Dulce Brito, MD, Ph.D, FESCHospital de Santa Maria, CHLN, CAML, Centro Cardiovascular

Universidade de Lisboa

Clinical research in Portugal: meet the players

Principal investigator: competencies andresponsibilities

� Clinicaltrialsarefundamentaltothedevelopmentofinnovative,investigationalproductssuchasdrugsorhigh-risk medicaldevices.

� Manyproductsarefoundtobesafeandeffectiveinbenchtesting, invitro testingoranimalstudies,butfailtodemonstratethesameeffectinhumans.1,2

� Theseinvestigationalproductsmustbeprovensafeandeffectiveinaclinicalstudyinhumansbeforeuseinthegeneralpopulation.

1- Canadatrials.(2008,April26.)Whatisclinicalresearch? RetrievedJuly13,2012,http://www.canadatrials.com/AboutClinicalResearch.php.2- PeoplefortheEthicalTreatmentofAnimals.(n.d.). AnimalExperiments:Overview.RetrievedSeptember24,2012,from http://www.peta.org/issues/animals-used-for-experimentation/animal-experiments-overview.aspx. DB 2017

Clinical Trial/Study

� Anyinvestigationinhumansubjectsintendedtodiscoverorverifytheclinical,pharmacologicaland/orotherpharmacodynamiceffectsofaninvestigationalproduct(s),and/ortoidentifyanyadversereactionstoaninvestigationalproduct(s),and/ortostudyabsorption,distribution,metabolism,andexcretionofaninvestigationalproduct(s)withtheobjectofascertainingitssafetyand/orefficacy.

ICHTopic E6(R1)Guideline forGood Clinical PracticeJuly 2002CPMP/ICH/135/95

ClinicaltrialsandGoodClinicalPractice(GCP)

� Goodclinicalpractice(GCP)isaninternationalethicalandscientificqualitystandard fordesigning,conducting,monitoring,auditing,recording,analyses,andreporting clinicaltrials thatinvolvetheparticipationofhumansubjects.1

� Providesassurancethatthedataandreportedresultsarecredibleandaccurate,andthattherights,integrity,andconfidentiallyoftrialsubjectsareprotected.

� Regardlessofwhetheraclinicaltrialisalarge,multi-centrestudyinpatientsorasmallclinicalpharmacologicalstudyinhealthysubjects,therelevantGCPstandardshouldbefollowedbythesponsoringcompany ofthehealthcareproduct,theinvestigators,theethicscommitteesandanyclinicalresearchorganizations

1- Tobin,J.J.&Walsh,G.(2008).Chapter 5.Clinical trial.InMedicalproduct regulatory affairs.Pharmaceuticals,diagnostics,medicaldevices.Weinheim:Wiley-VCHVerlag GmbH &Co.KGaA.

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InternationalConferenceonHarmonisation (ICH)GCPGuideline

� “Objective: toprovideaunified standardforthe EU,Japan and theUStofacilitate the mutualacceptance of clinical databy theregulatory authorities inthese jurisdictions.

� The guideline was developedwith considerationof the currentgoodclinical practices of the EU,Japan,and the US,aswell asthose ofAustralia,Canada,the Nordic countriesand the WHO

� The guideline should be followedwhen generatingclinical trialdatathat areintended tobe submitted toregulatory authorities

� The principles established inthe guideline may also be applied tootherclinical investigations that may have an impact on the safety andwell-being of human subjects.”

ICHTopic E6(R1)Guideline forGood Clinical PracticeJuly 2002CPMP/ICH/135/95

GoodclinicalpracticeandtheICH

� PriortotheGCPguidancedocumentdevelopedbyICH,differentjurisdictionshaddifferentguidelinesrelatingtotheconductofclinicaltrials.

� WiththeintroductionofICHGCP,theconductofclinicaltrialsgloballyhasbecomemoreuniformandpracticable.Today,theimplementationofICHgoodclinicalpracticeinmostjurisdictionsisreasonablysimilarandthevastmajorityoftheregulationsarethesame.

� HealthcareproductdevelopersshouldthereforeworktoICHinthecontextoflocalregulations.

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ThirteencoreprinciplesofICHGoodClinicalPractice

1. Ethicalprinciples: declarationofHelsinki2. Favourable benefit(s)vs.Risk(s)

� Aclinicaltrialshouldbeinitiatedandcontinuedonlyiftheanticipatedbenefitsjustifytherisks.

