DIRECTING AND MANAGING CONFLICTS OF INTEREST IN SPONSORED RESEARCH
October 30-November 1, 2002
Jeanine Arden Ornt, Esq.
General Counsel to the University of Rochester
University of Rochester
Rochester, New York
PART TWO: APPLICABLE LAW AND GOVERNMENTAL REGULATIONS
I)
BACKGROUND
A) The federal governmental funding agencies (HHS (PHS, NIH); NSF) have imposed upon
applicants/grantees the responsibility to promote objectivity in research for which funding is
sought.
B) Following a Congressional Inquiry in the 1980’s, Congress mandated the National Institutes of
Health (“NIH”) to regulate financial conflicts of interests. The initial focus was on the
researchers’ conflicts, but as we will see, the concept has recently evolved to include both the
university and the researchers’ potential conflicts.
C) The NIH responded through its NIH Guide (January 1989):
1) Solicitation for Comments regarding Extramural Researchers’ Financial Conflicts of Interest.
This solicitation focused on circumstances that might affect objectivity or appear to affect
objectivity including circumstances where the research could either benefit, or be perceived
to benefit, the financial interests of the researcher or his/her immediate family.
2) There was general agreement that institutions receiving NIH funds needed to adopt conflicts
of interest policies to identify and manage conflicts of interest. Again, the initial focus was
on the investigators’, rather than the institutions’, conflicts.
3) Regulations
a. In September 1989, the NIH issued the first draft of regulations. The underlying rationale
of the first regulations, finally published in 1995, was to establish standards and
procedures to be followed by PHS-funded institutions to ensure that the design, conduct
or reporting of such research would not be biased by any conflicting financial interest of
those investigators responsible for the research.
b. In July 1995, National Science Foundation (“NSF”) “Investigator Financial Disclosure
Policy” (now changed to “Conflicts of Interest Policies”) & Public Health Service
(“PHS”) published final rules (PHS: http://grants2.nih.gov/grants/guide/noticefiles/not95-179.html and NSF: http://www.nsf.gov/bfa/cpo/gpm95/ch5.htm#ch5-6) which
in large part, parallel the NIH regulations.
c. The regulations impact all extramural research and development funded by the PHS or
NSF respectively. These regulations establish standards and procedures to be followed by
institutions that apply for research funding from the PHS (or NSF) to ensure that the
design, conduct, or reporting of research funded under grants, cooperative agreements or
contracts will not be biased by any conflicting financial interest of those investigators
responsible in any way for the research.
d. The FDA has had regulations requiring financial disclosure for clinical investigators
since 1998.
D) Scope: All Research, Not Limited to Clinical Research
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1) As explained in the preamble to the Notice to Proposed Rule Making (“NPRM”) for the PHS
regulations, the government concluded that experience has shown that financial conflicts of
interest can arise in all types of research. While the government recognized that the risk of
conflicts of interest will be higher in clinical research than in other types of research, the
government concluded that the risk in all types of research was sufficiently likely and,
therefore, that financial interests should be disclosed and reviewed for all research.
2) However, it is worth noting that the NIH regulations do not apply to SBIR and STTR Phase I
applications.
II)
NIH REGULATIONS
A) Purpose: Protect Objectivity in Research
1) Many states also regulate conflicts of interest but for purposes of today’s discussion, I am
focusing exclusively on the federal regulations.
2) The NIH regulations require that “[e]ach Institution must: [m]aintain an appropriate written,
enforced policy on Conflicts of Interest…and inform each Investigator of that policy, the
Investigator’s reporting responsibilities and of these regulations” (42 CFR 50.604(a)). In
summary, the regulations require that each Investigator disclose all “significant financial
interests”:
a. that would reasonably appear to be affected by the PHS-funded research; or
b. in entities whose financial interest would reasonably appear to be affected by the
research. (Worm: Disclosure Cartoon)
B) Key Terms for Purposes of Understanding NIH Regulations:
Note: Institutions may adopt more rigorous standards than the federal definition, but not
less vigorous. (Devil: Conscience Cartoon)
1) Significant Financial Interest
anything of monetary value, including but not limited to, salary or other payments for
services (consulting fees or honoraria); equity interests (stocks, stock options or other
ownership interests); and intellectual property rights (patents, copyrights and royalties from
such rights). The term does not include:
 salary, royalties, or other remuneration from the applicant institution;
 any ownership interests in the institution, if the institution is an applicant under the
SBIR or STTR Programs, Phase I;
 income from seminars, lectures, or teaching engagements sponsored by public or
nonprofit entities;
 income from service on advisory committees or review panels for public or nonprofit
entities;
 an equity interest that when aggregated for the Investigator and the Investigator's
spouse and dependent children, meets both of the following tests: does not exceed
$10,000 in value as determined through reference to public prices or other reasonable
measures of fair market value, and does not represent more than a five percent
ownership interest in any single entity; or
 salary, royalties or other payments that when aggregated for the Investigator and the
Investigator's spouse and dependent children over the next twelve months, are not
expected to exceed $10,000.
2) Investigator
Principal investigator and any other person who is responsible for the design, conduct, or
reporting of research funded or proposed for funding by PHS.
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3) Research
Systematic investigation designed to develop or contribute to generalizable knowledge
relating broadly to public health, including behavioral and social-sciences research. The
terms encompass basic and applied research and product development. The term includes
any activity for which research funding is available from a PHS Awarding Component
through a grant or cooperative agreement, whether authorized under the PHS Act or other
statutory authority.
