International Conference on Harmonization Good Clinical Practices for Clinical Research

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International Conference on HarmonizationGood
Clinical Practices for Clinical Research

• June 23, 2003
• Cheryl M. Chanaud, PhD, CCRA
• Vice President, Clinical Research

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Outline

• Creation of ICH GCPs
• Basic Content of ICH GCPs
• How to use GCPs
• GCPs in context

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International Conference on HarmonizationGood
Clinical Practices1997

• An effort to achieve consistent practices
  globally (originally Japan, Europe, USA)
• FDA recommends ICH GCPs is not law, but use
  is expected as a minimum standard

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History of Todays Ethical Principles The
Nuremberg Code, Declaration of Helsinki, Belmont
Report

• The Nuremberg Code, 1947
• statement of international standards for use of
  humans as subjects in scientific or medical
  experiments
• U.S. American Medical Association, 1940s
  1950s
• Declaration of Helsinki, 1964
• international doctrine of ethics in biomedical
  research

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History of Todays Ethical Principles The
Nuremberg Code, Declaration of Helsinki, Belmont
Report

• Belmont Report, 1979
• U.S. Department of Health, Education, Welfare
• The National Commission for the Protection of
  Human Subjects
• of Biomedical and Behavioral Research
• 3 Primary Principles
• informed consent
• assessment of risks benefits (beneficence)
• fair selection of subjects (justice)

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Application of Ethical Principles FDA regs, NIH
regs, ICH GCPs

• Regulations developed in 1970s 1980s addressed
  informed consent, IRB review and approval.
• Regulations refer to the ethical principles
  stated in these documents -- no practical advice
  or guidance for day-to-day issues
• Legal responsibility held by IRB (IEC in
  Europe)/Institution
• Legal and medical responsibility held by
  PI/Institution
• Legal responsibility held by Sponsor
• ICH GCPs is an effort to provide practical
  guidance.

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Ethical Norms Static or Evolving?

• Events triggering change in 20th Century
• Nazi experiments 1930s
• US Public Health Service conducted Tuskegee Study
  1932-1972 poor, black farmers not told they had
  syphilis and not given treatment for
  life-threatening condition
• New Zealand - women with cervical cancer not
  treated because they were controls
• Prisoners injected with infectious disease
• US - children injected with hepatitis virus
• 1963 - elderly Jewish patients injected with
  cancer cells
• US Dept. of Energy 1930s-1970s - human
  radiation experiments without informed consent

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Recent Examples

• 1996 Eli Lily using homeless people in studies
• 1999 Jesse Gelsinger, serious disease under
  control, dies in U. Penn study, U. Penn gene
  therapy studies suspended by FDA
• 1999-2000 discovery of massive lack of adverse
  event reporting across U.S.
• 2001 Ellen Roche, healthy volunteer, dies in
  Johns Hopkins University study, all human subject
  research suspended at JHU by OHRP

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Ethical Norms Static or Evolving?

• Idea 1 the gold standard of research
  methodology is that an experimental subject must
  have a control subject who receives no treatment
  that is, the experimental treatment is compared
  to no treatment
• Versus
• Idea 2 if a standard of care treatment
  exists, then, for ethical reasons, the control
  subject must receive this treatment and the
  experimental treatment must be compared against
  the standard treatment rather than no treatment

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• Beliefs, Perceptions, Judgments, and
• Consensus of Society Changes over Time
• Modern nations moved from Idea 1 to Idea 2 in
  the past two decades
• Awareness, Cumulative Knowledge, Context,
  Education, Action based on Explicit Principles
• Results in changes in human behavior

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Federal regulations, State statutes, and
Voluntary Guidelines

• Require certain actions
• Permit enforcement
• Permit punishment of violators

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Content of ICH GCPs

• IRB/IEC
• Investigator
• Sponsor
• Clinical Trial protocol and Protocol Amendments
• Investigators Brochure
• Essential Documents for the Conduct of a Clinical
  Trial

