The U.S. Regulatory Structure

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The U.S. Regulatory Structure

• Melody Lin, Ph.D.
• Deputy Director, OHRP
• Director, OIA
• Beijing, China
• March 2003

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Objectives

• 1. Background
• 2. IRB Review
• 3. IRB Memberships and Responsibilities/
  Authorities
• 4. Three Types of IRB Review
• 5. Criteria for IRB Approval
• 6. Five Types of IRB Submission/ Reporting
• 7. Record Keeping Requirements

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• 1. Background

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National Research Act1974
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Office of Protection from Research Risks (OPRR)
1974
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45 CFR 46 Subpart A1981
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45 CFR 46Subpart A,B,C,D1983
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45 CFR 46

• Subpart A -- Basic Protections
• Subpart B -- (1975)Pregnant Women, Fetuses,
  Human In Vitro Fertilization
• Subpart C -- (1978) Prisoners
• Subpart D -- (1983) Children
• Subpart E -- (proposed?) Mentally Disabled

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Federal Policy for the Protection of Human
Subjects (45 CFR 46 Subpart A)The Common
RuleJune 18, 199117 Departments and Agencies
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Office of Human Research Protections (OHRP)2000
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Food and Drug Administration

• Regulations
• IRB - 21 CFR 56
• Informed Consent - 21 CFR 50

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Health and Human Services (HHS) vs. FDA
Regulations

• Basic requirements for IRBs and for Informed
  Consent are congruent
• Differences center on differences in
  applicability
• HHS regulations based on federal funding of
  research
• FDA regulations based on use of FDA regulated
  product drugs, devices, or biologics

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HHS vs. FDA Regulations
IRB
DHHS
FDA
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• 2. Institutional
• Review Board Review
• (IRB)

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What is an IRB?

• A review committee
• Protects rights welfare
• Also called, Ethics Committee, Research Ethics
  Committee, Research Ethics Board, etc.

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Why IRB Review?

• HHS, FDA
• Research Institutions
• Professional Organizations
• Scholarly Journals

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• 3. IRB Membership
• and Responsibilities/ Authorities

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IRB Membership (1)

• At least five members of varying backgrounds
• Sufficiently qualified
• Not solely of one profession
• Gender diversity
• At least one non-scientist
• At least one non-affiliated member

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IRB Membership (2)

• Experience Expertise
• Sensitivity to Community Attitudes
• Knowledge of Local Laws and Standards
• Knowledge of Vulnerable Populations
• Ad Hoc Consultants

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IRB Responsibilities

• Review, approve, modify, or disapprove all
  covered research
• Require informed consent
• Require documentation of informed consent or may
  waive documentation
• Notify investigators in writing of decisions
• Conduct continuing review of research no less
  than once per year

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IRB Authorities

• Suspend/Terminate Research
• Observe/Verify Changes

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• 4. Three Types of IRB Review

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IRB Review Procedures

• A. Full Board Review
• B. Expedited Review
• C. Review for Exemption Status

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A. Full Board Review

• 1. Studies involving risks that are more than
  minimal

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Minimal Risk

• ... probability and magnitude of harm or
  discomfort anticipated in the research are not
  greater in and of themselves than those
  ordinarily encountered in daily life or during
  the performance of routine physical or
  psychological examinations or tests

45 CFR 46.102(i)
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Full Board Review

• 2. Specify review procedures and conditions

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Full Board Review

• 3. Convened meeting - no mail reviews (telephone
  participation OK)
• 4. Quorum
• Majority of IRB present
• At least one non-scientist present
• Approval by majority of those present

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Full Board Review

• 5. Members with conflict of interest should be
  absent during discussion and vote
• 6. Should the quorum fail during a meeting (e.g.
  those with conflicts being excused, early
  departures, loss of a non-scientist), no further
  votes can be taken unless the quorum can be
  restored

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IRB Meeting Minutes (1)

• Attendance at the meetings.
• Actions taken by the IRB.
• Vote on these actions including the number of
  members voting for, against, and abstaining.

