Protecting Subjects, Preserving Trust, Promoting Progress
Policy and Guidelines for the Oversight of Individual
Financial Interests in Human Subjects Research
Task Force on Financial Conflicts of Interest
in Clinical Research
December 2001
AAMC Task Force on Financial Conflicts of Interest In
Clinical Research
Task Force
Chair
William Danforth, M.D.
Chancellor Emeritus and Vice-
Chairman, Board of Trustees,
Washington University at St. Louis
John Thomas Bigger, M.D.
Professor of Medicine and
Pharmacology
Columbia University
Frank Davidoff, M.D.
Editor
Annals of Internal Medicine
Martin J. Delaney
Founding Director
Project Inform
Susan Dentzer
NewsHour with Jim Lehrer
Susan H. Ehringhaus, Esq.
Vice Chancellor and General Counsel
University of North Carolina at Chapel
Hill
Ginger Graham
Group Chairman
Guidant Corporation
Susan Hellmann, M.D., M.P.H.**
Chief Medical Officer
Genentech
Jeffrey Kahn, Ph.D., M.P.H.
Director
Center for Bioethics
University of Minnesota
Marvin Kalb
Executive Director, Washington Office
Joan Shorenstein Center for the Press,
Politics and Public Policy
John F. Kennedy School of Government
Russel E. Kaufman, M.D.
Vice Dean
Education and Academic Affairs
Duke University School of Medicine
Robert P. Kelch, M.D.
Dean
University of Iowa College of Medicine |
Mark R. Laret
Chief Executive Officer
University of California, San Francisco
Medical Center
Joan S. Leonard, Esq.
Vice President and General Counsel
Howard Hughes Medical Institute
Ronald Levy, M.D.
Robert K. and Helen K. Summy
Professor in the School of Medicine
Stanford University
Constance E. Lieber
President
NARSAD
Joseph B. Martin, M.D., Ph.D.
Dean, Faculty of Medicine
Harvard Medical School
Edward D. Miller, M.D.
Dean, Johns Hopkins School of
Medicine
CEO, Johns Hopkins Medicine
Thomas H. Murray, Ph.D.
President and Chief Executive Officer
The Hastings Center
Charles P. O'Brien, M.D., Ph.D.
Chief of Psychiatry
Philadelphia Veterans Affairs Medical
Center
Kenneth Appel Professor and Vice-
Chair of Psychiatry
University of Pennsylvania
Hon. John E. Porter, Esq.
Partner
Hogan and Hartson, L.L.P.
Roger Porter, M.D.
Vice President Clinical Research and
Development
Wyeth-Ayerst Research
Paul G. Ramsey, M.D.
Vice President for Medical Affairs and
Dean of the School of Medicine
University of Washington
Dorothy K. Robinson, Esq.
Vice President and General Counsel
Yale University |
Hedrick Smith*
President
Hedrick Smith Productions, Inc.
Frances M. Visco, Esq.
President
The National Breast Cancer Coalition
Savio Woo, Ph.D.
Director and Professor
Institute for Gene Therapy
Mount Sinai School of Medicine
Alastair J.J. Wood, M.D.
Assistant Vice Chancellor for Research
Professor of Medicine
Professor of Pharmacology
Vanderbilt University School of Medicine
AAU Liason
Richard J. Turman
Director of Federal Relations
The Association of American
Universities
1200 New York Avenue, NW, Suite 550
AAMC Staff
David Korn, M.D.
Senior Vice President
Association of American Medical
Colleges
Division of Biomedical and Health
Sciences Research
Jennifer Kulynych, J.D., Ph.D.
Director
Association of American Medical
Colleges
Division of Biomedical and Health
Sciences Research
* Due to unanticipated professional
obligations arising from the September
11th, 2001, attacks, Hedrick Smith
was unable to participate in the drafting
of this report.
** Susan Hellman, M.D., declines to
endorse the report, primarily due to
her concern that its recommendations
present an impediment to research
innovation. |
The work of the Task Force was supported in part by a
grant from the Howard Hughes Medical Institute.
Preface
In October of 2000, in a speech entitled Trust Us to Make A Difference,
Dr. Jordan Cohen, President of the Association of American Medical Colleges
(AAMC), announced the formation of a new Task Force on Conflicts of Interest
in Clinical Research chaired by Dr. William Danforth, Chancellor Emeritus
of Washington University of St. Louis.(1) Dr. Cohen
charged this Task Force to respond to deepening public concern over researchers'
perceived conflicts of interest by forging consensus principles and guidelines
for the oversight of financial interests in research involving human
subjects.
To achieve a broad consensus in support of new policy recommendations,
the AAMC selected Task Force members not only from the leadership of
academic medicine, but also from the ranks of prominent clinical investigators,
patient representatives, former legislators, drug and device company
executives, and journalists. The Task Force met in May and September
of 2001 and engaged in consultation and extensive deliberations.(2)
The first product of these efforts is this document, entitled Guidelines
for Developing and Implementing A Policy Concerning Individual Financial
Interests in Research. The 2001 Guidelines are intended
to augment and impart greater specificity to the AAMC's 1990 Guidelines
for Dealing with Faculty Conflicts of Commitment and Conflicts of Interest
in Research.
In creating new guidance, Task Force members drew upon their varied experience
as discoverers, developers, producers, and consumers of medical products,
but remained focused on a shared objective: to preserve public trust
in clinical research while sustaining medical progress. As a result,
the 2001 Guidelines recommend policies that will strengthen
the protection of human subjects, while enabling the robust, productive
collaborations between industry and academic medicine that have developed
in the past three decades and have contributed greatly to improvements
in patient care and to the success of American medicine.
