Identifying and Managing Conflict of Interest in Research

1
Identifying and Managing Conflict of Interest in
Research

• Gerald S. Gotterer, M.D., Ph.D.
• Senior Associate Dean for Faculty and Academic
  Administrative Affairs
• April 22, 2004

2

• Background and Principles
• The Issue at Vanderbilt
• Assessment Issues
• Case Studies

3
The Belmont Report Ethical Principles and
Guidelines for the Protection of Human Subjects
of Research The National Commission for the
Protection of Human Subjects of Biomedical and
Behavioral Research April 18, 1979
http//ohsr.od.nih.gov/mpa/belmont.php3
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Belmont Report

• Boundaries between practice and research
• Basic ethical principles
• Respect for persons
• Beneficence
• Justice
• Applications
• Informed consent
• Assessment of risks and benefits
• Selection of subjects

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Bayh-Dole Act of 1980

• Designed to promote use, development and
  promotion of technology invented with federal
  funding.
• Recipients of federal funding have the right to
  retain ownership to inventions developed with
  federal funding.
• Recipient must share royalties, or other income,
  derived from the invention with the inventor(s).

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Patents to Universities1986-1999
Source Association of University Technology
Managers
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U.S. University Hospital Royalties(millions
of dollars)
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Conflicts of Interest
Conflicts of interest are ubiquitous and
inevitable in academic life, indeed, in all
professional life. The challenge for academic
medicine is not to eradicate them, which is
fanciful and would be inimical to public policy
goals, but to recognize and manage them sensibly
and effectively. David Korn JAMA 284,
2234-2236, 2000
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Conflicts of Interest in Academic Medicine

• Non-Financial Pressures
• Desire for faculty advancement
• Compete for sponsored research
• Receive accolades from peers
• Receive prestigious prizes
• Alleviate pain and suffering

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Existence of Conflict of Interest

• Describes a situation
• Not a judgement on appropriateness of behavior

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Factors Stimulating Review of Conflict of
Interest Policies and Procedures at Vanderbilt

• N.I.H. Proposed Guidelines for Policies on
  Conflicts of Interest (September 15, 1989)
• A.M.A. Conflicts of Interest in Medical
  Center/Industry Research Relationships (December,
  1989)
• A.A.M.C. Guidelines for Dealing with Conflicts of
  Commitment and Conflicts of Interest in Research
  (February, 1990)
• Conflict of Interest Hearing. Clinical Evaluation
  of Products. N.I.H. (November 30, 1990)

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A.A.M.C. GuidelinesFebruary, 1990

• Academic institutions should have
• Standards of conduct
• Timely disclosure
• Review of disclosed information
• Procedures for enforcing standards and providing
  sanctions.
• Policies and procedures consistent with
  government policies and rules.

13
Vanderbilt School of Medicine Administrative
ReviewJanuary, 1991

• Vanderbilt University policy called for annual
  report of consulting activities and arrangements
  that might lead to conflict-of-interest
  situations.
• University Standards for Conflict of Interest had
  been written in 1969, addressed primarily
  consulting, and were not written in a manner that
  easily translated to working standards.
• Policies were being implemented unevenly, if at
  all, in the various departments.

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Recommendations of the VUSM Administrative
Review TeamJanuary, 1991

• Develop system for required annual written
  disclosure by all faculty.
• Appoint a committee of senior faculty to review
  and make recommendations to the Dean concerning
  situations of potential or actual conflict of
  interest.
• Appoint a committee to develop operational
  standards based on the principles established in
  the Vanderbilt Faculty Manual, but made
  applicable to the broader issues of current
  concern.

15
http//www.aamc.org/members/coitf/2002coireport.pd
f
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A.A.M.C. Policy GuidelinesDecember, 2001

• Conflict of Interest Official and Committee
• Process for financial reports and review prior to
  I.R.B. final approval
• Written policy
• Rebuttable presumption that financially
  interested individuals may not conduct human
  subject research.
• Monitoring

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A.A.M.C. Policy GuidelinesDecember, 2001
(2)

• Reporting by faculty
• Reporting to supervisor
• Investigator certification to IRB
• COI Committee review of significant financial
  interest created by licensing agreements
• Disclosure of significant financial interests,
  including in consent form

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A.A.M.C. Policy GuidelinesDecember, 2001
(3)

• Prohibition on payments for results.
• Affirmation of institutional policies on
  intellectual property and publication rights.
  (Ability for P.I. to receive, analyze and
  interpret all data generated by research and to
  publish results independent of outcome
  reasonable period for prepublication review)

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A.A.M.C. Policy GuidelinesDecember, 2001
(4)

