Regulatory requirements for Clinical Trials´Authorization€¦ · EU Directives & Regulation *...

28
Regulatory requirements for Clinical Trials´Authorization Marcos Maroto, BSc, PhD QA Manager II Workshop in translational Nanomedicine

Transcript of Regulatory requirements for Clinical Trials´Authorization€¦ · EU Directives & Regulation *...

Page 1: Regulatory requirements for Clinical Trials´Authorization€¦ · EU Directives & Regulation * Applicable to all Member States * 2001/83/EC • 2001/20/EC: Implement principles and

Regulatory requirements for Clinical Trials´Authorization

Marcos Maroto, BSc, PhD QA Manager

II Workshop in translational Nanomedicine

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PhaseIClinicalTrials

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3RMaciulaitisetal,MolecularTherapyV20,Issue3;p479-482,2012

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4RMaciulaitisetal,MolecularTherapyV20,Issue3;p479-482,2012

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5

Outline

*  Regulatory Authorities Overview

*  Regulations & Directives Framework

*  Phase I CT Authorization Process

*  Steps and Documentation

*  Advanced therapy specific regulatory requirements

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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)

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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.

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EudraLex–EULegislation

*  EULegislationincludes*  Directives,Regulationsandnon-legislativeactsfor

medicinalproducts*  Scientificandregulatoryguidelines*  Guidelinesforclinicaltrialsandpharmacovigilance

*  Exceptions:Medicinalproductsforpaediatricuse,orphans,herbalmedicinalproductsandadvancedtherapies

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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

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*  RelatedtoAdvancedTherapy*  ApplicabletoallMemberStates

•  2001/83/EC:•  AmendedbyCommissionDirective2009/120/EC

•  1394/2007:RegulationonAdvancedTherapymedicinalproducts

•  EC/668/2009:CommissionRegulationontheevaluationandcertificationofqualityandnon-clinicaldatarelatingtoadvancedtherapymedicinalproductsdevelopedbymcro,smallandmediumenterprises

*  Nationallawsalsoapply:InSpain477/2014(Authorizationforuse,notforcommercialization)

EUDirectives&Regulation

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EudraLex-Volume10

*  Outlinesallguidelinesregardingclinicaltrials:*  informationtobesubmittedtocompetentauthoritiesand

ethicscommittees.*  requirementsonsafetymonitoringandthereportingof

adversereactions.*  requirementsregardingGCP,includingdocumentationof

clinicaltrials.*  specificrequirementsregardingtheproductsandtheclinical

trials.*  inspectionsofcompetentauthoritiesandtheapplicable

procedures.

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EudraLex-Volume10

ChapterI*  Thedossierforthecompetentauthority(CT1)*  ThedossierfortheEC

ChapterII:Safetyreporting(CT3).ChapterIII:Pharmaceuticaldata.ChapterIV:InspectionsChapterV:GCPandEudraCTChapterVI:Legislation

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ICH

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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)

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RegulatoryapprovalprocedureforCTs

SeparatelyineachMemberState…

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EudraCT

EuropeanUnionDrugRegulatingAuthoritiesClinicalTrials

*  Databaseofallclinicaltrialscommencinginthecommunityfrom

1May2004onwards*  EstablishedinaccordancewithCTDirective*  AccesstoEudraCTdatabaseitselfisconfidentialandremains

accessibleonlytotheCAoftheMemberStates,theEMAandtheCommission

*  EudraCTnumber1.  UniqueidentifierforeachCTwithatleastonesiteinthe

EU2.  MustbeincludeedonallCTapplications

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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)

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ConductofPhase1Trials

*  ApprovalbyCompetentAuthorityrequired*  CompetentAuthorityalsoresponsiblefor:*  ReviewofApplicationForm:*  safetyinformationofinvestigationalmedicinalproduct(IMP)*  ReviewofInvestigatorBrochure(IB)*  InformedConsent*  Protocol*  Insurancepolicy*  Financialdisclosure*  Feasibilities

*  ConductofinspectionsofstudysitestoensureGCPcompliance

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ConductofPhase1Trials

*  Sponsorresponsibilities:

*  QualityAssuranceandControl*  TrialDesign,Management*  DataHandlingandRecordkeeping*  Investigatorandtrialsiteselection*  NotificationsandsubmissionstoRegulatoryAuthoritiesand

EthicsCommittees(EC)*  Manufacturingandpackagingofmedicinalproduct*  Safetyandadversedrugreactionreporting*  Monitoringofthetrial

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ConductofPhase1Trials

*  DrugsafetySponsorresponsibilities:

* Haveapharmacovigilancesysteminplacetorecordandanalyzeadverseeventsinthetrial* Promptlynotifyinvestigators,CAsandECsonallresultsthatcouldadverselyaffecthealthofsubjectsparticipatinginthetrial

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ConductofPhase1Trials

*  Drugsafety

*  Investigatorsmustreportseriousadverseeventstosponsorwithin24h*  Ifsuspectedunexpectedseriousadversereaction(SUSAR),submissionbySponsortoEudravigilancedatabase(EVCTM),CAs,ECsinvestigators(variationsinlocalrequirements)*  InformEConanyadditionalsafetyinformationanddeathsinthestudy

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ConductofPhase1Trials

*  DevelopmentSafetyUpdateReport*  “ICHguidelineE2Fondevelopmentsafetyupdatereport”*  Includesimportantsafetyinformationupdates*  HastobesubmittedannuallytoCAsandECsoftheMemberStatewheretrialisconducted*  “DevelopmentInternationalBirthDate”*(DIBD)usedtodeterminethestartoftheannualperiod(dateofsponsor’sfirstauthorizationforaclinicaltrialinanycountryworldwide.

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ConductofPhase1Trials

* Recordretention* basedonlocallaw* upto15years* includesCaseReportForms(CRF),TrialMasterFile(TMF)

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ConductofPhase1Trials

*  InvestigationalMedicinalProduct(IMP)Requirements*  LabelmustbeinaccordancewithAnnex13ofDirective2001/83/EC*  LanguagerequirementsforlabellingvarybetweenMemberStates*  SponsorisresponsiblefordestructionofunusedIMP*  IMPbatchrecordretention:>5yearsaftercompletionordiscontinuationoftrial

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RegulatorypathwaysforATMPsinEurope

ATMP:AdvancedTherapyMedicinalProduct//CAT:CommitteeforAdvancedTherapiesEMA:EuropeanMedicinesAgency//SME:smallandmedium-sizeenterprise

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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

26/9/1727

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MarcosMarotoPérez,B.Sc.&Ph.D.

QualityAssuranceManager

Mail: [email protected] www.ifth.es


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