The 2001 Guidelines provide a model for baseline standards and practices
in the oversight of financial interests in research. This guidance addresses
the financial interests of individual faculty, staff, employees, students,
fellows and trainees of our member institutions. Currently, the Task
Force is considering principles for oversight of the financial interests
that institutions and their officers may hold in human subjects research.
Informed by these deliberations, the AAMC intends to issue a second guidance
document on institutional financial interests in human subjects research
within the coming year.
I. Introduction
Institutions in which faculty, staff, or students conduct research involving
human subjects must ensure that the safety and welfare of those subjects
and the integrity of the research are never subordinated to, or compromised
by, financial interests or the pursuit of personal gain. The AAMC Task
Force on Financial Conflicts of Interest in Clinical Research acknowledges
significant ongoing public concern about the existence of financial interests
in human subjects research, and strongly encourages academic institutions
to respond in ways that instill confidence in their capacity to identify
these interests and to manage them safely and effectively.
Competing interests, particularly those engendered by a desire to advance
scientific knowledge or to achieve professional recognition, are an inescapable
fact of academic life. Most are managed through institutional policies
and practices, and through the constraints imposed by the scientific
method.(3) Yet financial interests in human subjects
research are distinct from other interests inherent in academic life
that might impart bias or induce improper behavior, because financial
interests are discretionary, and because the perception is widespread
that they may entail special risks. Specifically, opportunities to profit
from research may affect - or appear to affect - a researcher's judgements
about which subjects to enroll, the clinical care provided to subjects,
even the proper use of subjects' confidential health information. Financial
interests also threaten scientific integrity when they foster real or
apparent biases in study design, data collection and analysis, adverse
event reporting, or the presentation and publication of research findings.
At the same time, a principled partnership between industry and academia
is essential if we are to preserve medical progress and to continue to
improve the health of our citizenry. The generous public support of scientific
research in America's universities since World War II has been predicated
on the expectation that scientific advancements will yield tangible public
benefits - a robust economy, strong national security, and a healthy
citizenry. Yet, public research support is, for the most part, purposefully
limited in scope to basic research, and essentially ceases at the point
at which scientific invention enters the pathway of product development.
In biomedicine, with rare exceptions, it is the private sector, not academia,
that develops diagnostic, therapeutic, and preventative products and
brings them to market. At the crucial interface between innovation and
development, researchers from academic medicine often play a critical
role by conducting the early translational research that gives rise to
new products, and by testing these novel products for safety and efficacy.
As the AAMC first noted in its 1990 Guidelines for Dealing with Faculty
Conflicts of Commitment and Conflicts of Interest in Research, the opportunity
for researchers to receive financial rewards from these endeavors is
not intrinsically unacceptable, as long as this opportunity does not
adversely influence scientific or clinical decision-making. Importantly,
however, though a researcher may strive to insulate his or her decision-making
from bias, the mere appearance of a conflict between financial interests
and professional responsibilities may weaken public confidence in the
researcher's objectivity. The real and apparent risks posed by financial
interests likewise have the potential to threaten public support for
the research mission of academic institutions. The credibility of academic
medicine - and the public trust we prize so highly - could be undermined
by revelations that an institution has failed to exercise rigorous oversight
of financial interests in human subjects research and may thereby have
exposed those subjects to avoidable harms.
Because the safety and welfare of human beings are at stake, financial
interests in human subjects research are rightly the focus of intense
scrutiny. Renewed attention to what are often termed "financial
conflicts of interest" is occurring at a time when academic medical
institutions are turning increasingly to private funds as a source of
support for clinical research. Moreover, current federal policies encourage
institutions to seek private investment as a vehicle for translating
academic biomedical research into medically useful products. Under the
regulations implementing the Bayh-Dole Act of 1980,(4)
institutions and researchers are to share in the return on successful
inventions arising from federally-funded research.
Bayh-Dole is widely viewed as having created incentives for socially
useful collaboration between academia and industry. The resulting commercialization
of research harnesses the collective intellectual and creative talents
of university faculty, speeds the development of new and improved therapies,
stimulates regional economic growth, and contributes to the economic
viability of research institutions.(5) Notwithstanding
these benefits, the increasing involvement of academics in commercially-sponsored
research places new demands on institutions to be scrupulous in crafting
and enforcing their conflict of interest policies, and on investigators
to be diligent in adhering to them.
Current federal regulations concerning financial interests in research
were intended to promote objectivity in federally-funded research and
to ensure the reliability of data submitted to the Food and Drug Administration
(FDA) - not to protect human subjects per se.(6) Under
these regulations, institutions applying for Public Health Service (PHS)
funding (7) must solicit annual financial disclosure
statements from each investigator who plans to participate in PHS-funded
research, review these statements for evidence of a"significant
financial interest" that "would reasonably appear to be affected
by the research,"
and then "manage, reduce, or eliminate" the interest within
60 days.(8) Institutions must report to the funding
agency the existence, though not the nature or details, of any"conflicting" financial
interest that the institution determines could directly and significantly
affect the research, and assure the funding agency that the interest
has been appropriately managed, reduced, or eliminated.(9)
In 1999 the FDA adopted financial disclosure regulations that require
parties who submit applications for approval of a new drug, device, or
biological product to provide certain information about financial relationships
between sponsors and investigators. Typically academic institutions are
not required to collect this information; instead, the responsibility
rests with the sponsoring company.(10) FDA's regulations
for marketing applicants differ from the rules that apply to recipients
of PHS research funds in important respects: the FDA requirements are
retrospective, meaning that financial interests must only be reported
to the agency once the research is complete and the data are submitted
in a marketing application; FDA exempts a greater dollar amount from
the disclosure obligation; and FDA's disclosure obligation is narrower,
applying only to certain "covered clinical studies" and requiring
the applicant to submit only information about the investigator's financial
interests in the research sponsor.