C) Institutional Conflicts of Interest are not addressed in the current regulations. The government
has recognized the need to carefully consider that issue through a separate process and through a
separate rule (which is anticipated within the next 1-2 years).
D) Fundamental Elements: Disclosure, Management, Reporting, Sanctions
1) Disclosure
Under the NIH regulations, an institution’s policy must require all investigators with a
substantial research responsibility to file a financial disclosure form with the institution;
this disclosure form identifies any significant financial interests of the investigator, his/her
spouse and dependent children, that would reasonably appear to be affected by the
proposed research or in any entities that would reasonably appear to be affected by the
research. It is the investigator’s responsibility to consider ALL significant financial
interests. However, the federal regulations require the investigator to actually disclose only
those which would reasonably appear to be affected by the specific research proposal.
a. Again, an institution may require greater, but not lesser, disclosure than that required by
the federal regulations.
b. Financial Disclosure Form: the Investigators must file either annually or as new
reportable significant financial interests are obtained.
c. While Institutions may choose either of these disclosure update periods, many institutions
opt for the annual reporting because it serves as a reminder to the investigators to assess
prior disclosures, as well as an opportunity for the institutions to review all forms.
Therefore, those institution’s policies require an annual disclosure plus more frequent
than annual disclosures of new significant financial interest determined to exist.
d. The existence of a significant financial interest does not, alone, create a conflict of
interest. Rather, there must be a nexus between the significant financial interest and the
scope of the research to be performed by the investigator(s).
e. Note that institutions are not required to “ensure” that Investigators have disclosed all
significant financial interests, but must “require” all investigators to disclose.
2) Management
In contrast to the first element – disclosure -- which is the responsibility of the individual
investigator, the second element – management -- is the responsibility of the institution.
a. Note: At this time, the management responsibility relates solely to the investigators’
conflicts; the NIH is currently considering how to address the management of
institutional conflicts of interest.
b. The purpose of the institutions’ management responsibilities is to reduce, manage or
eliminate the risk that the conflict of interest poses to the credibility of the research.
These responsibilities may be divided into two main categories: Procedural Management
Responsibilities and Substantive Management Responsibilities.
c. Procedural Management Responsibilities
(i)
Acquire and Maintain Data. The sponsoring institution’s management
responsibilities include the following:
(1) Maintaining a written policy on Conflicts of Interest, consistent with the NIH
regulations;
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Informing each investigator of the policy, the investigator’s reporting
responsibilities, and the NIH regulations;
(3) Obtaining assurances from – or otherwise assuring compliance by – all
subgrantees, contractor or collaborators through which the institution carries out
PHS-funded research;
(4) Designating institutional officials to obtain and review all financial disclosure
statements from all PHS-funded Investigators; in order to do so, the institution
must require, by the time an application is submitted to PHS, each Investigator
to have submitted a listing of all Significant Financial Interests (with the
“nexus” described above);
(5) Providing guidelines for the designated institutional officials to identify
conflicts of interest;
(6) Maintaining records, of all financial disclosures and all actions taken by the
institution regarding each conflict of interest, for at least three years from the
date of submission of the final expenditure report (or other dates specified in 45
CFR 74.53(b));
(7) Establishing adequate enforcement mechanisms and providing for sanctions;
(8) Certifying in each application for PHS funding that the institution has a written
and enforced administrative process to identify and manage conflicts of interest;
(9) Reporting, to the PHS “Awarding Component” (prior to the institution’s
expenditure of any fund under the award); any conflicting interest identified by
the institution and assuring that the interest has been managed, reduced or
eliminated;
a. this report need NOT describe the nature of the conflict of interest or any
other details
b. if the institution identifies any conflict of interest after the initial report, a
subsequent report must be made within sixty (60) days of identification;
(10) Making available to HHS, upon request, all information relating to conflicts of
interest.
d. Substantive Management Responsibilities:
(i)
Assess and Manage. In addition to complying with the above “Processes,” the
institutions are required to do the following in order to manage, reduce or eliminate
conflicts of interest:
(1) Review all financial disclosure forms and make a determination whether a
conflict of interest exists. (Collecting the forms is challenging enough; finding the
time and expertise needed to actually review and make determinations from the
forms is very difficult.)
(a) Recall the NIH definition of conflict of interest: 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 CFR Part 50.605(2)).
(2) Determine who is an “Investigator.” The NIH determined that “based on their
knowledge of the specific institutions, the institutions are in the best position to
determine who is responsible for the design, conduct or reporting of the research
to such a degree that his/her financial interest should be reviewed.” NIH Guide,
Vol. 24, No. 25, July 14, 1995 (¶ 3 regarding 50.603 Definitions).
(3) Determine what actions should be taken by the institution in order to achieve the
desired purpose: reduction, management, or elimination of the conflict of interest.
(2)
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The regulations cite the following examples of actions an institution may take,
recognizing that these are not all-inclusive:
 Public disclosure of significant financial interests (in publications,
presentations, to students and other research staff);
 Monitoring of research by independent reviewers;
 Modification of the research plan;
 Disqualification from participation in all or a portion of the research funded by
the PHS;
 Divestiture of significant financial interests; or
 Severance of relationships that create actual or potential conflicts.