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IRB Meeting Minutes (2)

• Basis for requiring changes in or disapproving
  research.
• Documentation of specific findings required by
  the regulations.
• Written summary of the discussion of issues and
  concerns, and their resolution.

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B. Expedited Review (1)

• Carried out by IRB chair or one or more
  experienced IRB members
• An IRB may use expedited review for
• Research on list of eligible categories
• Minor changes in previously approved research
• All IRB members must be informed of research
  approved under expedited review

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Expedited Review (2)

• Research activities that
• present no more than minimal risk to human
  subjects, AND
• involve only procedures listed in one or more of
  9 categories

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Expedited Review (3)

• The categories in the list apply regardless of
  the age of subjects, except as noted
• May not be used where identification of the
  subjects and/or their responses would reasonably
  place them at risk

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Expedited Review (4)

• May not be used for secret government research
  involving human subjects
• The standard requirements for informed consent
  (or its waiver, alteration, or exception) apply
  to all types of IRB review
• First seven categories pertain to both initial
  and continuing IRB review

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Expedited Review Categories

• 1. Clinical studies of drugs and medical devices
  where Investigational New Drug application (IND)
  or Investigational Device Exemption (IDE) not
  required or device has been approved for
  marketing and is used as such
• 2. Collection of blood samples by finger stick,
  heel stick, ear stick, or venipuncture with
  restrictions on age, weight, and amount

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Expedited Review Categories

• 3. Prospective collection of biological specimens
  for research purposes by noninvasive means
• 4. Collection of data through noninvasive
  procedures routinely employed in clinical
  practice

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Expedited Review Categories

• 5. Research involving materials (data, documents,
  records, or specimens) that have been collected,
  or will be collected solely for non-research
  purposes
• 6. Collection of data from voice, video, digital,
  or image recordings made for research purposes
• 7. Research on individual or group
  characteristics or behavior or research employing
  survey, interview, oral history, etc.
  methodologies

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Expedited Review Categories

• 8. Continuing review of research previously
  approved by the convened IRB with no further
  direct subject participation
• 9. Continuing review of research (not under IND
  or IDE) where the IRB has determined and
  documented at a convened meeting that the
  research involves no greater than minimal risk
  and no additional risks have been identified.

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C. Exempt Research (1)

• Some research is exempt from federal
  regulations
• Institutions (not investigators) must certify
  that the research qualifies as exempt
• Research is not exempt from ethical requirements
  or from institutional policies

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Exempt Research (2)

• Research that is exempt includes
• Normal educational practices
• Educational tests, surveys, interviews, or
  observation of public behavior unless identified
  and sensitive
• Research using existing data, documents, records,
  pathological specimens, or diagnostic specimens,
  if publicly available or unidentifiable

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Exempt Research (3)

• Survey, interview, or observation research on
  elected or appointed public officials or
  candidates for public office
• Survey, interview, or observation research where
  Federal statutes require without exception that
  confidentiality will be maintained.
• Evaluation of some public programs
• Taste and food quality evaluation and consumer
  acceptance studies

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Exempt Research (4)

• Does not apply to these vulnerable populations
• Pregnant Women
• Fetuses
• Human In Vitro Fertilization
• Prisoners

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Research with Children

• Most research exemptions apply
• But children have special protections

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Regulatory Categories for Research Involving
Children45 CFR 46, Subpart D

• No more than minimal risk (46.404)
• More than minimal risk, but holding prospect of
  direct benefit to subjects (46.405)
• More than minimal risk, no direct benefit to
  individual subjects, but likely to yield
  generalizable knowledge about their disorder
  (46.406)
• Not otherwise approvable, with review by the HHS
  Secretary (46.407)

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NIH Initiatives to Promote Inclusion of Children
in Research, 1998

• It is the policy of the NIH that children (i.e.
  under the age of 21) must be included in all
  human subjects research, conducted or supported
  by the NIH, unless there are scientific and
  ethical reasons not to include them
• Scientific and Ethical Reasons for Exclusion
• Irrelevant to children
• Laws or regulations prevent inclusion
• Knowledge is available through other studies
• Separate, age-specific studies are warranted
• There are insufficient data from adults to judge
  risks to children
• Longitudinal study of adults started before 1998

