Overview of Research Oversight: U.S. Perspective

Leslie K. Ball, M.D., F.A.A.P.Office for Human Research Protections

Department of Health and Human Services

Email: LBall@osophs.dhhs.gov

FDA Pediatric Oncology SubcommitteeJuly 15, 2003

2

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

International Clinical Trials for New Drugs

0

1000

2000

3000

4000

5000

6000

7000

8000

'91 '92 '93 '94 '95 '96 '97 '98 '99 '00

Developed CountriesLess Developed Countries

Sources: FDA Biomonitoring Research database; Parexel’s Pharmaceutical R&D Sources: FDA Biomonitoring Research database; Parexel’s Pharmaceutical R&D Statistical Sourcebook 1999; Aculaunch; Washington Post ResearchStatistical Sourcebook 1999; Aculaunch; Washington Post Research

Courtesy of Dr. Melody Lin, Deputy Director, OHRP

0

20,000,000

40,000,000

60,000,000

80,000,000

100,000,000

120,000,000

140,000,000

1994 1995 1996 1997 1998 1999 2000

Visiting Program

Direct Foreign Research Awards

Foreign Components of Domestic Awards

Training Grants

NIH International Research ExpendituresNIH International Research ExpendituresD

olla

rs

Fiscal Years 1994 to 2000Fiscal Years 1994 to 2000

Training = $103 million (34%)

Research = $203 million (66%)

Fiscal Year 2000Fiscal Year 2000

Courtesy of Dr. Melody Lin, Deputy Director, OHRP

5

Clinical Research Balance

Scientific advancementProduct development

Regulatory oversightHuman subject protections

6

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

7

Regulatory Framework: Drug Development

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

Regulatory Protection of Human Subjects:

OHRP FDA

Applies to:

*Domestic institutions may elect to apply 45 CFR 46 to all of its research

regardless of source of support

Secretary of HHS

Commissioner

FDA

Assistant Secretary of Health

Office of Public Health and

Science

Director

OHRP

Department of Health and Human Services

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

11

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

12

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

13

Research Involving Children: Historical Context

Ethical lapses in the conduct of clinical research

Beecher HK. NEJM 1966; 274:1354-60 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)

14

Research Involving Children: Historical Context (cont.)

1998: FDA’s 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: Children’s 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: FDA’s 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 ReportEthical 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

17

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 assurance…that it will comply with the requirements set forth in this policy.” [45 CFR 46.103(a)]

Negotiated and approved by OHRP

19

Assurances: Research conducted or supported by HHS (cont.) Formalizes institution’s

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

20

Institutional Assurances

Institution

Investigator

Sponsor

Assurance of Compliance with OHRP

21

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

23

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 subject’s 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

24

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

25

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 institution’s protections are at least as equivalent, the U.S. Department or Agency Head may approve the substitution of foreign procedures

26

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

27

International Assurances (cont.)

45 CFR 46 Subparts A, B, C, D

45 CFR 46 Subpart A 21 CFR 50, 56 ICH-GCP-E-6 CIOMS Int’l Ethical

Guidelines

Canadian Tri-council Policy

Indian Council of Medical Research Guidelines

Other standards recognized by U.S. Federal Departments

Institution assures that its activitiesWill comply with procedural standards (one or more)*

*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/assurance/fwas.htm

Search for international assurances:

http://ohrp.cit.nih.gov/search/asearch.asp