The NSF regulations cite other management examples including:
 Segregation of graduate students from any conflict of interest situation of the
student’s mentor,
 Requiring regular reporting (more often than annually) to the Dean, Conflict of
Interest Committee or other institutional authority,
 Identification of “Overseer” or Oversight Committee who/which has the
responsibility to oversee the research and investigator on a regular basis and to
report any issues or concerns to institutional authority,
 Modification of research plan,
 Divestiture (temporarily through a trust or permanent) of the investigator’s
equity interest,
 Appointment of an alternative investigator (with sponsoring entity’s approval)
who may act independently of the conflicted investigator,
 Disqualification from participation in all or part of the federally-funded
research,
 Severance of the relationship that creates the conflict of interest situation,
 Elimination of the conflict of interest: this is an extreme measure and generally
considered only when other management options are deemed ineffective. This
issue arises most frequently in the context of clinical and other human subject
research. If faced with prohibition, the investigator/faculty member then has
the difficult decision of foregoing a business opportunity or leaving his
position at the institution.
(4) Promptly notify the PHS Awarding Component of any corrective action the
institution is considering for an investigator who failed to comply with the
conflict of interest policy, or who has biased the design, conduct or reporting of
the research. The PHS will consider the institution’s corrective action, take
appropriate action or refer the matter to the Institution for further action.
(5) Submit for review by HHS, upon request, the institutional procedures and actions
regarding conflicts of interest, including all pertinent records:
(a) HHS “to extent permitted by law” will maintain confidentiality of all records
of financial interest.
(b) On basis of this review, HHS may decide that a particular conflict of interest
will so bias the research that either further action is needed or funding must be
suspended.
(6) Require the Investigator to disclose the conflict of interest in each public
presentation of the research results, in all cases wherein the HHS determines that
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clinical research has been designed, conducted, or reported by an Investigator
with a conflict of interest that was not disclosed or managed appropriately.
(7) Exceptions: If management restrictions would be ineffective or inequitable, and
the potential negative impact of prohibiting the research due to a significant
financial interest is outweighed by interests of scientific progress, technology
transfer, or public health and welfare, then the research may be allowed to go
forward without imposing such conditions or restrictions.
3) Reporting
If a Conflict of Interest is determined to exist after the submission of the application, the
institution must (prior to any expenditure of awarded funds):
a. Report the existence of such conflicting interests to the Public Health Service Awarding
Component (but not the nature of the interest or other details);
b. Assure that the interest has been managed, reduced or eliminated in accordance with the
regulations (to the extent verifiable);
c. Act to protect PHS-funded research from bias due to the conflict of interest;
d. For any interest that the Institution identifies as conflicting subsequent to the Institution’s
initial report under the award, make the report and describe how the conflicting interest is
being managed, reduced, or eliminated, at least on an interim basis, within sixty days of
that identification.
e. If the conflict of interest has biased the design, conduct, or reporting of the PHS-funded
research, the Institution must promptly notify the PHS Awarding Component of the
corrective action taken or to be taken. The PHS Awarding Component will consider the
situation and, as necessary, take appropriate action, or refer the matter to the Institution
for further action, which may include directions to the Institution on how to maintain
appropriate objectivity in the funded project.
f. Note: The requirement to report to PHS is not consistent with the NSF, which requires
reporting only if the institution is unable to satisfactorily manage a Conflict of Interest.
The institution must keep the NSF Office of the General Counsel informed if the
institution is unable to satisfactorily manage a Conflict of Interest.
g. Maintain records of all financial disclosures and of all actions taken to resolve conflicts
of interest for at least three years beyond the termination or completion of the grant to
which they relate, or until the resolution of any governmental action involving those
records, whichever is longer.
4) Sanctions
a. Access to records: The federal regulations (45 CFR 74.53) provide the government with
the authority to have access to all records pertaining to grants, which would include the
records relating to financial conflicts of interest of investigators carrying out the funded
research. The exception is that the funding agencies will require the submission of
records or retain copies from audits at the institution rarely, but when that occurs the
records will be maintained confidentially “to the extent possible.”
b. Suspension: such suspension action would be necessary to protect Federal funds only in
unusual situations. The PHS Awarding Component may determine that suspension of
funding under 45 CFR 74.62 is necessary until the matter is resolved.
5) Final Note
On December 1, 2000, the Public Health Service announced a new "PHS Policy on
Instruction in the Responsible Conduct of Research (RCR)" which requires institutions to
establish an education program on certain core areas of instruction for responsible research
(including conflict of interest and commitment) for research staff at the institution who have
direct and substantive involvement in proposing, performing, reviewing, or reporting
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research, or who receive research training, supported by PHS funds or who otherwise work
on the PHS-supported research project even if the individual does not receive PHS support.
The research institution may make reasonable determinations regarding which research staff
fall within this definition. For more information on the RCR policy, including the full text
and commonly asked questions and answers, see the ORI website http://ori.hhs.gov under
"news."
III)
RECENT FOCUS ON HUMAN SUBJECT RESEARCH AND THE RISKS THAT
CONFLICTS OF INTEREST MAY POSE
1) University of Pennsylvania gene therapy death of 18 year-old boy, Jesse Gelsinger
a. The principal investigator for this study reportedly had a financial interest in the company
sponsoring the study. “The U.S. Food and Drug Administration has asserted that
Gelsinger, who died just days after receiving the first dose of a genetically engineered
virus meant to combat his hereditary liver disease, had been ineligible to participate in the
trial. The FDA also contended the researchers failed to notify the agency of previous,
serious adverse effects of the treatment in other volunteers.”
http://www.stanford.edu/dept/news/report/news/february21/policies-221.html
2) Genetically Engineered Food
a. “When expert panels are convened to direct government policy, their recommendations
may appear to be biased if the researchers have financial or organizational ties to
industries that may benefit from a change in the rules. … a recent report from the
National Academies indicating that genetically engineered food is safe to eat has been
controversial because many of its panel members had ties to biotechnology companies.”
