[Federal Register Volume 69, Number 92 (Wednesday, May 12, 2004)]
[Notices]
[Pages 26393-26397]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 04-10849]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES


Financial Relationships and Interests in Research Involving Human 
Subjects: Guidance for Human Subject Protection

AGENCY: Office of the Secretary, Office of Public Health and Science, 
HHS.

ACTION: Notice.

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SUMMARY: The Office of Public Health and Science (OPHS), Department of 
Health and Human Services (HHS) announces a final guidance document for 
Institutional Review Boards (IRBs), investigators, research 
institutions, and other interested parties, entitled ``Financial 
Relationships and Interests in Research Involving Human Subjects: 
Guidance for Human Subject Protection.'' This guidance document raises 
points to consider in determining whether specific financial interests 
in research could affect the rights and welfare of human subjects, and 
if so, what actions could be considered to protect those subjects. This 
guidance applies to human subjects research conducted or supported by 
HHS or regulated by the Food and Drug Administration.

DATES: The guidance is effective as of the date of publication.

ADDRESSES: Office for Human Research Protections, The Tower Building, 
1101 Wootton Parkway, Suite 200, Rockville, MD 20852, (301) 402-4994, 
facsimile (301) 402-2071.

FOR FURTHER INFORMATION CONTACT: Submit requests for single copies of 
the guidance document to the address identified below for further 
information. Requests may be made by mail or e-mail. Persons with 
access to the Internet also may obtain the document at http://ohrp.osophs.dhhs.gov/humansubjects/finreltn/finreltn.htm. Glen Drew, 
Office for Human Research Protections, Office of Public Health and 
Science, The Tower Building, 1101 Wootton Parkway, Suite 200, 
Rockville, MD 20852, (301) 402-4994, facsimile (301) 402-2071; e-mail 
[email protected].

SUPPLEMENTARY INFORMATION:

[[Page 26394]]

I. Background

    In the March 31, 2003, Federal Register, (68 FR 15456) OPHS 
published a notice seeking comments on the HHS draft guidance for IRBs, 
investigators, and research institutions, entitled ``Financial 
Relationships and Interests in Research Involving Human Subjects: 
Guidance for Human Subject Protection.'' The Department has considered 
the 40 comments that were submitted and has made appropriate changes in 
the guidance.
    The guidance recommends consideration of approaches and methods for 
dealing with issues of financial interests that could affect HHS human 
research subject protections in research subject to 45 CFR part 46 for 
HHS conducted or support research and 21 CFR parts 50 and 56 for FDA 
regulated clinical investigations. The guidance expressly does not 
address regulatory requirements designed to enhance data integrity and 
objectivity in research found in 42 CFR part 50, subpart F, 45 CFR part 
94, and 21 CFR part 54.
    The guidance recommends that, in particular, IRBs, institutions 
engaged in research, and investigators consider whether specific 
financial relationships create financial interests in research studies 
that may adversely affect the rights and welfare of subjects. The 
guidance poses general considerations in evaluating financial 
relationships and their possible effects on human subjects. More 
detailed points for consideration are also offered for institutions, 
IRBs, and investigators.

Department of Health and Human Services

Final Guidance Document

Financial Relationships and Interests in Research Involving Human 
Subjects: Guidance for Human Subject Protection
    This document replaces the ``HHS Draft Interim Guidance: Financial 
Relationships in Clinical Research: Issues for Institutions, Clinical 
Investigators, and IRBs to Consider when Dealing with Issues of 
Financial Interests and Human Subject Protection'' dated January 10, 
2001. This document is intended to provide guidance. It does not create 
or confer rights for or on any person and does not operate to bind the 
Department of Health and Human Services (HHS, or the Department), 
including the Food and Drug Administration (FDA), or the public. An 
alternative approach may be used if such approach satisfies the 
requirements of the applicable statutes and regulations.