What the existing federal financial disclosure regulations do not require
is a comprehensive system of disclosure and oversight, pursuant to which
institutions would collect and carefully review information on all significant
financial interests in human subjects research, whether such research
is federally-funded or privately sponsored. Equally important, federal
financial disclosure regulations do not mandate special scrutiny of financial
interests in human subjects research, nor do they acknowledge the unique
obligations that attend research involving human beings.
Mindful of these obligations, the Task Force asserts that academic medicine
must look beyond the scope of current federal financial disclosure requirements
and delineate more fully the bounds of acceptable conduct for those who
conduct research with human subjects. Some institutions have made exemplary
efforts in this regard. For others, revising policies and practices in
the manner that we recommend might require a significant investment of
time and resources, and perhaps a discomfiting change in institutional
culture. We are convinced nonetheless that all institutions can rise
to this challenge. These 2001 Guidelines for Developing and Implementing
a Policy Concerning Individual Financial Interests in Human Subjects
Research are evidence of our collective willingness to seek, to merit,
and to sustain public trust in the research mission of academic medicine.
Core Principles to Guide Policy Development
This document offers guidance to institutions in their efforts to provide
responsible and effective oversight of financial interests in human subjects
research. Academic institutions share common concerns, yet each retains
its own unique culture and mode of selfgovernance. Institutional procedures
for the oversight of financial interests in research will vary accordingly.
These guidelines create a model for baseline standards and practices,
without limiting the prerogative of institutions to implement conflict
of interest policies in a manner best suited to local needs. The Task
Force recognizes that some institutions may determine that additional
restrictions are appropriate. Likewise, we do not discourage institutional
variations in process or in the allocation of the oversight responsibilities
described in this guidance, provided that the review and management functions
that we advocate are performed fully.
As a starting point, we emphasize that the Task Force does not assume
that financial interests in human subjects research are categorically
improper, or that those who hold such interests cannot conduct research
with the requisite scientific objectivity and integrity or protect the
welfare of human research subjects. Recognizing, however, that research
with human subjects is a privilege that imposes unique obligations, the
Task Force believes that the following principles should animate institutional
policies concerning financial interests in such research:
A. With the welfare of research subjects always of foremost concern,
an institution should regard all significant financial interests
in human subjects research as potentially problematic and, therefore,
as requiring close scrutiny. Institutional policies should establish
the rebuttable presumption that an individual who holds a significant
financial interest in research involving human subjects may not conduct
such research. The intent is not to suggest that every financial
interest jeopardizes the welfare of human subjects or the integrity
of research, but rather to ensure that institutions systematically
review any financial interest that might give rise to the perception
of a conflict of interest, and further, that they limit the conduct
of human subjects research by financially interested individuals
to those situations in which the circumstances are compelling. The
presumption against significant financial interests in human subjects
research should apply whether the research is funded by a public
agency, a non-profit entity, or a commercial sponsor, and wherever
the research may be carried out.
B. In the event of compelling circumstances, an individual holding
significant financial interests in human subjects research may be
permitted to conduct the research. Whether the circumstances are
deemed compelling will depend in each case upon the nature of the
science, the nature of the interest, how closely the interest is
related to the research, and the degree to which the interest may
be affected by the research. When the financial interest is directly
related to the research and may be substantially affected by it,
(e.g., an equity interest in a start-up company that manufactures
the investigational product) the risk is greatest and the bar must
be high; however, even direct and potentially lucrative financial
interests may be justified in some circumstances. For example, when
the individual holding such interests is uniquely qualified by virtue
of expertise and experience and the research could not otherwise
be conducted as safely or effectively without that individual, he
or she should be permitted the opportunity to rebut the presumption
against financial interests by demonstrating these facts to the satisfaction
of an institution's conflict of interest (COI) committee.(11)
The COI committee might approve the involvement of such an individual
in the research, subject to conditions that ensure effective management
of the conflict and credible oversight of the research.(12)
C. Institutional policies should require full prior reporting of
each covered individual's significant financial interests that would
reasonably appear to be affected by the individual's research, updated
reporting of any relevant change in financial circumstances, and
review of any significant financial interests in a research project
by the institution's COI committee prior to final IRB approval of
the research. COI committee findings and determinations should inform
the IRB's review of any research protocol or proposal, although the
IRB may require additional safeguards or demand reduction or elimination
of the financial interest. The Task Force recommends that, as between
the COI committee and the IRB, the more stringent determination should
be dispositive. Institutional policies should specify which responsible
institutional officials are empowered to make final and binding decisions
about who may conduct IRB-approved research.
D. Institutional policies governing financial interests in human
subjects research should be comprehensive, unambiguous, well-publicized,
consistently applied, and enforced through effective sanctions. Moreover,
in today's research environment, which is both increasingly entrepreneurial
and subject to intense public scrutiny, transparency must be the
watchword for the oversight of financial interests. Transparency
is achieved through full and ongoing internal reporting and external
disclosure of significant financial interests that would reasonably
appear to affect the welfare of subjects or the conduct or communication
of research.