http://www.stanford.edu/dept/news/report/news/february21/policies-221.html
3) HHS Secretary Shalala Initiatives: May 2000
http://www.hhs.gov/news/press/2000pres/20000523.html
a. The actions taken by HHS focused on expanding education and training for all clinical
investigators and IRB members and staff; enhancing the informed consent process and
ensuring more vigilant monitoring and oversight; ensuring that researchers understand
and comply with federal conflict of interest regulations; and pursuing efforts to provide
the Food and Drug Administration (FDA) with additional enforcement tools to enhance
its oversight role.
b. Education and Training. HHS will undertake an aggressive effort to improve the
education and training of clinical investigators, IRB members, and associated IRB and
institutional staff. NIH, FDA and the Office for Protection from Research Risks (OPRR)
will work closely together to ensure that all clinical investigators, research administrators,
IRB members and IRB staff receive appropriate research bioethics training and human
subjects research training. Such training will be a requirement of all clinical investigators
receiving NIH funds and will be a condition of the NIH grant award process and of the
OPRR assurance process.
c. Informed Consent. NIH and FDA will issue specific guidance on informed consent,
clarifying that research institutions and sponsors are expected to audit records for
evidence of compliance with informed consent requirements. For particularly risky or
complex clinical trials, IRBs will be expected to take additional measures, which, for
example, could include third-party observation of the informed consent process. The
guidance will also reassert the obligation of investigators to reconfirm informed consent
of participants upon the occurrence of any significant trial-related event that may affect a
subject's willingness to participate in the trial.
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d. Improved Monitoring. NIH will now require investigators conducting smaller-scale early
clinical trials (Phase I and Phase II) to submit clinical trial monitoring plans to the NIH at
the time of grant application, and will expect investigators to share these plans with IRBs.
The NIH already requires investigators to have such plans and they also require large
scale (Phase III) trials to have Data and Safety Monitoring Boards (DSMBs). For
research on medical products intended to be marketed, FDA will also issue guidelines for
DSMBs that will delineate the relationship between DSMBs and IRBs, and define when
DSMBs should be required, when they should be independent, their responsibilities,
confidentiality issues, operational issues and qualified membership.
e. Conflict of Interest. NIH will issue additional guidance to clarify its regulations regarding
conflict of interest, which will apply to all NIH-funded research. HHS is planning further
discussions to find new ways to manage conflicts of interest so that research subjects are
appropriately informed, and to further ensure that research results are analyzed and
presented objectively. In addition, these public discussions will focus on clarifying and
enhancing the informed consent process. Based on these public forums, NIH and FDA
will work together to develop new policies for the broader biomedical research
community, which will require, for example, that any researcher’s financial interest in a
clinical trial be disclosed to potential participants.
f. Civil Monetary Penalties. HHS will pursue legislation to enable FDA to levy civil
monetary penalties for violations of informed consent and other important research
practices-up to $250,000 per clinical investigator and up to $1 million per research
institution. While FDA can currently issue warning letters or impose regulatory sanctions
that halt research until problems are rectified, financial penalties will give the agency
additional tools to sanction research institutions, sponsors and researchers who do not
follow federal guidelines. As an interim step, NIH, OPRR and FDA will work more
closely together to enforce and target existing penalties.
4) August 2000: HHS Conference on Human Subject Protection and Financial Conflict of
Interest (http://ohrp.osophs.dhhs.gov/coi/8-16.htm#Koski)
a. There was a strong sense that the human research review boards cannot be the sole
implementer of the protections against conflicts of interest.
b. There are certain points in the research process where an unavoidable conflict of interest
is most likely to produce a negative impact:
(i)
The level of the direct interaction between the investigator and the research
subject that the greatest potential for doing harms exists e.g. obtaining informed
consent.
(ii)
During the analysis and interpretation of data, it is important to identify these hot
spots so that there can be focused guidances and policies to assist the IRB on
implementing appropriate provisions to minimize risks and optimize benefits.
c. Conclusion at that meeting: there is the need to be sure that the policies and the
protections are up to the task of meeting the goal of protecting the individual research
subjects and to do so in such a way that the successful process of biomedical research
does not come to a complete halt.
5) January 2001: OHRP Draft Interim Guidance
a. Key Points Made in this Guidance (not yet a regulation):
(i)
HHS is offering a guidance to assist Institutions, Clinical Investigators, and IRB’s
in their deliberations concerning potential and real conflicts of interest, and to
facilitate disclosure, where appropriate, in consent forms. (OHRP Draft Interim
Guidance, January 10, 2001 [following the August 2000 HHS conference on Human
Subject Protection and Financial Conflict of Interest].
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(ii)
Clear demonstration by sponsors, institutions and investigators to potential
subjects that conflicts are being eliminated when possible and effectively managed
when they cannot be eliminated, can help to develop a stronger bond of trust that can
actually facilitate enrollment and the conduct of research.
(iii) A focus on institutional conflicts of interest:
 While institutions clearly need to have policies and procedures for managing
conflicts of interest among their employees, they should not lose sight of the need
to manage their own conflicts of interest as well. Increasingly, academic
institutions and corporate entities are entering into agreements that are mutually
beneficial, and which may also bring the institution's interests into direct conflict
with those of research participants.
