[Federal Register Volume 68, Number 61 (Monday, March 31, 2003)]
[Notices]
[Pages 15456-15460]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-7691]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 02N-0475]
Draft ``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, Department of Health
and Human Services (HHS) is soliciting public comment on a draft
guidance document for Institutional Review Boards (IRBs),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 This draft
guidance document raises points to consider in determining whether
specific financial interests in research 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DATES: Submit written or electronic comments on the draft guidance on
or before 4:30 p.m. on May 30, 2003. Comments on HHS guidance documents
are welcome at any time.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Docket Number 02N-0475, Food and Drug Administration, 5630
Fishers Lane, Room 1061, Rockville, MD 20852. Submit electronic
comments to http://www.fda.gov/dockets/ecomments. All comments
submitted should be identified with the docket number found in brackets
in the heading of this notice. Comments received may be viewed on the
Food and Drug Administration (FDA) Web site at http://www.fda.gov/ohrms/dockets/default.htm or may be seen in the FDA Docket Management
Branch at 5630 Fishers Lane, Room 1061, Rockville, MD 20852 between 9
a.m. and 4 p.m., Monday through Friday.
Submit requests for single copies of the draft guidance document to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://www.fda.gov/ohrms/dockets/GUIDANCES/DGUIDES.HTM.
FOR FURTHER INFORMATION CONTACT: 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:
I. Background
OPHS is 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.'' 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 conflicts 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. This document will replace that draft
interim guidance.
The draft guidance recommends consideration of approaches and
methods for dealing with issues of financial interests under the HHS
human research subject protections regulations, 45 CFR part 46 and 21
CFR parts 50 and 56. The draft 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 draft 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.
II. Request for Comments
OPHS is distributing this draft guidance document for public
comment. The Secretary is interested not only in reactions to the
Guidance in general, and specifically the Points for Consideration, but
also wishes to solicit views and ideas as to how to best assess any
impacts of this guidance, as well as related non-Federal
recommendations on enhancing the protection of human subjects. HHS
guidance on consideration of financial interests in human subjects
research will be issued after the public comments have been considered.
[[Page 15457]]
III. Draft Guidance Document
Department of Health and Human Services
Draft Guidance Document
March 31, 2003.
Financial Relationships and Interests in Research Involving Human
Subjects: Guidance for Human Subject Protection \1\
This document will replace 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.
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\1\ 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 HHS, including FDA, or the public. An alternative approach may
be used if such approach satisfies the requirements of the
applicable statutes and regulations.
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I. Introduction
A. Purpose
In this draft guidance document the Department of Health and Human
Services (HHS, or the Department) raises points to consider in
determining whether specific financial interests in research affect the
rights and welfare of human subjects \2\ and if so, what actions could
be considered to protect those subjects. This draft guidance applies to
human subjects research conducted or supported by HHS or regulated by
the Food and Drug Administration (FDA). This document addresses only
requirements for human subject protection (45 CFR part 46, 21 CFR parts
50, 56) \3\ This document is nonbinding and does not change any
existing regulations or requirements, and does not impose any new
requirements.
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\2\ 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.
\3\ This document does not address HHS Public Health Service
regulatory requirements that cover institutional management of the
financial interests of individual investigators who conduct 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 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 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 if
it will, or may be reasonably expected to, create a bias stemming from
that financial interest. Furthermore, the Department recognizes that
some financial interests in research may potentially or actually affect
the rights and welfare of subjects, and this document provides some
possible approaches to consider in assuring that 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.
B. Target Audiences
The principal target audiences include institutions engaged in
human subjects research and their officials, investigators, IRB members
and staffs, and other interested parties.
C. Underlying Princinles
The regulations protecting human research subjects are based on the
ethical principles described in the Belmont report: \4\ respect for
persons, beneficence, and justice. Financial relationships in human
research should not compromise any of these principles. Openness and
honesty are indicators of respect for persons, characteristics that
promote 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 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 by such an IRB. Under these regulations, IRBs are
responsible for, among other things, determining that:
[sbull] Risks to subjects are minimized (45 CFR 46.111(a)(1), 21
CFR 56.111(a)(1));
[sbull] 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));
[sbull] Selection of subjects is equitable (45 CFR 46.111(a)(3), 21
CFR 56.11 1(a)(3));
[sbull] Informed consent will be sought from each prospective
subject (45 CFR 46.111(a)(4), 21 CFR 56.111(a)(4)); and,
[sbull] The possibility of coercion or undue influence is minimized
(45 CFR 46.116, 21 CFR 50.20).
In addition the IRB may
[sbull] 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
[[Page 15458]]
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
research subjects. Financial interests are not prohibited, and not all
financial interests cause conflicts of interest or harm to 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/humansubiects/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:
[sbull] 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 (httn://
www.georgetown.edu/research/nbcbl/nbac/human/overvoll.pdf).
[sbull] The HHS Office of the Inspector Genera] (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).