3. Subject’s rights� Therights,safetyandwell-beingofthetrialsubjectsoverridetheinterestsofscienceandsociety.

4. Adequate supporting data� Theavailablenon-clinicalandclinicalinformationonaninvestigationalproductshouldbeadequatetosupporttheproposedclinicaltrial.

5. Scientifically sound protocol6. Independent ethics committee oversight

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ThirteencoreprinciplesofICHGoodClinicalPractice

7. Medicalcarebyqualifiedinvestigator� Themedicalcaregiventosubjects,andthemedicaldecisionsmadeon

theirbehalf, shouldalwaysbetheresponsibility ofaqualifiedphysician..

8. Qualified personnel� Eachindividual involvedinconductingaclinicaltrialshouldbequalifiedby

education, trainingandexperiencetodotheirrespectivetask(s).

9. Informed consent� Freely-giveninformedconsentshouldbeobtained fromeverysubjectprior

toparticipation intheclinicaltrial.

10. Record-keeping11. Subject confidentiality12. GMPmanufacturingoftheinvestigationalproduct13. Quality assurance&monitoring

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Investigator(PI)

Apersonresponsiblefortheconductoftheclinicaltrialatatrialsite.

Ifatrialisconductedbyateam,theinvestigatoristheresponsibleleaderoftheteamandmaybecalledtheprincipalinvestigator(PI)

Subinvestigator§ Anyindividualmemberoftheclinicaltrialteamdesignatedand

supervisedbythePIatatrialsitetoperformcriticaltrial-relatedproceduresand/ortomakeimportanttrial-relateddecisions(e.g.,associates,residents,researchfellows).

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PIresponsibilitiesQualificationsandAgreements

Theinvestigator(s)should

§ bequalifiedbyeducation,training,andexperience toassumeresponsibilityfortheproperconductofthetrial,(…)andshouldprovideevidenceofsuchqualificationsthroughup-to-dateCVand/orotherrelevantdocumentationrequestedbythesponsor,theIRB/IEC,and/ortheregulatoryauthority(ies)

§ complywith,GCPandtheapplicableregulatoryrequirements

§ permitmonitoringandauditingbythesponsor,andinspectionbytheappropriateregulatoryauthority(ies)

§ maintainalistofappropriatelyqualifiedpersonstowhomhasdelegatedsignificanttrial-relatedduties

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PIresponsibilities

AdequateResources

ThePIshould

§ beabletodemonstrate(e.g.,basedonretrospectivedata)apotentialforrecruitingtherequirednumberofsuitablesubjectswithintheagreedrecruitmentperiod

§ havesufficienttimetoproperlyconductandcompletethetrialwithintheagreedtrialperiod

§ haveavailableanadequatenumberofqualifiedstaffandadequatefacilitiesfortheforeseendurationofthetrialtoconductthetrialproperlyandsafely

§ ensurethatallpersonsassistingwiththetrialareadequatelyinformed abouttheprotocol,theinvestigationalproduct(s),andtheirtrial-relateddutiesandfunctions

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PIresponsibilities

CommunicationwithIRB*/IEC**

ThePIshould:

§ Beforeinitiatingatrial,havewrittenanddatedapproval/favourableopinionfromtheIRB/IECforthetrialprotocol,writteninformedconsentform,consentformupdates,subjectrecruitmentprocedures,andanyotherwritteninformationtobeprovidedtosubjects

§ ProvideacurrentcopyoftheInvestigator´sBrochure(andtheupdatesduringthetrial,plusalldocumentssubjecttoreview)

*InstitutionalReview Board**Independent Ethics Committee

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PIresponsibilities

CompliancewithProtocol

ThePIshouldnot

§ Implementanydeviationfrom,orchangesoftheprotocolwithoutagreementbythesponsorandpriorreviewanddocumentedapproval/favourableopinionfromtheIRB/IECofanamendment,exceptwherenecessarytoeliminateanimmediatehazard(s)totrialsubjects (…)

§ Anydeviationfromtheapprovedprotocolmustbedocumentedandexplained(theimplementeddeviationorchange,thereasonsforit,and,ifappropriate,theproposedprotocolamendment(s))andshouldbesubmittedtotheIRB/IEC,tothesponsorand,ifrequired,totheregulatoryauthority(ies)