 Any financial relationships that the institution has with the commercial sponsor
of a study should be documented and the specific relationships submitted to the
Chair/Staff of the IRB as described above. Items to be identified include: any
equity interest in the commercial sponsor; any “up front” payments to the
Institution beyond those payments directly applicable to carrying out a particular
protocol; any funds given to the Institution (or an entity within the Institution, e.g.
an Institute); any equity ownership in the commercial sponsor that was transferred
to the Institution, including the percentage ownership of any patents related to
articles under study in the protocol; any royalties; any licenses granted to the
commercial sponsor by the Institution; whether or not the Institution stands to
gain financially if the study shows the “article” to be successful for its proposed
use.
(iv)
Clinical Investigators should consider the potential effect that having a financial
relationship of any kind with a commercial sponsor of a study might have on his or
her conduct of a clinical trial or interactions with research subjects. All aspects and
types of relationships need to be considered, including commitments of financial
support unrelated to the study in question, financial incentives, serving as a paid
consultant or speaker on behalf of a commercial sponsor, non-monetary inducements
or rewards to investigators or their family members.
(v)
Any agreements between Investigators and a sponsor should be reviewed by the
Institution’s Conflict of Interest Committee or equivalent body. It is desirable to
avoid conflicts of interest whenever possible. If a potential conflict cannot be
eliminated, the committee’s determination of how the potential conflict is to be
managed/reduced should be shared with the IRB for consideration during its
discussion of the protocol.
(vi)
The IRB Chair should ask the IRB members about whether they have any
potential financial conflict of interest related to any of the protocols that the IRB is
about to consider. The IRB should have clear procedures for recusal of IRB members,
including the Chair, from deliberating/voting on all protocols for which there is a
potential or actual financial conflict of interest. Many IRBs remind their members of
these policies at the outset of each meeting and incorporate this reminder in the
minutes of the meeting. The IRB minutes should also specifically reflect such
recusals as they occur during meetings.
(vii) The IRB Policy and Procedures Manual should contain Institutional/ IRB
Financial Conflict of Interest/financial relationship policies. Additionally, the manual
should contain references to Conflict of Interest medical literature and the HHS
August 2000 conference website (OHRP) where PHS/FDA policies, requirements,
guidelines, and guidance may be found. http://ohrp.osophs.dhhs.gov/coi/index.htm
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(viii) When the Institutional official or Conflict of Interest Committee or equivalent
determines that a Clinical Investigator has a potential conflict of interest that cannot
be eliminated, and must be reduced or managed in some way, IRBs should consider
not only what modifications might need to be made to the protocol or Consent, but
other approaches as appropriate. To assist, the IRB might wish to consider the
answers to the following questions in its deliberations:
(1) Who is the sponsor?
(2) Who designed the clinical trial?
(3) Who will analyze the safety and efficacy data?
(4) Is there a Data Safety Monitoring Board (DSMB)?
(5) What are the financial relationships between the Clinical Investigator and the
commercial sponsor?
(6) Is there any compensation that is affected by the study outcome?
(7) Does the Investigator have any proprietary interests in the product including
patents, trademarks, copyrights, and licensing agreements?
(8) Does the Investigator have equity interest in the company?
(9) Does the Investigator receive significant payments of other sorts? (e.g. grants,
compensation in the form of equipment, retainers for ongoing consultation, and
honoraria)
(10) What are the specific arrangements for payment?
(11) Where does the payment go? To the Institution? To the Investigator?
(12) What is the payment per participant? Are there other arrangements?
(ix)
IRBs should consider the specific mechanisms proposed to minimize the potential
adverse consequences of the conflict in an effort to protect the interests of the
research subjects. In general, if there are any financial conflict of interest issues on
the part of the Clinical Investigator, he or she should not be directly engaged in
aspects of the trial that could be influenced inappropriately by that conflict. These
could include: the design of the trial, monitoring the trial, obtaining the informed
consent, adverse event reporting, or analyzing the data. In all cases, good judgment,
openness of process and reliance upon objective, third party oversight can effectively
minimize the potential for harm to subjects and safeguard the integrity of the
research. IRBs (institutionally based and non-institutionally based) should consider
including in the consent document the source of funding and funding arrangements
for performing the IRB review of that protocol.
(x)
Additional Thoughts:
(1) The Institutional official may wish to distribute copies of letters relating to the
management of significant financial conflict of interest that are submitted to PHS
or FDA Grants Management by the Institution to the IRB, when appropriate.
(2) The Institution should collect and review information from IRB staff, Chair, and
all members on their financial interests with commercial sponsors, at least on an
annual basis. Institutional policies and procedures should include specific
guidance for all of the above regarding potential and actual financial conflicts and
their management.
6) September 2002: NIH convened a meeting to reassess individual and institutional conflicts of
interest. There is the potential for revisions to individual Conflict of Interest regulations and
it is anticipated that Institutional Conflict of Interest regulations will be proposed in the near
future.
7) AAMC Task Force Issues Report on Institutional Conflicts of Interest in Research
http://www.aamc.org/coitf.
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a. September 2002: The AAMC Issued "Protecting Subjects, Preserving Trust, Promoting
Progress II," which proposes a framework for the oversight of institutional financial
conflicts of interest that conduct human subjects research.
b. The Task Force's key recommendation is that institutions separate their financial and
research management functions as cleanly as possible. According to the report, the
welfare of human subjects and the objectivity of the research could be -- or reasonably
appear to be -- compromised whenever an institution holds a significant financial interest
that might be affected by the research outcome. The report further recommends that,
under some circumstances, human subjects research not be conducted at a conflicted
institution, unless compelling circumstances warrant.