[sbull] The National Human Research Protections Advisory
Committee (NHRPC) offered advice to HHS regarding the content and
finalization of the HHS Draft Interim Guidance in August, 2001
(httn://ohrp.osophs.dhhs.gov/nhrpac/documents/augo1a.pdf).
[sbull] 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/).
[sbull] 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 (httn:/
/jama.ama-assn.org/issues/v287n1/abs/jsc10070.html), the American
Society of Gene Therapy, April 2000 (http://www.asgt.org/policy/index.html), 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/policv/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
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. These
entities may elect to include the following questions in their
deliberations:
[sbull] What financial relationships and resulting financial
interests cause potential or actual conflicts?
[sbull] At what levels could those interests cause potential or
actual conflicts?
[sbull] What procedures would be helpful, including those to
--collect and evaluate information regarding financial relationships
related to research,
--determine whether those relationships potentially cause a conflict,
--determine what actions are necessary to protect human subjects and
ensure that those actions are taken?
[sbull] Who should be educated regarding financial conflict of
interest issues and policies?
[sbull] What entity or entities would examine individual and/or
institutional financial relationships and interests?
B. Points for Consideration
Financial interests may be managed by eliminating them or
mitigating their potentially negative 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. 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 for protection of the rights and welfare of human research
subjects.
[sbull] Does the research involve financial relationships that
could create 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?
[sbull] What interests are created by the financial relationships
involved in the situation?
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--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, and licensing agreements?
+have an equity interest in the research sponsor and is it 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, and honoraria)
+receive payment per participant or incentive payments, and are those
payments within the norm?
[sbull] Given the financial relationships involved, is the
institution an appropriate site for the research?
[sbull] 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 Issues for Consideration Regarding
1. Institutions
The Department recommends that institutions engaged in federally
conducted or supported human subjects research consider the following
actions or other actions regarding financial conflicts of interest:
[sbull] Separate responsibilities for financial decisions and
research decisions.
[sbull] Establish conflict of interest committees (COICs) \7\ or
identify other bodies or persons to deal with individuals' financial
interests in research or verify their absence.
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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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[sbull] Extend the responsibility of the COIC to address
institutional financial interests in research or establish a separate
COIC to address institutional financial interests in research.
[sbull] Establish 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.
[sbull] Establish clear channels of communication between COICs and
IRBs.
[sbull] Establish policies on providing information,
recommendations, or findings from COIC deliberations to IRBs.
[sbull] Establish measures to foster the independence of IRBs and
COICs.
[sbull] Include IRB members and staff and appropriate officials of
the institution, along with investigators, among the individuals who
report financial interests to COICs.
[sbull] Establish procedures for disclosure of institutional
financial relationships to COICs.
[sbull] Provide training to appropriate individuals regarding
financial interest requirements.
[sbull] Use independent organizations to hold or administer the
institution's financial interest.
[sbull] Include individuals from outside the institution in the
review and oversight of financial interests in research.
[sbull] Establish policies regarding the types of relationships
that may be held by parties involved in the research and circumstances
under which those financial relationships and interests may 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
establishing policies and procedures addressing IRB member potential
and actual conflicts of interest as part of overall IRB policies and
procedures. These might include:
[sbull] Reminding members of conflict of interest policies at the
start of each meeting.
[sbull] Polling members to verify that no conflicts of interest
exist regarding any protocols to be considered during the meeting.
[sbull] Recording the polling results in the meeting minutes.
[sbull] Recording in the meeting minutes verification for each
protocol that any conflicted members did not participate in discussion
or vote on protocols involving their conflict of interest, except to
provide information as requested by the IRB (45 CFR 46.107(e), 21 CFR
56.107(e)).
[sbull] Developing educational materials about the regulations'
requirements for IRE members.
3. IRB Review
The Department recommends that IRBs reviewing HHS conducted or
supported human subjects research or FDA regulated human subjects
research consider the following actions, or other actions related to
conduct or oversight of research, based on particular situations:
[sbull] Determine whether methods being considered or used for
management of financial interests of parties involved in the research
adequately protect the rights and welfare of human subjects.
[sbull] Determine when an IRB needs additional information to
decide whether the financial interests of parties involved in research
could affect the rights and welfare of subjects as well as mechanisms
for obtaining the additional information.
[sbull] Determine what actions are necessary to minimize risks to
subjects.
[sbull] Determine 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 consider the potential
effect that a financial relationship of any kind might have on a
clinical trial, including interactions with research subjects, and
whether to take any of the following actions:
[sbull] Including information in the 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.
[sbull] Using special measures to modify the consent process when a
potential or actual financial conflict exists, such as
--having a non-biased third party obtain consent, especially when a
potential or actual conflict of interest could influence the tone,
presentation, or type of information presented during the consent
process.
[[Page 15460]]
[sbull] Considering independent monitoring of the research, e.g.,
using a data and safety monitoring committee.
Dated: March 21, 2003.
Tommy G. Thompson,
Secretary, Department of Health and Human Services.
[FR Doc. 03-7691 Filed 3-28-03; 8:45 am]
BILLING CODE 4150-28-P