisclear;programcontentandorganizationareaddressedinthebodyofthereport.

TheIOMcommitteerecommendsthattheFDAestablishasystematicorientationandtrainingprogramthatisdirectedmainlytowardnewadvisorycommitteemembersbutthatwillalsobeusefulforcurrentmembersandforFDAstaffwhodealwithcommittees.TheOfficeoftheCommissionershouldexerciseleadershipinthedesignofthisprogram,incooperationwiththethreecenters.Thedesignshouldconsciouslysearchforagency-widesimilaritiesaswellascenter-specificanddivision-specificcontent.Thepublicserviceandpublichealthcontributionofadvisorycommitteemembershipshouldbeemphasizedinthisprogram.

AgencyManagementandAccountability

ThisreportrecommendsmanyconcretestepsforimprovingtheuseofadvisorycommitteesbytheFDAintheevaluationofdrugs,biologics,andmedicaldevices.Throughoutthereportaregeneralexpressionsofconcernaboutagencymanagementandaccountability,whichmaynotbecapturedfullybyitsspecificrecommendations.Thus,theIOMcommitteedeemsitnecessarytosummarizethelatterinrelationtotheselargerconsiderations.

AgencyManagement

InthejudgmentoftheIOMcommittee,itisimportanttodifferentiatebetweenthemanagementoftheadvisorycommitteesystemandthemanagementoftheproductevaluationprocessasaffectedbythe

advisorycommitteesystem.Regardingadvisorycommitteesystemmanagement,theIOMcommittee'smostimportantrecommendationisthatahigh-levelpositionbeestablishedintheOfficeoftheCommissionertoprovideadministrativepolicyandmanagementguidancetotheadvisorycommitteesystem.AlthoughthepreciselocationofsuchanofficeisproperlydeterminedbytheCommissioner,anappropriateplacemaybetheOfficeoftheDeputyCommissionerforOperations,towhichthedirectorsofthethreerelevantcentersnowreport.

Advisorycommittees,theIOMcommitteebelieves,havebecomeapermanentfixtureintheFDA'sevaluationofproducts,andtheireffectiveuseshouldbearesponsibilityofFDAofficialsatalllevels.ImprovementsinmanagementwouldflowfromclarifyingtherolesandresponsibilitiesofallofficialsinvolvedintheadvisorycommitteesystemfromtheCommissionerthroughthecenter,office,anddivisiondirectors,downtotheexecutivesecretaries.Suchclarificationshouldincludechangingthejobdescriptionsoftheseofficialsasnecessary.TheIOMcommitteeacknowledgestheimportantroleofFDAofficeanddivisiondirectorsintheworkofadvisorycommittees;itdoesnotrecommendcircumventingtheseofficialsbyproposingtolocateoperationalresponsibilityforcommitteeselsewhere,buturgesclarificationoftheirresponsibilitiesfortheeffectiveperformanceofthesystem.

Anorientationprogramforadvisorycommitteemembers,whichcouldalsobeusedintrainingresponsibleFDAofficials,wouldimprovetheperformanceoftheentiresystem.Othermanagement-relatedrecommendationspertaintotherecruitmentofqualifiedmembersandestablishmentofapoolofpotentialmembers;greaterinvolvementbytheOfficeoftheCommissionerinconflictofinterestissues(bothindevelopinginternalFDApoliciesandproceduresandinnegotiatingwiththeDHHSOfficeoftheSpecialCounselforEthicsandtheOfficeofGovernmentEthics);andmoreattentiontopreparationforandconductandfollow-upofadvisorycommitteemeetings.

VariousrecommendationsoftheIOMcommitteeaddressimprovementoftheproductevaluationprocessandtheroleofadvisorycommitteesinthatprocess.Inparticular,webelievethatadvanceschedulingofcommitteemeetingsandagendas,withattendantdeadlinesforthesponsorandtheagency,wouldbringgreaterdisciplinetotheproductevaluationprocessandmakemore

effectiveuseofadvisorycommittees.

TheIOMcommitteerecognizesthatitsrecommendationsforimprovedmanagementoftheadvisorycommitteesystemwillrequireadditionalresources.Therefore,thereportprovidesanestimateoftheincrementalcostsoftheIOMcommittee'srecommendations.TheIOMcommitteeregardstherecommendedreviewofadvisorycommitteemembercompensationasanimportantmanagementissuethatdeservesattentionbytheCommissionerandtheSecretaryofHealthandHumanServices.Thecompensationofcommitteemembersshouldbereviewedinrelationtothenewly-adopteduserfeesystemforproductevaluation.

AgencyAccountability

TheFDAasanentity,andnotjustitscomponentparts,shouldbeaccountablefortheeffectiveperformanceofitsadvisorycommitteesystem.TheIOMcommittee'srecommendationsleadtowaysofincreasingagency-wideaccountability.Here,asintherecommendationsaboveonimprovingmanagement,thecommitteeemphasizestheimportanceofdesignatingahigh-levelofficialintheOfficeoftheCommissionerwhoshouldberesponsibleforadministrativepolicyandmanagementguidancefortheadvisorycommitteesystem.

ItisalsoimportantasacomponentofaccountabilitytorecognizethatadvisorycommitteesareadvisorytotheFDA,andthattheauthorityfordecisionsrestswiththeagency.Itwouldbeunnecessarytoreiteratethisbasicdistinctionwereitnotthatsomeagencycriticsregardadvisorycommitteesasindependentadjudicatorybodiesthatshouldhearsponsors'views,ontheonehand,andagencyviews,ontheother,anddecideinfavorofonepartyortheother.Acknowledgingthisbasicauthority-advisorydistinctionshouldfacilitateadvisorycommitteesbecomingevenmoreeffectiveandinfluentialthantheyareatpresent,whichtheIOMcommitteeendorses.

Consequently,theIOMcommittee'srecommendationsemphasizepracticalways(especiallyinChapter7)toensuretheintellectualindependenceofadvisorycommittees.Therationaleforthisemphasisistoincreasethelikelihoodthatadvisorycommitteeswillrenderthatimpartial,expertadvicethattheagencyandthepublicshouldexpect.

AConcludingRecommendation

Intheconductofthisstudy,theIOMcommitteehasdiscoveredthemultifacetedcomplexityoftheFDAadvisorycommitteesystem.It

hasbenefitedfrommanythoughtfulletters,memoranda,andcommunicationsonaspectsofthiscomplexity.Asaresult,thecommitteebelievesthatitsreportcouldservetoincreaseagencyaccountabilityfortheadvisorycommitteesystem.

TheIOMcommitteerecommendsthattheCommissionercirculatethisreportwidelywithintheFDA,toalladvisorycommitteemembers,andtootherinterestedparties.ItalsorecommendsthatthereportbesubmittedtotheSecretaryofHealthandHumanServicesandtotheappropriatecommitteesoftheCongressforthepurposeofseekingconcurrenceofgoalsandbudgetarysupportfortheimplementationofthereport'srecommendations.

Notes

1.MemorandumfromBruceBurlington,M.D.,DeputyDirectorforScientificandMedicalAffairs,toCarlC.Peck,M.D.,Director,andGeraldF.Meyer,DeputyDirector,CenterforDrugEvaluationandResearch,"AdvisoryCommittees.PolicyandPracticesinSelectionofAgendaItemstobeConsideredbyCenterforDrugEvaluationandResearchAdvisoryCommittees,"September1991.

2.Kutak,Rock&Campbell.FDASafeguardsAgainstImproperDisclosureofFinanciallySensitiveInformation.FinalReport.Washington,D.C.,November14,1991.

1IntroductionOnJuly1,1992,theFoodandDrugAdministration(FDA)hadatotalof41technicaladvisorycommitteesorpanelsthatsupportedtheworkofthethreecentersresponsiblefortheevaluationandregulationofdrugs,biologics,andmedicaldevices.*In1991,thesecommitteesmetatotalof67times,usuallyfortwodayspermeeting,foranaverageof3.2meetingdaysperyear.Theytypicallyconsistofseventoninememberseach,noneofthememployeesoftheFDA,whoaresupportedbyFDAprofessionalstaffandbyanumberofconsultants.Inthisreport,werefertotheseadvisorycommitteesandtheiradministrativesupportastheFDA'sadvisorycommitteesystem.

FDAtechnicaladvisorycommitteesplayanimportant,multifacetedroleinthedevelopmentandevaluationofnewdrugs,biologics,andmedicaldevices.Althoughtheyareinvolvedtosomeextentintheearlystagesofproductdevelopment,andsometimesinpostmarketingissues,theirprimaryuseliesinassistingtheFDAtoevaluatespecificapplicationsformarketingapprovalnewdrugapplications(NDAs)fordrugsandbiologics,productlicensingagreements(PLAs)forbiologics,orpre-marketapprovals(PMAs)formedicaldevices.

Inaddition,FDAadvisorycommitteeshelptheagencydevelopgeneralguidelinesregardingscientificandtechnicalissuesrelatedtotheagency'sbroaderregulatoryresponsibilities,mostoftenforbiologicsandlessoftenfordrugsanddevices.InthecaseoftheCenterforBiologicsEvaluationandResearch,theyreviewintramuralresearchprogramsandpersonnel.

AlthoughtheadviceofadvisorycommitteesisnotbindingontheFDA,therecommendationsofacommitteearewidelyregardedasa

predictorofagencyaction.Asaresult,FDAadvisorycommitteeshavebecomehighlyvisibletothepublic,theCongress,themedia,andthefinancialinvestmentcommunity.Acommitteemeetinginvolvingaparticularlycontroversialmattermaydrawanaudienceof300to400individuals,includingFDAstaff,

*Thesecentersare,respectively,theCenterforDrugEvaluationandResearch(CDER),theCenterforBiologicsEvaluationandResearch(CBER),andtheCenterforDevicesandRadiologicalHealth(CDRH).

sponsoremployees,observersfromcompetitorfirms,thenationalandtradepress,includingcableandnetworktelevision,andinvestmentadvisors.

TheimportanceandvisibilityofFDAadvisorycommitteesmakethisstudyatimelyeffort.TheInstituteofMedicine(IOM)committeethatconductedithopesthatitsanalysesandrecommendationswillbeusefultotheagencyandtothepublicinhelpingtheFDAfulfillitsresponsibilitiestotheAmericanpeople.

OriginsoftheStudy

ThestudyoriginatedinremarksmadebyDr.DavidA.Kessler,theCommissionerofFoodandDrugs,atameetingoftheIOM'sForumonDrugDevelopmentinMarch1991.BeforehisappointmentasCommissionerinlate1990,Dr.KesslerhadchairedtheSubcommitteeonDrugsandBiologicsoftheDepartmentofHealthandHumanServices(DHHS)AdvisoryCommitteeontheFoodandDrugAdministration(knownastheEdwardsCommittee,afteritschairman,formerCommissionerDr.CharlesE.Edwards).Inthatcapacity,Dr.KesslerhadheardtestimonythatchallengedthecredibilityoftheFDA'sadvisorycommitteesystem,and,totheForummembers,heexpressedthedesiretomakemoreeffectiveuseofthesecommittees.

TheresultinginteractionbetweentheIOMandtheFDAledtothisstudy.ThatinteractionbeganwhentheFDArequestedthattheIOMexaminetheoptimaluseofFDAadvisorycommitteesintheevaluationofdrugs,biologics,andmedicaldevices.TheagencyalsoaskedtheIOMtoconsidertheiruseinrelationtoagencymanagementandagencyaccountability.

Inresponse,theIOMappointedacommitteetoconductthestudy.Itsmembersbroughtexpertiseinmedicalresearch;developmentofdrugs,biologics,andmedicaldevices;designandconductofclinical

trials;medicine,surgery,andnursing;regulationofdrugs,biologics,devices,consumerproducts,andhealthcareservices;administrationofmedicalresearch,healthcarefinancing,andthedeliveryofhealthcareservices;andhealthandsciencepolicyresearch.ThreemembersoftheIOMcommitteecurrentlyserveonFDAadvisorycommittees,twoothershaveservedinthepast,andthreewerepreviouslyinvolvedasFDAofficialsinthedesignofthecurrentsystem.

Intheearlymonthsofthestudy,twomeetingswereheldbetweenthecommitteechair,Dr.LaurenceE.Earley,andtheCommissioner,thesecondinvolvingtheactingpresidentoftheIOMandseniorIOMstaff.Thesemeetingswereheldtoclarifycertainquestionsaboutthescopeandpurposeofthestudy.Then,whenthestudycommitteeconvenedforitsfirstmeeting

onDecember67,1991,itheardapersonalpresentationfromCommissionerKesslerofhisviewsonthestudy.

TheCommissionermadethreemajorpointsattheDecembermeeting.First,heindicatedthattheimproveduseofadvisorycommitteeswasoneofseveralmanagementimprovementinitiativesthathewasundertaking.Consequently,heaskedforareportthatwouldprovidehimandtheFDAwithoperationalguidance.Second,heexpressedhishopeforthedeepinvolvementinthisstudyofFDAseniorstaff,ahopethathasbeenrealizedincommitteedeliberationsandinthestudy'sdatacollectionefforts.Finally,heemphasizedtheimportanceoftheIOMcommittee'saddressingtheprocessforcontrollingfinancialconflictofinterestbecauseitwasaffectingtheoperationsoftheadvisorycommitteesystem.

StudyObjectives

ThepurposesoftheIOMstudythataroseoutoftheinitialFDArequest,theconcernsofCommissionerKessler,andthedeliberationsofthestudycommitteearethefollowing:

TounderstandtheFDA'sprocessofproductdevelopmentandevaluationsothattheIOMcommitteecouldrecommendhowbesttouseadvisorycommitteesinthecontextoftheFDA'soverallmission,policies,andprocedures.

TounderstandhowFDAadvisorycommitteesareusedinthethreecentersresponsiblefortheevaluationofdrugs,biologics,andmedicaldevices.

ToprovidetheFDAwithoperationalguidanceregardingtheselectionofadvisorycommitteemembersandtheoperationandmanagementoftheadvisorycommitteesystem.

Tostudyandanalyzetheimpactontheuseofadvisorycommitteesof

financialconflictofintereststatutes,regulations,andadministrativepractices,andtherelatedissueofscientificbias.

Toconsidertheuseofadvisorycommitteesforimprovingagencymanagementandincreasingagencyaccountability.

ScopeoftheStudy

ThisstudyexaminestheusebytheFDAoftechnicaladvisorycommitteesinthereviewoftherapeuticanddiagnosticmedicalproductsdrugs,

biologics,anddevices.*PriorstudieshaveusuallydealtwithFDAadvisorycommitteesthatareusedfortheevaluationofdrugsorsometimesdrugsandbiologics;theyhaveseldomincludedmedicaldevices.ThisstudyencompassestheuseofadvisorycommitteesbytheCenterforDrugEvaluationandResearch(CDER),theCenterforBiologicsEvaluationandResearch(CBER),andtheCenterforDevicesandRadiologicalHealth(CDRH).

Thestudyconsiderstheuseofpolicyadvisorycommitteesonlyinpassing.ItdoesnotexamineanyadvisorycommitteesservingtheCenterforFoodSafetyandAppliedNutrition,theCenterforVeterinaryMedicine,ortheNationalCenterforToxicologicalResearch.ThestudyalsoexcludestheBoardofTeaExperts,atechnicaladvisorycommitteecreatedbytheTeaImportationActof1897toadvisetheCommissionerregardingstandardsforimportedteas.

Otherlimitationsofthestudyshouldbementionedhere.ThiswasarelativelyshortstudybyIOMstandards.ThecontractranfromSeptember23,1991,untilOctober22,1992,duringwhichthecommitteemetonlyfourtimes.Asaresultofthistimetable,theIOMcommitteefocuseditsattentiononmattersthatitconsideredtobeofgreatestconcerntotheagencyandtotheadvisorycommitteesthemselves,withtwoconsequencesworthnotinghere.

First,althoughthecommittee'sreport(inChapter6,''EnsuringCommitteeIntegrity'')dealswithbothfinancialconflictofinterestandintellectualbias,theformerreceivesthelion'sshareofattentionandforverypracticalreasons.ThecommitteewasaskedbytheFDAtoconsidertheproblemsofregulatingthepotentialfinancialconflictofinterestofadvisorycommitteemembers,mainlybecausetheseissueswerethreateningtoimpairtheagency'sabilitytouseadvisorycommittees.Moreover,theexistingstatutesregulatingconflictof

interestdealsolelywithfinancialconflict.

Second,intellectualbias,whichisimportantinitsownright,wasconsideredbythecommitteebutreceivedlesscommitmentofcommitteetimethandidfinancialconflict.Foronething,thelegalprinciplesoperativeinthiscontextareamatterofsomeuncertainty.Thestatutesgoverningconflictofinterestdonotaddressintellectualbias.AndalthoughtheFederalAdvisoryCommitteeActdoesrequirethatadvisorycommitteemembershipbe"fairlybalanced,"themeaningofthisfortechnicaladvisorycommitteescannotbespecifiedeasilyinadvanceofaspecificmeetingagenda.EventhoughintellectualbiashasyettogeneratefortheFDAtheadministrativedifficultiesthathavecharacterizedthematteroffinancial

*Thedefinitionsofdrugs,biologics,anddevicesarediscussedintheAppendixtothischapter.

conflictofinterest,theIOMcommitteerecommendsthatagencybeginnowtoaddressthisissue.

Inrecentyears,researchuniversitiesandscientificjournalshavebeenamongtheinstitutionsactivelypursuingthegeneralissuesrelatedtointellectualbias.Butthetreatmentofbiasbyscientificregulatoryagenciesinrelationtoadvisorycommitteesremainsundeveloped.Astudyofgreaterscope(thanjusttheFDA)andofgreaterdurationwouldhavebeenrequiredtoploughthisnewground.

TheRolesofFDAAdvisoryCommittees

Ingeneral,advisorycommitteesarethemajorwaybywhichtheFDAobtainsindependenttechnicalandscientificadvice.Othermeansforobtainingsuchadviceincludeworkshops,symposia,consultants,andextensive,ofteninformal,contactsamongagencyprofessionalsandthescientificandmedicalcommunities.Althoughthisreportfocusesonadvisorycommittees,theIOMcommitteerecognizesandendorsestheappropriateuseoftheseothermeansofobtainingindependentexpertadvice.

TheIOMcommitteebelievesthatitisessentialfortheFDAtosystematicallyacquireindependentexternalscientificadvice.Thescopeoftheagency'sregulatoryresponsibilitiesissovastanditsinvolvementinleading-edgescientificandtechnicalmatterssodeepthattheagencycannotmaintaincontactwiththefrontiersofscienceandmedicinewithoutsuchexpertadvice.Hence,itiscriticalthattheFDAavailitselfofallmeansofobtainingsuchadviceofwhichtechnicaladvisorycommitteesareone.

WhentheFDAbeganusingexternalsourcesoftechnicaladvice,followingthe1962drugamendmentstotheFood,Drug,andCosmeticAct,itdidsotocompensateforthelimitedtechnicalcapabilitiesofitsprofessionalstaff.Today,however,thesituationis

muchchanged,andforthemostparttheagencyhasahighlytrained,scientificallyqualifiedprofessionalstaff.Inthiscontext,theFDAobtainsexternaladvice,whetherfromadvisorycommittees,workshops,orconsultants,tocomplementthecapabilityofitsprofessionalstaff.

TheFDAinitiatedanadvisorycommitteesystemintheearly1970stoprovidetechnicalassistancerelatedtothedevelopmentandevaluationofdrugs,biologics,andmedicaldevices.Thesystemwasalsodesignedtolendcredibilitytotheagency'sdecisionsanditsdecision-makingprocesses.Inaddition,itwasameansbywhichtheFDAcouldprovideaforumforpublicdiscussionofcertaincontroversialissues.

Ingeneral,theIOMcommitteebelievesthattheexistingFDAadvisorycommitteesystemisfundamentallysound,hasservedtheagencywell,anddoesnotneedwholesalereorganization.Itshouldberetainedandstrength-

ened.However,laterinthisreport,thecommitteerecommendsanumberofadministrativeandproceduralchangesthataredesignedtoimprovetheperformanceandusefulnessofthesystem.

TheIOMcommitteebelievesthattheprimaryroleofFDAadvisorycommitteesisandshouldbetoprovideindependentexpertscientificadvicetotheagencyinitsevaluationofspecificdrugs,biologics,ormedicaldevicesatanystageofconsiderationbytheagency.ArelatedroleistoadvisetheFDAongeneralcriteriaforevaluationandonbroadregulatoryissuesthatarenotrelatedtoaspecificproduct.

Severalkeytermswarrantfurthercomment.First,independencereferstofreedomfrominfluencebythesponsoroftheproductunderconsideration,byanyotherentitiesorpersonsthatcouldgainorloseasaresultoftheoutcomeoftheprocess,andbytheFDAitself.However,thefocusofconcernaboutcommitteeindependencehaschangedovertime.Forexample,in1976,theFountainCommittee(seeChapter4)believedthatcommitteesmightbetooindependentofFDAprofessionalstaffandsubjecttotheinfluenceofdrugsponsors.By1990,theconcernwastheopposite:itwasclaimedbysomethatadvisorycommitteesweresubjecttoexcessiveinfluencebytheFDA'sreviewingdivisions.

ThehighstakesassociatedwithFDAdecisionsmeanthatpartiesdisappointedbytheagency'sactionhavestrongincentivestochargethattheindependenceofadvisorycommitteesiscompromisedbyundueFDAinfluence.Yet,theissuesofindependenceandundueinfluencearequiteelusiveandpertaintomanyfacetsoftheprocessforexample,therecruitmentofcommitteemembers,delaysinadvancedistributionofmaterials,thecontentandtoneofagendaquestions,andseatingarrangements.TheIOMcommitteemakesrecommendationsonalloftheseissues,thedirectionofwhichpointstogreatersafeguardsoftheindependenceofcommittees.

Second,expertscientificadviceimpliesthatmembersofadvisorycommitteeswillbeacknowledgedexpertsinsometechnicalorscientificfieldthatisrelevanttothepurviewofthespecificadvisorycommittee.

Third,advisorycommitteesadvisetheFDAanddonotthemselveshaveauthoritytomakedecisionsthatobligatetheagencyoranyprivatepartytoacourseofaction.

Fourth,advisorycommitteesrespondtospecificquestionsthathavebeenidentifiedbytheprofessionalstaffoftheagency.Thesequestionsmaydealwithstudydesignormethodology,adequacyofdata,andassessmentandinterpretationofrisksandeffectiveness.

Finally,althoughadvisorycommitteeshaveaprominentroleintheproductlicensingstage,theyaresometimesusedearlierintheproductdevelopmentcycleandsometimesinvitedtoconsiderpostmarketingissues.

TheIOMcommitteebelievesthatitisproperfortheFDAtousecommitteesatanystageofreviewwhenscientificadviceisneeded.

PracticalLimitsontheUseofAdvisoryCommittees

ItisimportanttoacknowledgethattherearesignificantpracticallimitsontheFDA'suseofadvisorycommittees.Themostimportantgenerallimitistheamountoftimethatcommitteemembersareabletocommittotheactivity(measuredinmeetingsperyear,dayspermeeting,daysofpreparationpermeeting,andtraveltime).TheamountofresourcesthattheFDAhasavailabletosupportadvisorycommitteesalsolimitstheiruse.InAppendixA,weestimatetheadditionalresourcesthattheFDAwillrequiretoimplementtherecommendationsofthisreport.TheIOMcommitteerecognizesthatresourcesforadvisorycommitteesmustbeconsideredinthecontextofoverallFDAbudgetprioritiesandthatthereiswidespreadconcernabouttheadequacyoftheagency'sbudgettomeetitsgrowingstatutoryresponsibilities.

Therearealsospecificlimitsonwhatanygivenadvisorycommitteemeetingcanaccomplish.Onesuchlimitisthenecessityfortheagencytobeselectiveinchoosingquestionsforcommitteesfromanenormousamountofmaterialunderreview.Anotheristhedifficultyfacedbyanadvisorycommitteechairinattemptingtocontrolagendatimeatmeetings,withtheconsequencethatcommitteediscussiontimeisoftenseverelytruncated.

TheFederalAdvisoryCommitteeAct

FDAadvisorycommitteesoperatewithinthelegalframeworkoftheFederalAdvisoryCommitteeAct(FACA).Thepost-WorldWarIIera,andespeciallythe1960s,sawtheevolutionofwidespreaduseofadvisorycommitteesbymanyfederalgovernmentagencies.In1972,CongressenactedtheFACAtoregulatethisdevelopment.Although

notwrittenprimarilyfortechnicaladvisorycommittees,theFACAwaspassedandbecameeffectivejustastheFDAwasbeginningtomakeextensiveuseofsuchcommittees.Itprovidesthestatutoryframeworkforallfederaladvisorycommittees,includingthoseoftheFDA.*BecausereferencestotheFACAaremadethroughoutthisreport,wedescribeitbrieflyatthispoint.

TheFACAincorporatesthreeconflictingthemes.OneconcernofCongresswastointroduceuniformproceduralstandardsforfederaladvisorycommittees.

1Theothercongressionalobjectivesweretopromoteanopen,transparentprocessandtoreducethenumberofadvisorycommittees.These

*Certainadvisorycommitteesareexceptedbylaworaresubjecttospecialrequirements.

themesreflectedaconcernintheU.S.Senatethatindustry-orientedadvisorycommittees,actinginclosedmeetings,hadassumedtoolargearoleinagencydecisionmaking.

ThemajorrequirementsoftheFACAareasfollows.Toformanadvisorycommittee,anagencyheadmust:

determinethatitisnecessaryandinthepublicinterest,

consultwiththeGeneralServicesAdministration(GSA),

fileaGSA-approvedcharter,and

announceitsformationintheFederalRegister.

Committeesmustberecharteredeverytwoyearsusingthesameprocedures.

TheFACArequiresaformalnominationprocessforadvisorycommitteemembers,includingaFederalRegistersolicitation;thatcommitteemembershipbe"fairlybalanced"andthatmeetingsbeannouncedintheFederalRegister15daysinadvanceandbeopenandprovideforpublicparticipation.*TheoriginalFACAopennessrequirementwasreinforcedin1977bytheGovernmentintheSunshineAct,whichrequiresthatdeliberationsofgovernmentcollegialbodies,includingadvisorycommittees,occurinopensession.

TheFACAalsorequiresthatafederalofficialoverseealladvisorycommitteemeetings,includingcallingameeting,approvingtheagenda,beingpresentatalltimes,andadjourningthemeetingifnecessary.Detailedrecordsminutesandatranscriptofadvisorycommitteemeetingsmustbekept.UnlessexemptedundertheFreedomofInformationAct,theserecordsareavailabletothepublic.

StudyMethods

TheIOMcommitteethatconductedthisstudydrewonseveralsourcesofinformationandusedavarietyofmethodsinitsanalysis.

Thecommitteemetonfouroccasions,inDecember1991andinFebruary,May,andAugust1992.Thesemeetingsweretwodayslong,exceptforthefinalmeeting,whichwasaone-dayexecutivesession.

ThreeIOMcommitteemembershadbeenpersonallyresponsiblefordesigningandmanagingtheFDAadvisorycommitteesysteminprior

*Ameetingmaybeclosedonlyifabasisexistsforinvokingoneofseveralexceptions.InthecaseoftheFDA,theseexceptionsare,asapracticalmatter,restrictedtothediscussionofproprietaryortradesecretinformationortomattersinvolvingconfidentialinformationaboutindividuals.OnlytheCommissionercanmakethedecisiontocloseameeting.

capacitiesasFDAofficials.Theythusprovidedthecommitteewithaninvaluablehistoricalperspectiveandakeensenseofagencydynamics.

FivemembersoftheIOMcommitteehadservedorwereservingonFDAadvisorycommitteesintheareasofdrugs,biologics,andmedicaldevicesandthusbroughtdirectexperiencetobearontheIOMcommittee'sdeliberations.

TheIOMcommitteeanditsstaffinteractedwithseniorFDAprofessionalsthroughoutthestudy.ThisincludedtheparticipationofthelatterinthefirstthreemeetingsoftheIOMcommittee;threehalf-daymeetingswithleadersoftheCDER,CBER,andCDRH(mentionedbelow);andindividualmeetingsoftheIOMcommitteechairwiththedirectorsoftheCDER,CBER,andCDRH,aswellaswiththeDeputyCommissionerforOperationsandtheSeniorAdvisortotheCommissioner.Inaddition,projectstaffhadseverallargemeetingsonFDApremiseswithseniorFDAstaffinJanuary,April,andJune1992,aswellasmanysmallermeetings.

TheIOMcommitteealsoorganizedthreeworkgroupstoconductitsactivities.Oneworkgroupconsistedmainlyoftheacademicclinicalmembersofthecommittee,andtheseindividualspersonallyinterviewednearly50currentorformerFDAadvisorycommitteemembers.

AnothercommitteeworkgroupdealtmainlywithFDAofficials.Itheldthreehalf-daymeetingsinFebruary,respectively,withtheleadersoftheCDER,theCBER,andtheCDRH.

TheIndustryLiaisonPanel,convenedbytheIOMcommittee,wasestablishedtoobtaintheviewsofthepharmaceutical,biotechnology,andmedicaldeviceindustriesonFDAadvisorycommittees.Itdrewitsmembersfromtheprescriptiondrug,over-the-counterdrug,

biotechnology,andmedicaldeviceindustries.Itsreport,ausefulinputtotheIOMcommittee,waswidelycirculatedtotheFDA,consumerorganizations,andotherinterestedpartiesand,inturn,elicitedveryusefulcommentary.

Thethirdworkgroup,onindustryandconsumers,heldahalf-daymeetingwiththeIndustryLiaisonPaneltodiscussthelatter'sreport.

TheIOMprojectstaffcontactedconsumerorganizations,includingallmembersoftheFDAConsumerConsortium,andsolicitedtheirviewsonadvisorycommittees.Theyalsoconductedinterviewslaterwithseveralconsumerorganizationrepresentatives.

TheIOMcommitteesentalettertoanumberoffoodanddrugattorneyswhohadexperiencewiththeagencyorwithclientswhodealtwiththeagency,solicitingtheirviewsonFDAadvisorycommittees.Thecommitteereceivedseveralusefulresponses.

TheIOMprojectstaffinterviewedtheexecutivesecretariesofallFDAadvisorycommitteesacrossthethreecenters(CDER,CBER,and

CDRH).TheyalsointerviewedtheCDERofficeanddivisiondirectorsresponsibleforadvisorycommittees.

NumerousmeetingsortelephoneconferencecallswereheldbetweenmembersoftheIOMcommitteeanditsstaffandrepresentativesoftheFDA,theDepartmentofHealthandHumanServices,andothers.TheseincludedtheDivisionofEthicsandProgramIntegrity,theOfficeofConsumerAffairs,seniorFDAstaff,theChiefCounseloftheFDA,theDHHSSpecialCounselforEthics,andtheOfficeofGovernmentEthics.

IOMprojectstaff,atthedirectionofthecommittee,requestedinformationfromFDAstaffonnumerousoccasions.Theserequestsweretypicallyfulfilledwithdispatchandefficiency.

IOMprojectstaffcompiledanextensivecollectionofdocumentspertainingtoFDAadvisorycommittees,onwhichthecommitteedrewinpreparingitsreport.

ThestudyalsodrewoninformationfromaconcurrentFDAsurveyofthemembersofdrugadvisorycommitteesbytheOfficeofPlanningandEvaluation.

Thestudycommissionedpapersonthefollowingtopics:theuseofadvisorycommitteesindrug,biologics,anddeviceapprovalintheUnitedKingdom,France,Germany,theNetherlands,andtheEuropeanCommunity;ahistoryoftheAnti-ViralDrugsAdvisoryCommittee;thefederalconflictofintereststatutes;theFederalAdvisoryCommitteeAct;andtheprospectsforandproblemswithearlyinvolvementofadvisorycommitteesintheproductevaluationprocess.Thesepapersarenotprintedinthisreport;nevertheless,theyallprovidedusefulinputtotheworkofthecommittee.

InJanuary1992,atameetingthatfollowedtheIOMcommittee'sfirstmeeting,FDAseniorstaffadvisedtheIOMstaffofthenecessityto

conductinterviewswithkeyFDApersonnel.AlthoughtheamountofrawdataonFDAadvisorycommitteeswasenormous(e.g.,listsofmembers,agendas,meetingtranscripts,andothersuchmaterials),verylittlehadbeenanalyzedordigested,muchlessshapedintoamanageableform.

Evenso,thecommitteeanditsstaffwereunpreparedfortheextentofvariationinpracticeregardingadvisorycommitteesthatexistsamongandwithincenters.Asonecommitteememberputit,"Onnooccasionwhentwoormorecenterswerepresentinthesamemeetingwasthereasingleanswertoanyquestion."Althoughthereportrefersfrequentlytothisphenomenon,noattempthasbeenmadetodocumenttheextentofvariationamongthecentersintheiruseandmanagementofadvisorycommittees.Tohavedonesowouldhaverequiredanenormousdatacollectioneffort,withquiteuncertainbenefits.TheIOMcommitteeinsteadhasaddresseditselftotheneedforanincreasedmeasureofconsistencyandstandardizationacrossand

withincentersininstancesinwhichnoprogrammaticorfunctionalreasonforvariationcouldbeidentified.

ReportOrganization

Thisreportisorganizedintothreeparts,whicharedividedintoeightchapters.PartI,Overview,includesthesummaryofthereportandthischapter.Thesummaryincludesallofthestudy'srecommendations.PartII,Background,constitutesanhistoricalaccountoftheevolutionoftheFDAadvisorycommitteesystem(Chapter2),adescriptionofthecurrentsystem(Chapter3),and,inChapter4,aconsiderationoftherecurringissuesthatpertaintotheadvisorycommitteesystem.

PartIII,TheFDAAdvisoryCommitteeSystem,addressesthemattersonwhichoperationalguidancewasrequested.Chapter5dealswithcommitteemembershipissuesofrecruitment,nomination,andappointmentandbrieflywithpotentialfinancialconflictofinterest.However,Chapter6isdevotedtothesubjectsoffinancialconflictofinterestandintellectualbiasastheseissuesaffecttheoperationofadvisorycommittees.Chapter7dealswithanumberofoperationalissuesrelatedtoadvisorycommittees.Chapter8,inturn,considersmattersinvolvingtheorganizationandmanagementoftheadvisorycommitteesystem.

ANoteonCross-NationalComparisons

ItisoftenthecaseindiscussionsoftheFDA,especiallyintheareaofdrugevaluationandregulation,thatreferenceismadetoEuropeancountriesthatprovideforfasterintroductionofnewdrugstothemarket.Forexample,thepracticesoftheCommitteeonSafetyandMedicines(CSM),anadvisorybodyservingtheDepartmentofHealthandSocialServices'MedicinesControlAgencyintheUnitedKingdom,areoftenheldupasanalternativeapproachtothatoftheFDA.

TheIOMcommittee,insupportofthisstudy,commissionedaverythoughtfulpaperontheuseofadvisorycommitteesindruganddeviceapprovalintheUnitedKingdom,theNetherlands,Germany,France,andtheEuropeanCommunity.*InallcountriessavetheNetherlands,anofficialgovernmentagencymakesthedecisionaboutapprovingdrugs,biologics,and,insomecases,medicaldevicesforintroductiontothemarket.The

*Thispaper,"AdvisoryCommitteesintheApprovalProcessofDrugsinEurope,"waspreparedbyLaurieM.C.Faro,Ph.D.,J.D.,DepartmentofHealthPolicy,ErasmusUniversity,Rotterdam,TheNetherlands.ItisavailablefromtheInstituteofMedicineDivisionofHealthSciencesPolicy.

Netherlandshasacommissionofpart-time,nongovernmentexperts,andthisbodymakestheofficialdecisionstoapprovenewdrugs.

Althoughtherearepotentiallyinterestinglessonstobelearnedfromcross-nationalcomparisons,itisimpossibletodisentangletheissueoftheuseofadvisorycommitteesfromthelargerpolitical,economic,andinstitutionalquestionsofproductevaluationandregulation.TheIOMcommitteedecidedthatthepursuitofcross-nationalcomparisonsintheuseofadvisorycommittees,howeverintriguing,wouldtakeittoofarafieldfromitschargetoprovidetheFDAwithoperationalguidanceonitsuseoftechnicaladvisorycommittees.

Appendix

Foritspurposes,theIOMcommitteehasadoptedoperationalratherthanformalscientificorlegaldefinitionsofthethreegroupsofproductswhoseregulationandreviewarethesubjectofthisreport.Ourreportconsiders"drugs"tobethoseproductsthatarereviewedandregulatedbyFDA'sCenterforDrugEvaluationandResearchand,correspondingly,"biologics"thoseregulatedbytheCenterforBiologicsEvaluationandResearchand"devices"thoseregulatedbyitsCenterforDevicesandRadiologicalHealth.TheseoperationaldefinitionsobviouslymatchtheadministrativeresponsibilitiesoftheFDA.

Theredonotappeartobewell-establishedscientificdefinitionsofthesethreeproductgroups.Thereare,however,officialregulatorydefinitionsinstatuteoragencyregulations.TheFDA'sstructureparallelsthedichotomythatthelawdrawsbetweendrugsanddevices,butthedistinctionbetweendrugsandbiologicschieflyreflectshistoricalfactorsand,inturn,administrativeconvenience.Althoughbiologicsareformallyregulatedmainlyundertheso-calledBiologicsActof1902,nowSection351ofthePublicHealthServiceAct,they

alsofitthedefinitionof"drug"inthe1938FederalFood,Drug,andCosmeticAct,andarealsosubjecttosomecontrolsbasedonthelaterlaw.

Thesituationisfurthercomplicated,fromatechnicallegalperspective,becausesomemedicalproductsmayintegrateascomponentsbothdrugs(orbiologics)anddevices,makingthempotentiallysubjecttotheseparatelegalrequirementsapplicabletoeachcategory.Thesedual-classorcombinationproductshavesometimesprovokedjurisdictionalconflictsamongthethreecenterswithintheFDA.However,theagency,actingunderrequirementsoftheSafeMedicalDevicesActof1990,hasinthepastyearadoptednewregulationsfordealingwithcombinationproductsandproductjurisdictionissuesandhasnegotiatedthreeinter-centeragreementsinsupportoftheseregulations.

DrugsaredefinedinSection201(g)(1)oftheFederalFood,Drug,andCosmetic(FDC)Act,asamended,mainlybythecriterionthattheyare"articlesrecognizedintheofficialUnitedStatesPharmacopeia,officialHomeopathicPharmacopeiaoftheUnitedStates,orofficialNationalFormulary,oranysupplementtoanyofthem[whichare]intendedforuseinthediagnosis,cure,mitigation,treatment,orpreventionofdiseaseinmanorotheranimals."Thisdefinitionisbroadenoughtoencompassbiologicsforregulatorypurposes;thestatutealsospecifiesthatthisdefinition"doesnotincludedevicesortheircomponents,parts,oraccessories."

BiologicsaredefinedunderSection351ofthePublicHealthServiceActas"anyvirus,therapeuticserum,toxin,antitoxin,vaccine,blood,bloodcomponentorderivative,allergenicproduct,orarsphenamineoritsderivatives(oranyothertrivalentorganicarseniccompound),applicabletotheprevention,treatment,orcureofdiseasesorinjuriesofman."Themeaningofthesetermsiselaboratedin(21CFR600.3(h).

DevicesaredefinedinSection201(h)oftheFDCActas"aninstrument,apparatus,implement,machine,contrivance,implant,invitroreagent,orothersimilarorrelatedarticle,includinganycomponent,part,oraccessory,whichisrecognizedintheofficialNationalFormulary,ortheUnitedStatesPharmacopeia,oranysupplementtothem,intendedforuseinthediagnosisofdiseaseorotherconditions,orinthecure,mitigation,treatment,orpreventionofdisease,inmanorotheranimals,intendedtoaffectthestructureoranyfunctionofthebodyofmanorotheranimals,andwhichdoesnotachieveanyofitsprincipalintendedpurposesthroughchemicalactionwithinoronthebodyofmanorotheranimalsandwhichisnotdependentuponbeingmetabolizedfortheachievementofanyofitsprincipalintendedpurposes."Thisdefinitionalsoincludes"devicesintendedforuseinthediagnosisofconditionsotherthandisease,such

aspregnancy,andinvitrodiagnosticproducts,includingthosepreviouslyregulatedasdrugs."

Note

1.BruceL.R.Smith,TheAdvisers:ScientistinthePolicyProcess(Washington,D.C.,TheBrookingsInstitution,1992).

2HistoricalEvolutionofFDAAdvisoryCommitteesTheFoodandDrugAdministrationisresponsible,amongotherthings,forensuringthesafetyandeffectivenessofdrugs,biologics,andmedicaldevices.Itsscientificandregulatoryresponsibilitiesintheseareasarisefromdifferenthistoricalperiods,derivefromdifferentstatutorybases,affectdifferentindustries,andareembeddedindifferentorganizationsandprocesses.Itsresponsibilitiesencompassinvestigationaldrugs,biologics,anddevices;theevaluationandregulationofnewproducts;postmarketingsurveillanceofsomeproducts;licensingofestablishments;oversightofmanufacturingprocesses;productlabelingandadvertisingofprescriptiondrugsandrestricteddevices;andotherfunctions.

Publicadvisorycommitteesareusedwidelythroughoutthefederalgovernmentforawidearrayofpurposes.

1,2TheyaresubjecttotheprovisionsoftheFederalAdvisoryCommitteeAct(FACA).AsusedwithintheFDA,suchcommitteesmaybeadhocorstanding;theyarefurtherclassifiedaspolicyadvisorycommitteesandtechnicaladvisorycommittees.Theformeradviseon''broadandgeneralmatters'';thelatterdealwith"specifictechnicalorscientificissues,whichmayrelatetoregulatorydecisionsbeforeFDA(21CFR14.1(b)(2),1991).Inthisreport,weareprimarilyconcernedwithstandingtechnicaladvisorycommitteestotheFDAthatdealwithdrugs,biologics,andmedicaldevices.Onlybriefconsiderationisgiventopolicyadvisorycommittees.

TheCodeofFederalRegulations(CFR)setsforththeFDA'sdefinitionoftheprimarycharacteristicsofanadvisorycommittee:

Anadvisorycommitteeordinarilyhasafixedmembership,adefinedpurposeofprovidingadvicetotheagencyonaparticularsubject,regularorperiodicmeetings,andanorganizationalstructure,forexample,achairmanandstaff,andservesasasourceofindependentexpertiseandadviceratherthanasarepresentativeoforadvocateforanyparticularinterest(21CFR14.1(b)(5),1991).

TheFDAusestechnicaladvisorycommitteesofoutsidescientificexpertstoadviseitontheapprovabilityofspecificproductsandonthescientificandclinicalpolicyissuesitconfrontsregardingproductdevelopmentandevaluation.Theagencyalsousesthesecommitteestolegitimatethesoundnessofitsanalysisofagivenproduct,asapublicforumfordiscussionofcontroversialissues,and,onoccasion,asan"appealscourt"fordisputedagencydecisions.*

ThischapterrecountsthehistoryofFDAadvisorycommitteesasithasevolvedalongsomewhatdifferentpathwaysfordrugs,biologics,andmedicaldevices.Variationsareduepartlytothedifferencesinregulatoryresponsibilitiesintheseareasandpartlytotheadministrativeentitiesandtheircultures.Attheendofthechapter,abriefsectioncontrastsFDAadvisorycommitteeswiththestudysectionsoftheNationalInstitutesofHealth.

TheFDAinitiatedtheuseofadvisorycommitteesinthe1960sand1970sfortheevaluationofdrugs.Itextendedtheiruseintheearly1970stothereviewofbiologicssoonaftertheDivisionofBiologicalSciencesoftheNationalInstitutesofHealthwastransferredtotheFDAastheBureauofBiologics.Finally,followingtheCooperreportof1970,FDAintheearly1970sbegantousesuchcommitteestoclassifymedicaldevices,astepthatCongresslatermandatedintheMedicalDeviceAmendmentsof1976forbothclassificationandproductevaluationpurposes.

Drugs

TheFDA'suseofagency-charteredadvisorycommitteesfordrugevaluationhasevolvedoverthethreedecadessincethe1962**drugamendmentstotheFood,Drug,andCosmeticAct.ThoseamendmentsrequiredFDAtoassessallnewdrugsforeffectiveness,inadditiontosafety(asrequiredbythe1938amendments),andto

reassessforeffectiveness

*TheFDAdoesnotconsiderthefollowingtobeadvisorycommittees:(1)aninternalcommitteecomposedexclusivelyoffull-timefederalgovernmentemployees,evenifitincludesoneortwoconsultantswhoarespecialgovernmentemployees;(2)agroupofpersonsconvenedonanadhocbasistodiscussamatterofcurrentinteresttotheFDAbutthathasnocontinuingfunctionororganizationandinvolvesnosubstantialpreparation;(3)agroupoftwoormoreFDAconsultantsmeetingwiththeagencyonanadhocbasis;(4)agroupofexpertsemployedbyaprivatecompanyortradeassociationthathasbeenaskedbytheFDAtoprovideitsviewsonaregulatorymatterbeforetheagency;and(5)aconsultingfirmhiredbytheFDAtoprovideadviceonsomematter(21CFR14.1(b)(4,5,&7),1991).**Incontrast,theuseofstudysectionsbytheNationalInstitutesofHealthbeganintheperiodimmediatelyfollowingWorldWarIIasthatagency'sextramuralresearchprogramcameintoexistence.

nearly4,000prescriptiondrugsthathadbeenintroducedtothemarketbetween1938and1962beforeproofofeffectivenesswasrequired.

TheFDArespondedbyseekingexternaladvicefromtheNationalAcademyofSciences-NationalResearchCouncil(NAS-NRC)onpreviouslymarketedprescriptiondrugs,establishingitsownreviewcommitteesforover-the-counterdrugs,andextendingsuchcommitteestonewprescriptiondrugs.Theevolutionofthisuseofoutsidescientificexperts,recountedbyCooperforthe1960s,isbrieflysummarizedhereandthendiscussedatgreaterlengthbelowfortheNAS-NRCDrugEfficacyStudyandfortheOTCreview.

TheThalidomidecontroversybroughttheteratogenic,mutagenic,andcarcinogeniceffectsofdrugstopublicandscientificconsciousnessandprovidedapowerfulstimulusforenactingthe1962drugamendments.Inpartialresponse,CommissionerGeorgeLarrickestablishedanAdvisoryCommitteeonTeratology.HealsoestablishedanadhoccommitteetoreviewthenewdrugapplicationforEnovid,thefirstoralcontraceptive.*

Dr.JosephSadusk,Jr.,directoroftheBureauofMedicine(predecessortoCDER)underLarrick,createdaMedicalAdvisoryBoardandaseriesofstandingandadhocadvisorycommittees.Hisjustificationforthelatterwastobroadentheflowofcommunicationtothebureaudirectorbeyondtheimmediate,full-timestaff,therebeingnowayinSadusk'sjudgmentfortheFDAtoacquireallofthestaffexpertiseneededfordrugevaluation.Hehopedthatadvisorycommitteeswouldupgradethequalityofinputstotheevaluationprocess.Saduskvisualizedopenadvisorycommitteediscussions,withindustryscientificandmedicalpersonnelpresent,alongwitharepresentativeoftheAmericanMedicalAssociation'sCouncilonDrugs,andexecutivesessionsinvolvingonlycommitteemembersandFDAstaff.

Dr.JamesGoddard,whosucceededLarrickasCommissionerin1966,suspendedthedevelopmentoftheseadhocadvisorycommitteesandreviewedtheiruse.Subsequently,GoddardandDr.HerbertLey,initiallydirectoroftheBureauofMedicineandthenCommissioner,reactivatedaprogramforstandingadvisorycommitteesin1967.InAugust1967,theagencyestablishedanumberofcommitteesfordrugs,withstaffsupportofonemedicalofficerandoneexecutivesecretaryprovidedbytheDivisionofResearchandLiaison.OneparticularlyactivecommitteewastheObstetricsandGynecologyAdvisoryCommittee,chairedbyDr.LouisHellman.The

*Apolicycommittee,theNationalAdvisoryFoodandDrugCouncil,wasestablishedinMarch1964,underLarrick,toaddresstrendsinscienceandtechnologyandrelatedeconomic,demographic,andpoliticaldevelopments.ThisgroupmetfirstinDecember1964,butitsusedeclinedundersuccessiveCommissioners,anditwasdisestablishedin1968.

Anti-InfectiveAgentsAdvisoryCommittee,chairedbyDr.CalvinKunin,wasalsoactive.

Cooper,analyzingthe1960sexperiencewithadvisorycommittees,observedthatthedynamicofcommitteedeliberationsdependedonthepersonalityofthecommitteechairman,theadvancepreparationofagendamaterialsbystaff,thesignificanceoftheitemsthatcamebeforethecommittee,andtheextenttowhichFDAstaffgenuinelywishedtoobtainindependentinputs.Thesesamequestionsremainsalienttoday,asthisreportindicates.

In1969,anewRepublicanadministrationtookofficeandplacedFDAAdvisorycommitteeoperationsonholdwhileitreviewedtheagency'sresourcesandassessmentcapabilities.ItpermittedtheObstetricsandGynecologyAdvisoryCommitteetocontinueitswork,andthecommitteeconsequentlyissueditssecondreportonoralcontraceptivesinAugust.InDecember1969,Dr.CharlesEdwardsbecameCommissionerand,withinarelativelyshorttime,reactivatedstandingadvisorycommitteesinthefollowingprogramareas:anti-infectiveagents,biometricsandepidemiologicalmethodology,cardiovascularandrenaldisorders,dermatology,endocrinologyandmetabolism,foodstandards,methadonemaintenance,neuropharmacology,obstetricsandgynecology,psychomimeticagents(jointlywiththeNationalInstituteofMentalHealth),radioactivepharmaceuticals,andrespiratoryandanalgesicdrugs.

Thisperiodicuseofadvisorycommitteesinthe1960seventuallyledtothepresentprescriptiondrugsadvisorycommitteesystem,whichiscurrentlyadministeredbytheCenterforDrugEvaluationandResearch(CDER).Twoothereventshelpedformthesystem:theDrugEfficacyStudyofthemid-1960sandthereviewofover-the-counter(OTC)drugsinthe1970s.Thesedevelopmentsarereviewedbelow.Importantly,notoneoftheseeffortswasrequiredbytheFood,

Drug,andCosmeticAct;eachwasinitiatedbytheFDAasawaytoimplementkeyportionsofthestatute.

DrugEfficacyStudy

TheDrugEfficacyStudy,conductedbytheNAS-NRCattherequestoftheFDA,beganinmid-1966andconcludedin1969.Thestudycameaboutbecausethe1962drugamendmentsrequired,amongotherthings,thatdrugsapprovedbetween1938and1962onthebasisofsafetyalonebereviewedfortheireffectivenessaswell.CommissionerGoddard,inaMarch31,1966,memorandumtoDr.KeithCannan,directoroftheNAS-NRCDivisionofMedicalScience,wrote:

Althoughthisisaonetimetaskrequiringevaluationofmaterialsomewhatdifferentfromthatnowobtainedincurrentdrugapprovalprocedures,itslongrangesignificanceexceedsthatofallotherdrugactivitycurrentlypursuedbytheFoodandDrugAdministration.RecommendationsfromthemostexpertsourcesareessentialifthisAdministrationistosuppressflagrantclaims,eliminateworthlessproductsandatthesametimeprotectthephysician'stherapeuticresources.

3

GoddardindicatedthattheFDAhadestimatedthattherewere3,000marketedproductsforwhichapplicationshadbeenfiledinthe19381962periodandperhapsanother1,000thatwerebeingmarketedwithoutapplications.Theseproductsinvolvedonlyafractionofthisnumberofchemicalmoieties;theagencyestimatedtheirsumasbetween300and400,whichcouldbegroupedintoabout60categoriesoftherapeuticeffect."Thesecategories,"Goddardwrote,"couldbecombinedintotenortwelvegroups,eachgroupbeingappropriateforconsiderationbyadifferentpanelofexperts."4Thus,theDrugEfficacyStudybeganwiththejudgmentbytheFDAthatexpertoutsideadvicewasrequired.GoddardsawnoconflictbetweentheNAS-NRCeffortandexistingFDAadvisorygroups.Thelatter,hewrote,"arenotequippedtoundertakeataskofthismagnitudeandcannotbeexpectedtoaltertheirotheractivitiestotheextentthatwouldberequired.''5

WhatisalsointerestinginretrospectisthatGoddardalsowrotethatnoproblemswereanticipatedwithconflictofinterest:

TheFoodandDrugAdministrationispreparedtoaccepttheprincipleofprofessionalintegritywherebypanelistswithpersonalinterestinatherapeuticentitywillnotpersonallyparticipateindeliberationswheretheirpersonalinterestisinvolved.LikewiseFDAisconfidentthatprofessionalpersonnelofthecaliberutilizedonNAS-NRCpanelswould

notputinformationobtainedfrompaneldiscussionstoimproperuseinotheractivitiesconflictingwiththeinterestsofFDA.6

TheNAS-NRCrespondedfavorablyinApril,andthetwopartiessignedacontractinmid-June.Indicatingtheagency'seagernesstogetunderway,aMay1FDApressreleaseannouncedthestudy:

TheFDAsoughttheassistanceoftheNAS-NRCincarryingouttheefficacystudybecauseofthatgroup'suniqueabilitytotapthetopmedicalandotherscientifictalentoftheNation.NAS-NRCsponsorshipalsowillassureanobjective,independentreview.TheFDAitselfdoes

nothavesufficientmedicalpersonneltocarryoutaprojectofthisscope,Dr.Goddardsaid.Recruitingonatemporarybasistheskilledscientistsrequiredwasnotconsideredfeasible,headded.

TheNAS-NRCproposedthataPolicyAdvisoryCommitteebeestablishedtodevelopguidelinesforthereviewpanels,ofwhichthereweretobeapproximately30.

7Thecommitteeconsistedof29membersandthechairmenofaninitial27evaluationpanels.8ThisbodymetinJulywithmedicalandpharmacyprofessionals,thepharmaceuticalindustry,andtheFDA,andgeneratedproceduralguidelinesforsubmissionofdataondrugsunderreview.The27panels(laterincreasedto30)werestaffedby10PublicHealthServicephysiciansassignedtotheNAS-NRCeffortbytheFDA.Eachpanelhad6members.

ThePolicyCommittee,inconsultationwiththeappropriatechairman,assigneddrugstoapanelforreview.Eachpanelwasaskedtodesignatearevieweddrugaseffective,probablyeffective,possiblyeffective,orineffective.Thefactualbasisforthesedeterminationswastobeinformationsubmittedbysponsoringfirms,themedicalliterature,informationsuppliedfromFDAfiles,andtheexperienceandjudgmentofpanelmembers.

Accordingtoa1968report,237firmssubmittedatotalof3,637drugpreparationsforreview;9alaterreportputthefigureat2,824.10Accordingtothelatter,mostwereprescriptiondrugs,butabout15percentwereover-the-counterproducts;two-thirdsweresingle-entitydrugs,therestwerecombinations.Thepanelscompletedtheirworkin1968,andin1969theNAS-NRCsubmittedreportstotheFDAonmorethan2,800drugs.Eachpanel,itwasestimated,reviewedapproximately150drugs.

AlthoughthereportsoftheDrugEfficacyStudywereonlyadvisory,inthesensethatFDAretainedboththeauthoritytodisagreeandtheresponsibilityforallimplementingdecisions,theywereoftendecisiveintheagency'sdecisionmaking.Implementation,however,requiredthattheFDAformallyacceptthestudy'srecommendations;ifitdecidedtowithdrawapprovalforadrug,itwasobligedtoannounceitsplantodosoandaffordthesponsoranopportunitytorespond.

HowwastheNAS-NRCDrugEfficacyStudyreceived?Inretrospect,itsreceptionappearstohavebeenmixed.Apparently,thestudyearnedsomerespectfromthepharmaceuticalindustry,inpartbecausetheexpeditiousreviewcontrastedwithcurrentindustryconcernsaboutthelengthofFDAreviewsofnewdrugapplications.However,becausethestudyrecommendedthewithdrawalofsomeproductsfromthemarket,litigationresulted.ThisgeneratedadvicetotheFDAthattherecommendationsoftheadvisorypanelsnotbeaccordedundueweight.11Forexample,WarrenWhyte,seniorattorneyforAbbottLaboratories,wrote:

Inmyview,[theNASstudyreports]areopinionsrenderedbygroupsofeminentscientistsontheeffectivenessorineffectivenessofdrugs.Although,becauseofthebasicallysecretivemannerinwhichtheNASreviewwasconducted,wedonotknowverymuchastohowthepanelsproceeded,itdoesappearfairlyclearthateachmemberofthepanelscouldnotpossiblyhavereviewedtheNewDrugApplications,theclinicalstudies,andtheliteratureoneachofthemanydrugsbeforeeachpanel.

