GCP Presentation 6-1-10

8/6/2019 GCP Presentation 6-1-10

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General Principles for

Meeting RegulatoryResponsibilities

Terry VandenBosch, RN, PhD, CIP, CCRPSenior Research Compliance AssociateOffice of Human Research Compliance ReviewUniversity of MichiganJune 1, 2010


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Todays Discussion

Describe Best Research Practices (BRP) andGood Clinical Practices (GCP)Compare GCP requirements for FDA regulatedstudies and regulatory requirements for non-FDAregulated studiesIdentify common sense principles for

implementing best practices and GCP in clinicalstudies


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What is Best Practice

Experience-basedEvidence-based?Effective and efficient practices to meet

1) ethical principles2) federal regulations & guidance4) state laws & practice acts5) university policies and procedures6) any applicable study SOPs

Best Practices = Responsible Research Practices


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Ultimate Goal:

Responsible Research Practices

The University of Michigan is committed to the

highest standards of ethical behavior by faculty,staff, and students engaged in the conduct andadministration of research and other scholarlyactivity.

UM Provost Policy Statement on Academic and Research Integrity


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Ethical Principles & BestPractices

Ethical principles inform decision-making and basisfor federal regulations and guidancePast abuses stimulate use of Best Practices

NuremburgTuskegee syphilis studyWillowbrook retarded children hepatitis study

Are these ethical lapses and abuses all in the past?Nicole Wan (healthy volunteer- died), 1996

Jesse Gelsinger (ineligible-died), 1999Ellen Roche (healthy volunteer-died), 2001Inadequate monitoring with overdose of pediatric subjects-Pfizer FDA warning letter, April 9, 2010


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Ethical Principles-Belmont

Belmont Report 1979 Summarized ethical principals identified by National

Commission for the Protection of Human Subjects Prompted by the Tuskegee Syphilis Experiment and

the Willowbrook hepatitis study 3 basic ethical principles: (1) Respect for persons (2) Beneficence (3) Justice

Peter Buxtun, PHSvenereal diseaseinvestigator, theTuskegee whistle -blower

The Tuskegee Study Groupwere invited to receive"special treatment", whichwas actually a diagnosticlumbar puncture
http://en.wikipedia.org/wiki/Image:Buxton_media.jpg


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Respect for Persons

Ethical convictionsAcknowledge autonomy of the individualProtect those with diminished autonomy

Applying the principleInformed consent

The elements of informed consentInformation, comprehension, voluntaryVulnerable populations


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BeneficenceEthical convictions

Do no harmMaximize possible benefits

Minimize possible harms

Applying the principleInvestigator & IRB

Minimize risksWeigh risks and benefitsWhen appropriate, a plan to monitor andensure safety


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JusticeEthical Convictions

Fairness in distribution of burdens and benefits ofresearch participation

Applying the principleInvestigator-subject selectionIRB asks Is the selection of subjects equitable?


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RegulationsRegulations developed in response to egregious, harmfulresearch conductDeveloped on ethical principlesCongressional legislation signed into law by PresidentLaws interpreted in CFR (Code of Federal Regulations)by responsible federal agency

CFR regulations detail how law is implementedNoncompliance with CFR may result in criminalprosecution, fines, sanctions or debarment from research


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Federal Guidance andInformation Sheets

Published by federal agencies to provide moreinformation or to recommend best practicesInterprets application of regulationsCurrent thinkingNOT legally bindingFDA An alternative approach may be usedif such approach satisfies the requirements ofthe applicable statue, regulations, or bothGuidance should be met


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University of MichiganPolicies and Procedures

Standard Practice GuideApproved by RegentsSection 303, http://spg.umich.edu/section/303

Human Research Protection Program(HRPP) Operations Manual

http://www.hrpp.umich.edu/om/

IRB Guidance & SOPsSee IRB websites


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What is GCPA type of Best Practice term coined by theInternational Conference on Harmonization(ICH) and used by FDARefers to FDA regulations, guidance and notices

for Drugs, Devices & BiologicsFDA assures the safety and efficacy of pharmaceuticals, biologics, and medical devices onthe market in the U.S.A.