I. Introduction

A. Purpose

    In this guidance document, HHS raises points to consider in 
determining whether specific financial interests in research affect the 
rights and welfare of human subjects \1\ and if so, what actions could 
be considered to protect those subjects. This guidance applies to human 
subjects research conducted or supported by HHS or regulated by the 
FDA. The consideration of financial relationships, as discussed in this 
document relates to human subject protection in research conducted 
under the HHS or FDA regulations (45 CFR part 46, 21 CFR parts 50, 
56).\2\ This document is nonbinding and does not change any existing 
regulations or requirements, and does not impose any new requirements.
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    \1\ Under the Public Health Service Act and other applicable 
law, HHS has authority to regulate institutions engaged in HHS 
conducted or supported research involving human subjects. For a 
description of what is meant by institutions engaged in research see 
the Office for Human Research Protections (OHRP) engagement policy 
at http://ohrp.osophs.dhhs.gov/humansubjects/assurance/engage.htm. 
Under the Federal Food, Drug, and Cosmetic Act, FDA has the 
authority to regulate Institutional Review Boards (IRBs) and 
investigators involved in the review or conduct of FDA-regulated 
research.
    \2\ This document does not address HHS Public Health Service 
regulatory requirements that cover institutional management of the 
financial interests of individual investigators who conduct Public 
Health Service (PHS) supported research (42 CFR part 50, subpart F, 
and 45 CFR part 94). This document also does not address FDA 
regulatory requirements that place responsibilities on sponsors to 
disclose certain financial interests of investigators to FDA in 
marketing applications (21 CFR part 54). Guidelines interpreting the 
application of the PHS regulations to research conducted or 
supported by the National Institutes of Health (NIH) that involve 
human subjects are available at http://grants.nihgov/grants/guide/notice-files/NOT-OD-00-040.html. Guidance interpreting the 
provisions of the FDA regulations appears at http://www.fda.gov/oc/guidance/financialdis.html.
    The PHS regulations require grantee institutions and contractors 
to designate one or more persons to review investigators' financial 
disclosure statement describing their significant financial 
interests and ensure that conflicting financial interests are 
managed, reduced, or eliminated before expenditure of funds (42 CFR 
50.604(b), 45 CFR 94.4(b)). The PHS threshold for significant 
financial interest is $10,000 per year income or equity interests 
over $10,000 and 5 percent ownership in a company (42 CFR 50.603, 45 
CFR 94.3). The regulations give several examples of methods for 
managing investigators' financial conflicts of interest (42 CFR 
50.605(a), 54 CFR 94.5(a)).
    Sponsors are required to disclose certain financial interests of 
clinical investigators to FDA in marketing approval applications 
under the Federal Food, Drug and Cosmetic Act (FD&C Act) (21 CFR 
part 54). FDA regulations at 21 CFR part 54 address requirements for 
the disclosure of certain financial interests held by clinical 
investigators. The purpose of these regulations is to provide 
additional information to allow FDA to assess the reliability of the 
clinical data (21 CFR 54.1). The FDA regulations require sponsors 
seeking marketing approval for products to certify that 
investigators do not have certain financial interests, or to 
disclose those interests to FDA (21 CFR 54.4). These regulations 
require sponsors to report (1) financial arrangements between the 
sponsor and the investigator whereby the value of the investigator's 
compensation could be influenced by the outcome of the trial; (2) 
any proprietary interest in the product studied held by the 
investigator; (3) significant payments of other sorts over $25,000 
beyond costs of the study; or (4) any significant equity interest in 
the sponsor of a covered study (21 CFR 54.4).
    Note that when the PHS regulations were promulgated, the 
National Science Foundation (NSF) Investigator Financial Disclosure 
Policy was revised to match closely the PHS regulations. The NSF 
conflict of interest policy appears at http://www.nsf.gov/bfa/cpo/gpm95/ch5.htm#ch5.
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    Institutions and individuals involved in human subjects research 
may establish financial relationships related to or separate from 
particular research projects. Those financial relationships may create 
financial interests of monetary value, such as payments for services, 
equity interests, or intellectual property rights. A financial interest 
related to a research study may be a conflicting financial interest. 
The Department recognizes that some conflicting financial interests in 
research may affect the rights and welfare of human subjects. This 
document provides some possible approaches to consider in assuring that 
human subjects are adequately protected. Institutional review boards 
(IRBs), institutions, and investigators engaged in human subjects 
research each have appropriate roles in ensuring that financial 
interests do not compromise the protection of research subjects.\3\
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    \3\ The Department recognizes that some non-financial 
conflicting interests related to research also may affect the rights 
and welfare of human subjects. However, non-financial interests are 
beyond the scope of this guidance document.
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B. Target Audiences

