[Federal Register: May 12, 2004 (Volume 69, Number 92)]
[Notices]
[Page 26393-26397]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr12my04-54]
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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
gdrew@osophs.dhhs.gov.
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published a notice seeking comments on the HHS draft guidance for IRBs,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), 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://
http://www.jco.org/cgi/ 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/).
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
[[Page 26396]]
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