What entities covered by FDA GCP?IRBInvestigatorResearch Sponsor

NIH- Scientific and ethical standards of human

subject research


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ICH E6 InternationalConference on Harmonization

Multi-national body, USA, EU & Japan, est. 1989Meets periodically to resolve different technicalrequirements for drug registration

Goal: Create guidelines and standards for conductingclinical trials allowing sponsors to generate a single setof data to meet submission requirements of the threeregions

Originally based on ethical principles from theDeclaration of Helsinki-1964 with revisionsAdopted as guidance for drugs/biologics by FDAin 1997Also used by FDA in reference to devices


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ICH-E6 GCP DefinitionA standard for the design, conduct,performance, monitoring, auditing, recording,analyses , and reporting of clinical trials that

provides assurance that:the Data and Reported Results are Credible ,and Accurate , and thatthe Rights , Integrity , and Confidentiality of TrialSubjects are ProtectedAdopted as guidance by FDA in 1997

= Quality Data

= Ethics


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FDA Regulations and ICHGuidelines

Companies that wish to have study data acceptedby the regulatory agencies in the US, EU, and/orJapan need to follow the ICH guideline.Differences between FDA Regulations and ICHGCP Guidelines:

ICH Guideline states general principles is moreprescriptive than regulationse.g., 21 CFR 50 requires signature and date of subjectwhile ICH E6 says one should also have the signature ofthe investigator.


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Why GCP?Failures

Ethical AtrocitiesPreventable Research Deaths/InjuryScientific Fraud

Subject safetyPublic trust and support of research missionAssure valid data for evidence-based Health CareDrug development trajectory long, arduous,expensive (GCP assures safety and quality data)Useful products brought to market with known safetyprofile and effectivenessThe better the GCP-the sooner the product isavailable for patients


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Best Practices, GCP & Typesof Studies

Investigator InitiatedMay or may not be FDA regulated

NIH (HHS) supported

45 CFR 4617 Federal agencies and the common rulePart A of 45 CFR 46e.g., Dept. of Energy, Dept. of Education

FDA Regulated21 CFR 312 Drugs & Biologics21 CFR 812 Devices21 CFR 50 Protection of Human Subjects21 CFR 56 Institutional Review Boards


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Research Clinical Trials BestPractices and ICH E6 GCP

Both can be viewed as a series of key activitiesor practices

Order of activities may vary and may be simultaneousMultiple parties participate but PI remains accountable

Study scientific and ethical quality achieved bydefining key study best practices and assuringoversight to implement them


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Best Practices Key ActivitiesObtain Informed consentProvide for Subject Safety & Medical CareFollow the IRB approved protocol or submit amendment to IRBMaintain Confidentiality

Record keeping-Maintain accurate, current, organized records andsubmit reportsMaintain communication with IRBProvide appropriate oversight of qualified staffFDA-Investigational Product AccountabilityFDA-Essential Documents BinderAdditional areas

Conflict of interestCommunication with sponsor (FDA)Shipping regulations


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People and Paper Skills

NegotiationCommunicationTime managementRecord keepingComputerOrganization

Oversight of other research staffDetail-orientedKnowledge of regulations and their applicationIntimate knowledge of protocol


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Informed Consent as aProcess

Interpersonal communication skills assess subject understandingand motivation to participateInformed consent is freely given and is obtained from each subjectprior to study participation

The consent discussion is in language understandable to theparticipant or the representative and is done by a qualified personThe consent process provides sufficient opportunity for theparticipant or the participants legally authorized representative toconsider whether to participate

The consent process minimizes the possibility of coercion or undueinfluence (Research is not the same as therapeutic txmt)The consent discussion is free of exculpatory languageThe IRB approved document without any changes and with theelements of informed consent is used

Childrens assent & Parental Permission Adapted from AAHRPP, 2009


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Informed Consent MonitoringPrivacy respectedVoluntaryConducted as a process by PIProcess follows the IRB approved protocol

Waiver of consent possibleCopy of consent given to subjectConsent signed prior to any study proceduresRe-consent completed and documented asappropriate100% of consents used correct IRB approvedversion and were appropriately signed anddated


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What does the public think?

