Overview of Research Oversight: U.S. Perspective

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Overview of Research Oversight U.S. Perspective
Leslie K. Ball, M.D., F.A.A.P.Office for Human
Research ProtectionsDepartment of Health and
Human ServicesEmail LBall_at_osophs.dhhs.gov
FDA Pediatric Oncology Subcommittee July 15, 2003
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Regulatory Oversight of Clinical Research in
International Settings U.S. Perspective

• Increasing pace and scope of international
  biomedical research
• Framework of U.S. regulatory oversight
• Role of OHRP in relation to FDA
• Research involving children
• International Research
• Issues and Obstacles

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International Clinical Trials for New Drugs
Sources FDA Biomonitoring Research database
Parexels Pharmaceutical RD Statistical
Sourcebook 1999 Aculaunch Washington Post
Research
Courtesy of Dr. Melody Lin, Deputy Director, OHRP
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NIH International Research Expenditures
Fiscal Years 1994 to 2000
Dollars
Courtesy of Dr. Melody Lin, Deputy Director, OHRP
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Clinical Research Balance
Scientific advancement Product development
Regulatory oversight Human subject protections
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Regulatory Oversight of Clinical Research in
International Settings U.S. Perspective

• Increasing pace and scope of international
  biomedical research
• Framework of U.S. regulatory oversight
• Role of OHRP in relation to FDA
• Research involving children
• International Research
• Issues and Obstacles

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(No Transcript)
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Regulatory Framework Drug Development
OHRP
FDA

• HHS conducted or supported research
• Domestic
• International
• 45 CFR 46
• Subpart A (Common Rule)
• Subpart B (Fetus, Pregnant Women)
• Subpart C (Prisoners)
• Subpart D (Children)

• Research that involves products regulated by FDA
• 21 CFR 50, 56
• Part 50 Protection of Human Subjects
• Subpart D (Children) Interim Rule
• Part 56 IRBs
• 21 CFR 312 INDs
• 21 CFR 361 Drugs used in research

Applies to
Regulatory Protection of Human Subjects
Domestic institutions may elect to apply 45 CFR
46 to all of its research regardless of source of
support
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Department of Health and Human Services
Secretary of HHS
Assistant Secretary of Health Office of Public
Health and Science
Commissioner FDA
Director OHRP
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U.S. Regulatory Oversight for Clinical Research
HHS conducted or supported (OHRP)
HHS conducted or supported and FDA regulated
FDA regulated (FDA)
Studies that are neither HHS conducted or funded
nor FDA regulated
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Office for Human Research Protections (OHRP)

• Mission
• Develop and implement regulations, policies and
  programs for protecting the rights and welfare of
  human subjects participating in research that is
  conducted or supported by the U.S. Department of
  Health and Human Services

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Regulatory Oversight of Clinical Research in
International Settings U.S. Perspective

• Increasing pace and scope of international
  biomedical research
• Framework of U.S. regulatory oversight
• Role of OHRP in relation to FDA
• Research involving children
• International research
• Issues and obstacles

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Research Involving Children Historical Context

• Ethical lapses in the conduct of clinical
  research
• Beecher HK. NEJM 1966 2741354-60
• 1974 National Research Act
• Creation of the National Commission
• Charge included recommendations on research
  involving children
• 1979 Belmont Report
• 1981 Final Rule 45 CFR 46
• 1983 Final Rule 45 CFR 46 Subpart D
• Additional DHHS Protections for Children Involved
  as Research Subjects
• 1997 FDAMA 1997
• Economic incentives to conduct pediatric
• drug studies (marketing exclusivity)

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Research Involving Children Historical Context
(cont.)

• 1998 FDAs Pediatric Rule
• Requirement for assessing the safety and
  effectiveness of certain drugs in pediatric
  subjects
• 10/02 Court ruling FDA did not have authority to
  issue Pediatric Rule and barred FDA from
  enforcement
• 2000 Childrens Health Act
• Directed Secretary of HHS to require all research
  involving children conducted, supported or
  regulated by HHS (incl. FDA) to be in compliance
  with Subpart D
• 2001 FDAs Subpart D (Interim Final Rule)
• 2002 Best Pharmaceuticals For Children Act
• Reauthorized pediatric exclusivity incentives for
  drug products
• IOM review of research involving children

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Belmont Report

• Ethical Principles
• Respect for persons
• Individuals should be treated as autonomous
  agents
• Persons with diminished autonomy are entitled to
  protection
• Beneficence Maximize benefits and minimize
  possible harms
• Justice Relevant on individual and societal
  levels. Selection of subjects deserves scrutiny
  to determine whether some classes of subjects are
  unduly targeted for research

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Belmont Report (cont.)