E. Transparency, though necessary to sustain public confidence in
academic research, is not sufficient to protect human subjects. When
an institution finds that financial interests in human subjects research
are justified by compelling circumstances, those interests and the
research in question must be managed through rigorous, effective,
and disinterested monitoring undertaken by individuals with no financial
or professional ties to the research or direct reporting relationships
to the researchers. Approaches to monitoring might include the following:
regular audits of the informed consent and enrollment process, the
involvement of a patient representative or ombudsman when subjects
are recruited and informed consent is obtained, a requirement to
escrow the financial interest until the investigational product has
been approved and on the market for a specified time period, and
the use of data safety monitoring boards. In some circumstances monitoring
boards might be composed wholly of institutional representatives;
however, when the institution itself holds a financial interest in
the research, disinterested monitoring might require the participation
of individuals from outside the institution.
F. Institutions and individual faculty, staff, employees, students,
fellows, and trainees bear a shared responsibility for the oversight
of financial interests in human subjects research, yet each remains
accountable for the effectiveness of the oversight system. Individuals
who conduct human subjects research must familiarize themselves with
their institutions' COI policies and act diligently to fulfil the
requirements imposed by these policies.
II. Policy Guidelines
An institutional policy on individual financial interests in human subjects
research should be consistent with PHS regulations, and should contain
the following elements:
-
Definitions of key terms.
-
A description of the scope and substantive requirements of the policy.
-
A description of the process by which covered individuals will report
significant financial interests in human subjects research to
institutional officials.
-
A description of the process by which financial reports will be reviewed
by institutional officials (e.g., the institution's COI committee).
-
A description of the criteria the COI committee will apply to determine
whether a "financially interested individual" has demonstrated
compelling circumstances that justify allowing that individual
to conduct human subjects research.
-
A description of the process by which summary information concerning
the nature and amount of any significant financial interest in
human subjects research, COI committee determinations concerning
that interest, and any conditions or management plan will be
reported to IRBs and to appropriate institutional officials.
-
A description of the process by which significant financial interests
in human subjects research will be disclosed to research subjects,
editors of publications, the public, and as otherwise required
by the policy.
-
A description of the process by which the institution will implement
and monitor compliance with the policy.
-
A description of the sanctions to be imposed for violations of the
policy and the procedures for adjudication and appeal.
A. Definitions
Compelling Circumstances are those facts that convince
the institution's COI committee that a financially interested individual
should be permitted to conduct human subjects research. When considering
a request by a financially-interested individual to conduct human
subjects research, the circumstances that the COI committee should
evaluate include the nature of the research, the magnitude of the
interest and the degree to which it is related to the research, the
extent to which the interest could be directly and substantially
affected by the research, and the degree of risk to the human subjects
involved that is inherent in the research protocol. The committee
should also consider the extent to which the interest is amenable
to effective oversight and management.
Conducting Research means, with respect to a research
protocol, designing research, directing research or serving as the
principal investigator, enrolling research subjects (including obtaining
subjects' informed consent) or making decisions related to eligibility
to participate in research, analyzing or reporting research data,
or submitting manuscripts concerning the research for publication.
Covered Individual includes any faculty (fully-,
partially-, or non-salaried) or faculty agent, staff, student, fellow,
trainee, or administrator who, under the aegis of the institution
or pursuant to the review and approval of the institution's IRB,
conducts research involving human subjects.
Disclosure means a release of relevant information
about significant financial interests in human subjects research
to parties outside the institution's COI review and management processes
(e.g., to research subjects or journal editors).
Financially Interested Company means a commercial
entity with financial interests that would reasonably appear to be
affected by the conduct or outcome of the research.13 This term includes
companies that compete with the sponsor of the research or the manufacturer
of the investigational product, if the covered individual actually
knows that the financial interests of such a company would reasonably
appear to be affected by the research. This term also includes any
entity acting as the agent of a financially interested company (e.g.,
a contract research organization).
Financially Interested Individual means a covered
individual who holds a significant financial interest that would
reasonably appear to be affected by the individual's human subjects
research.
Human Subjects Research includes all research meeting
the definition of "research"
performed with "human subjects" as these terms are defined
in the federal Common Rule (45 C.F.R. Part 46 and 21 C.F.R. Part
56), regardless of the source of research funding or whether the
research is otherwise subject to federal regulation. In the event
that the Common Rule definitions of "human subjects" or "research" are
modified through rulemaking, any such revisions shall apply for the
purposes of this guidance.
Rebuttable Presumption Against Financial Interests in Human
Subjects Research means the institution will presume,
in order to assure that all potentially problematic circumstances
are reviewed, that a financially interested individual may not
conduct the human subjects research in question. This rule is
not intended to be absolute: a financially interested individual
may rebut the presumption by demonstrating facts that, in the
opinion of the COI committee, constitute compelling circumstances.
The individual would then be allowed to conduct the research
under conditions specified by the COI committee and approved
by the responsible IRB.
Reporting means the provision of information about
significant financial interests in human subjects research by a covered
individual to responsible institutional officials and to the institutional
COI committee, or the transmission of such information within institutional
channels (e.g., from the COI committee to the IRB).
Responsible Institutional Official means a Dean,
Provost, CEO, or other institutional official who is responsible
for the oversight of research programs within the institution.
