Legal Responsibilities for Studies Conducted or Supported by HHS

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Legal Responsibilities for Studies Conducted or
Supported by HHS
Pediatric Oncology Subcommittee of the Oncologic
Drugs Advisory Committee March 17, 2004

Michael A. Carome, M.D. Associate Director for
Regulatory Affairs Office for Human Research
Protections Department of Health and Human
Services
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Presentation Overview

• Applicability of the Department of Health and
  Human Services (HHS) regulations for the
  protection of human subjects (45 CFR part 46)
• Major requirements of 45 CFR part 46, subpart A
• Major requirements of 45 CFR part 46, subpart D
  (Additional Protections for Children Involved as
  Subjects in Research)

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Title 45Code of Federal RegulationsPart 46

• Protection of Human Subjects
• (Last revised November 13, 2001)

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Applicability of the HHS regulations for the
protection of human subjects (45 CFR part 46)
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Applicability of 45 CFR Part 46

• Research conducted or supported by HHS that is
  not otherwise exempt 45 CFR 46.101(a)
• Research conducted at an institution holding an
  applicable Assurance of Compliance approved by
  OHRP

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Applicability of HHS Versus FDA Human Subject
Protection Regulations

HHS regs Research conducted or supported by
HHS or conducted under OHRP-approved assurance
FDA regs Clinical investigation regulated by
the FDA
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Major requirements of 45 CFR part 46, subpart A
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Ethical Framework for 45 CFR Part 46The Belmont
Report

• Respect for Persons
• Beneficience
• Justice

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Fundamental Provisions of45 CFR Part 46,
Subpart A

• Assurance of Compliance
• IRB requirements
• Legally effective informed consent

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• Assurance of Compliance (1)

• Each institution engaged in research covered by
  45 CFR part 46 and which is conducted or
  supported by HHS shall provide assurance
  satisfactory to the HHS Secretary that it will
  comply with the requirements set forth in 45 CFR
  part 46 45 CFR 46.103(a).

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• Assurance of Compliance (2)

• Statement of principles governing institution in
  the discharge of its responsibilities for
  protecting the rights and welfare of human
  subjects
• Designation of one or more IRBs
• List of IRB members
• Written IRB procedures
• 45 CFR 46.103(b)

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IRB Requirements

• Membership
• Functions and operations
• Review of research (initial and
  continuing)
• Expedited review procedures
• Criteria for IRB approval
• Records
• 45 CFR 46.107-111

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Legally Effective Informed Consent

• General requirements
• Basic elements
• Additional elements, when appropriate
• Documentation requirements
• Waiver provisions
• 45 CFR 46.116-117

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Major requirements of 45 CFR part 46, subpart D
(Additional Protections for Children Involved as
Subjects in Research)
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Applicability of Subpart D

• All research involving children as subjects,
  conducted or supported by HHS regulations for the
  protection of human subjects 45 CFR 46.401(a)
• Children are persons who have not attained the
  legal age for consent to treatments or procedures
  involved in the research, under the applicable
  law of the jurisdiction in which the research
  will be conducted.

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Subpart D Requirements

• All requirements of subpart A must be fulfilled.
• The additional requirements of Subpart D must be
  fulfilled.

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46.404 Research not involving greater than
minimal risk

• IRB finds that adequate provisions are made for
  soliciting assent of the children and the
  permission of their parents or guardians, as set
  forth in 46.408.

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46.405 Research involving greater than minimal
risk but presenting the prospect of direct
benefit to the individual subjects

• The risk is justified by the anticipated benefit
  to the subjects.
• The relationship of the anticipated benefit to
  the risk is at least as favorable to the subjects
  as that presented by available alternatives.
• Adequate provisions for assent of children and
  parental/guardian permission.

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46.406 Greater than minimal risk and no
prospect of direct benefit to the individual
subjects, but likely to yield generalizable
knowledge about the subjects disorder or
condition (1)

• The risk represents a minor increase over minimal
  risk.
• The intervention or procedure presents
  experiences to the subjects that are reasonably
  commensurate with those inherent in their actual
  or expected medical, dental, psychological,
  social, or educational situation.

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46.406 Greater than minimal risk and no
prospect of direct benefit to the individual
subjects, but likely to yield generalizable
knowledge about the subjects disorder or
condition (2)

• The intervention or procedure is likely to yield
  generalizable knowledge about the subjects
  disorder or condition which is of vital
  importance for the understanding or amelioration
  of the subjects disorder or condition.
• Adequate provisions for assent of children and
  parental/guardian permission.

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46.407 Research not otherwise approvable
which presents a reasonable opportunity to
understand, prevent, or alleviate a serious
problem affecting the health or welfare of
children (1)

• The IRB finds that the research presents a
  reasonable opportunity to further the
  understanding, prevention, or alleviation of a
  serious problem affecting the health or welfare
  of children

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46.407 Research not otherwise approvable
which presents a reasonable opportunity to
understand, prevent, or alleviate a serious
problem affecting the health or welfare of
children (2)

• The Secretary, after consultation with a panel of
  experts in pertinent disciplines and following an
  opportunity for public review and comment, has
  determined either
• That the research in fact satisfies the
  conditions of 46.404, 405, or 406 or
• (i) the research presents reasonable
  opportunity (ii) the research will be
  conducted in accordance with sound ethical
  principles and (iii) adequate provisions for
  assent and parental permission.

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Additional Provisions of Subpart D

• Soliciting assent 45 CFR 46.408(a)
• Soliciting permission of each parent or guardian
  (one sufficient for 46.404 or 405) 45 CFR
  46.408(b)
• Waiver of parental or guardian permission 45 CFR
  46.408(c)
• Protections for wards of state or any other
  agency, institution or entity for research
  approved under 46.406 or 407 45 CFR 46.409

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Summary

• Applicability of the Department of Health and
  Human Services (HHS) regulations for the
  protection of human subjects (45 CFR part 46)
• Major requirements of 45 CFR part 46, subpart A
• Major requirements of 45 CFR part 46, subpart D
  (Additional Protections for Children Involved as
  Subjects in Research)