12

HequotedDr.LouisLasagna,aprincipalintheDrugEfficacyStudy,whostatedinanaffidavitthat"thefindingsoftheNAS-NRCpanelsshouldnotberegardedasfinal,conclusive,orirrevocablescientificdeterminations,decisions,orrecommendations."13

Inasimilarvein,in1971,RodneyMunsey,thenassociategeneralcounselofthePharmaceuticalManufacturersAssociation,offeredthefollowingjudgment:

Manypeoplehaveerroneouslyassumedthattherecommendations[oftheNAS-NRCDrugEfficacyStudy]submittedwere,infact,officialrecommendationsoftheNAS-NRCoroftheDrugResearchBoard[oftheNAS].Theywerenot.TheNAS-NRCappointed30panelsofsixmemberseachtoreviewtheevidenceonthedrugsinvolved.ManypanelmemberswerenotaffiliatedwiththeAcademyortheCouncil.TherecommendationtransferredtoFDAconcerninganyparticulardrugwasnotanAcademy-Councilproduct,butwasonlyaconsensusrecommendationofthesix-manpanel.ItwasnotreviewedbytheAcademy,theCouncil,oranyoneontheDrugResearchBoard.Somepanelsreviewedhundredsofdrugsand,ofcourse,everymemberwasnot,anddidnotclaimtobe,anexpertoneachandeverydrug.Further,everymemberdidnothavethetimetoconsiderthemeritsofeachdryreviewed.Manydecisionsweremadebysplitvoteandcompromise.14

Over-the-CounterDrugs

AlthoughtheDrugEfficacyStudydealtprimarilywithprescriptiondrugs,theNAS-NRCpanelsalsoconsidered420over-the-counterdrugs(outofatotalof3,500drugsreviewed).15In1972,theFDAfacedthemammothproblemofreviewingalloftheOTCdrugsthathadbeenmarketedbetween1938andtheenactmentofthe1962DrugAmendments.ItssolutionwastoestablishanOTCreviewsystem.Thisreviewfocusedoningredients,notfinishedindividualproducts,andonassessingthosethatwere"generally

recognizedassafeandeffective"(GRAS/E)andthatwerenotmisbranded.Theregulatoryproductofthisprocesswasaseriesofmonographsconsistingofapprovedactiveingredients,labeling,andothergeneralrequirements.

AregulationpromulgatedinMay1972describedtheadministrationofthisOTCreviewsystem,whichincludedfourphases.

16ThecriticalfirstphasewasthereviewofOTCingredientsbyexpertpanelsresponsibleforspecificproductclasses(e.g.,analgesics).Thiswasfollowedbypublicationofaproposedmonographonthebasisofthepanelrecommendations;publicationofatentativefinalmonograph,basedontheagencyresponsetocommentsontheproposedmonograph;andtheissuanceofafinalmonograph.

Tolaunchthefirstphase,theFDAestablished17panelsofexpertadviserstoreviewtheliterature,data,andstudiesthatappliedtothelabelingandactiveingredientsfor27categoriesofOTCdrugs.ItsintentwastogivecredibilitytotheOTCreviewbyhavingoutsideexpertsbringtheirindependentjudgmentstobearonthesafetyandefficacyofeveryactiveingredientintheOTCmarketplace.Arelatedobjectiveinestablishingthepanelswastohandleaheavyworkload,forwhichtheFDAstaffwerelimitedinnumberandscientificcompetence.17Indeed,inthisinstance,thebasicroleoftheFDAstaffwastoadministertheOTCpanelprocess.

Eachpanelhadthreetypesofmembers:sevenscientificvotingmembers,onenonvotingconsumermember,andonenonvotingindustryrepresentative.Thescientificvotingmembersincludedphysicians,pharmacologists,andtoxicologistsfrombothactivemedicalpracticeandacademia;forthemostpart,however,these

individualsweresubspecialtyacademicphysicians,dependingonthedrugcategory.Approximately185expertsservedonthesepanels,assistedbyanother74experts.Allservedasspecialgovernmentemployees.18TheOTCDrugDivisionmanagedallofthesepanels;inessence,thiswasitsmajorfunction.

Baumgartner'shistoryoftheOTCreviewconcludedthattheFDAgrosslyunderestimatedthesizeandcomplexityofthepanelphase,whichlasted10years.Thepanelsreviewed,bytherapeuticcategory,722individualactiveingredientsthathad1,454activeusesinthehundredsofthousandsofmarketedOTCdrugproducts;intheprocess,theyevaluatedmorethan14,000volumesofsubmitteddataandotherscientificmaterials.Collectively,thepanelsmetmorethan513timesonmorethan1,050calendardays,andtheirdeliberationsspannedanaverageof4.5yearseach.

Thissystem,whichwasheavilyinfluencedbyPeterBartonHutt,FDAChiefCounselatthetimethatitwasestablished,articulatedsomegeneralprinciplesofFDAadvisorycommittees.Suchcommitteesshouldincludenonvotingindustryandconsumerrepresentatives,forexample,toincreasethelikelihoodthattheresultsofthereviewwouldbeacceptedinboth

quarters.Theparticipationoftheformerhelpedtoavoidsurprisingtheindustry,tomaintaincontactwithit,todetectproblemsearly,andtominimizeopposition.

TheOTCreviewadvisorycommitteesoperatedundertheFederalAdvisoryCommitteeAct(adoptedin1972),federalconflict-of-intereststatutes,and,beforethereviewwasfinished,theGovernmentintheSunshineAct.ThisenvironmentofopennessandpublicscrutinywasverydifferentfromthatoftheDrugEfficacyStudyandmuchmorecharacteristicofourpresentperiod.

PrescriptionDrugReview

Intheearly1970s,followingtheepisodiceffortsofthepriordecade,anadvisorycommitteesystemevolvedforprescriptiondrugs.Itspurposewastosecureexpertadviceontheevaluationandapprovalofnewtherapeuticproducts.Anumberofcontroversialcasesinfluencedthedesignofthissystem.OneconcernedthedrugPromalin,*forwhichtheBureauofDrugsestablishedanadhoccommitteetoreviewthedataaboutitsapproval.Theexpertcommitteeheardpresentationsfromindustry,theAmericanAcademyofAllergy,andtheFDAstaff.

Dr.CharlesEdwards,thenCommissionerofFoodandDrugs,satthroughthisentiremeeting.Afterward,heinstructedtheFDAstafftocreatesimilaradvisorycommitteesforalldrugareas.Hismainaimwastogroundtheregulatoryprocessinthemainstreamofscience;healsohopedtogeneratesomeprotectivecoverforagencydecisionsandtoestablishasoundreviewprocess.

19

ThepurposeofthecommitteesystemthatwasestablishedwastoadvisetheFDAondrugapprovaldecisionsandonguidelinesfordrugdevelopmentinordertobringcredibilitytoapprovaldecisionsandto

enhancetheirquality.Advisorycommitteesservedbothasconsultinggroupsandasopenforumsfordiscussingcontroversialissues,afunctionthattheagencyconsideredparticularlyimportant.

TheFDAusedinternalmemorandatocreatetheseprescriptiondrugadvisorycommitteesadministratively.Subsequently,theagencypromulgatedgeneralregulationsgoverningtheformationandoperationofadvisorycommittees,whicharenowcodifiedin(21CFR14).Ingeneral,fromonetothreecommitteesadvisedeachofthesixtoeightFDAprescriptiondrugproductsdivisions.Theadvisorycommitteesystemthatemergedduringthis

*Dr.MarionFinkelremembersitastheMaternalHealthCommittee,notthePromalinCommittee.

periodfulfilledthecontinuingfunctionofreviewingnewdrugs,unlikethebacklog-clearingtaskoftheOTCreview.

Managementofthesecommitteeshasnotalwaysbeenwithoutcontroversy,astheFountainCommitteereportof1976(seeChapter4)makesclear.Nevertheless,intheseearlyyears,theFDAdidlearntheimportanceofaskingprecisequestions,offormulatingfixedagendas,andofreachingclosureonwhatthecommitteeactuallythoughtusuallybysolicitingavote.CommitteememberslaterfeltthattheyhadbeenwellorbadlyusedasafunctionofhowwelltheFDAperformedthesetasks.

20

TheFDAcreatedasystemofstanding,ratherthanadhoc,committeessothatcommitteememberswouldseethefruitsoftheirlabor.*Termsforadvisorycommitteememberswerefouryearsbutwereoftenshortenedbysuchfactorsasslowappointmentsandearlydepartures.Committeememberswereprimarilyacademicphysicians,althoughitsoonbecameclearthatotherexpertisewasalsoneeded.Asaresult,mostcommitteeshavehadastatistician,somehaveanepidemiologist,andoccasionallyacommitteehasatoxicologistmember.

Inthelate1970s,theFDAaddedconsumerrepresentativestoitsprescriptiondrugadvisorycommittees.Thisarrangementdidnotworkwell,becausesuchrepresentativeswerefrequentlyatascientificdisadvantageindiscussionswithothercommitteemembers.Subsequently,theagencybegantoappointtechnicallyqualified,consumer-nominatedmemberstodrugadvisorycommittees,whichprovidedtheFDAwithqualifiedexpertswithpersonaltiestotheconsumercommunity.(Chapter5discussesthistopicatgreaterlength.)

Summary

IntheDrugEfficacyStudy,theFDAturnedtotheNAS-NRCtoobtainaccesstoindependentexpertisethroughanorganizationwhosemodusoperandiwasexpertcommittees.Indoingso,itsoughttoclearalargebacklogofworkforwhichitlackedadequatestaffinashortperiodoftime.Itlearnedinimplementingthatstudy'srecommendationsthepracticallimitsoftimeandresources,andtheconsequentinabilityofexpertadvisorypanelstoreviewallrelevantdata.Theyagencylearnedaswellthatitwasnotrelievedoftheresponsibilitytodecideissues.Mostimportant,however,the

*Theagencyhadbeencriticizedearlierforformingadhoccommittees,bringinginexperts,obtainingadvice,andthendischargingthecommittee.Thesecriticsmaintainedthatsuchasystemproducedtheappearanceofexternalexpertreviewwithoutthereality,inaddition,theadvisersdisappearedandneverlearnedtheresultsoftheirwork.

studyestablishedthepatternwithintheFDAofseekingoutsideexpertadviceonmajordecisions.

SeveralnoteworthydifferencesbetweentheDrugEfficacyStudyandcurrentFDApracticescanbenoted.Forexample,havingchargedtheNAS-NRC,theFDAturnedthereviewtaskovertotheNAS-NRC;ithadnoroleinselectingpanelmembers,andthecompositionofpanelmembershiporiginallywasnotdisclosed.Thepanelsmetinsecret,andthefrequencyandlocationoftheirmeetingswerenotknown.Indeed,theFDAatfirstwasnotwillingtodisclosethestudyreports.Inaddition,thefederalconflict-of-interestrequirementswerenotapplicable,andtheNAS'sownprocedureswerenotverystringentbytoday'sstandards.

TheFDAsetuptheOTCreviewpanelstobringindependentexpertjudgmentstodecisionsaboutthesafetyandefficacyofover-the-counterdrugs.Akeyobjectiveofthereviewwastogenerateoutcomesthattheagencycouldenforce.AsecondaryjustificationfortheactionwasthatthepanelswereneededtotakeoveraworkloadthatwastoogreatfortheFDAstafftohandleandthatitwasnotcompetenttohandle.

TheprescriptiondrugreviewprocessevolvedtoassisttheFDAinitscontinuingworkofreviewingnewdrugs.Assuch,itdepartedfromthelarge-scale,one-timeeffortsoftheDrugEfficacyStudyandtheOTCdrugreview.Thedrugadvisorycommitteeswereintendedtoensurethescientificsoundnessoftheagency'sregulatorydecisions,toestablishthecredibilityoftheprocess,andtoprovideawaytoaircontroversialissues.

Ineachoftheseefforts,theFDAinitiatedtheuseofadvisorycommittees.TheDrugEfficacyStudysuggestedamodel,andtheOTCreviewmovedadvisorycommitteesunderthedirectmanagementoftheFDA..Prescriptiondrugreviewactivities

incorporatedadvisorycommitteesintothecontinuingoperationsoftheagencyinitsreviewofnewdrugs.

Biologics

Thefederalgovernmentregulatedbiologicalproductsintendedforhumanuseevenbeforeitbegantoregulatedrugsandmedicaldevices.IntheUnitedStates,biologicsregulationdatestotheVirus,Serum,andToxinsActof1902(laterexpandedandconsolidatedinthePublicHealthServiceAct).DrugregulationbegansomefouryearslaterwithpassageoftheFoodandDrugActin1906;itwasextendedsubstantiallyin1938andthenagainin1962.Comprehensivedeviceregulationdidnotreceiveexplicitstatutoryunderpinninguntil1976.

Thebiologicalproductscoveredbythe1902actwerethosethathadcomeintogeneralusebythattimethatis,viralvaccines,bacterialvaccines,antitoxinsandtoxoids.(ItisofsomehistoricalinterestthattheBiologics

Actalsoincludedarsphenamineanditsderivativesandothertrivalentarseniccompounds,becauseatthattimetherewasnoexistingseparatestatutoryprovisionfortheregulationofdrugs.)Later,asbloodandbloodfractionsandallergenicextractscameintomedicaluse,they,too,wereregulatedasbiologics.Thus,Section351ofthePublicHealthServiceAct,ascurrentlyamended,definesbiologicalproductsas''anyvirus,therapeuticserum,toxin,antitoxin,vaccine,blood,bloodcomponentorderivative,allergenicproduct,oranalogousproduct,orarsphenamineoritsderivatives(oranyothertrivalentorganicarseniccompound),applicabletotheprevention,treatment,orcureofdiseasesorinjuriesofman."*

Themainuseofearlybiologicswastocontrolcommunicablediseases,apublichealthpurposelogicallypursuedbythegovernment.Indeed,thedevelopmentandregulationofbiologicalproductsareembeddedinapublichealthrationaleandpublicinstitutionalcontext.Asaresult,intheearlyyearsofthiscentury,nationalgovernments,states,andsometimesevencitieswereinvolvedintheproductionanduseofbiologicsthroughpubliclaboratories.Noequivalentoftoday'sindustrialcapabilityinbiologics,biotechnology,ordrugsthenexisted;onepublichealthtaskwastocreatesuchacapability.Thesepublichealthoriginsofbiologicalproductsgiveadistinctivecasttothisareaofregulation.

IntheUnitedStates,responsibilityforregulatingbiologicswasinitiallyassignedtotheU.S.PublicHealthServiceandtothelaboratoriesthatlatercametobetheNationalInstituteofHealth(NIH).Inthepost-WorldWarIINationalInstitutesofHealth,biologicsregulationwasoriginallypartoftheMicrobiologicalInstitute;theNIHcreatedaseparateDivisionofBiologicStandards(DBS)in1956.

TheNIHyearsofthebiologicsprogramleftseverallegacies.First,the

present-dayCenterforBiologicsEvaluationandResearch(CBER)isaregulatoryunitdeeplyembeddedinamedicalscienceresearchorganization.Itsprofessionalsengageinboththeregulationofbiologicalproductsinspectingmanufacturersandsamplingvaccineproductionlotsandscientificresearchdealingwithbiologicalproducts,oftenincollaborationwiththelaboratoriesofotherpublichealthagencies.Theaimsofthisresearcharetoimproveexistingproductsand,insomecases,toexplorethefeasibilityofdevelopingnewones.Othertasksincludethedevelopmentofnewtestsfordeterminingsafetyandefficacyandtheproductionoflaboratoryreferencestandards.

Onoccasion,theFDA'sbiologicsorganizationhasalsoconductedclinicaltrialsofeitherexperimentalorlicensedproducts(sometimesincollaborationwithotherNIHcomponentsortheCentersforDisease

*SeeAppendix,Chapter1.

Control).ItsresearchandregulatorydecisionsaretiedtosimilarprogramsinthebiologicscontrollaboratoriesofothernationsthroughtheWorldHealthOrganization(WHO)anditsCommitteeonBiologicalStandards,aswellasthroughthevariousWHOworkinggroupsthatreporttotheCommitteeonBiologicalStandards.

Thisextensiveinvolvementwiththepublichealthcommunityandthescientificresearchcommunitycreatedaclimatefavoringtheseekingofscientificconsensusinregulatorydecisionmaking.Forexample,thelengthydevelopmentofamajornewproduct,suchasavaccine,includestheorganizationofnumerousnationalandinternationalscientificworkshopsandconferences.Thebiologicsregulatoryorganizationtypicallywastheorganizeroftheseconferences,oftenwithjointsponsorshipbyinterestedcomponentsofotherpublichealthagencieshereandabroad.Althoughtheseconferencesdidnotprovideadviceonspecificregulatorydecisions,theycontributeddataanddiscussionsthatofteninfluencedthedevelopmentofrequirementsfortheproductand,intheprocess,generatedinternationalconsensusaboutstandards.*

DuringtheyearsinwhichthebiologicsregulatoryprogramwasacomponentoftheNIH,adhocadvisorycommitteesweresometimesformedtodealwithmattersofhighpublicvisibility,suchasamajornewproductthatwasbeingconsideredforapprovaloranimportantproblemthatoccurredwithanexistingmarketedproduct.Themembershipofthesecommitteesgenerallyincludedexpertsfromgovernmentaswellastheacademiccommunity.Althoughtheworkofacommitteemightextendoveraperiodofmonthsoryears,itschargewaslimitedtoadvisingontheparticularproductorproblemunderreview.CommitteememberswouldroutinelyparticipateinanypertinentworkshopsorconferencesandbefamiliarwithlaboratoryprogramsoftheDBS.Thus,theyacquiredgreatunderstandingoftheissuesbeforethecommittee.Adhoccommitteemeetingswereclosed

tothegeneralpublic.Initially,thesecommitteesreportedtotheSurgeonGeneralofthePublicHealthService;later,theyreportedtotheDirectoroftheNIH.

Historically,manufacturersofbiologicalproductshavesubmittedlicenseapplicationsas"rollingsubmissions";thatis,theysubmittedportionsoftheapplicationduringtheentiredevelopmentprocess,withsupplementsaddedasadditionalstudiesarecompleted.Consequently,unlikemostnewdrugapplications,anapplicationforabiologictypicallywasreviewedinitspartslongbeforeitwasformallysubmittedincompleteform.Thus,anyadhoccommitteewouldusuallymeetonseveraloccasionstoreviewaproduct(or

*BecausetheWHOhaslongbeendeeplyinvolvedinbiologics,standardsdiscussionsinthisareawerealwaysinternational.

groupofsimilarproducts)underdevelopmentbeforeallofthestudiesneededforlicensurehadbeencompleted.Bythetimeoflicensure,thecommitteewouldhavehadampleopportunitytobecomefamiliarwithallresearchdatarelatingtotheproductandwouldhaveparticipatedinthedevelopmentoftheregulatoryrequirementsforit.TheSurgeonGeneral'sadhoclivepoliovirusvaccineadvisorycommittee,forexample,hadmanymeetingsandparticipatedinanumberofconferencesoveranextendedtimebeforethelicensingdecisionarose.Duringthistime,boththecommitteeandtheagency'sscientificstaffhadformedcloseworkingrelationshipswiththeresearchpersonnelofthepotentialmanufacturersofthevaccine,aswellaswithotherscientistsinthenationalandinternationalpublichealthcommunitiesinvolvedinpoliovirusvaccineresearch.

Inthissameperiod,licensingapplicationsforlesserbiologicalproductsusuallyreceivednooutsideattentionandwerereviewedandactedonsolelybythestaffofthebiologicsregulatoryorganization.Thus,theadhoccommitteeshadsubstantialinvolvementwithcertainhigh-visibilityproducts,buttheyprovidednocomprehensiveoversightoftheoverallregulatoryprogramorofbiologicsdevelopmentgenerally.

TheotheruseofadvisorycommitteesbythebiologicsprogramthatdevelopedattheNIHandhasbeenextendedtotheFDAwasinthereviewofintramuralresearch.(NocomparablefunctionexistsforadvisorycommitteesoftheothertwoFDAcenters,thecentersforDrugEvaluationandResearchandforDevicesandRadiologicalHealth.)JustaseachNIHinstitutehadoneormorestandingcommitteesforthereviewofintramuralresearch,theDBShadits"boardofscientificcounselors,"expertswhoreviewedthequalityandappropriatenessofintramuralbiologicsresearchaswellasthequalificationsofindividualscientistsandmaderecommendationstotheDirectoroftheDBS.TheDBSspecificallychargedthereview

committeenottoreviewregulatorymatters.ThecurrentCBERadvisorycommitteescontinuethistradition.

Intheearly1970s,theDivisionofBiologicStandardsattheNIHcameunderfirefromSenatorAbrahamRibicoff'sSubcommitteeonGovernmentOperations.TheDBSandtheNIHmanagementdidnotfarewellintheensuingcontroversy.ThisembarrassedtheNixonadministration,whichinspiredtheadministrativetransferofthebiologicsregulatoryfunctionfromtheNIHtotheFDA.Thus,inthesummerof1972,theDBSwastransferredfromtheNIHtotheFDA,andrenamedtheBureauofBiologics.Theintentionofthemovewastostrengthenthedivision'sregulatoryroleanddilutethepublichealthemphasis.TheFDAitselfhadbecomeacomponentofthePublicHealthServiceinthe1960s.YetdespiteitstransfertotheFDA,manyoftheCBER'spresentpolicies,procedures,andpracticesstemfromitsyearswithintheNIH.Forexample,CBERheadquartersandits

principallaboratoriescontinuetobelocatedontheNIHcampus,andithasmaintainedextensiveresearchcontactswiththeNIH.

Thetransferwasfollowedbyanumberofmanagementchangesinthebiologicsorganizationandadecisiontoreexaminetheefficacyofallexistinglicensedbiologicalproducts.Atthattime,therewerenostandingcommitteesforbiologicsregulatorydecisions,andtheadhoccommitteesthatwereinvolvedhadanarrowfocus.Tocarryoutitsregulatoryfunctions,thebureaucreatedaprocesssimilartothecomprehensiveOTCdrugreviewandformedsixstandingcommitteestoreviewtheprincipalcategoriesofbiologicalproducts:majorvaccines,bacterialvaccines,bloodproducts,andproductsforwhichthesciencebasewassubstantiallyless,suchasallergenicextracts.

Eachcommitteehadapproximatelysevenscientificallyqualifiedvotingmemberswhowereexpertintheparticularareaunderreview.Inaddition,thebureauchoseanonvoting''consumer"representativeandanonvoting"manufacturing"representativeforeachofthepanels.ThesecommitteeshadFDAstaffsupportandwereresponsibleforreviewinglicensedproductsandmakingrecommendationstotheCommissioneraboutthosethatdidanddidnotmeetcontemporarystandardsofefficacy.(Safetywasconsideredindirectlybecauseitborearelationtoefficacy.)Theprocess,whichwasquitesimilartotheOTCreview,beganinlate1972andearly1973andtookseveralyears.

Thescaleandscopeofthereviewweresubstantialinbothadministrativeandlogisticalterms.Asthecommitteesbegantheirwork,itbecameapparentthatthesesameexpertscouldbehelpfultotheagencyinotherways:givingongoingadviceaboutnewproducts(assumingtheroleofearlieradhoccommitteesinthisregard);advisingongeneralproblemsthatoccurredwithbothmarketedandexperimentalproducts;andreviewingintramuralresearchsimilarlyto

thefunctionoftheNIHDBSBoardofScientificCounselors.Astheagencycompleteditsone-timecomprehensivereviewsofexistingproducts,itreducedthenumberoftheseoriginalcommitteesandrecharteredthemtoprovidecontinuingadviceonalloftheorganization'sregulatoryandresearchprograms.

In1982,thebiologicsbureauwasconsolidatedwiththeBureauofDrugsintotheCenterforDrugsandBiologics.Thisarrangementlastedfiveyears;theFDAseparatedthetwounitsin1987intotheCenterforBiologicsEvaluationandResearchandtheCenterforDrugEvaluationandResearch.

MedicalDevices

TheuseofadvisorycommitteesbytheCenterforDevicesandRadiologicalHealth(CDRH)differsfromthatoftheCDERandCBERin

onecriticalaspect:itisrequiredbystatute.TheRadiationControlActof1968mandatedtheestablishmentoftheTechnicalElectronicProductsRadiationSafetyStandardsCommittee(seethelaterdiscussion),whichwasthefirstacknowledgmentbyCongressthatadvisorycommitteescouldbeusefulintheadministrationoffoodanddruglaw.ItwastheMedicalDeviceAmendmentsof1976,however,thatrequiredtheextensiveuseofadvisorycommitteesasanintegralaspectofthedeviceregulationauthorizedbythatact.

TheCooperReport

InanOctober30,1969,messagetoCongressonprotectingtheinterestsofconsumers,PresidentRichardM.Nixoncalledfor"certainminimumstandards"formedicaldevicesanddeclaredthat"thegovernmentshouldbegivenadditionalauthoritytorequirepremarketingclearanceincertaincases[ofmedicaldevices]."Inresponse,theSecretaryofHealth,Education,andWelfare(HEW)appointedacommitteetostudytheregulationofmedicaldevicesandtorecommendalegislativeprogramtoimplementthePresident'smessage.

TheStudyGrouponMedicalDevicesoftheDepartmentofHEWissueditsreport,MedicalDevices:ALegislativePlan,inSeptember1970.

21ThiscommitteeanditsreportwereknownastheCooperCommitteeandCooperreport,respectively,afterthechairman,Dr.TheodoreCooper,thenDirectoroftheNationalHeartandLungInstituteoftheNIH.AmongthecommitteememberswereDr.CharlesEdwards,CommissioneroftheFDA,andDr.MarkNovitch,thenSpecialAssistantforPharmaceuticalAffairs,OfficeoftheAssistantSecretaryforHealthandScientificAffairs,andlaterDeputyCommissionerandActingCommissioneroftheFDA.

Thecommittee'schargewastorecommendproceduresforestablishingstandardsforcertainmedicaldevicesandforthereviewandregulationofotherdevicesbeforemarketing.Itfoundthreeissuescentraltoasoundlegislativeproposal:(1)animmediateandsystematicreviewofalldevices"availableandinuse"inordertogrouptheminoneofthreecategoriesthosethatshouldbeexemptfromstandardsandpremarketingreview,thoseforwhichstandardsshouldbeestablishedtoensure"safetyandreliability,"andthoserequiringpremarketingreview;(2)delineationofanacceptableplan"forassuringexpertscientificreviewofthesafetyandeffectivenessofmedicaldevicesattheclinicalapplicationphase''andbeforemarketing;and(3)definingthegovernment'sroleinstandardsettingandenforcement.22Regardingclassification,thereportrecommendedthat"appropriatescientific,health,andengineeringexperts"beorganizedtoconducttheinitialreviewofexistingdevicesandtoadviseontheir

classification.Forpremarketingreview,itrecommendedtheestablishmentof"standingpermanentadvisoryscientificreviewpanels...toassistinthereviewofdataonnewmedicaldevicesandtoadvisetheSecretaryoftheirsafetyandeffectiveness."Inaddition,thereportrecommendedthattheSecretarybegrantedauthoritytocertifyexistingstandardsorestablishnewonesandtoauditmanufacturersforcompliance.Itnotedthatpriorexperiencewiththeinitialandlong-termsafetyandeffectivenessofmedicaldeviceswasoftenlimited,thatdevicedevelopmentwasdynamic,thathazardsarosefromuseaswellasfromdesignandmanufacture,andthatexistingdatawerequiteinadequate.

Althoughvariousprivateorganizationshadtriedtoprovidemanufacturerswithstandardsinspecificareas,theseeffortswerepoorlyfinancedandcoordinated,werenotcomprehensive,andlackedtheforceoflaw.TheFDAwastheonlygovernmentagencywithauthoritytoregulateallmedicaldevices,butitsauthoritywaslimitedtopreventingmisbrandingandadulteration.Althoughthecourtshadrecentlyupheldtheagency'seffortstoregulatecertaindevicesthroughdrugpremarketingcontrols,thescopeofthisauthorityhadnotbeenclearlydefined.Manufacturerconcernsforproductliabilityfurtherunderlinedtheneedfor"asystemofdeviceregulation."

ConsultantstotheCooperCommitteeagreedthat"thepublicdeservesmoreprotection,"buttheyregardeddrugregulationasaninappropriatemodelthatwaslikelytoinhibitinnovationifappliedtodevices.However,theapproachesfavoredbytheconsultantsrangedfromself-regulationtoinsistenceonGoodManufacturingPracticestopremarketingnotificationtopremarketingapproval,anddidnotreflectconsensus.

Thereportnoted"thatasystemof'peergroup'reviewofscientificdatawouldinduceconfidencewithinthemedicaldevicecommunity

thatdecisionsrelatedtodevicesandstandardsweresoundlybased."Thebasiclogicregardingtheuseofoutsideexperts,whetherforclassification,standardsetting,orpremarketingreview,wasspelledoutasfollows:

Thevarietyofmedicaldevicesalreadyinuseareproducedfromanequallywidevarietyofmaterials.Moreover,thebasesofscientificdatarangefromalmostpureempiricismtoreasonablywellsystematizedinformation.Asaresult,therearemanyscientificandtechnicalissuesinvolvedintheevaluationofmedicaldevicesthatrequirejudgmentbyexpertprofessionalsallalongthedevelopmentalcontinuumfromresearchthroughdevelopmenttotesting,evaluation,andpreparationforsale.Accordingly,unilateraldecisionsbygovernmentagencieswithoutexpertadvicewouldbeasunwiseasunilateraldecisionsbydevelopersorproducers.Instead,thisstudyrecommendsthatregulationofmedical

devicesbeaccomplishedwiththerecognitionthatscientificproblemsshouldbesolvedscientifically,withsoundscientificadviceprovidedtotheFederalauthorityexercisingtheresponsibilityessentialtoeffectivecontrol.

23

Tosummarize,theCooperreportrecommendedthatthreecategoriesofdevicesbeestablishedthose"sowellrecognizedassafeandeffective"thatneitherstandardsnorpremarketingapprovalwasneeded,thosethatcouldberegulatedbystandards,andthose"newandunprovencriticaldevicesthatareattheleadingedgeoftechnologicalinnovationandbiomedicalexplorations"andthatrequiredpremarketingreview.Forthelatter,itrecommendedthattheSecretarybeauthorizedtoestablishstandingadvisorypanels''generallypatternedalongclinicalsub-specialtylines,composedofappropriateexpertsfromthephysicalandbiologicalsciences,engineering,medicine,anddentistryqualifiedtoevaluatemedicaldevices."Thesepanelsshouldbepermanent,meetregularly,haveappropriateregulationsgoverningconflictsofinterest,andadvisetheSecretaryabouttheacceptabilityofeachdeviceforclinicalapplicationormarketing.ThereportalsorecommendedthataMedicalDevicesAdvisoryCouncilshouldbeavailabletotheSecretaryforpolicyissuesrelatedtomedicaldevicesandshouldincludeexpertsindevicedevelopmentandrepresentativesofmanufacturers,users,andpatients.

OnthebasisoftheCooperreport'srecommendation,theFDAinitiatedaninventoryofmedicaldevicesandbeganclassifyingmedicaldevicesthatwerealreadyonthemarket.24TwopilotpanelsonefororthopedicsandanotherforcardiovasculardevicesmetinNovember1971todevelopasystemforclassifyingdevices,andbylate1972,theFDAhadindicateditsintentiontoclassifyalldevices

overthenext12to18monthswiththeaidofoutsideexpertpanels.25Theagencyalsoannouncedthatitwasinitiatingeffortstodevelopdevicestandards.

TheMedicalDeviceAmendmentsof1976

IntheperiodfollowingtheCooperreport,abroadconsensusdevelopedregardingtheneedforincreasedlegislativeauthorityovermedicaldevices.TheFDAauthoritytoregulatedrugsasdeviceswascumbersome,time-consuming,andinadequate.Theconsensuswasstimulatedinpartbymanufacturersseekingtoalleviatetheirconcernsaboutproductliability.26*

*OneappendixtotheCooperreportwasalengthylawreviewarticleonproductliability,whichlisted10pagesofrepresentativecourtcasesondefectivemedicalandsurgicalinstruments.

Thelegislativeprocessmovedslowly,culminatinginnewlegislationsixyearsaftertheCooperreport.Inearly1976,theHouseCommitteeonInterstateandForeignCommerceissueditsreportonpendingdevicelegislation.ItreviewedthecontentsandrecommendationsoftheCooperreportindetail.Inaddition,itapprovinglynotedtheseveralreferencesoftheCooperreportto"peerreview"groupsforreviewofscientificdataaboutdevices,consistingofrepresentativesfromindustry,thefederalgovernment,theacademiccommunity,andotherconcernedorganizations,includingconsumers.

TheHouseCommerceCommittee,drawingontheCooperreportrecommendations,"andinanefforttoaffordthe[FDA]thebestpossiblescientificadviceandexposetheagency'sdecisionstopublicscrutiny,"draftedabillthatreliedheavily"ontheproceedingsofexperts,withultimateauthorityvestedintheSecretary."Thisproposedlegislationprovidedforclassificationpanels,whichweretousethepriorFDAclassificationpaneleffortsandreviewthem"inlightofthestatutoryclassificationcriteria."Italsoprovidedforestablishingadvisorycommitteesforproductapprovalevaluation.

TheMedicalDeviceAmendments,whichwereenactedinlate1976,wereheavilyinfluencedbytheCooperreport.Theyrequiredthecreationofadvisorypanelsorcommitteesfortwopurposes.Thefirstwastheclassificationofmedicaldevices(Section513).Followingadoptionoftheamendments,theFDArevisitedtheclassificationprocessinaccordancewiththeact.Thenewclassificationadvisorypanelshadthebenefitofpriorefforts,whichwereausefulpointofdeparture.

Thesecondpurposewastheevaluationofmedicaldevicesregulatedbyrisktier.ClassIdevicesrequirednostandardsorpremarketingreview.ClassIIdevicesweretoberegulatedbyperformancestandards(Section514).ClassIIIdevicesrequiredpremarketing

approval(Section515).GiventhatnoperformancestandardshavebeenissuedbytheFDAsincethe1976amendments,itischieflythepremarketingapprovalprocessofClassIIIdevicesthatconcernstheIOMcommittee.

Forproductevaluation,theamendmentscalledforestablishmentofpermanentadvisorycommittees.TotheseadvisorycommitteestheFDAwastoappoint"personsqualifiedinthesubjectmattertobereferredtothecommitteeandofappropriatelydiversifiedprofessionalbackgrounds";theagencywasalsomandatedtoappointachairmanandprovidenecessaryclericalsupport.Theperformancestandardssectioncalledfortheappointmentofnonvotingconsumerandindustrymembers;thisprovisionwasomittedfromthepremarketingapprovalsection,butthepracticewas

adoptedfortheproductreviewcommitteesneverthelessandisthebasisforcurrentpolicy.*

AlthoughtheSafeMedicalDevicesActof1990modifiedtheoriginal1976legislationincertainrespectsgivingtheagencygreaterdiscretionintheuseofadvisorycommitteesitdidnotchangethebasicmandatetousesuchcommittees.Forexample,the1976amendmentsrequiredtheFDAtobringallpre-marketapprovals(PMAs)toadvisorycommittees;nowithasdiscretiontodosoafter"thefourthdeviceofakind"hasbeenapproved.

Inadditiontotherequirementsofthemedicaldeviceamendments,theCenterforDevicesandRadiologicalHealthadministersthe1968RadiationControlforHealthandSafetyAct,whichisasectionofthePublicHealthServiceAct.Congressenactedthislegislationtoprotectthepublicagainstthedangersofelectronicproductradiationthroughthedevelopmentofperformancestandardsforcontrollingtheemissionofsuchradiation.ImplementationofthislawrequiredthecreationoftheTechnicalElectronicProductRadiationSafetyStandardsCommittee(TEPRSSC).

In1990,theCDRHrechartereditsadvisorycommitteesintoasingleMedicalDeviceAdvisoryCommitteewithanumberofpanels.Concurrently,theagencyimplementedthecombinationproductsrequirementsoftheSafeMedicalDevicesActbyissuingregulationsonproductjurisdiction(whichencompassedcombinationproducts)andnegotiatingthreeintercenteragreementsonthissubject.TheCDRHrecharteringofitsdeviceadvisorycommitteesconvergedwiththeseproductjurisdictioneffortsandledtoarecharteringofCDERandCBERadvisorycommitteesaswell.ThesedevelopmentsarereviewedingreaterdetailinChapter3.

NIHStudySections

ItisworthcontrastingFDAadvisorycommitteeswiththestudysectionsoftheNationalInstitutesofHealth,ifonlybecauseacademicmedicalscientistsareveryfamiliarwiththelatterandoftenextrapolatetheseexperiencestotheoperationsoftheformer.Thefunctionsofthetwosortsofcommittees,andthecontextsinwhichtheyoperate,arequitedifferent.Thepertinentdistinctionsarethese:

*Section520ofthedevicelawalsomandatedthecreationofamanufacturingprocessadvisorycommitteetoadvisetheFDAonthemethods,facilities,andcontrolsusedforthemanufacture,packaging,storage,andinstallationofadevice.ThedeviceGoodManufacturingAdvisoryCommitteeconsistsofninemembers:threeemployeesoffederal,state,orlocalgovernments,andtwoeachrepresentingthedevicemanufacturingindustry,physiciansandhealthprofessionals,andthegeneralpublic.

The21originalNIHstudysectionswereannouncedinlate1946;theyhadclearpolicypurposesandrelativelysimpleadministrativeneedsrelatedtothereviewofextramuralresearchgrantproposalsbyacademicscientistsandtheawardingofgrants.

27Asdiscussedearlier,FDAadvisorycommitteeshaveamorerecenthistory,areusedformultiplepurposes,andlacktheacademicscienceconstituencyoftheNIHstudysectionsystem.

AnNIHstudysectionisresponsibleforreviewinganumberofresearchgrantproposalsintheirentirety.Incontrast,theFDAreviewofanewdrugapplication(NDA),aproductlicenseapplication(PLA),orapre-marketapproval(PMA),involvesalarger,morecomplicatedapplication.Moreover,suchareviewisthelegalresponsibilityoftheFDAand,asapracticalmatter,cannotfeasiblybeperformedbyanadvisorycommittee.

Aresearchproposalmaytakeseveraldaystoreview;anevaluationofaproductapplication(NDA,PLA,orPMA)requiresmonthsorevenyears.

Astudysectionreviewsonlydocumentsandhearsnopresentations,butanFDAadvisorycommitteehearssponsorandFDApresentationsandsometimesotherexperts.

FDAmedicalreviewersdevelopdetailedknowledgeofagivenapplicationandoftenfirmjudgmentsregardingit,basedontheirownviewsofwhatconstitutesgoodscienceandgoodmedicine.(FDAexecutivesecretariesindrugsandbiologicsareunlikelytodevelopanindependentviewofthemeritsofaproposal;indevices,theyoftenarealsoproposalreviewers).Bycontrast,althoughNIHexecutivesecretariesmayhaveasenseforgoodscience,theyarenotformallyresponsibleformorethantheefficientperformanceofthestudy

section.

FDAprofessionalstaffincurfewcostsiftheyholdupanapplicationbutconfrontgreatpressurestoreachthe"right"decision.Incontrast,itisexpectedthatallresearchproposalsreceivedbytheNIHbyacertaindatewillbereviewedataspecifiedtimeandthatthestudysectionwilldeterminewhatis"right"intermsofscientificmerit,technicalfeasibility,budget,andpriority.

Althoughmedicalscientistscareintenselyaboutstudysectionreviews,societyislargelyuninterestedinwhichscientistgetswhatresearchdollars.Bycontrast,societyisnotindifferenttotherecommendationofanFDAadvisorycommitteeonthepublicavailabilityofamedicaltechnology(asevidencedbythepressandtelevisioncoverageofsuchmeetings).

Thus,aswillbeclearthroughoutthisreport,FDAadvisorycommitteesdifferinimportantpolicy,administrative,andoperationalrespectsfromthemorefamiliarNIHstudysections.

Summary

AnumberofthemescanbeidentifiedinthehistoricaldevelopmentoftheuseofadvisorycommitteesbytheFDA.Amongthemostprominentarethefollowing:

FDAleadershiptooktheinitiativeinintroducingadvisorycommitteesforthereviewofdrugsandbiologics;thesecommitteeswerenotimposedontheagencybytheCongress.Thedeviceamendments,whichdorequiresuchcommitteesforevaluationofmedicaldevices,constitutecongressionalrecognitionoftheirimportancefortheagency.

InthecaseoftheDrugEfficacyStudy,theOTCdrugreview,andthebiologicsreview,thesecommitteesfulfilledmajorworkloadfunctionsclearingabacklogofworkforwhichtheagencylackedadequatepersonnelandprovidedindependentexpertise.Overtime,theycametoplayacentralroleintheassessmentofnewproductsandtechnologies.

Theuseofadvisorycommitteesinthebiologicsprograminvolvedthereviewofintramuralresearchprogramsandpersonnel,inadditiontoproductevaluation.Inaddition,invaccinedevelopment,thecommitteeswereusedthroughouttheproductdevelopmentcycleandparticipationincludedscientistsfromotherunitsofthePublicHealthServiceaswell.

Formedicaldevices,theanticipatedusesofadvisorycommitteeswereproductclassification,standardsetting,andreviewofnewproducts.Theinitialclassificationpanelsdidtheirworkandwerenotcontinued;thefunctionisnowfulfilledbyproductreviewpanels.Thestandard-settingfunctiondidnotdevelopasanticipatedandcommittees,savetheTechnicalElectronicProductRadiationSafetyStandardsCommittee,werenotusedforthispurpose.Theprimarypurposeof

deviceadvisorycommitteestodayisthereviewofnewproducts.

IntheFDAsetting,advisorycommitteesplayasupportiveroletoagencyprofessionals.Theydoexercisegreatinfluenceinagencydecisions,buttheirroleasadvisersismoreliterallysothanisthecaseforNIHstudysections.

Notes

1.SheilaJasanoff,TheFifthBranch:ScienceAdvisersasPolicymakers(Cambridge,Mass.:HarvardUniversityPress,1990).

2.BruceL.R.Smith,TheAdvisers.ScientistinthePolicyProcess(Washington,D.C.:TheBrookingsInstitution,1992).

3.MemorandumfromJamesLGoddard,M.D.,CommissionerofFoodandDrugs,toDr.KeithCannan,DivisionofMedicalScience,NationalAcademyofSciences-NationalResearchCouncil(NAS-NRC),"EfficacyReviewofPre-1962Drugs,"March31,1966.[FromthearchivesoftheNAS-NRC.]

4.Ibid.

5.Ibid.

6.Ibid.

7.NationalAcademyofSciences-NationalResearchCouncil,"ProposalforaReviewoftheClaimsforEfficacyofDrugsMarketedintheUnitedStatesDuringthePeriodBetween1938and1962,May16,1966."[FromtheArchivesoftheNAS-NRC.]

8.R.KeithCannan,"StatusoftheDrugEfficacyStudyoftheNationalAcademyofSciences-NationalResearchCouncil."Food,DrugCosmeticLawJournal(January1968):3235.

9.Ibid.

10.WarrenE.Whyte,"EffectivenessoftheNAS-NRCDrugEffectivenessStudy,"Food,DrugCosmeticLawJournal(February1970):91100.

11.Ibid.

12.Ibid.

13.Ibid.

14.RodneyR.Munsey,"PrivateRemedies,IncludingClassActions,ArisingOutofImplementationofNAS-NRCDrugEfficacyReview."FoodDrugCosmeticLawJournal(December1971):668682.

15.KennethC.Baumgartner,"AHistoricalExaminationoftheFDA's

ReviewoftheSafetyandEffectivenessofOver-the-CounterDrugs,"Food,Drug,CosmeticLawJournal43(1988):463494.

16.Ibid.

17.PresentationbyJ.RichardCrout,M.D.,totheIOMcommittee,December6,1991.CroutservedatthetimeasdirectoroftheFDA'sBureauofMedicine.

18.Ibid.

19.Ibid.

20.Ibid.

21.DepartmentofHealth,Education,andWelfare,StudyGrouponMedicalDevices,MedicalDevices.ALegislativePLan(Washington,D.C.,September1970).

22.Ibid.

23.Ibid.

24.DavidM.Link,"CurrentMedicalDeviceRegulationActivities,"Food,Drug,CosmeticLawJournal(September1972):552556.

25.DavidM.Link,"CooperCommitteeReportandItsEffectonCurrentFDAMedicalDeviceActivities,"Food,DrugCosmeticLawJournal(October1972):624628.

26.EdwardM.Swartz,"ProductsLiability.Manufacturer'sresponsibilityfordefectiveornegligentlydesignedmedicalandsurgicalinstruments,"DePaulLawReview18(2&3,Summer1969):348407.

27.C.J.VanSlyke,"NewHorizonsinMedicalResearch,"Science104(2711,13December1946):559567.

3TheFDAAdvisoryCommitteeSystemThischapterdescribesthecurrentadvisorycommitteesystemoftheFoodandDrugAdministration.Itfirstprovidesanoverviewandthenconsiderstheofficialpurposesofsuchcommittees.Italsoexaminestheiractualuses,includingthevariationsinuseamongthedifferentcentersandthecomplementarywaysthattheagencyobtainsexpertadvice.Thechapteralsodiscussesthe''goldfishbowl"environmentwithinwhichFDAadvisorycommitteesfunction.

TheProductEvaluationProcess

ThethreeunitsoftheFoodandDrugAdministrationthatconcernusinthisreportaretheCenterforDrugEvaluationandResearch(CDER),theCenterforBiologicsEvaluationandResearch(CBER),andtheCenterforDevicesandRadiologicalHealth(CDRH).Theworkofthethreecentersismainlybutnotexclusivelyrelatedtotheevaluationofnewtherapeuticanddiagnosticproducts.Thediscussioninthischapterisfrequentlyorganizedaroundthethreedifferentcategoriesofmedicaltechnologiesthatis,drugs,biologics,anddevices.

TheDrugEvaluationProcess

When,afterinvitrotestingandanimalstudiesoftoxicity,anewchemicalentityappearspromisingenoughtoconsiderclinicaltrialsinhumans,thesponsormustnotifytheFDAofitsintentiontoconductsuchtrials.

1Theinvestigationalnewdrug(IND)applicationthatthesponsorfilescontainsbothcurrentdataanddetailsofthestudydesign.The

FDA,onreceiptofanIND,has30dayswithinwhichtoreviewthesubmission.Iftheagencyjudgesthatnosafetyproblemsbartheinitiationofthetrial,itmayallowtheINDtobecomeeffectiveandthetrialtogoforward.Ifproblemsexist,itmayplacea"clinicalhold"onthetrialuntilthesponsorcorrects

theproblemorwithdrawstheapplication.IftheFDAdoesnotrespondwithinthe30-dayperiod,thesponsormaybegintheclinicaltrial.

Drugdevelopmentinvolvesthreestagesofclinicaltrials.InaPhaseItrial,arelativelysmallgroupofhealthyvolunteerstakethedrugforseveralmonthstoprovideinitialdataonsafetyandthedrug'sactioninhumans.IfPhaseIresultsareacceptable,oneormorePhaseIItrialswillbeinitiated.PhaseIItrialsassesstheeffectivenessofthedrug,withcontinuedattentiontosafetyandnoncriticalsideeffects,anddefinetheclinicalendpointsfortheassessmentofPhaseIIandIIIdata.PhaseIIstudiesmayinvolveuptoseveralhundredparticipantswhohavethediseaseunderstudy,comparedwith20to100healthyindividualsinPhaseItrials,inwhichsubjectsareoftenrandomized.

IfPhaseIIresultsarepromisingandthesubstanceisnotbeingevaluatedforthetreatmentofalife-threateningorseriousdiseaseandthereforebeingconsideredforexpeditedapproval(e.g.,technologiestotreatcancerorAIDS)thenPhaseIIItrialsareundertaken.*Thesetrialsarebothlarger(severalhundredorevenmorepatients)andlonger(onetofouryears).Often,initiationofPhaseIIItrialsoccursafterameetingbetweentheFDAandthedrugcompanysponsoringthetrialandtheFDAtoclarifyandagreeonthebasisforevaluatingthedrug.

TheresultsofPhaseIII,becauseofthelargerpoolofpatientsandlongerdurationofuse,providethedetailedinformationnecessaryforuseofthedruginclinicalpracticeappropriatedosagelevels,lessfrequentsideeffects,andsoforth.ThemanufacturersubmitsthedatafromallthreeclinicaltrialphasesandfromthepreclinicalstudiestotheFDAinanewdrugapplication(NDA)tomarketthesubstanceforspecificindications.AnNDAalsocontainsdetailedinformationonthelaboratoryformulationandchemistryofthedrug,the

manufacturingprocess,qualitycontrolprocedures,theproposedlabelingofthedrug,andsamplesofthedruginitsproposeddoseandform.**Thedatafromallthreephases,butparticularlythosefromPhaseIII,formthebasisfortheFDA'sdecisiononapproval,includingitsspecificationofindicationsandotherpartsoftheofficiallabel.

*TheFDAissuedproposedregulationsinApril1992fortheacceleratedapprovalofdrugsforseriousorlife-threateningillnesses(57FederalRegister13234,April15,1992).Atthesametime,thePublicHealthServiceannouncedafinalpolicymakingpromisinginvestigationaldrugsforAIDSandotherHIV-relateddiseasesmorewidelyavailableunder"paralleltrack"procedures(57FederalRegister13250,April15,1992).**Ingeneral,onlyprescriptiondrugsgothroughtheNDAprocess.

TheBiologicsApprovalProcess

Theapprovalprocessforbiologicsisquitesimilartothatfordrugs,

2inpartbecausetheFDAmergedthetwoBureausofDrugsandBiologicsfrom1982to1987intotheCenterforDrugsandBiologics.Biologics,however,areregulatedunderaregimebasedonthePublicHealthServiceActof1944ratherthantheFood,Drug,andCosmeticsAct.Althoughtheevaluationprocessparallelsthedrugevaluationprocess,manufacturerssubmitaproductlicenseapplication(PLA)ratherthananNDA.Theydosoona"rollingsubmission"basisbeginningbeforetheendofPhaseIIIclinicaltrials,submittingpiecesoftheapplicationastheyarecompletedwithoutwaitingtoassembleacompleteapplication.Inaddition,manufacturersalsosubmitanestablishmentlicenseapplication(ELA).IftheFDAapprovestheproduct,boththeproductandthemanufacturingestablishmentreceivelicenses.

TheDeviceApprovalProcess

Forregulatorypurposes,theFDAclassifiesmedicaldevicesforhumanuseintooneofthreerisk-relatedcategories,asrequiredbytheMedicalDeviceAmendmentsof1976.Allthreeclassesofdevicesaresubjectto"generalcontrols,"whichare"sufficienttoprovidereasonableassuranceofsafetyandeffectiveness"ofadevice.GeneralcontrolsempowertheFDAto:

prohibitadulteratedormisbrandeddevices;

requiredomesticandforeigndevicemanufacturersandinitialdistributorstoregistertheirestablishmentsannuallyandlisttheirdevices;

bancertaindevices;

demandnotificationofrisksandrequirerepairandreplacementofrefundfordefectiveproducts;

restrictthesale,distribution,oruseofcertaindevices;and

requireconformancewithregulationspertainingtoGoodManufacturingPractices,recordsandreports,andinspections.3,4

ClassIdevicesareregulatedsolelythroughgeneralcontrols.ThestatutedefinedClassIIdevicesasthosedevicesthatcouldnotbedesignatedasClassIbutforwhichsufficientinformationexistedtoestablisha"performancestandard."Standardswerevisualizedasamorestringentformofregulation;however,theFDAhaspromulgatednoperformancestandardsbetween1976andthepresent.Consequently,theSafeMedicalDevicesActof1990providesforregulationunder"specialcontrols."Inadditiontopotentialregulationbyperformancestandards,ClassIIdevicesaresubject

tothegeneralcontrolslistedabove,includingSection510(k)oftheFood,Drug,andCosmeticAct.

Section510(k)requiresthatforanydevicebroughttomarketafterMay28,1976thedateofenactmentofthe1976amendmentsthesponsormustprovide''premarketnotification"totheFDAofitsintenttomarketthedevice.*Tobeeligibleforimmediatemarketing,thedevicemustbejudgedbytheFDAtobesubstantiallyequivalenttoadeviceinusebeforethatdate.TheFDAisrequiredtoruleona510(k)notificationwithin90daysofreceivingit;iftheagencydoesnotrespond,thecompanymayproceedwithmarketing.IftheFDAdeterminesthatadeviceisnotsubstantiallyequivalenttoonethathasbeenmarketedpreviously,itautomaticallyplacesthedeviceinClassIII.

Thepremarketapproval(PMA)routeforaClassIIIdeviceisanalogoustotheNDAsandPLAsofdrugsandbiologics.Themanufacturermustpresentdatafrom"wellcontrolledinvestigations"orotherappropriateteststoprovide"reasonableassurance"ofthedevice'ssafetyandeffectiveness.Beforetheinitiationofhumanclinicaltrialsonadevice,theInstitutionalReviewBoard(IRB)oftheinstitutionatwhichthetrialsaretobeconductedmustdecidewhetherthedeviceposesa"significantrisk"topatients.Ifitdoes,themanufacturermustapplyforaninvestigationaldeviceexemption(IDE)fromtheFDAinordertoconductthetrial.Ifitdoesnot,theFDA'spermissionisnotrequired,andthemanufacturermustonlyadheretothesectionsoftheIDEregulationthatpertaintononsignificant-riskdevices.

AgencyWorkloadandAdvisoryCommittees

Thethreecentersvaryintheirworkloadfornewproductevaluations,withtheCDERhavingtheheaviestworkload,theCDRHhavingthe

nextheaviest,andtheCBERhavingthelightest.Figures3-1and3-2indicatethebudgetandthetotalnumberofpersonnelforeachcenterforfiscalyear1991.

Aquantitativeindicationoftheworkofthethreecentersispresentedinthefollowingtables.Table3-1indicatesthenumberandtypeofsubmissionsorapplicationsthatwerereceivedbyCDERfortheyears1986

*Medicaldevicemanufacturersarerequiredtosubmitapremarketnotificationiftheyintendtointroduceadeviceintocommercialdistributionforthefirsttimeortointroduce,orreintroduce,adevicethatwillbesignificantlychangedormodifiedtotheextentthatitssafetyoreffectivenesscouldbeaffected...."Premarketnotification[510(k)]isnotrequiredforpreamendmentdevices,devicesundertheIDEregulation,mosttransitionaldevices[devicespreviouslyregulatedasdrugsorantibiotics],andcustomdevices.Inaddition,anumberofclassIdeviceshavebeenexemptedbyregulationfrom510(k)requirements.

Figure3-1Fiscalyear1992operatingbudgetsfor

CDER,CBER,andCDRH.

Source:FDA/CDER/CBER/CDRH.

Figure3-2Allotmentoffull-time-equivalentpositionsin

CDER,CBER,andCDRH.

Source:FDA/CDER/CBER/CDRH.

through1991.Althoughthefigurefororiginalnewdrugapplications(NDAs)fluctuatessomewhatfromyeartoyear,ingeneral,itrevealsasteadypattern.Investigationalnewdrug(IND)applicationshavereachedthe2,000level,ofwhichnearly20percentarecommercial.

Table3-2showsthesamedataonsubmissionstoCBERfortheyears1987through1991.Althoughthenumberoforiginalproductlicensingapplications(PLAs)fellbacksharplyin1990and1991fromthethreeprecedingyears,itisexpectedthattheywillriseagainasthebiotechnologyrevolutiongeneratesanincreasingnumberofnewtherapeuticproducts.ThisexpectedincreaseindemandcanbeseeninthedoublingoforiginalINDsfrom1987to1991.

Table3-3revealsthelevelandnatureofCDRHsubmissions.ThenumberoforiginalPMAapplicationsappearsrelativelystableatfewerthan100peryear.However,the510(k)applicationshaveconsistentlyrunabove5,000eachyear,indicatingthehighvolumeofmedicaldevicesubmissionsthatclaim"substantialequivalence"toapre-1976device.

Table3-4indicatesthestreamofCDERapprovalsduringtheyears1986through1991.Thecriteriafor"refusaltofile"anapplicationarecurrentlybeingtightenedup,andthesefiguresmayshowanincreaseintheimmediatefuture.

CBERapprovalsareshowninTable3-5.ThenumberofPLAapprovalsrevealsasteadyandsignificantincreaseduringthefiveyearsfrom1987through1991.

Table3-6showsastablepatternfororiginalPMAapprovalsforthe1987through1990period.However,adding1986and1991tothesedatapresentsapictureofdecliningPMAapprovals.Again,approvalsof510(k)applicationsrunveryhigh,consistentwiththevolumeofsuchapplicationsreceived.ApprovalsofIDEs(originals,

amendments,andsupplements)isstableandhigh.

Table3-7listsallstandingFDAtechnicaladvisorycommitteesasofJuly1,1992.

Table3-1SubmissionsReceivedbytheCenterforDrugEvaluationandResearch,CalendarYears19861991SubmissionType 1986 1987 1988OriginalNDAsreceived 120 142 126NDAresubmissions 18 24 30Majoramendments 344 286 408NDAsupplements NA 1,889 1,857OriginalANDAs&AADArec'd. NA NA NAMajoramendments NA NA NAOriginalINDs 1,596 1,346 1,337CommercialINDs 330 302 363Note:NDA,newdrugapplication;NA,notavailable;ANDA,abbreviatednewdrugapplication;AADA,abbreviatedantibioticnewdrugapplication;IND,investigationalnewdrug.Source:"SelectedCalendarYear1991InformationandAccomplishmentData,"DHHS/PHS/FDA/CDER/OMB.