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PIresponsibilities

Investigationalproducts

TheInvestigator/otherpersondesignatedbytheinvestigator,should

§ Maintainrecordsoftheproduct´sdeliverytothetrialsite,theinventoryatthesite,theusebyeachsubject,andthereturntothesponsororalternativedispositionofunusedproduct(s)

§ Ensurethatinvestigationalproducts arestoredasspecifiedbythesponsorandusedonlyinaccordancewiththeapprovedprotocol

§ Explainthecorrectuseofinvestigationalproducts toeachsubjectandcheck,atintervalsappropriateforthetrial,thateachsubjectisfollowingtheinstructionsproperly

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PIresponsibilities

RandomizationProceduresandUnblindingTheinvestigatorshouldfollowthetrial´srandomizationprocedures,if

any,andshouldensurethatthecodeisbrokenonlyinaccordancetoprotocol

Ifthetrialisblinded,theinvestigatorshouldpromptlydocumentandexplaintothesponsoranyprematureunblinding(e.g.,accidentalunblinding,unblindingduetoseriousAE)oftheinvestigationalproduct

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PIresponsibilities

MedicalCareofTrialSubjects

Aqualifiedphysician(thePIorasubinvestigator forthetrial),shouldberesponsibleforalltrial-relatedmedicaldecisions

§ Duringandfollowingasubject´sparticipationinatrial,theinvestigator/institutionshouldensurethatadequatemedicalcareisprovidedtoasubjectforanyadverseeventsrelatedtothetrial

§ Itisrecommendedthattheinvestigatorinformthesubject´sprimaryphysicianaboutthesubject´sparticipationinthetrialifthesubjecthasaprimaryphysicianandifthesubjectagreestotheprimaryphysicianbeinginformed

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PIresponsibilities

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?Informed consent ?

PIresponsibilities

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PIresponsibilities

Informedconsent

ThePIorasubinvestigator forthetrial,shouldfullyinformthesubject,*ofallpertinentaspectsofthetrialincludingthewritteninformationandtheapproval/favourable opinionbytheIRB/IEC

§ Thelanguageusedaboutthetrial,includingthewritteninformedconsentform,shouldbeasnon-technicalaspracticalandshouldbeunderstandabletothesubject*

§ Provideampletimeandopportunitytoinquireaboutdetailsofthetrialandtodecidewhetherornottoparticipate.Allthequestionsshouldbeansweredtothesatisfactionofthesubject*

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PIresponsibilities

Recordsandreports

� TheInvestigatorshouldensuretheaccuracy,completeness,legibility,andtimelinessofthedatareportedtothesponsorintheCRFsandinallrequiredreports

� AnychangeorcorrectiontoaCRFshouldbedated,initialed,andexplained(ifnecessary) andshouldnotobscuretheoriginalentry(thisappliestobothwrittenandelectronicchangesorcorrections)

� Theinvestigator/institutionshouldmaintainthetrialEssentialDocuments*asrequiredbytheapplicableregulatoryrequirements

� Uponrequestofthemonitor,auditor,IRB/IEC,orregulatoryauthority,theinvestigator/institutionshouldmakeavailablefordirectacess allrequestedtrial-relatedrecords

*Those documents which individually and collectively permit evaluation of the conduct of a trial and thequality of the data produced

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PIresponsibilities

Progressreports

� TheInvestigatorshould

SubmitwrittensummariesofthetrialstatustotheIRB/IECannually,ormorefrequently,ifrequested

Providewrittenreportstothesponsor,theIRB/IECand,whereapplicable,theinstitutiononanychangessignificantlyaffectingtheconductofthetrial,and/orincreasingtherisktosubjects

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PIresponsibilitiesAll SAEs should bereported immediatelyto the sponsor (and befollowed by detailed,written reports)

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PIresponsibilities

PrematureterminationorsuspensionofaTrial

� Ifthetrialisprematurelyterminatedorsuspendedforanyreason,theinvestigator/institutionshould

ØpromptlyinformthetrialsubjectsØAssureappropriatetherapyandfollow-upforthesubjects

Finalreport(uponcompletionofthetrial)ØTheinvestigatorshouldinformtheinstitutionandprovidetheIRB/IECwithasummaryofthetrialoutcome

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