• Application of Ethical Principles
• Informed consent special provisions should be
  made when comprehension is limited
• Assessment of benefits and risks when
  vulnerable populations are involved in research,
  the appropriateness of involving them should be
  demonstrated
• Selection of subjects order of preference in
  selection of classes of subjects (e.g., adult
  before children) some classes of potential
  subjects may be involved as research subjects, if
  at all, only under certain conditions

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Basic Protections of U.S Federal Regulations 45
CFR 46

• Informed consent of research subject
• Independent review of research
• Institutional assurances of compliance

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Assurances Research conducted or supported by
HHS

• Each institution engaged in research which is
  covered by this policy and which is supported by
  a Federal Department or Agency shall provide
  written assurancethat it will comply with the
  requirements set forth in this policy. 45 CFR
  46.103(a)
• Negotiated and approved by OHRP

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Assurances Research conducted or supported by
HHS (cont.)

• Formalizes institutions commitment to protect
  human subjects
• Requires filing of an Assurance by both "awardee
  receiving HHS funds and collaborating
  institutions
• Requires designation of IRB or Independent Ethics
  Committees

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Institutional Assurances
Assurance of Compliance with OHRP

• Investigator

Institution
Sponsor
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45 CFR 46 Subpart A Selected provisions relevant
to children

• IRB membership
• If an IRB regularly reviews research that
  involves a vulnerable category of subjects, such
  as children consideration shall be given to
  inclusion of individuals who are knowledgeable
  about and experienced in working with these
  subject 45 CFR 46.107(a)
• Criteria for IRB approval
• Selection of subjects is equitable IRB should
  be particularly cognizant of the special problems
  of research involving vulnerable subjects,
  including children 45 CFR46.111(a)(3)

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45 CFR 46 Subpart D Additional Protections for
Children

• IRBs review research and approve only research
  which satisfies the conditions specified by
  Subpart D regulations (e.g., minimal risk more
  than minimal risk but prospect of direct benefit,
  etc.)
• Generally, as risk increases in relation to the
  presence or absence of direct subject benefit,
  criteria for IRB approval under Subpart D
  categories become more stringent

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45 CFR 46 Subpart D Additional Protections for
Children

• 46.404 Research not involving more than minimal
  risk
• 46.405 Research involving more than minimal risk
  but presenting prospect of direct benefit to
  individual subjects
• Risk justified by anticipated benefit
• The relation of anticipated benefit is at least
  as favorable to subjects as that presented by
  available alternatives
• Adequate provisions for assent and permission
• 46.406 Research involving minor increase over
  minimal risk and no prospect of direct benefit
  but likely to yield generalizable knowledge about
  subjects disorder or condition
• 46.407 Research not otherwise approvable which
  presents opportunity to understand, prevent or
  alleviate a serious problem affecting health or
  welfare of children
• Review by panel of experts in relevant disciplines

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Regulatory Oversight of Clinical Research in
International Settings U.S. Perspective

• Increasing pace and scope of international
  Biomedical Research
• Framework of U.S. regulatory oversight
• Role of OHRP in relation to FDA
• Research involving children
• International research
• Issues and obstacles

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International Research

• Regulatory requirements for HHS conducted or
  supported research are the same, wherever
  research takes place
• 45 CFR 46.101(h) Procedures normally followed in
  foreign countries to protect human subjects may
  differ from those set forth in this policy
• If foreign institutions protections are at least
  as equivalent, the U.S. Department or Agency Head
  may approve the substitution of foreign procedures

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International Assurances

• Institution assures that its activities
• Will be guided by ethical principles (one of the
  following)
• Declaration of Helsinki
• Belmont Report
• Other appropriate international ethical standards

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International Assurances (cont.)

• Institution assures that its activities
• Will comply with procedural standards (one or
  more)

• 45 CFR 46 Subparts A, B, C, D
• 45 CFR 46 Subpart A
• 21 CFR 50, 56
• ICH-GCP-E-6
• CIOMS Intl Ethical
• Guidelines

• Canadian Tri-council Policy
• Indian Council of Medical Research Guidelines
• Other standards recognized by U.S. Federal
  Departments

Under FWA Terms of Assurance, all U.S.
federally-supported research must comply with
requirements of any applicable U.S. federal
regulatory agency.
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Issues and Obstacles in Regulatory Oversight of
International Research

• Regulatory harmonization
• Different requirements of each regulatory agency
• Development of consistent approaches for
• Study monitoring
• Reporting requirements
• Ensuring review by IRB/Ethics Review Committees
  having knowledge of local research context
• For developing countries building of host
  country capacity to conduct and review research

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For more information

• OHRP website
• http//ohrp.osophs.dhhs.gov/pdjay/pdjayindex.htm
• Assurances
• Assurance information
• http//ohrp.osophs.dhhs.gov/humansubjects/assuranc
  e/fwas.htm
• Search for international assurances
• http//ohrp.cit.nih.gov/search/asearch.asp