Table3-2SubmissionsReceivedbytheCenterforBiologicsEvaluationandResearch,CalendarYears19871991SubmissionType 1987 1988 1989OriginalPLAs 92 98 99PLAamendment 379 421 445OriginalELAs 33 36 39ELAamendment 93 162 198OriginalINDs* 266 294 277Note:PLA,productlicenseagreement;ELA,establishmentlicenseagreement;IND,investigationalnewdrug.*INDsarereportedbyfiscalyear.Source:CenterforBiologicsEvaluationandResearch/OfficeofManagement.

Table3-3SubmissionsReceivedbytheCenterforDevicesandRadiologicalHealth,FiscalYears19861991SubmissionType 1986 1987 1988 1989OriginalPMAs 69 81 96PMAsupplements 478 700 727OriginalIDEs 206 218 268IDEamendments 365 265 316IDEsupplements 2,884 2,836 3,391 3,038510(k)s 5,063 5,265 5,536 7,022Note:PMA,pre-marketapproval;IDE,investigationaldeviceexemption.Source:"OfficeofDeviceEvaluationAnnualReport(s)FiscalYears198691,"DHHS/PHS/FDA/CDRH.

Table3-4ApplicationApprovalsbytheCenterforDrugEvaluationandResearch,CalendarYears19861991ApplicationType 1986 1987 1998NDAsapproved 98 69 67NDAsapprovable 71 39 31NDAsrefusaltofile 14 22 17NDAsnotapprovable 109 116 114NDAswithdrawn 36 34 53ANDA&AADAapprovals NA NA NAANDA&AADAnotapprovables NA NA NANote:NDA,newdrugapplication;ANDA,abbreviatednewdrugapplication;AADA,abbreviatedantibioticnewdrugapplication;NA,notavailable.Source:"SelectedCalendarYear1991InformationandAccomplishmentData,"DHHS/PHS/FDA/CDER/OMB.

Table3-5ApplicationApprovalsbytheCenterforBiologicsEvaluationandResearch,CalendarYears19871991SubmissionType 1987 1988 1989PLAsapproved 33 44 52PLAswithdrawn 6 19 14PLAsinactive 3 2PLAsdenied 0 0ELAsapproved 15 16 24ELAswithdrawn 2 4ELAsinactive 2 2ELAsdenied 0 0Note:PLA,productlicenseagreement;ELA,establishmentlicenseagreement.Source:CBER/OM.

Table3-6ApplicationApprovalsbytheCenterforDevicesandRadiologicalHealth,FiscalYears19861991SubmissionType 1986 1987 1988 1989OriginalPMA 72 46 46PMAsupplement 477 565 652OriginalIDE 213 224 260IDEamendment 330 253 327IDEsupplement 3,599 2,784 3,405 3,023510(k)s 5,359 4,992 5,513 6,136Note:PMA,pre-marketapproval;IDE,investigationaldeviceexemption.Source:''OfficeofDeviceEvaluationAnnualReport(s),FiscalYears198691,"DHHS/PHS/FDA/CDRH.

Table3-7FDAStandingAdvisoryCommittees(asofJuly1,1992)CenterforDrugEvaluationandResearch(CDER)AdvisoryCommittees

AnestheticandLifeSupportDrugs(5/1/78;4/27/92)Anti-InfectiveDrugs(10/7/80;10/7/90;newcharterinprocess)AntiviralDrugs(2/15/89;2/15/91;newcharterinprocess)Arthritis(4/5/74;4/3/91)CardiovascularandRenalDrugs(8/27/70;8/10/90;newcharterinprocess)DermatologicDrugs(10/7/80;10/7/90;newcharterinprocess)DrugAbuse(5/31/78;4/27/92)EndocrinologicandMetabolicDrugs(8/27/70;8/21/90;newcharterinprocess)FertilityandMaternalHealthDrugs(3/23/78;3/29/92)GastrointestinalDrugs(3/3/78;2/24/92)GenericDrugs(1/22/90;1/21/92)MedicalImagingDrugs(2/24/92);previouslyRadio-pharmaceuticalDrugs(8/30/67)OncologicDrugs(9/1/78;8/8/90;newcharterinprocess)Over-the-CounterDrugs(8/27/91;newcharterinprocess)PeripheralandCentralNervousSystemDrugs(6/14/74;6/4/92)PsychopharmacologicDrugs(6/4/74;6/4/92)Pulmonary-AllergyDrugs(2/17/72;5/22/92)

CenterforBiologicsEvaluationandResearch(CBER)AdvisoryCommittees

AllergenicProducts(7/4/84;7/9/90;newcharterinprocess)BiologicalResponseModifiers(10/28/88;10/26/90;newcharterinprocess)BloodProducts(5/13/80;5/13/92)VaccinesandRelatedBiologicalProducts(12/31/79;12/31/91)

CenterforDevicesandRadiologicHealth(CDRH)AdvisoryCommitteesMedicalDevices(10/27/90)

AnesthesiologyandRespiratoryTherapyDevicesPanel

CirculatorySystemDevicesPanelClinicalChemistryandClinicalToxicologyDevicesPanel

continued

Table3-7ContinuedCenterforDevicesandRadiologicHealth(CDRH)AdvisoryCommittees

DentalProductsPanelEar,Nose,andThroatDevicesPanelGastroenterology-UrologyDevicesPanelGeneralandPlasticSurgeryDevicesPanelGeneralHospitalandPersonalUseDevicesPanelHematologyandPathologyDevicesPanelImmunologyDevicesPanelMicrobiologyDevicesPanelNeurologicalDevicesPanelObstetrics-GynecologyDevicesPanelOphthalmicDevicesPanelOrthopedicandRehabilitationDevicesPanelRadiologicDevicesPanel

TechnicalElectronicProductRadiationSafetyStandardsCommittee(10/18/68)DeviceGoodManufacturingPracticeAdvisoryCommittee(5/17/87)Note:Thedatesinparenthesesindicatetheinitialcreationofacommitteeanditsmostrecentreauthorization,whichoccurseverytwoyears.NearlyallCDERandCBERadvisorycommitteeshavebeenrecharteredbytheCommissionerfollowingthecharteringofasingleCDRHMedicalDevicesAdvisoryCommitteewith16panels.Ifacommitteehasnotyetbeenrechartered,referenceismadeto''newcharterinprocess."PriorchartersweresignedbytheSecretary;newchartersaresignedbytheCommissioner.Source:TheFoodandDrugAdministration.

Thenatureandextentofuseofadvisorycommitteesbythethreecentersareindicatedinthefollowingfigures.Figure3-3indicatesthetotalnumberofsuchcommittees,bycenter,from1988through1991.Forthethreecenterscombined,therearenearly40committees.

Figure3-3Numberofadvisorycommittees(andpanels)forCDER,CBER,andCDRH.

Source:AnnualReport,FDA/OC/OCM.

ThetotalnumberofcommitteemembersservingonthesecommitteesisindicatedinFigure3-4.Over300individualscurrentlyserveonthecommitteesthatadvisethethreecenters.Boththenumberofcommitteesandthenumberofmembershaveremainedrelativelystableinrecentyears.However,theleveloftheiractivityhasincreased.

TheincreasednumberofadvisorycommitteemeetingsisshowninFigure3-5,whichindicatesmorethana50percentincreasefrom1988to1991forCDER,stabilityforCBER,andadecreaseforCDRH.

Figure3-4NumberofadvisorycommitteememberswithinCDER,CBER,andCDRH.

Source:AnnualReport,FDA/OC/CMO.

Figure3-5NumberofadvisorycommitteemeetingsperyearforCDER,CBER,and

CDRH.Source:AnnualReport,FDA/OC/CMO.

OfficialPurposesofAdvisoryCommittees

TheFDAestablishedadvisorycommitteestogainaccesstoindependentexternalexpertise.OnlyinthecaseofmedicaldeviceswereadvisorycommitteesrequiredbyCongress.ThissectiondescribestheannouncedpurposesofsuchFDAcommitteesasoutlinedinthefollowingFDAdocuments:theCodeofFederalRegulations(CFR),theNDARewrite,theMedicalDeviceAmendmentsof1976,andtheofficialcommitteecharters.

TheFDARegulations

AlthoughtheFDAinitiateditsadvisorycommitteesystembyinternaladministrativememorandaintheearly1960s,itdidnotcodifythesystem'spoliciesandproceduresuntilthelate1970s.ThesepoliciesandproceduresappeartodayintheCodeofFederalRegulations(CFR),Title21,Part14.*

Part14statesthepurposesofadvisorycommitteesinverygeneralterms.Theagencyadvocatestheirusewhen:

theCommissionerconcludes,asamatterofdiscretion,thatitisinthepublicinterestforastandingoradhoccommittee(advisorycommitteeorcommittee)[emphasisinoriginal]toholdapublichearingandtoreviewandmakerecommendationsonanymatterbeforeFDAandforinterestedpersonstopresentinformationandviewsatanoralpublichearingbeforetheadvisorycommittee.

5

ThischapteralsodiscussesotherprovisionsofPart14thatpertaintothepurposesofadvisorycommitteesinrelationtocommitteecharters.

TheNDARewrite

Thepreambletothe1985FDAfinalruleonNewDrugandAntibiotic

Regulationscontainsadetailedstatementofthepurposesofadvisorycommitteesasappliedtodrugs.6**KnownastheNDARewrite,thisrule

*AllFDAregulationsarecodifiedinTitle21oftheCodeofFederalRegulations.Part14,"PublicHearingBeforeaPublicAdvisoryCommittee,"dealswithgeneralprovisions,meetingprocedures,establishmentofadvisorycommittees,recordsofmeetingsandhearingsbeforeadvisorycommittees,membersofadvisorycommittees,standingadvisorycommittees,theTechnicalElectronicProductsRadiationSafetyStandardsCommittee,coloradditiveadvisorycommittees,andadvisorycommitteesforhumanprescriptiondrugs.**Atthistime,thetwobureausondrugsandbiologicsweremerged.

wasthefirstphaseofReaganadministrationeffortstoimprovetheefficiencyofthedrugevaluationprocess.Althoughtheproposedrule

7hadnotdealtwiththeroleofoutsideexpertsinthenewdrugevaluationprocess,theFDAreceivedenoughcommentsonthismatterthatitdecidedtousethepreambletothefinalruleasawaytosetforth"FDApolicyinthisarea."

InthepreambletotheNDARewrite,theFDAagreedthattheuseofoutsideexperts"addstothequalityandcredibilityofthedecisionmakingprocess."Theagencystateditsbeliefthat"theprimarygoaloftheadvisorycommittee(andoutsideconsultant)systemshouldbetohelptheagencymakesounddecisionsbaseduponthereasonedapplicationofgoodscience."Itindicatedthattheagencyusedadvisorycommitteestobringoutsideexpertsintothenewdrugevaluationprocessfortwomainreasons:(1)tosupplementtheagency'sinternalexpertiseand(2)tohelptheagencystaffstaycurrentwith"state-of-thearttechnology"byencouragingcloseworkingrelationshipsbetweenthestaffandoutsideexperts.Advisorycommitteemeetings,italsonoted,"serveanimportantfunctionbyprovidingapublicforumfordiscussionofissues."

Thepreamblealsostatedthatadvisorycommittees"generally"advisetheCommissioneronthe"safetyandeffectivenessandregulatorycontrolofhumanprescriptiondrugs,"including"whethertheavailableinformationisadequatetosupportadeterminationthataparticulardrugmeetsthestatutorystandardsforproofofsafetyandeffectivenessnecessaryformarketingapproval."AttheFDA'srequest,suchcommitteesreview"certaincriticalstudiesorcriticalelementsofstudiesondrugproductsunderconsiderationandlabelingissues";theyalsorespondtospecificFDAquestionsthataskthemtoidentify''theadequateandwell-controlledstudieswhichdemonstrate

effectiveness,theseriousnessofcertainadverseeffects,andwhetheradditionalstudiesordataarenecessarybeforeadecisioncanbereached.''

TheFDAidentifiedthefollowingashigh-priorityitemsonwhichitsoughtadvicefromadvisorycommittees:

drugssubjecttoactiveIND'sandpendingNDA'sthatofferpotentialtherapeuticadvances,thatposesignificantsafetyhazards,thatpresentnarrowbenefit/riskconsiderations,thathavenoveldeliverysystemsorformulations,thatarethesubjectofamajorscientificorpubliccontroversy,orthatarethesubjectofspecialregulatoryrequirements,suchasalimitationonclinicaltrials,apatientfollow-uprequirement,postmarketingstudies,orboxedwarnings.

Theagencyalsoindicatedthatitsoughtadviceonbroaderclinicalresearchissuesandhaddevelopedapproximately25clinicalresearch

guidelineswiththehelpofadvisorycommittees,professionalsocieties,andconsultantstothedrugindustry.Theseguidelinesconsistedof"generallyacceptedprinciplesforreachingvalidconclusionsaboutthesafetyandeffectivenessofdrugs,and[the]viewsofrecognizedexpertsaboutappropriatemethodsforstudyingspecificclassesofdrugs."

ThepreamblealsonotedthatFDAusedindividualadvisorycommitteemembersasconsultantsinseveralways.Forexample,theFDAincludedtheminmeetingswithsponsorstodiscussspecificscientificissues,toparticipatein"end-of-PhaseII"conferencesthathelpedtoplanPhaseIIIstudies(asnotedinthe"INDRewriteproposal"),

8andonanadhocbasisastechnicalconsultantsorexpertreviewers,especiallyincasesinwhichtheagencylackedresourcesorexpertise.

"Insummary,"thepreamblestated,"FDAbelievesthattheprimarygoaloftheadvisorycommittee(andoutsideconsultant)systemshouldbetohelptheagencymakesounddecisionsbaseduponthereasonedapplicationofgoodscience."

MedicalDeviceStatutes

Inthecaseofmedicaldevices,thelawrequirestheuseofadvisorycommittees.TheRadiationControlActof1968,whichamendedthePublicHealthServiceAct,directedtheSecretarytoestablishaTechnicalElectronicProductRadiationSafetyStandardsCommittee(TEPRSSC)"toprovideconsultationbeforetheCommissionerprescribesanyperformancestandardsforanelectronicproduct."InadvisingtheCommissioner,theTEPRSSCmayproposestandardsforhisconsideration,consultonstandardshehasproposed,andrecommendactionon"anyothermatter"relatedtotheact.Authority

toactontheadviceoftheTEPRSSCisexplicitlyvestedintheCommissioner.TheFDAhasalwaysadministeredthisprovisionofthelaw,currentlythroughtheCDRH,anditisthefirstinstanceoftheagencybeingrequiredbystatutetoestablishandmaintainanadvisorycommittee.

TheMedicalDeviceAmendmentsof1976directedtheSecretarytouseadvisorycommitteesintwoways.First,theydirectedhimtoestablish"panelsofexperts"forclassifyingmedicaldevicesintendedforhumanuse"accordingtothevariousfieldsofclinicalmedicineandfundamentalscience"inwhichthesedevicesweretobeused.Second,theyrequiredhimtoestablishadvisorycommittees(otherthanclassificationpanels)toreviewproposedregulationsformedicaldeviceperformancestandards,toreviewallPMAapplications,andtomakerecommendationsonGoodManufacturingPracticeregulations.Forthepurposesofthisstudy,theuseofadvisorycommitteesforpremarketingapprovalisthemostimportantconcern.

FDAAdvisoryCommitteeCharters

ThechartersofspecificFDAadvisorycommitteesindicatethattheirpurposeistoadvisetheCommissioneronthesafetyandeffectivenessoftheproductinquestion.ThetypicalCDERadvisorycommitteecharterreadsasfollows:

[Thecommittee]reviewsandevaluatesavailabledataconcerningthesafetyandeffectivenessofmarketedandinvestigationalhumandrugproductsforusein[specifieddiseasetreatments]...andmakesappropriaterecommendationstotheSecretary,theAssistantSecretary,andtheCommissionerofFoodandDrugs.

ThechargesoftwoCDERcommitteesarecouchedinslightlydifferentlanguage.TheGenericDrugsAdvisoryCommitteeistoadviseonthesafetyandeffectivenessofhumangenericdrugproductsforuseintreating"abroadspectrumofhumandiseases."TheDrugAbuseAdvisoryCommittee,withabroadcharge,advisestheFDACommissioneron"thescientificandmedicalevaluationofallinformationgatheredbytheDepartmentofHealthandHumanServicesandtheDepartmentofJusticewithregardtosafety,efficacy,andabusepotentialofdrugsorothersubstancesandrecommendsactionstobetakenbytheDepartmentofHealthandHumanServiceswithregardtomarketing,investigation,andcontrolofsuchdrugsorothersubstances."

ThechartersofthefourCBERadvisorycommitteesalsofocusontheevaluationofdatarelatedtosafetyandeffectiveness.Inaddition,thechargestotheBiologicalResponseModifiersAdvisoryCommitteeandtheVaccinesandRelatedBiologicalProductsAdvisoryCommitteerequirethemtoconsider"appropriateuse,"andthosetotheAllergenicProductsAdvisoryCommitteeandtheBloodandBloodProductsAdvisoryCommitteetoconsiderlabelingissues.*YetthescopeofCBERadvisorycommitteesextendsbeyondthese

functionsinoneimportantrespect,inwhichtheydifferfromCDERandCDRHcommittees.WithitsoriginsinthebiologicsprogramoftheNIH,theCBERalsousesitsadvisorycommitteestoreviewthequalityandrelevanceofthecenter'sintramuralresearchprogram,whichprovidesscientificsupporttoitsproductregulationresponsibilities,andthequalityandperformanceofitsresearchpersonnel.

*TheBloodandBloodProductsAdvisoryCommitteealsofunctionsasadeviceadvisorycommitteeforblood-relateddevices,examiningissuesrelatedtoclassification,safetyandeffectiveness,formulationofproductdevelopmentprotocols,reviewofPMAs,andthe"reclassification,exemption,andbanningofdevices."

TheCDRH,asnotedinChapter2,usedadvisorypanelstoclassifypre-1976medicaldevicesintooneofthreerisk-relatedcategories;itterminatedtheseclassificationpanelsoncetheirresponsibilitieshadbeencarriedout.Thecenteralsousedapproximately16separatelycharteredadvisorycommitteesforproductevaluationpurposes.In1990,theCDRHformallyterminateditsexistingadvisorycommittees,establishedasingleMedicalDevicesAdvisoryCommittee,andreconstitutedthepreviouscommitteesas16"panels"ofthenewcommittee.Thecenterdidsotoenableittobringneededexpertisetobearonagivenproductreviewandtomeettherequirementforaquorumofvotingmembersmoreeasily.Thesinglecommitteeconsistsofamaximumof148members,ofwhom114arestandingvotingmembersand34arenonvotingmembers(16consumerrepresentativesand18industryrepresentatives);themembersaredistributedtopanelsasbefore.

Underthisarrangement,thedevicepanelsfunctionastheydidbeforeascommittees,exceptthattheresponsibleFDAofficialcaninvitecommitteemembersfromotherpanels,aswellasdesignatedconsultants,toserveasvotingpanelmembersataparticularmeeting.Thiscanoccurundertwocircumstances:first,"whenexpertiseisrequiredthatisnotavailableamongthecurrentvotingstandingmembersofthepanel,"andsecond,tomeettheneedforaquorumwhenoneislacking.

9

TheCDRHdescribesthepurposesofitsrecharteredadvisorycommitteestructureasfollows:

Reviewsandevaluatesavailabledataconcerningthesafetyandeffectivenessof[specifieddevices]currentlyinuseandadvisestheCommissionerregardingrecommendedclassificationofthesedevicesinto

oneofthreeregulatorycategories;recommendstheassignmentofapriorityfortheapplicationofregulatoryrequirementsfordevicesclassifiedinthestandardsorpremarketapprovalcategory;reviewsclassificationofdevicestorecommendchangesinclassificationasappropriate;recommendsexemptionofcertaindevicesfromtheapplicationsofportionsoftheAct;advisesonthenecessitytobanadevice;andrespondstorequestsfromtheAgencytoreviewandmakerecommendationsonspecificissuesorproblemsconcerningthesafetyandeffectivenessofdevices.

SomevariationexistswithintheCDRHpanels.Forexample,theDentalProductsPanelfunctionsattimesasanonprescriptiondrugadvisorypanel.Inaddition,theRadiologicDevicesPanelistoadviseon"acoordinatedprogram"forthemedicalapplicationofradiationthatmaximizesdiagnosticinformationandtherapeuticbenefitsperunitofexposure.

Aboutthesametimethatthisrecharteringoccurred,CongressenactedtheSafeMedicalDevicesActof1990.

10Section16ofthatactrequiredthatregulationsbeissuedtodeterminetheprimarymodeofactionofaproductthatcombinedadrug,device,orbiologicalproductandtoassignprimaryjurisdictiontotheresponsibleFDAcenter.TheFDA,inimplementingthisrequirement,expandedittoincludeallproductjurisdictionissues.Theresultsofthiswerenewregulations;threenewintercenteragreements,andtherecharteringofCDERandCBERadvisorycommitteestopermittheuse,whenexpertiseisneededoraquorumislacking,ofanyFDAtechnicaladvisorycommitteemember(anddesignatedconsultants)asavotingmemberonanyothercommittee.TheimplicationsofthisrecharteringarediscussedinChapter7.

TheCDRHhastwocommitteesthatarenotengagedinproductevaluation.TheDeviceGoodManufacturingPracticeAdvisoryCommitteeisresponsibleforreviewingproposedregulationsfor"goodmanufacturingpracticesgoverningthemethodsusedin,andthefacilitiesandcontrolsusedfor,themanufacture,packing,storage,andinstallationofdevices,and...thefeasibilityandreasonablenessofthoseproposedregulations."TheTEPRSSC,asmentionedearlier,advisestheCommissioner"onthetechnicalfeasibilityandreasonablenessofperformancestandards"tocontrolradiationemissionfromelectronicproducts.

TheUsesofAdvisoryCommittees

TheabovediscussionindicatestherangeofofficialpurposesofFDAadvisorycommitteesintheareaofdrugs,biologics,andmedicaldevices.Notsurprisingly,then,theagencyor,moreaccurately,itsprogramunitsusessuchcommitteesinanumberofdifferentways.

Thesevariationsderivefromthefollowingsources:

thethreeseparatecenterstheirhistories,technicalandregulatoryresponsibilities,workloads,andtheirorganizational"cultures";

thestageofproductdevelopmentandevaluationprelicensing,licensing,postmarketingapproval;

themeansbywhichthecentersseekexternaladviceadvisorycommittees,SpecialGovernmentEmployee(SGE)consultants,primaryreviewers,andworkshops;and

otherfactors.

The"otherfactors"maycomprise:theclassoftherapeuticproductsunderconsideration;thestageofscientificdevelopmentofthepertinentclinicalfieldorarea;thespecifictasksofagivenadvisorycommittee;thedifferent

reviewingdivisions,includingtherelationshipbetweentherevieworganizationsandtheadvisorycommittees;thepersonalitiesofdifferentreviewofficials;andtheabsenceofsustainedFDA-widepolicyguidance.Howthesefactorsinteracttoaffectvariationintheuseofadvisorycommitteescanbeaddressedbytakingeachcenterinturn.

VariationsAmongCenters

TheCDER,whichistheoldestFDAuserofadvisorycommitteesandthecenterwiththemostcomplicatedhistoryofuse,broughtthemintoexistenceinthedecadefollowingthe1962drugamendments.Thatlegislationrequiredthat,inadditiontosafety,theeffectivenessofdrugsbeestablishedforallolddrugsprescriptionandoverthecountermarketedbetween1938and1962onthebasisofsafetyalone;allnewdrugsweretobeevaluatedforbothsafetyandeffectivenessaswell.Theagencythushadbothanimmediateneed,toacquireexpertisethatitdidnothaveonitsstaff,andalong-termneed,torecruitpersonnelwithgreatermedicalandscientificexpertisethanitthenhad.Thelegislationalsoreinforcedtheadversarialrelationshipbetweentheagencyandtheregulatedindustry.Notsurprisingly,amongthethreecentersconsideredinthisreport,agency-industryrelationshavebeenmostconfrontationalfordrugs.

TheCDERadvisorycommitteesystemthatdevelopedisorganizedalongthelinesoftherapeuticagentsorproductlines,fromanindustryperspective,asindicatedinTable3-7.ThisorganizationparallelsthedrugevaluationunitsofthecenterthetwoOfficesofDrugEvaluationandtheirrespectivedivisions,thePilotDrugEvaluationOffice,theOfficeofGenericDrugs,andtheOfficeofOver-the-CounterDrugs.

Inbiologics,vaccinedevelopmenthasbeenjustifiedbyapublichealthrationaleandembeddedinapublichealthinstitutionalframework.Theneedforgovernmentregulationofsafetyisnot

subjecttodispute.Theeconomicincentivesforcommercialvaccinedevelopershavebeenweakerhistoricallythanfordrugmanufacturers,andagency-industryrelationsarelessconfrontationalthanfordrugs.

TheCBERadvisorycommitteesystemisorganizedaccordingtotherapeuticcategoriesorproductlines,asTable3-7makesclear.ThereviewingofficesoftheCBER,however,donotcorresponddirectlytotheadvisorycommitteestructure.Instead,severalunitsmayreviewagivenPLA,dependingonthebiologicunderconsideration.

TheCBERsystem,unlikethoseoftheCDERandCDRH,extendsbeyondproductevaluationtothereviewbythefouradvisorycommitteesofCBERintramuralresearchprogramsandresearchpersonnel.Onequestionraisedbythispracticeiswhetherfouradvisorycommittees,eachreviewing

aportionoftheintramuralresearchprogram,fragmenttheoversightofthateffort.Itispossiblethatasingle"boardofscientificcounsellors,"chargedwithreviewingallCBERintramuralresearch,mightbeamoreappropriatestructure.

ManyobservershaveviewedtheCDRH'simplementationofthe1976amendmentsassensitivetotheneedsastothedeviceindustryandfavorabletoproductinnovation,ofwellastothephysiciansandotherhealthprofessionalswhousethedevices.AlthoughtheSafeMedicalDevicesActof1990imposedanumberofnewrequirementsontheFDAthatmayaffectitsrelationswithmanufacturers,itgavetheagencygreaterdiscretionintheuseofadvisorycommittees,asnotedearlier.

TheCDRHadvisorycommitteesystem,liketheCDERsystem,isorganizedalongthelinesoftherapeuticagentsorproductlines.InternalorganizationoftheOfficeofDeviceEvaluationparallelstheseadvisorycommittees.OnefeaturethatdiffersbetweentheCDRHandCDER,however,isthatexecutivesecretariesanddivisiondirectorsplaydifferentrolesinproductevaluation.TheCDRHexecutivesecretaryistypicallyamedicalreviewofficertowhomadditionalexecutivesecretarialfunctionshavebeenassigned,whereasthedivisiondirectormaybemainlyamanager.

AmajortensionintheCDRHsystem,notfoundinthoseoftheCDERandCBER,isthatadvisorycommitteeshavebeentheprimarymeanstoobtainexpertclinicaladviceforproductreviewsthatareconductedbyaprofessionalstaffcomposedpredominantlyofengineers.Consequently,CDRHusuallydesignatesonememberofanadvisorycommitteeasa"primaryreviewer"foreachPMAthatcomesbeforeit,andthecommitteememberreceivesadditionalcompensationforsuchwork.*

CenterWorkloadandStageofAdvisoryCommitteeUse

TheCDERworkloadofINDs,NDAs,andotherapplicationsisthegreatestofanyofthethreecenters,asreflectedinTables3-1through3-4.ThisworkloadhasledtheCDERtofocusitsuseofadvisorycommitteesonissuesthatariseintheproductevaluationstage,ratherthanonearlierorlaterstages.Theevaluationstageinvolves(1)reviewofspecificNDAsand(2)considerationofscientificandtechnicalpolicyissuesrelatedtothereviewofaclassofproducts.AlthoughtheCDERdevotessomecommitteetimetothepreapproval(e.g.,clinicaltrial)andpostmarketingstagesofdrug

*FDAregulationsauthorizepaymenttoadvisorycommitteemembersforhomeworkonanhourlybasisforassignmentsthatrequire"adefinitivestudy"and"tangibleendproduct,"suchasawrittenreport,providedthatthisendproductdoesnotrepresenttheendproductoftheadvisorycommittee[21CFRPart14.95(c)].See''Compensation''inChapter8.

development,theCBER,incontrast,isinvolvedearlier,moredeeply,andonamoresustainedbasiswiththedevelopmentofaspecificbiologic,suchasavaccine,inpartbecauseofitslowervolumeofwork.

Untilrecently,theCBERhashadthesmallestworkloadofthethreecenters.Coupledwiththepublichealthcharacterofitspurviewanditslessconfrontationalrelationshipwithindustry,thishasmeantthattheCBERhasbeeninvolvedinproductdevelopmentandevaluationearlierandmoreextensivelythanistrueforeitherdrugsordevices.Consequently,CBERadvisorycommitteesalsohavebeenengagedintheevaluationofbiologicsatearlierstagesthanisusualfordrugs.

Thebiotechnologyrevolution,however,isgeneratinganincreasingstreamofnewtherapeuticbiologicalproducts.ThistrendhasledtheFDAtoincreasethenumberofprofessionalmedicalandscientificpersonnelonitsstaff.NewbiologicaltherapeuticsnowdrivethegrowthoccurringintheCBER'swork,theimpactofwhichisfeltlargelybytheBiologicalResponseModifiersAdvisoryCommittee.Asthesedevelopmentsunfoldinthecomingdecade,theCBERworkloadwillcontinuetoincrease,andthepressuresofscarceprofessionalpersonnelresourcesmayimpelthecentertofocusmoreonthelicensing,ratherthantheprelicensing,stage.

TheCDRHworkloadiscomplicated;unlikedrugsandbiologics,itisbasedonrisk-relatedclassificationofdevices.ForClassIImedicaldevices,theFDAmustdeterminewhetheradeviceisthesubstantialequivalentofonemarketedbeforethe1976amendments.Asdescribedearlier,someClassIIIdeviceshavebeenonthemarketsincebefore1976,whileothershavereachedthemarketsincethenthroughthe510(k)procedureandstillothersbythePMAroute.ThePMAworkloadthatadvisorycommitteesnowfaceissubstantialandgrowing;recharteringofmultipleadvisorycommitteesintoasingle

committeewithmultiplepanelspresumablyhasmadethisworkloadeasiertomanage.

ThelawrequiresthesponsorofaClassIIIdevicemarketedbeforethe1976amendmentstosubmitaPMAapplicationwhentheagencycallsforsafetyandeffectivenessdataonalldevicesinthatcategory.TheSafeMedicalDeviceAmendmentsof1990requiredtheFDA,byDecember1,1995,tocallforPMAsortoreclassifyasClassIIapproximately130suchdevices.Althoughtheagencyclaimsthatitlackstheresourcestofulfillthisstatutoryrequirementcompletely,itiscallingforPMAapplicationsforsomeofthesedevices.ItislikelythattheresultingPMAswillbereviewedbyadvisorypanels.Forexample,thetwomeetingsoftheGeneralandPlasticSurgeryAdvisoryPanelthatconsideredthesafetyandeffectivenessofsiliconegelbreastimplantsinNovember1991andFebruary1992werereviewingoneofthesepre-1976devices.

OtherMeansofSeekingAdvice

Inadditiontotheuseofadvisorycommittees,thethreecentersformallyseekexternalexpertadvicethroughSpecialGovernmentEmployee(SGE)consultantsandworkshops.

Consultants:TheFDAappointsallvotingmembersofitstechnicaladvisorycommitteesasSpecialGovernmentEmployeestopermitthemtobepaidandreimbursedforexpenses.AllFDAconsultantsarealsoSGEs,butnotallSGEconsultantsareadvisorycommitteemembers.Conversely,ascientistcanbebothaconsultantandacommitteemember.TheSGEstatusismainlyusedtopayorreimbursescientificexpertise.

TheCDERusesconsultants,someofwhomareadvisorycommitteemembersandsomeofwhomarenot,throughoutthedrugevaluationprocess.Forexample,itmaybringanadvisorycommitteemember,asaconsultant,intoan"EndofPhaseIIConference"withadrugsponsor.OritmayuseanSGEconsultantwhoisnotanadvisorycommitteememberforthatpurpose.TheFDAmayalsouseanonmemberSGEconsultantasaconsultanttoanadvisorycommittee.Allthreecentersuseconsultantsinthesevariousways.

Insomesituations,theCDERmaydrawontheexpertiseofconsultantswhohavebeenengagedbyproductsponsors.IftheFDAhasaproblemwithasponsor'sapplication,theagencymayaskthefirmtocometoameetingtodiscusstheproblemandtobringwithitoneorseveralofitsprincipalconsultants.Theagencythusmayextenditsaccesstoexternalexpertise,whenitdeemsituseful,toconsultantstotheindustry.

FormalWorkshops:Thethreecentersdifferintheextentoftheiruseofworkshops.TheCDERoftenusesthisapproach,describingameetingasaminisymposiumandorganizingitinconjunctionwithan

advisorycommittee.Anexampleofthiskindofactivitywasaone-daymeetingondose-responsemeasurementofangiotensin-convertingenzymeinhibitorsthatwasorganizedbytheCardiovascularandRenalDrugsDivision.TheseconddaywasaformalCardio-RenalDrugsAdvisoryCommitteemeeting,focusedonspecificsubmissions.

Perhapsbecauseofthepublichealthlinkagewithvaccinedevelopment,theCBERsponsorsorcosponsorsanumberofworkshopseachyeardevotedtoscientificissuesthatbearonitsregulatoryresponsibilities.Thedistinctionsbetweenanadvisorycommitteemeetingandaworkshopareseveral:workshopsaregenerallycalledtoexplorethestateofthescienceinrelationtoagivenissueandnottoadvisetheFDA;theworkshops,includingalltechnicalpresentations,areopentothepublic,especiallytherelevant

technicalcommunity,withoutregardtoorganizationalaffiliationorconflictofinterest;andworkshopsarenotgovernedbytheFederalAdvisoryCommitteeAct.*

11

Acentralquestionaboutconsultantsandworkshopsiswhethereitherofthesemechanismsprovidesvalueequivalenttothatofadvisorycommittees?Ifso,inwhatcontexts?TheFDAwantstobeabletosayofadvisorycommittees,"Weassembledthebestpeopleinthecountry;theyheardtheevidence,debateditsimplications,andprovideduswiththisadvice."Consultantsmayprovidedetailedadviceofgreatvalueonspecificmatters;however,theirroledoesnotprovideaforumforpublicdiscussion,nordotheyperforminafashionthatallowstheFDAtomaketheaboveclaimtothepublicandpress.Ontheonehand,workshopsallowtheagencytogenerateasynthesisofthestateofscientificdevelopmentinanarea.Ontheotherhand,becausetheymaynotresultinadvice,workshopsareunabletoperformcertainrolesthatadvisorycommitteesfulfill.Theissuemaybewhethertheseothermechanismsaregenuinealternativestoadvisorycommitteesoraremoreappropriatelyunderstoodasadjunctstothem.

AnotherquestioniswhethertheseothermethodsfortappingtheexpertiseofoutsidescientistsescapethestricturesoftheFederalAdvisoryCommitteeAct?Inthiscontext,theconflict-of-interestrestrictionsdoapplytoagencyconsultants,buttheregulationsallow"twoormoreFDAconsultants"tomeetwiththeagencyonanadhocbasis.12

Summary

TheFDAadvisorycommitteesystemhasbeenanintegralpartoftheproductevaluationprocessfordrugs,biologics,andmedicaldevices.Theagencyhasmadeincreasinguseofthesecommitteesovertime.

Proceduresforusingadvisorycommitteesvaryfromcentertocenterandoftenwithincenters.Thesevariationshavemanyexplanations,somequiteclearlyjustifiableinoperationaltermsbutothersseeminglytheproductofneglectbytheagency'scentraladministrationortheidiosyncraticpreferencesofagencyofficialsdirectlyresponsiblefortheirongoingmanagement.Formuchofthepastdecade,littleattentionappearstohavebeendevotedtoestablishingandmaintaininganoptimumlevelofagency-wideuniformityincommitteeprocedureandmanagement.

*AnexampleofaCBER-relatedworkshopwasatwo-daymeetingorganizedbytheInstituteofMedicine'sForumonDrugDevelopmentonthe"microheterogeneityofbiologicalmacromolecules."TheworkshopconsideredthescientificissuesunderlyingsmallchangesinlargebiologicalmoleculesandtheimplicationsoftheseissuesforFDApolicies.

TheprimarypurposeofFDAadvisorycommittees,asstatedintheNDARewrite,istoassisttheagencyinmaking"sounddecisionsbaseduponthereasonedapplicationofgoodscience."Theydosobyadvisingontheapprovabilityofspecificproductapplicationsbasedonanexaminationoftheadequacyofthedatasupportingclaimsofsafetyandeffectiveness.Inaddition,advisorycommitteesprovidetechnicaladviceonbroaderissuesrelatingtoproductevaluationgenerally.

AdvisorycommitteesarenottheonlywaysbywhichFDAseeksexternalexpertadvice.Theagencyalsomakesuseofconsultantsandworkshops.Theseothermechanismsarebestviewedascomplementarytoratherthanalternativestoadvisorycommittees.Theyreflectanaturalresponsebyaregulatoryagencythatdependsonaccesstoexpertscientificandclinicalinformationtofulfillitsstatutoryresponsibilities.

TheIOMcommitteewasveryconsciousthattheuseofadvisorycommitteesbytheFDAwasembeddedinthisbroadercontextofseekingandobtainingexternalexpertadvice.Ithasfocusedalmostexclusivelyontheuseofthesetechnicaladvisorycommittees,however,because,bycommonjudgment,thatisthecomponentcurrentlymostinneedofattention.

Notes

1.FoodandDrugAdministration,NewDrugDevelopmentintheUnitedStates(Rockville,Md.:FoodandDrugAdministration,January1988).

2.PharmaceuticalManufacturersAssociation,InDevelopment:BiotechnologyMedicines(Washington,D.C.:PharmaceuticalManufacturersAssociation,1991).

3.FoodandDrugAdministration,EverythingYouAlwaysWantedtoKnowAbouttheMedicalDeviceAmendmentsandWeren'tAfraidtoAsk,HHSPub.FDA90-4173,3rded.(Washington,D.C.,August1990).

4.Ibid.,pp.12and15.

5.21CFR14.1(a)(1),1991.

6.50FR7452,February22,1986.

7.47FR46622,October19,1982.

8.48FR26732,June9,1983.

9.FoodandDrugAdministration,"Charter,MedicalDevicesAdvisoryCommittee,"(Washington,D.C.,October27,1990).

10.PublicLaw101-629,November28,1990.

11.InstituteofMedicine,MicroheterogeneityofBiologicalMacromolecules:ReportofaWorkshop(Washington,D.C.,1991).

12.21CFR14.1(b)(5)(ii).

4RecurringIssuesAlthoughtechnicaladvisorycommitteeshavebeenanimportantpartofFoodandDrugAdministrationoperationsformorethantwodecades,anumberofissuesabouttheirusehavebeenthefocusofrecurringcontroversy.ThischapterexaminestheseissuesthroughthelensofpriorreportsontheFDAthathavedealtinsomeimportantwaywithadvisorycommittees.

Oneclusterofissuesinvolvesthepurposes,roles,andfunctionsofadvisorycommittees.ViewsontheseissuesappeartovaryasafunctionoftheobserverFDAleadership,FDAmiddlemanagers,academicmedicalscientists,industryspokesmen,andconsumerrepresentatives.Asecondsetofissues,moreprominentinthe1970sthantoday,reflectthesuspicionofapopulistCongress,whichhassometimesseenscientificexpertsastoocloselyalliedwiththeregulatedindustryoratleastastooinclinedtoendorsenewtechnologiesattheexpenseofrisktopatients.Third,theissueoftheindependenceofadvisorycommittees,mainlyfrominfluencebytheagency,butalsofromproductsponsors,haslongpersistedasatopic.

Thediscussionthatfollowsexaminesthesemajorissuesandmoredetailedquestionsaboutcommitteeoperationsandmanagement.Thechapteralsodescribesthe"goldfishbowl"withinwhichtheFDAanditsadvisorycommitteesoperate.

MajorPriorReports

ThehistoryoftheFDAisahistoryofreportsabouttheFDA,asHutthasnoted.

1Inthissection,wereviewseveralreportsthathavedealtwithFDAadvisorycommittees,usuallyinthecontextofreformofthedrugapprovalprocess:theFountainCommitteereportof1976,theDorsenCommitteereportof1977,theMcMahonCommissionreportof1982,andtheLasagnaCommitteereportof1990.ThisbriefhistoricalreviewmakesclearthatmanyoftheissuessurroundingFDAadvisorycommitteesthatare

addressedinthisreporthavebeenconsideredbefore,raisingquestionsaboutwhatisrequiredtomaintainasystemthathasbroadpublicacceptance,iswelladministeredandadequatelyfunded,andcontributestothepublichealthofthecountry.

TheFountainCommitteeReport(1976)

In1976,theHouseCommitteeonGovernmentOperationsissuedareport,UseofAdvisoryCommitteesbytheFoodandDrugAdministration,

2followinghearingsin1974and1975beforeitsSubcommitteeonIntergovernmentalRelationsandHumanResources.IlesubcommitteecriticallyreviewedtheuseofadvisorycommitteesbytheFDA'sBureauofDrugsinthelightofthe1972FederalAdvisoryCommitteeAct(FACA),overwhichthefullcommitteehadjurisdiction.*

TheFACAhadimposedfourrequirementsforestablishinganadvisorycommittee:(1)aformalprocessshouldbeusedtodeterminetheneedforacommittee;(2)membershipshouldbe"fairlybalanced"aswellastechnicallyexpert;(3)meetingsshouldbeconductedaccordingtoproceduresofadvancenoticeandaquorumrequirement,andshouldbeopentothepublic;and(4)detailedminutesandtranscriptsshouldbemaintainedasthemeetingrecord.3

TheFountainCommitteereport,concurringwithamajorgoalofCongressinenactingtheFACAthatagenciesshould"limitthenumberofadvisorycommitteestotheminimumnecessary"(p.3),recommendedthattheFDAreducethenumberofadvisorycommitteestothosehavingaclearjustification,limitthefrequencyoftheirmeetings,andeliminateallnonessentialuses.ThereportemphasizedimprovedmanagementandcompliancewiththeactFDAstaffandadvisorycommitteemembersshouldadheretoitsstandards,

andCongressshouldmonitortheagencytopreventinadequatefiscalandmanagementoversightofcommittees.ItrecommendedthattheFDAremedyaperceivedlackofbalanceinthecompositionofadvisorycommittees,thatitceasetoclosemeetingsimproperly,thatmeetingsnotbeheldinplacesthatdiscouragedpublicattendance,thatcompleteminutesofmeetingsbekept,andthatverbatimtranscriptsnotbedestroyedprematurely.

SeveralrecommendationssoughttostrengthenadvisorycommitteesandtheirindependencefromtheFDA.ThereportrecommendedthattheFDA

*ThesubcommitteewaschairedbyRepresentativeLH.Fountain(D.,N.C.).HuttindicatesthatRep.Fountainheldhearings(asmanyasthreeorfourayear)onallaspectsoftheFDAfrom1964untilheretiredfromCongressin1982.Hissuccessorassubcommitteechairman,Rep.TheodoreWeiss(D.,N.Y.),continuedthattraditionuntilhisdeathinSeptember1992.

takesteps"toassurethatadvisorycommitteesareproperlyinstructedandprovidedadequatetimeandinformationforthoroughandappropriatescientificanalysisandreview,"thatcommitteesbepermitted"toarriveatindependentscientificfindingswithoutfurtherinterventionbyFDAtoinfluencetheirjudgmentonthebasisofnon-scientificconsiderations,"andthattheFDAendthepracticeof"seekingrecommendationsfromadvisorycommitteesonmattersthathavealreadybeendecided,orinordertobypasscriticalstaffreviewofthedatasubmittedinnewdrugapplications."

Ontheotherhand,thesubcommitteedeploredunduerelianceonadvisorycommitteesbytheagency.ItrecommendedthattheFDArelyprimarilyonitsownstafftocarryoutitsresponsibilitiesanduseadvisorycommitteesonlyinexceptionalcircumstancesinvolvingdifficultmedicalorscientificissuesforwhichoutsideexpertisewasclearlyrequired.TheFDAwasalsoenjoinedtoutilizeitsfull-timeprofessionalsmoreeffectivelyand,wherenecessary,toupgradeitsmedical,scientific,andtechnicalpersonnelthroughadvancedtraining,participationinscientificresearch,andsimilarprofessionaldevelopmentactivities.

TheFountainCommitteereportrevealscongressionalsuspicionabouttheFDA'suseofadvisorycommitteesandasuspicionthatexpertcommitteeswerebeingusedtoreinforcecloseddecision-makingprocessesthatfavoredindustryviews.Hence,itsrecommendationthattheFDAstrengthenitsownprofessionalstaffandavoidbecomingoverlydependentonoutsidecommittees.Infact,thereportemphasizedthetechnicalcapabilitiesoftheFDAstaffandarguedthatthesestaffcouldhandlesome,ifnotmost,oftheagency'stechnicaldecisions.

Echoesofthedebateaboutinternalstaffcompetenceversusexternalexpertisearestillheardtoday.AlthoughtheFDAstaff,intheperiod

immediatelyafterthe1962amendments,typicallylackedthetechnicalcompetencetoevaluatedrugsforeffectivenessaswellassafety,theagencylongagoupgradedthequalityofitsprofessionals.Today,theissueofstaffversusoutsideexpertstakestwoforms:someobserversseeadvisorycommitteesasapartialcounterweighttocautious,risk-aversegovernmentregulators;othersseethemasanecessarymeansbywhichtheFDAstaffstaysabreastofthefrontiersofscienceandclinicalmedicine.

TheDorsenCommitteeReport(1977)

Inearly1975,astheFountainCommitteewasholdingitsfirsthearingsonFDAadvisorycommittees,theDepartmentofHealth,Education,andWelfare(DHEW)establishedtheDHEWReviewPanelonNewDrugRegulationtoexamineFDApoliciesandproceduresrelatedtotheapprovalanddisapprovalofnewdrugs.ChairedbyNormanDorsen,professoroflaw

atNewYorkUniversity,thepanel'sfinalreport*

4declaredthatthesystemofnewdrugregulationwasfundamentallysoundbutneededsubstantialimprovement.

Thereportidentifiedfourshortcomingsthatneededremedying.First,theregulatorysystemoftheBureauofDrugswasunnecessarilyclosedtopublicreviewandparticipation,andoverlydependentoninformal,unreviewablecommunicationsbetweentheFDAanddrugcompanies.Second,thescientificcapacityoftheagencywasinadequateand,unlesscorrected,likelytodeterioratefurther.Third,thebureauemployedunacceptablyimprecisestandardsandunstructured,inefficientproceduresforreviewingnewdrugapplications.Fourth,theagencyhadnotdevotedenoughattentiontoapproveddrugs(pp.106107).

Inthecontextofthesecriticisms,apanelofthefullcommitteemadeanumberofrecommendationsregardingtheadvisorycommitteesoftheBureauofDrugs.Ingeneral,itcalledontheFDAtoclarifyitspoliciesandprocedurestoensuretheuniformuseandfunctioningofadvisorycommitteesamongdivisions.Regardingadvisorycommitteemembers,thepanelrecommendedthattheFDAshouldissuewrittenguidelinesforselectingmembers;DHEWshouldabolishitspolicybarringconcurrentmembershiponmorethanonedepartmentalcommittee;shouldestablisha"committeeoncommittees"torecommendnominationprocedures;shouldrescindexistingregulationsconcerningconsumerrepresentationandprovideforvotingpublicinterestmembersonallstandingcommittees.

Onfinancialconflictofinterest,theDorsencommitteerecommendedthatrulesandproceduresshouldbestrictenoughtoguaranteetheintegrityofadvisorycommitteesbutflexibleenoughtoallowtheFDA

toattractandretainqualifiedmembers;theagencyshouldusespecificrulestodisqualifymemberswithseriousconflictsbutapplygraduatedrestrictionstodifferentdegreesofconflict;allcommitteemeetingsshouldbepublic,allsignificantpotentialconflictsofinterestshouldbefullydisclosed;committeesshouldberestrictedtoadvisingonnarrowscientificquestionsratherthanbroadregulatorymatters;andeffortsshouldbeincreasedtofindqualifiedcandidateswithfewerpotentialconflicts.

Advisorycommittees,thereportrecommended,shouldbeinvolvedinreviewingbothinvestigationalnewdrugs(INDs)andnewdrugapplications(NDAs).TheFDAshouldprovidealladvisorycommitteesalistofINDsandNDAscurrentlyunderreviewbytheirrespectivedruggroups;theagencyshouldusememberstoreviewsignificantINDs;theFDAshould

*ThecommitteehadissuedtwointerimreportsinApril1977:"TheUseofStandingAdvisoryCommitteesbytheBureauofDrugsofFDA"and"ConflictsofInterestonStandingAdvisoryCommitteesoftheBureauofDrugs,FDA."

documentitsdecisiontoreferanINDorNDAtoacommittee;andancommitteesshouldadoptthepracticeofassigningindividualmembersasprimaryreviewersofINDsandNDAs.

Recommendationsdealingwithcommitteeoperationsincludedthefollowing:theFDAshouldcontinueitseffortstosendmaterialstoadvisorycommitteemembersatleastthreeweeksbeforeameeting;sponsoringcompaniesshouldreceivethequestionssentbyFDAtothecommittee;andtheBureauofDrugsshouldadoptapolicyagainstindustrycommunicatingdirectlytoadvisorycommitteemembers.Inaddition,theFDAshouldaskadvisorycommitteesprecisequestionsaboutthosemattersonwhichitwishedassistanceandrefrainfromaskingaboutevidenceofsafetyandefficacy;FDAstaff,inpresentationstoacommittee,shouldrefrainfromstatingtheirownviewsabouttheadvicethecommitteeshouldoffer;draftminutesshouldbedistributedtomembersassoonastheyarewritten;andtheFDAshouldperiodicallyinformitscommitteemembersofthestatusoftheirrecommendations.ItalsorecommendedthattheFDAshouldlimitthecriteriaforremovalofanadvisorycommitteemembertobehaviorsodisruptivethatitsignificantlyimpedestheproperfunctioningofthecommittee;theagencyshouldensurethatmembersdonotdiscusscommitteebusinessinprivate;andcommitteemembersshouldrefrainfromdiscussingnonscientificissuessuchaseconomicormalpracticequestionsatmeetings.

ThepanelreportrecommendedthatthehandbookunderpreparationfororientingadvisorycommitteemembersshouldincludetherelevantFDAstatutes,theregulationsfornewdrugapproval(includingthestandardsofsafetyandeffectiveness)andforadvisorycommittees,adescriptionofthemattersFDAwillrefertocommittees,andastatementofhowFDAhopestousecommitteemembersasreviewersofINDsandNDAs.

RecommendationsoftheDorsenReporttoexpandthescopeofadvisorycommitteeresponsibilitiesalsofindexpressionintheMcMahonandLasagnareports(seethelaterdiscussions).Suggestionsthatcommitteesguidesponsorsintheearlystagesofproductdevelopment,especiallythedesignandconductofclinicaltrialsareseldomaccompaniedbydetailedsupportinganalysis.Theagencyhaspredictablyresistedsuchexpansion,notingthatitwouldrequiregreateragencyresourcesandwouldincreasecommitteeworkloadssubstantially.Ingeneral,theFDApreferstofocusmoreonusingcommitteesforproductevaluationandforassessingbroadissuesofdrug,biologic,ordeviceevaluation.*

*Asnotedinpriorchapters,theCenterforBiologicsEvaluationandResearchinvolvesitselfanditsadvisorycommitteesmoredeeplythantheothercentersinearlystagesofproductdevelopment,apatternderivedfromitshistoryandregulatoryresponsibilities.

TheMcMahonCommissionReport(1982)

In1981,attheinitiativeofRepresentativesScheuerandGore,CongressauthorizedthecreationofaCommissionontheFederalDrugApprovalProcess(knownastheMcMahonCommission,afteritschairman).TheCommissionreportedinMarch1982on''changesthatwouldenhancethespeedandqualityoftheapprovalprocesswhilemaintainingtheexistinglevelofprotectionofthepublichealth''

5(p.2).Itsreportfocusedonfourquestions:thescientificevidenceneededtoconcludethatadrugwassafeandeffectiveandwhoshouldassessthesufficiencyandmeaningoftheevidence;thedocumentationneededbytheFDAtosupportmarketingortestingandthetimingofitssubmission;themostefficientuseofFDAresourcestoperformtheagency'sdutiesintheINDandNDAprocesses;andthe"styleofinteraction"betweentheFDAandthepharmaceuticalindustrymostappropriatetoensureefficiencyandqualityinthedrugreviewprocess.

TheMcMahonCommissionproposedthefollowingreforms:outsidereviewboardsshouldbeusedintheapprovalprocess;newindicationsforapproveddrugsshouldbecompletelyexemptfromINDrequirements;astreamlinedapprovalprocessforgenericdrugsshouldbeestablished;andmanufacturersshouldnolongerberequiredtosendrawdatatotheFDA.Thereportwasoptimisticaboutspeedingthedrugapprovalprocess,althoughaminorityreportcommentedthatitfailedtorecognizethesubstantialprogressFDAhadmadeinthisregard.

Amongitsrecommendations,thecommissioncalledforgreateruseofoutsideexpertsintheapprovalprocess:reviewproceduresshouldberevised"toaffordamoresignificantrole"toexpertsfromthe

academicandgovernmentbiomedicalresearchcommunities,and"dueweight"shouldbegiventothejudgmentofclinicalinvestigatorsastowhetherthestandardofeffectivenesshadbeenmet.Italsoproposedthatoutsideexpertsshould"becomemoreactivelyinvolved,"attherequestoftheFDAoradrugsponsor,inplanningclinicaltrials,advisingonINDsornewindicationsofanapproveddrug,andreviewingofNDAs.

TheMcMahoncommissionfurtherrecommendedthattheCommissionerseekthehelpof"leadingprofessionalsocieties,universities,andotherappropriatebodies"inobtainingthe"mostqualifiedexpertsinvariousfieldsofpharmacologyandtherapeutics"asconsultantsandadvisorycommitteemembers.ItagreedwiththeDorsenreport'sproposalfora"committeeoncommittees"tobroadentheselectionofadvisorycommitteemembers.

Regardingconflictofinterest,thecommissionrecommendedthattheFDAcommissionerrequestfromtheDepartmentofJustice"alessrestrictiveinterpretation"ofthefederalconflict-of-intereststatutethanthatissuedin

1978,reflectingitsbeliefthatgreateruseofexperts,asconsultantsandadvisorycommitteemembers,couldreducethetimeneededforreview(pp.7882).Withalessconservativeinterpretation,itargued,"moreexpertscouldparticipate,andthustheycouldbeinvolvedearlierandmorecontinuouslyinthecourseofdevelopingimportantnewdrugs,[which]could...avertclinicalstudiesthatarenotneededforNDAapproval,expeditereviewofresearchdata,andenhancethequalityofFDAdecisionmaking"(p.3).

TheMcMahonCommissionreportreflectedanoptimisticviewthatgreateruseofadvisorycommitteeswouldshortenthedrugapprovalprocess.Thisview,whichreappearsovertime,assumesthatadvisorycommitteescansubstituteforagencypersonnel.Advocacy,again,drawslittlesupportfromanalysis.TheFDAtendstorespondthatgreateruseofadvisorycommitteesrequiresmore,notfewer,agencystaff.

TheLasagnaCommitteeReport(1990)

TheNationalCommitteetoReviewCurrentProceduresforApprovalofNewDrugsforCancerandAIDS,chairedbyDr.LouisLasagna,wascreatedinlate1988bythePresident'sCancerPanel,inresponsetoaJunerequestofthen-VicePresidentGeorgeBush.Itsreport,issuedinAugust1990,madeanumberofrecommendationsaboutthedrugdevelopmentandevaluationprocess.

6

TheLasagnaCommitteereportmadeseveralrecommendationsregardingadvisorycommittees.ItfirstrecommendedthatastandingpolicyandoversightcommitteebeestablishedbytheSecretaryofHealthandHumanServices.Thiscommittee,whichwouldreporttotheSecretary,would"monitortheFoodandDrugAdministration's

needsandperformancewithregardtotheregulationofdrugsandbiologicsforhumanuse."

Thereportalsocalledfor"afundamentalrestructuring"ofthetechnicaladvisorycommitteesystem,withallcommitteeshavingtheirindependentstafflocatedintheOfficeoftheCommissioner.TheOfficeoftheCommissionerwastomanageappointmentstothecommitteesdirectly,andcommitteesweretoreportdirectlytothatoffice.TheLasagnaCommitteefurtherrecommendedthatcommitteesberesponsiblefortheirownagendasand"morecloselymonitor"thenewdrugapprovalsystem.

TheLasagnaCommitteereportnotedapotentialforincreaseduseofadvisorycommitteesintheearlystagesofdrugdevelopment;inevaluatingINDsandNDAs,insettingprioritiesamongdrugs;inmediatingbetweentheFDAandindustry;andinoverseeingFDAimplementationofcommitteerecommendations.Finally,"tofostercloserelationshipsbetweenthegovernmentagenciesinvolvedwithAIDSandcancerdrugs,theNational

CancerInstitute,theNationalInstituteofAllergyandInfectiousDiseases,andFDAshouldeachhaveapermanentrepresentativesittingasavotingmemberoftheappropriateadvisorycommitteeintheotheragencies"(p.v).

