Regulatory requirements for Clinical Trials´Authorization€¦ · EU Directives & Regulation *...
Transcript of Regulatory requirements for Clinical Trials´Authorization€¦ · EU Directives & Regulation *...
Regulatory requirements for Clinical Trials´Authorization
Marcos Maroto, BSc, PhD QA Manager
II Workshop in translational Nanomedicine
PhaseIClinicalTrials
3RMaciulaitisetal,MolecularTherapyV20,Issue3;p479-482,2012
4RMaciulaitisetal,MolecularTherapyV20,Issue3;p479-482,2012
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Outline
* Regulatory Authorities Overview
* Regulations & Directives Framework
* Phase I CT Authorization Process
* Steps and Documentation
* Advanced therapy specific regulatory requirements
REGULATORY AUTHORITIES
* “competent authorities” * guarantee transparent information and decision-
making * give regulations, active consultation and participation * require explanations of any actions * require following principles that promote non-arbitrary
and responsive decisions * review of administrative decisions by courts or other
bodies * review submitted clinical data and those that conduct
inspections
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* FDA(USA)* EMA(EU)* MHLW(Japan)* CDSCO(India)* MHRA(UK)* TGA(Australia)* HEALTHCANADA(Canada)* MCC(SouthAfrica)* ANVISA(Brazil)* SFDA(China)* SWISSMEDIC(Switzerland)* …
PermanentMembersofICH(InternationalConferenceon
Harmonization)
WhydoweneedarobustregulatoryapprovalsystemfotCTs?
* (1) In clinical trial the rights, safety, dignity and well-being of subjects should be protected and the data generated should be reliable and robust. The interest of the subjects should always take priority over all other interests.
* (2) In order to allow for independent control as to whether these principles are adhered to, a clinical trial should be subject to prior authorization.
EudraLex–EULegislation
* EULegislationincludes* Directives,Regulationsandnon-legislativeactsfor
medicinalproducts* Scientificandregulatoryguidelines* Guidelinesforclinicaltrialsandpharmacovigilance
* Exceptions:Medicinalproductsforpaediatricuse,orphans,herbalmedicinalproductsandadvancedtherapies
EUDirectives&Regulation* ApplicabletoallMemberStates* 2001/83/EC• 2001/20/EC:ImplementprinciplesanddetailedguidelinesforGCP/
GMP• 726/2004:RegulationonCommunityproceduresforthe
authorisationandsupervisionofmedicinalproducts.DescribetherequirementsfortheconductofclinicaltrialsintheEU.IsindiviadullyimplementedineachEUstatemember.Simplifyandharmonise.Ensurereliabilityofgenerateddata.Allowcost-efficientclinicalresearch
• 536/2014:Regulationonclinicaltrialsonmedicinalproductsforhumanuse
• 658/2014:Regulationfortheconductofpharmacovigilanceactivities
* Nationallawsalsoapply:InSpain29/2006and1090/2015
* IftrialisconductedbyasponsoroutsideEuropeanEconomicArea,alocallegalrepresentativeisneeded
* RelatedtoAdvancedTherapy* ApplicabletoallMemberStates
• 2001/83/EC:• AmendedbyCommissionDirective2009/120/EC
• 1394/2007:RegulationonAdvancedTherapymedicinalproducts
• EC/668/2009:CommissionRegulationontheevaluationandcertificationofqualityandnon-clinicaldatarelatingtoadvancedtherapymedicinalproductsdevelopedbymcro,smallandmediumenterprises
* Nationallawsalsoapply:InSpain477/2014(Authorizationforuse,notforcommercialization)
EUDirectives&Regulation
EudraLex-Volume10
* Outlinesallguidelinesregardingclinicaltrials:* informationtobesubmittedtocompetentauthoritiesand
ethicscommittees.* requirementsonsafetymonitoringandthereportingof
adversereactions.* requirementsregardingGCP,includingdocumentationof
clinicaltrials.* specificrequirementsregardingtheproductsandtheclinical
trials.* inspectionsofcompetentauthoritiesandtheapplicable
procedures.
