principal investigator: competencies and...
TRANSCRIPT
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*
*Or ,if the subject is unable toprovide informed consent,the subject´s legally acceptable representativeDB 2017
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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