OtherReports

TwootherrecentreviewsofFDA'sperformancedeservebriefmention,althoughneitherdwelledatlengthonadvisorycommittees.TheDepartmentofHealthandHumanServices(DHHS)AdvisoryCommitteeontheFoodandDrugAdministration,otherwiseknownastheEdwardsCommittee,issueditsreportin1991afterayearofconsideringtheFDA'smission,structure,andresponsibilities.

7Itsmainrecommendationsaddressedtheseneeds:toclarifytheFDA'smissionandpriorities;toelevatetheagency'sstatusandauthority;tostrengthenitsenforcementoperations;toimproveagencymanagement;andtoincreaseitsresources.

Aspartoftherecommendationforincreasedresources,theEdwardsCommitteestatedthat"TheCommissionermustbeempowered,tothelimitsofstatutoryauthority,tomanagetheFDA'sscientificandtechnicalpersonnel,andtoimprovetheFDA'saccesstoscientificexpertiseincludingadvisorycommitteeappointments"(p.v).Itnotedthattheprocessforrecruitingandusingadvisorycommitteememberswasburdensomeandcostlyintimeandeffort.Itcitedpotentialconflictsofinterestasaspecificreasonforthedelaysanddifficultiesinappointingandconveningadvisorycommitteesandasabarriertotheuseof"manyhighlyqualifiedandrespectedadvisors."ItadvocatedpriordisclosureofpotentialconflictsaspreferabletoprematuredisqualificationwhenaconflictisanticipatedandurgedtheagencytodrawontheAugustineCommissionreportontheNational

AeronauticsandSpaceAdministrationofMarch1991andtheFDARevitalizationActtoreducetheimpedimentsintroducedbythecurrentprocessformanagingconflictofinterest(pp.4546).

ThesubcommitteeonhumandrugsandbiologicsoftheEdwardscommitteenotedthattheFDAappearedtouseadvisorycommitteesinconsistentlyandthatserviceonadvisorycommitteeshadtobemadeappealingenoughtoattracttheappropriateexperts.Itrecommendedbothexpandedandearlieruseofthecommitteestoreducedelaysintheapprovalprocess.UnliketheLasagnacommittee,however,theEdwardscommitteereportopposedthecreationofapolicyoversightboard,butdidrecommendthattheCommissionerincreasetheaccountabilityandusefulnessofthereportingrelationshipbetweenadvisorycommitteesandtheFDA.Thesubcommitteeondevices,radiologicalhealth,andbiomedicalresearchmadesimilarrecommendationsonadvisorycommittees.

Thesecondreporttoemergein1991wasfromtheCouncilonCompetitiveness,whichrespondedtomanyoftheLasagnaCommitteerecommendations.

8Itproposedmajorchangesinthedrugapprovalprocesssuchascontractingwithexpertsoutsideofthefederalgovernmentforreviewingdrugapprovalapplications.TheoverallgoaloftheCouncilreportwastoshortenthereviewandapprovalprocess.OnerecommendationtothisendwastheincreaseduseofadvisorycommitteesforevaluatingNDAsandINDs,which,citingLasagna,meanttheuseofadvisorycommitteesearlierintheresearchanddevelopmentprocess.

TheGoldfishBowl

Thereportsdiscussedaboveindicate,asHutthasaptlyobserved,thatFDAoperatesinanenvironmentofintensepublicscrutiny.Itsactionsarecloselyfollowedbythegeneralpublic,Congress,thepress,theregulatedindustries,andthefinancialcommunity.It,asmuchasanyfederalgovernmentagency,functionsinagoldfishbowl.Inthissection,weconsiderseveralaspectsofthatgoldfishbowlcongressionaloversight,mediacoverage,andattentionbythefinancialcommunity.

CongressionalOversight

TheFDAinteractswiththeCongressinmanyways.Itdealswithtwolegislativecommittees:theHouseCommitteeonEnergyandCommerce,anditsSubcommitteeonHealthandtheEnvironment,andtheSenateCommitteeonLabor,Health,andHumanResources,anditsSubcommitteeonHealth.Itdealswithtwoothercommitteesforitsannualappropriations:theHouseCommitteeonAppropriations,SubcommitteeonAgriculture,RuralDevelopment,

FoodandDrugAdministration,andRelatedAgencies,andtheSenateCommitteeonAppropriations,SubcommitteeonAgricultureandRelatedAgencies.*

Inaddition,theHouseCommitteeonAgriculture,SubcommitteeonDomesticMarketing,ConsumerRelations,andNutrition;theHouseCommitteeonGovernmentOperations,SubcommitteeonHumanResourcesandIntergovernmentalRelations;theHouseCommitteeonScienceandTechnology,SubcommitteeonOversight;theSenateCommitteeonGovernmentalAffairs;theSenateCommitteeonAgriculture,Nutritionand

*TheFDAbeganastheBureauofChemistryoftheU.S.DepartmentofAgriculture.ItsappropriationscontinuetobethejurisdictionoftheagriculturesubcommitteesinbothHousesofCongress.

Forestry,SubcommitteeonNutritionandInvestigations;theSenateJudiciaryCommittee,SubcommitteeonAntitrust,Monopolies,andBusinessRights;andtheSenateSpecialCommitteeonAgingalldealwithaspectsoftheFDAanditsprogramsonaratherroutinebasis.Inshort,nearlyadozencongressionalcommitteestakeanactiveinterestintheaffairsoftheFDA.

Controversialdecisionsbytheagencyorclaimsofproceduralirregularitiescanquicklyresultinahearingbeforeoneofthesecommittees,atwhichtheresponsibleagencyofficialsarecalledtoaccount.Suchhearingsusuallyreceivewidemediacoverage,bothfromnewspapersandtelevision.Frequently,MembersofCongressandtheirstaffpinpointlowerechelonFDAofficialswhoareresponsibleforagivenactionandinvitethemintothespotlightofthehearingroom.Notsurprisingly,thisoversightencouragesrisk-aversebehavioronthepartofFDAofficialswelldownonthebureaucraticladder.

CongressionalinterestintheFDAspanstheentirerangeoftheagency'sactivities.Examplesincludethefollowingcongressionalhearingsheldduringthe101stand102ndCongresses(from1989tothepresent):thegenericdrugscandalinvolved10hearingson19separatedays;theamendmentstotheOrphanDrugActwerethesubjectof2separatehearings;artificialheartvalveswereconsideredin2separatehearings;andtheuseofplentopheresisinthetreatmentofsclerodermawasthesubjectofonehearing.Inaddition,hearingsaddressedthereportsoftheAdvisoryCommitteeontheFoodandDrugAdministration(theEdwardsCommittee)andthereportofthePresident'sCouncilonCompetitivenessonimprovingthedrugapprovalprocess.

MediaCoverage

CoverageoftheFDAbybothnewspapersandtelevisioniscopious

andgrowing.TheIOMcommitteesampledoneyear'sworthofarticles(June1991toJune1992)fromTheNewYorkTimes,TheWallStreetJournal,TheWashingtonPost,andTheLosAngelesTimesonselectedtopicsbeforetheFDA.Considerthefollowingexamples:

EventhoughtheIOMsearchofthesenewspapersbeganaftertheFDAhadpubliclyconcludedthattherewasnosolidevidencethatProzac,apopularantipsychoticdrug,causedsuicidalideation,thefournewspaperssubsequentlycarried11articlesonthedrug(4eachinTheWallStreetJournalandTheNewYorkTimes,2inTheLosAngelesTimes,and1inTheWashingtonPost).

Similarly,whentheFDAreviewedthedataonthesafetyofHalcion,apopularsleepingpill,afteritsremovalfromseveralEuropeanmarkets

becauseofconcernsoveritssideeffects,18articlesappearedinthefourpapers(2inTheWallStreetJournal,andnofewerthan7inTheNewYorkTimes).

SiliconegelbreastimplantsreceivedtremendousattentionastheFDAreviewedthemforsafetyandeffectivenessinlate1991andearly1992.Thefourpaperspublished167articlesonthistopicalone,including14editorials.TheNewYorkTimesledwith50articlesand3editorials;TheWashingtonPostcarried27articlesand3editorials.

AglimpseofthisintensepressandtelevisioncoverageoftheFDA'sadvisorycommitteemeetingsisprovidedbytheiteminBox4-1,whichappearedinTheWashingtonPostonOctober1,1991.

TheFinancialCommunity

ThefinancialcommunitymonitorstheFDAclosely,buttheintensityofthisscrutinyisarelativelynewphenomenon.IndicativeofinvestmentcommunityinterestinFDAadvisorycommitteeswasthestockmarket'sresponsetotheadvisorycommitteethatdealtwithproductsmadebyXomaandCentocorinSeptember1991,andwhichrecommendedapprovalofthelatterfirm'santisepticbiologic,andthelaterresponsetotheFDA'sdecisioninMay1992tofailtoactonthisrecommendation.

HeightenedinterestinthefinancialcommunityrecentlypromptedtheFDAtocommissionastudybyKutakRock&Campbell,aWashington,D.C.,lawfirm,examiningthetreatmentoffinanciallysensitiveinformationbytheagency.TheconcernoftheFDA,asexpressedbytheNovember1991KutakRock&Campbellreport,

9waswith"theadequacyoftheagency'sinstitutionalsafeguardsagainsttheimproperdisclosureoruseofinformationaboutAgencyactions[thatmight]affectthefinancialmarkets."

TheKutakRock&CampbellreportexaminedtheFDA'shandlingoffinanciallysensitiveinformationandproposedgeneralimprovementsinFDAprocedures.Amongitsgeneralobservations,thereportnotedthatproceduralinconsistenciesincreasedtherisksofinappropriateorunauthorizedactions,andspecifically,thedisclosureoffinanciallysensitiveinformation.Thereportconcludedthat"FDA'sultimategoalofadequatelyandreasonablyprotectingconfidentialinformationcanbemetinonlytwoways:byimposingappropriatesafeguardsorbyeliminatingtheneedforconfidentiallythroughdisclosure."Itrecommendedsomenewandsomemodifiedproceduralsafeguardsand"broaderandearlierdisclosure"ofcertaincategoriesofinformation,withthespecificgoalofreducingtheeffectsofsuchdisclosuresonfinancialmarkets.

Box4-1AtanFDAPanelHearingLights,Cameras,Action!

Whenapanelofexpertsmetrecentlytoconsidertheevidencefortwonewdrugsagainstsepsis,astanding-roomonlycrowdofdrugcompanyofficials,analysts,scientistsandreporterspackedintoaconferenceroomattheFoodandDrugAdministrationheadquartersinRockvilletoobserve.Atstake:anestimated$1billionmarketfortwonewgeneticallyengineereddrugs.OneanalysttoldTheWallStreetJournalthemeetingwaslike"thegunfightattheRockvillecorral."ThetwodrugcompaniesinvolvedCentocorCorp.ofMalvern,Pennsylvania,andXOMAofBerkeley,CaliforniabroughttheirownTVcrewstorecordtheevent.CNNwasthere.Sowasarowoftradejournalreportersandothernewsmedia.Ileyscribblednoteswithonehandandheldtaperecordersintheother.Twophotographerssetuptripodsinacornerandmethodicallyclickedthreeshotsofeverydata-filledslidewithtelephotolenses.Mendressedinstripedshirtsandbowties,theircuffsadornedwithgold,reachedforcompactcellularphonesthroughouttheday.Theywhisperedthelatestworddecidedbyan11-memberadvisorypaneltotheFDAandapanelofexpertswhoadvisedtheadvisorypanel.Drugcompanyrepresentativesmadewell-rehearsedpresentationsabouttheresultsoftheirclinicaltrials.Expertsquestionedtheirwork.Bytheday'send,theFDApanelhaddecidedthatCentocor'sHA-1Awassafeandeffectivebutstoppedshortofrecommendingthatitbelicensed.AdecisiononE5,theXOMAdrug,waspostponedformorereviewsasthreerowsofcompanyofficialsglumlylookedon.Buttheshootoutwasn'tnecessarilyover,sinceasFDAspokeswomanFayePetersonlaternoted,allpaneldecisionsarerecommendationsonly.It'suptoanotherFDAbodytodecidewhenandifeachdruggoestomarket.

SallySquiresWashingtonPost"Health"section,p.12

October1,1991

Asmentionedabove,thereportdevotedachaptertoFDAadvisorycommitteesandtheattentiontheyreceivefromthefinancialcommunity.Historically,itnoted,theFDA'sfinaldecisionsonapprovingordisapprovingadrugusuallyagreewiththepriorrecommendationsofadvisorycommittees.Asaresult,thefinancialcommunitypaysgreatattentiontothediscussionandfinalrecommendationsatanadvisorycommitteemeeting.

Thisattentionisbroaderthanasimpleconcernfortheproductbeingreviewed:

ThemeetingsalsoprovidesomeinsightintotheviewsofFDAabouttheproduct,andthusserveaspredictorsofthelikelihoodandspeedofproductapprovalbytheAgency.Indeedthe[financial]analystsregardthemereschedulingofanadvisorycommitteemeetingforaproductasanindicationthatFDAwillreachadecisionaboutaproductwithinarelativelyshorttime.

10

Giventheintenseinterestofthefinancialcommunityandtheeffecttheadvancepublicreleaseofquestionspreparedfortheadvisorycommitteemighthaveontradinginthesecuritiesmarkets,thereportbasicallyconcurredwithcurrentFDApracticeofpubliclyreleasingsuchquestionsonthemorningofacommitteemeeting.Advisorycommitteemembers,asspecialgovernmentemployees,thereportnoted,aresubjecttofederalconflictofintereststatutes.Consequently,"theregulatoryprohibitionsagainstdisclosureof'insideinformation'bySGEsaremorestringent,moreexplicit,andfarlengthierthantheonesforactualFDAemployees."Butadvisorycommitteemembersreceivenoparticulartrainingaboutsafeguardingfinancially-sensitiveinformation,andmightthemselvesbesourcesofinformationleaksaboutaproduct'spositionintheapprovalprocessaccordingtoseveraloftheFDAemployeesinterviewedbyKutakRock&Campbell.Amongitsmanyrecommendations,therefore,thereportproposedthattrainingmaterialsforSGEsbeexpandedtoexplaintheimportanceoftheseissues.

Conclusions

Ingeneral,fromthehistoryoftheFDAadvisorycommitteesystem(chapter2),theanalysisofthecurrentsystem(chapter3),andthe

examinationoftheforegoingreportsandtheenvironmentofpublicscrutinyinwhichtheagencyoperates,thefollowingpreliminaryconclusionsemerge.

1.Itisworthaskingwhytherecommendationsofthesepriorreportshavenotresultedinawell-organized,efficientlyfunctioningFDAadvisorycommitteesystem.Theanswersarefarfromclearbutseveralhypothesesmaybeadvanced.Onepossibilityisthatfinancialresourceshavealwaysbeentooscarcefortheagencytogivesufficientattentiontothesystem.Asecondhypothesisisthatrecommendationsaboutadvisorycommitteeshavetendedtobeburiedinhigherpriorityconcernsaboutthedrugapprovalprocess.YetathirdexplanationisresistancebytheFDAprofessionalstaff.Equally

plausibleistheargumentthatthetopleadershipoftheagencyhasnotdevotedadequatesustainedattentiontoadvisorycommittees,includingeffortstoinstitutionalizethemwithclearauthority,strongmanagement,andsufficientresources.Finally,itmaybethatFDAadvisorycommitteeslackapoliticalconstituencycomparabletothesupportofacademicmedicinefortheNIHstudysectionsystem.

Thesehypothesescannotbetestedinanyscientificwayandremainthebasesforspeculationandargument.Notwithstandingtherangeofpossibleanswerstothequestionaboutthelimitedimpactofpriorreports,weoptimisticallyhopethatthereceptionaccordedtothisreportwillbedifferent.

2.AwideconsensusexiststhattheprimarypurposeoftheFDA'stechnicaladvisorycommitteesistobringindependentscientificexpertisetobearonagencydecisions.Theagencyaffirmsthisview,industryendorsesit,andthemedicalcommunityclearlybelievesinthispremise.

3.Thevariousinterestedpartiesbegintodiverge,however,intheirviewsoftheirbenefitsoftechnicaladvisorycommittees.Theagencyseestheirbenefitsasprovidingtechnicalassistanceonquestionsbeforeit,addingcredibilitytothedecisionsitmakesandtoitsdecision-makingprocedures,andprovidingapublicforuminwhichitcanventilatecontroversialissuesandhearfromdirectlyaffectedinterests.Forthepublic,andespeciallyCongress,advisorycommitteeshavehelpedlegitimizethescientificbasesforFDAdecisionsandhavecometobeseenasacounterweighttobothbureaucraticoverreachingandcaution.Industryhasbecomemoresupportiveofthesecommitteesovertimebecauseitbelievestheyhavebeenmorestronglyorientedtowardtherapeuticinnovationthantheagencyandthattheyprovidesomeopportunityforfairreviewofagencydecisionsthatwouldotherwisegounscrutinized.

4.TheFDAexperiencewithadvisorycommittees,bothhistoricallyandcurrently,revealsthattheirusehasusuallyresultedfromagencyinitiative.Consequently,agencyofficialshavegenerallydeterminedthefunctionalrolesthatadvisorycommitteeswillplay,whatmatterstheywillconsider,whentheywillbeaskedtoprovideadvice,whatinformationtheywillbegiven,andveryclearlywhatweighttheiradvicewillhave.

5.TechnicaladvisorycommitteesareseenbothwithinFDAandbymostexternalobserversasadviserstotheagency.Theyarenotjudicialbodies,saveintheirinfrequentuseasappealsbodies.Thus,theirchargeisnottoadjudicatecompetingclaimsbuttoprovideindependentadvicetotheagencyonthequestionsonwhichtheagencydecidesitneedsadvice.

6.AmajorrationaleforusebytheFDAofoutsideexpertpanelsinthe1960sand'70sespeciallyintheNationalAcademyofSciences-NationalResearchCouncilDrugEfficacyStudy,theOver-the-Counterdrugreview

panels,andthebiologicsreviewadvisorycommitteeswastoclearabacklogofworkthattheagencywasnotequippedtohandlebecauseithadtoofewprofessionalstaffandthesewereoftenlackingintheneededtechnicalcompetence.Thisworkload-clearingfunctionofadvisorycommitteesisseldomadvocatedtoday.

7.Thepropositionthatadvisorycommitteeswouldspeedtheproductapprovalprocess,especiallyfordrugs,hasbeenadvancedonanumberofoccasions,usuallywithoutstrongsupportinganalysis."TheIOMcommitteebelievesthatthejustificationofadvisorycommitteesderiveslessfromtheireffectontheefficiencyoftheproductevaluationprocessandmorefromtheirimpactonthequalityofthatprocess.Inthatregard,advisorycommitteesreflecttheagency'sdesireforexpertadvice,forcredibledecisionsanddecision-makingprocesses,andfortheabilitytodiscusscontroversialissuesinapublicarena.

8.Anunderlyingissueistheindependenceofadvisorycommitteesfromsourcesthatmightwishtoinfluencetheoutcomesoftheirdeliberations."Thesesourcesincludeproductsponsorsand,inparticular,agencyofficials.Consequently,thisreporttakesupthematterofindependenceinthenarrativeandrecommendationsofthenextfourchapters.

9.AcontinuingfactoflifefortheFDAistheenvironmentofintensepublicscrutinywithinwhichitoperates.Consequently,anysignificantchangesinhowtheagencyfunctionsrequiresomeworkingconsensusthatincludestheagency,itsleadership,anditslargecadreofprofessionals;theCongress;theExecutiveBranch,fromtheWhiteHousetotheSecretaryofHealthandHumanServicesandtheotheragenciesofthePublicHealthServices;theregulatedindustriespharmaceuticals,biotechnology,andmedicaldevices;theacademicmedicalsciencecommunity;andorganizedgroups

representingtheconsumers,voluntaryhealthorganizations,andthepublic.

Thefollowingfourchaptersexamineanalyticallymanyoftheissuesthathaveconcernedthedesigners,managers,andusersoftheadvisorycommitteesystemovertime.Chapter5dealswithcommitteemembershipissues.Chapter6examinesconflict-of-interestissuesingreatdetail,aswellasthematterofscientificbias.Aclusterofissuesconcernedwithcommitteeoperationsisaddressedinchapter7.Finally,inChapter8,theorganizationandmanagementoftheadvisorycommitteesystemisconsidered.

Notes

1.PeterBartonHutt,"InvestigationsandReportsontheFoodandDrugAdministration,"inFoodandDrugLaw,FoodandDrugLawInstitute(Washington,D.C.,1991),p.48.

2.U.S.House,CommitteeonGovernmentOperations,UseofAdvisoryCommitteesbytheFoodandDrugAdministration,11threport,basedonastudybytheIntergovernmentalRelationsandHumanResourcesSubcommittee,94thCong.,2ndSess.,ReportNo.94-787(January26,1976).

3.Stockman,PaulK,ApplicabilityoftheFederalAdvisoryCommitteeActtoAlternativeSourcesofScientificInput,reporttotheIOMFDAadvisorycommitteestudy(July31,1992).

4.DepartmentofHealth,Education,andWelfare.ReviewPanelonNewDrugRegulation:FinalReport(Washington,D.C.,May1977).

5.CommissionontheFederalDrugApprovalProcess,FinalReport(Washington,D.C.,March31,1982).

6.President'sCancerPanel,NationalCommitteetoReviewCurrentProceduresforApprovalofNewDrugsforCancerandAIDS.(Washington,D.C.,August15,1990).

7.U.S.DepartmentofHealthandHumanServices.FinalReportoftheAdvisoryCommitteeontheFoodandDrugAdministration(Washington,D.C.,May1991).

8.CouncilonCompetitiveness.FactSheet:ImprovingtheNation'sDrugApprovalProcess(Washington,D.C.,1991).

9.KutakRock&Campbell.FDASafeguardsAgainstImproperDisclosureofFinancially-SensitiveInformation(Washington,D.C.,November1991).

10.Ibid.,p.69.

5CommitteeMembershipFDAregulationsdifferentiatebetweenpolicyadvisorycommitteesandtechnicaladvisorycommittees.Thisreportdealsmainlywithtechnicalcommittees.Theregulationsalsodistinguishbetweenvotingandnonvoting(orrepresentative)members.Thischapterdealsprimarilywithvotingmembersoftechnicaladvisorycommittees,althoughrepresentativemembersarealsodiscussed.

TheabilityoftheFoodandDrugAdministrationtoattractandretainqualifiedindividualsasmembersofitstechnicaladvisorycommitteesiscriticaltothesuccessfulperformanceoftheadvisorycommitteesystem.Ageneralcriterionforvotingmembersisthattheymusthave''expertiseinthesubjectmatterwithwhichthecommitteeisconcerned''(21CFR14.80(b)(1)-(i)).

The"subjectmatter"ofadvisorycommittees,asindicatedelsewhereinthisreport,pertainstotheevaluationofdrugs,biologics,andmedicaldevicesregardingtheirsafetyandeffectiveness,includingindicationsandcontraindicationsforuseandrelatedissuesoflabeling,andtobroadertechnicalissuesofproductevaluation,suchasspecificmethodologiesforassessingaparticularclassoftherapeuticagents.

Inthischapter,weaddressthecriteriaformembership,recruitmentprocedures,appointmentauthority,andprovisionforconsumerandindustryrepresentativesonadvisorycommittees.

NominationCriteria

GeneralandSpecificCriteria

TherangeofproductsthattheFDAregulatesisextensive,andtheexpertiseitneedsisequallygreat.Consequently,theFDAinitiateditsadvisorycommitteesystemasawaytoobtainscientificandclinicaladvicethatwasnotavailabletoitthroughitsprofessionalstaffbutthatwasneeded

tocarryoutitsregulatoryresponsibilitiesregardingdrugs,biologics,andmedicaldevices.

Thescopeofasingleadvisorycommitteemayalsobequitebroad;sometopicsmayconstituteadisciplineorsubspecialtyinthemselves.Consequently,theagencyneedsabroadarrayofexpertise,bothclinicalandnonclinical;italsohasaninterestinselectingandrecruitingadvisorycommitteememberswhoarerecognizedbytheirpeersfortheirprofessionalcompetence.TheFDAregulationscitedabovedonotgobeyondthegeneralcriterionof"expertiseinthesubjectmatter"toaddressspecificqualificationsordesiredcharacteristicsforadvisorycommitteemembership.Here,weexaminethequalifications.

Itisonlyreasonablethatifcandidatesarebeingsoughtfortechnicaladvisorycommittees,scientificortechnicalcompetenceshouldbetheprimarycriterion.THEIOMcommitteebelievesthattheadvisorycommitteesystemwillfunctionmosteffectivelyandbestservetheneedsofthepublicandtheagencyiftheFDAroutinelyattractsandretainsindividualswhomeetahighstandardofexcellenceascliniciansandscientists.

TheIOMcommitteestronglyendorsesthecriterionorscientificortechnicalcompetenceasarequirementforselectingallvotingmembersofFDAtechnicaladvisorycommittees.

TheIOMcommitteeadoptedtheviewthatthecompetenceneededonanadvisorycommitteeshouldincludetheclinicalexpertisenecessarytoevaluateasponsor'ssubmission.*Thisexpertiseinvolvesnotonlycliniciansandscientistsfromthepertinentdisciplinesbutclinicalinvestigatorswhoareexperiencedinthedesign,conduct,andinterpretationofdrugormedicaldeviceclinicaltrials.However,initsdeliberationstheIOMcommitteedidnotsupporttheviewthattheFDAshoulddevelopguidelinestodefineeithertheminimumorthe

optimumlevelofqualificationsorexpertiseforpotentialadvisorycommitteemembers.Thereasonsfornotpursuingthiscourseareindicatedlaterinthediscussionof"balance."

DiversityObjectives

Inthiscontext,theIOMcommitteeacknowledgesthat"diversitygoals"ofgender,race-ethnicity,andgeographyguidetheselectionofadvisorycommitteemembers.Inthecommittee'sview,thesediversitygoalsarenotincompatiblewiththecriterionofscientificandtechnicalcompetencebut

*TheIndustryLiaisonPanel,whichadvisedthecommittee,stronglyemphasizedthisviewpoint.

reflectlegitimatepolicyobjectivesofapluralisticsocietythatarewellfounded,appropriate,anddesignedtoensurearangeofviewpointsonwhatareseldompurelytechnicalissues.Thecommitteebelievesthatitisimpracticalandundesirabletoconsiderretreatingfromthesegeneralgoals.

Incomposinganadvisorycommittee,theFDAhastraditionallyfollowedDepartmentofHealthandHumanServices(DHHS)policies,whichaimatatargetcommitteerostercomposedof20percentwomenand10percentminorities.TheIOMcommitteerecognizesthattheagency,someadvisorycommitteemembers,andsomeexternalobserversregardthesegoalsasonerousandtending,onoccasion,tounderminethequestforscientificandclinicalexcellence.Therearereportsthatstaffofthethreecenters*spendconsiderabletimeandeffortinidentifyingandrecruitingindividualswhorepresentthesedemographiccharacteristicsandthatsomeindividualswithgreaterexpertisemaybeexcludedasaresult.

Thisparticularrecruitmentproblemhasseveralsources.Historically,itstemsfromtherelativelyfewwomenandminoritymembersofmedicalandscientificprofessions,especiallyinhighlyspecializedfields.OtherfactorsincludethedifficultiesofidentifyingsuchindividualsandalowrateofacceptanceofappointmenttoFDAadvisorycommitteesbyidentifiedindividualsfromthesegroups.**

Theidentificationproblemstemsinpartfromthefactthattheagency'scurrentpracticesareinsufficienttouncoveracriticalmassofthesecandidates.Womenandminoritiesmaybeunderrepresentedintheleadershipofprofessionalsocieties,wherepeercontactisestablishedandmaintained,andintheprofessionalliterature,bothofwhichareusedextensivelybytheFDAinseekingcandidatesforadvisorycommitteevacancies.

TheIOMcommitteebelievesthatmeetingFDA'sdiversitygoalsmay

requirespecialeffortsbytheagencytoidentifywomenandminoritygroupmemberswhoarescientificandmedicalexperts.

TheIOMcommitteerecommendsthattheFDAcontinueitspolicyofactivelyseekingqualifiedwomenandmembersofminoritygroupsaspotentialcandidatesforadvisorycommitteemembership.

*ThesearethecentersforDrugEvaluationandResearch(CDER),forBiologicsEvaluationandResearch(CBER),andforDevicesandRadiologicalHealth(CDRH).**Thelowacceptancerateproblemseemstobeaparticularlyperniciousissueandonethatisnotpeculiartowomenandminoritycandidates.

TheFDAshouldwaivethispolicy,however,inthoseinfrequentcasesinwhichthenumberofwomenandminoritycandidatesinafieldissolimitedthatitisnotfeasibletoexpecttobeabletorecruitthemtoserveonacommittee.

SomeconstraintsmaylimittheaccessoftheFoodandDrugAdministrationtoscientificandtechnicalcompetenceasitseekstomeetitsdiversityobjectives.CurrentpolicyoftheDHHSpreventsanindividualfromservingconcurrentlyonmorethanonePublicHealthServiceadvisorycommitteewithoutaspecialdepartmentalwaiver.Thispolicylimitstheexpertisethatcanbetappedforaparticularcommitteeandimpedesmeetingdiversityobjectives.Thus,forexample,somehighlyqualifiedindividualswhomaybeservingonNationalInstitutesofHealth(NIH)studysectionsareprecludedfromserviceonanFDAadvisorycommittee,andviceversa.

TheIOMcommitteerecommendsthattheDepartmentofHealthandHumanServiceseliminateitspolicyprohibitingdualcommitteemembershipandthatqualifiedcandidatesforFDAadvisorycommitteesbeallowedtodecidewhethertheywishtoserveonmorethanonePublicHealthServicecommittee.However,itrecommendsthattheFoodandDrugAdministrationexhaustothermeansofrecruitmentbeforeitresortstoselectingpersonswhoserveonotheradvisorycommittees.

Balance

TheFederalAdvisoryCommitteeAct(FACA)requiresthatadvisorycommitteemembershipbe"fairlybalancedin...thepointsofviewrepresentedandthefunctionstobeperformed"andthattherebe"appropriateprovisionstoassurethattheadviceandrecommendationsoftheadvisorycommitteewillnotbeinappropriatelyinfluencedby...anyspecialinterest,butwillinsteadbetheresultoftheadvisorycommittee'sindependentjudgment"[FACA§5(b)].Thiscriterion,however,provideslittleoperational

guidancetothenominationandselectionofmemberstoserveoncommitteeslikethoseatFDA.

This"balance"requirement,asapracticalmatter,cannotbeeasilyappliedtoFDAtechnicaladvisorycommittees,becauseitcontemplatesbalancingknownorassumeddivergentviews.Achievingfairbalance,forexample,onalabor-managementrelationsadvisorycommittee,wouldleadtotheappointmentofrepresentativesofbothindustryandorganizedlabor.Fortechnicaladvisorycommitteesresponsibleforadviceonawideandunpredictablerangeofissues,thesolutionislessobvious.

Inthecaseoftechnicaladvisorycommittees,"balance"shouldbeinterpretedasamixofrelevantscientificdisciplinesandadiversityof

scientificviews.Thecriticalskillsmaysometimesbebroad,atothertimesnarrowanddeep;theymaybetheaddedexperienceandwisdomofseniorfiguresinafield,inadditiontotechnicalexpertise,ortheenergyandwillingnesstoexaminetechnicaldataingreatdetailcharacteristicofjunior"workhorses."Attimes,theymayrequireexperienceinthedesignandconductofclinicaltrials,ortheanalysisandinterpretationofdata,aswellasknowledgeofpatientcare.Atothertimes,elusive"committeeskills"maybeneededtoensuretheeffectiveperformanceofanadvisorycommittee.

Thebalanceofviewpointsrequiredonagivenadvisorycommitteecannotbespecifiedeasilyinadvanceofaspecificmeetingagenda.Consequently,ageneralcommitmenttoexpertiseandexcellence,limitedonlybylegitimate"diversitygoals,"isappropriateasastatementofagencypolicy.TheIOMcommitteebelieves,andcourtdecisionsnowsupport,thatitisultimatelytheCommissioner'sresponsibilitytoseethatsuchbalanceisachieved.

TheIOMcommitteeconsideredthewisdomofrecommendingthat"balance"beinterpretedascommitteemembershipthatincludedrepresentatives(oradvocates)ofspecificconstituencies,irrespectiveofscientificcompetence.Thecommitteerejectedthisconceptonthegroundsthattheprimaryroleofadvisorycommitteesistoprovidetheagencywiththebestscientificinterpretationsandadviceandnottorepresentspecificconstituencies.Furthermore,under"CommitteeOperations"theIOMcommitteerecognizedtheimportanceofinputtoadvisorycommitteedeliberationsfromnonscientificsourcessuchaspatients,industry,andconsumergroupsandconcludedthatsuchinputcanbebestachievedbypublictestimonythatrelatesdirectlytothespecificagendaofanadvisorycommitteemeeting.

Implications

Threeimplicationsflowfromtheabovediscussion.First,theFDA

shouldformallyorganizetherecruitmentofadvisorycommitteemembersinasystematic,aggressiveway(notsimplyinapassivelyformalandvariablyactiveinformalwayasatpresent).Second,recruitmentshouldbeorientedtowardincreasingthepoolofpotentialadvisorycommitteemembersfromwhichcandidatesareselected,ratherthansimplyfillingvacancies.Third,intheabsenceofdetailedspecificselectioncriteria,andtheabilityofthisoranyothercommitteetodesignsuchcriteria,itisimperativethatadvisorycommitteememberrecruitmentbegiventhesustained,continuingattentionofagencyprofessionalsfromtheOfficeoftheCommissionerdownthroughthecenters,offices,anddivisionsresponsibleforproductevaluation.Executivesecretariesshouldbedeeplyinvolvedinrecruitment,asmanyof

themarenow,buttherecruitmentfunctionshouldnotbedelegatedexclusivelytothem.

TheissueofbalancearoseintheIOMcommittee'sIndustryLiaisonPanelrecommendationthatthecompositionofagivenadvisorycommitteebetailoredtotheexpertiserequiredbyaspecificmeeting'sagenda.These"customtailoring"possibilitiesarenowopentotheagencyasaresultoftherecharteringofadvisorycommitteesinallthreecenters.TheadvantagesanddisadvantagesofthisapproacharediscussedindetailinChapters7and8;theyarenotconsideredherebecausetheydonotaffecttherecommendationsonmemberrecruitment.

RecruitmentProcedures

TheFDAcurrentlyrecruitsadvisorycommitteemembersthroughamixofformalandinformalmeans.FACAdefinestheformalprocedure,whichinvolvesanannualFederalRegisternotice(21CFR14.80(b)(1)(i)).Theannualnoticeliststhespecificadvisorycommitteesforwhichitisknownthatvacanciesofvotingmemberswilloccurinthenext12months;alsopublishedisalistofcommitteesforwhichvacanciesarenotexpectedbutmayoccur.TheFederalRegisternoticerequestsnominationsforvotingmemberstofillthesevacanciesandforcandidatesforpotentialvacancies.

Anyinterestedpersonorgroup,includingindustry,maynominateoneormoreindividuals.Theregulationsrequirethatanominationspecifytheadvisorycommitteeforwhichthenomineeisrecommended,includeacompletecurriculumvitaeofthenominee,andstatethatthenomineeisawareofthenomination,iswillingtoserve,andappearstohavenoconflictofinterestthatwouldprecludemembership.AlthoughfewadvisorycommitteenomineesandfewermembersresultfromtheFederalRegisterprocess,itistheonlyexisting

agency-wideformalmechanismforidentifyingandrecruitingapoolofpotentialnominees.

Mostnominationsresultfrominformalprocesses.InterviewswiththeCDER,CBER,andCDRHdivisionandofficedirectorsandexecutivesecretariesidentifiedthefollowingsourcesofnominees:

Recommendationsbyprofessionalsocieties.

ContactsmadebyFDAstaffatprofessionalsocietymeetings.

ReferralsbyformeroroutgoingFDAadvisorycommitteemembers(notlimitedtoaparticularcommittee,FDAdivision,orcenter).

PersonalinquiriesbyanFDAprofessionalbasedonhisorherknowledgeofexpertsinaparticularfield.

Identificationofexpertsinthemedicalliterature.

ManyvariationsexistintheinformalrecruitmentprocessesdiscussedaboveasaresultofthedifferentapproachesofparticularFDArecruitingofficialsandtheabsenceofanyclearagency-widepolicybeyondtheFederalRegisternotice.

TheIOMcommitteerecommendsthattheFDAadoptanagency-widerecruitmentpolicyanddevelopamoresystematicapproachtoseekingnominationsonacontinuingbasisforpotentialadvisorycommitteemembership.Theagencyshouldactivelyseeknomineesfrommanysourcesacademicmedicine,professionalsocieties,othergovernmentagencies,industry,andconsumerandpatientorganizations.Itshouldnotrelysolelyonitsownstaffforsuchnominations.Eachcentershoulddevelopandperiodicallyupdateapoolofqualifiedcandidates,ratherthansimplyseeknominationstofillvacancies.

TheFDAshouldusemultipleapproachestodevelopthesecandidatepools,includinguseoftheNIH-Alcohol,DrugAbuse,andMentalHealthAdministrationcomputerizedfile(aswellasmaintenanceandupdatingofthisdatabase);creationofanFDAcomputerizeddatabase;routinenomineesolicitationofcurrentandformeradvisorycommitteemembers,professionalmedicalandscientificsocieties,medicalschooldeansanddepartmentchairmen,industry,andinterestedconsumerandpublicinterestorganizations.TheFDAshouldexploreavenuesforseekingnominationssuchasannouncementsintheJournaloftheAmericanMedicalAssociation,theNewEnglandJournalofMedicine,andspecialtyjournals.Routinesolicitationcouldbeextendedtoidentifycandidatesforconsultanciesaswellasadvisorycommitteemembers.

Inadditiontoaggressivelyseekingnominationsfrommedicalandscientificsocieties,theFDAshouldseektoenlisttheseorganizationsintheroutinesupportoftheadvisorycommitteenominationprocess.

TheIOMcommittee,addressingitselftothesemedicalandscientificsocieties,urgesthemtoacceptasacontinuingobligationtheidentification

andnominationofindividualstothepoolofpotentialFDAadvisorycommitteemembers.

Externalendorsement,however,shouldconstituteonlyinputtotheFDA;itshouldnotinvolvethereviewofnomineesorselectionofcandidates.

TheNIHOfficeofResearchonWomen'sHealthandsimilarorganizationsshouldberoutinelysolicitedfornominations.Professionalsocietygroups,suchastheWomeninNephrologyoftheAmericanSocietyof

Nephrology,shouldalsobeenlistedinthiseffort.Workinggroupsofwomenandminoritymedicalscienceexpertsshouldberoutinelyaskedtoidentifycandidatesforthepool.

TheIOMcommitteedisagreedwiththerecommendationoftheIndustryLiaisonPanelthat"animpartialgroup,suchastheInstituteofMedicine,[should]reviewproposedadditionstothedrugsandbiologicsadvisorycommitteerostertoascertainthatallindividualsare,indeed,recognizedasexpertsbytheirpeers."(TheLasagnaCommitteeadvancedasimilarrecommendation.)Rather,theIOMcommitteebelievesthattherecruitmentofpotentialcandidatesandthenominationandtheappointmentofmembersarefunctionsthatshouldbeexercisedbytheFDAandthattheagencyshouldbeheldaccountablefortheireffectiveperformance.Itunderstandsitsneedsforadvicebetterthananyexternalorganization.

TheresponsibilityforimplementingthesestepswithintheFDAshouldnotbedelegatedbyneglectsolelytoexecutivesecretaries.Althoughtheseindividualsmaywelldothelion'sshareoftheworkinrecruitingadvisorycommitteemembers,theCommissionerofFoodandDrugsshouldissueclearguidancetoallFDAstaffthattheresponsibilitymustbedischargedatthecenter,office,anddivisionlevelsaswell.

ConsumerMembers

TheFDAseekstwotypesofconsumerparticipationinitstechnicaladvisorycommitteesnonvotingconsumerrepresentativesforitsCDRHadvisorypanelsandconsumer-nominated,technicallyqualifiedmembersforitsCDERandCBERcommittees.

FDAregulationslistasastandardthatanadvisorycommitteemustmeet"wheneverfeasible,orrequiredbystatute,[acommittee]includerepresentativesofthepublicinterest"(21CFR14.40(f)(5)).Although

theregulationsaresilentonthemeaningof"representativesofthepublicinterest,"theylaterstate(21CFR14.80(b)(2))thattheCommissioner

shall,whenrequiredbystatute,andmaywhennotrequiredbystatute,providefornonvotingmembersofatechnicaladvisorycommitteetoserveasrepresentativesofandliaisonwithinterestedorganizations[emphasisadded].Nonvotingmembers(i)Shallbeselectedbytheinterestedorganizations,asprovidedin14.84;technicalexpertiseinthesubjectmatterwithwhichthecommitteeisinvolvedisnotarequirement;and(ii)MaybespecialGovernmentemployeessubjecttotheconflictofinterestlawsandregulations,exceptasprovidedin14.84(e).

Theproceduresfornominationandselectionofnonvotingmembersofstandingtechnicaladvisorycommitteesarespecifiedin21CFR14.84.The"rightsandresponsibilities"ofthesemembersaredelineatedin21CFR14.86.

Therearenononvotingconsumerorindustryrepresentativeswhoserveondrugorbiologicsadvisorycommittees.Inthe1970s,nonvotingconsumerrepresentativesservedondrugadvisorycommittees,buttherewerenoindustryrepresentatives.Thesenonexpertswereoftenunabletoparticipateincommitteedeliberations.Consequently,thethen-BureauofDrugsdecidedonadifferentapproach.Itnowseeksconsumer-nominatedindividualswhoaretechnicallyqualifiedtoserveasvotingmembersofdrugandbiologicsadvisorycommittees.Alldrugandtwooffourbiologicsadvisorycommitteesnowhavesuchmembers.

TheMedicalDeviceAmendmentsof1976requiredthatalladvisorycommitteesorpanelsincludeonenonvotingconsumerrepresentativeandonenonvotingindustryrepresentative.Inaccordancewith21CFR14.80(b)(2),theseindividualsaretorepresentinterestedorganizationsandprovideliaisontotheadvisorycommittee.Thesenonvotingmembersarenotrequiredtobeexpert.TheIOMcommitteeconsideredandrejectedtheextensionofthestatutorilyrequiredCDRHapproachofnonvotingconsumerandindustryrepresentatives,butitalsochosenottorecommendmodificationofthedeviceprovisionofthelaw.

Currently,theFDAOfficeofConsumerAffairs(OCA),whichisresponsibleforseekingconsumerstoserveasadvisorycommitteemembers,solicitsnominationsfromanumberofsources.ItdoessobothfortheCDRHnonvotingconsumerrepresentativesandfortheCDERandCBERconsumer-nominated,technicallyqualifiedvotingmembers.TheOCAisassistedinthisprocessbyaconsortiumof

consumerorganizationsthatidentifiesandevaluatesindividualswhoaretechnicallyqualifiedtoserveonFDAtechnicaladvisorycommitteesandwhoalsohavetiestoconsumerorganizations.Alongwithotherinterestedparties,theconsortiumnominatesindividualsforappointmentbothasqualifiedvotingmembersofCDERandCBERcommitteesandasconsumerrepresentativesofCDRHpanels.Theconsortium'sprincipalroleistointerviewconsumernomineesonbehalfofFDAandevaluatetheirqualifications.

Inseekingnomineesfromconsumerorganizations,theFDAshouldcontinuetosolicitnominationsfromtheconsumerconsortium,butitshouldalsoreachouttootherinterestedparties.InthejudgmentoftheIOMcommittee,thepracticeofallowinganyoutsideorganizationtoscreen(andthustoscreenout)nomineesfromothersourcesisunsound.

Inaddition,theIOMcommitteebelievesthattheconceptof"consumer"bothforconsumer-nominatedmembersandmedicaldeviceconsumer

representativesshouldbeexpandedtoincludepatientsorpatient-nominatedindividuals,whoseviewpointscanbevaluableintheproductevaluationprocess.

TheIOMcommitteebelievesthatconsumerinputtothedeliberationsofFDAtechnicaladvisorycommitteescanbequitevaluable.Itrecognizesthattherearevariouswaystoobtainsuchinput,especiallythroughpublictestimonybyconsumersorpatientsasappropriatetothespecificagenda.

TheIOMcommitteerecommendsthattheFDAactivelyseektechnicallyqualifiednomineesfromconsumerorganizationsandotherinterestedpartiesforallofitstechnicaladvisorycommitteesandpanels.Selection,however,shouldrequireevidenceofscientificandtechnicalqualifications.Thecommitteealsorecommendsthattheconceptof"consumer"beexpandedtoincludepatientandpatient-orientedorganizations.Furthermore,noprivateindividualororganizationshouldbegiventherighttoscreennominationsfromothersourcesonbehalfoftheagency.

AppointmentAuthority

Untilearly1991,theSecretaryofHealthandHumanServicesappointedmembersofFDAtechnicaladvisorycommittees.ThissometimesresultedinnomineeswhomaynothavebeenscientificallyqualifiedorwhowereselectedtobringapoliticallypreferredviewonscientificandregulatorymattersbeforetheFDA.FollowingenactmentoftheFoodandDrugAdministrationRevitalizationActof1990,theCommissionerhasappointedadvisorycommitteemembers,butheremainsunderanobligationtosendnominationpackagestotheOfficeoftheSecretary10daysinadvanceofanyappointment.

TheIOMcommitteebelievesthatvestingpowertoappointcommitteemembersintheCommissionerconstitutesasubstantialstepforwardinbothexpeditingtheappointmentprocessandensuringthatsuchappointmentsareresponsivetothespecificscientificandtechnical

needsoftheagency.

TheIOMcommitteecommendstheOfficeoftheSecretaryforitsconcurrencethattheRevitalizationActvestsformalauthoritytoappointadvisorycommitteemembersintheCommissionerofFoodandDrugs.

AdministrativeResponsibilityforAppointments

TheCommissioner,underhisauthoritytoappointadvisorycommitteemembers,shouldclearlyindicatetoallFDAstaffthatcenterdirectors,office

anddivisiondirectors,andexecutivesecretariesshareresponsibilityforrecruitingqualifiedadvisorycommitteemembers.NominationstotheCommissionershouldcomefromthecenterdirectors.

TheIOMcommitteerecommendsthatthejobdescriptionsoftheFDAcenter,office,anddivisiondirectors,andoftheexecutivesecretariesbeexpandedtoreflecttheirresponsibilitiesforrecruiting,nominating,andrecommendingadvisorycommitteemembers.

6EnsuringCommitteeIntegrityThischapterdealswithtwoimportantissues:HowshouldtheFDAprotectthedeliberationsofitsadvisorycommitteesagainstpotentialfinancialconflictsofinterestonthepartofindividualcommitteemembers?Andwhatstepsshouldtheagencytaketoguardagainstpossibleintellectualbiasofcommitteemembers.Thecommitteedealtwiththefirstoftheseissuesextensively,givingitmoreattentionthananyothersinglesubject.ItwasspecificallyaskedtodosobytheFDACommissionerKessler,becausethisperplexingissuewasaffectingtheagency'sabilitytouseadvisorycommitteesintheevaluationofnewproducts.

Weuse''intellectualbias''torefertoadifferentconcern,namely,thepossibilitythatacommitteemembermaybesoconvincedabouttherightanswertoaquestionofscienceormedicineorsoclearlyidentifiedwithaparticularviewthatheorshemaynotbe(orappeartobe)abletoapproachamatterbeforethecommitteewithanopenmind.Thisconcernissometimesdiscussedunderthelabel"conflictofinterest,"butthecommitteehastreateditseparatelypreciselybecausethefederallawcontainsanelaboratesetofrestrictionsaddressedsolelytothematteroffinancialconflict.

Concernaboutintellectualbias,whichisaddressedinthefinalsectionofthischapter,provestobeequallyperplexingandmayassumecomparableimportanceattheFDA.Butitcameintoclearfocusonlyneartheendofourstudy,andthushasreceivedlessthoroughdiscussionandassessment.ThetopicisacandidateforfurtherattentioninconnectionwiththeworkoftheFDAadvisorycommittees,justasitisnowreceivingextensivescrutinyanddebate

amongpolicymakersandacademicscientistswhoconfrontitinothercontexts.

PotentialfinancialconflictofinterestandintellectualbiasareobviouslycriticalmattersfortheFoodandDrugAdministrationandforthepublic.FortheFDA'sadvisorycommitteestoservetheirpurposes,theirjudgmentsmustbeandmustbeseentobetheproductofthemembers'independent

assessmentofthescientificevidencepresentedtothem.Atthesametime,thecriteriabywhichcandidatesforcommitteeappointmentarescreenedandtheparticipationofappointedmembersisregulatedmustbebothrealisticandfair.Thesecriteriamustprotecttheagency'sprocessesfromrealrisksofinappropriateinfluenceandyetnotdisqualifyorembarrassallscientistsandclinicianswhohavehadanyconnectiontothedrug,biologics,ordeviceindustries.

Thechapterdealsfirstwithfinancialconflictofinterest,indicatingtheoriginsoftheIOMcommittee'sconcernforthisissue,reviewingthestatutoryframeworkthatgovernsthearea,examiningthesystembywhichtheFDAadministerstheconflict-of-interestlaws,analyzingtherapidchangesinthatsystem,includinganumberofcontroversialcasesandsomeencouragingprospectsforimprovement,andconcludingwithanumberofrecommendations.Thechapteraddressestheissueofintellectualbiasinaconcludingsection.

FinancialConflictofInterest

TherealityfacingtheFDAisthatoverthepastdecade,perhapslonger,sponsorsofdrugs,biologics,anddeviceshaveturnedincreasinglytoacademicresearcherstohelpdevelopandtestnewproducts.Thispatternisparticularlyobviousinthebiotechnologyindustry.Consequently,manyofthesameexpertswhoseadvicetheFDAwishestoobtainhaveaffiliationswithregulatedfirms,somewithmanysuchfirms.Therecognizedexpertiseofsuchindividualsmakesthemattractivetobothgovernmentandindustry.

Inaddition,theagencyhassoughtadvisorycommitteeadviceonagrowingrangeofscientificandregulatoryissues,anditisunderpressuretoincreasetheagendaitemsconsideredbyitscommittees.Oneresultofthesecoincidentdevelopmentshasbeentogeneratepotentialfinancialconflictsofinterestforoneormorecommittee

membersinconnectionwitheverycommitteemeeting.

Thetensionsthatresultfromthissetofrelationshipscannotbeeliminatedbutmustnotbeignored.ThegoalsofanysystemformediatingthesetensionsmustbetoprotecttheintegrityoftheFDA'sdecisionsandatthesametimetoallowtheagencyaccesstoessentialexpertise.TheIOMCommitteeisconcernedthatthecurrentsystemformanagingpotentialfinancialconflictsofinterest,asnowadministered,maybejeopardizingthelattergoalwithoutsignificantlyadvancingthefirst.

WhenCommissionerKesslermetwiththeIOMCommitteeonDecember6,1991,heemphasizedhisdesireforguidancein"solving"theFDA'scurrentproblemswithconflictofinterestanditsadvisorycommittees.

TheCommissionerstressedthat,"If[thecommittee]doesnothingelsebutsolveourconflictofinterestproblem,thenwewillhavebeenwellserved."

However,neithertheCommissionerthennortheFDAseniorstafflaterprovidedtheCommitteewithadetailedpictureofthis"conflict-of-interestproblem."Thefulldimensionsoftheproblemwerenotthenappreciated,webelieve,becausetheywereundergoingsignificantchangeevenasthestudybegan.IttookthebetterpartofthisstudyfortheCommitteeanditsstafftogainanunderstanding,whichmaystillbeincomplete,ofthe"problem."

TheIOMcommitteeentertainedthehypothesisthatnumerousmembersoftheFDAadvisorycommitteeswereparticipatingindecisionsinwhichtheyhadsignificantpersonalfinancialinterestswithorwithoutpermissiontodoso.Wedidnotfindevidencethatthiswasthecase.

TheIOMcommitteealsoconsideredthepossibilitythatthe"problem"wasbasicallyoneofperceptionawidelyheldbeliefthatsomeadvisorycommitteemembers,evenifnotinviolationofthelaw,werecompromisedbytheirrelationshipswithindustry.Althoughitisnoteasytomeasurepublicperceptionsonsuchamatter,andwehavenotattemptedtodoso,thecommitteebelievesthisisnotatrivialconcern.Therangeofrelationshipsthatthecurrentlaw,asinterpreted,treatsaspresumptivelydisqualifyingfinancialinterestshasbecomesobroadthatvirtuallynoadvisorycommitteememberisuntouched.ThustheFDAconfrontstheneedtoconsidergrantingconflict-of-interestwaiversforoneormoremembersatalmosteverymeeting,creatingorbolsteringanimpressionthatthesystemisseriouslycompromised.

Inthecommittee'sjudgment,however,thecoreoftheproblem,oratleasttheportiononwhichthoughtfulrecommendationsmightmakeanimmediatecontribution,isinternaltotheFDAandthedepartment.

Theproblemresidesinthesystemforidentifyingpotentialfinancialconflicts,fortheagency'sdeterminingwhethertoseekawaiver(whichisspecificallyprovidedforinthegoverninglaw)thatwouldpermittheparticipationofaspecificmemberinadvisorycommitteedeliberations,andforevaluatingthatrequestforawaiverinaparticularcase.

Asometimesbewilderingnumberoforganizationalentitiesareinvolvedinadministeringconflict-of-interestlaws.TheyareidentifiedinTable6-1onthefollowingpage.

Table6-1TheFDAConflict-of-InterestPlayers

FoodandDrugAdministrationCDER,CBER,andCDRHandtheirrespectivecommitteemanagementstaffsDivisionofEthicsandProgramIntegrity(DEPI)CommitteeManagementOfficeOfficeoftheChiefCounsel,FDADepartmentofHealthandHumanServicesOfficeoftheSpecialCounselforEthics(OSCE),intheOfficeoftheGeneralCounselOtherFederalAgenciesOfficeofGovernmentEthics(OGE)GeneralServicesAdministration(GSA)DepartmentofJusticeOfficeofPersonnelManagement(OPM)OfficeofManagementandBudget(OMB)

TheStatutoryFramework

Afamiliaritywiththecurrentfederalconflict-of-interestlawasitappliestotheFDAadvisorycommitteemembersisnecessarytounderstandthe"problem"thatDr.Kessleraskedustoevaluate.Thekeystatutoryprovisionis18U.S.C.§208,whichispartoftheU.S.CriminalCode,anditappliestoallfederalgovernmentemployees.MembersoftheFDA'stechnicaladvisorycommitteesarecoveredbecausetheyareappointedas"specialgovernmentemployees"(SGEs)whoservethegovernmentonapart-timeorintermittentbasis.*AppointmentasanSGEallowsanadvisorycommitteemembertobepaidandcompensatedforexpenses;italsofacilitatesdisclosuretocommitteemembersofconfidentialorproprietaryinformation,whichisoftenthebulkofthematerialinadrug,biologic,ordeviceapplication.

Section208(summarizedinTable6-2)hastwomainparts.Subsection(a)prohibits(i.e.,makescriminal)agovernmentemployeefromparticipating"personallyandsubstantially"inany"particularmatter"inwhich,tohis/herknowledge,"he,hisspouse,minorchild,generalpartner,organization

*AsdefinedintheFDAStaffManualGuide3118.6,April18,1986,thiscategoryincludes"anyonewhoisretained,designated,appointedoremployedtoperformserviceswithorwithoutcompensationforaperiodnottoexceed130daysduringanyperiodof365dayswhetheronafulltimeorintermittentbasis."

inwhichheisservingasofficer,director,trustee,generalpartner,oremployee,oranypersonororganizationwithwhomheisnegotiatingorhasanyarrangementconcerningprospectiveemployment,hasafinancialinterest."*Thelawdoesnotdistinguishamongtypesoffinancialinterests,norbetweenlargeandsmallorsignificantandinsignificantinterests.Bycommonconsensusitgoeswellbeyondsuchthingsasmonetarypaymentsormarketablesecurities.

Thisbroadreachofsubsection(a)isqualifiedbysubsection(b),whichallowsforthreeexceptions(orwaivers)tothisgeneralprohibition.Subsection(b)(1)allowstheofficialresponsibleforappointinganemployeetograntanexceptiontoparticipateinamatterinwhichtheemployee'sinterest"isnotsosubstantialastobedeemedlikelytoaffecttheintegrityoftheserviceswhichtheGovernmentmayexpect."Subsection(b)(2)authorizesthepromulgationofregulationsthatcategoricallyexceptcertaintypesofinterests.Asthelawwasamendedin1989,thisauthoritycanbeexercisedonlybytheOfficeofGovernmentEthics(OGE).Finally,subsection(b)(3),whichwasaddedtothelawthesameyear,exclusivelyforadvisorycommitteemembers,allowstheofficialresponsibleforappointingacommitteemembertograntanexceptionifhe/sheconcludesthattheagency'sneedforthemember'sserviceintheparticularmatteroutweighsanyriskthatthisimpartialitywillbecompromised.Eachofthesethreewaiverauthoritiesisexaminedingreaterdetailbelow.

