Overview of Good Clinical Practices (GCPs)

Barbara Pennington, RN, MSPPD

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Why Regulate Clinical Research?

Ensure the rights, safety, and well-being of participants

Scientific Integrity of data

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Good Clinical Practices (GCPs)

Standards for designing, conducting, performing, monitoring, auditing, recording, analyzing, and reporting clinical trials.

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GCP

FDA OHRP ICH

21 CFR 45 CFR 46 International• Electronic Docs. • Inf. Consent • $ Disclosure • IRBs • IND regs.

• IRBs • Inf. Consent•Women•Prisoners•Children

• glossary • principles• IRBs • Investigator • Sponsor • Essential Docs

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U.S. FDA(Food and Drug Administration)

Branch of the United States Department of Health and Human ServicesRegulates all aspects of pharmaceutical industryTitle 21 of the Code of Federal Regulations (CFR)

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CFR Title 21

Parts applicable to clinical research: Part 11 - Electronic Records and Signatures

Part 50 - Protection of Human Subjects

Part 54 - Financial Disclosure by Clinical Investigators

Part 56 - Institutional Review Boards

Part 312 - Investigational New Drug Application

Part 314 - Applications for FDA Approval to Market a New Drug or an Antibiotic Drug

Part 600 - Biological Products

Part 812 - Medical Devices

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Form FDA 1572

Contract between FDA and InvestigatorLogistics such as names and addressesSection 9

Commitments of the Investigator

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Investigator of Record (IOR) Agreement

For Non-IND studiesIdentifies key personnel, facilities, labs, IRBsAlso lists the commitments of the investigator

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Commitments of the IOR

Comply with protocolEnsure compliance of IRB and consent process with 45CFR 46Report AEsAccurate record keeping and accessNo changes to study without permission of Sponsor and IRB

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This is a Non-IND Study

Do we have to worry about FDA?

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Office for Human Research Protections

(OHRP)OHRP responsible for ensuring the safety and welfare of people who participate in HHS sponsored researchUnder the DHHS Assistant Secretary of Health45 CFR part 46Formerly OPRR

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45 CFR part 46

IRBInformed ConsentProtection of Fetuses, Pregnant Women Protection of PrisonersProtection of Children

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45CFR 46 Subpart A

The “Common Rule”

Protection of Human SubjectsIRB/IECInformed Consent

Variations from FDA Regulations

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45CFR 46 Subpart B

Protections for Pregnant Women, Fetuses and Neonates

DefinitionsRecent revisions

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45CFR 46 Subpart C

Additional Protections for Prisoners involved in research

Definition of PrisonerAdditional IRB DutiesPermitted Research

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45CFR 46 Subpart D

Additional Protections for Children involved in Research

AssentMinimal risks

International Conference on Harmonisation (ICH)

Guidelines for Good Clinical Practices

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Objectives of ICH guidelines

Provide a unified standardEU; US; JapanTo facilitate mutual acceptance of clinical dataDeveloped in accordance with existing standards in US, EU, Japan, Australia, Canada, Nordic Countries, and WHO

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ICH GCP Consolidated Guideline E6

Glossary Principles of ICH GCP Information regarding:

IRB/IEC Investigator Sponsor Protocol Investigator’s BrochureEssential Documents

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Principles of ICH GCP

Conduct trials according to GCP Weigh risks vs. benefitsProtect the subjectsHave adequate information to justify trialWrite a sound protocolReceive IRB/IEC approvalUse qualified physicians

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Principles of ICH GCP

Use qualified support staffObtain informed consentRecord information appropriatelyProtect confidentialityHandle investigational products appropriatelyImplement quality systems

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Local Regulations

May have more detailed regulations that apply locallyDo not conflict with national regulations

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Sponsor Policies

US Department of Health and Human Services

NIH/DAIT/DAIDSEssential Document and Source Document SOP

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Internal SOPs

Standard Operating Procedures (SOPs)

Detailed instructions describing the what, when, where, and by whom of performing an activity