• Protection of students and trainees
• Legal obligations
• Sanctions

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Rebuttable PresumptionAAMC Policy on Human
Subject Research (December, 2001)
Rebuttable Presumption that Financially Interest
Individuals May Not Conduct Human Subjects
Research. The policy should state that, in the
absence of compelling circumstances, a
financially interested individual may not conduct
human subject research. p.18
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Rebuttable PresumptionAAMC Policy on Human
Subject Research (December, 2001)
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. p.10
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Rebuttable PresumptionAAMC Policy on Human
Subject Research (December, 2001)
When the financial interest is directly related
to the research and may be substantially affected
by it, 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,
her or she should be permitted the opportunity to
rebut the presumption against financial interests
by demonstrating these facts to the satisfaction
of an institutions COI committee. p.7
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Faculty Conflict of Interest Disclosures
Annual DisclosureForm
Office of Research
I.R.B.
Faculty Member
Tech Transfer/ Legal
Source of Disclosure
Triage by Associate Dean (Tom Hazinski)

• C.O.I. Subcommittees
• Human Investigation
• Basic Research/Technology
• Consulting/Business

Seek more information
Approval
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Medical Center Conflict of Interest Committee
Tom Hazinksi (Gerald Gotterer), Chair
Sherrie Leach, Staff
Clinical Investigation Italo Biaggioni Tom
Graham John Murray Alastair Wood Basic Research/
Technology Richard Caprioli Peng Liang Donald
Rubin Consultations/Business Lonnie
Burnett Rolanda Johnson
At-Large Richard Chappell Stuart Finder Fred
Goad, Jr.

• Ex Officio
• Diana Marver (Research Training)
• Leona Marx (General Counsel)
• Chris McKinney (Tech Transfer)

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Faculty Conflict of Interest Disclosures
Annual DisclosureForm
Office of Research
I.R.B.
Faculty Member
Tech Transfer/ Legal
Source of Disclosure
Triage by Associate Dean (Tom Hazinski)

• C.O.I. Subcommittees
• Human Investigation
• Basic Research/Technology
• Consulting/Business

Seek more information
Approval
26
Annual Disclosure Form

• Web-based Fall, 2003
• New Vanderbilt University Policies

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(No Transcript)
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(No Transcript)
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Faculty Conflict of Interest Disclosures
Annual DisclosureForm
Office of Research
I.R.B.
Faculty Member
Tech Transfer/ Legal
Source of Disclosure
Triage by Associate Dean (Tom Hazinski)

• C.O.I. Subcommittees
• Human Investigation
• Basic Research/Technology
• Consulting/Business

Seek more information
Approval
30
Faculty Conflict of Interest Disclosures
Separate Disclosure Form
Annual DisclosureForm
Office of Research
I.R.B.
Faculty Member
Tech Transfer/ Legal
Source of Disclosure
Triage by Associate Dean (Tom Hazinski)

• C.O.I. Subcommittees
• Human Investigation
• Basic Research/Technology
• Consulting/Business

Seek more information
Approval
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Vanderbilt University Institutional Review
BoardApplication for Human Research
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Relationship of I.R.B. to C.O.I. Committee

• I.R.B. is responsible for assuring that
  patients/subjects are appropriately aware of
  conflict of interest situations.
• The Medical Center Conflict of Interest
  Committee, and where appropriate the Chair of the
  University Conflicts Committee or the University
  Conflicts Committee itself, are responsible for
  assuring that conflict of interest situations are
  managed so as to avoid or minimize influence on
  research effort.
• No research program involving human subjects
  can be initiated until approvals from both the
  I.R.B. and the appropriate conflict committee(s)
  are received and reconciled.

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Faculty Conflict of Interest Disclosures
Annual DisclosureForm
Office of Research
I.R.B.
Faculty Member
Tech Transfer/ Legal
Source of Disclosure
Triage by Associate Dean (Tom Hazinski)

• C.O.I. Subcommittees
• Human Investigation
• Basic Research/Technology
• Consulting/Business

Seek more information
Approval
34
Office of Research

• Grants to U.S.P.H.S. and N.S.F.
• Separate disclosure form for information about
  P.I. and all participants.
• Significant financial interest (10,000 annually,
  the equity interest exceeds 5 ownership or a
  value of 10,000 at fair market value, or royalty
  payments exceed 10,000 annually).

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Office of Research (continued)

• Reviewed when notice of funding received.
• Any conflicts of interest issues must be resolved
  before funding is released.
• Further information available from Office of
  Research website
• http//medschool.mc.vanderbilt.edu/oor/gm/
  index.php?GM5

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Issues in Assessing COI Involving Human
Investigation

• Financial Consulting fees, stock equity, stock
  options
• Patient/Subject risk
• Study design
• Phase I Phase III trial
• Multi-center trial Single-center
  trial
• Double blind Open label study
• Presence of Absence of
• independent safety monitoring
  board
• Independent analysis Involvement of
  investigator
• in the analysis of
  data

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http//frwebgate2.access.gpo.gov/cgi-bin/waisgate.
cgi?WAISdocID263613481400100WAISactionretrie
ve
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Underlying Principles

• The regulations protecting human research
  subjects are based on the ethical principles
  described in the Belmont Report respect for
  persons, beneficence, and justice. Financial
  relationships in human research should not
  compromise these principles. Openness and honesty
  are indicators of respect for persons,
  characteristics that promote ethical research and
  can only strengthen the research process.

