Legal Responsibilities for Studies Conducted or Supported by HHS Michael A. Carome, M.D. Associate Director for Regulatory Affairs Office for Human Research Protections Department of Health and Human Services Pediatric Oncology Subcommittee of the Oncologic Drugs Advisory Committee March 17, 2004

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)

Title 45 Code of Federal Regulations Part 46 Protection of Human Subjects (Last revised November 13, 2001)

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

Applicability of 45 CFR Part 46 Research conducted or supported by HHS that is not otherwise exempt [45 CFR (a)] Research conducted at an institution holding an applicable Assurance of Compliance approved by OHRP

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

Major requirements of 45 CFR part 46, subpart A

Ethical Framework for 45 CFR Part 46 The Belmont Report Respect for Persons Beneficience Justice

Fundamental Provisions of 45 CFR Part 46, Subpart A Assurance of Compliance IRB requirements Legally effective informed consent

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 (a)].

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 (b)]

IRB Requirements Membership Functions and operations Review of research (initial and continuing) Expedited review procedures Criteria for IRB approval Records [45 CFR ]

Legally Effective Informed Consent General requirements Basic elements Additional elements, when appropriate Documentation requirements Waiver provisions [45 CFR ]

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

Applicability of Subpart D All research involving children as subjects, conducted or supported by HHS regulations for the protection of human subjects [45 CFR (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.

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

§ : 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 §

§ : 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.

§ : Greater than minimal risk and no prospect of direct benefit to the individual subjects, but likely to yield generalizable knowledge about the subject’s 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.

§ : Greater than minimal risk and no prospect of direct benefit to the individual subjects, but likely to yield generalizable knowledge about the subject’s 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.

§ : 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

§ : 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 § , 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.

Additional Provisions of Subpart D Soliciting assent [45 CFR (a)] Soliciting permission of each parent or guardian (one sufficient for § or 405) [45 CFR (b)] Waiver of parental or guardian permission [45 CFR (c)] Protections for wards of state or any other agency, institution or entity for research approved under§ or 407 [45 CFR ]

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)