Responsible IRB is the institutional review board
(or boards) with jurisdiction over the research as specified in the
multiple projects assurance (MPA) (or the federalwide assurance (FWA))
that the institution has provided to the U.S. Department of Health
and Human Services, or as otherwise established under DHHS or FDA
regulation or policy.
Significant Financial Interests in Research include
the following interests of the covered individual (and his or her
spouse and dependent children), or of any foundation or entity controlled
or directed by the individual or his or her spouse:
-
Consulting fees, honoraria (including honoraria from a third party,
if the original source is a financially interested company),
gifts or other emoluments, or "in kind" compensation
from a financially interested company (or entitlement to the
same), whether for consulting, lecturing, travel, service on
an advisory board, or for any other purpose not directly related
to the reasonable costs of conducting the research (as specified
in the research agreement), that in the aggregate have in the
prior calendar year exceeded the de minimis amount established
in PHS regulation (presently $10,000), or are expected to exceed
that amount in the next twelve months.
-
Equity interests, including stock options, of any amount in a non-publicly-traded
financially interested company (or entitlement to the same).
-
Equity interests (or entitlement to the same) in a publicly-traded
financially interested company that exceed the defined de minimis
amount (see exceptions below).
-
Royalty income or the right to receive future royalties under a patent
license or copyright, where the research is directly related
to the licensed technology or work.(14)
-
Any non-royalty payments or entitlements to payments in connection
with the research that are not directly related to the reasonable
costs of the research (as specified in the research agreement
between the sponsor and the institution). This includes any bonus
or milestone payments to the investigators in excess of reasonable
costs incurred, whether such payments are received from a financially
interested company or from the institution (note prohibition
in B(11) on milestone payments tied to the achievement of particular
research results).
-
Service as an officer, director, or in any other fiduciary role for
a financially interested company, whether or not remuneration
is received for such service.
Exceptions. Significant financial interests in research do not include
the following:
-
Interests of any amount in publicly traded, diversified mutual funds.
-
Stock in a publicly-traded company that (when valued in reference
to current public prices) meets the de minimis criteria established
in PHS financial disclosure regulations (presently, an interest
that does not exceed $10,000 in value and does not represent
more than a 5% ownership interest in any single entity).
-
Stock options in a publicly-traded company that (when valued using
accepted valuation methods) meet the de minimis criteria established
in PHS financial disclosure regulations (presently, an interest
that does not exceed $10,000 in value and does not represent
more than a 5% ownership interest in any single entity).
-
Payments to the institution, or via the institution to the individual,
that are directly related to reasonable costs incurred in the
conduct of research as specified in the research agreement(s)
between the sponsor and the institution.
-
Salary and other payments for services from the institution.
B. Scope and Substance of Policy
-
Conflict of Interest (COI) Official and Committee. Federal
regulations require PHS-funded institutions to appoint a COI
official to review financial interests in PHS-sponsored research.15
The Task Force recommends that institutions also establish a
standing COI committee.16 COI committee membership should include
individuals who conduct human subjects research at the institution,
as well as the institution's COI official and other officials
experienced in the oversight of conflicts of interest and familiar
with applicable laws and regulations. A liaison to the IRB is
recommended. Institutions might also consider means of involving
community or patient representatives in the COI oversight process.
Institutions should ensure that the COI committee responsibilities
include the following:
-
Review of any request by a financially interested individual
to rebut the presumption that he or she may not conduct human
subjects research.
-
Documentation of the committee's findings and the bases for
any recommendation to permit or to recommend against permitting
a financially interested individual to conduct human subjects
research. In either case the COI committee should prepare
a summary report describing the nature and amount of the
financial interest and the committee's recommendations. This
summary report should be made available to the IRB. When
the COI committee has recommended that a financially interested
individual be permitted to conduct human subjects research
and the IRB has approved the research and the individual's
participation, the summary report should be provided to research
subjects or the public, upon request.
-
Management and oversight when a financially interested individual
is permitted to conduct human subjects research. As a first
principle, the COI committee should encourage the financially
interested individual to minimize the potential for conflict
of interest by reducing or eliminating the interest or the
individual's direct involvement in the research. The COI
committee should specify the monitoring procedures or other
conditions to be imposed when a financially interested individual
will be permitted to conduct human subjects research.
-
Communication to the IRB, and to responsible institutional
officials, of summary information about the nature and amount
of any significant financial interest in human subjects research,
along with the committee's findings and recommendations concerning
requests by financially interested individuals to conduct
such research.
-
Process. Every institution should adopt mechanisms
that ensure the following:
-
The financial reports of covered individuals are collected
and maintained in a format that is readily accessible to
the COI committee and responsible institutional officials;
-
The responsible IRB and responsible institutional officials
are alerted whenever a financially interested individual
proposes to conduct human subjects research;
-
Prior to the IRB's final approval (whether initial or continuing
approval) of human subjects research, the COI committee has
informed the IRB and responsible institutional officials
of any significant financial interests held by financially
interested individuals who will conduct the research, as
well as the COI committee's findings and recommendations
concerning the same;
-
Financially interested individuals are provided an avenue
for appealing decisions of the COI committee; and
-
When financially interested individuals will be permitted
to conduct human subjects research, the financial interests
in question are disclosed in accordance with the institution's
COI policies.