29%

9% 10%

40%

13%

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0.45

A person whogives blood

A person whovolunteers totake part in aclinical trail

A person whoraises money for

charity byrunning in a race

A person whodonates an

organ

Not sure/Refused

P e r c e n t

N=900

Which one of the following do you think makes a greatercontribution to mankind?

CISCRP/ODC Survey, 12/2006


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It is a confusing time to be asubject-or to be thinking about

becoming one

Moreno, 2001


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Subject Safety

Provide for Subject Safetyand Clinical Care


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Adverse Events & Harms.

Adverse event (AE) definedPrevent, monitor for, identify, provide immediate care for,track, analyze cause, report to IRB, may submit protocolamendment or changes to consent document & notifySponsor (FDA)IRBMED Guidance and timetable for reporting AEs athttp://med.umich.edu/irbmed/ae_orio/ae_report.htmHarms

Physical

PsychosocialSocialEconomicLegalDignitary


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What Can Result in Harms?

The protocol/treatmentSide effects of drugs/biologics or adverse device effectsNOT following the protocolNOT maintaining up-to-date recordsNOT maintaining communication with investigator and/or

study sponsorPrevent harmQualified person monitors overall studyMonitor laboratory results and tests and treat as appropriateMay withdraw subject from study

Know emergency procedures for breaking a study blindKeep primary care provider in communication as appropriateAEs are graded by

SeriousnessRelatedness to the study

Expected/Unexpected


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The Protocol

Follow the Protocol or Amend it


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The Tension in Research

The principal duty of a physician is to thewell-being of the individual.The principal duty of society (social ethics) isto the greatest good for the greatest numberof people.Research is protocol drivenClinicians often want to adapt the protocol foran individual


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Know and Follow the ProtocolChanges to the protocol, may not be initiated without IRB reviewand approval except when necessary to eliminate apparentimmediate hazards to the subject.Read it

FDA-each person on study team signs it

Protocol Readily AvailableNo mix ups-Clearly label current version

Follow itPrevent and track any protocol deviations

Notes to file-circumstances, CAPAReport to IRB and sponsor as applicableAmend protocol with IRB as needed

Follow randomization proceduresIf applicable, procedures follow data safety and monitoring plan(DSMP) submitted to IRB and funding agencies


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Confidentiality

Maintain Confidentiality


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Data Confidentiality & Security:Outcomes

Data maintained according to IRB approvedprotocolAccess to confidential data is restricted

Safe & secure storageDont share passwords!Mobile device security for researchers athttp://www.safecomputing.umich.edu/MDSUM Electronic data security Questions to GuideResearch Protections at OHRCR websitehttp://www.ohrcr.umich.edu/news/electronicdata.pdf


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Implications for Confidentiality

Being notified only, with no re-consent or opt out process, before their information goes to a national database

47% completely unacceptable20% somewhat unacceptableNo notification or re-consent at all, before their information is sent to a national database

54% completely unacceptable16% somewhat unacceptable

How much do current and potential subjectswant to be informed, give consent and maintain

confidentiality of their data?


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Record Keeping &Reports

Maintain Accurate, Current,Organized Records and SubmitReports


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Study FilesOrganized, accurate, up-to-dateDirect/Indirect subject identifiers

Direct-subject identifiers stored with dataIndirect-subject identifiers in key & not stored with data

Informed consent-stored with files?FDA-Complete, sign and submit FDA Form 1572Work efficiently

Study schema of subject progress for complex procedures

Checklist of forms completedMaintain records for:

FDA- two years after FDA approves NDANIH- three years after study terminatedHIPAA- six years after study terminated


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ALCOA (FDA)

FDA Documentation GuidanceA Attributable (who, when)

L Legible (readable, pen, no white out, single line)C Contemporaneous (up-to-date)O Original (source document)

A Accurate (verifiable with source)


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Source Data and Documents(FDA)

All clinical trial information should be recorded, handled,and stored in a way that allows its accurate reporting,interpretation, and verification

Source Document DefinitionOriginal documents, data, and records, (e.g., ALL study records suchas visits, CRF/Data Collection Forms, and,Subjective self-report instruments, hospital, clinical and office charts,laboratory notes, notes to file, subject diaries, checklists, pharmacy

dispensing records, recorded data from automated instruments, X-Rays, digital records