*Section208(a)reads:"Exceptaspermittedbysubsection(b)hereof,whoever,beinganofficeroremployeeoftheexecutivebranchoftheUnitedStatesGovernment,...includingaspecialGovernmentemployee,participatespersonallyandsubstantially...throughdecision,approval,disapproval,recommendation,therenderingofadvice,investigation,orotherwise,inajudicialorotherproceeding,application,requestforarulingorotherdetermination,contract,claim,controversy,charge,

accusation,arrest,orotherparticularmatterinwhich,tohisknowledge,he,hisspouse,minorchild,generalpartner,organizationinwhichheisservingasofficer,director,trustee,generalpartneroremployee,oranypersonororganizationwithwhomheisnegotiatingorhasanyarrangementconcerningprospectiveemployment,hasafinancialinterestshallbesubjecttothepenaltiessetforthinsection216ofthistitle."

Table6-2FederalConflictofInterestLawAffectingAdvisoryCommitteeMembers(18USC§208)SectionofStatute BasesforDeterminationofFinancialConflict208(a),from1978EthicsinGovernmentAct

Prohibitsanyfederalofficeroremployeefromparticipatingpersonallyandsubstantiallyinaparticularmatterinwhich,tohis/herknowledgetheemployee,his/herspouse,minorchild,orgeneralpartner,anorganizationinwhichhe/sheisservingasanofficer,director,trustee,generalpartner,oremployee,orapersonororganizationwithwhichhe/sheisnegotiatingfororhasanarrangementconcerningprospectiveemploymenthasafinancialinterest.

TypesofWaivers TestforGrantingWaiver CurrentStatus208(b)(1),from1978EthicsinGovernmentAct

IftheFDACommissionerdeterminesthat"theemployee'sinterestisnotsosubstantialastobedeemedlikelytoaffecttheintegrityoftheserviceswhichtheGovernmentmayexpect."

NowusedbyFDAforconsultants;formerlyusedforadvisorycommitteemembers

208(b)(2),amendedby1989EthicsReformAct

IftheFDACommissioner,onthebasisoftheOGEgovernment-widerule,determinesthatanemployee'sinterest"istooremoteortooinconsequentialtoaffecttheintegrityoftheservices."

OGErulenotyetproposed;agencieswithsucharulethe1989EthicsReformActmaycontinuetouseituntiltheOGEissuesitsrule;theFDAlackssucharule

208(b)(3)addedin1989EthicsReform

IftheFDACommissionerdeterminesforanadvisorycommitteememberthat"theneedforindividualservicesoutweighsthepotentialforaconflictofinterestcreatedbythefinancialinterestinvolved."

NowusedbytheFDAforallcommitteemembers;requiresthattheOSCEandtheOGEoccur.

Subsection208(b)(1)

Subsection(b)(1)permitsthegovernmentofficialresponsibleforappointingtheemployeetoissueanadvancewrittendetermination,a(b)(1)waiver,findingthat"theemployee'sinterestisnotsosubstantialastobedeemedlikelytoaffecttheintegrityoftheserviceswhichtheGovernmentmayexpect."Althoughthislanguageappearstorequireanassessmentofthemagnitudeorcharacteroftheemployee'sinterest,thesectionallowsconsiderationofotherfactors,accordingtotheOGF.Theseincludethemagnitudeoftheemployee'sotherholdings(e.g.,asawayofasking"howmuchwoulditreallymatterifhis/herstockinCompanyXdoubledinvalue?"),thelikelihoodthattheinterestcouldbemateriallyaffectedbyadecisionmadeoradvisedonbytheemployee,andthetypeofinterestinvolved).Thepresenceofsubsection(b)(1)inthelawarguablysupportstheconclusionthatsection208(a)coversanyfinancialinterest,nomatterhowsmall.

Undera1990ExecutiveOrder,anagencythatcontemplatesgrantinga(b)(1)exceptionmustfirst"consult"withtheOGEifitispracticaltodoso.ThisdoesnotnecessarilymeanthattheOGEmustapprovetheagency'sdecision.Any(b)(1)exceptiongrantedwithoutconsultationwith,orevenindefianceofadvicefrom,theOGEwillnonethelessbevalid.However,underDHHSpolicy,anyexceptiongrantedunder(b)(1)doesrequireapprovalbytheOfficeoftheHHSSpecialCounselforEthics.Inotherwords,theCommissionerisnotauthorizedtoapproveawaiverwithoutOSCEapproval.

Subsection208(b)(2)

Subsection(b)(2)ofsection208authorizestheissuanceofregulationsthatcategoricallyexemptcertainclassesoffinancialinterestsasbeing"tooremoteortooinconsequentialtoaffecttheintegrityoftheserviceofthe"employee.Beforethe1989amendmentof(b)(2),individual

agencieshadauthoritytograntsuchcategoricalwaivers;iftheydidso,thoseregulationsremainineffecttoday.Afterthelegislation,however,thepowertoissuesuchregulationswaslodgedexclusivelyintheOGE,andagencieswithouttheserulesarenowprecludedfromissuingthem.SincetheFDAhadno(b)(2)regulationsbeforethe1989amendments,andbecausetheOGEhasnotyetissuedsuchregulations,theFDAhasnobasistogrant(b)(2)waivers.

Thelanguageofsubsection(b)(2)allowsclassexemptionsbasedoneitheroftwocriteria.Theinterestmaybe"tooinconsequential,"i.e.,toosmall,whichimpliesanabsolutecriterionindependentofthelikelihoodthat

aninterestmightbeaffectedor,evenifaffected,mightthreatenanemployee'sintegrity.Alternatively,theinterestmaybe"tooremote,"whichseemstospeaktothelikelihoodthatthevalueoftheinterestwouldnotbeaffectedbytheadvicegivenorbyanydecisionbasedonthatadvice.Pursuingthelatterprong,subsection(b)(2)mightallowtheOGEtoissuearegulationexemptingendowmentholdingsofeducationalinstitutionsfromtheclassofemployerfinancialintereststhatwouldotherwisedisqualifyanadvisorycommitteemember.

TheOGEsaysitisdevelopingregulationstoimplement(b)(2).AsdescribedtotheIOMcommittee,theregulationswillspeaktoboththemagnitudeandtypeofinterestsandtothefunctionsperformed.Theymayinitiallycoveronlyownershipinterestsinbusinessenterprises,e.g.,sharesofstockandperhapsotherequityinterestsuchaspartnerships.

ThusfartheOGEhasnotdeveloped,andmaynotevenhaveconsidered,criteriaforevaluatingtheremotenessofothertypesofinterests,suchasresearchgrants.However,theDHHSSpecialCounselforEthicsisengagedindiscussionswithcounselforotherscience-orientedagenciestoexplorecriteriaforwaivingresearchgrant"conflicts."Anycriteriaultimatelydevelopedbythisgroupwill,ofcourse,stillneedtheOGEapprovalandthenpromulgationasregulations.

Quiteobviously,adoptionofany(b)(2)regulationsismanymonths,andprobablyyears,away.Theprocessrequiresconsultation,beforeanyproposalispublishedintheFederalRegister,betweentheOGEandtheOfficeofPersonnelManagement,theDepartmentofJustice,andtheOfficeofManagementandBudget.AfterpublishingtheproposalasaNoticeofProposedRule-Making(NPRM),theOGEmustallowforpubliccomment,respondtothiscommentbychangesintheproposalorjustificationoftheproposedaction,andproceed

onceagainthroughtheexecutivebranchreviewprocess(OPM,Justice,OMB)todevelopthefinalrule.

Subsection208(b)(3)

Subsection(b)(3),themostsignificantofthewaiverauthorities,andofmostimmediateconcerntotheFDAandtheIOMcommittee,appliesspecificallyandexclusivelytomembersofadvisorycommittees.Underthisprovision,theappointingofficialisallowedtograntawaiverforacommitteemember,whowouldotherwisebedisqualifiedfromdiscussingaparticularmatter,i.e.,aspecificagendaitem,toparticipateindeliberationsonthatmatterwithoutviolatingthelaw."Theexerciseofthisauthoritycallsforajudgmentinwriting"thattheneedfortheindividual'sservicesoutweighsthepotentialforaconflictofinterestcreatedbythefinancial

interestinvolved."Thisexemptionwasaddedtothelawin1989tofacilitatetheparticipationofmembersofexpertadvisorycommittees.

ForantheFDAadvisorycommittee,subsection(b)(3)requiresajudgmentbytheFDACommissionerthatthevalueofacommitteemember'sparticipationoutweighstheriskofconflictofinterestposedbyhisorherfinancialinterest.Itprovidestheframeworkwithinwhichvirtuallyall"waivers"fortheFDAadvisorycommitteemembersareprocessed.Subsection(b)(3)clearlycallsforacontext-specificjudgment,onethattakesintoaccountnotonlytheinterestinvolvedbutthecontributionthatthemembercanmaketothecommittee'sdeliberationsonthematterbeforeit.Thus,thelawpresumablyallowsanassessmentofthemember'sexpertise,familiaritywiththeissues,anduniquenessonthecommitteeinlightoftheissuestobeaddressed.AndexerciseoftheauthoritywouldseemtocallforapersonaljudgmentbytheFDACommissionerorbytheofficialtowhomhedelegatedhisauthority.

TheCommissioner'sauthoritytograntwaiversunder(b)(3)isinadditiontotheauthoritytograntwaiversunder(b)(1)and,iftheOGEregulationsareeverpromulgated,under(b)(2).Thus,ifantheFDAadvisorycommitteememberqualifiedfora(b)(1)waiveroracategorical(b)(2)waiver,therewouldbenoneedtoconsiderhis/hereligibilitytoparticipateunder(b)(3).Ontheotherhand,thisalsomeansthatamemberwhocouldnotqualifyforawaiverunder(b)(1)or(b)(2),e.g.,becausehisorherinterestistoolargeortoolikelytobeaffected,maystillbeeligiblefora(b)(3)waiverbasedonhisorherimportancetothecommittee'sdeliberations.TheFDACommissioner'sauthoritytograntwaiversundersubsections(b)(1)and(b)(3)is,underDHHSpolicies,subjecttoreviewbytheOfficeoftheSpecialCounselforEthics(OSCE);hisauthorityundertheExecutiveOrderrequiresconsultationwiththeOGE.

Thus,theimpactofthislegalregimeontheFDAadvisorycommitteemembers,andontheadvisorycommitteesystem,willbeafunctionofthreefactors:(1)thetypesofinterestsheldtofallundertheprohibitionofsection208(a);(2)thekindandnumberofrelationshipsthatadvisorycommitteemembers(andtheirfamilymembersandemployers)havewithmanufacturersoftheFDA-regulatedproducts;and(3)thespecificissuesonwhichtheFDAseekscommitteeadvice.Importantly,forthisstudy,eachofthesefactorshasbeenundergoingchange.

Itisimportanttoemphasizethat18U.S.C.§208isacriminalstatutewhoseviolationcarriescriminalpenaltiesandwhoseenforcementinvolvescriminalinvestigationprocedures.Accordingly,itisentirelyappropriatefortheFDAandtheDHHStotakeseriouslytheirobligationstoprotectboththeagency'sdecisionalprocessandthemembersofadvisorycommitteesfromcommittingviolations.

Thegrantingofawaivermustbeunderstoodinthiscontext.Whatisbeingwaivedbytheagencyisnotanindividual'sconflict(orpotentialconflict);awaiverisanacknowledgementofaconflict.Instead,whatisbeingwaivedisthecriminalliabilityoftheadvisorycommitteememberthatwouldattachtoparticipationwithaprohibitedinterest.Seeninthislight,thesystemhasanobviousjustification.Somecommitteememberswhohavecomplainedabouttheintrusivenessoftheagency'squestionsordelaysinapprovaloftheirappointmentsortheirparticipation,maynothavefullyappreciatedtheimportanceoftheexerciseinprotectingthemaswellastheagency.

FDA'sAdministrationofConflict-of-InterestRestrictions

Federalconflict-of-interestlawsimpingeontheFDAadvisorycommitteeoperationsattwostages,eachofwhichhasmultiplesteps.Thefirststageiswhenanindividualscientistorclinicianisbeingconsideredforinitialappointmentandinvolvesscreeningprospectivecommitteemembersforpotentialconflictsofinterest.Itisthispointatwhichmostoftheinformationaboutandindividual'spersonal,family,andemployerorinstitutionalfinancialinterestsissoughtandprovided.Theidentificationofpotentialconflictsofinterest,however,doesnotresultinrejectionofmanycandidatesatthisstagesimplybecausethespecificissuesonwhichtheiradvicewillbesoughtarenotgenerallyknown.

Theconflict-of-interestlawsdonotforbidtheFDAtoappointasadvisorycommitteemembersindividualswhohavefinancialrelationshipswiththeFDA-regulatedfirms.Theydoforbidtheparticipationofacommitteememberina"particularmatter"inwhichheorshehasafinancialinterest.Thus,ajudgmentofwhetherthelawappliescanonlybemadebyconsidering,inthecaseofadvisorycommitteemembers,thespecificagendaitemsonwhichtheiradvicewillbesought.Eachcommitteeagendaitem,therefore,presentsan

occasionforevaluatingamember'spotentialconflict-of-interest.

Consequently,agencyanddepartmentaladministrationofconflict-of-interestlawsfocusesonthesecondstage,whenmeetingagendasareknownandthe"particularmatters"tocomebeforethecommitteehavebeenidentified.Thisstageinvolvesidentifyingpotentialconflictsanddeterminingwhentoseekwaivers,preparationofwaivers,andprocessingwaivers.

ScreeningPotentialCommitteeMembers

Therecruitment,nomination,andappointmentoftheFDAadvisorycommitteemembershasbeendescribedinChapter5.ThissectionfocusesonthestageatwhichtheFDAseekstoidentifyaprospectivemember'spotentialfinancialinterestsandtherebyequipitselftomonitorcompliancewithsection208.

Onceanomineeforcommitteemembershiphasbeententativelyapprovedatthecenterlevel,amemberoftheFDAstaff,usuallythecommitteeexecutivesecretaryoramemberoftheadvisorycommitteemanagementstaff,contactstheindividualbytelephonetodeterminehisorheravailabilityandtoidentifyanyfactorsthatmightprecludeappointmentordiminishtheindividual'seffectiveness.Inallthreecenters,thisinitialconversationalsoincludes''prescreening''questionsthatsolicitinformationaboutthenominee'sfinancialinterestsandrelationships.Thepurposeistodiscoverfuturepotentialconflictsofinterest.Atthetimeofthisstudy,theprescreeningformsbeingusedwereseveralyearsoldanddidnotelicitinformationaboutspousaloremployerfinancialinterests.

AlthoughtheFDAhasnoformalthreshold,anadvisorycommitteenomineeatthisinitialstagemaybejudgedtohavesomanyattachmentstothedrug,biologics,ordeviceindustriesthattheappointmentshouldnotbemade.Therationaleisthatnumerouspotentialconflictswilllimittheindividual'sabilitytoparticipateincommitteediscussions.Occasionallyapotentialmemberisruledoutbecausehisorherattachmentstoindustryaresimplytoogreattopassan"appearances"test,eventhoughtheymightnotrequirefrequentdisqualifications.Anydecisionnottopursuerecruitmentofaprospectivecommitteememberbecauseofexcessivepotentialconflictsistakenwiththeconcurrenceofthedivisionorofficedirector.

Followingthispreliminaryscreeningofaprospectivecommitteemember,he/sheissentan"appointmentpackage"thatsolicitsmorespecificprofessionalandfinancialinformation.Althoughtheappointmentpackagessentbythethreecentersdifferinsmalldetails,theyareroughlyequivalent.OfparticularinterestisForm2637theConfidentialStatementofEmploymentandFinancialInterests.Form2637seeksinformationaboutfinancialholdingsorbusinessarrangementswithanyfirm,regardlessofwhetheritisknowntoberegulatedbytheFDA,aswellasemploymentbyand/orconsultantshipswithFDA-regulatedfirms.(CurrentinstructionsforcompletingtheformdonotclearlyspecifythattheSGEshouldincludethefinancialinterestsofhisorherspouse,minorchildren,partner,andanyorganizationinwhichhe/sheservesasofficer,director,trustee,generalpartneroremployee,andofanypersonororganizationwithwhomhe/sheisnegotiatingorhasanyarrangementforprospectiveemployment.)The

prospectiveadvisorycommitteememberreturnsthecompletedappointmentpackage,includingForm2637andacurrentcurriculumvitae.

Uponreceivingtheappointmentpackagefromthepotentialmember,thecenterstaffpreparesanominationpackagethatissenttotheCommitteeManagementOfficewithintheOfficeoftheCommissioner.TheCommitteeManagementOfficeservesastheliaisonbetweenthecentersandtheCommissioner'sofficeandbetweentheFDAandtheDHHS.Atthesametime,relyingonForm2637,anSGEprogramofficerwithinthecenterpreparesalistofexclusions,i.e.,alistofcompanies,products,members,ortopicsthediscussionofwhichthemembermaynotparticipateinbecauseofapotentialconflictofinterestundersection208(a).Theseexclusions,whicharelistedona(HHS)Form410andhencearereferredtoas"410exclusions,"aregeneratedbycomparingForm2637againstanow-outdateddatabaseofFDA-regulatedcompaniessuppliedbytheFDA'sDivisionofEthicsandProgramIntegrity(DEPI)andsupplementedbyfurtherinvestigationsbytheSGEprogramofficers.Copiesofthis"410exclusions"listandthecompletedForm2637arethenreturnedtothenewcommitteememberandarealsosenttothedivisiondirectorresponsibleforthecommitteeandtotheDEPI.

Theinitialdecisiontoappointcommitteemembersislargelytheresponsibilityofthedivisionandorcenterresponsibleforthecommittee.theFDA'sOfficeofChiefCounselisrarelyinvolved.TheCommissioner'sofficeusuallyplaysonlyaformalroleincommitteeappointments.Beyondsigningtheappointmentpackage,theCommissionerhimselfisseldominvolved.NoDHHSconflict-of-interestreviewiscarriedoutatthisstage.NordoestheOGEhavearoleintheinitialappointmentprocess.

Asaresult,theFDAofficialsexercisesignificantdiscretionaboutthe

magnitudeandtypeoffinancialinterestsorrelationshipsthatshouldbeconsideredwhollydisqualifying.theFDAStaffManualGuide,Section3118.2,part6,providesgeneralinstructionsforthescreeningofindividualsforpotentialfinancialconflicts,butitoffersnoconcreteguidanceregardingacceptabletypesormagnitudesoffinancialrelationships.

TheusualresultsoftheFDA's"financialinterestreview"attheappointmentstageare,first,toconfirmthenomination,andsecond,tocreatearecordofthemember'spotentiallydisqualifyingfinancialinterests.Thelatterprovidestheinformationonwhichadeterminationwillbebasedeithertodisqualifyfromparticipationortoseekawaiverwhenaspecificmeetingagendagivesrisetoapotentialconflict.

IdentificationofConflictandDecisiontoSeekaWaiver

Theprocessforreviewofconflict-of-interestcompliancebeginswiththeefforttoidentifyadvisorycommitteememberswhomayhaveapotentialconflictwithrespecttooneormoremattersscheduledfordiscussionatacommitteemeeting.Toidentifysuchindividuals,thecenter'sSGEprogramofficerobtainsfromeachexecutivesecretary:(1)atentativeagenda,usuallytakenfromtheFederalRegisterannouncementofameeting,aswellasanyadditionaltopicalinformationsuppliedbytheexecutivesecretary;(2)thenamesofcompanysponsorsofproductsscheduledforreview;(3)theproductstobediscussedandanycloselycompetingproducts;and(4)alistofotherissuestobediscussed.

Tomaintainacurrentrecordofthefinancial/employmentrelationshipsofcommitteemembers,beforeeachmeetingtheSGEprogramofficersendsanupdateformtoeachmember.ThisandtheoriginalForm2637completedbyamemberarethebasisonwhichexclusionsareidentified.TheSGEprogramofficerdetermineswhich,ifany,committeemembersarepresumptivelyexcludedfromamatterscheduledfordiscussionattheupcomingmeeting.Anexclusionrequiresdisqualificationfromthatmatterunlessawaiverissoughtandapproved.

TheSGEprogramofficer,theexecutivesecretary,thedivisiondirector,andtheofficedirectormayallbeinvolvedindecidingwhethertoseekawaiverforacommitteememberwhohasanexclusion.Thisdecisionisostensiblybasedontheneedfortheindividualmember'sexpertiseandpotentialcontributiontotheplanneddiscussion.However,theimportanceofassuringaquorumatthemeetingisalsooftenafactorinassessingtheneedforamember'sinvolvement.Foracommitteememberwhohasonlyafewexclusions,thedecisiontoseekawaiverappearstobealmost

automatic.

ARapidlyChangingSystem

Throughoutthe1980sthesystemforidentifyingpotentialconflictsofadvisorycommitteemembersand,inappropriatecases,processingwaivers(generallybasedonsubsection(b)(1)ofthelaw)wasinternaltotheFDA.ItalsoappearstohaveescapedcloseoversightbytheCommissioner'sofficeandtherewasrarelyanylegalreviewofwaiverdecisions.Thesystemransmoothly,ifinretrospectsomewhatunprofessionally.

Butlatereventsrevealedthattheinsulationfromhigh-leveladministrativeandlegaloversighthadresultedinneglectatboththecenterlevelwherenecessaryinformationaboutcommitteememberinterestwasoftennotsolicitedandatheadquarterswhichcontinuedtoadheretooutdated

internalguidelines.Importantly,theresponsibletheFDAunits,forsomeperiodoftime,ignored,perhapsunknowingly,theimportantchangesCongressmadeintheconflict-of-interestlawin1989.Absentlegalguidance,theycontinuedtooperateonproceduresbasedonthenow-outdatedpre-1989law.Specifically,theydidnotmodifytheproceduresregardingtheeligibilityofadvisorycommitteemembersforsubsection208(b)waivers.

Thissystembegantocomeundermountingstressin1991,shortlyafterDr.KesslerwasappointedCommissionerofFoodandDrugs.KesslercametotheFDAwithacommitmenttorestoretheagency'sintegrity,ontheheelsofascandalinvolvinggenericdrugapprovals.Healsoprofessedacommitmenttoseektheadviceofthenation'sbestscientistsandsupportedtheFDA'slongrelianceonexpertadvisorycommittees.

NotableControversies

Inthelatterhalfof1991,however,theagencybroughtbeforeseveraldifferentadvisorycommitteesaseriesofhigh-profileanddeeplycontroversialissuesinvolving,forexample,theapprovabilityofanewdrugforAlzheimer'sdisease,thecontinuedmarketingofsilicon-gelbreastimplants,andthealledgedsuicide-inducingpropertiesofthenation'sbest-sellingantidepressant.ThesemeetingsbroughttheconflictofinterestoftheFDAadvisorycommitteemembers,andtheagency'ssystemforcontrollingit,underunprecedentedscrutiny.

ThescrutinyoccurredpartlybecausetheFDAofficialsthemselvesrealizedthatthecontroversialnatureoftheissuesrequiredthattheagencytakeprecautionstoassurecommitteeintegrity.Evenso,outsidepartieswhoweredisappointedbytheagency'sdecisionsoftenchallengedtheobjectivityofadvisorycommitteemembers.theFDA'scriteriaandproceduresforidentifyingpotentialfinancialconflictsandprocessingwaiverscaughttheattentionnotonlyoftheCommissioner

andhisadvisersbutofotherofficialsinsideandoutsidetheagency.

Scrutinywasalsoheightenedbecausethesecontroversialcasesoccurredinaverycompressedperiodoftime,fromlate1991throughmid-1992.Inmanyways,theywereunrelatedtoeachotherinsubstance.Butthecumulativeeffectproducedbytheirrapid,sequentialoccurrencewassubstantiallygreaterthanitwouldhavebeeniftheyhadbeenspacedoveralongerperiod.

Theeventsof1991and1992exposedthedimensionsoftheconflict-of-interest"problem"onwhichDr.KesslerurgentlysoughttheIOMCommittee'sguidance.Accordingly,weprovideachronologicalaccountoftheseadvisorycommitteemeetings.

PsychopharmaceuticalDrugsAdvisoryCommittee:MeetingofSeptember20,1991

ThismeetingwascalledtodiscussanincreasednumberofreportsofadversereactionslinkinguseofthedrugProzac(fluoxetine),manufacturedbyEliLilly,andotherantidepressantstosuicidalideationinclinicallydepressedpersons.Theobjectivewastoconsidertheadversereactiondatatodeterminetheexistenceofcausalitybetweenthesedrugsandsuicidalorotherviolentbehavior.AlthoughitwasapparentlynottheFDA'splantoinvitediscussionofspecificproductsubmissionsortosolicitadviceonremedialactionsthatwouldimpactmanufacturersofProzacorotherantidepressantdrugs,theagencyrealizedthatthecommitteecouldpotentiallyrecommendactionthatmightbearontheuseofthesedrugs.

Accordingly,becausetheadvisorycommitteemightrecommendactionsthatcouldaffectmanufacturersofantidepressants,CDER'sOfficeofConsultantsandAdvisorsdecidedtorequestwaiversforallcommitteememberswhoreportedanyfinancialinterestwithanymanufacturerofantidepressantdrugs.Therefore,waiversweresoughtforfourmembersandtwoconsultantswhowerefoundtohaveanexclusion(s).

Theexclusionsforthememberswere:

Member#1:ThememberwasinvolvedinMerck'sPhaseIVstudyoftheclinicalsafetyandefficacyofanewneurolepticdrug(remoxipride).Thestudywasfundedat$95,000fortheperiodfromFebruary1991toJanuary1992.Thememberreceivednopersonalremunerationfromthestudy.

Member#2:ThememberwastheprincipalinvestigatorunderagrantfromSandoztostudyHLAphenotypesandvulnerabilitytoClozapine-inducedagranulocytosis.Thegrantcoveredtheperiod

fromSeptember1988toJanuary1999.Thehospitalthatemployedthecommitteememberwasnamedasthegrantrecipientof$65,790.Inaddition,themembergivesSandoz-sponsoredlecturesonanadhocbasisatvariousprofessionalsocietiesandmedicalinstitutionsandispaidforthesebySandoz.

Member#3:ThememberhadareportedfinancialinterestinBristolMyersSquibbbecausehisorherspouseisemployedbythisfirm.

Member#4:Themember'semployer,anacademicinstitution,hadvariousresearchgrantswithantidepressantmanufacturers.Theseincluded:(1)agrantofapproximately$100,000fromA.H.Robinsforwhichthememberwasaco-investigatoronastudyofZacoprid;(2)agrantofapproximately$100,000fromWyeth-Ayerstforwhichthememberwastheprincipalinvestigator(PI)onthestudyofZalosperone;

(3)twopendingstudiestobefundedat$100,000eachfromEliLilly,themakersofProzac,onedealingwithdepressantsandtheotherwithsexualdysfunction;(4)agrantofapproximately$100,000fromSmithKlineBeechamforwhichthememberwasthePIonastudyofParoxetine;(5)agrantofapproximately$100,000fromPfizerforwhichthememberwasthePIonastudyofTandosperone;and(6)agrantofapproximately$100,000fromCiba-GeigyforwhichthememberwasthePIinanongoingresearchstudyofantidepressantdrugs.

TheFDAprocessforgeneratingwaiversforthismeetingdifferedfromthepracticethathasrecentlyevolved.Theidentificationofexclusions,theneedforawaiver,thesufficiencyofthedocumentationjustifyingawaiver,andtheapprovalofthewaiverwerehandledentirelywithintheFDA.Thefollowingstepswereinvolved:

1.ExclusionswereidentifiedforcommitteemembersandconsultantstheweekofSeptember12,1991.

2.(b)(1)waiversrequestswereinitiatedtheweekofSeptember1217.

3.TheDEPIsignedoffontherequestfor(b)(1)waiversonSeptember17,1991.

4.Atthetimeofthemeeting,theCDERDirectorhadapprovedwaiversformembersandconsultantswiththeconcurrenceoftheAssociateCommissionerforManagement.

5.ThecommitteemeetingwasheldonSeptember20,1991.

Threedaysafterthemeeting,onSeptember23,1991,theCitizen'sCommissiononHumanRightswrotetotheFDAallegingthatcertainmembersofthecommitteehadconflictsofinterest.Theirspecificchargewasthatanumberofindividualsonthecommitteeaswellas

severalconsultantstothecommitteehadinterestsincompaniesthatmanufactureantidepressantdrugsorwereconflictedwithrespecttothe"psychiatricindustry"becausetheywerepsychiatrists.

Inreplytothesecharges,theFDAnotedthat18USC§208(b)(1)permitswaiverswhentheappointingauthoritycertifiesthatthe"interestisnotsosubstantialastobedeemedlikelytoaffecttheintegrityoftheserviceswhichtheGovernmentmayexpectfromsuch...employee."AtthetimeoftheSeptember1991meeting,theFDAprogramstaffswereoperatingundertheoldconflict-of-intereststatutes,ignoringsubsection(b)(3),whichhadbeenaddedtothelawbytheEthicsReformActof1989.

Thefactsthatthewaiverprocessoperatedwithoutlegaloversightandwasoblivioustothelatestchangesintheconflict-of-interestlawsuggestedthattheprocesswasinsevereneedofscrutiny.Therelianceonsubsection

(b)(1),insteadofthemoreliberal(b)(3),seemeddifficulttoreconcilewiththemembers'andconsultants'interestsasdescribedabove.

GeneralandPlasticSurgeryDevicesAdvisoryPanel:MeetingofNovember1213,1991

ThepurposeofthemeetingofNovember1213,1991wastoreviewsevenpremarketapprovalapplicationsfrommanufacturersofsilicone-gelbreastimplants.Theagencywishedtoelicitrecommendationsregardingthecontinuedmarketabilityofthesedevices.

TwentyvotingmembersandconsultantsweretoattendtheNovember1213,1991,committeemeeting.Theprogramstaffidentifiedthreevotingmembersandtwoconsultantswhohadexclusionswithrespecttomattersthatwouldbediscussed.

Members#13:ThreememberswerepracticingplasticsurgeonswhoweremembersoftheAmericanSocietyofPlasticandReconstructiveSurgeons,Inc.SincetheSocietyhasassesseditsmembershipapproximately$4milliontocounteractthenegativepublicityonbreastimplantsgeneratedbytheFDAmeetingandthemedia,thecenterdecidedthattheplasticsurgeonshadapotentialconflictofinterest.Consequently,(b)(1)waiversweresoughtfortheseindividuals,butnotforfullparticipation;rathertheyweretobeallowedtoparticipateinthediscussionasnonvotingconsultants.

Consultants#1and2:TwoconsultantstoCDRHhadindicatedthattheyhadservedas"expertwitnesses"incasesinvolvingwomenallegedlyinjuredbysiliconebreastimplants.Waiversweresoughttoallowthemtoparticipateinthemeetingasnonvotingconsultants.

ThewaiverprocessfortheNovember1991meetinginvolvedtwo"new"layersofreview.Giventheexpectedpublicattentiontothis

meeting,theCDRHtookgreatcareinchoosingmembersandsolicitedlegaladvicefromtheFDA'sChiefCounsel'sOffice,whichhadnotpreviouslybeeninvolved.Inaddition,theOfficeoftheSpecialCounselforEthics(OSCE)becameinvolvedinthesediscussionsand,forthefirsttime,reviewedtheproposedwaiversforlegalsufficiency.ThewaiverreviewandapprovalprocessnowincludedtheCDRH,theDEPI,theFDAChiefCounsel'sOffice,theCommissioner,andtheOSCEforthedepartment.

Theagencywaswellawarethatthesubjectofsiliconebreastimplantswasattractingintensepublicscruity.Inanunusualmove,theCDRHscheduledover100interestedpartiestogivetestimonyintheopenpublicsessionofthemeeting.Themeetingwascoveredandreportedby

newspapers,television,andthetradepress.CommitteememberssatthroughthemeetingfacingtelevisioncamerasandKleiglights.

Meetingarrangementsprovokedsharpnegativereactionsfromthemembersoftheadvisorycommittee.TheregularchairoftheGPSDevicesPanel,Dr.G.Warden,amale,wasreplacedforthismeeting(andforaFebruary1992follow-onmeeting)bythefemalechairoftheOB-GYNDevicesPanel.Oneapparentreasonforthiswastoassureprominentrepresentationbyfemales.Asadirectresultofthesetwomeetings,Dr.Wardenresignedfromthecommittee.InahighlypublicizedmovebeforetheFebruarymeeting,theFDAstrippedthevotefromanotherstandingpanelmemberbecauseofstatementsgiventothemassmedia,whichpromptedtheagencytoquestionwhetherhecouldrender,orwouldbeseenascapableofrendering,objectiveadvice.

ArthritisDrugsAdvisoryCommittee:MeetingofDecember6,1991

ThepurposeofthismeetingwastodiscusstheTherakosNDAforacombinationdrug-devicetreatmentofsclerodermausingmethoxypsoraleninconjunctionwithphotopheresis.TheNDAinvolvedthedrug,sincethedevicehadpreviouslybeenapprovedforarelatedapplication.Thisapplicationattractedconsiderableattentionbecausethedrug'ssponsoranditsclinicalinvestigatorschargedthattheFDAhadmishandledthereview.TheHouseSubcommitteeonOversightandInvestigationsoftheEnergyandCommerceCommitteelaterheldaverycriticalhearingontheissueandhastakenacontinuinginterestintheepisode.

Thesalientconflict-of-interestissuesinvolvedCDER'sdecisionnottoseekawaiverforaconsultantwhowas(later)allegedtohaveaconflictofinterest.Adescriptionoftheeventsofthissituationfollows.

Afterhistermexpired,theformerchairofCDER'sArthritisDrugsAdvisoryCommitteecontinuedasaconsultanttothePilotDrugEvaluationStaff.Inthatcapacityheservedastheprimaryclinicalreviewerofthemethoxysporalen/photophoresisNDAmentionedabove.Atthesametime,hewasinvolvedinpreliminarynegotiationstoparticipateinastudyofD-penicillamine,analternativetherapyfortreatmentofscleroderma.ThisstudywasfundedbytheFDA'sOfficeofOrphanDrugs.Theconsultantwastoserveasprincipalinvestigatoratoneofseveralcentersparticipatinginamulticentertrial.ThegrantfortheD-penicillaminestudywouldnothavebeenmadedirectlytotheconsultant'semployer,auniversity,buttoanotherorganization.Theconsultantwouldhavereceivednocompensationfromthegrant.

CDERdecidednottoseekawaiverfortheconsultantbecauseitconcludedthat,underprevailingtheFDApolicy,hehadnoconflictofinterest.Thisdecisionwasnotsubjecttoanylegaloversight.TheconsultanthadnofinancialinterestintheD-penicillaminestudy,orinthecompanythatmanufacturedit,orinanycompetingfirm.AllfundingfortheproposedstudywouldhavebeensuppliedbytheFDA.

Subsequently,Therakosanditsclinicalinvestigatorschargedthattheconsultanthadbeenbiasedagainstthemethoxypsoralen/photophoresisapplicationbecausehewaslikelytobeinvolvedinresearchonarivaltherapy.TheirclaimwasthatiftheTherakosapplicationhadbeenapproved,theconsultant'sownresearchwouldhavebeenthreatened.TheallegationprecipitatedaninvestigationbytheDHHSOfficeofInspectorGeneralintopossibleviolationsofthelaw.

Inthiscase,theFDA'spoliciesfailedtoprotectitsconsultantfromacriminalinvestigation.Beyondthepersonaltribulationsoftheconsultant,manysuchincidentswouldsurelyimpairtheagency'sabilitytoattractcapableclinicians/researcherstoserveonitsadvisorycommittees.

BloodProductsAdvisoryCommitteeMeeting:December1213,1991

ThepurposeofthemeetingwastodiscussaProductLicenseAgreement(PLA)fortworecombinantfactorVIIIproducts.ThesponsorsofthePLAswereBaxterHealthcare/HylandDivisionandGeneticsInstitute,itsdevelopmentpartner,andMilesLaboratories,adivisionofBayer,A.G.

Threecommitteememberswereexcludedforspecificportionsofthemeeting:

Member#1:ThismemberwastheprincipalinvestigatoronastudyofBaxter'srecombinantfactorVIIIproduct.Inaddition,asa

consultanttoBaxterheoccasionallylecturedabouttheVIIIproduct,forwhichhereceivedanhonorariumandtravelexpenses.CBER'sDivisionofTransfusionSciencesdidnotrequestawaiverforthismember.

Members#2and3:Thesemembershadan(unspecified)interestintheGeneticsInstitute.Accordingly,theDivisionexcludedthemfromdiscussionoftheBaxterproduct.Nowaiversweresoughtfortheotherpartsofthemeeting,inwhichtheyparticipated.

ThisrevealsaheightenedsensitivitytoconflictofinterestwithintheFDA.Largelybecauseofthisincreasedsensitivity,theCBERdivisionelectednottoseekwaiversforthethreecommitteemembers.However,duetoamiscommunicationwithintheprogramstaff,Member#1wasnot

informedofhisexclusionuntilthedaybeforethecommitteemeeting.BelievingthathisparticipationinBaxterstudiesshouldnothavedisqualifiedhimfromparticipationinthediscussion,themembervigorouslyprotestedtotheCommissioner.

BiologicsResponseModifiersAdvisoryCommittee:MeetingofJanuary1617,1992

ThepurposeofthismeetingwastoreviewtwoPLAs:(1)Proleukin(Interleukin2),madebyCetus/HoffmanLaRoche,and(2)Oncoscint,madebyCytogen.Twocommitteemembers,oneofthemthechair,hadexclusionsfortheProleukindiscussionduetotheirconsultingactivitieswithHoffmanLaRoche.

Bythetimeofthismeeting,theFDA'ssystemforprocessingwaivershadexpandedtoincludedthisCBERprogramarea,theDEPI,theFDAChiefCounsel'sOffice,theDHHSOfficeofSpecialCounsel,theOfficeofGovernmentEthics,andfinally,theCenterDirector'sOffice.Theprocesshadbecomebothcontentiousandtimeconsuming.ThelatediscoveryofabusinessrelationshipbetweenCetusandHofftnanLaRochetriggeredaneleventh-hourreevaluationofthemembers'interests.Thechronologyinthiscasefollows:

1.ExclusionswereidentifiedbyCBERcommitteemanagementstaffonJanuary13,1992,4:00p.m.,foranadvisorymeetingscheduledforthe16th.

2.WaiverrequestswereinitiatedbyCBERcommitteemanagementstafffortwomembersonJanuary14.

3.Becauseofthescheduledmeetingdate,thewaiverrequestswerefaxedsimultaneouslyonthe14thtotheDEPI,theFDAChiefCounsel'sOffice,andtheOfficeoftheSpecialCounselforEthics.Telephoneconferencecallswereheldthatdaytoexpeditetheprocess.TheChiefCounsel'sOfficesoughtadditionaldetails

ofthefinancialinterestsofthetwomembers.

4.OnJanuary15,uncomfortablewiththe"appearanceofarush"ingettingthewaiversapproved,theDHHSSpecialCounselofferedacompromise.Thetwocommitteememberscouldbegrantedwaiverstoparticipateandvote,butthechairofthecommitteewould,inexchange,berequiredtorelinquishthechairmanshipforthisportionofthemeeting.Accedingtothis"compromise,"theCBERcommitteemanagementstaffaskedthecommitteechairtostepdownforthediscussionoftheCetusPLA.

5.TheCBERDirectorsignedthewaiverrequestsonJanuary16,justafewhoursbeforethemeetingwasscheduledtobegin.

Thiscaseillustratesseveralproblems.First,thewaiverprocesshadbecometoocumbersometocopewiththelastminute''discovery''offinancialconnections.Giventhecomplexrelationshipsbetweencompanies,suchlastminutediscoveriesmaynotbeaninfrequentoccurrence.Second,programofficesandlegalreviewersdisplayednoinclinationtocooperate,leavingbothfeelingsofdistrustandfrustration.Third,thelegalbasisforconditioningthechair'sfullwaiveronhisacceptanceofadiminishedroleisunclear.

DermatologicDrugsAdvisoryCommittee:MeetingofApril10,1992

Webelievethiscommitteemeetingwasoneofthefirstinstancesinwhichwaiversforinterestsheldbyemployers(universityorotherinstitutions)ofcommitteememberswererequired.InanApril6,1992,memorandumtotheCDERcommitteemanagementoffice,theDEPIadvised:"Anadditionalconcernistherequirementunder(sub)section208(a)thatthefinancialinterestsofanSGE'semployer,andotheraffiliationsbeconsidered,andmustbeaddressedinthewaiver.ThepotentialimpactoftheseentitieshasnotalwaysbeenconsideredinwaiverswhichwererequestedpriortoFebruary,1992.Therefore,underthenewrequirementseachwaiverrequestmustaddresstheseconcerns,beforetheyareforwardedtotheOSCE.WehavelearnedthattheOfficeofGovernmentEthicsplanstodraftaclasswaiverforalluniversityaffiliations.Untilthisclasswaiverhasbeenapproved,each18U.S.C.208waivermustaddresstheSGE'suniversityaffiliations."Thiswasthefirstwrittennoticethatthecentersreceivedregardingthischangeinpolicy.

Consequently,onApril9,onedaybeforethescheduledDermatologicCommitteemeeting,theCDERcommitteemanagementofficewasfacedwiththetaskofpreparing11(b)(3)waiversformemberswho

wereemployedbyuniversities.ThewaiversweresignedbythecenterDirectorandDEPIonthe9th,andweredeliveredtotheCommissioner'sOfficethenextmorningforhissignature.

Therequirementofwaiversforuniversityaffiliationsgreatlyaffectedthecenter'sworkload.Sincemostadvisorycommitteemembersareaffiliatedwithuniversities,whosehospitalsdispenseproductsmanufacturedbyvariouscompanieswithapplicationsbeforetheFDA,fromthispointonnearlyeverymemberrequiredawaivertoparticipate.BytheendofJune,suchwaiversaccountedforroughlytwo-thirdsofallwaiveractivitywithinCDER.

CirculatorySystemsDevicesPanel:MeetingofMay11,1992

ThepurposeofthemeetingwastoreviewaPMAforacoronaryatherectomysystem.Thiscaseisadramaticillustrationofhowmiscommunicationamongtheofficesinvolvedinthewaiverprocessdelayedconsiderationofasmallmanufacturer'sapplication,probablywithseverefinancialconsequencesforthecompany.Theeventsleadinguptothemeetingare:

1.InearlyMarch1992,theCDRHprogrammanagementofficewasnotifiedofapanelmeetingscheduledforMay11.

2.OnMarch13,exclusionswereidentifiedbythecommitteemanagementoffice,andonthatbasis,13(!)waiversrequests(for8membersand5consultants)wereprepared.OneoftherequestedwaiverswasforamemberwhohadbeendesignatedastheleadreviewerfortheatherectomycatheterPMA.Thepresumptive"conflict"forthismemberwasthathisinstitutionwasinvolvedinthecoordinationalarge-scalerandomizedtrialevaluatingcoronaryatherectomyversusballoonangioplasty(knownastheCAVEATTrial).Thistrial,fundedbyDevicesforVascularInterventionandEliLillyinagrantfor$2.3million,isaprospectiveclinicaltrialinvolving35clinicalsitesthroughouttheUnitedStatesandEurope.

3.OnMarch24,thesponsoringcompanieswerenotifiedthattheirapplicationswouldbereviewedonMay11.ThenoticeofthemeetingwaspublishedintheFederalRegisteronApril20.

4.ByApril21,waivershadnotbeenapprovedformanypanelmembers.TheCDRHDivisionofCardiovascular,RespiratoryandNeurologicalDevicesinformedthecommitteemanagementofficethatthemeetingmighthavetobecancellediftherequestedwaiverswerenotapprovedbyApril24.

5.OnApril24,thecenter'scommitteemanagementofficeconveyedverbalclearancetotheprogramarea,whichpermittedmailingofallmeetingmaterialtocommitteemembersforreview.

6.OnFriday,May8,CDRH'scommitteemanagementofficewasinformedbytheDHHSOfficeoftheSpecialCounselforEthicsthatnowaiverwouldbeallowedforthememberwhohadbeenassignedasleadreviewerfortheatherectomycatheter.Unsuccessfulattemptsweremadetoreversethedecisionandafinalrefusaltograntawaiverwasreceivedat3:45p.m.ThecenterdecidedtocancelthereviewoftheatherectomycatheterPMAduetotheinabilitytofindasubstitutereviewerovertheweekendbeforetheMondaymeeting.

7.LateonFriday,thesponsorofthePMAandthecommitteememberswerenotifiedofthischangeintheagenda.Thesponsorwasoutragedandthreatenedtotakeallmeasurespossibleto"exactcompensation"forthedelay.

8.OnSaturday,theCommissioner'sofficecontactedthesponsortoallowittopresentitsapplicationtothecommittee.Anattemptwasmadetonotifycommitteemembersofthischangeinagenda,butmostcouldnotbereached.

9.AtthecommitteemeetingonMonday,May11,themembersweretoldthatthePMAhadbeenrestoredtotheagenda.Thechairpolledthememberstodeterminewhethertheyfeltcomfortableproceedingwiththereview.Allofthemembersfeltthattheywereinadequatelypreparedandvotedunanimouslytopostponereviewoftheapplication.

Theproblemsevidentinthiscasespeakforthemselves.Thereviewingdivisionapparentlyassumedthattheleadreviewer'spresumptiveconflictwaswaiverable.However,theSpecialCounselforEthicsOffice,exercisingindependentjudgment,determinedthathisinvolvementinresearchonacompetingtechnologyprecludedawaiver.Thisjudgmentwascommunicatedonlyattheeleventhhour,disruptingthecommitteemeetingandfrustratingthesponsor'shopesforproductdevelopment.TheissueofwaiversforcommitteemembersinvolvedinresearchoncompetingtechnologiesstillpresentsproblemsfortheFDA.

Theprecedingcasesillustrateseveraloftheconfusingandfrustratingeventsthathaveoccurredwithinthecenters'respectivecommitteemanagementofficesbetweentheperiodfromSeptember1991andJune1992.Therapidlyescalatingscrutinyofpotentialconflicts,thenumberofpartiesinvolvedinthewaiverprocess,theexpandingcriteriaforidentifyingpotentialconflicts,andthezealwithwhich

thesecriteriawereappliedcombinedtowreakhavocintheFDA'sadvisorycommitteeoperations.

AnalysisofWaiverProcessing

Tofullyappreciatetheimpactoftheseevents,itisinstructivetolookatthewaiverprocessthatthecentersfollowedduringthisperiod.Beforethefallof1991,thewaiverdraftingandreviewprocesswasentirelyinternaltotheagency.Thecenters(committeemanagementstaff)decidedwhenawaiverwasnecessaryandwrotethejustificationforthewaiver.DEPIreviewedthewaiverjustificationandusuallyrecommendeditsapprovalwithoutchange.WaiverswereapprovedbytheauthorityofthecenterdirectorwiththeconcurrenceoftheAssociateCommissionerforManagement.Therewasnolegaloversightofthisprocess.

BytheendofJune1992,draftingandreviewofwaivershadbecomeamuchmorearduousprocess.Eachwaivermustnowstatethepreciseexclusionsforwhichthememberisbeingwaivedaswellasprovidingaclearexplanationofthe"need"fortheindividual'sparticipation.Incurrentwaiverstheexclusionsarelistedinextremedetail;e.g.whatpercentageoftheindividual'sincomeisrepresentedbyaparticularfinancialinterest.Additionally,the"needforthemember"portionofthewaiverisbeingreviewedmorecritically;inthepast,statementstotheeffectthatamemberwasapreeminentscientistandamemberofthecommitteegenerallysufficedasarationale.

Averyseriousflawinthecurrentwaiverprocessisthelackofrelevantwrittenstandards,atanylevel,forgrantingwaivers,i.e.,forrankingpotentialconflicts,fordecidingwhetheramember'simportanceoutweighsanyriskofconflict,orforexplainingdecisionstogrant(ordeny)waivers.Thishasresultedinacustomized,time-andresource-consumingprocessofcase-by-casediscoveryandrationalization.Notinfrequently,theprocessleadstoburdensomeiterations;onenewdiscoveryraisesseveralmorequestionsaboutotherpossiblefinancialconnections,requiringthatthecommitteememberbecontactedagainandaskedtoprovidemoreinformation.

Alikely,buthardtoquantify,costofthissystemisthedisillusionment,andperhapsultimatewithdrawal,ofadvisorycommitteememberswhoresentthedisclosureofpersonalfinancialinformation,therepetitiousrequestsformoreinformationandclarification,theeleventh-hourdecisionabouttheireligibility(ordisqualification)forparticipation,andtheresidualinnuendothattheycannotbetrusted.

Anotherconsequenceofthelackofwrittenstandardsforapprovingwaiversisthattheprocessoftenbecomesahurried,sometimesfrantic,rushtocompletethewaiverrequestjustbeforeanadvisorycommittee

meetingisscheduledtobegin.Thisfrustratesallparticipants.TheFDAstaffresponsibleforinitiatingwaiverrequestsaremostfrustratedbecausetheyviewtheprocessasobstructingprogramgoalsandbecausedecisionsgetmadelate,oftenlongaftertheirinvolvement,andwithoutclearexplanation.Thoseneartheendoftheprocessdisplaylessfrustration,savewiththosewhoinitiatewaiverrequests,becausetheyhaveverydifferentprogramobjectives,suchaspreservationofdepartment-orgovernment-wideuniformity,avoidanceofembarrassmentfortheadministration,andmaintenanceofdecisionalintegrity.

Evenifoneexaminesanumberofpriordecisions,aswehavedone,thecurrentoperationalcriteriaforapprovingawaiverareelusive.Thestatuterequiresajudgment,ostensiblybytheCommissioner,thatacommitteemember'sparticipationinaparticularagendaitemisimportantenoughtojustifythepotentialconflict.Recently,thisdecisionhasbeenmadeatthe

leveloftheOSCEortheOGEandtheOSCE,severallevelsremovedfromresponsibleauthority.

Ontheotherhand,theparticipationoftheseofficesinthewaiverprocesshasintroducedaleveloflegalrigorthatwaslackinginthepre-1991process.Thedesiretoconformexistingpracticestothe1989lawiscommendablegiventhestakesinvolved,althoughthezealwithwhichthistaskhasbeenapproachedmayhaveobscuredtheneedtofashionanorderlyandpredictablesystemfordeterminingwhetherwaiversareneededandjustified.

TheOSCEandtheOGE,basedonguidancefromtheDepartmentofJustice,haveinterpretedSection208asreachingaverywiderangeofinterests.Thestatutehasbeeninterpretedasembracingnearlyallpersonal,spousal,minorchild,andemployerfinancialrelationships,regardlessofsize,aspresumptivelydisqualifying.Forexample,amember'semployermayhaveafinancialrelationshipwiththecompanywhosesubmissionwillbethesubjectofthecommitteemeeting.Becausethereisnothresholdlimitonthesizeorremotenessofsuchemployerconnections,thepracticaloutcomeisthateverymemberwhoisemployedbyauniversitywhosehospitaldispensesdrugsmadebythemanufacturerwhosesubmissionisunderreviewrequiresawaiver.Similarly,waiversarerequiredformemberswhoseinstitutionmayownstockin,orreceivedanendowedchairfrom,themanufacturer.

Thereachofthelawhasalsospreadwithimaginativeanalysisintothematterofcompetingproductsandtechnologies.TheOSCEhastakenthepositionthatamemberwithaconnection,e.g.,aresearchgrant,withacompanythatisdevelopingatechnologythatcouldbesubstitutedfortheproductbeforehisorhercommitteewillrequireawaivertoparticipate.Rigorousimplementationofthistheorymeans,forexample,thatifadevicependingapprovalwillbeofferedtotreat

thesameconditionasanexistingdrug,membersofthedevicepanelmustbescreenedfortheir,theirspouse's,andtheiremployer'sfinancialrelationshipwiththemaker(s)ofthosedrugs.

TheOSCEandtheOGEhavealsodisplayedconcernabout"appearances"ofconflictofinterest.Intheproposedregulations(56FR33778)thatfollowedExecutiveOrders12674and12731andtheEthicsReformActof1989,theOGEannouncedthatevenemployees(includingSGEs)whowouldnotviolatethelawiftheyparticipatedmaynonethelessbedisqualifiedfromparticipatingbecauseofanapparentconflict.Usually,concernsaboutappearancesofconflictsurfaceinconnectionwithhigh-profileadvisorycommitteemeetingsinwhichpotentialpresscoveragemaycausetheOSCEtobemorecautiousthanusual.Insomesuchcases,theOSCEhasinsistedon"restricted"waivers:i.e.,waiversthatlimitthemember'sparticipationinsomeway,typicallybyexcludingthememberfromvotingonaparticularmatter.TheOSCEhasarguedthatappearancesofconflict

demandan"appearancesolution"and,further,thatrestrictingtheparticipationofmemberswithanappearanceofconflictwillreducethechancesforanactualconflictofinterest.

Interpretation

TheforegoingpictureofthesystemmanagingpotentialfinancialconflictsofinterestbymembersoftheFDAadvisorycommitteesvividlyrevealswhyCommissionerKesslerreportedtotheIOMcommitteethattheagencyfacedaseriousproblem.Itwouldbeeasytoassignblamefortheemergenceoftheproblemtothedivisionsandcentersforfailingtoappreciatethesensitivityofpotentialconflictsandviewingwaiversasamatterofroutine;totheDEPIforadheringtooutdatedpoliciesandfailingtoappreciatetherequirements(andperhapseventheenactment)ofsubsection(b)(3);tolawyersintheOfficeoftheChiefCounselforfailingtoprovideeitherthecentersorDEPIsystematiclegalguidance;totheOfficeoftheSpecialCounselforEthicsforexcessiveconservatismandfailingtodevelopandconveygeneralstandardsforapprovingwaivers;totheOfficeofGovernmentEthicsforlast-minuteandoftenunexplainedsecond-guessingofwaiversonwhichitwasconsulted;andtoeveryleveloftheprocessforindifferencetoanyreasonablesetofdeadlinesforthedevelopmentandapprovalofwaivers.

Thereis,however,analternative,lesscriticalaccount.Itisastoryofofficesandagenciescaughtsuddenlyinaconfluenceofforcesthatweremovingtoorapidlyforanyonetostepbackfromthecascadeofindividualwaivercasestoexplainwhatwasoccurringanddecidehowthesystemshouldberighted.Theseforcesincludedtheheightenedconcern,withintheadministrationandinCongress,overconflictsofinterestinvolvingfederalemployees;PresidentBush'sdecisiontocentralizeintheOGEoversightofthewaiverprocessfortheentiregovernment;SecretarySullivan'sdecisiontocreateaSpecialCounsel

forEthicsresponsibleforreviewingallwaiversgrantedwithinthedepartment;therippleeffectsofDr.Kessler'sowndemandsthattheFDAofficialsandproceduresshouldbe,andshouldbeseentobe,freefromanyhintofconflictofinterest;arevivedappreciationthatthecarelessnessinidentifyingconflictsandgrantingwaiversmightnotonlyjeopardizeagencydecisionsbutleavecommitteemembersexposedtocriminalprosecution;andthereintroductionoflawyers,whowerethemselvesconfrontingissuesforthefirsttime,intoasystemthathadpreviouslydisplayedanamateurunderstandingofthelaw.Underthecircumstances,itishardlysurprisingthatconfusion,acrimony,andfrustrationresulted.

GlimmersofProgress

AstheIOMcommitteecompleteditswork,thereweresignsthattheparticipantsinthisprocesshadthemselvescometoappreciatethenatureofthe"problem"andhadresolvedwithinthepracticallimitsofcurrentlawandexecutiveorderstoimprovethesystem'soperation.ThemostpromisingofthesestepswasameetingheldbetweenMaryPendergast,SeniorAdvisortoCommissionerKessler,andJackKress,DHHSSpecialCounselforEthics.RepresentativesofallfivetheFDAcenters,includingthethreewhosecommitteesarethesubjectofthisreport,werealsoinattendance.Basedonindividualaccountsofthemeeting,itispossibletosketchthebroadoutlinesofthereformstentativelyagreedon.

Workload

OSCErepresentativesagreedtoconsiderone-timewaiversforadvisorycommitteememberswhosedisqualifyinginterestisthatoftheiruniversityorhospitalinsalesofmedicalproductsofacompanywithaproductunderreviewbytheFDA.Suchone-timewaiverswouldallowthecommitteemembertoparticipateinallfuturecommitteemeetings.Sinceoverhalfofall(b)(3)waiversnowsoughtbythecentersareforemployerinterestsofthissort,approvalofone-timewaiversshoulddramaticallyreducethewaiverworkload.

WaiverPreparationandReview

TheFDA'scenterswillremainresponsiblefortheinitialscreeningofadvisorycommitteemembers,fordeterminingwhetheramemberconfrontsapotentialconflictrelativetoanagendaitem,fordecidingwhethertorecommendawaivertotheCommissioner,forpreparingwaiverrequests,andforobtaininginformationfromcommitteemembers.TheOSCEwillhavefinalauthorityfortheagencyandthedepartmenttodeterminewhetheramember'sparticipationabsenta

waiverwouldviolatethelaw,i.e.,whetherapotentialconflictofinterestexists.AuthoritytodecidewhethertograntawaiverwillrestwiththeCommissioneror,athischoice,theDeputyCommissionerforOperations.ThisunderstandingrepresentsaconstructiveclarificationandallocationofresponsibilitybetweentheCommissioner,whounderthelawisempoweredtograntwaivers,andtheOSCE,whichSecretarySullivanhasmaderesponsibleforassuringthattheconflict-of-interestlawsarecompliedwith.

