GOOD CLINICAL PRACTICES

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GOOD CLINICAL PRACTICES

• (GCP)
• Joyce Williams

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Good Clinical Practices

• 21 CFR Part 50 - Informed Consent
• 21 CFR Part 56 - Institutional Review Board
• ICH - E6 Good Clinical Practice Consolidated
  Guideline (Drugs Biologics)

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ICH GCP

• IRB/EC
• Investigator
• Sponsor
• Protocol
• Investigators Brochure
• Essential Documents

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Institutional Review Board/ Ethics Committee

• Independent body
• Constituted of medical/scientific professionals
  and nonmedical members
• Ensures protection of rights, safety, and
  well-being of human trial subjects
• Provide public assurance by review

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IRB/EC Review

• Trial protocol and amendments
• Written informed consent
• Recruitment advertisements
• Written information provided to subjects
• Investigators Brochure
• Investigators curriculum vitae
• Subject compensation information

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IRB/EC Review

• Initial review of trial
• Approval required prior to study start
• Continuing review as appropriate to degree of
  risk to subjects, but at least once per year

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IRB/EC Membership

• Collectively have qualifications/experience to
  evaluate the trial science, medical aspects, and
  ethics
• At least five members
• At least one in a nonscientific area
• At least one independent of the institution
• Voting/opinions only by members independent of
  investigator/sponsor

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IRB/EC Functions

• SOPs
• Written records and minutes of meetings
• Decisions at meetings with quorum present
• Investigator can provide information, but not
  participate in deliberations
• Can invite nonmembers with special expertise

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Institutional Review Board/Ethics Committee

• Ongoing study review
• Adverse events (serious and unexpected)
• Review study amendments/deviations to eliminate
  hazards
• Periodic (yearly) review
• Final study summary

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Investigator - Qualifications/Agreements

• Qualified to conduct the trial
• Familiar with product and protocol
• Comply with GCP/regulatory requirements
• Permit monitoring/auditing by sponsor inspection
  by regulatory authorities
• List of delegated persons

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Investigator - Adequate Resources

• Subject recruitment - required number within
  agreed period
• Sufficient time
• Adequate and qualified staff
• All persons informed about protocol, duties

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Investigator - Medical Care

• Qualified physician (dentist) responsible for
  medical decisions
• Adequate care for trial-related adverse events
• Inform subjects primary physician about trial
• Determine reason for subject withdrawals

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Investigator - Communication with IRB/EC

• Approval of protocol and other materials before
  trial starts
• Provide Investigators Brochure
• Provide other information during trial

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Investigator - Compliance with Protocol

• Conduct trial in compliance with protocol
• Not deviate from protocol without sponsor/IRB
  approval
• Documentation of deviations by investigator
• Deviations to eliminate immediate hazard without
  IRB approval

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Investigator - Investigational Product

• Accountability at trial site Pharmacist
• Document - receipt, inventory, subject use,
  disposition
• Proper storage
• Use only in accordance with protocol
• Explain proper use to subjects

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Investigator - Randomization/Unblinding

• Follow trials randomization procedures
• Code only broken according to protocol
• Document premature unblinding

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Investigator - Informed Consent

• Comply with regulatory requirements, GCP, ethical
  principles of Declaration of Helsinki
• Updated as necessary
• No coercion of subject to participate
• No waiving of legal rights of subject
• Subject should be informed of all trial aspects

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Investigator - Informed Consent (cont)

• Nontechnical, understandable
• Opportunity to ask questions
• Written informed consent signed by subject and
  person conducting discussion
• If subject unable to read, need impartial
  witness, witness also signs
• Copy to subject
• Emergency situation - special rules

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Informed Consent - 21 CFR 50

• Written consent must be obtained prior to
  participation in a clinical study
• In some cases, consent of a subjects legally
  authorized representative is necessary
• children
• mentally not capable

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Informed Consent

• Elements of Informed Consent
• Statement that study involves research
• Purpose of the research
• Duration of subjects participation
• Description of procedures, identify experimental
  procedures
• Description of risk or discomforts

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Informed Consent

• Elements of Informed Consent (cont)
• Description of benefits to subject or others
• Disclosure of appropriate alternative procedures
  or treatment (e.g., marketed medications)
• Description of confidentiality procedures
• Note FDA, sponsor, and IRB may see the patient
  records

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Informed Consent

• Elements of Informed Consent (cont)
• Explanation of any compensation or medical
  benefits
• Contact for questions on research subjects rights
• Contact for research related injury
• Statement that participation is voluntary

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Informed Consent

• Additional Elements (when appropriate)
• Statement concerning risks to subject, embryo, or
  fetus if the subject is or may become pregnant
• Circumstances where the subjects participation
  may be stopped by the investigator, sponsor

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Informed Consent

• Additional Elements (cont.)
• Significant new information will be provided to
  the subject
• Number of subjects involved in the study
• Note The reading level of the informed consent
  should be eighth grade level.