Source DataGenerate and Keep source documents in original recordsMay be using Electronic Data Capture (EDC)


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The IRB

Maintain Communicationwith the IRB


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IRB Communications andSubmissions

Interact with IRBAsk questionsGet to know UM IRB contacts

Initial IRB submission and approvalOngoing oversight

AEs, protocol deviations, unanticipated problems, DSMCreports or safety officer reports, UM OHRCR report, new

information that changes risk/benefit of studyparticipationContinuing review

Terminate a studyDont let it expire!


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Study Oversight &Qualifications


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Overall PI/InvestigatorResponsibilities

Ensure a study is conducted according to theprotocol or study plan and applicable

regulationsFDA Form 1572Protect the rights, safety, and welfare ofsubjects under the investigators careFDA-Control drugs, biological products, anddevices under investigation

FDA Guidance for Industry: Investigator Responsibilities, Oct 2009


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Study Oversight by thePI/Investigator

Are individuals who are delegated studytasks qualified to perform them?Have individuals received training to theprotocol and to the tasks?Oversight and involvement in ongoingconduct of the studyWhere reasonably possible, oversight of 3 rdparties

Guidance for Industry: Investigator Responsibilities, Oct. 2009


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Adequate Resources

Appropriate facilitiesAppropriate equipment

Correct equipment available

CalibratedPreventive maintenanceStudy staff training

Proper laboratory facilities (FDA=CLIA certified)

Reference ranges for laboratory testsDetails of analytical methodsQuality assurance information


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Study logs & Oversight

Delegation log with study roles, tasks anddates worked on studySignature log with initials logTrain to protocolTraining logStay up-to-date on subject and overall studyprogress

Regular staff meetings (FDA-take minutes)


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InvestigationalProduct (FDA)

Accountability for theInvestigational Product


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Investigational Product

Process investigational productReceipt (shipping) and DispensingLabelingAccountability to reconcile records for each tablet,

compounded drugSecure storage of device & device returnReturn/Destroy drug as determined by sponsorInterface with Investigational Drug Services /

Biomedical Engineering staff, as neededInvestigational products should bemanufactured, handled, and stored inaccordance with applicable goodmanufacturing practice (GMP)


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Essential Documents(FDA)

Maintain Study Binder


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Binder Index

1. Contents2. Subject Logs and Lists3. Contact Logs and Monitoring

4. Communications: General5. Protocol and Amendments6. Case Report Forms7. Investigator Information8. IRBMED Documents9. Laboratory Information


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Binder Index (contd)

10. Equipment11. Investigational Product Information12. Investigational Product Accountability

Records13. Adverse Events/Effects14. Investigator Meeting Documents15. Regulatory Information

16. Study Reports17. References18. Contracts and Grants19. Patient Data


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Additional Best Practices

Conflict of Interest DisclosureApplies to all members of the study teamIncludes spouses and dependentsMay have a management planFDA forms for financial disclosure from sponsor

Communication with sponsor (FDA)Annual reports to sponsorMaintain ALL sponsor communications

Letters, reports, emails, phone log, faxesReport AEs and unanticipated problemsReport protocol deviationsMonitoring log/visits


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Shipping Regulations for Biologics

University personnel who ship infectious substances includingpatient (clinical) specimens, human-derived researchmaterials, infectious micro-organisms, certain genetically-modified organisms, etc. must complete a training program

prior to shipping infectious or biological substances.The Department of Occupational Safety and EnvironmentalHealth (OSEH) offers the IATA/DOT Shipping InfectiousSubstances Class on a monthly basis. More information and

schedule can be found on the OSEH websitewww.oseh.umich.edu.

Those who complete training receive a trainingcertificate which is valid for two years.