EudraLex-Volume10
ChapterI* Thedossierforthecompetentauthority(CT1)* ThedossierfortheEC
ChapterII:Safetyreporting(CT3).ChapterIII:Pharmaceuticaldata.ChapterIV:InspectionsChapterV:GCPandEudraCTChapterVI:Legislation
ICH
AdvancedTherapyMedicinalProducts
GeneTherapy&BiologicsMP
CellTherapy&TissueEngineeredMP
ICHQ5BAnalysisoftheexpressionconstructincelllinesusedforproductionofr-DNAderivedproteinproducts(CPMP/ICH/139/95)ICHQ5DDerivationandcharacterisationofcellsubstratesusedforproductionofbiotechnological/biologicalproducts(CPMP/ICH/294/95)ICHQ5AViralsafetyevaluationofbiotechnologyproductsderivedfromcelllinesofhumanoranimalorigin(CPMP/ICH/295/95)ICHTopicQ5EComparabilityofbiotechnological/biologicalproducts(CPMP/ICH/5721/03)ICH5QCStabilitytestingofbiotechnological/biologicalproducts(CPMP/ICH/138/95)ICHQ6BSpecifications:Testproceduresandacceptancecriteriaforbiotechnological/biologicalproducts(CPMP/ICH/365/96)ICHQ7Goodmanufacturingpracticeforactivepharmaceuticalingredients(CPMP/ICH/4106/00)ICHQ8(R2)Pharmaceuticaldevelopment(CHMP/ICH/167068/04)ICHQ9Qualityriskmanagement(EMA/CHMP/ICH/24235/2006)ICHQ10Pharmaceuticalqualitysystem(EMA/CHMP/ICH/214732/2007)
ICHQ2(R1)Validationofanalyticalprocedures:textandmethodology(CPMP/ICH/381/95)ICHQ5A(R1)Viralsafetyevaluationofbiotechnologyproductsderivedfromcelllinesofhumanoranimalorigin(CPMP/ICH/295/95)ICHQ5CStabilitytestingofbiotechnological/biologicalproducts(CPMP/ICH/138/95)ICHQ5DDerivationandcharacterisationofcellsubstratesusedforproductionofbiotechnological/biologicalproducts(CPMP/ICH/294/95)ICHQ5EComparabilityofbiotechnological/biologicalproducts(CPMP/ICH/5721/03)ICHQ7Goodmanufacturingpracticeforactivepharmaceuticalingredients(CPMP/ICH/4106/00)ICHQ8(R2)Pharmaceuticaldevelopment(CHMP/ICH/167068/04)ICHQ9Qualityriskmanagement(EMA/CHMP/ICH/24235/2006)ICHQ10Pharmaceuticalqualitysystem(EMA/CHMP/ICH/214732/2007)
RegulatoryapprovalprocedureforCTs
SeparatelyineachMemberState…
EudraCT
EuropeanUnionDrugRegulatingAuthoritiesClinicalTrials
* Databaseofallclinicaltrialscommencinginthecommunityfrom
1May2004onwards* EstablishedinaccordancewithCTDirective* AccesstoEudraCTdatabaseitselfisconfidentialandremains
accessibleonlytotheCAoftheMemberStates,theEMAandtheCommission
* EudraCTnumber1. UniqueidentifierforeachCTwithatleastonesiteinthe
EU2. MustbeincludeedonallCTapplications
Phase1SD/MDEscalationStudies
* Typicallythefirst-in-humanstudy(orstudies)* Randomized,placebo-controlled,healthyvolunteers(or
patients,incertaincases)* Startingdosedeterminedbypreclinicaltoxicologystudies.* Informationgained:* Safety/tolerability,identifyMTD* GeneralPKcharacteristics,variability,linearity/proportionality* Steady-stateparameters(accumulation,time-dependency)* Preliminaryexplorationofdrugelimination(urinePK,metaboliteidentification)
ConductofPhase1Trials
* ApprovalbyCompetentAuthorityrequired* CompetentAuthorityalsoresponsiblefor:* ReviewofApplicationForm:* safetyinformationofinvestigationalmedicinalproduct(IMP)* ReviewofInvestigatorBrochure(IB)* InformedConsent* Protocol* Insurancepolicy* Financialdisclosure* Feasibilities