    The principal target audiences include investigators, IRB members 
and staffs, institutions engaged in human subjects research and their 
officials, and other interested members of the research community.

C. Underlying Principles

    The regulations protecting human research subjects are based on the 
ethical principles described in the Belmont report: \4\ respect for 
persons, beneficence, and justice. The Belmont principles should not be 
compromised by financial relationships. Openness and honesty are 
indicators of respect for persons, characteristics that promote

[[Page 26395]]

ethical research and can only strengthen the research process.
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    \4\ http://ohrp.osophs.dhhs.gov/humansubjects/guidance/belmont.htm.
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D. Basis for This Document

    The HHS human subject protection regulations (45 CFR part 46) 
require that institutions performing HHS conducted or supported non-
exempt research involving human subjects have the research reviewed and 
approved by an IRB whose goal is to help ensure that the rights and 
welfare of human subjects are protected. The comparable FDA regulations 
(21 CFR parts 50 and 56) require that FDA regulated research involving 
human subjects is reviewed and approved by such an IRB. Under these 
regulations, IRBs are responsible for, among other things, determining 
that:
    Risks to subjects are minimized (45 CFR 46.111(a)(1), 21 CFR 
56.111(a)(1));
    Risks to subjects are reasonable in relation to anticipated 
benefits, if any, to subjects (45 CFR 46.111(a)(2), 21 CFR 
56.111(a)(2));
    Selection of subjects is equitable (45 CFR 46.111(a)(3), 21 CFR 
56.111(a)(3));
    Informed consent will be sought from each prospective subject (45 
CFR 46.111(a)(4), 21 CFR 56.111(a)(4)); and,
    The possibility of coercion or undue influence is minimized (45 CFR 
46.116, 21 CFR 50.20).
    In addition the IRB may

    Require that additional information be given to subjects ``when 
in the IRB's judgment the information would meaningfully add to 
protection of the rights and welfare of subjects'' (45 CFR 
46.109(b), 21 CFR 56.109(b)).