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Overall

Legal or regulatory is not always adequateA personal commitment to integrity needs to becoupled with a firm understanding of BestPracticesThe public support of research rests on its trustof scientists, scholars and the institutions

Individual actions can bolster trust andconfidence or, unfortunately, undermine it aswell


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FDA GCP BIMO Program

Clinical Investigator InspectionSponsor/Monitor/CRO InspectionInspection programs allow the agency to

determine:Adherence to applicable regulationsValidity of studies in support of pending marketingapplicationsWhether the rights and safety of subjects havebeen protected

FDA Common Investigator


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FDA Common InvestigatorDeficiencies

Failure to follow the investigational plan &Protocol deviations (38%)Inadequate recordkeeping, sourcedocumentation, case hx, record retention (27%)Inadequate accountability for investigationalproduct, shipping, handling, storage, labeling

(10%)Inadequate subject protection-including informedconsent (11%) and adverse event (8%) issues

Toth-Allen, J. APEC GCP Inspection Workshop, 2008


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Most Common FDA SponsorDeficiencies

Inadequate monitoringFailure to bring investigators into

complianceInadequate accountability for theinvestigational product


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Selected Recent OHRPNoncompliance Determinations

Informed ConsentFailure to obtain the legally effective informed consent of subjects orof the IRB to appropriately waive the requirements to obtaininformed consent

Failure to document informed consent or of the IRB to appropriatelywaive the requirements to document informed consentFailure to provide a copy of the informed consent document (ICD) tothe subject or the subject's legally authorized representativeInadequate ICD for specific research/lack of basic elements

Inadequate ICD for specific research/lack of additional elementsICD language too complexExculpatory language in ICDsEnrollment procedures did not minimize possibility of coercion orundue influence


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Selected Recent OHRPNoncompliance Determinations

Initial and continuing reviewResearch conducted without IRB review and/or approvalIRB lacks sufficient information to make determinations required forapproval of researchInadequate IRB review at convened meetings

IRB review of protocol changesChanges to research initiated without IRB review and approvalInadequate IRB review and/or approval of protocol changes

IRB membership, expertise, staff support and workloadIRB documentation, findings and procedures

OHRP, http://www.dhhs.gov/ohrp/compliance/findings.html#D20


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Questions?


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ResourcesUM IRBMED & HBHS WorkshopsJoin MICHR research coordinator email networkClinical Trials Network (Duke U)

Forms, education, etc. at https://www.ctnbestpractices.orgFDA Device Advice & training

http://www.fda.gov/medicaldevices/deviceregulationandguidance/default.htmVirtual Regulatory Binder

http://www.partners.org/phsqi/vrb/files/index.htmNIH-Office of Human Subject Research

http://ohsr.od.nih.gov/

OHRP Guidance documentshttp://www.dhhs.gov/ohrp/policy/

ICH E6http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm073122.pdf
http://www.dhhs.gov/ohrp/policy/http://www.dhhs.gov/ohrp/policy/


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ICH E6 PrinciplesClinical Trials should be conducted in accordance with theethical principles that have their origin in the Declaration ofHelsinki and that are consistent with applicable regulatoryrequirements.

Foreseeable risks should be weighed against anticipatedbenefits for the individual and for society as a whole; a trialshould only be initiated if anticipated benefits justify the risks.The rights, safety and well being of the trial subjects are themost important considerations and should prevail overinterests of science and society.The non-clinical and clinical information on an investigationalproduct should be adequate to support the proposed clinicaltrial.


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ICH E6 Principles

Clinical trials should be scientifically sound, and describedin a clear, detailed protocol.A trial should be conducted in compliance with the protocoland amendments that have received prior IRB approval.

The medical care given to, and medical decisions made forsubjects should always be the responsibility of a qualifiedphysician.Each individual involved in conducting a trial should bequalified by education, training, and experience to performhis or her respective task(s).Freely given informed consent should be obtained fromevery subject prior to clinical trial participation.


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ICH E6 PrinciplesAll clinical trial information should be recorded, handled,and stored in a way that allows its accurate reporting,interpretation, and verification.The confidentiality of records that could identify subjects

should be protected, respecting the privacy andconfidentiality rules in accordance with the applicableregulatory requirements.Investigational products should be manufactured, handled,and stored in accordance with applicable goodmanufacturing practice (GMP). They should be used inaccordance with the approved protocolSystems with procedures that assure the quality of everyaspect of the trial should be implemented.

GCP Presentation 6-1-10

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