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• 5. Criteria for IRB Approval

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Criteria for IRB Approval (1)

• Risks to subjects are minimized
• Risks are reasonable in relation to anticipated
  benefits
• Selection of subjects is equitable
• Informed consent is sought from each subject
• Informed consent is appropriately documented

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Types of Risk

• Physical Harms
• Psychological Harms
• Social and Economic Harms

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Physical Harm

• Pain, discomfort, injury or loss of function
• Direct result of procedure or side effect
• Permanent or transitory

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Psychological Harm

• Change in thought processes or emotional state
• Emotional Distress
• Psychological Trauma
• Invasion of Privacy

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Social or Economic Harm

• Embarrassment
• Loss of Social Status
• Loss of Employment
• Loss of Insurability

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Non-Physical Harms (1)

• Primary source of social harm results from a
  breach of confidentiality.
• Confidentiality and anonymity are not the same
• Names are not the only identifiers
• Subjects participation in the research may need
  to be kept confidential as well as their data

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Non-Physical Harms (2)

• Social and Psychological harms are real harms
• All research interactions, including biomedical
  research, are social interactions with social and
  psychological implications

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Identifying Risks

• IRBs should not rely on investigators to
  identify risks
• IRBs should do an independent analysis of risk

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Criteria for IRB Approval (2)

• When appropriate
• data collection is monitored to ensure subject
  safety
• privacy and confidentiality of subjects is
  protected
• additional safeguards are included for vulnerable
  populations

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IRB Decision Matrix
Subject selection Inclusion/exclusion Recruitment
Risk/Benefit Analysis Experimental
Design Qualifications of PI
J. Cooper, Albany Medical Center
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• 6. Five Types of IRB Submissions

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Types of IRB Submission

• A. Initial Review
• B. Continuing Review
• C. Amendments/Modifications
• D. Adverse Events Reporting
• E. Noncompliance Reporting

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A. Initial Review

• First Request for Approval
• Full or Expedited

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B. Continuing Review (1)

• Appropriate to the degree of risk and not less
  than once per year
• Should be set for each protocol, not a routine
  annual review
• Must be substantive and meaningful

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Continuing Review (2)

• Protocol summary and a status report on the
  progress of the research
• the number of subjects accrued
• a description of any adverse events or
  unanticipated problems involving risks to
  subjects or others and of any withdrawal of
  subjects from the research or complaints about
  the research

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Continuing Review (3)

• a summary of new information relevant to human
  subjects, especially information about risks
  associated with the research and
• a copy of the current informed consent document

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Continuing Review (4)

• Same Review Criteria
• Full Board or Expedited Review

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C. Amendments/Modifications

• Any change that would impact subjects needs IRB
  approval
• Recruitment procedures
• Inclusions/exclusion criteria
• Procedures
• When in doubt
• Call IRB office

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D. Adverse Events Reporting

• Serious
• Unexpected
• Protocol Related
• Promptly

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Reporting

• Any reports from DSMB

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E. Noncompliance Reporting

• Not adhering to inclusion/exclusion criteria
• Breach of confidentiality
• Not adhering to approved protocol informed
  consent
• Falsification of data

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• 7. Record Keeping Requirements

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Record Keeping

• Signed consent document
• IRB correspondence
• Research records
• 3 years after completion

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Possible Consequences of Not Following the
Regulations (1)

• Suspension of research project
• Suspension of all PI research projects
• Inability to use data or publish results

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Possible Consequences of Not Following the
Regulations (2)

• Notification of sponsors, regulatory agencies and
  funding agencies of noncompliance
• Prohibition by FDA from using investigational
  products
• Inability to receive funding from federal grants

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Possible Consequences of Not Following the
Regulations (3)

• Additional monitoring and oversight by the IRB
  and/or third party monitoring of research
  activities
• Termination of employment
• Loss of licenses

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Possible Consequences of Not Following the
Regulations (4)

• Immediate shut-down of ALL research at an
  organization
• Duke University
• Johns Hopkins University