    For HHS conducted or supported research, the funding agency may 
impose additional conditions as necessary for the protection of human 
subjects (45 CFR 46.124).
    IRBs are also responsible for ensuring that members who review 
research have no conflicting interest. 45 CFR 46.107(e) directly 
addresses conflicts of interest by requiring that ``no IRB may have a 
member participate in the IRB's initial or continuing review of any 
project in which the member has a conflicting interest, except to 
provide information requested by the IRB.'' FDA regulations include 
identical language at 21 CFR 56.107(e).
    Concerns have grown that financial conflicts of interest in 
research, derived from financial relationships and the financial 
interests they create, may affect the rights and welfare of human 
subjects in research. Financial interests are not prohibited, and not 
all financial interests cause conflicts of interest or affect the 
rights and welfare of human subjects. HHS recognizes the complexity of 
the relationships between government, academia, industry and others, 
and recognizes that these relationships often legitimately include 
financial relationships. However, to the extent financial interests may 
affect the rights and welfare of human subjects in research, IRBs, 
institutions, and investigators need to consider what actions regarding 
financial interests may be necessary to protect those subjects.
    In May 2000, HHS announced five initiatives to strengthen human 
subject protection in clinical research. One of these was to develop 
guidance on financial conflict of interest that would serve to further 
protect research participants. As part of this initiative, HHS held a 
conference on the topic of human subject protection and financial 
conflict of interest on August 15-16, 2000. A draft interim guidance 
document, ``Financial Relationships in Clinical Research: Issues for 
Institutions, Clinical Investigators, and IRBs to Consider when Dealing 
with Issues of Financial Interests and Human Subject Protection,'' 
based on information obtained at and subsequent to that conference was 
made available to the public for comment on January 10, 2001.\5\ This 
document replaces that draft interim guidance. The Department notes 
that other organizations have also addressed financial interests in 
human research via reports, guidance and recommendations.\6\ Many of 
these contain strong and sound ideas for actions to deal with potential 
financial conflicts of interest on the part of institutions, 
investigators and IRBs.
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    \5\ http://ohrp.osophs.dhhs.gov/humansubjects/finreltn/finguid.htm.
    \6\ Recent Federal and Private Sector Activities: In addition to 
the HHS initiative, several Federal organizations have examined the 
issues related to financial relationships in human subjects 
research:
     The National Bioethics Advisory Commission (NBAC), in a 
comprehensive examination of the ``Ethical and Policy Issues in 
Research Involving Human Participants,'' in Chapter 3 recommended 
development of federal, institutional, and sponsor policies and 
guidance to ensure that research subjects' rights and welfare are 
protected from the effects of conflicts of interest (http://www.georgetown.edu/research/nrcbl/nbac/human/overvol1.pdf).
     The HHS Office of the Inspector General (OIG) has 
issued a series of reports examining regulation and activities of 
IRBs. A June 2000 OIG report addressed recruitment practices and 
found that about one-quarter of the surveyed IRBs consider financial 
arrangements with sponsors of research as part of their protocol 
review (http://oig.hhs.gov/oei/reports/oei-01-97-00195.pdf).
     The National Human Research Protections Advisory 
Committee (NHRPAC) offered advice to HHS regarding the content and 
finalization of the HHS Draft Interim Guidance in August, 2001 
(http://ohrp.osophs.dhhs.gov/nhrpac/documents/aug01a.pdf).
     In December 2001, the General Accounting Office 
released report 02-89 ``Biomedical Research: HHS Direction Needed to 
Address Financial Conflicts of Interest.'' The report recommended 
that the Secretary of Health and Human Services develop specific 
guidance or regulations concerning institutional financial conflicts 
of interest (http://www.gao.gov/).
     A number of nongovernmental organizations recently have 
addressed financial interests in reports and issued new or updated 
policies or guidelines of varying scope and specificity, including 
the Association of American Universities, October 2001 (http://www.aau.edu/research/COI.01.pdf), the Association of American 
Medical Colleges, December 2001 and October 2002 (http://www.aamc.org/members/coitf/firstreport.pdf and http://www.aamc.org/members/coitf/2002coireport.pdf), the International Committee of 
Medical Journal Editors October 2001 (http://www.icmje.org/sponsor.htm), the American Medical Association, January 2002 (http://jama.ama-assn.org/cgi/content/short/287/1/78 cgi/content/short/287/1/78), and opinions E-
8.0315 Managing Conflicts of Interest in the Conduct of Clinical 
Trials (http://www.ama-assn.org/ama/pub/category/8471.html) and E-
8031 Conflicts of Interest: Biomedical Research (http://www.ama-assn.org/ama/pub/category/8470.html), the American Society of Gene 
Therapy, April 2000 (http://www.asgt.org/policy/index.html), the 
American Society of Clinical Oncology, June 2003 (http://www.jco.org/cgi/content/full/21/12/2394 content/full/21/12/2394), and the Institute of 
Medicine, October 2002, report ``Responsible Research: A Systems 
Approach to Protecting Research Participants'' (http://www.nap.edu/books/0309084881/html/ books/0309084881/html/).
     Two accrediting bodies for human subject protection 
programs have included elements addressing individual and 
institutional conflicts of interest in their accreditation 
evaluations, the Association for the Accreditation of Human Research 
Protection Programs (http://www.aahrpp.org/images/Evaluation_Instrument_1.pdf) and the National Committee for Quality Assurance, 
(http://www.ncqa.org/Programs/QSG/VAHRPAP/vahrpapfindstds.pdf).Internationally, the World Medical 
Association's revision in 2000 of the Declaration of Helsinki, 
(http://www.wma.net/e/policy/17-c_e.html) principle 22, includes 
``sources of funding'' among the items of information to be provided 
to subjects. A number of individual institutions also have developed 
policies for their own situations, as noted in the NIH Guide Notice 
issued in June 2000 (http://grants.nih.grants/guide/notice-files/NOT-OD-00-040.html). Some of these policies involve conflicts of 
interest management methods and address institutional financial 
interests as well as individual interests.
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II. Guidance for Institutions, IRBs and Investigators