8) NSF Regulations: “Conflict of Interest Policies”
a. The NSF regulations are almost identical to those of the NIH. Both have the same
effective date, October 1, 1995. Therefore, I will not repeat the requirements but will
highlight the two significant differences:
(i)
The NSF regulations exempt institutions which employ fifty (50) persons or less; and
(ii)
The requirement to report to PHS is not consistent with the NSF, which requires
reporting only if the institution is unable to satisfactorily manage a conflict of interest.
ALL conflicting interests must be reported to the PHS.
b. It is worth noting that the HHS and NSF have worked collaboratively and continue to
work together to develop common regulations, guidances and a set of questions and
answers that may be found at http://grants2.nih.gov/grants/policy/coifaq.htm.
IV)
IMPLEMENTATION OF A CONFLICT OF INTEREST POLICY AND PROCESS
A) Start with a premise: Conflicts of Interest are neither unusual nor bad – just a fact of life that
requires attention.
B) Pressures to Recognize
1) No other employer allows and encourages its employees to participate in “outside business
activities;”
2) The private sector wants and needs the participation of university researchers, resulting in
conflicts of interest, time and commitment;
3) Economic development objectives stimulate and encourage entrepreneurship on the part of
academicians, but present challenges:
a. Ownership of intellectual property;
b. Risks of equity ownership (by investors or institutions);
4) Engaging in business activities in the academic enterprise blurs the margins of propriety;
5) Academia has not always kept its house in order (e.g., misuse of graduate students, university
property for personal gain);
6) These are major issues with much to gain and even more to lose;
7) A new spotlight mandates that we pay attention.
C) Policy Questions to Answer Before Drafting a Policy
1) How to reconcile various approaches (Note: personalities may drive a result (“bad facts make
bad law”)):
a. strictly prohibitive,
b. completely permissive,
c. general rules with exceptions?
2) How does the institution want to relate to industry?
a. Grantee of sponsored research
b. IRB considerations
c. Consulting policies and intellectual property
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3) Process: What should the process for implementation of the policy include:
a. Should there be a Committee on Conflicts of Interest
(i) Will the Committee be a decision-making body?
(ii) Will the Committee be only an advisory body? If so, advisory to whom?
b. Who will be responsible for determining and monitoring management techniques
designed to manage identified conflicts of interest?
c. How can the institution assure consistency in the application of its Conflict of Interest
Policy:
(i)
Different schools: different decision makers
(ii)
Different circumstance (investigator, amount of money, sponsoring organization)
may be subject to different decisions.
d. Who will provide the education?
(i)
To whom?
(ii)
By whom?
(iii) Necessary updates.
e. How to play “Catch up:” how to address existing conflict of interest situations (so not to
paralyze the institution and its investigators or, by pocket veto, force investigators to
forego opportunities) while attempting to create a whole new set of rules for the future.
(The train has already left the station…)
4) Recommendations for Policy Drafting
a. An “Introduction” or “Purpose” section indicating the intent of the policy is to promote
objectivity in research by establishing standards to ensure there is no reasonable
expectation that the design, conduct, or reporting of research funded under grants or
cooperative agreements will be biased by any conflicting financial interest of an
investigator. (Title 45 CFR Part 50, Subpart F)
b. State an effective date for the policy, including dates for all revisions.
c. Identify a contact point within the institution who investigators and others may contact
for questions and discussion.
d. Specify that the policy applies to investigators participating in PHS/NSF (and any other
included by the institution) research, including subgrantee/contractor/collaborating
Investigators, but excluding applications for Phase I support under the SBIR and Small
Business Technology Transfer (STTR) programs.
e. Define key terms, such as Investigator, PHS Awarding Component, Research, Significant
Financial Interest, and SBIR.
f. Specify the investigator’s reporting responsibilities to the institution (what needs to be
reported and to whom).
g. Identify an institutional official(s) to solicit and review financial disclosure statements
from investigators submitted annually or as new reportable interests are obtained.
h. Provide guidelines and examples for both the investigators and the designated official(s)
to identify conflicting interests.
i. Specify that records of all financial disclosures and all actions taken by the institution
will be maintained for at least three years from the date of submission of the final
expenditures report.
j. Identify the enforcement mechanisms available to the institution and specify the
sanctions where appropriate.
k. Provide a “Reporting” section that specifies what the institution must report:
l. Specify that the institution:
(i)
agrees to make conflict information available, upon request, to HHS;
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(ii)
will, if the investigator has biased the research, promptly notify the awarding
component of the corrective action taken or to be taken.
5) Real Life Statistics Relating to Conflict of Interest Policies
http://grants1.nih.gov/grants/policy/coi/nih_review.htm)
a. The NIH studied over 100 conflicts of interest policies to “develop a broad view of how
these policies are implemented by an array of institutions” and found the following
aspects of policies that would benefit from clarification:
(1) 96 percent did not mention the Small Business Innovation Research (SBIR)
program in the policy document(s);
(2) 86 percent did not define “Research;”
(3) 52 percent did not identify the applicable PHS regulation;
(4) 47 percent did not address “records management;”
(5) 74 percent did not state agreement to make conflict information available to
HHS;
(6) 45 percent did not require the reporting of the conflict to the PHS awarding
component that issued the award;
(7) 54 percent did not mention compliance regarding
subgrantees/contractors/collaborators;
(8) 76 percent did not require notification to the awarding component within 60
days regarding conflicting interest identified subsequent to initial report;
(9) 68 percent did not indicate that if the investigator has biased the research, the
institution would promptly notify the awarding component of corrective action
taken or to be taken;
(10) 87 percent did not state that if HHS determines that a PHS-funded project to
evaluate a drug, medical device or treatment was conducted by an investigator
with a conflict that was not disclosed or managed, the institution must require
investigators to disclose the conflict in each public presentation of the results of
the research.