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Compliance =

Adherence to GCPsSponsor policieslocal regulations

Investigator Responsibilities

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Investigator Responsibilities*

Investigator Qualifications and Agreementsqualified by education, training and experiencefamiliar with protocol, IB, IPaware of and compliant with GCPs and applicable regspermit monitoring list of qualified personnel who are delegated duties

*(ICH 4.1-9)

SAMPLE

Delegation of Responsibility Log/Signature ListStudy:InvestigatorName

Site Number PageNumber

Name and Title of Site Staff Signature InitialsResponsibilities* Involved

FromInvolved To PI Initials

Use Block Capitals (See below) DD-MMM-YY DD-MMM-YY

A B C D E F G H I

A B C D E F G H I

A B C D E F G H I

A B C D E F G H I

A B C D E F G H I

A B C D E F G H I

A B C D E F G H I

DELEGATION OF RESPONSIBILITIES CODES NOTES FOR COMPLETING THIS FORM

A. Obtaining consentB. CRF entriesC. Dispensing MedicationD. Physical ExaminationE. PhlebotomyF. Essential Documents

G. IP Receipt/ReturnH. Query ResolutionI. Authorized Signatory forresolved queries

J. Other_____________

Please PRINT CLEARLY when completing this form Please enter all dates in the DD-MMM-YY format (e.g., 21-JAN-01) Use ‘Involved From’ and ‘Involved To’ to record staff changes during the study Enter a new line and applicable dates when responsibilities change PI should initial each line as individuals are assigned responsibilities

*Delete those which do not apply

Principal Investigator Signature (Close Out):_______________________________________ Date:_____________________________________

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Investigator Responsibilities*

Adequate Resourcesrecruit adequate subjectssufficient timequalified staff and adequate facilities

Medical Care of Subjectsresponsible for all trial related medical decisions

*(ICH 4.1-4.9)

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Investigator Responsibilities*

Communication with IRBapprovalsensure compliance

Compliance with ProtocolInvestigational Product (IP)

proper delegation of duties*(ICH 4.1-4.9)

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How can the PI be held responsible for what the IRB does or does not do?

Document ALL interaction (verbal, electronic, written) with IRB including reminders of upcoming review requirements

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Investigator Responsibilities*

Regulations require IRB is aware of changes in research activity

“…OHRP finds that changes to research protocol were implemented by investigators without IRB approval…”

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Investigator Responsibilities*

Randomization & UnblindingInformed ConsentRecords and Reports

ensure accuracy, completeness, legibility and timeliness of datadata on CRF derived from Source Documentschanges made appropriatelyallow direct access

*(ICH 4.1-4.9)

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Regulatory Authorities will

inquire about:Source of study subjectsDid they have the disease under studyDid they meet inclusion/exclusion criteriaWas the protocol precisely followed Were AEs reported appropriately

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Common OHRP Findings

IRB failed to review the research at a convened meeting

failure to review grant applications

Investigators failed to promptly report unanticipated problems involving risks to subjects to IRB, OHRP and Sponsor

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Common OHRP Findings

Continuing review of research was NOT substantive nor meaningful

include a summary of AEs and unanticipated problems# of subjects accruedsummary of recent literature, findings amendments, modifications since last reviewrelevant reports, information current consent form

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Common OHRP Findings

IRB did not ensure additional protections for vulnerable subjectsIRB members with conflicting interest participated in reviewIRB meeting convened without Quorum (Non-scientist absent)

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Common OHRP Findings

IRB review of NIH approved consent

any changes to the sample consent form related to risks or alternative procedures must be justified in writing by the investigator, approved by IRB and reflected in the IRB minutes

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OHRP Finds that the IRB:

Lacks diversityis overburdened by large volumelevel of staff support is insufficientmembers lack detailed understanding of regs. for protection of human subjectsinadequate procedures for reporting of unanticipated problems

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We Applaud COMPLIANCE

GCPs

Protocol

DAIT/DAIDS procedures

Local regulations