WithintheFDA,waiverreviewandapprovalistobeexpedited.CenterswillforwardrecommendedwaiverstotheOSCEatthesametimetheyare

submittedtotheDEPI.TheDEPIwillbegiven48hourstorespond,andsilencewillbeconstruedasacquiescence.Meanwhile,presumably,theOSCElawyersmaycarryouttheirownreview.ThisarrangementwouldappeartosubordinatetheroleoftheDEPI,aswellastoexpeditereview,andweconsiderbothtobesensible.WiththeOSCEabletoprovideauthoritativelegalreviewoftheneedfor,andformof,anywaiver,theFDA'sconcernthatwaiversshouldbegrantedjudiciouslyandonlywhennecessarytoassureeffectivecommitteefunctioningcanbefullyprotectedbytheOfficeoftheCommissioner.

ScheduleforReviewofWaivers

CentersaretosubmitrecommendedwaiverstotheOSCE(andtotheDEPI)atleasttwoandpreferablythreeweeksbeforethecommitteemeeting.TheOSCEhascommitteditselftoreviewsuchrecommendationspromptlyandtouseitsbesteffortstocompleteallcorrectionsatleastthreedaysbeforethemeeting.Underthisarrangement,theDeputyCommissionershouldhaveallwaiverrecommendations,approvedastoneedandformbytheOSCE,threedaysbeforethemeeting,whichshouldprovideadequatetimetoexerciseindependentjudgmentand,ifnecessary,conferwiththeOSCE.Understandably,exceptionstothisschedulemaybeneededforconsultantsinvitedtoassistthecommitteeattheeleventhhour.

WaiverForm

Waiverformswillbedividedintotwoparts.PartIwillbeastraightforwardrecitationthattheCommissionerorDeputyCommissionerhasgrantedawaiverforacommitteemembertoparticipateinthediscussionofanagendaitemwithrespecttowhichhe/shewouldotherwisehaveaconflict.PartIIwillconsistofamoredetailedexplanationofthecircumstancesthatgiverisetothepotentialconflictandthereasonswhythecenter(andagency)concludesthatthe

member'sparticipationoughtnonethelesstobeapproved.

TheIOMCommitteeviewsthismeeting,andtheagreementsreached,asasignificantfirststep.GivenSecretarySullivan'sdecisiontolodgeconflictofinterestoversightauthorityfortheentiredepartmentintheOSCE,thisofficewillinescapablyhaveacentralroleintheFDA'sadministrationofconflictofinterestrestrictionsapplicabletoadvisorycommittees.Accordingly,foranysystemtoworkeffectively,itmusthavethesupportandactivecooperationofbothOSCEandtheFDA.Theagreementtograntone-timewaiversforcertainattenuatedemployerinterestsshouldcuttheFDA'swaivercaseloadsignificantly,buttherewillremainanumber

ofindividualcasesintersectionsbetweencommitteeagendasandmemberexclusionsthatwillrequiresensitivejudgmentandactive,timelycooperationbetweentheFDA,includingthecenters,andtheOSCE.Ourrecommendationbelowthatthetwoorganizationsmakeanefforttoagreeon,andinsomefashioncodify,thecriteriaforevaluatingwaiversinthesemoredifficultcaseswilldemandamuchgreatercommitmenttocooperativepolicymakingthanhasbeenevidentsofar.

RecommendationsonFinancialConflictofInterest

TheIOMcommitteebelievesthatitisessentialthatthemembersoftechnicaladvisorycommitteesbeimpartialandobjectiveandnotcompromisedbyfinancialconflictsofinterest.Toachievetheseends,theIOMcommitteehasaddressedthestandardsandproceduresforcontrollingconflictofinterest.

Anyattempttoaddresstheproblemmustdealwithissuesoflaw,ofbureaucraticprocedure,andofadministration.TheIOMcommitteeconsideredreformsthatwouldrequirenewlegislationandthosethatcouldbeimplementedwithinexistingstatutoryauthority.

OptionsRequiringLegislation

TheIOMcommitteeconsideredseveraloptionsthatwouldrequirenewlegislation.Forexample,arecentreporttotheAdministrativeConferenceoftheUnitedStatesadvocatedasystemunderwhichtherewouldbenodisqualificationofanyadvisorycommitteememberforfinancialconflictofinterest,buteachmemberwouldberequiredtomakefullpublicdisclosureofallfinancialdealings,holdings,andrelationships.

1Thisproposaldiffersfromthecurrentsystemintwoways.First,fullpublicdisclosureofallofeachmember'sfinancialinterestsgoeswell

beyondthepresentextensivedisclosuretotheFDAandpublicdisclosureonlyofagenda-specificconflictsthatmaydisqualifyorconstitutethebasisforawaiver.Second,itholdsthatnointerestwouldprecludeamemberfromparticipatingincommitteedeliberations.

TheIOMcommitteeconcludedthatthelatterfeatureoftheproposalwasunacceptable.Itwouldpermitanadvisorycommitteemembertoserveininstancesinwhichhisorherfinancialinterestswouldconstituteaclearconflictofinterestandinwhichtheremedyshouldbedisqualificationfromparticipation.Suchasystemwouldunderminetheappearanceofobjectivityofthecommittee'sadvice.

Asecondoptionwouldbeasystemthatcoupledfulldisclosureofallinterestswithageneralrulebarringparticipationbymemberswithsignificantfinancialinterests.

Althoughthisproposalmaycontainthecoreofapromisingreformofthesystemforregulatingconflictofinterest,theIOMcommitteedidnotexplorefullyitsramifications.Thecommittee'sjudgmentconfirmedbymanywespoketo,includingofficialsoftheFDA,OSCE,theOGEwasthatsuchamajorlegislativeoverhaulofthismagnitudewassimplynotapossibilityinthenearterm.Thus,giventheFDA'spressingneeds,ourcharge,andourtimetable,itseemedimperativeforthecommitteetoturntoreformsthatcouldbeimplementedwithintheexistingstatutoryframework.However,thispossibilityisclearlyacandidateforfurtherstudy.

OptionsAvailableWithinExistingAuthority

Whatcanbedoneunderexistingauthority?Potentiallyagooddeal,asthefollowingrecommendationssuggest.AlthoughthefirstandsecondrecommendationsbelowcouldbeimplementedbytheFDAitself,thesuccessfulimplementationoftheotherrecommendationswouldrequiretheactiveinvolvementoftheCommissionerandhisoffice,thecollaborationoftheOSCE,andatleastthetoleranceoftheOGE.

AtheoreticaloptionfortheFDAwouldbetoavoidappointingadvisorycommitteemembersasspecialgovernmentemployees,thuscircumventingtherestrictionsofthefederalconflict-of-interestlaw.Thissolutionhasthenotabledisadvantageofattemptingtodefinetheproblemaway,hardlyawaytoinstillconfidenceinthesystem.Moreover,newlegislationmightbeneededtoallowpaymentofmembersandsharingwiththemoftradesecretinformation.

Second,theFDAitselfcouldexercisegreatercareintheinitial

appointmentofadvisorycommitteemembers.Itcoulddemandevenmoreinformationthatwouldenableittoidentifyinadvancepotentialmemberswhosefinancialinterestswouldclearlydisqualifythemforsomecommitteemeetings.Ontheotherhand,becausetheinterpretationofaprohibitedinterestisalreadyextremelybroad,andbecausepotentialconflictscannotbeidentifiedbeforemeetingagendasareset,vigorouspursuitofthisapproachmightdisqualifyvaluablemembersandproducenogaininintegrity.

Third,theFDA,workingwiththeOSCE,couldformulateandcodifycriteriaforgranting208(b)(3)waivers.TheIOMcommitteebelievesthatthisisessential.Codificationwouldbealengthyprocess,butsomemutualunderstandingofthegroundsforjustifyingawaiverisbadlyneeded.Achecklistofvariablesshouldbeformulatedthatincludes:thesizeofthe

interest;thecharacteroftheinterest;thelikelihoodthananinterestwillbeaffectedbyagencyactionbasedonthecommittee'sadvice;andtheactualimportanceofthemembertothecommitteedeliberations.Regardingthelatterpoint,webelievethatcommitteemembershipaloneshouldnotbetakenautomaticallyasadecisionmeasureofamember'simportance.

Ofimmediateimportanceistheneedtoclarifythecriteriafordealingwithpotentialconflictsarisingfrominstitutionaloremployerfinancialinterests,researchgrantsandcontractstocommitteemembers,andmemberinvolvementwithcompetingproductsandtechnologies.*Mostadvisorycommitteemembersareuniversityemployees;mostoftheiremployersoperatemedicalschools,hospitals,andhospitalpharmacies.TheOSCE,withtheFDA,shoulddevelopclearcriteriafordealingwithwaiverrequeststhatarisebecauseacommitteememberisaffiliatedwithaninstitutionthatoperatessuchsubordinateentities,whichinturnderiveincomefromthedispensingofuseoftheFDA-regulatedproducts.Mostuniversitiesalsoowndiversifiedendowmentfundsanditiscommonforsomeportionofthesetobeinvestedinpharmaceutical,biotechnology,ormedicaldevicesecurities.TheOCSE,withtheFDA,shouldclarifythecriteriafordealingwiththese''employerinterests''aswell.

TheIOMcommitteerecommendsthattheFDAandtheOSCEbegintheprocessofcodifyingthecriteriaforgranting208(b)(3)waivers,especiallywithrespecttoemployerinterests,researchgrantsandcontracts,andcompetingproductsandtechnologies.

Fourth,theFDAhastheauthoritytostreamlineitsowninternalpoliciesandproceduresfordecidingwhentoseekwaiversandhowtopreparetheirjustifications.TheIOMcommitteebelievesthatthisalsoisessential.Responsibilityforpreparingtheinitialwaiverrequestshouldresidewiththedivision.Thedecisiontorequestawaivershouldbemadebythecenterdirector.TheIOMcommitteeseesno

needforindependentreviewofthisdecisionbytheDEPIorbytheFDA'sChiefCounsel,solongastheOSCEcontinuestoexerciseanoversightrole.Centralagencyreviewofwaiverrequestsshouldbebyahigh-levelpolicyofficialintheOfficeoftheCommissioner.

TheIOMcommitteerecommendsthattheFDAstreamlineitspoliciesandproceduresforrequestingandprocessingwaivers.Thisclarificationshouldfixtheprimaryadministrativeresponsibilityforimplementing

*TheIOMcommitteenoteswithapprovalthatinitialstepsalongtheselineswereinitiatedintheSummerof1992.

thesechangesatthelevelofthecenterdirectorswhileretainingfinalauthoritytoapprovewaiversattheCommissioner'slevel(i.e.,attheleveloftheappointingauthority).

Fifth,theFDAshoulddevelopandadheretostrictschedulesforprocessingwaivers.ItshouldpresentwaiverrequeststotheOSCEnolaterthanthreeweeksinadvanceofameeting.*TheCommissionershouldseekagreementfromtheOSCEthatitwillreviewanyproposedwaiverwithinthreedays.TheCommissioner,whohastheultimateresponsibilityforapprovingwaivers,mayevenwishtoestablishdefaultrulesthatpenalizecentersforfailuretocompletetheirpartoftheprocessinatimelyway(e.g.,thememberisdisqualifiedortheagendaitemispostponed).Thisorotherdefaultrulesshouldbedesignedtoensureanexpeditiousprocessandalsotoguaranteethatatnotimewouldanadvisorycommitteememberofquestionableimpartialitybeallowedtoparticipateonthecommittee.

TheIOMcommitteerecommendsthattheFDA,withthecooperationoftheOSCE,adoptapolicyofstrictschedulingforprocessingwaiversandthatsuchapolicyincludedefaultrulesforlatesubmissionofwaivers.

Sixth,theFDAmustupdateitstrainingofofficialswhohaveresponsibilityforimplementingconflict-of-interestpolicieswithrespecttoadvisorycommitteemembers.Trainingprogramsshouldbuildaroundthesubstantiveandproceduralchangessuggestedabove.ParticipationshouldberequiredofalltheFDAprofessionalstaffwhodealwithadvisorycommitteemembers.

TheIOMcommitteerecommendsthattheFDAdevelopaconflict-of-interesttrainingprogramforallofitsprofessionalstaffwhodealwithadvisorycommittees.Thisprogramshouldbebasedonthepolicyandproceduralchangessuggestedinthisreport.

Seventh,theFDAmustalsoinitiateandmaintainaformalorientationprogramforadvisorycommitteemembers.Individualmembers

shouldclearlyunderstandthelawsthatgovernfinancialconflict-of-interestandthejustificationsforgrantingwaivers.However,theIOMcommitteebelievesthatguidanceonconflictofinterestshouldbepartofabroaderorientation

*TheIOMcommitteenotesthatiftheFDAadoptstherecommendationforadvanceschedulingofadvisorycommitteemeetingsproposedbelowandinChapter7,itmaybepossibletoincreasethisperiodoftime.

program(discussedbelowandatlengthinChapter8).Thislinkageisimportantbecauseanexclusivefocusonconflictofinterestwillnecessarilyemphasizetheriskofcriminalprosecutionandtheneedforintensiveinquiryintopersonalfinancialmattersanemphasisthatwouldsurelyobscurethepublicservicedimensionofadvisorycommitteemembership.

TheIOMcommitteerecommendsthattheFDAdevelopanorientationprogramforitsadvisorycommitteemembersandthatthisprogramincludeexplicitattentiontoconflictofinterestinthecontextofabroaderorientationtothepublicserviceaspectsofadvisorycommitteemembership.

Eighth,theFDAandOSCE,onbehalfofthedepartment,shouldcontinuetopresstheOGEtoissuegovernment-widegeneral(b)(2)waiverregulationsassoonaspossible.Thisyet-to-be-exercisedstatutoryauthorityisintendedtoremovecertainclassesofpotentialconflictsfromacase-by-casedetermination.Employerfinancialinterestsandsomeresearchgrantsandcontractscouldbedealtwithbysucharule.

TheIOMcommitteerecommendstotheOfficeofGovernmentEthicsthatitdevelopandissuegovernment-wide208(b)(2)waiverrulesassoonaspossible.ItfurtherrecommendsthattheFDAprovideinputtothescopeoftheserulesandthattheFDAandOSCEcontinuetoimpressontheOGEtheurgentneedforsuchrules.

Finally,theFDA,andthedepartment,shouldseektherevisionofExecutiveOrder12674,whichrequirescase-by-caseconsultationwiththeOGEonallwaiverrequests.

TheIOMcommitteerecommendstothePresidentthatExecutiveOrder12674beamendedtoremovefromtheOGEtheresponsibilityforcase-by-casereviewofadvisorycommitteememberwaiverrequests,thatauthorityforsuchcase-by-casereviewbedelegatedtothedepartments,andthattheOGEbedirectedtofocusonagencies'policiesandprocedures.

IntellectualBias

Thischapterthusfarhasfocusedonthemethodsforprotectingcommitteedeliberationsagainstjustonethreattoimpartialitythepossibilitythatcommitteememberswillmodifytheiradvicebecauseoftheprospectofpersonaloremployerfinancialgainorloss.Thisfocusisjustifiedbecause

theadministrationofthefinancialconflict-of-interestrestrictionsapplicableeventoshort-termfederalemployeesisthemainsourceoftheproblemonwhichouradvicewassought.

ButtheFDAneedstoguardagainstanotherpotentialthreattoadvisorycommitteeobjectivity.AsarecentseriesofarticlesinSciencemagazinerecounts,

2,3,4,5thereisagrowingconcernaboutandconsiderablepublicitysurroundingthesubtlyandperhapsevenovertlybiasingeffectsonobjectivityofascientist'spriorresearchandpublicpositions,particularlypositionstakeninformaladministrativeorjudicialproceedings.

Forconveniencewehavetermedthispotentialeffect"intellectualbias,"whichismeanttodistinguishtheproblemathandfromfinancialconflictofinterest.Toofrequently,wethink,bothmembersandobserversofthescientificcommunityapplytheterm"conflictofinterest"totheproblemofintellectualbias,whichismorecomplexandelusivethanthesortsoffinancialconflictswehaveheretoforebeendiscussing.

Makingthisdistinctionisparticularlyimportantinthepresentcontext,becausetheFDA(anditsadvisorycommitteemembers)aresubjecttoasetofformalcriminalrestrictionsthatapplyonlytofinancialconflictsofinterest.Section208(a)saysnothingaboutpossibleintellectualbiasorprejudgmentthatisuntaintedbyfinancialinterest.Acommitteemembermaybeincapableofentertainingaparticularhypothesis,howeverconvincingtheevidence,butheorshedoesnotviolatesection208(a)byparticipatingincommitteedeliberationsonanissuetowhichthehypothesis'plausibilityiscrucial.Byparticipating,however,heorshenotonlythreatensthecommittee's

capacitytorenderimpartialandthususefuladvicetotheagency,heorshemayinsodoingtherebyjeopardizethevalidityofanydecisionthattheFDAmayreachbasedontheadviceithasheard.

Whatlegalrestrictionsapplyinthiscontextisamatterofsomeuncertainty.Itcouldbearguedthatacommitteewhosemembersincludesomeonewithaclosedmindonanimportantissueisnot"balanced"astheFederalAdvisoryCommitteeActrequires.Evenifthiswereplausible,recentcaseshavecastdoubtontheenforceabilityoftheFACA's"balance"requirement.Furthermore,theFACArequirementofbalancecannotbetranslatedeasilyintooperationalsafeguardsagainstpossiblecommitteememberintellectualbias.Whenanewcommitteeisformed,oranewmemberisappointedtoanexistingcommittee,itisimpossibletoanticipatealloftheissuesorapplicationsonwhichtheFDAwillseekthecommittee'sadvice.Thegeneraljurisdictionofthecommitteewillofcoursebeknown,butitsfutureagendacannotbe.Anditispossiblebiaswithrespecttoaparticularagendaitemthattheagencyshouldbeconcernedabout.Anypracticalapproachtothisproblemmustoperateatthepointthatthe

committee'sagendaissetandtheissuestobeaddressedataspecificmeetingaredetermined.

ThevulnerabilityofanydecisionreachedbytheCommissioner,theofficialdecision-maker,islikelytobeafunctionofhisownratherthananycommittee'simpartiality.ThekeyfactorseemstobewhethertheCommissioner'sdecisionisrequiredtobebasedonaformaladjudicatoryrecord.MostofthedecisionsonwhichtheFDAseeksadvicefromitscommitteesdonotrequiretheagencytoholdaformaladjudicatoryhearing.Evenso,itcannotbesaidwithassurancethattheparticipationofcommitteememberswhoseviewsoncrucialmatterswerealreadyinvariablyformedmightnotprovidealegalbasisforsettingasidetheFDA'sultimatedecision.Provingintellectualbiasofsuchcharacterwould,ofcourse,bedifficult,andperhapsinallbutclearcases,impossible.

Evenassumingtheriskofjudicialreversalissmall,however,thereareverygoodreasonswhytheFDAshouldbeconcernedtoassurethatcommitteemembersarecapableofmaintaininganopenmindinevaluatingthetheoriesandevidencebroughtbeforethem.Oneisthatacommitteewhoseadviceisnotimpartialdefeatstheverypurposeofseekingindependentexpertadvice.Asecondisthatthewidespreadbeliefthatsomecommitteemembersare,ifonlyrarely,immunetopersuasionbyevidencewouldsurelyerodepublicconfidenceinamechanismtheFDAhasdevisedpreciselytoenhanceconfidenceinitsowndecisions.

WedonotconsiderintellectualbiastobeacommonproblemamongmembersoftheFDAadvisorycommittees.Scientistsaretrainedtobeskeptical,toinsistonevidencetosupporthypotheses,andtoberigorousintheirassessmentofevidence.Weareconvincedtheoverwhelmingmajoritysucceed.Furthermore,theFDAadvisorycommitteecontextprobablypresentsfeweroccasionsforchallengeto

long-heldviewsthanmanyothercontextsinwhichindividualscientistsarecalledontooffertheiropinions.Onereasonisthatadvice-givingbyacommitteeisacollectiveprocessandnotanindividualexercise.

However,itcannotbesaidthattheFDAhasnobasisforconcernaboutintellectualbiasornoreasontotakeprecautionstoguardagainstit.TheIOMcommitteebelievesthattheagencyshouldbesensitivetothepossibilitythat,onparticularissues,anadvisorycommitteemembermightbesodeeplycommittedtoapointofview,orsopubliclyidentifiedwiththatview,thathisorherobjectivitycannotbeassumedorwillnotbecreditedbythosewhoareinterestedinthecommittee'sdeliberations.WhatstepstheFDAshouldtakewhensuchacasearisesprobablycannotbeprescribedinadvance;theappropriateremedyislikelytodependonthecircumstances.Perhapsevenmoredifficultisdesigningaformalsystemtoscreenforpotentialintellectualbias.

Remedies

Becausenoclearsetoflegalrestrictionsisoperativehere,theagencyhasawiderrangeofremediesfromwhichtochoosethanithasundersection208.Ifthedeterminationofbiasrestsonpubliclystatedpositions,exclusionisprobablywarranted.Theremaybeothercasesinwhichthismayalsobeappropriate,e.g.,whenamemberisaninventorofthetechnologyunderreview(evenifheorshehasnofinancialinterestinitsapproval).Anddenialofparticipationsurelywouldreducetheriskofrecriminationandembarrassment.

Theremay,however,beinstancesinwhichexclusionofamemberforpossiblebiaswoulddeprivethecommitteememberswhodoparticipateofinformationhelpfulintheirindependentevaluation.Ifexclusionstemsfromthemember'spriorresearch,especiallyasaprincipalinvestigator,theFDAshouldnothavetoforegothatindividual'sexpertise.Thiscanbesolvedbyinvitingthepersontoaddressthecommitteeasawitness(orasa"guest").Insuchaninstance,itwouldbedesirabletosituatetheindividualsothatheorshedoesnotappeartooccupyhisusualroleasavotingmemberofthecommittee.

Ontheotherhand,thereissomedisadvantagetocreatingtoolargeasetofrolesatcommitteemeetingstoaccommodatevariousperceivedlevelsofpartiality.Asensibleruleofthumbmightrecognizejustthreerolesforcommitteemembersinthecaseofintellectualbias:(a)fullvotingparticipation;(b)fullexclusionfromameetingoranagendaitem;or(c)appearanceas"witness"or"guest"oftheagency.

Shortofcompleteexclusion,thesuccessofanymorelimitedremedywilldependonfullpublicdisclosureofthefactsthatgiverisetotheconcernthattheobjectivityofanerstwhilecommitteemembermaybe,ormaybethoughttobe,indoubt.Itmaybepossibletosaythat"Dr.JoneshasagreedtorecusehimselffromthediscussionofProduct

Ybecauseofconcernsthat,basedonpriorworkinthefield,hisobjectivitymaybechallenged.Hethereforewillnotparticipateinthecommittee'sformulationofadvice,norwillhevote.HehasbeenaskedbytheFDAtobeavailableasawitnesstoanswerquestionsfromvotingcommitteemembers."

Screening

ThedevelopmentbytheFDAofasystemtoscreenforpotentialintellectualbiaswillrequireconsiderablethought.Amember'spriorresearchwillprobablyberevealedinthescreeningforfinancialconflictofinterest.Allrelevantpublicationspresumablywillbeincludedinapotentialmember'scurriculumvitae.However,itmaybenecessaryfortheagencyto

inquirespecificallyaboutpublicpositions,especiallyanytakenbeforeregulatoryagenciesorjudicialproceedings.

Thisbriefdiscussionbarelypenetratesthesurfaceofacomplexandverysensitiveissue.Itissensitive,inpart,becausecommitteememberswhoseobjectivitymightbechallengedonotherthanfinancialgroundsareoftenlikelytoresentthesuggestionthattheycannotbetrusted.Thisisparticularlytrueifthesuggestioncomesfromtheagency,whichhasappealedtotheirspiritofpublicservice.Perhapstheheightenedattentiongiventothesubjectwithinthescientificcommunitywillgenerategreatersensitivityonthepartofindividualcommitteemembers.

Onefurtherobservationisinorder.WeconsiderthematterofintellectualbiastobeaproblemfortheFDAtoaddressandresolve.Itisnotcoveredbythefederalconflict-of-interestlawsanditspossibleoccurrenceisthereforenotproperlyaddressedthroughtheformalwaiverprocess.Itobviouslyhaslegalramificationstotheextentthatagencydecisionsmightbesubjecttoattackbecauseoftheparticipationofacommitteememberwholacked,orwasaccusedoflacking,therequisiteobjectivity.ButtheseareramificationsthattheFDA'sChiefCounselisverycapableofassessingandprovidingguidanceontotheagency.

TheIOMcommitteerecommendsthattheFDAdevelopcriteriaandproceduresforidentifyingpotentialintellectualbiasofadvisorycommitteemembersandprotectingtheobjectivityandimpartialityofadvisorycommittees.Thecommitteerecommendsthattheagencyroutinelyrequestinformationaboutresearchinterestsandpubliclystatedpositionsonscientificissuesfromadvisorycommitteemembers.Itrecognizesthattheagencymustrelytoalargeextentoncommitteemembersthemselvestoprovidesuchinformation.

Whentheagencyconcludesthatacommitteememberhasdemonstratedalackofobjectivityonamatter,themembershouldbeexcludedfrom

participationinthecommitteedeliberationsconcerningthatissue.Ifinformationrevealsonlythepossibilityofbias,theagencyshoulddeterminewhethertopermitthemembertoparticipate.Amemberwhoisexcludedfromparticipationincommitteedeliberationsmightneverthelessbeinvitedtoofferviewsasaguestorwitnesscalledbythecommittee.IndividualcasesshouldberuledonbytheCommissioner,afterconsultationwiththeappropriatecenterdirector.

Notes

1.Berg,RichardK.,Conflict-of-InterestRequirementsforFederalAdvisoryCommittees,ReporttotheAdministrativeConferenceoftheUnitedStates(Washington,D.C.,May1989).

2.Barinaga,M.ConfusionontheCuttingEdge.Science257:616619,1992.

3.Marshall,E.WhenDoesIntellectualPassionBecomeConflictofInterest?Science257:620621,1992.

4.Marshall,E.NSFDealswithConflictsEveryDay.Science257:624,1992.

5.Marshall,E.IntellectualConflictsBoonorBust?Science257:624,1992.

Appendix

ASuggestedApproachtotheCodificationofSection208(b)(3)WaiverCriteria

SupplementalStatementofRichardA.Merrill

TheIOMcommitteerecommends,appropriatelyinmyview,thattheFDAandtheDHHSOfficeoftheSpecialCounselforEthics(OSCE)"immediatelybegintheprocessofcodifyingthecriteriaforgranting208(b)(3)waivers,especiallywithrespecttoemployerinterests,researchgrantsandcontracts,andcompetingproductsandtechnologies."Thisstatutoryprovision,specificallyenactedformembersoffederaladvisorycommittee,holdsthatanagencyheadmaywaivethepotentialfinancialconflictsofanadvisorycommitteememberifhedeterminesthat"theneedfortheindividual'sservicesoutweighsthepotentialforaconflictofinterestcreatedbythefinancialinterestinvolved."ItisthisauthorityonwhichtheFDAnowexclusivelyreliesindecidingwhethertoallowmemberswithpotentialfinancialconflictstoparticipateincommitteedeliberationsonaparticularmatter.

TheIOMcommitteereportitselfdoesnotofferconcreteguidanceonhowthismightbedone.Thisapparentdeficiencyofthereportbecomesunderstandablewhenonegraspsthedifficultyoftheexerciseandrecallsthatthecommittee'sscheduleallowedforonlyfourface-to-facemeetings.Framingadiscussionofwhichkindsofpotentialconflictsshouldbeconsideredseriousandwhichnot,andofhowtoassesstheimportanceofasinglemembertoacommittee'sdeliberationsisacomplexundertaking.Reachingjudgmentsontheseissuesrequiresextendeddiscussionanddebate.Therewasscarcelytimetoattemptthefirstofthesechallenges,andnoopportunityatallforthefullcommitteetoengageintheextendeddiscussionneededto

reachagreementonthesecond.

Whatfollowsisonemember'sattempttooutlinetheanalysishewouldfollowinattemptingtocarryouttheIOMcommittee'srecommendation.Itdoesnotnecessarilyreflect,eitherinitsapproachorinthenormativejudgmentsimplied,theviewsofanyothercommitteemember.ItisofferedtoprovokefurtheranalysiswithintheFDAandOSCEratherthantoprescribeasolutiontotheproblemthattheyjointlyconfront.

Theproblemofcodifyingthecriteriaforapprovingwaiversunder208(b)(3)iscomplicatedbytwomainfacts.First,therangeofmattersonwhichtheFDAseeksadvicefromitsadvisorycommittees,whencoupled

withtheprominenceanddiverseactivitiesofthemembersofthesecommittees,generatesasubstantialnumberofpresumptive"exclusions"thatdictatenonparticipationorrequireconsiderationofwaivers.AnFDAcommitteemeetingseldomoccurstodaywithoutoneormoremembersfacingexclusionfromoneormoreitemsontheagenda.Inshort,theagencyfacesalarge"caseload"ofpotentialwaivers.

Second,thecaseloadislargeinmajorpartbecausetheconflict-of-interestlaw,section208(a),sweepsextremelybroadly,embracingaspotentiallydisqualifyingofanindividualcommitteemembernotonlysmallpersonal(andfamily)financialinterestsbutinterestsorrelationshipsofthemember'semployer.Asmostcommitteemembersworkforuniversitiesorotherresearchandhealth-careprovidinginstitutions,mosthave,throughtheiremployers,traceableifindirecttiestomultipleresearchgrants,clinicalresearcharrangements,andavastarrayofpaid-forhealthcareservices.Asthelawisnowinterpreted,anyoftheseinterconnectionscangiverisetoapotentialconflictandthusrequireeitherexclusionorawaiverforanadvisorycommitteemember.

Relativelyfewsuchinterconnections,inmyjudgment,oughtrealisticallytobeviewedasjeopardizingtheimpartialityofacommitteemember'sadvice.Andthis,asIunderstandit,isthecentralconcernoftheconflict-of-interestlaws,i.e.,aconcerntopreventgovernmentaldecisionmaking,orinthiscontextadviceobtaining,frombeingcompromisedbytheself-interestoftheadvicegiver.Theimplicationofthisjudgmentisthatalarge,butindeterminate,percentageofthepresumptiveexclusionsrevealedbytheFDA'ssystemofcomparingcommitteememberinterests(includingemployerinterests)withcommitteeagendasareplausible,ifnotcompelling,candidatesfortheexerciseoftheCommissioner'swaiverauthority.

ThegoalsoughtbytheIOMcommittee'srecommendationisthedevelopmentofgeneralcriteriaorguidelinesthatfacilitatedecisionmakingabouttheappropriatenessofwaiversinindividualcases.Webelievethatitshouldbepossibletoidentifyandarticulatecategoriesofintereststhatordinarilyoughtnotbeconsidereddisqualifying,i.e.,shouldbeconsideredwaiverable.Italsomaybepossibletoidentifyothercategoriesthatordinarilyshouldbeconsidereddisqualifying.Anditmayevenbepossibletoenunciatecriteriafordecidingwhetheracommitteemembershouldbeallowedtoparticipateevenwithasignificantpotentialconflictinaparticularmatterbecauseofhisorherimportancetothecommittee'sdeliberations.

Therecenthistoryofthedevelopment,review,andapprovalof(b)(3)waiverrequestsformembersoftheFDAadvisorycommittees,recountedintheIOMcommitteereport,illustratestheconsequencesofthefailuretodevelopgeneralcriteriaforapprovingsuchrequests.Forsomemonthsnow,eachnewwaiverrequestappearstohavebeentreatedasanovelcase,

requiringextendednegotiationsovertheappropriatenessandtermsofgrantingawaiverandthecontentandformatofthedocumentexplainingtheagency'sdecision.Suchacase-by-caseapproachvirtuallyassuresthattheprocesswillprovebothburdensomeanddeeplyfrustrating.

TheIOMcommitteefoundsignsthatofficialsintheFDAandOSCErecognizetheneedtoregularizethewaiverreviewprocessandreachagreementonthetreatmentofcertaincategoriesofpotentialconflicts.Thecommittee'srecommendationisessentiallythatthiseffortbeextendedandgivenpriority.

Theproductwevisualizewouldbeaseriesofwrittenguidelines,orevenagrid,fordecisionmaking.Forexample,one''guideline''nowunderconsiderationbytheFDAandOSCEwouldsaysomethinglike:"Thefactthatacommitteemember'sinstitutionalemployeroperatesahospitalorclinicthatdispensesandchargesfortheFDA-regulatedproducts,includingproductsofthemanufacturerwhoseapplicationistobereviewed,willnotordinarilybedeemeddisqualifying.Accordingly,awaivertoallowhimorhertoparticipateincommitteedeliberationsisappropriate."Withoutnecessarilyendorsingthisillustration,theIOMcommittee'shopeisthatotherclassesofintereststhatunderthelawwouldbepresumptivelydisqualifyingcanbegenericallycategorizedaswaiverableorasnotwaiverable.

Therearemanyobstaclestotheachievementofthisgoal.Someareempirical.ItrequirescomprehensiveknowledgethatmaynotbeeasilyassembledaboutthetypesandmagnitudesofintereststhattheFDAcommitteemembersreportthatnowtriggerexclusions.Weweregivenmanyexamples,butnoinformationthatwouldallowajudgmentaboutwhichpotentialconflictswererepresentativeorhowoftenanyoneoccurred.

Anothersetofobstaclesisinstitutional.Sincemanydecisionsabout

whetheratypeorsizeofinterestshouldbeviewedasdisqualifyingare,ultimately,mattersofjudgment,itistobeexpectedthatindividualswilldisagreeabouttheproperdispositionofparadigmcases.Thepresentarrangementsarguablyrequiretheconcurrence,oratleasttheacquiescence,ofthreeofficestheFDACommissioner,theOSCE,andtheOfficeofGovernmentEthicsbeforeanywaivercanbeapproved.Achievingagreementatthislevelonanysetofgenericguidelinesislikelytobealong-termtask.

ThisAppendixaddressesathirdsetofobstaclestotheachievementofwhattheIOMcommitteehastermed"codification."Forlackofabetterword,Iwilllabelthese"analytical."Inordertodecidewhetheraparticularkindofinterestshoulddisqualifyacommitteemember,or,sincethestatutetreatsmostinterestsasdisqualifying,whetherawaiverisappropriateforagivencommitteemember,oneneedstohavesomeunderstandingoftheunderlyinggoalsoftheconflict-of-interestlaw.Isuggestthattheprimary

goalshouldbetopreventtheparticipationofcommitteememberswhoseadvicemight,becauseofself-interest,bedistorted.Onecouldaddtothisformulation,asthepresentlawdoes,aqualification:Ifamember'svaluetothecommittee'sdeliberationsisgreatenough,evensomeriskofdistortionmaybeaccepted.

Thisformulationofthestatutorygoalisnotquitecongruentwiththelanguageof208(b)(3),whicharguablycallsforanindividualizedjudgmentaboutamember'svaluetocommitteedeliberationsineverycase.However,becausethedeterminationofamember'svalueappearstobeamorecomplexinquiry,Ibelieveitwouldbemorefruitfultoconcentratefirstonthedimensionthatrequiresconsiderationofawaiverinthefirstplacethepresumptivelydisqualifyingfinancialinterestandseeifitisnotpossibletocategorizeandthenranksuchinterestsintermsoftheirpotentialtoundermineimpartialadvice-giving.Ialsobelievethatthisisnotonlypossiblebutcompatiblewiththestatute.

Itseemstomequiteplausibletoargue,forinstance,thatforsomesortsofintereststhoughperhapsnotmanythethreattoimpartialityissonegligiblethatthefactofselectionforcommitteemembershipshouldbetakenassufficientevidenceofamember'svaluetothecommittee'sdeliberations.ThewillingnessoftheFDAandOSCEtoconsideragreeingthatemployerhealthcaredeliveryactivities,e.g.,universityhospitals,shouldnever(orrarely)beviewedasdisqualifyingi.e.,shouldbeautomaticallywaiverableisevidencethatthislegalinterpretationisnotpreposterous.

Ishouldaddthatevenifitprovesdifficulttoreachagreementonmanyotherautomaticallywaiverableclassesoffinancialinterests,theexerciseofcategorizationandrankingshouldhelpimproverelationsbetweentheagencyandtheOSCE.OnefrequentcomplaintthatweheardfromtheFDAofficialswasthattheyneverknewwhattherules

were.Thiscanbetranslatedas"weneverknowwhatsortsofinterestswouldreallyraiseeyebrowsatOSCE."ThewaiverreviewprocesswouldbegreatlyimprovedifitwerepossiblefortheOSCEtosay,andtheFDAofficialstoknow(eveniftheydonotagree),whatsortsofinterestswillbemostdifficulttograntwaiversfor.

Ontheotherhand,OSCEstaffmembersmightdevelopagreaterunderstandingfortheagency'spositioniftheFDAofficialswereabletoarticulatethefactorsthattheyconsiderimportantinassessingacommitteemember'svaluetocommitteedeliberations.Theattitudethatcommitteemembershipanotherlivebodyeligibletovoteisallthatisnecessarytoconvincecenterpersonnelthatanindividualmember,despiteasignificantpotentialconflict,isabsolutelycrucialtodeliberationscannotinspireconfidencethattheFDAisexercisingthesortofdiscriminatingjudgmentthatthelawseemstocontemplate.

TheeffortsuggestedcouldhavevaluebeyondassistingtheFDAandtheOSCEinpreparingandreviewingproposed(b)(3)waivers.ThepartofthetaskdiscussedinthisAppendixclassificationofdisqualifyingfinancialinterestsintermsoftheirlikelyeffectoncommitteememberimpartialitywouldbedirectlyrelevanttotheOfficeofGovernmentEthics'considerationofpossible(b)(2)waiverregulations.Thereaderwillrecallthatsection208(b)(2)allowstheOGEandonlytheOGEtopromulgateregulationscategoricallyexemptingcertaintypesofmagnitudesoffinancialinterestas"tooremoteortooinconsequential'toaffectagovernmentemployee'shonestperformanceofhisorherfunctions.Thissortofwaiverdoesnotrequireanassessmentoftheemployee's,e.g.,thecommitteemember's,importancetocommitteedeliberations.ThustheefforttoidentifytypesoffinancialinterestwhosepotentialinfluenceissoimprobablethatmeremembershipcanbeconsideredoutweighingisalogicalpreludetotheexercisethattheOGEmusteventuallyundertaketoimplement(b)(2).

TheOGEshouldwelcometheFDA/OSCEeffort,evenifitdoesnotagreewitheverypartoftheirclassification.TheFDA/OSCEanalysisshouldadvancethinkinginthismostdifficultareaandprovideexamplesof(b)(2)-waiverableintereststhatarecommonamongmedicalandscientificresearchersbutperhapsnotfrequentlyencounteredamongotherfederalpersonnel.

Whatcanbesaid,ifanything,aboutthesortsofintereststhatoughttobeconsideredasjeopardizingacommitteemember'simpartiality?Althoughthefollowingdiscussionreflectspersonaljudgments,itmayofferthebeginningofaframeworkforthinkingaboutthatquestion.

Forme,certaingeneralizationsseemplausible,thoughnotincontestable.Themagnitudeofafinancialinterestsurelyislikelytomakeadifference;wewouldworrymoreaboutacommitteemember's

objectivity,inassessingacompany'sproduct,ifheorsheownedsharesofstockinthecompanythanifheorsheownedoneshare.Thelawmaynotseeadifferencehere,butmostpeopledo.Andthelawwouldappeartoallowthisdifferencetobeaccordedweightinadecisionwhethertograntawaiver.

Differencesofmagnitudeatleastinownershipinterestsordirectpaymentsarerelativelyeasytodiscernanddealwith.Atleasttheyareeasytoarrayonachartorgrid.Itmaynotbeeasytoagreeonwhatthreattoimpartialityispresentedbyinterestsofdifferentsizes.Andsearchingforagreementatseveraldifferentlevelsmaynotbeworthwhile.Perhapsitshouldbeenoughtoreachagreementon"deminimis"levelsthatwould,ifnotexceeded,ordinarilyallowawaiver.(Wearenotspeakingaboutestablishingademinimusstandardforapplyingthepresumptivedisqualificationof208(a),butratherareseekingonemeasureofthepresumptivelydisqualifyinginterestthatdefineitseligibilityforwaiver.Inshort,wearenot

quarrelingherewiththeprevailinginterpretationof208(a),whichholdsthatevenasingleshareofstockora$100speakinghonorariumisaprohibitedinterest,althoughinanothercontextmanyofussurelywoulddoso.)

Mattersgetmorecomplicatedwhenonetriestocategorizefinancialinterestsbytype.Buttheexerciseisnotfutile.Itispossibletoframegeneralizationsaboutwhatkindsofinterestsaremoreworrisomethanothers.Thecentralquestionthatseemslikelytohelpclarifythinkingaboutwhichinterestsreallythreatenimpartialityis"whoseinterestisit?"Thisquestioncanbeexaminedwithreferencetoemployerinterestsandpersonalinterests.Thestatuteforbidsacommitteemember'sparticipationinanymatterinwhichheorshe,afamilymember,oranemployerholdsanyfinancialinterest.Isuggestthatpersonal(includingfamily)interestsaremorelikelytothreatenanindividual'sobjectivitythanthefinancialinterestsofhisorheremployer.Tobesure,onecanthinkofexamplesofbothsortsthatwoulddefythisgeneralization,andperhapsoncloseexaminationthoseexampleswouldswallowtheprinciple.Evenso,asonestartingplaceforanalysis,itislikelytoprovehelpfultomakethepersonal-employerdichotomyoneofthedimensionsofagridoffinancialinterests,allofwhichunderthecurrentlawaredeemedpresumptivelydisqualifying.

Wehavebeenprovidedexamplesofthreetypesofemployers'intereststhatarebelievedtotriggersection208(a):(1)salesbytheemployer,orbyasubordinateunitoftheemployer,oftheFDA-regulatedproductsmadebycompaniesthathavenewproductapplicationspendingbeforetheFDA;(2)researchorothergrantsfromsuchcompanies;and(3)giftsfromsuchcompaniestosupportinstitutionalprograms,e.g.,anendowedchair.Nodoubtthereareothermanyothers,amongwhichitoughttobepossibletodrawdistinctionsbasedonthelikelihoodthatacommitteemembermight

modifyhisorheradviceinordertoprotectanemployer'srelationshipwithacompany.Itwouldnotbeimprudent,inmyview,fortheFDAtotakethepositionthatinterestsfallinginthefirstcategoryoughtalwaystobewaiverableabsentclearevidencethattheemployerreceivesasubstantialamountofitsincomefromsuchsalesorthatthecommitteememberhim-orherselfbenefittedpersonallyfromdecisionsaffectingtheusageorsaleofthecompany'sproduct.Asimilarjudgmentmightbesupportableforresearchgrantsotherthanthosemadetoacommitteememberpersonally.

Mygoalhere,however,isnottoofferconclusionsaboutwhichkindsofemployerinterestsoughttobeconsideredroutine,possible,orunlikelycandidatesforwaiver,butsimplytosuggestanapproachtothinkingaboutthisquestion.Theapproachinvolves,first,thecategorizationofthevarioustypesofemployerintereststheFDAcommitteemembershavedisplayedand,second,thoughtfulassessmentofthelikelihoodthatinterestswithina

particularcategorywillundermineanindividualcommitteemember'simpartiality.

Thesamesortofexerciseisappropriateinassessingthepersonalinterestsofcommitteemembers.Tosimplifythetask,itmightwellbeprudenttoconflatememberinterestsandfamilyinterests,i.e.,toassumethataspouse'sorminorchild'sfinancialinterestisaslikely(orunlikely)toaffectamember'simpartialityashisorherown.Itwouldbeacrudegeneralization,tobesure,butcrudegeneralizationswillbenecessarytodevelopaframeworkthatcanguideand,whichistheultimategoal,simplifyandthusexpeditereviewofindividualwaiverrequests.

Withinthecategoryofpersonalinterests,individualresearchgrantsareapparentlyacommonsourceofpresumptivedisqualification.Thedollarvalueofagrantprobablyoughttobeaconsiderationinassessingthelikelihoodthatitmayaffectacommitteemember'simpartiality.Butequallyimportant,itseemstome,istheextenttowhichagrantcontributestoaresearcher'spersonalincome,asdistinctfrominstitutionalincome.Iwouldbeinclined,aswell,todifferentiatebetweenresearchgrantsprovidedinthepastandgrantsthatcurrentlysupportamember'sresearch.Theinfluence,ifany,oftheformermustbeinthemember'shopeforfutureresearchsupportfromthesamesource,andIdonotfinditimplausiblethatanindividual'sjudgmentislesslikelytobeinfluencedbyahopethatsupportmightsomedayberenewedthanbythefearthatcurrentsupportmaybeterminated.

Iwould,atleasttentatively,drawasimilardistinctionbetweenothersortsofcompanypaymentstoacommitteemember.Aconcludedconsultingarrangementthatoncepaida$2,500yearlyhonorariumstrikesmeaslessworrisomethatanon-goingrelationshipthatprovidesrewards,evenofsmallermagnitude,infutureyears.

Indeed,itmaybeappropriatetodrawabroaderdistinctionbetween

intereststhatamemberalreadyowns,andwhosevaluewillnotsignificantlychange,andinterestswhoseenjoyment,orwhosevalue,maydependonthesuccessofthecompanythatisthesourceoftheinterest.Aconsultingfeepaidinthepastmaybethesourceofhopeforfuturebeneficialrelationships,butitsvaluewillnotbediminishedifthecompanyneverprovidessupportagain.Bycontast,thevalueofstockownedbyacommitteememberinacompanywhoseproductsheorsheisaskedtoevaluateisclearlyaffectedbythefuturesuccessofthefirm,andverypossiblybytheprofitabilityofthenewproduct.

TherangeofpersonalfinancialintereststhatonecanassemblefromexamplesprovidedbytheFDAislarge,andtheirvarietymayappeartodefyanysystematiceffortatdescription,muchlessacategoricalassessmentoftheirlikelyaffectonimpartiality.Butonecannotknowthiswithoutmaking

theeffort.Andthereisavaluetotheintellectualexerciseevenifaformaldecisionmakinggridorsetofdecisionalguidelinesremainsincomplete.Itwillforcethoseinvolvedtoarticulateandexplaintheirjudgmentsabouttheappropriatenessofgrantingwaiversinspecificcases.Itmayalsoyieldandthiswouldbenosmallachievementacommonvocabularyfordescribingandanalyzingindividualcases.And,ifengagedinjointlybyofficialsfromboththeFDAandtheOSCE,itmayhelptorevealcommongroundandtoclarifydifferences.

Thediscussionthusfarhasfocusedononlythefirstelementofthestatutoryformulaforgranting(b)(3)waiversthepotentialofdifferenttypesandmagnitudesoffinancialintereststoundermineacommitteemember'simpartiality.Section208(b)(3)alsorequiresconsiderationofamember'simportancetocommitteedeliberations.Thesuggestionmadehereisthatsomeinterestscanbeclassifiedassounlikelytothreatenimpartialitythatselectionforcommitteemembershipcanbetakenassufficientevidenceofimportancetooffsettheremoterisk.Buttheremaybefewsuchinterests,andtheyarelikelytobeanemployer'sratherthanpersonalorfamilyinterests.Thus,inevaluatingmanywaiversattentionmustbegiventoamember'simportancetocommitteedeliberations.Ibelievethatthissecondelementshouldalsobesusceptibletocategoricalanalysis,i.e.,itshouldbepossibletoformulateguidelinesforevaluatingindividualcases.Andthecommittee'srecommendsthatthisshouldbedone.

Thereisoneadditionalpointtobemade.Manyreadersmayaskhowtheexercisesketchedintheforegoingparagraphsfitswiththestatutoryregimeforregulatingfinancialconflictofinterest.Theanswerhasalreadybeensuggestedbutwarrantsreiteration.Section208(a)oftheconflict-of-intereststatutesweepsverybroadlyand,Iacknowledge,asconstruedmakesthesortsofdistinctionsdiscussedaboveirrelevanttoadeterminationofwhetheraninterest

presumptivelydisqualifiesacommitteememberfromparticipatinginadviceonaparticularmatter.Butsection208(b)(3)callsforanassessment,bytheCommissionerofFoodandDrugs,ofthelikelihoodthatadisqualifyinginterestwillinfactaffectthemember'sobjectivity,aswhenasofhis/herimportancetothecommittee'sdeliberations.Suchanassessmentlogicallyinvites,andsurelypermits,considerationofthesortsofdistinctionsIhavesuggested.

7CommitteeOperationsTheconductofanadvisorycommitteemeetinginvolvesmanyelements.Thischapterconsidersthefollowing:settingtheadvisorycommitteeagenda,schedulingcommitteemeetings,meetingpreparation,theconductofameeting,andmeetingfollow-up.

AlthoughsomeexplicitpoliciesguideFDAadvisorycommitteeoperations,relativelyfewcurrentpoliciesaredocumented.OnequestionthatconfrontedtheIOMcommittee,therefore,wastodeterminehowmuchwrittenpolicyguidancewasneededtoensureeffectiveperformance.Althoughsuchguidanceprovidesthebasisforuniformpractices,itmayalsointroduceunnecessaryandunwantedinflexibilities.

JustastherearedifferencesamongFDA'scentersintherecruitmentofmembersandtheassignmentoffunctionstocommittees,committeeoperationscurrentlyrevealsubstantialvariationamongandoftenwithincenters.Thisvariationoriginatesfromdifferencesintheirstatutorymissions,histories,administrativecultures,thescientificandclinicalfieldinquestion,andthepersonalhabitsoftherelevantFDAofficials.

Somevariationamongandwithincentersisjustified,andtheIOMcommitteewishestoavoidrecommendinginappropriatestandardizationinsuchcases.Ingeneral,however,substantialstandardizationofpoliciesandproceduresinadvisorycommitteeoperationsisbothdesirableandfeasible,thebenefitsofwhichwillaccruetotheagency,thesponsors,andthegeneralpublic.

TheIOMcommitteerecommendsthattheFDAdevelopuniformmanagementguidelinesforadvisorycommitteesapplicableacrossallthree

centersandthatiteliminateunnecessarydifferencesinthemanagementofcommittees.

SchedulingAdvisoryCommitteeMeetings

TheIOMcommitteedeliberatedatlengthaboutrecommendingthatFDAadoptapolicyofschedulingadvisorycommitteemeetingsaslongasoneoreventwoyearsinadvance.Meetingsscheduledinthiswaywouldrequirethefollowingassociateddeadlines:agency(andpresumablysponsor)agreementtoreviewanapplicationatascheduledmeeting;timelysponsorsubmissionofalldatatogototheadvisorycommittee;timelycompletionbytheagencyofitsreview;andon-scheduledistributionofmaterialtotheadvisorycommitteemembers.

TheprofferedreferentinthiscaseisthesubmissionofaresearchgrantproposaltotheNationalInstitutesofHealth(NIH)byaspecifieddatetoensureitsreviewataparticulartime.Includedinthisschemeisadecisionrulethatlateapplicationsarenotrevieweduntilthenextcycle.AlthoughthecommitteerecognizesthattheNIHexperienceprovidesanimperfectcomparisonforthesubmissionandevaluationofanapplicationtotheFDA,itbelievesthatthereisgreatmeritinintroducingsomecomparabledisciplineintheFDAreviewprocess.

Atleastthreereservationsaboutsuchaproposalhavebeenexpressed.First,schedulingconflictswithmajorprofessionalsocietymeetingscouldoccur.ThisistheleastseriousproblemandcouldbehandledsimilarlytoNIHprocedures.(NIHschedulesgrantproposalcyclesandstudysectionmeetingsoneortwoyearsinadvanceandconsultswiththemajorprofessionalsocietiesinparticularfieldsbeforedoingso.)

Second,ininformaldiscussionsindustryrepresentativesrespondedfavorablytoadvanceschedulingprovidedtheparticularadvisorycommitteemetatleastthreetimesperyearandonaregularbasis.The

"cost"ofthreeorfourmonthsdelayifameetingdeadlineweremissedundersuchcircumstanceswasseenastolerable.Indeed,workingtodeadlineselicitedagenerallyfavorableindustryresponse.However,forthoseadvisorycommitteesthatmetonlytwiceayear,failuretomeettheassociateddeadlineswouldresultinaslippageofsixmonths;theindustryrepresentativesdidnotfindthisperiodacceptable.

ThemostseriousreservationwasvoicedbyFDArepresentatives,whoexpressedtheviewthatestablishingacertaindatesome6to12monthsinadvancefortheendofanFDAreviewwouldbeverydifficult.Furthermore,meetingsuchadvancedeadlineswouldimposeademandonscarceagencyresourcesofmedicalreviewers,whichwouldmakeitdifficultfortheagencytocomplyeasily.

TheIOMcommitteesawthebenefitsofadvanceschedulingastwofold:imposinggreaterdisciplineontheinternalproductevaluationprocess,andmakingiteasiertoschedulethetime,andthusensuretheparticipation,of

busyadvisorycommitteemembers.Currently,theschedulingofadvisorycommitteemeetingsisaffectedbytheavailabilityofcommitteemembers,thelengthofFDAreviewtimes,deferencetoasponsor'sdesiretosubmitdatauptothelastminute,andlong-standingagencypracticeofschedulingmeetingsonanadhocbasis.

Modificationofcurrentpracticewouldrequirethattheagencyissueanexplicitpolicyonadvancescheduling,planforanappropriatetransitionperiod,andcarefullymonitortheimplementationofschedulinginthetransitionperiod.TheIOMcommitteebelievesthatadvanceschedulingwouldbejustifiedasameansformakingbetteruseofadvisorycommittees.

TheIOMcommitteerecommendsthatFDAadoptapolicyofannualadvanceschedulingofadvisorycommitteemeetingsandofmeetingagendas,withreviewcycleshavingdeadlinesforsponsorsubmissionofdata,FDAcompletionofreviews,andadvancedistributionofmaterialstocommitteemembers.

MeetingPreparation

GeneralCriteriaforSettingtheAgenda

Thecriteriafordeterminingthematterstobebroughttoanadvisorycommitteevaryfromcentertocenter.CDRH,forexample,wasobligatedbylawtobringallPMAstoanadvisorycommitteeuntiltheSafeMedicalDevicesActof1990gaveitsomelimiteddiscretion.CBERbringsbothproduct-relatedbiologicsdevelopmentandintramuralresearchissuestoitsadvisorycommittees.

Onlyonecenterhasawrittenpolicy.CDERrecentlyclarifieditsgeneralcriteriainaSeptember1991document,

1thatidentifiedarangeofmattersthattheagencymightbringtoanadvisorycommittee.Theseincludeadviceontheapprovabilityof

specificdrugs,generaldrugdevelopmentissues,issuespertainingtomarketeddrugs,andmanagementofthenewdrugevaluation(NDE)program.Weexaminethecomponentsofthisdocumentbelow.

ProductEvaluationandGuidelinesDevelopmentatCDER

Thefirstofthesematters,adviceontheapprovabilityofspecificdrugs,usuallypertainstoanewchemicalentity(NCE)butmayalsoincludeanewindicationforamarketeddrug.Advicemaybesoughtonthefollowingaspectsofagivenapplication:adequacyoftheclinicaltrialdesignandtheconductofstudiestoprovidesubstantialevidenceofeffectiveness;adequacy

ofthedatasupportingsafety;adequacyofthedataaboutdosingandscheduling;considerationofsurrogateendpoints,asappropriatetothecompound;theneedforpostmarketingsurveillanceoradditionalstudies;theneedforlimitingindicationstospecificpopulations;theoverallrisk-benefitofanewagent;speciallabelingconcerns;andswitchesofprescriptiondrugstoover-the-counter(OTC)status.Onoccasion,thecentermayaskanadvisorycommitteemembertoconductaprimaryreviewofselectedportionsofanewdrugapplication(NDA).

Issuesofdrugdevelopmentthatgobeyondtheevaluationofspecificproductsonwhichadvicemaybesoughtincludedevelopmentguidelinesforclassesofdrugs,discussionofclinicalstudydesignissues,andspecificsafetyissuesforparticulardrugs.TheCardio-RenalDrugsAdvisoryCommittee,forexample,heldatwo-dayadvisorycommitteemeetingthispastyear,thefirstofwhichdealtwiththequestionofdose-responsemeasurementofangiotensin-convertingenzymeinhibitors.Inaddition,thecentermayseekadvisorycommitteecounselonmarketeddrugswhenadversedrugreactiondataemergefromsurveillance,animalstudies,ornewclinicaltrials.

ProgramManagementatCDER

Productevaluationissues,broadlyconstrued,receivethegreatestattentionintheCDERdocumentonadvisorycommitteeagendaitems.However,thedocumentalsosuggestsseveralsubjectsforadvisorycommitteeagendasthatrelatetothemanagementoftheNDEprogram.Thefirstdealswiththeperiodicreview(usuallyannually)byanadvisorycommitteeofthependingNDAsandthemajornewindicationsofotherdrugsintheCDERpipeline.Thecenter'semphasisisonthosedrugsthatmayhaveanimportantpublichealthimpact,whosedevelopmentisunusuallycomplex,orthataresubject

togreatpublicscrutiny.