6) Suggestions for Implementation (http://grants1.nih.gov/grants/policy/coi/nih_review.htm)
a. Addresses directly the mandate of the PHS regulations by developing the Conflict of
Interest Policy as a complete, self-contained document with citations and web links to
supporting policies, procedures, and federal and state regulations.
It is implementation of the management processes that presents the greatest challenge to
institutions.
Joan and I will discuss, in Part III of our presentation, various approaches either recommended or
taken by different organizations and institutions.
PART III: IMPLEMENTATION OF CONFLICT OF INTEREST POLICIES AND
PROCESSES: CASE STUDIES
I)
UNIVERSITY OF ROCHESTER
Drafting an “appropriate written and enforced conflict of interest policy” can be challenging for a
university. However, the even greater challenge is in the implementation of the processes.
(Moses: Compliance Cartoon)
A) Issues to Balance
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1) The University of Rochester encourages researcher/faculty members to engage in outside
activities:
a. Consulting
b. Science Advisory Boards
c. Technology Transfer activities
2) As second largest employer in the Rochester community, there has been much
encouragement for faculty entrepreneurship…which raised issues of intellectual property
ownership, conflicts of commitment and conflicts of interest relating to faculty equity and
start-up companies.
3) The business community wanted the University of Rochester researcher’s participation – but
on its terms
4) The University of Rochester and its researchers rely heavily on private sector support of
research
B) University of Rochester’s Policy (A work in progress…)
1) The University of Rochester has had a conflict of interest policy, as part of our Faculty
Handbook, since before NIH/NSF regulations took effect. However, this policy had been
implemented decentrally – and inconsistently – by the various schools/centers and institutes.
Also, policy and processes did not provide the flexibility the changing environment required.
(Truck: Divided Cartoon)
2) In the late 1990’s the University revised its Intellectual Property/Technology Transfer policy,
which imposed a new requirement: a “Conflict of Interest Committee.”
3) The University Committee:
a. Challenges
(i)
Who should sit on the Conflict of Interest Committee?
(1) Institutional/administrative representatives vs. researcher/entrepreneur
representatives; ultimately, the University of Rochester’s Committee added
faculty/researcher representation
(2) Medical center representatives vs. undergraduate college departments
representatives
(3) Conflict of Interest Committee comprised of: Provost, Associate Provost, General
Counsel, Associate Counsel, Director of University Technology Transfer,
Director of Medical Center Technology Transfer, Director of the Research
Subjects Review Board, Director of the Office of Research and Project
Administration, Chief Operating Officer for the Medical Center, Dean of
Research and Graduate Studies for the University, Senior Associate Dean for
Academic Affairs, Executive Director for Government Relations, two Professors
from the University, and two Professors from the Medical Center.
b. Review and revise the Conflict of Interest Policy: As part of that process, refine and redefine what our institutional approach would be: reducing, managing and/or eliminating
conflicts of interest. There was much debate regarding: if/when to prohibit.
(i)
Goal: The goal of the policy is to avoid or to manage situations that call into
question the credibility and objectivity of the research and findings by the faculty
member. An additional goal is to promote the best interest of students and others
whose work depends on faculty direction. The UR is an institution of trust; faculty
must respect this principle and conduct their affairs in ways that do not compromise
the integrity of the University. In addition the University recognizes that even the
perception that faculty have financial interests in the outcome of their research can
call in to question the credibility and objectivity of this research.
(1) Disclosure is a key focus
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(2) All “investigators” (as defined by the federal regulations) as well as the Office of
Technology Transfer, Office of Research and Project Administration and Senior
Administrators are required to complete disclosure forms.
c. Define the process(es) by which the Conflict of Interest policy would be implemented.
d. Should clinical research conflicts of interest be treated differently than other conflicts of
interest?
(i)
Some favored absolute prohibition
(ii)
Others favored case-by-case management
(iii) Decision: As a general rule, prohibit conflicts of interest, but allow for exceptions.
The University of Rochester policy states:
(1) An individual who holds a significant financial interest in clinical trial research
may not conduct such research unless he or she can show compelling reasons to
do so. This prohibition extends to all who report (directly or indirectly) to the
financially conflicted individual. The determination of whether or not there exist
compelling circumstances for the financially conflicted individual to conduct the
trial will be made by the Dean after examining the investigator’s written
justification, and seeking the advice of the department chair(s) as appropriate. In
the event of compelling circumstances, an individual holding a significant
financial interest in clinical trials research may be permitted to remain involved in
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 (e.g., the phase of the trial). However, when the equity
interest is in a start-up company that manufactures the investigational product,
participation in anything other than a consulting role is prohibited.
