Regulatory Issues in Clinical Research

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Regulatory Issues in Clinical Research

• Barbara Pennington, RN, MS

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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 Services
• Regulates all aspects of pharmaceutical industry
• Title 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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Office for Human Research Protections (OHRP)

• OHRP responsible for ensuring the safety and
  welfare of people who participate in HHS
  sponsored research
• Under the DHHS Assistant Secretary of Health
• 45 CFR part 46
• Formerly OPRR

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45 CFR part 46

• IRB
• Informed Consent
• Protection of Fetuses, Pregnant Women
• Protection of Prisoners
• Protection of Children

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45CFR 46 Subpart A

• The Common Rule
• Protection of Human Subjects
• IRB/IEC
• Informed Consent
• Variations from FDA Regulations

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45CFR 46 Subpart B

• Protections for Pregnant Women, Fetuses and
  Neonates
• Definitions
• Recent revisions

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45CFR 46 Subpart C

• Additional Protections for Prisoners involved in
  research
• Definition of Prisoner
• Additional IRB Duties
• Permitted Research

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45CFR 46 Subpart D

• Additional Protections for Children involved in
  Research
• Assent
• Minimal risks

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Why Regulatory Documents are Required for
Clinical Trials

• Regulatory documents are submitted to track and
  evaluate the ethical and procedural conduct of a
  trial and the quality of the data that is
  produced.
• Regulatory documents demonstrate the compliance
  of the Investigator, Sponsor and IRB/IEC with the
  standards of Good Clinical Practice and with all
  applicable regulatory requirements.

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Initial Minimum Required Documents

• For IND studies
• Form FDA 1572
• Final signed/dated Protocol Amendments
• IRB approved Informed Consent Form
• IRB approved advertisements
• IRB Approval Letter for protocol, amendments,
  informed consents, advertisements, etc.
• IRB membership list or assurance and compliance
  statement

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Initial Minimum Required Documents

• CVs for PI and Sub-Investigators
• Laboratory Certifications and Normal Ranges
• Investigators Statement of Financial Disclosure
  for PI and Sub-Investigators
• Documentation of satisfactory site assessment (or
  waiver)
• Documentation of Protocol Training
• Signature Log

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Form FDA 1572

• Contract between FDA and Investigator
• Logistics such as names and addresses
• Section 9
• Commitments of the Investigator

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Investigator Agreements

• Non-IND studies generally have an Investigator of
  Record (IOR) agreement
• Sometimes referred to as the investigator
  statement
• What is the PI agreeing to do?

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Commitments of the PI/IOR

• Comply with protocol
• Ensure compliance of IRB and consent process with
  45CFR 46
• Report AEs
• Accurate record keeping and access
• No changes to study without permission of
  Sponsor and IRB

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Form FDA 1572

• Who should be listed in section 6
  (subinvestigator section) of the 1572?

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Curriculum Vitae (CV)

• All investigators (listed on 1572 or IOR
  agreement) must submit a current CV and/or other
  relevant documents
• evidence of qualification to conduct the trial
  and to provide medical supervision of subjects
• CV should be updated to reflect significant
  changes

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Financial Disclosure(IND Studies Only)

• Required for anyone listed on 1572
• Documents any potential conflicts of interest
  regarding
• compensation
• equity
• proprietary information

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IRB/IEC Regulatory Documents

• Investigator submits
• protocol, amendments, informed consent, and any
  other information given to the subject to the IRB
  for review and approval
• The IRB reviews
• Investigator Brochure
• Safety Reports
• Protocol Violations/Departures
• Unanticipated problems
• grant application

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Laboratory Certification and Normal Ranges

• Required for
• Central
• Local Lab
• Investigator submits laboratory certification(s)
  and a listing of reference ranges.

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Additional Documents

• IRB/IEC or IB updates
• Continuing IRB/IEC review
• SAE notifications to the IRB/IEC and reports
• Any amendments to protocol, consent forms, and
  IRB/IEC documentation
• Updates to Investigator team list
• CVs for new investigators or staff
• Revised Form FDA 1572
• Any IND safety reports
• Laboratory reference ranges

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Additional Documents

• Copies of Study Drug shipment and receipt records
• Site visit log
• CRF guidelines
• Subject screening, enrollment, and identification
  logs
• Site initiation, monitoring, and close-out
  reports
• Study Drug accountability records
• Unblinding procedures, if applicable
• Copies of regulatory compliance authorization

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Additional Documents

• Communication/Correspondence (letters, meeting
  notes, email messages)
• documents agreements, significant discussions,
  trial conduct, AE reporting
• Communication can be between the Sponsor, Sponsor
  representatives (contractors) and/or study team
• Clarification memos

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Investigator Files

• Kept at trial site
• Contain all required essential documents for each
  study
• Monitors should review the file at least annually
  to ensure accuracy and completeness

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Specimen Records

• What kind of record am I required to maintain for
  body fluids/tissue samples?