Second,theperiodicreviewof"importantproductsunderdevelopment"involvesusingcommitteesearlierintheproductdevelopmentprocessthanthelicensingstage.TheLasagnaCommitteereportcalledforthiskindofearlyinvolvement,especiallyforcancerandAIDSdrugs.TheFDAarguescorrectly,inthejudgmentoftheIOMcommitteethatdefiningearlyinvolvementasparticipationinthereviewofinvestigationalnewdrugs(INDs)isapracticalimpossibility.TheinventoryofactiveINDsisquitelarge,asubstantialnumberofnewINDsarereceivedeachyear,andtheagencyisrequiredbylawtoassessthesafetyofaplannedclinicalstudywithin30daysoftheIND'sreceipt(lackofresponsebytheagencyallowsthesponsortoinitiatetheclinicaltrial).Thus,itisnotfeasibletoroutinelyinvolveadvisorycommitteesininitialINDreviews.

Nevertheless,theimpactofAIDSondrugdevelopmentandevaluationhasbeentoinvolveCDERmoredeeplyinclinicaltrialprotocolsthanhasbeentruehistorically.Asimilarearlyinvolvementistakingplaceinoncologicaldrugdevelopment.

TheCDERstatementexplicitlycontemplatesthatreviewingdivisionswillperiodicallyreviewtheIND''portfolio''withtheiradvisorycommittees.Thepresumedbenefitsofsuchareviewareguidancetotheagencyandaclearersenseofparticipationbyadvisorycommitteemembers.Thefactorslimitingthepursuitofthispolicyincludetheresourcecoststoagencypersonnelandtoadvisorycommitteemembers,aswellasthedisclosureofearly-stageproprietaryinformationtoanincreasednumberofindividuals.*

Thethirdinnovationsuggestedinthedocumentisthemostfar-reaching.ItisthatadvisorycommitteesconsidertheperiodicanalysisofprioritiesandresourceallocationformanagementofINDapplications,NDAs,abbreviatednewdrugapplications(ANDAs),andNDAsupplements.

TheIOMcommitteecommendsCDERforthisclarifyingdocumentandrecommendsthatCBERandCDRHdevelopsimilarstatements.TheIOMcommitteealsorecommendsthateachcenterscheduleanannualreviewbyeachadvisorycommitteeofthemajorNDAsandINDs(ortheirequivalents)thatareanticipatedtocomebeforetheirrespectivereviewingdivisions.

SettingtheAgenda

Settingtheagendaofanadvisorycommitteemeetinginvolvestwostages:(1)formallyschedulingameetingandpublishinganannouncementofthatmeetingintheFederalRegister,and(2)afewdaysbeforethemeeting,sendingcommitteemembersadetailedagendawithspecificquestionsonwhichadviceissought.

ThefirststageofthisprocessisinitiatedbytheFederalRegisterannouncement,whichmustbepublishedatleast15daysbeforeameetingisheld.Publicationleadtimerequiresthatanannouncementbesubmittedbythecenteraboutsixweeksbeforeameeting.Theannouncementsometimesincludesageneraldescriptionoftheagenda,forexample,the

*TraditionalvaccinedevelopmenthasinvolvedCBERwithvaccinesponsorsfromtheinceptionofaproductthroughitsclinicaltrialstotheproductlicensingstage.ThisreflectsboththepublichealthnatureofvaccinedevelopmentaswellasarelativelymodestCBERworkload.Theimpactofthebiotechnologyrevolution,however,isbeginningtoincreasetheCBERworkloadandmayforcethecentertowardlessinvolvementinearlystagereviews.

specificNDAofagivensponsor(identifiedbynumber)andthegeneraltopicsofthemeeting.*

TheIOMcommitteerecommendsthatFederalRegisterannouncementsofscheduledadvisorycommitteemeetingsroutinelyincludethemostdetailedstatementoftheagendathatisfeasiblewithexistingtimeconstraints.

MembersoftheIOMcommitteewhoserveonFDAadvisorycommitteesnotedthattheyseldomseetheFederalRegisterannouncement.

TheIOMcommitteerecommendsthattheFederalRegisterannouncementbesentroutinelytoadvisorycommitteememberswhenitissubmittedforpublication.

ThegeneralquestionsthattheFDAmustconsiderinassessingthesafetyofdrugsandbiologicsarewhethertherisksofacompoundareoutweighedbyitsbenefitsandwhetherthereis"substantialevidence"fromwell-controlledtrialstosupporttheclaimsofeffectiveness.Itwouldhelpthereviewprocessifadvisorycommitteememberswereregularlyremindedofthesedecisioncriteriaastheyreviewasponsor'sdata.

TheIOMcommitteerecommendsthattheFDAroutinelysendthegeneralstatementoftheregulatorycriteriagoverningproductevaluationtoeachadvisorycommitteememberinadvanceofameetingtoassistmembersinframingtheirreviewofthedata.

Thesecondstage-settingthedetailedagendaofcommitteemeetingsinvolvesestablishingthespecificmeetingtopicsandtimeallocationsandpreparingthespecificquestionsthattheadvisorycommitteewillconsider.Ofthesesteps,preparingthequestionsisthemostimportant.

TheFDAisprimarilyresponsiblefordeterminingthesequestions.It

hasthestatutoryresponsibilitytoreviewandapproveapplications,andconvenescommitteestoassistitinthatprocess.Asapracticalmatter,thisistheonlyfeasiblewaytoproceed.Thedivisiondirector,inconsultationwiththeofficedirector,usuallydevelopsthespecificquestions.FDApreparation,review,

*TheGenericDrugsAdvisoryCommitteemeetingofSeptember2627,1991,example,wastoconsiderthe"assessmentofpharmacokineticstopics(rateandextentofabsorption)inthedeterminationofbioequivalence"and"statisticaltopics(datatransformation,sequenceeffect,andoutlieranalysis)inthedeterminationofbioequivalence"onsuccessivedays.

andapprovalofquestionsmaytakeseveralweeks;theyareoftensenttocommitteemembersjustafewdaysbeforeameeting.

Threeissueshavebeenraisedaboutthisprocess.First,someobserversbelievethattheadvisorycommitteeshouldsetitsownagenda.(TheLasagnaCommitteecomesclosetorecommendingthis.)Ifadvisorycommitteeswereadjudicatorybodiesresponsibleforweighingboththesponsor'sdataandanalysisandtheFDA'scritique,andthenrenderingajudgment,anargumentcouldbemadethattheyshouldhavecontrolovertheirownagendas.BecausethecommitteesareadvisorytotheFDA,however,andareconvenedtoassistitintheadministrativereviewofdrugs,biologics,andmedicaldevices,itislogicaltoarguethattheagencyshoulddevelopthecommitteeagendaaroundthemattersonwhichitwishesadvice.

TheothertwoissuesareofgreaterconcerntotheIOMcommittee.ArecurringcriticismofFDA'sbehaviortowardadvisorycommitteesisthatagencyofficialstypicallythereviewingdivisionseektocontrolorinfluence,orevenmanipulate,acommitteetoachieveanoutcomethattheydesire.Thischargeof"undueinfluence"isoftenmadeabouttheteleologyofthequestionsposedtoacommittee;thatis,theyappeartosomeobserverstobephrasedororderedsoastoleadthecommitteetoaconclusionthatreflectsthepreferenceofthedivisioninthematter.Theothercomplaint,whichiscloselyrelated,isthatadvisorycommitteemembersseldomhaveanopportunitytomodifythequestionspreparedbytheagencyortoaddothersthattheywishtoconsider.

Theseissuescanbeaddressedtogether.Itisseldomfeasibletoinvolvethecommitteedeeplyinadvanceconsultationonquestionsbecauseoftimeconstraintsandthelackoffamiliarityofmemberswiththespecificissuespresentedbyanapplication.Twoactionsarepossible,however,bothofwhichwouldimprovetheprocessand

mitigatethechargeofundueinfluence.First,thequestions,whichareoftendevelopedsolelybyFDAstaff,couldbepreparedinconsultationwiththecommitteechair.Second,theagencycouldandshouldinformcommitteemembersthattheyhavearighttomodifyagencyquestionsoraddquestionsoftheirown.

TheIOMcommitteerecommendsthatintheformulationofmeetingagendasandofquestions,theadvisorycommitteechairberoutinelyconsultedasastandardprocedure.ItfurtherrecommendsthatcommitteemembersberoutinelyinformedthattheymaymodifyFDA-preparedquestions,basedontheirreviewofthedata,andintroducequestionsoftheirownbeforeoratanadvisorycommitteemeeting.

ContentoftheAgendaQuestions

OneissueraisedbytheIndustryLiaisonPaneliswhetherFDAquestionsshouldberestrictedtoanapplication'sscientificandclinicalmattersorwhethertheyshouldalsoextendtotheregulatoryquestionsthattheFDAmustface.Thepanel'sreportstatedthefollowing:"Incaseswhereadrugorbiologicmarketingapplicationisunderconsiderationbyacommittee,theFDAshouldnotaskthecommitteetoadviseitonwhetherornottheapplicationshouldbeapprovedbut,rather,onwhethersubstantialevidenceofsafetyandeffectivenesshasbeenprovided."Thepanelrecognizedthatthisquestionwasusuallybutnotalwaysaskedofdrugsandbiologicscommittees,andrecommendeditsuniformuse.ItalsoacknowledgedthattheCDRHinterpretsitsstatutoryauthorityasrequiringthattheadvisorypanelbespecificallyaskedwhetheranapplicationshouldbeapproved.

Theagencydecisiontoapproveadrugorbiologicisbasedontwocriteria:whetherthereis"substantialevidence"(consistingofadequateandwell-controlledtrials)tosupporttheclaimsofeffectiveness;andwhethertherisksofaproducthavebeenshowntobeoutweighedbyitsbenefits.Giventhesecriteria,Dr.RobertTemple,DirectoroftheCDER'sOfficeofDrugEvaluationI,commentedonthepanel'spointaboutthedistinctionbetweenthescientificandregulatoryquestions."Onceacommitteehassaidthereissubstantialevidenceofeffectivenessderivedfromadequateandwell-controlledstudiesandthatthebenefitsoutweightherisks,"hewrote,"itisbeingundulycoytosuggestthatweshouldnotaskwhetherthecommitteerecommendsapproval."

2TheIOMcommitteeconcurswithTempleregardingthe"distinctionwithoutadifference."

TheIOMcommitteebelievesthatFDAreviewingunitsshouldbefreeto

askadviceonbothscientificquestionsandrelatedregulatoryimplications,astheydeemimportant.

ArelatedissueisthechargethattheFDAsometimesasks"loaded"orleadingquestions.ItisnecessarytodistinguishherebetweenthetoneandobjectivityofquestionsandthefactthattheaskingofparticularquestionswillindicatetheproblemsthattheFDAhaswithanapplication.

TheIOMcommitteerecommendsthatquestionsaskedofadvisorycommitteesbefairandobjectiveintoneandavoidlanguagethatmightbeconsideredbiasedorinflammatory.However,thecommitteeisnottroubledthatprecisequestionsoftenwillrevealtheagency'sconcernsaboutanapplication.

TimelyDistributionofMaterials

AmajorrecurrentcomplaintfromadvisorycommitteemembersisthattheFDAoftenfailstodistributematerialssufficientlyinadvanceofacommitteemeetingtopermittheircarefulreviewbymembers.Delaysinthedistributionofmaterialsareattributedprimarilytolimitedpersonnelandadministrativeresources,thenaturaltendencyofreviewstogetdoneatthelastminute,andthetoleranceofsuchpracticesbytheagency.Amoresinisterchargeisthatsuchdelaysarepartofadeliberateeffortbyagencyofficialstomanipulatetheworkofadvisorycommittees.

Thereisavirtualconsensusthattheeffectiveuseofadvisorycommitteemembersrequiresthattheyhavereviewmaterialsintheirpossessionforareasonableperiodoftimebeforeameeting,preferably,foratleastthreeweeks.

TheIOMcommitteerecommendsthattheagencyadoptandfollowastrictscheduleforadvancedistributionofmaterials.Themeetingagenda,sponsor'sdataandanalyses,andagencyreviewsshouldbedeliveredtomembersatleastthreeweeksinadvanceofameeting.Thespecificquestionsforthemeetingshouldbedeliverednolaterthan10daysbeforeameeting.

TheIOMcommitteebelievesthattheresponsibilityforfulfillingthisrecommendationrestsnotonlywithcommitteeexecutivesecretaries,butalsowiththedirectorsandtheapplicationreviewersoftheappropriatedivision.Italsobelievesthatadvanceschedulingofcommitteemeetingsshouldfacilitatecompliancewiththisrecommendation.

SummariesofMaterialsSenttotheCommittee

Advisorycommitteememberscomplainthatoftentheformatofmaterialstheyreceivefromasponsorisnotconducivetoacareful

reviewofthedata.SometimesthiscomplaintisaccompaniedbyarequestthattheFDA"repackage"sponsormaterialstofacilitatereview.Theagencydoesnotwishtoberesponsibleforthepresentationofasponsor'swork,sincethiscouldbecitedasameansofinfluencingacommittee'sanalysis.Amajordeficiencycouldberemedied,however,throughtheuseofconcise(2025pages),complete,andintegratedsummariesofthesponsor'sapplicationandtheagency'sreview.

TheIOMcommitteerecommendsthattheFDAdevelopastandardformatforsponsorstosummarizetheirapplicationbrieflyyetcompre-

hensively,aswellasacomparableformatforasummaryoftheagency'sreview.Thesesummariesshouldbeprovidedinadditiontothematerialsnormallysenttoadvisorycommitteemembers.

UseofPrimaryReviewers

TheCDRHassignsprimaryreviewresponsibilityforaparticularPMAtooneadvisorycommitteemember,mainlytoobtainaclinicalevaluationoftheapplication.TheIOMcommitteebelievesthatthispracticealsoensuresamorethoughtfulcommitteediscussionanddistributestheworkloadwithinthecommittee.Inaddition,thispracticehasgreatutilityinthosesituationsinwhichthematchbetweencommitteeexpertiseandaparticularagendaitemmaybeweak.(Seethe"customtailoring"discussionbelow.)

TheIOMcommitteerecommendsthatthethreecentersconsidertheroutineassignmentofonememberoftheadvisorycommitteetoconducttheprincipalreviewofeachapplication.

CommunicationsIssuesBeforeanAdvisoryCommitteeMeeting

Fivetypesofcommunicationbeforeanadvisorycommitteemeetingdeserveattention:FDAcommunicationtocommitteemembers;communicationamongmembers;communicationbetweensponsorsandmembers;FDAcommunicationtosponsors;andFDAcommunicationtothepublic.

FDACommunicationtoAdvisoryCommitteeMembers

AdvancecommunicationbyFDAofficialswithadvisorycommitteemembersbeforeameetinghasgenerallybeenlimitedtoonememberatatime.TheimpressiongainedbytheIOMcommitteeduringitsstudy,basedondiscussionswithFDAstaff,wasthatagencypersonnelbelievedthattheycouldnotdiscussanysubstantiveissuewithmorethanasingleadvisorycommitteememberatatimewithoutviolatingtheFederalAdvisoryCommitteeAct(FACA).Thisimpressionwas

reinforcedbytheIOMcommitteememberswhowereorhadbeenFDAadvisorycommitteemembers.

However,whenaskedbytheIOMcommitteeaboutthegroundrulesforcommunicationsfromFDApersonneltocommitteemembers,theChiefCounseltotheFDArespondedinthisway:

Inourview,FDAstaffcouldlegallydiscusssuchpreliminaryissuesasagendatopics,materials,andquestionswithapartofanadvisory

committeethatwaslessthanthefullcommitteewithouttheindividualshavingtheconversationbeing"utilized"asanadvisorycommitteeandwithouthavingtheconversationdeemedameeting.Indeed,theNationalAnti-HungerCoalitioncasesuggeststhatacombinationofagencystaffandcommitteemembersmayevenholdsubstantivediscussionsoutsideofannouncedcommitteemeetings,ifthediscussionsarepreliminary,areofastaffnature,anddonotinvolvegivingadvicetoanagency,andsolongasanypreliminaryadvicearrivedatisrenderedtotheagencybythefullcommittee.

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ThepracticesofsomeFDAcenters,shesuggested,maybestricterthannecessarytoreduceanylegalrisk.

OnecaveatsuggestedbytheChiefCounselwasthattheOfficeofGovernmentEthics(OGE)mayholdtheopinionthatreviewofmaterialsbyanadvisorycommitteememberbeforeacommitteemeetingmayconstituteparticipationin"aparticularmatter"andthusrequirescreeningforconflictofinterestand,ifnecessary,theissuanceofawaiverbeforeittakesplace."Thisisnot,"shewrote,"currentpracticeatFDA."TheextensionoftheOGEviewtoFDAcommunicationwithsomecommitteemembersmightrequireconflictscreeningandtheissuanceofawaiver,evenfordiscussionsthatarepreliminary.SeveralattorneyswhocommunicatedwiththeIOMstudycontendedthatanyagencycommunicationswithadvisorycommitteemembersbeforeameetingshouldberegardedasexpartecommunicationsandthatproceduralguidelinesshouldbeestablishedtorestrictthem.Thelawdoesnottreatagencycommunicationsasexparte;thus,proceduralguidelinesofthekindenvisionedarenotrequired.Theneedforsuchguidelinesturnsontheconceptualizationofadvisorycommittees:whethertheyareadjudicatorybodieshearingthepresentationsoftwocontendingpartiesoradvisoryadjunctstothe

administrativeprocess.Iftheformer,detailedguidelinesforcommunicationbetweenagencyandadvisorycommitteemembersbeforeameetingmaybeappropriate.Ifthelatter,theneedforsuchguidelinesbecomeslesscompelling.TheIOMcommitteestronglybelievesthatthelatterdefinitionappliestotheadvisorycommitteesusedbytheFDA.Thus,thecurrentlevelofconcernaboutinteractionsbetweenFDAstaffandadvisorycommitteemembersmaybemisplaced.

TheIOMcommitteenotesthisdiscrepancybetweenwhatguidesagencypracticeandtheviewsoftheChiefCounsel,endorsestheopinionofthelatter,andrecommendsthattheFDAclarifyitsguidancetoFDAstaffandtoadvisorycommitteemembers.

CommunicationAmongAdvisoryCommitteeMembers

TheFACAhasalsobeeninterpretedbysomeFDAofficials,andinconsquencebymanyadvisorycommitteemembers,asprecludingtelephoneorface-to-facecommunicationbetweentwoormorecommitteemembersintheperiodafterreceiptofthematerialstobereviewedataforthcomingmeetingbutbeforethemeetingitself.Thispresumedlimitationhasbeeninterpretedtoprohibit,forexample,consultationbyacliniciancommitteememberwithastatisticianmemberonmattersofclinicaltrialdesign,dataanalysis,ordatainterpretation.Therationaleforsuchaprohibitionstemsfromadesiretoprecludeaminorityofanyadvisorycommitteefromestablishingapositionbeforeameetingandexertinginfluencefavoringthatpositionincommitteediscussions.

ThepresumedlimitationunnecessarilyrestrictsdiscussionamongcommitteemembersandisnotrequiredbytheFACA.*Again,theFDAChiefCounselhaswrittenthat"thatpreliminarydiscussionsamongcommitteemembersdonotviolateFACA."Inshort,staffinstructionsagainstsuchconsultationsmayseemoverlycautious.

TheIOMcommitteenotesadiscrepancybetweenpracticeinsomepartsoftheagencyandtheviewsoftheChiefCounsel,endorsestheopinionofthelatter,andrecommendsthattheagencyclarifythelegalbasesgoverningcommunicationamongadvisorycommitteemembers.If,asexpected,theChiefCounsel'sopinionreflectsagencypolicy,thisshouldbeclearlycommunicatedinwritingtoallFDApersonnelwhodealwithadvisorycommittees,tocommitteemembersthemselves,andtootherinterestedparties.Preliminarydiscussionsamongmemberstoclarifytechnicalissuesforinformationpurposesonlyshouldnotbediscouraged;thelimitsonsuchconsultationsshouldbeclearlydefined;committeemembersshouldbeinstructedtodocumentsuchconsultationsbyalogorother,similarmeans;andtheseconsultationsshouldbedisclosedateachcommitteemeeting.

TheissueofFDAcommunicationtoadvisorycommitteemembersandcommunicationamongmembersispoorlyunderstoodbothwithinFDAandoutsidetheagency.Itisveryimportantthattheagencyclarifythelegalissuesgoverningsuchcommunicationandprovideappropriatewritten

*Whenthislimitationiscoupledwithcommitteemeetingsthatarealmostentirelypublic,itgreatlyattentuatesthebenefitoftheintellectualgive-and-takeamongexpertsthatprovidestheinitialimpulseforconveningadvisorycommittees.

guidancetoFDAstaff,alladvisorycommitteemembers,andotherinterestedparties.

CommunicationBetweenSponsorsandAdvisoryCommitteeMembers

AsamatterofFDApolicy,sponsorsarediscouragedfromcommunicatingdirectlyorindirectlysavethroughtheagencywithadvisorycommitteemembersbeforeameeting.Theagencyinformssponsorsandcommitteemembersofthisstricture.Thispolicyisdesigned,ingeneral,toprotecttheindependenceofthecommitteefromlobbyingbysponsors.

TheIOMcommitteeaffirmsthesoundnessofthispolicy.

AgencyCommunicationtoSponsors

TheFDAisgovernedbytheFreedomofInformationAct,(21CFR20),andfederalconfidentialitylawswithregardtothepublicdisclosureofmaterialsitprovidestoadvisorycommitteemembers.Theagencyisnotobligatedtosharewithsponsors,orthegeneralpublic,alloftheinformationprovidedtoadvisorycommittees."Draftquestions,proposedagendas,andFDAstaffanalyses"areexemptfromthepublicdisclosurerequirementsof5USC552(b)(5).

TheFDAtakestheviewthatitisnotobligatedtosharewithsponsorsitscommunicationstoadvisorycommitteemembersinadvanceofameeting.TheIOMcommitteebelieves,however,thatitisappropriatefortheFDAtoprovidesponsorswithcopiesofallinformationthatitsendstoadvisorycommittees.Thisfacilitatesthepreparationbythesponsorofitsresponsetoagencyquestions.

TheIOMcommitteerecommendsthattheFDAprovidesponsorsofapplicationswiththesamematerialsthatitsendstoadvisorycommittees.Questionsshouldbesenttocommitteesandsponsorsonthesameschedule.

CommunicationBetweentheFDAandthePublic

Regardingthepublicreleaseofthequestionspreparedfortheadvisorycommitte,thegeneralpracticeoftheFDAhasbeentomakethemavailabletothepubliconthemorningofameeting.TheIOMcommitteeagreeswiththispracticeanddoesnotrecommendearlierreleasetothepublic.ThereportbyKutak,Rock&Campbell,whichdealtwithFDA'shandlingoffinanciallysensitiveinformation,basicallyconcurredthatFDAreleaseofthe

questionstothepubliconthemorningofacommitteemeetingwassoundpractice.

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TheIOMcommitteedidnotexamineatanylengththequestionsregardingFDAadvisorycommitteesandtheeffectoftheirmanagement,includingthetimeofthepublicreleaseofthequestionspreparedforcommittees,ontradinginthesecuritiesmarkets.TheFDAhasbeforeittheKutakRockreportonfinanciallysensitiveinformationandthisIOMreportonadvisorycommitteesandmustaddresstheimplicationsofwherethesetworeportsintersectandmaketheappropriatepolicydetermination.

ConductinganAdvisoryCommitteeMeeting

Theprimaryobjectiveofanadvisorycommitteemeetingshouldbetofacilitatetheindependent,thoroughdeliberationsofcommitteemembers.Inthiscontext,independencemeansfreedomfrominfluencebythesponsoroftheproductunderconsideration,byanyotherinterestedparties,andbytheagencyitself.Toprovidethisindependence,asecondaryobjectiveshouldbetominimizetheopportunitiesfortheFDA,orotherparties,toexertundueinfluence,ortoappeartodoso,overcommitteedeliberations.Thediscussionandrecommendationsofthissectionaredirectedtowardachievingtheseobjectives.

RolesofthePrincipalParticipants

Thereareinvariablyfourprincipalparticipantsinthetypicaladvisorycommitteemeeting:thecommitteemembers,thechair,theFDAprofessionalstaff,andthesponsorofanapplication.Consultantsalsofunctioninsignificantwaysinmanycommitteedeliberations.

Theroleofadvisorycommitteemembersistoprovideindependent,expertscientificadvicetotheagencybyrespondingtospecificquestionsaboutstudydesignormethodology,adequacyofdata,andassessmentandinterpretationofrisksandeffectivenessthathavebeenidentifiedbytheFDAprofessionalstaff.Theabilityofcommitteememberstocarryoutsucharoleisfacilitatedbytheirexpertise,theprovisionsforadvancepreparationdiscussedabove,andthe"rulesofthegame"forcommitteemeetings,whicharediscussedhere.

Theroleoftheadvisorycommitteechairiscriticaltotheeffectiveperformanceofacommittee.Thechairshouldcontrolagendatimeefficiently;protectcommitteediscussiontime;ensure,inconsultationwithagencystaff,thatthemeetingarrangementsfacilitatecommitteedeliberations;regulate,asnecessary,mediacoverageofmeetings;andensurethat

committeedeliberationsarebroughttoclosurebyprovidingclearadvicetotheagencyonthequestionsaskedofthecommittee.

FDAstaffareinvolvedinthesubstantiveevaluationofanapplicationandintheorganizationofanadvisorycommittee.Thosewhoreviewanapplicationhavetheresponsibilitytoevaluatethecompleteness,adequacy,andrelevanceofthedata;theanalysesofandconclusionsdrawnfromthedata;andthecompletenessoftheinformationpresentedintherequestforapproval.Whennecessary,FDAstaffmayarrangeforaconsultanttocarryoutfurtheranalysesofthedataorassessmentsoftheirsufficiency.

InCDERandCBER,theexecutivesecretariesareprimarilyresponsiblefortheorganizationandlogisticsoftheadvisorycommitteemeeting.InCDRH,theyplayasomewhatdifferentrolethatderivesfromtheirdualresponsibilitiesasmanagersofthesubstantivereviewandasadministrativesupporttothecommittee.Intheirformercapacity,theyparticipateinthedeliberationsinamannersimilartodivisiondirectorsinCDERandCBER;intheirlattercapacity,theyperformsimilarlytotheexecutivesecretariesintheothertwocenters.

Productsponsorsarethefinalsignificantgroupthatparticipatesinanadvisorycommitteemeeting.Thesponsorsusuallymakeapresentationofthedataontheirproductinpreparationforanargumentthattheproductshouldbeapproved.Thesponsorsmayuseconsultantstopresentthesedata,aswellasindividualpatientsorpractitionerstotestifyontheirbehalf.

AllocationandControlofAgendaTime

Twophenomenaareregularlymentionedbyadvisorycommitteemembersasimpedingcommitteedeliberations.Oneisthatsponsors'presentationsoftenabsorbmoretimethanisinitiallyallocatedbythe

agenda.Thepossiblereasonsforthisareseveral:theinitialtimeallocationmaynotberealistic,whichcallsforpriorconsultationbetweenagencystaffandthechair;themembersmaywishtoquestionthesponsoratgreaterlengththananticipated,whichsuggeststheneedtopollmembersinadvancefortheirquestionssothattheconcernsofseveralmemberscanbeaggregated;orthesponsormayconsciouslypresentmoredatathantheallocatedtimeallows,whichcallsforapriorcommitmentfrommeetingparticipantstoadheretotheschedule.Similarly,FDAstaffpresentationsmayexceedallocatedtimeandthusimpedecommitteedeliberationsaswell.

TheIOMcommitteerecommendsthattheFDAroutinelyconsultcommitteechairsintheallocationoftimetoagendaitemsandthatthisallocationtrytoanticipatepointsthroughoutthemeetingatwhichcommitteequestioningwillbelikelyItfurtherrecommendsthat

committeechairsbeinstructedthatthecontrolofagendatimeisoneoftheirprimaryresponsibilities,*andthattheymustworktoprotectcommitteediscussiontime,includingexercisingstrictcontrolonthepresentationsofsponsorsandtheFDAbeforethecommitteeandattendantquestionsanddiscussionsbycommitteemembers.

Theprincipalreasonforexercisingstrictcontrolovertheagendaistoprotectcommitteediscussiontime,whichisvulnerabletoerosionbythefactorslistedabove.Inaddition,becausecommitteediscussionisoftenscheduledattheendofameetingitmaylacktheparticipationofallmembers,especiallythosefromtheWestCoast,whobeginleavingfortheairportinthelateafternoon.

ElectronicCoverageofMeetings

Televisionnewsnetworks,withcameras,kleiglights,andassociatedequipment,areacommonandoftenintrusivepresenceatFDAadvisorycommitteemeetings.Guidelinesgoverning''electronicrecordingequipment,''**butpertainingmainlytotelevision,havebeensetforthin(21CFR10,SubpartC(200206)).Theseregulationsvestauthorityfortheiradministrationinthe"designatedpresidingofficer,"presumablythechairofanadvisorycommittee.

TheIOMcommitteerecommendsthatadvisorycommitteechairsberoutinelyorientedtotheirauthoritiesandresponsibilitiesinregardtothecontrolofelectroniccoverageofadvisorycommitteemeetings,forthepurposeoffacilitatingcommitteedeliberationswithoutcompromisingthepublic'srighttoknow.

Inadditiontotelevision,theaudienceofanadvisorycommitteemeetingoftenincludesindividualswithotherelectronicdevices,suchasrecordingmachines,telephones,andcameras.Theseareoftenreferredtoasnuisanceitemsbutposerelativelyfewproblemsforadvisorycommittees,whichconductpracticallyalloftheirbusinessinopensessions.

*FDAregulationsgrantauthoritytoadvisorycommitteechairto"conducthearingsandmeetings,includingtheauthoritytoadjournahearingormeetingifthechairmandeterminesthatadjournmentisinthepublicinterest,todiscontinuediscussionofamatter,toconcludetheopenportionofameeting,ortotakeanyotheractiontofurtherafairandexpeditioushearingormeeting"[21CFR14.30(a)].**Thetermisdefinedas"anyvisualoraudiorecordingmadebyvideotaperecordingequipmentormovingfilmcamera,and/orotherelectronicrecordingequipment."

Voting

VariationsexistintheuseofvotingbyFDAadvisorycommittees.InCDRH,allcommitteesareaskedtovoteontheregulatoryissueofwhetheragivenmedicaldeviceshouldbeapproved.ThispracticeisbasedonCDRH'sinterpretationthatavoteisrequiredbytheprovisionoftheMedicalDeviceAmendmentsof1976thatcallsforanadvisorypaneltosubmita"reportandrecommendation...withrespecttoanapplication"[Food,Drug,andCosmeticAct,§515(g)(2)(B)].CDRHadvisorypanelsarenot,however,askedtovoteonthescientificquestionsofwhetherinformationinanapplicationshowsa"reasonableassurance"thatadeviceissafeandeffective''undertheconditionsofuseprescribed,recommended,orsuggestedintheproposedlabellingthereof"[Food,Drug,andCosmeticAct,§515(d)(2)(A,B].

InCDERandCBER,votingpracticesfollowthediscretionofthecommitteechairorthetraditionofthereviewingdivision.Somedivisiondirectorstakenovotes,someaskforvotesonlyonscientificquestions,andothersrequestvotesonregulatoryquestions.

TheIOMcommitteerecommendsthatFDAadoptapolicy,consistentacrossalladvisorycommittees,bywhichcommitteesareaskedforavoteonimportantquestionsbeforethecommittee.Totheextentfeasible,thechairshouldidentifyinadvancetheissuesonwhichvotesaretobetaken.

TheIOMcommitteediscussedatlengthaproposalbyonemember

5thatadvisorycommitteevotesonquestionsbeforethembescaled(forexample,fromonetonine),ratherthanbinary(yes,no).Thisproposalisbasedonthreepremises.First,safety,effectiveness,andotherfactorsconsideredinadvisorycommitteerecommendationsarecontinuousvariables.Second,giventhattherearenodefinitiveempiricalbasesfordecidingissuesbeforeanadvisorycommittee,the

FDAshouldseektodetermineboththerangeandstrengthoftheexperts'opinions.Third,agooddealcouldbelearnedbyfrequentscaledvotesaboutthemultiplefacetsofcomponentquestionsthatcomebeforeacommittee,includingthedistributionofviewsamongmembersonparticularissues,aswellasanypersistentvotingpatternsorapparentbiases.

TheelementsoftheproposalarebasedonthemodifiedDelphisystemusedbytheRANDCorporation'sappropriateness-of-carestudies.IntheRANDapproachtovoting,allvotesarescaledfromonetonine;individualvotesaresecret,buteachmemberreceivesthedistributionandhisorhervoteaftereachround;thereareusuallytworoundsofvotesperquestion,

withcommitteediscussionbetweeneachround;summarystatisticsaregeneratedoneachquestion(e.g.,themedianafteromittingoutliers);andthevotedistributionandsummarystatistics,butnotindividualvotes,becomeamatterofrecord.

TheIOMcommitteewasintriguedbytheproposalbutfoundittoonovelandformalistictorecommendforgeneraladoptionbytheFDA.Thecommitteefavoredbinaryvotesthatforcedindividualmemberstoresolveuncertaintyinanup-or-downmannerandprovideunambiguousadvicetotheagency.Itthoughtthatscaledvotesonregulatorydecisionstoapproveordisapproveaproductmightbeconfusingtotheagencyandtointerestedparties,atleastinitially.However,theIOMcommitteecommendedtheproposaltousenonbinary,sophisticatedvotingproceduresandtallyingtotheFDAforconsiderationonapilotordemonstrationbasis.

AgencyNeutrality

Severalissueswereconsideredthatrelatetotheneutralityoftheagencyinitsrelationswithadvisorycommittees.Theseincludeagencypresentations,agency-committeeinteractions,andseatingarrangements.

AgencyPresentations

TheIndustryLiaisonPanelemphasizedtheimportanceitattachestoneutralityofpresentationbytheagency.Suchneutralityincludesboththeadoptionofadispassionatetoneandthewithholdingofanyjudgmentaboutasubmission,evenifasked.

Agencyresponsestotheimplicationsofthisviewvary.SomeFDAofficialscounterthatsponsorpresentationsroutinelylackneutralityandreflect(charitably)a"bestfootforward"posturethatminimizestheproblemsandhighlightsthepromisesofanapplication.Thoseholdingthisviewseethemselvesasobligatedunderthestatutes

governingFDAtoacttoprotectthepublichealthandtoexposetheweaknessesofasponsor'ssubmissionandpresentation.Neutrality,underthecircumstances,isneitherpossiblenordesirable.

OtherFDAofficialsviewtheagency'sresponsibilityasoneofpresentingathorough,faircritiqueinascientificallyobjectivewayandwithholdinganyexpressionofajudgmentaboutwhatshouldbedonewiththeapplication.Ifaskedforajudgment,someofficialsfeelobligedtorespond,whileothersdeclinetodoso.

TheresponseofDr.RobertTempletotheIndustryLiaisonPanelreportdeservesquotation:

Whileitiscriticaltobecertainthecommitteeisindependentinansweringourquestions,itisnotnecessarytopretendthatFDAhasnoviewpoint.WhileFDAmayhavereachedconclusionsinsomecases,itmaystillhaveothercriticalquestionsforthecommittee.Forexample,wedonotnecessarilyneedtoaskanadvisorycommitteewhetherstudiesareadequateandwell-controlled.Wehaveusuallygivenstudiesfargreaterscrutinythanthecommitteescanandmayhavereachedtheconclusionthatthey[thestudies]indeedarewell-controlled.Ontheotherhand,havingconcludedthatstudiesarewell-controlledisnotthesameassayingthattheeffectshownisofvalueorthattheadversereactionselicitedareacceptableinviewoftherisks.Wethusmightwellgotoacommitteebelievingthatthestudiesthemselvesarewell-designedandacceptablebutaskingthecommitteeaboutthepersuasive-nessoftheoutcome.InthatcasethereisnoreasontopretendthatFDAhasnoviewastotheadequacyofthestudies.Inothercases,wemightbelievethatstudieswerefatallyflawed,e.g.,notlongenough.Wewouldneedtoknowthecommittee'sviewsonthis,whichisobviouslyamatterofjudgment.Ourquestionsforthecommitteeneedtoposethequestionclearly,sothecommitteecanprovideaclearviewpoint,agreeingordisagreeing.ItisnotleadingthecommitteemerelytotellthecommitteewhereFDAstands.KnowingFDA'sinitialviewdoesnotpreventthecommitteefromreachingadifferentconclusionandFDAispreparedtoreviseevenconclusionsitthoughtithadreached.

Ithusstronglydisagreewiththe[panel's]recommendationthatquestionsposedtothecommitteeshouldbeneutralinallcases.Itisreasonabletotakeaquestiontothecommitteethatindicatesapointofviewbytheagencysolongasitisalsoentirelyclearthatthecommitteeisinvitedtoexpressadifferentviewifthatiswhatitbelievesandtoexplainitsreasoningtotheagency.

6

TheIOMcommitteebelievesthatagencypresentationsofitsreviewsofasponsor'sapplicationshouldreflectacriticalbutfairevaluationof

thedata.Iftheagencyhasproblemswiththeapplication,theidentificationofwhichrevealstheagency'sconclusion(tentativeorfixed),thecommitteeseesnoreasontoobjecttothecommunicationofthoseconcerns.Indeed,failuretodosomightbeconstruedasmanipulationbynotapprisingthecommitteeoffactorsthatwillbeimportantintheagency'sofficialdecision.

Ontheotherhand,theIOMcommitteestronglybelievesthatagencypresentationsaboutasponsor'sapplicationshouldbeprofessionalintone,andthorough,fair,andscientificallyobjectiveintheircritiques.Theagencyshouldacknowledgeitspublichealthresponsibilitiestoensurethatsponsorsprovideevidenceofproductsafetyandeffectiveness.

FDA-CommitteeInteraction

OnequestionthathasbeenraisedishowFDAstaffshouldinteractwithadvisorycommitteesintheconductofameeting.Asageneralproposition,agencystaffshouldnotattempttodominatecommitteediscussionsbutshouldseek(withthehelpandunderthecontrolofthechair)toelicittheviewsofadvisorycommitteemembers.ThechairofacommitteeshouldbeinstructedabouttheimportanceofappropriateuseofdiscussiontimebyFDAstaffandshouldexercisecontroloverthemeetingaccordingly.

SeatingArrangements

Complaintshavebeenmadethatsomeseatingarrangementsatadvisorycommitteemeetingssuggestanefforttoinfluencetheoutcomeofthedeliberations.TheIOMcommitteebelievesthatthegeneralprinciplethatshouldgovernseatingarrangementsisthattheyshouldbemade,totheextentphysicalfacilitiespermit,tofacilitatethedeliberationsofthecommittee.Thedivisiondirectorshouldnotsitnexttothecommitteechair.OtheragencypersonnelshouldbeplacedsothatademarcationbetweencommitteemembersandFDAstaffisapparent.

ClosedDeliberations

Manyadvisorycommitteemembers,bothpastandpresentandincludingthoseservingontheIOMcommittee,thoseinterviewedbythecommittee,andothers,havevoicedthecomplaintthattheyarealwaysrequiredtofunction"onstage"andwithouttheopportunityforcloseddiscussions.Thepreferenceforthelatterstemsmostoftenfromadesireofscientiststoengageincritical,oftenvigorousback-and-forthtechnicalargument,whichisimpededandoftenthwartedbytheconstraintsofatelevised,openmeetingbeforeanaudienceofseveralhundredindividuals.

Regrettably,fromthestandpointoffacilitatingscientificdeliberations,therequirementsofFACAandtheGovernmentintheSunshineActmakeitimpossibletoclosecommitteemeetingssaveexceptindefinedcircumstances.Theseincludethediscussionofproprietaryinformationor,onoccasion,confidentialinformationaboutindividuals.

CustomTailoringofCommitteeMembership

AsindicatedinChapter3,theCDRHreorganizeditsadvisorycommitteesystemin1990,formallydisestablishing17committeesandreconstitutingthemaspanelsunderasingleMedicalDevicesAdvisory

Committee.Subsequently,thecombinationproductrequirementsoftheSafeMedicalDevicesActof1990ledtheFDAtoissueproductjurisdictionregulationsinNovember1991;inthatsamemonthitannouncedthreeinter-centeragreementsonthesamesubject.TheseeffortsledtoarecharteringofboththeCDERandCBERadvisorycommittees,aprocessthatisbeingcompletedthisyear.

Underthesenewarrangements,eachofthesethreecenterswillhavetheauthoritytodrawneededexpertsfromalongslateofcommitteememberstoserveasfullvotingmembersatspecificpanelmeetings.Thispolicyisintendedtominimizethedifficultiesofassuringaquorum,tominimizeconflict-of-interestproblemsbyexpandingthepoolfromwhichadvisorycommitteemembersaredrawn,andtoallowabettermatchofexpertisetoagendaitems.

Inaddition,however,theseactionsmayengenderatensionbetweenincreasedflexibilitytomatchexpertisetoneedandthepossibleappearanceofagencyeffortstochoosemembersofanadvisorycommitteetoachieveadesiredoutcome.Ontheonehand,theIndustryLiaisonPanelrecommendedthecreationofalargepoolofexpertsonwhomFDAcoulddrawforadvisorycommitteemembersasameanstoensureamatchbetweenexpertiseandagendaitem.Thisproposalreflectstheviewthatthecompetenciessoughtonanadvisorycommitteeareoftenspecifictoagivenagenda.

Ontheotherhand,composinganadvisorycommitteefromalargerpoolofmembers,howeverthatpoolisconstituted,isnotwithoutproblems.Buildinganadvisorycommitteearoundaspecificagendaleavestheagencyopentoaccusationsthattheagencyismanipulatingthecommitteetoachieveadesiredoutcome.Given,however,thatthecommitteesareonlyadvisoryandthattheFDAisnotboundbytheiradvice,theargumentthattheFDAwoulddeliberatelyconstructacommitteearoundaspecificpointofviewisnotcompelling.

TheIOMcommitteecommendstheagencyforitsrecharteringoftheCDRH,CDER,andCBERadvisorycommitteestopermitgreaterflexibilityincomposingacommitteeinwhichexpertiseisrelatedtothesubjectmatteroftheagenda.However,theIOMcommitteealsourgescareincomposingcommitteesfromthelargerpoolofavailablemembers.

TheIOMcommitteerecommendsthat,ininstancesinwhichtheFDAmustmodifythecompositionofanadvisorycommitteeby"customtailoring,"itdosojudiciouslyandsparingly,augmentingthecorecommitteebyaddingtheneededexpertise.ThecommitteealsorecommendsthattheFDAactivelyconsultthecommitteechairinthe

process.Inaddition,itrecommendsthatthedirectoroftheappropriateFDAcenterapproveallsuchdecisions.

MeetingFollow-up

AdvisorycommitteemembersfrequentlycomplainthatFDAprovidesnofeedbacktothemontheresultsoftheirdeliberations.Theyhavenodirectknowledgeoftheeffectoftheircontributionsand,insomemeasure,regardtheirinputasdiminishedasaresult.

TheFDAdoesnotstronglydefenditscurrentpractice.Itoftennotesthatresourcelimitationsonprofessionalstaffpreventitfromfulfillingthisfunctionadequately.ItalsonotesthattheprogressofanNDAapprovaliscloselyfollowedbythefinancialinvestmentcommunity,andsimpleprudencearguesagainstinformingcommitteemembersofaforthcomingapprovalinadvanceofnotifyingasponsor.

TheIOMcommitteerecommendsthattheFDAfollowupeachadvisorycommitteemeetingasfollows:routinelyandimmediatelyprovidecommitteememberswithacopyofallpressreleasesissuedafteracommitteemeeting;informmembersbyFAXatthetimeofdecisionabouttheapprovalordisapprovalofanyapplicationthatthecommitteehasconsidered;routinelyreportonthestatusofmatterspreviouslyconsideredbythecommitteeatthebeginningofeachmeeting;andreportannuallythedispositionorcommittee-relatedmatters.

Notes

1.MemorandumfromBruceBurlington,M.D.,DeputyDirectorforScientificandMedicalAffairs,toCarlC.Peck,M.D.,Director,andGeraldF.Meyer,DeputyDirector,CenterforDrugEvaluationandResearch,"AdvisoryCommittees::PolicyandPracticesinSelectionofAgendaItemsToBeConsideredbyCenterforDrugEvaluationandResearchAdvisory,"September1991.

2.MemorandumfromRobertJ.Temple,M.D.,Director,Officeof

DrugEvaluationI,toRichardA.Rettig,InstituteofMedicine,"CommentsontheIndustryLiaisonPaneltotheIOMCommitteetoStudytheUseofAdvisoryCommitteesbytheFDA,"July8,1992.

3.LetterfromMargaretJanePorter,ChiefCounsel,FoodandDrugAdministration,toRichardA.Merrill,Professor,SchoolofLaw,UniversityofVirginia,June24,1992.

4.Kutak,Rock&Campbell.FDASafeguardsAgainstImproperDisclosureofFinanciallySensitiveInformation.FinalReport(Washington,D.C.,November14,1991).

5.MemorandumfromAlbertP.Williams,Ph.D.,toRichardA.Rettig,"BetterUseofFDAAdvisoryCommitteesThroughVotingRules,"March10,1992.

6.Op.cit.,MemorandumfromRobertJ.TempletoRichardA.Rettig.

8OrganizationandManagementTheIOMcommitteewasaskedtoconsiderwaysofimprovingFDAmanagementof,andaccountabilitywithrespectto,theadvisorycommitteesystem.Inthischapter,thecommitteeexaminesseveralissuesoforganizationandmanagementofFDAadvisorycommitteesthathavebeenraisedbythisstudy.Manyoftheseissueshavesurfacedinpriorreports.In1990,forexample,theLasagnaCommitteereportrecommended"afundamentalrestructuringof[theadvisorycommittee]system.Thecommitteesshouldhavetheirownindependentstaffandshouldbeappointedby,andreportdirectlyto,theOfficeoftheFDACommissioner[emphasisadded]."

TheIndustryLiaisonPanelrecommendedasomewhatdifferentapproach:

Webelievethatthecommitteesystemmustbeenlarged,thatmoreformaltrainingofcommitteemembersandexecutivesecretariesshouldbeinstituted,andthatguidelinesshouldbedevelopedsothateachFDADivisionoperatesitscommitteesunderthesameprinciples.Toaccomplishthisastrongcentralofficeforcommitteemanagementisrequired.Toassureuniformityandadherencetoestablishedpolicies,thisofficeshouldhandlebothdrugsandbiologics.Theindustryliaisonpanelfeelsthatstatutorydifferencesbetweendrugsandbiologicsontheonehandandmedicaldevicesontheotheraresuchthatitmaybemoreappropriateformedicaldevicestobemanagedseparately[emphasisadded].However,manyofthepolicies,proceduresandtrainingprogramswouldbeapplicabletomedicaldevicesaswellasdrugs/biologics.Theindustryliaisonpanelrecommendsthatuniformproceduresbeutilizedwherepossible.

Thesedifferentproposals,alongwithotherinputsreceivedbythe

IOMcommittee,highlighttheneedtoaddressissuesoforganizationandmanagement.Thischapter,therefore,considersthemanagementofthe

advisorycommitteesystem,thecompensationofadvisorycommitteemembers,theirorientationandtraining,andsuggestionsthatFDAcreateadvisorycommitteesinadditiontoitstechnicalcommittees.

SystemManagement

TheIOMcommittee,asitexaminedwaystoimprovethemanagementandaccountabilityoftheadvisorycommitteesystem,concludedthatanecessarypartofitsworkwastoconsiderhowtheFDAcurrentlysupportsandmanagesthissystem.ItfoundfewpriorreportsorcurrentassessmentsthatidentifiedthekeyFDAplayersandspecifiedtheirrespectiveroles.ThissectionconsiderstherelationshipsamongadvisorycommitteesandtheCommissionerandhisoffice,thecenterdirectors,theofficeanddivisiondirectorsresponsibleforproductevaluation,andtheexecutivesecretaries.Itspurposeistoclarifytherolesoftheserespectiveofficialsinadvisorycommitteemanagement.

TheCommissionerandHisOffice

FDAadvisorycommitteesareformallycharteredbytheCommissionerofFoodandDrugstoadvisehiminthedischargeofhisresponsibilitiesrelatedtoensuringthesafetyandeffectivenessofdrugs,biologics,andmedicaldevicesforhumanuse.Thus,thedejurereportingrelationshipofadvisorycommitteestotheCommissionerisnotinquestion.

TheIOMbelievesthattheauthoritytocreatetechnicaladvisorycommitteesshouldbevestedintheCommissionerofFoodandDrugs(andnotinanyhigherofficial)andthattheformalreportingresponsibilityofadvisorycommitteestotheCommissionerisappropriate.However,asapracticalmatter,itisnotfeasibleforcommitteestoconveytheiradvicetotheCommissionerdirectly,saveonafewoccasionsofhischoosing.CommissionerKessler,whomayhaveattendedmoreadvisorycommitteemeetingsthananyofhis

predecessors(perhapsmorethanallofthemtogether),indicatedattheinitialmeetingoftheIOMcommitteethatitwasnotfeasibleforadvisorycommitteestoreportdirectlytohimonaregularbasis.Advisorycommitteesusuallyreporttothedirectoroftheproductevaluationofficeandtothedirectoroftheresponsiblereviewingdivision,thesignificanceofwhichisexaminedbelow.

WhatistheroleoftheCommissioner?TheIOMcommitteebelievesthattheCommissionermustsetthetoneforallagencypersonnelregardingtheimportanceattachedtotheeffectiveperformanceofFDAadvisorycommittees.Heshouldalsocommunicateforcefullytoadvisorycommitteemembersthemselves,toacademicmedicalscientists,andtotheregulated

industries,bothformallyandthroughallinformalmeansavailable,theimportancethattheFDAattachestothisformofpublicservice,whichbenefitsthepublichealthofthenation.

TheIOMcommitteehasalsoconcludedthattheOfficeoftheCommissionerhasadistinctroletoplayintheFDAadvisorycommitteesystem.Theadvisorycommitteesystemhasincreasedinuse,inimportance,andinpublicvisibilityinrecentyears.Moreover,enoughcontroversiesinvolvingadvisorycommitteeshaveoccurredinthepasttwoyearstojustifycontinuingattentionbytheOfficeoftheCommissioner.Duringthistime,however,therehasbeennohigh-levelofficialintheOfficeoftheCommissionerwithadesignatedresponsibilityforagency-widepolicyandmanagementguidanceforadvisorycommittees.TheIOMcommitteeconcludesthatthisdeficiencyshouldberemedied.

TherearethreeunitsintheCommissioner'sofficeinvolvedinadvisorycommitteematters,twowithadministrativeresponsibilities,andoneinpolicy.TheOfficeofCommitteeManagementpreparestheannualreportonadvisorycommitteesthatisrequiredbytheFederalAdvisoryCommitteeAct(FACA).TheDivisionofEthicsandProgramIntegrity,asdiscussedinChapter6,reviewsinitialcommitteenominationsforconflictofinterestandalsoprocessesconflictwaiverrequests.Neitherentityprovides,norisequippedtoprovide,policyguidancetothevariouscenterswithrespecttotheadvisorycommitteesystem.Theadvisorycommitteefunctionsofeachshouldbeconsolidatedundertheauthorityofthepolicyofficialrecommendedhere.

TheOfficeoftheOmbudsman,however,hasbeenrecentlycreated(1990)withintheCommissioner'soffice.Itdealswithspecificcomplaintsinvolving,amongothersubjects,advisorycommittees.TheOmbudsmanhasalsobeenresponsibleforproductjurisdiction

andcombinationproductregulations,therelatedintercenteragreements,andtherecharteringofCDERandCBERcommitteesthatresulted.

Earlyinhistenure,CommissionerKesslerinitiatedareorganizationthatincludedthecreationoffivedeputycommissioners(ortheirequivalent)intheCommissioner'soffice.Theseweredeputiesforoperations,policy,andexternalaffairs,asenioradviserformanagement,andascienceadvisertotheCommissioner.Notably,thedirectorsofallFDAcenters,includingthosefordrugs,biologics,andmedicaldevices,nowreporttotheDeputyCommissionerforOperations.

WhatadvisorycommitteesystemfunctionsmightbeperformedbytheOfficeoftheCommissioner?InthejudgmentoftheIOMcommittee,aneedexistsforclearpolicyandmanagementguidancetotheFDAadvisorycommitteesystemfromtheCommissionerregardingtherole,importance,andgeneraloperationsofadvisorycommitteesintheworkoftheagency.

Specifically,thefollowingpotentialtasksmightbeconsideredasappropriate:

monitortheperformanceoftheadvisorycommitteesystemfortheCommissioner;

exerciseleadershipinstandardizingcommitteeproceduresandreducingunjustifiedvariationwhereverfeasible;

coordinateagency-wideadvisorycommitteefunctions;

overseethecomputerizationofcommitteeprocesses;

monitorchargesof''undueinfluence''ofFDAoveradvisorycommittees;

articulatepolicyandmonitorperformanceoftherecruitmentofadvisorycommitteemembers,especiallywomenandminorities;

coordinateconflict-of-interestpoliciesandproceduresaffectingadvisorycommitteesonbehalfoftheCommissioner,andnegotiatewiththeDHHSOfficeoftheSpecialCounselforEthicsandtheOfficeofGovernmentEthicsontheagency'sbehalf;

reviewallexistingregulations,forms,andimplementingdocumentspertainingtoadvisorycommitteesandrevisethemasappropriate;

reviseandupdatetheStaffManualGuide;and

exerciseleadershipinthedevelopmentandimplementationofanorientationandtrainingprogramfortheadvisorycommitteesystem.

Theabovefunctionsdealwithpolicyandmanagementissues;theyarenotintendedtoinvolvetheday-to-dayoperationsoftheadvisorycommitteesystem.

TheIOMcommitteeregardsthespecificorganizationoftheOfficeoftheCommissionerastheprovinceoftheCommissioner.However,

giventhatallFDAcenters,includingthethreeofconcerninthisstudy,reporttotheOfficeoftheDeputyCommissionerforOperations,itregardsthisofficeasthemostlikelylocationforahigh-leveladvisorycommitteefunction.

TheIOMcommitteerecommendsthatahigh-levelofficialintheOfficeoftheCommissionerofFoodandDrugsbeassignedprimaryresponsibilityfordeveloping,disseminating,enforcing,andmonitoringadministrativepolicyandmanagementguidancetotheadvisorycommitteesofthethreecenters.

CenterDirectors

Thecurrentdirectorsofthethreecentersallstronglysupporttheadvisorycommitteesystem,althoughtheirinvolvementintheworkofthe

committeesvaries.Therolesofthecenterdirectorsarenotspelledoutwithrespecttoadvisorycommittees,however,andtheIOMcommitteehasconcludedthatthiskindofclarificationwouldbeuseful.

Whatfunctionsmightcenterdirectorsbeformallyexpectedtocarryoutwithrespecttoadvisorycommittees?Thefollowingareimportant:

ensureimplementationintheirrespectivecentersofagency-widepolicytowardadvisorycommitteesdevelopedincooperationwiththeOfficeoftheCommissioner;

monitortherecruitmentofadvisorycommitteemembersforexpertise,externalendorsement,andspecialeffortstorecruitwomenandminoritymembers;

reviewall"customtailoring"advisorycommitteemeetingsthatinvolvematchingthecompositionofthecommitteetothetechnicalrequirementsofanagendatoavoidchargesof"undueinfluence";

helpdesignanorientationandtrainingprogramalongthelinesrecommendedbelow;

examineissuesthatmayariseintheworkofoneorseveraladvisorycommitteesthatmaycutacrosstheworkoftheentirecenterandrequireconsiderationonabroaderbasisthanasinglecommittee(ordivision)canprovide;and

supportinnovationintheuseofadvisorycommittees.

OfficeandDivisionDirectors

TheroleofadvisorycommitteescannotbespecifiedclearlywithoutclarifyingthemanagementresponsibilityforadvisorycommitteeswithintheFDA.TheexecutivesecretariesareoftenidentifiedasthekeyFDAofficialsresponsibleforadvisorycommittees.Althoughthis

istrueforadministrativesupportpurposes,itisnotgenerallytrueforthesubstantiveworkofthecommittees.

Authorityforproductapprovalofnewdrugs,biologics,andmedicaldevicesisvestedintheCommissioner,thendelegatedtootherFDAofficials.InCDER,authorityisdelegatedtothecenterdirector,thentothedirectorsofthetwoofficesofdrugevaluation;inthecaseofoncologydrugs,thedelegationisonestepdownwardtothedivisiondirectorforoncologyandpulmonarydrugproducts.Theworkingresponsibilityforproductevaluationandoperationalresponsibilityforapprovalresideswithinthethreecentersatthelevelofthedivisiondirector.Thus,insubstantiveterms,theprimaryresponsibilityformanagementofadvisorycommitteesresideswithdivisiondirectors.