A. General Approaches To Address Financial Relationships and Interests 
in Research Involving Human Subjects

    The Department recommends that in particular, IRBs, institutions, 
and investigators consider whether specific financial relationships 
create financial interests in research studies that may adversely 
affect the rights and welfare of subjects. These entities may find it 
useful to include the following questions in their deliberations:
    What financial relationships and resulting financial interests 
could cause potential or actual conflicts of interest?
    At what levels should those potential or actual financial conflicts 
of interest be managed or eliminated?
    What procedures would be helpful, including those to

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     Collect and evaluate information regarding financial 
relationships related to research,
     Determine whether those relationships potentially cause a 
conflict of interest, and
     Determine what actions are necessary to protect human 
subjects and ensure that those actions are taken?
    Who should be educated regarding financial conflict of interest 
issues and policies?
    What entity or entities would examine individual and/or 
institutional financial relationships and interests?
B. Points for Consideration
    Financial interests determined to create a conflict of interest may 
be managed by eliminating them or mitigating their impact. A variety of 
methods or combinations of methods may be effective. Some methods may 
be implemented by institutions engaged in the conduct of research, and 
some methods may be implemented by IRBs or investigators. Some of those 
may apply before research begins, and some may apply during the conduct 
of the research.
    In establishing and implementing methods to protect the rights and 
welfare of human subjects from conflicts of interest created by 
financial relationships of parties involved in research, the Department 
recommends that IRBs, institutions engaged in research, and 
investigators consider the questions below. Additional questions may be 
appropriate. The Department's intent is not to be exhaustive, but to 
suggest ways to examine the issues so that appropriate actions can be 
taken to protect the rights and welfare of human research subjects. The 
Department recognizes that a number of institutions currently address 
such issues in their consideration of financial interests of parties 
involved in human subject research.
    Does the research involve financial relationships that could create 
potential or actual conflicts of interest?
     How is the research supported or financed?
     Where and by whom was the study designed?
     Where and by whom will the resulting data be analyzed?
    What interests are created by the financial relationships involved 
in the situation?
     Do individuals or institutions receive any compensation 
that may be affected by the study outcome?
     Do individuals or institutions involved in the research:

--Have any proprietary interests in the product, including patents, 
trademarks, copyrights, or licensing agreements?
--Have an equity interest in the research sponsor and, if so, is the 
sponsor a publicly held company or non-publicly held company?
--Receive significant payments of other sorts? (e.g., grants, 
compensation in the form of equipment, retainers for ongoing 
consultation, or honoraria)
--Receive payment per participant or incentive payments, and are those 
payments reasonable?