-
Written Policy. Every institution engaged in
human subjects research should have a written policy on financial
interests in such research. This policy should define all key
terms clearly and should detail substantive prohibitions and
restrictions, as well as the procedures for reporting financial
interests, reviewing financial reports, disclosing reported information,
implementing the policy, appealing decisions concerning the policy,
and sanctioning non-compliance with the policy The written policy
should explain the criteria that the COI committee will apply
when reviewing a request by a financially interested individual
to rebut the presumption that he or she may not conduct human
subjects research. The policy and related information should
be readily accessible to covered individuals and to the public;
in addition to conventional means of communication, the policy
should be placed on the institution's website, if one exists.
-
Rebuttable Presumption that Financially Interested Individuals
May Not Conduct Human Subjects Research. The policy
should establish the presumption that, in the absence of
compelling circumstances, a financially interested individual
may not conduct human subjects research. This presumption
should be rebuttable when compelling circumstances exist.
-
The policy should allow the COI committee, after it reviews
the relevant facts and circumstances and documents the compelling
circumstances, to recommend that a financially interested
individual be permitted to conduct the research, and to make
recommendations for appropriate monitoring and oversight.
-
A summary report indicating the nature and amount of the
financial interest and COI committee recommendations should
be transmitted to the responsible IRB and to responsible
institutional officials.
-
Monitoring. The policy should specify procedures
for internal, and, when deemed necessary, external monitoring
when a financially interested individual is permitted to conduct
human subjects research.
-
Reporting by Covered Individuals. The policy
should require covered individuals to report to the institution
all significant financial interests that would reasonably appear
to be affected by the individual's current or anticipated human
subjects research. In making such reports, each covered individual
should be required to declare explicitly whether he or she does
or does not have such financial interests; the failure to report
is unacceptable.
-
Reports should be required at least annually, with prompt
updating whenever there is an interim, material change in
significant financial interests.
-
Some institutions currently require a researcher to indicate
on the institutional face sheet accompanying the research
proposal whether the researcher holds any significant financial
interest in the research. All institutions should consider
adopting this practice for research involving human subjects.
-
Reporting to Supervisor. When the COI committee
determines that a financially interested individual should be
permitted to conduct human subjects research, a copy of the committee's
summary report describing the financial interest and any conditions
to be imposed upon the research should be provided to the head
of the unit (e.g., department chair) in which the covered individual
resides administratively, and to the responsible dean, provost,
CEO, or other official who has institutional responsibility for
monitoring the activities of the covered individual.
-
Investigator Certification to IRB. When a research
proposal is submitted to the IRB for review, including continuing
review (where applicable), each covered individual who will conduct
the research should attest in writing to the IRB that financial
report information on file for that individual is current and
will be updated promptly to reflect relevant changes in financial
circumstances. The IRB should forward any information that it
receives concerning a significant financial interest in human
subjects research to the COI committee.
-
COI Committee Review of Significant Financial Interest
Created by Licensing Agreements. Prior to executing
a technology licensing agreement, the Office of Technology
Licensing must determine whether the agreement would create
a significant individual financial interest in ongoing or
proposed human subjects research, and if so, inform the institution's
COI committee of the proposed terms of the agreement. The
COI committee should either approve the conduct of the research
by the individual who will hold the financial interest, subject
to an appropriate monitoring plan, or determine that the
individual may not conduct the research if he or she wishes
to retain the financial interest.
-
Disclosure of Significant Financial Interests.
-
The policy should require disclosure of the existence
of significant financial interests in human subjects
research as follows: to state and federal officials,
as required by statute or regulation; to research funders
or sponsors; to the editors of any publication to which
a covered individual submits a manuscript concerning
the research;(17) and in any substantive
public communication of the research results, whether
oral or written.
-
If an institution participating in a multi-center trial
has judged a financiallyinterested individual eligible
to conduct human subjects research at its site, that
fact should be made known to the Principal Investigator
or Sponsor, and to the IRBs of other institutions participating
in the trial.
-
Research consent forms should, as a matter of institution's
COI policy, disclose the existence of any significant
financial interest held by a covered individual who is
conducting the human subjects research. The precise wording
of disclosure in the consent form should be determined
by the IRB, but should include an explanation of the
fact that the financial interest in question has been
reviewed by the COI committee, approved subject to committee
oversight, and determined by both the committee and the
IRB not to pose any additional significant risk to the
welfare of research subjects or the integrity of the
research.
-
If the institution's COI committee has authorized a financially
interested individual to conduct human subjects research,
the disclosure statement in the research consent form
should indicate that additional information (to include
the COI summary report describing the nature and amount
of the financial interest) will be provided to research
subjects upon request.(18)
-
Prohibition on Payments for Results. The policy
should prohibit payments from the institution or the sponsor
to a covered individual, if such payments are conditioned upon
a particular research result or are tied to successful research
outcomes. Payments for subject enrollment or for referral of
patients to research studies should be permitted only to the
extent that such payments:
-
Are reasonably related to costs incurred, as specified in
the research agreement between the sponsor and the institution;
-
Reflect the fair market value of services performed; and
-
Are commensurate with the efforts of the individual(s) performing
the research.