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IRB/IEC

• Safeguards the rights, safety and well-being of
  subjects
• Reviews protocol/amendments, consent form(s),
  advertising, Investigators Brochure, known
  safety information on the experimental product,
  Investigators qualifications
• Considers ethical issues
• Considers subject payment issues
• Reviews on a continuing basis (at least once per
  year)

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IRB/IEC

• Composition, Function, Operations, Records
• this has been an emphasis of OPRR/OHRP

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Institutions with Part 50, 56, 46 Violations
1999-2001

• Mulitple Project Assurance
• -all research abides by Part 46
• Temporary Suspensions
• Johns Hopkins University 7/01 (OHRP)
• UTMB 9/00 (OHRP)
• Univ. Oklahoma College of Med. 7/00 (OHRP)
• University of Pennsylvania 12/99 (OPRR)
• LA State University 12/99 (FDA)
• University of Colorado 9/99 (FDA OPRR)
• University of South Florida 9/99 (OPRR FDA)
• Virginia Commonwealth Univ. 8/99 (FDA)
• University of Illinois at Chicago 8/99 (OPRR)
• University of Iowa 6/99 (FDA)
• Duke University Medical Center 5/99 (OPRR)
• Mt. Sinai School of Medicine
• City University of New York 5/99 (FDA)
• West LA VA Medical Center 3/99 (VA)
• (DHHS/NIH/OHRP - Office of Human Research
  Protection)

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Definition of Investigator

• Title 21, Part 312
• Investigational New Drug Application
• Investigator
• an individual who conducts a clinical
  investigation (administers investigational
  product)

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Investigator

• Must be qualified

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• Must be familiar with protocol
• and investigational product

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• Must have IRB approval before enrolling
• Changes to protocol must be IRB approved

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• Must engage in informed consent process
• Is medically responsible for subject

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• When delegating to others, must make sure that
• they are qualified and properly trained

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• Must maintain complete documentation
• Investigators Brochure
• IRB Correspondence
• Correspondence with Sponsor
• Data documents (Case Report Forms)

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• Must abide by protocol
• Must use investigational product only as
  specified in protocol
• Must report Serious Adverse Events

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Definition of Sponsor

• Title 21, Part 312
• Investigational New Drug Application
• Sponsor
• a person or company who takes responsibility
  for and initiates a clinical investigation.
  Sponsor does not actually conduct the
  investigation.

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Sponsor

• Should have SOPs
• Make sure that protocol includes necessary
  specific sections
• Must provide Investigators Brochure
• Should select qualified Principal Investigators
• Must engage in quality control and monitoring of
  Investigators
• Must assure monitors responsibilities
• May delegate (to CROs)
• Must verify IRB approvals at sites
• Must address non-compliance of Principal
  Investigator
• Must notify regulatory authorities of SAEs
• Must notify sites and regulatory authorities if
  new safety information becomes available

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• Must keep product account records
• Must properly manufacture, package, label, ship
  investigational product
• Must follow appropriate methods for supplying and
  handling

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• Must appropriately terminate study
• Must provide reports as required by regulatory
  authorities

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Clinical Trial protocol and Protocol Amendments

• Scientifically appropriate design
• Selection of subjects inclusion/exclusion
  criteria
• Assess safety
• Assess efficacy
• Appropriate statistical analysis
• Data Handling Recordkeeping
• Publication

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Investigators Brochure

• A compilation of clinical and nonclinical data on
  the investigational product(s)
• Chemistry and toxicology summary of animal
  studies
• Chemistry and toxicology, pharmacokinetics
  summary of human studies
• Dose, dose frequency, method of administration

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Essential Documents for the Conduct of a
Clinical Trial

• A very long list!

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GCPs in context

• Federal regulations
• State regulations
• Example can a minor mother (who cannot legally
  provide consent for herself) provide consent for
  her child?
• Institutional Policies Procedures
• New regulations, new issues
• Investigators receive no formal training on these
  responsibilities during medical school or
  graduate school.
• How can an Investigator be responsible for all of
  this?