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Investigator - Records/Reports

• Accurate, complete CRFs, reports
• CRF consistent with source data
• Changes properly initialed, dated
• Storage of trial documents per regulatory
  requirements (2 years after marketing approval)
• Allow review by sponsor, IRB, FDA

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Investigator - Reports

• Written status summary to IRB
• Written report to sponsor/IRB regarding
  significant study changes
• Serious adverse events reported immediately
• Final study report to sponsor, IRB

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Sponsor - QA and QC

• Written SOPs
• Access to all data
• Data handling quality control
• Written agreements with investigator

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Sponsor - CRO

• May transfer responsibilities to CRO
• Written agreement
• Sponsor has ultimate responsibility for quality
  and integrity of data

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Sponsor

• Qualified medical expertise
• Other qualified individuals (e.g.,
  biostatistician)
• Qualified monitors
• Independent data monitoring committee
• Proper handling of electronic data

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Sponsor

• Retain essential trial documents (2 years after
  marketing approval)
• Selection of qualified investigators
• Notification/submission as required to regulatory
  authorities prior to study initiation
• Confirmation of IRB/EC approval and that IRB
  operates according to GCP

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Sponsor - Investigational Product

• Appropriately manufactured, labeled, handled,
  stable
• Proper storage and packaging
• Mechanism for unblinding in medical emergency
• Ship to investigator only after appropriate
  documentation from IRB/FDA

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Sponsor

• Responsible for ongoing safety evaluation
• Adverse reaction reporting to IRB, regulatory
  authorities

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Sponsor - Monitoring

• Purpose - To verify
• Protection of subjects rights and well-being
• Trial data that is accurate, complete, and
  verifiable from source documents
• Trial conduct in compliance with GCP and
  regulatory requirements

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Sponsor - Monitoring

• Selection of qualified monitors
• Adequate monitoring
• Monitor responsibilities
• Monitoring reports after each visit

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Sponsor - Audit

• Not required different than monitoring
• Evaluate trial conduct, compliance with protocol,
  GCP, regulations
• Auditors should be independent of the trial

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Protocol

• General identifying information
• Background information
• Trial objectives and purpose
• Trial design
• Selection and withdrawal of subjects
• Treatment of subjects

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Protocol (cont.)

• Assessment of efficacy
• Assessment of safety
• Statistics
• Direct access to source data/documents

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Protocol (cont.)

• Quality control and quality assurance
• Ethics
• Data handling and recordkeeping
• Publication policy

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Investigators Brochure

• Title page and confidentiality statement
• Table of contents
• Summary
• Introduction
• Physical, chemical, and pharmaceutical properties
  and formulation

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Investigators Brochure (cont)

• Nonclinical studies
• Effects in humans
• Summary of data and guidance for the investigator

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Essential Documents

• Trial master files, regulatory files
• Located at clinical site and sponsors office
• Lists documents required
• Before the trial commences
• During the trial
• At the end of the trial

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Responsibilities of Sponsors and Investigators
(21 CFR 312/812)

• Sponsors
• Select qualified investigators
• Maintain records on drug accountability
• Obtain signed investigator statement
• Provide protocol, case report forms, consent form
  and clinical investigators brochure to the
  investigator

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Responsibilities of Sponsors and Investigators

• Sponsors (cont.)
• Provide investigator with new information on
  adverse effects
• Monitor the clinical study (site visits)
• Make annual progress reports to the IND

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Responsibilities of Sponsors and Investigators

• Investigators
• Conduct study according to the protocol
• Personally conduct or supervise the study
• Inform subjects that drug/device is
  investigational

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Responsibilities of Sponsors and Investigators

• Investigators (cont.)
• Obtain informed consent from the subject
• Report adverse experiences to the sponsor
• Submit protocol to an IRB and get initial and
  continuing approval

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GCP Summary

• Protection of the rights of subjects
• Good documentation
• Monitoring