* ConductofinspectionsofstudysitestoensureGCPcompliance
ConductofPhase1Trials
* Sponsorresponsibilities:
* QualityAssuranceandControl* TrialDesign,Management* DataHandlingandRecordkeeping* Investigatorandtrialsiteselection* NotificationsandsubmissionstoRegulatoryAuthoritiesand
EthicsCommittees(EC)* Manufacturingandpackagingofmedicinalproduct* Safetyandadversedrugreactionreporting* Monitoringofthetrial
ConductofPhase1Trials
* DrugsafetySponsorresponsibilities:
* Haveapharmacovigilancesysteminplacetorecordandanalyzeadverseeventsinthetrial* Promptlynotifyinvestigators,CAsandECsonallresultsthatcouldadverselyaffecthealthofsubjectsparticipatinginthetrial
ConductofPhase1Trials
* Drugsafety
* Investigatorsmustreportseriousadverseeventstosponsorwithin24h* Ifsuspectedunexpectedseriousadversereaction(SUSAR),submissionbySponsortoEudravigilancedatabase(EVCTM),CAs,ECsinvestigators(variationsinlocalrequirements)* InformEConanyadditionalsafetyinformationanddeathsinthestudy
ConductofPhase1Trials
* DevelopmentSafetyUpdateReport* “ICHguidelineE2Fondevelopmentsafetyupdatereport”* Includesimportantsafetyinformationupdates* HastobesubmittedannuallytoCAsandECsoftheMemberStatewheretrialisconducted* “DevelopmentInternationalBirthDate”*(DIBD)usedtodeterminethestartoftheannualperiod(dateofsponsor’sfirstauthorizationforaclinicaltrialinanycountryworldwide.
ConductofPhase1Trials
* Recordretention* basedonlocallaw* upto15years* includesCaseReportForms(CRF),TrialMasterFile(TMF)
ConductofPhase1Trials
* InvestigationalMedicinalProduct(IMP)Requirements* LabelmustbeinaccordancewithAnnex13ofDirective2001/83/EC* LanguagerequirementsforlabellingvarybetweenMemberStates* SponsorisresponsiblefordestructionofunusedIMP* IMPbatchrecordretention:>5yearsaftercompletionordiscontinuationoftrial
RegulatorypathwaysforATMPsinEurope
ATMP:AdvancedTherapyMedicinalProduct//CAT:CommitteeforAdvancedTherapiesEMA:EuropeanMedicinesAgency//SME:smallandmedium-sizeenterprise
HELPFUL SOURCES
* Declaration of Helsinki (2013 version): http://www.wma.net/en/30publications/10policies/b3/index.html.pdf? print-media-type&footer-right=[page]/[toPage]
* TypicalpitfallsinapplicationsformarketingauthorizationofbiotechnologicalproductsinEurope.NatRevDrugDiscov.2008;7:893–899
* International Council for Harmonization (ICH) – all ICH guidelines: http://www.ich.org/home.html
* United Nations Universal Declaration of Human Rights: http://www.un.org/en/documents/udhr/
* World Health Organization - Handbook for Clinical Research Practice (WHO GCP): http://apps.who.int/prequal/info_general/documents/GCP/gcp1.pdf
* Council for international organizations of national sciences (CIOMS): http://www.cioms.ch/
* Eudralex – EU Legislation: http://ec.europa.eu/health/documents/eudralex/index_en.htm
* European Medicines Agency (EMA) – Scientific guidelines: http://www.ema.europa.eu/ema/index.jsp? curl=pages/regulation/general/general_content_000043.jsp&mid=WC0b01ac05800240cb
* FDA 2014: http://www.fda.gov/downloads/Drugs/NewsEvents/UCM443547.pdf
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