(2) If the Dean determines that the circumstances are compelling, a conflicted faculty
member seeking involvement in a clinical trial must devise a conflict management
plan to be approved by the Dean in advance of initiating the trial. In all clinical
trials with a conflicted faculty member, the conflict management plan must
include at a minimum: 1) a full disclosure of the interest (to research subjects and
others as appropriate), and; 2) requirement that informed consent be obtained by a
clinician with no financial ties to the research. Conflicted investigators may not
serve as the project's principal investigator. Rather, another principal investigator
must be identified to oversee the administration of the trial, including enrollment
of subjects, overseeing the subject consent process, testing the drug or device, and
analysis of results. The appointed investigator must be qualified to administer the
study protocol, and must not be junior within the department to the financially
involved investigator.
e. Integration with Consulting Policy: Key issues:
(i)
Intellectual Property ownership
(ii)
Insufficient resources to review consulting contracts and advise faculty; plus,
question of whether even appropriate
(iii) Scope of Consulting: Some issues addressed: e.g. Specific activities that require
explicit prior written approval of the department chair and Dean include, but are not
limited to, serving as a PI on behalf of another institution or entity; serving in a
significant managerial role of a for-profit entity; and assuming a board position in a
for-profit company in which he or she has a significant financial interest.
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f. What are respective roles of Conflict of Interest Committee, Deans, and Provost in
decision-making? Decision: Deans and Provost are decision-makers; Conflict of Interest
Committee: advisory to them.
(i)
The Deans of each School/College has the authority to decide how to reduce,
manage or eliminate the conflict of interest but must report his/her decision (along
with an explanation of the reasons for the decision) to the Conflict of Interest
Committee so that the “case law” may develop.
(1) The Policy imposes time limits for a Dean to respond, including time limits for
approval of a management plan if there is one.
(2) The Dean’s decision may be appealed through the usual faculty grievance
procedures of the Faculty Handbook.
(ii)
The Deans, faculty and other University of Rochester officials encountering
conflict situations may seek the advice of the Conflict of Interest Committee.
g. How to create a neutral/non-judgmental environment about something as loaded as the
term “Conflicts of Interest”
(i)
To maintain credibility with entrepreneur/faculty;
(ii)
To maintain focus on objective: encourage/increase sponsored research while
assuring its scientific objectivity and the credibility of the researchers while also
protecting and enhancing the reputations of the University and its researchers; and
(iii) To protect human subjects: most importantly
(iv)
Decision: Management, rather than reduction or elimination of conflicts of
interest was determined to be the guiding principle.
4) Requirements in addition to those contained in the federal regulations:
a. Faculty are prohibited from involving students, whom he or she directly supervises or
advises in a University graduate program, in business activities outside the University in
which the faculty has a significant financial interest and/or officer or director role, unless
approved by the Dean. If the Dean approves such involvement, the faculty advisor,
student, and Dean must agree in writing to a conflict management plan. The plan must
include, at a minimum: i) ongoing oversight by a faculty committee (e.g., the thesis
committee), ii) a guarantee that financial support will not decline before completion of
the degree requirements as long as the committee judges the student's progress to be
acceptable, and iii) a guarantee that a suitable advisor will be appointed to replace the
conflicted advisor if necessary;
b. Faculty are prohibited from assigning students, staff or postdoctoral scholars tasks, within
the University program, for purposes of potential or real financial gain of the faculty
member rather than the advancement of the scholarly field or the students' educational
needs;
c. Investigators may not hold an equity interest in any company that when aggregated for
the individual and family members meets both of the following tests,
(i)
is less than $10,000 in value as determined through reference to public prices or
other reasonable measures of fair market value, and
(ii)
is less than a one- percent ownership interest.
d. The Conflict of Interest Policy applies to ALL research, not just federally-funded
research.
e. The Conflict of Interest Policy was revised to include University-wide Conflict of Interest
Processes.
f. The Conflict of Interest Policy empowered the Conflict of Interest Committee to evaluate
Conflict of Interest cases, upon request as well as upon its own initiative.
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g. The Conflict of Interest Policy authorized the Conflict of Interest Committee to
recommend to the Provost, management actions to address conflicts of interest.
h. The Conflict of Interest Policy charges the Conflict of Interest Committee to compile and
maintain a listing of all conflict of interest situations brought to the attention of the
Conflicts of Interest Committee in order to develop “case law” (consistent rulings).
i. Conflict of Interest Decision-Making Process:
Researcher/Investigator/Faculty with Conflict of Interest  Chair  Dean  Conflict of
Interest Committee for advice  Provost.
Management plans are variable, per the situation. The Conflict of Interest Committee,
Deans and Provost work with faculty and the departments to establish a workable
management plan.
5) Work in Progress: Issues under Discussion
a. What to do with University/institutional conflicts? Deferred: Awaiting NIH guidance.
b. Integration of the Conflicts of Interest, Consulting and Intellectual Property/Technology
Transfer (ownership of Intellectual Property issues) policies.
c. Processes
(i)
Who will educate faculty regarding conflicts of interest?
(ii)
Who will review disclosure forms and bring questions to the attention of the
deans for decision?
6) Hoped-for Advantages of the Revised Policy and Process
a. Clearer expectations for faculty
b. Clearer expectations by faculty
c. More knowledgeable/experienced conflict of interest decision-makers and advisors
d. Greater consistency across campus
e. Broader historical perspective and underpinnings
f. Greater credibility among faculty
g. More realistic approach and greater compliance through a philosophy of management vs.
prohibition
h. Clarification regarding use of graduate students: generally prohibited
i. Greater protection and preservation of University and researcher reputations and
credibility
j. Clarification regarding and clearer protection of human subjects
C) Summary
1) Institutional conflict of interest policies continue to evolve, as both the science (e.g. gene
therapy, cloning) and the opportunities for technology transfer continue to evolve.
2) The challenge will be maintaining institutional commitment, focus, coordination, and
integration to keep pace with the evolution.
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