-
Affirmation of Institutional Policies on Intellectual
Property and Publication Rights. The COI policy
should affirm an investigator's accountability for the integrity
of any publication that bears his or her name. The policy
should also affirm the right of a principal investigator
to receive, analyze, and interpret all data generated in
the research, and to publish the results, independent of
the outcome of the research. Institutions should not enter,
nor permit a covered individual to enter, research agreements
that permit a sponsor or other financially interested company
to require more than a reasonable period of pre-publication
review,(19) or that interfere with an investigator's
access to the data or ability to analyze the data independently.(20)
-
Protection of Students and Trainees. Commercially
sponsored research may give rise to financial incentives that
conflict with a supervising researcher's responsibility to foster
the academic development of students and trainees. Agreements
with sponsors or financially interested companies that place
restrictions on the activities of students or trainees or that
bind students or trainees to non-disclosure provisions should
ordinarily be prohibited. When deemed unavoidable, such agreements
should be subjected to close scrutiny by the responsible university
official and the institution's COI committee, and should be fully
disclosed to all students and trainees prior to their involvement
in the research. Under no circumstance should a student or trainee
be permitted to participate in research if the terms and conditions
of participation would prevent him or her from meeting applicable
institutional degree requirements (e.g., completion and public
defense of a thesis or dissertation). The institution's policy
on financial interests in research should reaffirm, or explicitly
cross-reference, the relevant institutional documents that address
these matters.
-
Legal Obligations. The policy documents should
alert covered individuals to all state and federal requirements
applicable to financial interests in research, including state
financial disclosure laws (if applicable), state licensure and
professional conduct standards relevant to conflict of interest,
federal laws relative to "finders fees" for research
subjects, and SEC prohibitions against insider trading. The policy
should also direct investigators who conduct FDA-regulated research
to familiarize them selves with FDA policies concerning promotional
activities.
-
Sanctions. The policy should define the range
of possible sanctions for noncompliance, up to and including
dismissal. The policy should reference the procedures to be followed
for sanctioning violations and for appealing adverse determinations.
C. Policy Implementation
-
Information Flow. Institutions should implement
policies, procedures, and systems that will facilitate prompt
reporting of significant financial interests to the institution
and enable the timely flow of accurate and complete information
to and from the COI committee, the responsible IRB(s), the institutional
Office of Technology Licensing, and responsible institutional
officials.
-
Electronic Reporting Form. To enhance the efficiency
of the reporting process, institutions should consider adopting
an electronic disclosure form and permitting covered individuals
to make and update financial reports on-line and in real time.
-
Resources. Implementation of a comprehensive,
effective COI policy may require institutions to devote new resources
to their compliance effort. Institutions should ensure that adequate
resources and personnel are allocated to support effective, credible
oversight of financial interests in human subjects research.
-
Written Acknowledgement Required. Institutions
should require that all individuals who conduct human subjects
research read and acknowledge in writing that they understand
and agree to comply with the institution's COI policies.
-
Education and Training. Institutions should
adopt mechanisms for disseminating COI policies to all faculty,
staff, students, and trainees, and for providing appropriate
education and training in these policies.
-
Compliance Monitoring. Institutions should
regularly assess compliance with COI policies through the use
of internal audit mechanisms and other appropriate self-evaluation
strategies.
-
Accreditation. The effectiveness of COI policies
and a formal assessment of institution-wide compliance with these
policies should be examined as an element of any accreditation
process for the institution's human subjects protection program.
Epilogue
During the past two decades, remarkable advancements in biomedical research
and the stimulus of the Bayh-Dole Act have vastly increased the breadth
and depth of engagement of academic medicine with industry. The growth
of the biotechnology industry is a celebrated accomplishment of the U.S.
economy during the second half of the 20th century, and together with
the information technology industry has spurred public perception of
research universities as engines of economic development and social betterment.
But at the same time, the public insists that universities remain unblemished
by financial selfinterest and continue to serve society as trusted and
impartial arbiters of knowledge. This"conflict of public expectations" is
nowhere more intense than in academic medicine and in research involving
human subjects, where the steadily deepening engagement of clinical research
with the world of commerce is seen by many influential observers as threatening
both research integrity and the welfare of research participants.
The Task Force acknowledges the enormous benefits that have inured to
the public from the commercial development of medical inventions made
in academic medical centers and anticipates that the relationships of
these centers with industry will only continue to deepen in an era in
which terms like genomics, proteomics, and physiomics are becoming commonplace.
But the Task Force also recognizes that the public's extraordinary support
of academic biomedical research will remain critically dependent upon
public confidence and trust that are especially vulnerable in research
involving human subjects. This is the reality, and it must be appreciated
by industry as much as by academe if their future interactions are to
thrive.
This first report from the AAMC Task Force on Financial Conflicts of
Interest in Clinical Research deals with individual financial interests.
It intends to raise the standards of institutional oversight and management
of financial conflicts of interest, and make them more uniform across
academic medicine. The report respects institutional autonomy: the recommended
policy and guidance provide a floor that permits institutions to adopt
even more stringent provisions if they wish. The report eschews a "one
size fits all approach:" it recognizes that each case of potential
financial conflict of interest in research must be closely examined on
its merits, and must respect the particular institutional, individual,
and scientific circumstances that may attend it.
The Task Force does not believe, and does not intend, that adoption of
the recommended policy and guidelines by the academic medical community
should interfere with healthy academic- industry relationships or with
the continued robust flow of academic biomedical invention into beneficial
products. The Task Force does believe that these policies and guidance
can help to ensure that the relationships remain principled, protective
of research subjects and scientific integrity, and capable of withstanding
intense public scrutiny.
-
Cohen, J.J. Trust us to make a difference: Ensuring
public confidence in the integrity of clinical research. Acad. Med.
2001; 76:209-214.