AdvisorycommitteesexisttoprovideindependentexpertadvicetotheFDA,primarilytotheFDAofficialswhoapproveordisapproveapplications.Itisimportant,therefore,toclearlystatethattherelationshipbetweenofficeanddivisiondirectors,ontheonehand,andadvisorycommittees,ontheother,mustbeacomfortable,productiveworkingrelationshipbasedonmutualrespectandacommitmenttoscientificassessmentofnewtherapeuticproducts.Clarifyingthisrelationshipisimportantbothforinternaladministrativepurposesandforexternal"consumption."

Theroleofthedivisiondirectorsinadvisorycommitteemanagementshouldinclude,ataminimum,involvementintherecruitmentofadvisorycommitteemembers,preparationofthecommitteeagenda(withtheadvisorycommitteechair),andpreparationofthespecificquestionsthatthecommitteeisaskedtoconsider(alsowiththechair).

ExecutiveSecretaries

Executivesecretarieshavebothadministrativeandsubstantiverolestoperformintheadvisorycommitteesystem.Theprimaryadministrativeroleshouldbetopromotetheefficientperformanceofanadvisorycommittee.(Byextension,theorganizationoftheexecutivesecretariatshouldbetopromotetheefficientoperationofthesystem.)Specificfunctionsofexecutivesecretariesincluderecruitingcommitteemembersandpreparingnominationpackages;administeringconflict-of-interestreviewsoninitialappointmentandprocessingwaiversforspecificmeetings;arrangingmeetinglogistics(whetheronaninternalorcontractbasis);distributingmaterialstoadvisorycommitteemembers;andfollowingupcommitteemeetings.

Theadministrativeworkoftheexecutivesecretariesintersectswiththesubstantiveagendathatthereviewingofficesanddivisionswishtobringbeforeanadvisorycommittee.Thismayinvolveparticipationinformulatingtheagendaofagivenadvisorycommitteemeeting,

determiningtheappropriatesponsorandFDAmaterialstobesenttothecommittee,andpreparingthequestionsthatthecommitteeisbeingaskedtoconsider.

Currently,CDERisorganizedwithmostexecutivesecretariesassignedtoacentralunitbutwithsomeassignedtoreviewingdivisions.CBERalsohasacentralexecutivesecretariat.CDRHassignsprofessionalsfromreviewingdivisionstoserve,inaddition,asexecutivesecretaries.ExecutivesecretariesinCDERandCBERareengagedinthesupportofadvisorycommitteesonafull-timebasis.CDRHexecutivesecretaries,however,areusuallyprofessionalstaffinvolvedinproductevaluation;thus,theyareengagedinthesubstantiveworkofadvisorycommittees,aswellasprovidingadministrativesupport.

Giventheseadministrativeandsubstantiveresponsibilities,theIndustryLiaisonPanelrecommendedadualreportingarrangementwherebytheexecutivesecretariesreporttoacentralizedunitwithineachcenterforadministrativesupportofadvisorycommitteesandalsotothedirectorsofthereviewingdivisionsforsubstantivesupport.TheIOMcommitteeconcursinthisrecommendation.

TheorganizationoftheexecutivesecretariesisanissuethathasalonghistorywithinFDA,thefocalpointofwhichhasbeenthecentralizationoftheexecutivesecretariat.Thetermhasseveralmeanings.Onemeaningiscentralizationatthelevelofthethreerespectivecenters,whichistheprevailingpattern.Asecondmeaningisaconsolidatedcommitteemanagementstaffthatservesbothdrugsandbiologics,whileleavingCDRHwithitsdistinctivesystemofcommitteemanagement.Finally,thetermcentralizedcanbeextendedconceptuallytoincludeCDER,CBER,andCDRH,althoughthishasneverbeendoneandhasnotbeenseriouslyadvocated.

Historically,thesecondmeaningderivesfrom1982whentheorganizationalunitsresponsiblefordrugsandbiologicsweremergedintoasinglecenter.Acentralizedcommitteemanagementstaffwascreatedatthattime,andthisarrangementcontinuedbeyondthe1987reorganizationthatsplitdrugsandbiologicsintoCDERandCBER.In1991,thecommitteemanagementunitwasfinallysplitintoseparateunitsfortherespectivecenters.

TheIOMcommitteebelievesthattheprimaryfunctionofthecenter-basedexecutivesecretariatshouldbetoprovidetheadministrativeandlogisticalsupportofadvisorycommittees.Efficienciescanbeachievedasexecutivesecretarieslearnfromeachother.However,theargumentforaconsolidatedCDERandCBERunitrests,inpart,onaphilosophythatanexecutivesecretariatshouldhavesomeautonomyfromthereviewingdivisionsandshouldberesponsibleformanaging

theadvisorycommitteesystemtoensuretheindependenceoftheadviceprovidedbyadvisorycommittees.

TheIOMcommitteebelievesthatguaranteeingtheindependenceoftheadviceprovidedbyadvisorycommitteescannotbedonethroughtheexecutivesecretariat,howeveritmaybeorganized.Rather,itrequiresthediligenceofcenterdirectorsandpolicyoversightbytherecommendedhigh-levelofficialintheOfficeoftheCommissioner.

TheIOMcommitteerecommendsthattheexecutivesecretariesreporttoacentralunitintheirrespectivecentersforthepurposeofprovidingadministrativesupporttothatcenter'sadvisorycommittees.Italsorecommendsthattheyreporttotheappropriatedivisiondirectorstoprovideprogramsupporttothecommittees.

Ingeneral,theIOMcommitteebelievesthataclarificationoftherolesofallFDAofficialsresponsiblefortheadvisorycommitteesystemislongoverdue.Theobjectiveofthisclarificationshouldbetoensurethatadvisorycommitteesprovidetheindependentexpertadvicethattheagencyrequestsandneeds.

TheIOMcommitteerecommendsthattherolesandresponsibilitiesofallFDAofficialsinvolvedintheadvisorycommitteesystembeclearlyarticulatedinagencypolicythatiswidelydistributedtoFDAprofessionalstaff,advisorycommitteemembers,andotherinterestedparties.Thecommitteefurtherrecommendsthatthejobdescriptionsofallofficialsbechangedtoreflecttheirrespectiveresponsibilities.

Compensation

TheauthoritytosetthedailyrateofcompensationforFDAadvisorycommitteesresideswiththeCommissionerofFoodandDrugs.Heissubjecttofourconstraintstwolegal,onebudgetary,andoneadministrative.

ThestatutorylimitoncompensationforallfederalgovernmentadvisorycommitteemembersisthedailyrateforaSeniorExecutiveServiceIVposition,currently$429.50perday.RegulationsoftheGeneralServicesAdministrationfurtherlimitthedailyratetothatofaGS-15intheGeneralSchedule,currently$320perday,unlesstheagencyheadpersonallydeterminesthatahigherrate"isjustifiedandnecessary."Thebudgetarylimitistheobviousrequirementthatanagencyheadmusthavefundstocoverthecostsofwhateverrateisadopted.

Althoughagencyheadshaveauthoritytosetratesforthemembersofthecommitteesthatadvisethem,FDA'sstatusasapartofthePublicHealthServicealsolimitsthatauthority.Asapracticalmatter,nosinglePHSagencycanpayadvisorycommitteemembersatratesmuchhigherthanthoseoftheotheragencies.Currently,theCenters

forDiseaseControlpayscommitteemembers$188perday,theNationalInstitutesofHealthpays$150perday,andtheFDApays$150perday.*

*In1965,advisorycommitteemembersfordrugsandbiologicswerepaid$128.80perday.Thisratewasloweredin1984to$100;itwasraisedto$150inFebruary1990.Devicecommitteememberswerepaid$128.80perdayfrom1972untilthisratewasraisedto$150in1990.UsingtheConsumerPriceAll-ItemsIndextoinflateanddeflatethesefigures,the$128.80feetranslatesinto$572.67in1992dollars;conversely,$150in1992dollarsistheequivalentof$33.63in1965terms.MembersoftheEdwardsCommittee,incidently,whowereappointedbytheSecretaryofHealthandHumanServicesin1990toadviseonmatterspertainingtotheFDA,werepaidapproximately$300perday.

FDAadvisorycommitteemembersarepaidonlyforthosedaysonwhichtheyattendameeting.Theagencyisbarredbyregulationfrompayingthemforhomeworkfornormalmeetingpreparation,eventhoughanindividualmayspendfivedaysormoreinpreparation.However,CDRHdoescompensateindividualadvisorycommitteemembersforhomeworkiftheyconductan"agency-directedassignment"thatresultsinatangibleendproduct,usuallyareport,thatisnottheendproductoftheadvisorycommittee.Typically,thisinvolvesusingmembersasprimaryreviewersofapplications.NeitherCDERnorCBERcompensatescommitteemembersforhomework.

FDAregulationsalsopermitpaymenttoadvisorycommitteemembersatthedailyratefortraveltimethatinvolves50percentofanadditionaldaybeyondthemeetingandthatresultsinthelossofsomeregularcompensation.However,nouseismadeofthisauthority.

TheIOMcommitteebelievesthatallPublicHealthServiceadvisorycommitteemembersareunderpaid,includingthosewhoadvisetheFDA.ThisisclearlytruewithrespecttothemaximumdailyrateallowedbylawandGSAregulations.Itisalsotruewithrespecttotheopportunitycosttomembersofforegoneconsultingfeesfromdrugordevicefirmsof$1,000adayormore.Moreover,youngermembersinacademicmedicineoftenconfronttheperceptionthatserviceonanFDAcommitteecarrieslessacademicrewardthanthatofanNIHstudysection.

TheIOMcommitteebelievesthatpublicserviceshouldbeadequatelycompensated,althoughobviouslynotattheratesfoundintheprivatesector.ItisconcernedthatthecurrentmeagerrateofcompensationmaydissuadesomeindividualsfromservingasFDAadvisorycommitteemembersandmaydiminishtheincentivetootherstoprepareadequatelyformeetings.Ingeneral,theIOMcommitteeisconcernedthattheseratesdonotadequatelyreflectthevaluethat

FDAandthegeneralpublicattachtotheimportantworkperformedbyadvisorycommitteemembers.

TheIOMcommitteerecommendsthattheCommissioner,withtheSecretaryofHealthandHumanServices,reviewtheadequacyofcompensationforPublicHealthServiceadvisorycommitteemembers,includingFDAadvisorycommitteemembers,andtakeappropriatestepstomaintaindailyratesinrelationtoincreasesinthefederalsalaryschedule.ItfurtherrecommendsthatCDERandCBER,totheextentthattheyuseprimaryreviewersforapplicationspresentedtoadvisorycommittees,compensatethesereviewers,asCDRHcurrentlydoes,for"agency-directed"homework.

TheIOMcommitteenotesthatlegislationenactedinOctober1992authorizedtheFDAtochargeuserfeesforproductevaluation.Underthisnewauthority,itmaybeappropriatefortheFDAtoreviewthecompensationofadvisorycommitteemembersinrelationtotheircontributiontoproductevaluation.

OrientationandTraining

Insufficientorientationofadvisorycommitteemembersisarecurringcomplaint.ItwasraisedbytheIndustryLiaisonPanelreportandintheinterviewsofcurrentandformeradvisorycommitteemembersconductedbyaworkinggroupoftheIOMcommittee.Manyperhapsmostofthesepastandpresentadvisorycommitteemembersfeltthattheirtrainingandorientationhadbeeninadequate.SeveralstillhadonlyavagueknowledgeofthestructureoftheFDAandthecommittee'srelationtoitwhichraisesquestionsabouttheirunderstandingoftheirrolesandresponsibilities.Somesuggestedamoreformalorientation(perhapsusingaudiovisualmaterialsandaneworientationmanual),andasignificantnumberarguedforaclearerstatementofthecommittee'sroleinFDAfunctions.

Amongthecriticalcommentsofthoseinterviewedwerethese:"It'slikebeingatriallawyerwithouteverbeinginthecourtroom!"and"[Orientationwasa]30-minutephonecallandawrittenfolder."Therewerealso,however,somepositivecomments:''Ifeelthatthetrainingandorientationsessionwassuperb.Itmaybereasonabletorepeatsomeofthebasicprinciplesperiodically....[Fornewmembers]Imightsuggest...thattherealsobedirectcontactwiththeimmediatepredecessor."

Thefollowingwereamongthespecificrecommendationsforimprovingorientationofcommitteemembers:

Aone-daytrainingsessionfornewmembersbeforethemeetingofan

advisorycommittee.

Havingnewcommitteemembersattendameetingbeforebecominganactiveadvisorycommitteemember.

Anhour-longclosedsessiontointroducenewmemberstotheissues.Thisshouldbeatthefirstmeetingofthenewgroupandshouldincludeseasonedcommitteememberssothattheycanansweranyquestionsraisedbynewmembers.

ThetrainingandorientationofadvisorycommitteemembersandagencystaffwereaddressedinboththeDorsenreport(1977)andtheMcMahonreport(1982).Bothstudiesfound,afterinterviewingcommitteemembersandFDAstaff,thatalackofpreparatoryinformationledtofrustrations

amongcommitteemembers.Furthermore,becauseofalackofadvanceinformationabouttheprecisedutiesofmembersofadvisorycommittees,manyexperienceddisappointmentastheydiscoveredthatcertaindecisionsrequiredofthecommitteescouldbemoremundanethantheyhadoriginallyexpected.

Theneedforasystematicorientationprogramisgenerallyrecognizedthroughouttheagency.Amongadvisorycommitteemembers,oneencountersthebeliefthatamoresystematicorientationandtrainingprogramisneeded,especiallyfornewmembers,whoreportedlyoftencometotheinitialcommitteemeetingswithoutknowingwhatisexpectedofthemorhowFDAexercisesitsregulatoryresponsibilities.Asaresult,theyarenotalwayspreparedtoplayaneffectiveroleuntilwellintotheirterm.

Theneedfororientationandtrainingappearstobewidelyrecognized;what,then,hasbeentheagencyresponse?OneresponsewasthepreparationofahandbookentitledFDAPublicAdvisoryCommittees:AHandbookforAdvisoryCommitteeMembersandtheExecutiveSecretary,whichisroutinelydistributedtoprospectiveCDERandCBERadvisorycommitteemembers.Somecommitteemembershavereportedtoagencystaff,however,thatthehandbookdoesnotprovidethemwiththebackgroundtheyneedtoperformtheirtasks.CDRHhaspreparedavideotapeonthedutiesandresponsibilitiesofadvisorypanelmembersanddistributesittoallofitsprospectivecommitteemembers.

Responsibilityfortrainingadvisorycommitteemembersisdecentralizedtotherespectivecenters,usuallytoindividualexecutivesecretariesorcommitteemanagementstaff.Thestaffofthethreecentersdonotmeettodiscussthetrainingneedsofcommitteemembersortocollaborateindevelopingorientationprograms.Moreover,neithertheDivisionofHumanResourcesManagement,

whichdesignedFDA'strainingprogramsuntilabout10yearsago,northetrainingstaffsofthecentershavebeeninvolvedwiththeorientationofadvisorycommitteemembers.Consequently,orientationvariesgreatlybetweencentersandoftenwithinagivencenterfromday-longandhalf-dayorientationsessionstocommitteemember"apprenticeships"asconsultantsand"on-the-job"trainingofmembers.

InCDER,nosingleindividualsupervisestheorientationofadvisorycommitteemembers.Eachcommittee'sexecutivesecretaryisresponsibleforwhateverorientationisprovided.AlthoughtheexecutivesecretarieswhoarepartoftheAdvisorsandConsultantsStaffshareinformationonhowtoorientnewmembers,therearenomeetingsofallCDERexecutivesecretariestodiscussorientationortodevelopaconsistentCDERapproach.However,allprospectivecommitteemembersaregivenwritteninformationonconflictofinterest.Thehandbook,relevantregulations,andcommittee

chartersareoftenincludedintheorientationpackagespreparedbyindividualexecutivesecretaries,anddivision-specificmaterialsaresometimesalsoprovidedtonewmembers.Butthereisnostandardsetofmaterialsprovidedtonewmembers.

Directpersonalorientationofadvisorycommitteemembersisalsolefttothediscretionoftheexecutivesecretaries.(OneCDERexecutivesecretaryexpressedtheviewthattheinterestsofthemembersofCDER's17advisorycommitteesvariedtoomuchtoholdoneorientationsession.)Severalapproachesareused.Ifanumberofmembersatagivenadvisorycommitteemeetingarenew,partofthemeetingmaybeclosedfororientation.Anotheroptionistoholdanorientationsessiontheeveningbeforeanadvisorycommitteemeetingortoaskasinglenewmembertostayanextradayafterameeting.

CBER'stwoexecutivesecretariesarealsoresponsiblefororientingnewcommitteemembers.InMarch1992,however,itsDivisionofScientificAdvisoryCommitteesconductedapilotorientationsessiontoimproveitsorientationprogram,whichwasattendedbynewmembersfromallfourCBERadvisorycommittees.Thisprogramisstillinitsformativestagesand,ascurrentlyplanned,consistsofamorningplenarysessionthatcoverstopicsofinteresttoallcommitteemembers(e.g.,ethics,proprietaryinformation,personalliability,etc.)andaspecializedafternoonsessionforeachcommitteeforitsownnewmembers.Ithasnotbeendecidedwhethertoschedulesessionsthedaybeforeanewmember'sfirstadvisorycommitteemeetingortoholdaseparateeventforallnewmembers.

Ofthethreecenters,CDRHhasthemoststructuredorientationprogramfornewadvisorycommitteemembers.LikeCDERandCBER,newadvisorycommitteemembersreceivewrittenmaterialsthatexplaintheirresponsibilities.Inaddition,however,theAdvisoryPanelCoordinator(APC)withintheOfficeofDeviceEvaluationasks

anexecutivesecretaryinadvanceofapanelmeetingifthereareanynewmemberslocatedintheWashington,D.C.,area.Currently,costprohibitsbringinginout-of-townpanelmembersfororientation.Ifso,anorientationsessionwillbescheduledfortheseindividuals,andtheotherexecutivesecretarieswillbeaskedtoidentifynewpanelmembersintheareawhoshouldalsoattend.

ThepurposeofthetrainingistodiscusstherelationshipofthewrittenmaterialsprovidedtothenewpanelmemberstotheCDRHregulatorycontext.Inthisway,panelmemberscanfocustheirattentioninthemostproductiveandappropriatewaypossible.Thetwo-hourorientationsessionissometimesscheduledimmediatelybeforeapanelmeetingbeginsorsometimesonthepreviousday.TheCDRHexecutivesecretariesprovidefeedbacktotheAPCfromboththedivisionsandthepanelmembers.If

eitherseesdeficienciesintheorientation,theexecutivesecretariesconveythatinformationtotheAPC.

CDRHhasalsopreparedthreevideotapescriptsforuseinorientingnewpanelmembers.Thesedealwith"Mission&Organization";"MedicalDeviceApproval:TheProcess&ThePanel'sRole";and"AvoidingConflictofInterest."TheideaoftrainingvideosforpanelmemberswasdevelopedbytheOfficeofDeviceEvaluationandtheHealthIndustryManufacturers'Association(HIMA),andscriptswerewrittenbyacontractor(whowaspaid$10,000byHIMA).CDRHprovidedagreatdealofinput,andthescriptswereapprovedbythecenterin1991.TheprojectiscurrentlyonholdwhileCDRHawaitswordonwhetherHIMAwishestocontinue,whetherthecenterhasthefundstodoso,*andwhethertheirplanswillaccordwiththerecommendationsofthisstudy.

Thecentersalsouseothermeansoforientation.Adivisionwillsometimesinviteapotentialnewmembertoameetingasaguesttoacquaintthemwiththeadvisorycommitteeprocess.Oritmayhirethepersoninaconsultantcapacityasan"apprentice"committeemember,whichservesthedualpurposeofgivingthedivisionanopportunitytoevaluateanindividual'spotentialasacommitteememberandgivingtheindividualsomefamiliaritywiththeworkofamember.

Whatquestionsdeserveattentioninconsideringamoresystematicorientationandtrainingprogramforadvisorycommitteemembers?First,therationaleforsuchaneffortisstraightforward:systematicorientationandtrainingofadvisorycommitteememberswouldfulfillawidelyrecognizedneed;itwouldpromotetheefficientuseofcommitteemembers'talent;itwouldestablishclearexpectationsformembersabouttheirrolesandresponsibilities;anditwouldpermitagencyofficialstoexplicitlyacknowledgetheimportantpublicservicecontributionofadvisorycommitteeservice.

Inaddition,weretheprogramagency-wide,itmightencourage"softstandardization"acrossthethreecenters.Itwoulddosobypromotingconcernforcommonproblemswithoutoverridingthejustifiablevariationthatderivesfromaparticularclassoftherapeuticordiagnosticentities.IftheeffortwasdevelopedbytheOfficeoftheCommissionerinconcertwiththecenters,itwouldforceclarificationabouthowmuchthecontentofsuchaprogramshouldbeagency-wide,center-specific,orspecifictoagivendivisionorclassoftherapeuticproducts.

Whatshouldbethecontentofanorientationprogram?TheanswertothisquestionshouldbedevelopedbytheappropriateFDAstaffinconjunctionwithselectedadvisorycommitteemembers.Thecontent

*Estimatestoproducethevideosrangefrom$10,000to25,000each,dependingonwhetherprofessionalactorsareused.

criterionshouldbewhatanewmemberneedstoknowtobeeffectiveasacommitteemember.ItshouldprobablyincludeadescriptionandsomehistoryofFDA'sstatutoryregulatoryresponsibilities;adiscussionofthepurposesofFDAadvisorycommittees,includinghowtheydifferfromNIHstudysectionsandothersimilarcommittees;acarefulandsensitiveexaminationoftheconflict-of-interestlawanditsimplementation;andtheimportantpublicserviceandpublichealthcontributionofadvisorycommitteework.Newcommitteememberswouldalsobenefitfromadiscussionofthe''FormatandContent'guidelinesforsubmissionofanewdrugapplicationpreparedseveralyearsagobyDrs.RobertTempleandRobertO'Neil.

Arelatedneedistheorientationofadvisorycommitteechairstotheirroles,whichnoneofthecentersdoroutinely;theirorientationshouldincludeFDApoliciesandproceduresregardingelectroniccoverageofadvisorycommittees(21CFR10(200206)).Furthermore,assumingthatrecommendationsofthisreportaboutstrengtheningtheroleofcommitteechairsareaccepted,orientationcouldusefullyfocusontheseenlargedresponsibilities.

Shouldthescopeofanorientationandtrainingprogramberestrictedtoadvisorycommitteemembers,orshoulditalsoincludethetrainingofFDAofficialswhoroutinelydealwithadvisorycommittees?Althoughtheinitialemphasisshouldbeonmembers,awell-designedprogramshouldservebothgroups.

Whatkindoforientationandtrainingmaterialsshouldbeused?Ataminimum,acurrentorientationmanualshouldbeprepared(andmaintained)foralladvisorycommitteemembers.Inaddition,avideotapeshouldbepreparedtocapturetheviewsoftheFDACommissionerandrelevanthigh-levelFDAofficialsregardingtheimportanceoftheadvisorycommitteefunction.Finally,aprogramof

face-to-face,one-daysessionsshouldbeheldfornewcommitteemembers.

Acrossthethreecenters,approximately75newadvisorycommitteepositionsbecomeopeneachyear.Ifanagency-wideprogramwasdesigned,withcontentthatwasagency-wide,center-specific,anddivision-specific,oneortwoannualsessionscouldbeorganizedforallnewmembersfromallcenters.

PotentialorganizationsresponsibleforconductinganorientationandtrainingprogramincludetheFDADivisionofHumanResources;center-levelunits,suchastheCDERStaffCollegeortheCDRHtrainingoffice;anagency-wideeffortjointlyorganizedbythethreecenters;oranexternalcontractor.Thespecificdesignisanadministrativechoicetobemadewithintheagencyafterthebasicparametersoftheprogramhavebeenestablished.

TheIOMcommitteerecommendsthattheFDAestablishasystematicorientationandtrainingprogramthatisdirectedmainlytowardnewadvisorycommitteemembers,withaspecialcomponentforcommitteechairs,andthatwillalsobeusefulforcurrentmembersandforFDAstaffwhodealwithcommittees.TheOfficeoftheCommissionershouldexerciseleadershipinthedesignofthisprogram,incooperationwiththethreecenters.Thedesignshouldconsciouslysearchforagency-widesimilaritiesaswellascenter-specificanddivision-specificcontent.Thepublicserviceandpublichealthcontributionofadvisorycommitteemembershipshouldbeemphasizedinthisprogram.

TypesofAdvisoryCommittees

TheIOMcommitteehasfocuseditsattentioninthisreportonthetechnicaladvisorycommitteesusedbytheFDAfordrugs,biologics,andmedicaldevices.Inthecourseofthestudy,however,severalsuggestionshavebeenmadethatthecommitteeconsiderothertypesofadvisorycommitteesandthesearereviewedbrieflyinthissection.

PolicyAdvisoryCommittee

ThefirstissuewaswhethertheIOMcommitteeshouldrecommendthatapolicyadvisorycommitteebeestablishedtoadvisetheCommissioneronthebroadpolicyissuesrelatedtodrugs,biologics,anddevicesthatcomebeforetheagency.TheLasagnaCommittee,forexample,recommendedformationof"apermanentstandingPolicyandOversightCommittee...tomonitortheagency'sneedsandperformancewithregardtoregulationofdrugsandbiologicsforhumans."ItproposedthatthiscommitteemeetregularlyandreporttotheSecretaryofHealthandHumanServices;andthatitsmembersbe"knowledgeablenationalleaders"selectedbytheSecretaryfromcandidatesnominatedbytheInstituteofMedicine.

TheIOMcommitteediscussedthisissueatitsDecember7,1991,meetingandagainatitsmeetingonMay2930,1992,butonneither

occasionwasanygreatenthusiasmforsuchacommitteenoted.Instead,thecommitteeobservedthattheCommissionerofFoodandDrugs,liketheheadofanygovernmentagency,doesnotlackforfreeadvicefrommanysources.ItconcludedthattheutilityofsuchapolicyadvisorycommitteeshouldbedeterminedbytheCommissioner,whocanasktheSecretarytoappointsuchabodyifitwouldservehispurposes.

ThecommitteedidhearapresentationfromthenewlyappointedScienceAdviseroftheFDA,Dr.ElkanBlout,regardinghisplansforthecreationofascienceboard.Thisboard,whenchartered,mightfulfillsome

ofthefunctionsenvisionedforapolicyadvisorycommitteetotheCommissioner.

OtherIssues

SeveralotherissueswereraisedlateintheIOMcommittee'sstudy.First,thecommitteereceivedsuggestionsthatcross-cutting,discipline-basedadvisorycommittees(incontrasttothetherapeuticclassorproduct-linetechnicaladvisorycommittees)beestablishedforbiostatistics,chemistry,pharmacologyandtoxicology,andbiomaterials.

1,2Thebasicrationaleforsuchanactionwasthatexistingcommitteesoftenraisedissuesinproductevaluationsthathadbroaderimplicationsthanthoserelatedtoagivenapplication.Noadvisorycommitteeexistsforaggregatingandconsideringsuchissues.

Currentlyconstitutedtechnicaladvisorycommitteesfocusonproductevaluation,broadlyconstrued.Themembershipofsuchcommitteesusuallyincludesrepresentativesofseveralcritical,cross-cuttingdisciplinestoprovidevaluableperspectives;biostatisticsisalmostalwaysrepresented;andchemistryandpharmacology\toxicologyaresometimesincluded.However,discipline-basedissuesthatarisewithinproduct-orientedadvisorycommitteesandthathavecenter-wideoragency-wideimplicationsarenotsystematicallyexamined.Wenote,however,thatthesubstantiveissuesthatsuchcommitteesmightaddresscouldverywellbecandidatesfortechnicalworkshopsthattheagency,oroneofitscenters,mightsponsor,perhapsdrawingparticipantsfromthemembershipofexistingadvisorycommittees.

Twootherissueswereraisedwiththecommittee.Shouldeachofthethreecentershaveapolicyadvisorycommittee?AndshouldCBERestablisha"boardofscientificcounsellors"toreviewallitsintramural

researchprogramsandpersonnel,ratherthandividethatresponsibilityasitcurrentlydoes,amongfourtechnicaladvisorycommittees?

AlltheseissueswereraisedlateintheIOMcommittee'sstudy.Althoughtheymeritdiscussionanddebate,thecommitteedidnothaveextensiveopportunitytoconsideralloftheirimplications.ItregardsallofthesemattersasappropriatesubjectsforinternalFDAdiscussionanddecision.TheIOMcommitteewishestonotethatiftheFDAadoptsitsrecommendationthattheagencyestablishahigh-levelpositionwithintheOfficeoftheCommissionerforadvisorycommitteepolicyandmanagementguidance,theframeworkwouldexistwithinwhichsuchissuescouldeasilybeconsidered.

AgencyManagementandAccountability

ThisreportmakesmanyrecommendationsforimprovingtheuseofadvisorycommitteesbytheFDAintheevaluationofdrugs,biologics,andmedicaldevices.Throughoutthereporttherearegeneralexpressionsofconcernaboutagencymanagementandaccountability,whichmaynotbecapturedfullybythereport'sspecificrecommendations.Thus,theIOMcommitteedeemsitnecessarytosummarizethelatterinrelationtotheselargerconsiderations.

AgencyManagement

InthejudgmentoftheIOMcommittee,itisimportanttodifferentiatebetweenthemanagementoftheadvisorycommitteesystemandthemanagementoftheproductevaluationprocessasaffectedbytheadvisorycommitteesystem.Regardingsystemmanagement,theIOMcommittee'smostimportantrecommendationisthatahigh-levelpositionbeestablishedintheOfficeoftheCommissionertoprovideadministrativepolicyandmanagementguidancetotheadvisorycommitteesystem.AlthoughthepreciselocationofsuchanofficeisproperlyadecisiontobemadebytheCommissioner,anappropriateplacemaybetheOfficeoftheDeputyCommissionerforOperations,towhichthedirectorsofthethreerelevantcentersnowreport.

Advisorycommittees,theIOMcommitteebelieves,havebecomeapermanentfixtureintheFDA'sevaluationofproducts,andtheireffectiveuseshouldbearesponsibilityofFDAofficialsatalllevels.ImprovementsinmanagementwouldflowfromclarifyingtherolesandresponsibilitiesofallofficialsinvolvedintheadvisorycommitteesystemfromtheCommissionerthroughcenter,office,anddivisiondirectors,downtotheexecutivesecretaries.Suchclarificationshouldincludeexpandingthejobdescriptionsoftheseofficialsasnecessary.TheIOMcommitteeacknowledgestheimportantroleofFDAoffice

anddivisiondirectorsintheworkofadvisorycommittees;itdoesnotrecommendcircumventingtheseofficialsbyproposingtolocateoperationalresponsibilityforcommitteeselsewhere,buturgesclarificationoftheirresponsibilitiesfortheeffectiveperformanceofthesystem.

Anorientationprogramforadvisorycommitteemembers,whichcouldalsobeusedintrainingresponsibleFDAofficials,wouldimprovetheperformanceoftheentiresystem.Othermanagement-relatedrecommendationspertaintotherecruitmentofqualifiedmembersandestablishmentofapoolofpotentialmembers;greaterinvolvementbytheOfficeoftheCommissionerinconflictofinterestissues(bothindevelopinginternalFDA

policiesandproceduresandinnegotiatingwiththeDHHSOfficeoftheSpecialCounselforEthicsandtheOfficeofGovernmentEthics);andmoreattentiontopreparationforandconductandfollow-upofadvisorycommitteemeetings.

VariousrecommendationsoftheIOMcommitteeaddressimprovementoftheproductevaluationprocessandtheroleofadvisorycommitteesinthatprocess.Inparticular,webelievethatadvanceschedulingofcommitteemeetingsandagendas,withattendantdeadlinesforthesponsorandtheagency,wouldbringgreaterdisciplinetotheproductevaluationprocess.

TheIOMcommitteerecognizesthatitsrecommendationsforimprovedmanagementoftheadvisorycommitteesystemwillrequireadditionalresources.Therefore,thereportprovidesanestimateoftheincrementalcostsoftheIOMcommittee'srecommendations.TheIOMcommitteeregardstherecommendedreviewofadvisorycommitteemembercompensationasanimportantmanagementissuethatdeservesattentionbytheCommissionerandtheSecretaryofHealthandHumanServices.Ifauserfeesystemisadoptedtosupportproductevaluation,thecompensationofadvisorycommitteemembersshouldbereviewedinthatcontext.

AgencyAccountability

TheFDAasanentity,andnotitscomponentparts,shouldbeaccountablefortheeffectiveperformanceofitsadvisorycommitteesystem.TheIOMcommittee'srecommendationsleadtowaysofincreasingagency-wideaccountability.Here,asintherecommendationsaboveonimprovingmanagement,thecommitteeemphasizestheimportanceofdesignatingahigh-levelofficialintheOfficeoftheCommissionerwhoshouldberesponsibleforadministrativepolicyandmanagementguidanceforthesystem.

ItisalsoimportantasacomponentofaccountabilitytorecognizethatadvisorycommitteesareadvisorytotheFDA,andthattheformalauthorityfordecisionsrestsbylawwiththeagency.Itwouldbeunnecessarytoreiteratethisbasicdistinctionwereitnotthatsomeagencycriticsregardadvisorycommitteesasindependentadjudicatorybodiesthatshouldhearsponsors'views,ontheonehand,andagencyviews,ontheother,anddecideinfavorofonepartyortheother.Acknowledgingthisbasicauthority-advisorydistinctionshouldfacilitateadvisorycommitteesbecomingevenmoreeffectiveandinfluentialthantheyareatpresent,whichtheIOMcommitteeendorses.

Consequently,theIOMcommittee'srecommendationsemphasizepracticalways(especiallyinChapter7)toensuretheintellectualindependenceofadvisorycommittees.Therationaleforthisemphasisistoincrease

thelikelihoodthatadvisorycommitteeswillrenderthatimpartial,expertadvicethattheagencyandthepublicshouldexpect.

AConcludingRecommendation

Intheconductofthisstudy,theIOMcommitteehasdiscoveredthemultifacetedcomplexityoftheFDAadvisorycommitteesystem.Ithasbenefitedfrommanythoughtfulletters,memoranda,andcommunicationsonaspectsofthiscomplexity.Thecommitteehasblendedtheseviewsofothers,bothinsideandoutsidetheagency,withtheknowledgeandexperienceofitsmembersandwiththeinformationgainedinthisstudy.Asaresult,thecommitteebelievesthatitsreport,ifwidelydisseminated,couldservetoincreasebothinternalagencyaccountabilityandexternalsupportfortheadvisorycommitteesystem.

TheIOMcommitteerecommendsthattheCommissionercirculatethisreportwidelywithintheFDA,toalladvisorycommitteemembers,andtootherinterestedparties.ItalsorecommendsthatthereportbesubmittedtotheSecretaryofHealthandHumanServicesandtotheappropriatecommitteesoftheCongressforthepurposeofseekingconcurrenceofgoalsandbudgetarysupportfortheimplementationofthereport'srecommendations.

Notes

1.LetterfromLewisB.Sheiner,M.D.,UniversityofCalifornia,SanFrancisco,toRichardA.Rettig,May4,1992.

2.LetterfromJohnF.Beary,III,M.D.,PharmaceuticalManufacturersAssociation,toRichardA.Rettig,May20,1992.

AppendixAResourceImplications*TheimplementationoftheIOMcommittee'srecommendationsinthisreportdoesnotdependgreatlyonadditionalbudgetaryandpersonnelresources.Manyrecommendationsinvolvepolicydeterminationsthatwillleadtoproceduralchanges.Theone-time''costs"oftheformerwillbeabsorbedbytheagency'sreviewofthisreport.Theproceduralchanges,thecommitteebelieves,willresultingreatereffectivenessoftheadvisorycommitteesystem;somemayalsoresultinincreasedefficiencies.

ThisAppendixidentifiesfiverecommendations(orsetsofrecommendations)oftheIOMreportthatwillrequireadditionalmoniesorpersonnel.Itprovidesafirstapproximationtotheresourceimplicationsofthoserecommendations.Itdoesnotpurporttobeatechnicalcostestimateofallrecommendations,assuchaneffortwouldrequiremoredatathanarereadilyavailableandwoulddwarfthestudyitself.Theanalysisisprecededbyabriefdiscussionofthecostsofthecurrentsystem.

CurrentSystemCostsUnderestimated

Eachyear,theFDApreparesanAgencySummaryonthefiscalyearcostsofallofitsadvisorycommittees,incompliancewiththerequirementsoftheFederalAdvisoryCommitteeAct(FACA).ThisreportistheprimarysourceofpublicinformationaboutthecostsofFDAadvisorycommitteesanditsdataareusedintheagency'sbudgetsubmissiontoCongress.TableA-1summarizesthesedataforfiscalyears1987through1991intermsoftheFDA'scostcategories.

Thecommitteemanagementstaffsofthethreecenterscompilethe

datafortheannualreportinaccordancewithguidancefromtheFDA'sCommitteeManagementOffice.Althoughmostofthecostcomputationsare

*ThisappendixisbasedonananalysispreparedbyRebeccaWallace.

Table1FDA'sAdvisoryCommitteeCosts:FiscalYear1987throughFiscalYear1991DataElements 1987 1988 1989PersonnelPaymentsNonfederalMembers $65,849 $64,193 $77,391FederalStaff 441,388 518,484 696,228NonmemberConsultants 18,454 24,707 23,145

Subtotal 525,691 607,384 796,764TotalTravelandPerDiem

215,607 270,629 358,242

Other 75,815 78,194 113,484Total 817,113 956,207 1,268,490TotalFTEYears 11.90 12.40 17.82Note:FTE=full-timeequivalent.

straightforward,thereisreasontobelievethatthereportedcostsareunderstated,especiallythoseofpersonnelpaymentstofederalstaff.

First,notallcommitteemanagementsalariesareincluded.Federalstaffcostsforallthreecentersincludeonlythosecommitteemanagementstaffwhospend10percentormoreoftheirtimeindirectsupportofadvisorycommitteebusiness.Moreover,CDERfiguresincludeonlythesalariesofexecutivesecretariesandthecommitteemanagementassistants;CBERpaymentsexcludethesecretarialsupportofitscommitteemanagementstaff.Thesecostsdonotincludetheothermembersofthecommitteemanagementstaffs.Inaddition,CDRHcostsdonotincludethecostsofacontractor($95,000infiscal1991)thatprovidessupportservicestoitsdeviceadvisorycommittees.AlsoexcludedarethestaffoftheDivisionofEthicsandProgramIntegritywhoprocessconflict-of-interestwaivers,andtheFDA'sCommitteeManagementOffice,whichpreparestheannualreportonadvisorycommittees.Beyondtheseomissions,thecostsofdivisionpersonnel,frommedicalreviewersthroughdivisiondirectors,thatmightbeallocabletoadvisorycommitteeworkarealsoexcluded.

RecommendationsthatWillHaveResourceImplications

FiverecommendationsoftheIOMcommittee,ifadopted,willrequireadditionalresourcesforwhichtheincrementalcostscanbeidentifiedandcalculatedrelativelyeasily.Theyare:(1)improvingthemanagementoftheadvisorycommitteesystembyappointingahigh-levelofficialintheOfficeoftheCommissionertoprovidemanagementandadministrativepolicyguidancetothesystem;(2)strengtheningtheprocessforrecruitingadvisorycommitteemembers;(3)establishingneededtrainingandorientationefforts;(4)schedulingadvisorycommitteemeetingsayearormoreinadvance,andreviewingtheNDAandINDpipelineeachyear;and(5)possiblyincreasingadvisorycommitteemembers'compensation.

1.ImprovingtheManagementoftheAdvisoryCommitteeSystem

TheIOMcommitteerecommendationthatahigh-levelpositionbeestablishedintheOfficeoftheCommissionertoprovidemanagementandpolicyguidancefortheadvisorycommitteesystemwillrequiretheFDAtodevoteonefull-timeseniorstaffpositionandatleastpart-timeadministrativesupporttothisnewfunctionwithintheagency.Performingthetaskssuggestedbythepanelwillrequireanindividualwhoworkscloselyandonanevenfootingwithcenter,office,anddivisionpersonnel.

2.RecruitingCommitteeMembers

TheIOMcommitteerecommendsthattherecruitmentprocessbeorganizedinasystematic,formal,andaggressiveway,withspecialattentiontowomenandminorities.Therearethreepotentialsourcesofcosttoincreasedrecruitingefforts.First,itmaybethecasethatonefun-timeequivalent(FTE)ineachcenterwillbeneededtoperformtheday-to-dayresponsibilitiesofrecruiting(includingroutinelysolicitingideasforpotentialmembersfromcurrentandformeradvisorycommitteemembers;professionalmedicalandscientificsocieties;medicalschooldeansanddepartmentchairmen;andindustry,consumer,andpatientorganizations);contactingappropriateprofessionaljournals;usingtheNIH-ADAMHAcomputerizedfile;andcommunicatingwithpotentialcommitteememberstoincreasetheirinterestinservingonacommittee.

Second,iftheFDApursuestheoptionofcreatingandmaintainingitsowncomputerizeddatabaseofpotentialadvisorycommitteemembers,theagencywillincuradditionalcosts.TheNIH-ADAMHAsystemisanexampleofwhatsuchasystemmightcost.Mostofthedesignandmaintenanceofthissystemisdonebyacontractor,whosendsallthemailings,performsalldataentry,makesminorprogramchanges,offerssixtutoringsessionsonthesystemtotheprofessionalstaffeachyear,maintainsausersmanual,respondstoallquestionsonthesystem,andduplicatesallCVsandprovidesthemtorequestors.ThecontractoriscurrentlydesigningaprogramtoputallCVson-line.

Originaldesigncostsforthiscontractarenotknownbutcurrentoperatingcostsare$250,000peryear.Thecontractorusesoneprofessionaltomanagethesystemandtwoorthreestafffordataentryandtroubleshooting.Inadditiontotheannualcontractcosts,anNIHprojectdirectorspends10percentofhertimemonitoringthecontract.ADAMHA,throughaninteragencyagreementwithNIH,contributes

about$50,000peryeartotheeffort.Contractcostsareexpectedtodecreaseasthedatabasebecomesmorecompleteandmaintenancebecomesmoreroutine.

ThedevelopmentofthissystemrequiredtheNIHtoobtainclearancefromtheOfficeofManagementandBudgettoaskprivateindividualsforpersonaldata.Specialpermissionwasneededtoaskforgenderandraceinformation.Inaddition,theNIHhadtoobtainPrivacyActclearancetostoretheacquiredinformation.

Third,inlieuofdevelopingitsownautomatedsystem,theFDAmightenterintoaninteragencyagreementtosupporttheNIHsystemandseektohaveitmodifiedtomeetitsownspecialneeds.TheNIH,inAugust1992,wasformingataskforcetorecommendchangestothesystem.

3.EstablishinganOrientationProgram

TheIOMcommitteerecommendsthattheFDAdevelopanorientationprogramconsistingofanFDA-widecomponent,acenter-specificcomponent,andadivision-specificcomponent.Itfurtherrecommendsthatthisprogrambeofferedtwoorthreetimesayearandthatallnewmembersattendwithinsixmonthsoftheirappointments.Inaddition,thecommitteerecommendedthattheFDAdevelopatrainingprogramforitsstaffwhodealwithconflict-of-interestissues;thistrainingeffortcouldprovidethebasisfortheconflictcomponentoftheorientationprogram.

Coursedevelopmentwouldbeaninitialcosttotheagency,andasFDApolicieschange,thematerialwouldneedtobeupdated.AccordingtoanFDAstaffmemberwhohasdevelopedsuchprogramsinotheragencies,designinga36hourcoursein-housewouldtakeaboutone-quarterofanFTE,or$15,000$16,000.Thisamountwoulddepend,ofcourse,ontheaccessibilityofmaterialsandresourcesneededtodevelopthecurriculumandtheeaseofreachingagreementonsubstanceamongtherelevantseniorFDAstafffromthethreecenters.

Oncethecourseisdeveloped,theadditionalcostsofconductingtheprogramwouldincludeadvisorycommitteemembercompensation,travel,andperdiem;FDAstafftime;andspaceandfacilities,supplies,andincidentals.Factorsaffectingcostsincludethefrequencyoforientationsessions,thespecificFDAstaffwhowillparticipatewhenandwherethesessionsareheld,andwhattrainingmethodologyisused.

IftheFDAadoptstheIOMrecommendationtoholdtwoorthreeorientationsessionsinWashington,D.C.,peryear,separatefromanyscheduledcommitteemeeting,newadvisorycommitteemembersmustmakeanadditionaltriptoWashington.Assumingthatone-

quarterofthecommittees'staffsturnsovereachyear,approximately91advisorycommitteememberswillrequireorientationeachyear.Theestimatedadditionalcompensationtoadvisorycommitteemembers,travel,andperdiemeachyearfor91membersare:

membercompensationfor2days(at$150/day)travelandperdiemfor2days

$27,300,40,586.

ThelogisticalaspectsofthesessionsmightrequirefourtofivedaysofFDAadministrativestafftimepersession.Theamountofprofessionalstafftimeneededtoruntheorientationsessionswilldependontheextenttowhichvideotapesorothertrainingmethodscanbeusedinlieuofface-to-faceinstruction.Ataminimum,onestaffmemberfromeachcenterwouldneedtobepresentforeachdayoforientation.

Regardingvideotapes,theCDRHhasapprovedthreevideoscriptsforuseinitsadvisorycommitteeorientationsessions:''MissionandOrganization";"MedicalDeviceApproval:theProcessandthePanel'sRole";and''AvoidingConflict-of-Interest."Althoughthescriptswerepreparedbyacontractor,significantFDAstafftimewasinvolvedinprovidinginput,reviewingthescripts,and,insomecases,rewritingthem.Fundingforthecontractorof$10,000wasprovidedbytheHealthIndustryManufacturers'Association(HIMA).Productioncostswillrangefrom$10,000to$25,000pervideotape,dependingonwhetherornotprofessionalactorsareused.

4.SchedulingAdvisoryCommitteeMeetingsinAdvance;ReviewingtheNDAandINDPipelineAnnually

TheIOMcommitteerecommendsthattheFDAestablishameetingscheduleforeachcommitteeoneyearinadvance.Theserecommendationshavecostimplicationsintermsofstaffyearsforbothcenterstaffandcommitteemanagementstaff.Stafftimewithineachcenterwillneedtobedevotedtodevelopingameetingscheduleforallcommitteesoneyearinadvance,andtocontinuallyreviewingwhatisinFDA'spipelinetorevisethatscheduleasnecessary.

ThepotentiallymostsignificantadditionalcosttotheagencytoimplementthisrecommendationmaybetheneedformoreFDAmedicalreviewerstocompletereviewsonascheduledbasis.Thisneedisamatterthattheagencywillundoubtedlywishtoexaminecarefullyinitsevaluationofthisrecommendation.

5.IncreasingCompensationofAdvisoryCommitteeMembers

AlthoughtheIOMcommitteedoesnotrecommendanincreaseincompensationforadvisorycommitteemembers,iturgestheCommissionertoraisethismatterwiththeSecretaryofHealthandHumanServices.IftheCommissionerdoesso,andifcompensationis

increased,thereareobviousbudgetaryimplicationsofsuchaction.

BelowwecomparetheestimatedcosttotheFDAofthreeratesofcompensationforadvisorycommitteemembersinfiscalyear1991.Thesearethecurrentrateof$150perdayandtwohypotheticalratesof$250perdayand$320perday.The$250rateisarbitrarybutreasonable;the$320rateisthemaximumcurrentlypayable(GS-15,step10)underGSArules.Thecostcomputationsarebasedon899advisorycommitteemember/consultantreimbursabledays.

RateperDay Costs

$150250320

$134,813224,750287,680

IftheFDAweretopayforadvisorycommitteemembers'homework,whichitdoesnotnowdo,saveforclinicalreviewsbyCDRHcommitteemembers,thiswouldaddtothecostsofthesystem.Estimatesfollowoftheincrementalcostofallowingfivedaysofhomeworkpercommitteemember(assuminganaverageof10memberspermeeting)atthreedifferentcompensationrates,$150,$250,and$320perday.Theincrementalcostsrangefrom$500,000to$1millionayear.

RateperDay Costs

$150250320

$480,000800,0001,024,000

TheFDA'sregulatoryresponsibilitiesarevastandtheexpertiseneededtoeffectivelycarrythemoutareequallygreat.Itisneitherfeasibleordesirabletoeliminatetheuseofadvisorycommitteesasawaytoacquiresomeofthatexpertise.Thus,theFDAmustcommitresourcestoitsadvisorycommitteeprocess.InrelationtotheFDA'stotalbudget,theincrementalcostsofmodifyingtheadvisorycommitteesystemappearrelativelymodestwhencomparedtothepotentialbenefitsthatcanbeexpectedtoaccruetotheagency.

AppendixBGlossaryAbbreviatedNewDrugApplication,orANDA:Asimplifiedsubmissionpermittedforaduplicateofanalreadyapproveddrug.ANDAsareforproductswiththesameorverycloselyrelatedactiveingredients,dosageform,strength,administrationroute,use,andlabelingasaproductthathasalreadybeenshowntobesafeandeffective.AnANDAincludesalltheinformationonchemistryandmanufacturingcontrolsfoundinanewdrugapplication(NDA),butdoesnothavetoincludedatafromstudiesinanimalsandhumans.Itmust,however,containevidencethattheduplicatedrugisbioequivalent(see"Bioequivalence")tothepreviouslyapproveddrug.

ActionLetter:AnofficialcommunicationfromtheFDAtoanNDAsponsorthatinformsitofadecisionbytheagency.Anapprovalletterallowscommercialmarketingoftheproduct.Anapprovableletterlistsminorissuestoberesolvedbeforeapprovalcanbegiven(see"ConditionalApproval").Anotapprovableletterdescribesimportantdeficienciesthatprecludeapprovalunlesscorrected.

AdvisoryCommittee:ApanelofoutsideexpertsconvenedperiodicallytoadvisetheFDAonsafetyandefficacyissuesaboutdrugsandotherFDA-regulatedproducts.TheFDAisnotboundtofollowcommitteerecommendations,butitsdecisionsusuallyparalleltherecommendationsofitsadvisorycommittees.

AmendmenttoanNDA:SubmittedtochangeoraddinformationtoanotyetapprovedNDAorasupplement.

Approval:TheFDAapprovestheapplicationwithoutconditions,orifthecompanyagreestothespecifiedconditions,andthecompanymay

begintomarketthetechnologyuponreceiptoftheorder.

BenchTesting:Testingofadeviceagainstspecificationsinasimulatedenvironmentthatdoesnotincludethelivingbodyofahumanoranimal.Alsoknownasinvitrodevicereadinesstesting.

Bioavailability:Therateandextenttowhichadrugisabsorbedorisotherwiseavailabletothetreatmentsiteinthebody.

Bioequivalence:Thescientificbasisonwhichgenericandbrand-namedrugsarecompared.Tobeconsideredbioequivalent,thebioavailabilityoftwoproductsmustnotdiffersignificantlywhenthetwoproductsaregiveninstudiesatthesamedosageundersimilarconditions.Somedrugs,however,areintendedtohaveadifferentabsorptionrate.TheFDAmayconsideraproductbioequivalenttoasecondproductwithadifferentrateofabsorptionifthedifferenceisnotedinthelabelinganddoesnotaffectthedrug'ssafetyoreffectivenessorchangethedrug'seffectsinanymedicallysignificantway.

ClassI:AnFDAclassificationofdevicesforwhichthegeneralcontrolsoftheFood,Drug,andCosmeticActaresufficienttoprovideareasonableassuranceofsafetyandeffectiveness.Approximately30percentofdevicesareinClassI.

ClassII:DevicesforwhichClassIcontrolsalonearenotsufficientbutforwhichthesecontrolsplusspecialrequirementswinprovidereasonableassuranceofsafetyandeffectiveness.Approximately60percentofdevicesareinClassII.

ClassIII:ApremarketapprovalclassfordevicesthatcannotbeplacedineitherClassIorClassII.Adeviceinthisclasshasatleastoneofthefollowingcharacteristics:itispurportedforuseinsupportingorsustaininghumanlifeorforausethatisofsubstantialimportanceinpreventingtheimpairmentofhumanhealth;itpresentsapotentiallyunreasonableriskofillnessorinjury;oritisa

transitionaldevice.Approximately10percentofdevicesareinClassIII.

ClinicalStudies:Clinical,orhuman,studiesaimtodistinguishadrug'seffectfromotherinfluencesforexample,aspontaneouschangeindiseaseprogressionorintheeffectofaplacebo(aninactivesubstancethatlookslikethetestdrug).SuchstudiesconductedinthiscountrymustbeunderanapprovedIND(see"InvestigationalNewDrugApplication"),undertheguidanceofaninstitutionalreviewboard,inaccordwithFDArulesonhumanstudies,andwiththeinformedconsentofparticipants.

CNDA:ComputerizedNDA;see"NDA."

ConditionalApproval:TheFDAsendsanapprovableletter(see"ActionLetter"and"Approval"),citingspecificconditionstowhichthecompanyisaskedtoagree.ThismeansthattheFDAbelievesthereisreasonableassuranceofsafetyandeffectiveness,butthatcertainconditionsmustbeimposedonthecompany.

Diffusion:Theprocessbywhichuseofatechnologicalinnovationinagivensocialsystemspreadsoveraperiodoftime.(See"TechnologicalInnovation.")

DrugSubstance:Theactiveingredientintendedtodiagnose,treat,cure,orpreventdiseaseoraffectthestructureorfunctionofthebody,excludingotherinactivesubstancesusedinthedrugproduct.

Effectiveness:Inhealthcarepolicyandclinicalcare,"effectiveness"usuallyreferstotheperformanceandevaluationofahealthcaretechnologyingeneralclinicaluse."Efficacy,"bycontrast,isusedtodenotetheuseandevaluationofahealthcaretechnologyunderhighlycontrolledconditionsbyunusuallyqualifiedpractitioners.Unfortunately,invariouspiecesoflegislationpertainingtotheFDA,effectivenessisusedtorefertothecontrolled,highlyevaluativeuseusuallyassociatedwiththeevaluationofefficacy.Becausethedefinitionsofeffectivenessthataresetoutinlawarecontrarytotheusualmeaningoftheword,whenusedbytheFDA"effectiveness"oftenreferstowhatcanmorepreciselyorconsistentlybecalledefficacy.

Efficacy:See"Effectiveness."

Enforcement:Beforeaproductismarketed,enforcementisthemonitoringofclinicalinvestigatorsandproductsponsors.Onceaproductisonthemarket,enforcementalsoincludestheinspectionofproductsandmanufacturers.

InvestigationalNewDrugApplication,orIND:AnapplicationthatadrugsponsormustsubmittotheFDAbeforebeginningtestsofanewdrugonhumans.TheINDcontainstheplanforthestudyandissupposedtogiveacompletepictureofthedrug,includingitsstructuralformula,animaltestresults,andmanufacturinginformation.

Invitrobenchtesting:See"BenchTesting."

Invivotesting:Testinginthelivingbodyofaplantoranimal.

NewDrug:Adrugfirstinvestigatedorproposedformarketingafter1938,whentheFederalFood,Drug,andCosmeticActwaspassed.Thismeansthatthedrugwasnotgenerallyrecognizedassafeandeffectivebeforethatdate.

NewDrugApplication,orNDA:AnapplicationrequestingFDAapprovaltomarketanewdrugforhumanuseininterstatecommerce.Theapplicationmustcontain,amongotherthings,datafromclinicalstudiesneededforFDAreviewfromspecifictechnicalviewpoints,includingchemistry,pharmacology,medical,biopharmaceutics,statistics,andforanti-infectivesmicrobiology.

Pharmacology:Thesciencethatdealswiththeeffectofdrugsonlivingorganisms.

Post-MarketingSurveillance:FDA'songoingsafetymonitoringofmarketeddrugs.

Pre-ClinicalStudies:Studiesthattestadrugonanimalsandothernonhumantestsystems.TheymustcomplywiththeFDA'sgoodlaboratorypractices.Dataaboutadrug'sactivitiesandeffectsinanimalshelpestablishboundariesforsafeuseofthedruginsubsequenthumantesting(clinicalstudies).Also,becauseanimalshaveamuchshorterlifespanthanhumans,valuableinformationcanbegainedaboutadrug'spossibletoxiceffectsoverananimal'slife-cycleandonoffspring.

Pre-MarketApproval:Thedevicemanufacturermustprovidereasonableassuranceofsafetyandeffectivenessundertheconditionsofintendeduse.Underthe1976MedicalDeviceAmendments,theFDAhadtosubmitallpre-marketingapprovalapplicationstoanadvisorycommitteeforarecommendationonthedecision.TheSafeMedicalDevicesActof1990,however,allowstheFDAdiscretionin

decidingwhichapplicationstosubmittoanadvisorycommittee.

Pre-MarketNotification(510(k)):Themanufacturerpresentsevidencethatitsdeviceissubstantiallyequivalenttoanearlier,approveddevice.Approximately5,000to6,000510(k)sarereceivedinayear,andabout90percentofdevicesthussubmittedarejudgedtobesubstantiallyequivalent.Ifthedeviceisnotsubstantiallyequivalent,itisplacedinClassIII(whichrequirespre-marketapproval)andcannotbemarketeduntilapre-market

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