    Given the financial relationships involved, is the institution an 
appropriate site for the research?
    How should financial relationships that potentially create a 
conflict of interest be managed?
    Would the rights and welfare of human subjects be better protected 
by any or a combination of the following:
     Reduction of the financial interest?
     Disclosure of the financial interest to prospective 
subjects?
     Separation of responsibilities for financial decisions and 
research decisions?
     Additional oversight or monitoring of the research?
     An independent data and safety monitoring committee or 
similar monitoring body?
     Modification of role(s) of particular research staff or 
changes in location for certain research activities, e.g., a change of 
the person who seeks consent, or a change of investigator?
     Elimination of the financial interest?
C. Specific Points for Consideration
1. Institutions
    The Department recommends that institutions engaged in HHS 
conducted or supported human subjects research consider whether the 
following actions or other actions would help ensure that financial 
interests do not compromise the rights and welfare of human research 
subjects.
    Actions to consider:
    Establishing the independence of institutional responsibility for 
research activities from the management of the institution's financial 
interests.
    Establishing conflict of interest committees (COICs)\7\ or 
identifying other bodies or persons and procedures to
     Deal with individuals' or institutional financial 
interests in research or verify the absence of such interests and
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    \7\ The acronym COIC will be used to represent the body or 
person(s) designated to review financial interests.
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     Address institutional financial interests in research.
    Establishing criteria to determine what constitutes an 
institutional conflict of interest, including identifying leadership 
positions for which the individual's financial interests are such that 
they may need to be treated as institutional financial interests.
    Establishing clear channels of communication between COICs and 
IRBs.
    Establishing policies on providing information, recommendations, or 
findings from COIC deliberations to IRBs.
    Establishing measures to foster the independence of IRBs and COICs.
    Determining whether particular individuals should report financial 
interests to the COIC. These individuals could include IRB members and 
staff and appropriate officials of the institution, along with 
investigators, among those who report financial interests to COICs.
    Establishing procedures for disclosure of institutional financial 
relationships to COICs.
    Providing training to appropriate individuals regarding financial 
interest requirements.
    Using independent organizations to hold or administer the 
institution's financial interest.
    Including individuals from outside the institution in the review 
and oversight of financial interests in research.
    Establishing policies regarding the types of financial 
relationships that may be held by parties involved in the research and 
circumstances under which those financial relationships and interests 
may or may not be held.
2. IRB Operations
    The Department recommends that institutions engaged in human 
subjects research and IRBs that review HHS conducted or supported human 
subjects research or FDA regulated human subjects research consider 
whether establishing policies and procedures addressing IRB member 
potential and actual conflicts of interest as part of overall IRB 
policies and procedures would help ensure that financial interests do 
not compromise the rights and welfare of human research subjects. As 
noted, 45 CFR 46.107(e) and 21 CFR 56.107(e) prohibit an IRB member 
with a conflicting interest in a project from participating in the 
IRB's initial or continuing review, except to provide information as 
requested by the IRB.
    Policies and procedures to consider:
    Reminding members of conflict of interest policies at each meeting 
and documenting any actions taken

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regarding IRB member conflicts of interest related to particular 
protocols.
    Developing educational materials for IRB members to ensure their 
awareness of federal regulations and institutional policies regarding 
financial relationships and interests in human subjects research.
3. IRB Review
    The Department recommends that IRBs reviewing HHS conducted or 
supported human subjects research or FDA regulated human subjects 
research consider whether the following actions, or other actions 
related to conduct or oversight of research, would help ensure that 
financial interests do not compromise the rights and welfare of human 
research subjects.
    Actions to consider:
    Determining whether methods used for management of financial 
interests of parties involved in the research adequately protect the 
rights and welfare of human subjects.
    Determining whether other actions are necessary to minimize risks 
to subjects.
    Determining the kind, amount, and level of detail of information to 
be provided to research subjects regarding the source of funding, 
funding arrangements, financial interests of parties involved in the 
research, and any financial interest management techniques applied.
4. Investigators
    The Department recommends that investigators conducting human 
subjects research consider the potential effects that a financial 
relationship of any kind might have on the research or on interactions 
with research subjects, and what actions to take.
    Actions to consider:
    Including information in the informed consent document, such as
     The source of funding and funding arrangements for the 
conduct and review of research, or
     Information about a financial arrangement of an 
institution or an investigator and how it is being managed.
    Using special measures to modify the informed consent process when 
a potential or actual financial conflict exists, such as
     Having a another individual who does not have a potential 
or actual conflict of interest involved in the consent process, 
especially when a potential or actual conflict of interest could 
influence the tone, presentation, or type of information presented 
during the consent process.
     Using independent monitoring of the research.

    Dated: May 5, 2004.
Tommy G. Thompson,
Secretary, Department of Health and Human Services.
[FR Doc. 04-10849 Filed 5-11-04; 8:45 am]
BILLING CODE 4150-36-P