-
The Task Force acknowledges the prior efforts of
a group of leaders from academic medicine who met in November of
2000 for a consensus conference moderated by Dr. Joseph B. Martin,
Dean of the Faculty of Medicine at Harvard Medical School. The Consensus
Statement produced by this group contains a number of the recommendations
endorsed in the AAMC's 2001 Guidelines.
-
D. Korn, Conflicts of interest in biomedical research.
JAMA 2000; 284: 2234-2237.
-
"Rights to Inventions Made by Nonprofit Organizations
and Small Business Firms," codified at 37 CFR Part 401.
-
University-Industry Research Collaboration Initiative
of the Business-Higher Education Forum, Working Together, Creating
Knowledge: The University-Industry Research Collaboration Initiative
(June 2001).
-
The PHS regulations are found at 42 C.F.R. Subpart
F, the FDA regulations at 21 C.F.R. Parts 54, 312, 314, 320, 330,
601, 807, 812, 814, and 860. The National Science Foundation has
adopted a financial disclosure policy that is similar to that of
the PHS. 60 Fed. Reg. 132, 35809 (July 11, 1995).
-
This includes all institutions seeking research grants
from the National Institutes of Health, a PHS agency.
-
The PHS regulations define a "significant financial
interest" as "anything of monetary value" except for
the following: salary, royalties, or other remuneration from the
institution; ownership interests in institutional applicants for
SBIR grants; income from public or non-profit sources for lecturing,
teaching, or serving on advisory boards or review panels; equity
interests that do not exceed $10,000 or 5% ownership of a single
entity; or other payments that in the aggregate are not expected
to exceed $10,000 during the next 12 months. 42 C.F.R. §50.603.
-
The regulations state that a conflict of interest
exists "when the designated official(s) reasonably determines
that a Significant Financial Interest could directly and significantly
affect the design, conduct, or reporting of the PHS-funded research." 42
C.F.R. § 50.605.
-
The exception would occur when an academic institution
holds the investigational new drug (IND) application or investigational
device exemption (IDE) for the product studied in the research. FDA
has stated that in this circumstance, the IND or IDE holder must
collect financial disclosure information for the benefit of the party
who will eventually file the marketing application. Food and Drug
Administration, Guidance: Financial Disclosure by Clinical Investigators
(March 20, 2001)
<available at http://www.fda.gov/oc/guidance/financialdis.html>.
-
The Task Force recognizes that institutional practices
may differ in their allocation of responsibilities for COI reviews
between designated committees and officials, and that in some institutions
an IRB may perform a substantive review of financial conflicts of
interest. The Task Force strongly recommends that the COI process
be separate from the IRB, although with clear channels of communication
between them. In all cases the same rebuttable presumption against
the financial interest should apply, and the financially interested
individual should be given the opportunity to demonstrate "compelling
circumstances" to the cognizant authority.
-
To illustrate, the inventor of an implantable medical
device, who under the Bayh-Dole Act might receive royalty income,
and who might also be compensated by the device manufacturer for
training other physicians to use the device, may also be the individual
who is best qualified to implant the device in human subjects safely
under experimental conditions. The COI committee might, at its discretion,
agree to permit this financially-interested inventor to participate
in a clinical study of the device at the institution, subject to
management conditions crafted to minimize the potential conflict
of interest. These conditions could include, in addition to full
disclosure of the interest (to research subjects and others as described
in this guidance), requirements that informed consent be obtained
by a clinician with no financial ties to the research, and that the
research be overseen by a monitoring board.
-
Under the standard articulated in the PHS regulations,
institutions must solicit and review information about investigators'
significant financial interests in any entity "whose financial
interests would reasonably appear to be affected by the [PHS-funded]
research." 42 C.F.R. §50.604(c)(1)(ii).
-
When evaluating future royalty interests, in addition
to the factors listed in the definition of compelling circumstances,
the COI committee might consider the anticipated time interval between
the research and marketing approval of the investigational product.
-
42 C.F.R. § 50.604(b).
-
References in this guidance to the "institution's
COI committee" apply to the institution's COI official in the
event that an institution chooses not to establish a standing COI
committee.
-
Disclosure to journal editors should take the form
of an affirmative statement on behalf of each covered individual
who conducted the research that he or she either does or does not
hold significant financial interests in the research. This requirement
is consistent with the recent uniform disclosure requirements published
by a group of editors of major medical journals. F. Davidoff, C.
D. DeAngelis, J.M. Drazen, et al. Sponsorship, authorship, and accountability.
JAMA; 286;10:1232-1234.
-
The National Human Research Protections Advisory
Commission has recommended this approach to the disclosure of researchers'
financial interests to research subjects. Letter from Mary Faith
Marshall, Ph.D., Chair, NHRPAC, to Assistant Surgeon General/Acting
Principal Deputy Assistant Secretary for Health Arthur J. Lawrence,
Ph.D., dated August 23, 2001.
-
For sponsored research, a reasonable period of
review would be no more than 90 days, unless both parties agree that
extenuating circumstances require an extension of time. The Task
Force notes that for research involving NIH-funded research tools,
the NIH has stated that it would consider a 30-60 day review period
to be reasonable. National Institutes of Health, Principles and Guidelines
for Recipients of NIH Research Grants and Contract on Obtaining and
Disseminating Biomedical Research Resources, 64 Fed. Reg. 246, 72090
(Dec. 23, 1999).
-
When research involves more than one institution
and numerous investigators (e.g., a multi-center trial), the investigators
may delegate primary authorship to a subset who will take responsibility
for the publication.