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Screening Logs

• What exactly is needed on this log?

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Signature Log

• Who is required to be on this form?
• Whats the purpose?

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(No Transcript)
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Computer/Electronic Records

• Can any of these documents be kept/stored
  electronically? What requirements are there for
  electronic records?
• 21 CFR part 11

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Investigator Responsibilities

• Ensure the study is conducted according to the
  investigator statement/agreement, protocol,
  regulatory requirements.
• Ensure the protection of the participants
  rights, safety and welfare.
• Ensure the control of investigational drug.
• Obtain informed consent
• (21CFR 312.60 312.61)

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What happens if...

• Your clinic pharmacy is closed for construction
  for 1 month and drug is stored off site?
• A researcher from your institution borrowed
  from your supply of study drug since his study
  was using the same compound but his shipment of
  drug was delayed
• The research nurse decided that withholding NVP
  from an HIV pregnant woman was unethical so gave
  this study drug to women despite eligibility
  constraints

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Investigator Responsibilities

• Maintenance of records
• Disposition of drug
• Case histories including CRFs, ALL supporting
  data (research records, progress notes, labs,
  ECGs, etc.) and consent
• Record retention
• Financial Disclosure
• IRB/IEC Compliance
• Make records accessible
• (21CFR 312.62, 312.64, 312. 66 312.68)

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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

• Investigator Qualifications and Agreements
• qualified by education, training and experience
• familiar with protocol, IB, IP
• aware of and compliant with GCPs and applicable
  regs
• permit monitoring
• list of qualified personnel who are delegated
  duties
• (ICH 4.1-9)

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Investigator Responsibilities

• Adequate Resources
• recruit adequate subjects
• sufficient time
• qualified staff and adequate facilities
• Medical Care of Subjects
• responsible for all trial related medical
  decisions
• (ICH 4.1-4.9)

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Investigator Responsibilities

• Communication with IRB
• approvals
• ensure compliance
• Compliance with Protocol
• Investigational Product (IP)
• proper delegation of duties
• (ICH 4.1-4.9)

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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 Unblinding
• Informed Consent
• Records and Reports
• ensure accuracy, completeness, legibility and
  timeliness of data
• data on CRF derived from Source Documents
• changes made appropriately
• allow direct access
• (ICH 4.1-4.9)

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Regulatory Authorities will inquire about

• Source of study subjects
• Did they have the disease under study
• Did they meet inclusion/exclusion criteria
• Was the protocol precisely followed
• Were AEs reported appropriately
• Was consent obtained according to regulations?

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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 accrued
• summary of recent literature, findings
  amendments, modifications since last review
• relevant reports, information
• current consent form

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Common OHRP Findings

• IRB did not ensure additional protections for
  vulnerable subjects
• IRB members with conflicting interest
  participated in review
• IRB 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 diversity
• is overburdened by large volume
• level of staff support is insufficient
• members lack detailed understanding of regs. for
  protection of human subjects
• inadequate procedures for reporting of
  unanticipated problems

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INFORMED CONSENT

• The study coordinator speaks English. The
  potential participant speaks/reads only Xhosa.
  The consent is available in English and Xhosa.
• Can this study coordinator consent the subject?

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INFORMED CONSENT

• The subject refuses to take a copy of the consent
  form and says that she does not want her husband
  to know that she is participating in this trial.
• What should the person obtaining consent do?

PATIENT INFORMED CONSENT FORM
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INFORMED CONSENT

• Mother and Baby are enrolled in a long term HIV
  study. Mother dies shortly after the baby is
  born. Can the baby continue in the study? Who
  would be authorised to consent for the baby?

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INFORMED CONSENT

• A subject who is a 15 year old, has signed the
  consent document and no other signatures, apart
  from the person obtaining consent are present on
  the form.
• Would this ever be acceptable?

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IRB/IEC ISSUES

• What documentation should be on file if the PI is
  a current, voting member of the IRB/IEC?

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IRB/IEC ISSUES

• The HPTN 888 protocol approval is from 02 Nov 02
  - 01 Nov 03. The study coordinator received a
  notice from the IRB that an extension has been
  granted due to a delay in the meeting date.
• What should the coordinator do?