[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and Human Services (HHS) is soliciting public comment on a draft 
guidance document for Institutional Review Boards (IRBs), 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 This draft 
guidance document raises points to consider in determining whether 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DATES: Submit written or electronic comments on the draft guidance on 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    Submit requests for single copies of the draft guidance document to 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?


[[Page 15459]]


--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