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Points for Consideration

• Does the research involve financial relationships
  that could create conflicts of interest?
• How is the research supported or financed?
• Where and by whom was the study designed?
• Where and by whom will the resulting data be
  analyzed?

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Points for Consideration (2)

• What interests are created by the financial
  relationships involved in the situation?
• Do individuals or institutions receive any
  compensation that may be affected by the study
  outcome?
• Do individuals or institutions involved in the
  research
• Have proprietary interests in the product?
• Have equity interest in the research sponsor and
  is it a publicly or non-publicly held company?
• Receive payments of other sorts?

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Points for Consideration (3)

• Given the financial relationships involved, is
  the institution an appropriate site for the
  research?
• How should the financial relationships that
  create a conflict of interest be managed?

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Points for Consideration (4)

• Management options
• reduction of financial interest
• disclosure of financial interests to prospective
  subjects
• additional oversight or monitoring of the
  research
• independent data and safety monitoring committee
• modification of role of particular staff
• elimination of the financial interest

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Points for Consideration (5)Institutional Issues

• Separate responsibilities for financial decisions
  and research decisions.
• Extend the responsibility of COI Committees to
  address institutional financial interests in
  research
• Establish criteria to determine what constitutes
  an institutional conflicts, including those of
  leadership

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Points for Consideration (6)Institutional Issues

• Establish clear channels of communication between
  COI Committees and IRBs.
• Establish procedures for disclosure of
  institutional financial relationships to COI
  Committees.
• Include individuals from outside the institution
  in the review and oversight of financial
  interests in research.

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Case Study 1
Faculty member of a clinical department and
spouse own about 1,000 shares in each of two
major publicly traded pharmaceutical companies.
The value of each block of shares is in excess of
10,000, but the holdings represent considerably
less than 5 of the value of these
companies. Company A sponsors a large
multi-centered, double-blind study involving over
10,000 patients and 100 sites studying the
effects of a new pharmaceutical. The faculty
member is responsible for the Vanderbilt site,
which has 40 patients enrolled.
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Case Study 1 (continued)
Company B sponsors two studies, both
multicentered studies comparing the effects of
various drugs within a classification on their
abilities to modify the blood levels of a
particular blood component. These are open label
studies with the particular drug assigned
randomly. All the laboratory analyses are
carried out by an outside laboratory. Both the
I.R.B. application and the patient consent forms
indicate the existent of a potential conflict of
interest.
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Case Study 1 (continued)
The faculty member discloses his stock ownership
in all relevant publications and
presentations. There are no trainees involved
with the study.
48
Case Study 2
A faculty member has a significant financial
interest in a biotechnology company as a member
of its Scientific Advisory Board. The faculty
member receives research support from this
company that is administered through the Office
of Research. The research agreement provides
support for two postdoctoral associates,
technical assistance, and some support for the
faculty member as P.I.
49
Case Study 2 (continued)
The study involves the evaluation of novel genes
that have been identified by the sponsor in a
variety of cell and animal models. The results of
the research is made known to the sponsor prior
to publication under arrangements reviewed and
approved by the Office of Research. Trainees
participate in this research with the approval of
appropriate supervisors. Four published abstracts
and one submitted manuscript have so far resulted
from the collaboration.
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Case Study 3
A faculty member discovers a potentially useful
new application of an existing drug. Under
Vanderbilts policies, Vanderbilt licenses the
rights to the database concerning this new
application to a private pharmaceutical company.
The faculty member has a significant financial
interest in this activity as the medical director
of and with an ownership position in the private
pharmaceutical company. He also is actively
involved with the Vanderbilt I.R.B.
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Case Study 3 (continued)
It should be noted that successful development
and marketing of this new application will
financially benefit both the faculty member (the
inventor) and Vanderbilt University. The faculty
member proposes that studies in human subjects
relating to the efficacy of this new application
be undertaken at Vanderbilt. Though he himself
will not carry out the study, faculty members
reporting to him will do so. The proposed Data
Safety Monitoring Board contains a faculty member
at another medical school, a Vanderbilt
statistician, and physician in private practice
a former fellow of the faculty member.
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Case Study 3 (continued)

• Resolution (in outline)
• Special expertise of Vanderbilt faculty warranted
  study being carried out at Vanderbilt.
• Study reviewed by I.R.B. of another medical
  school.
• Principal Investigator on the study is faculty
  member who does not report to the inventor and
  who has no financial interest in the outcome.
• Data Safety Monitoring Board has no members with
  any relationship to inventor.

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Case Study 3 (continued)

• The only person with access to blinding code is
  statistician who prepared randomization sequence.
• Statistical analysis of the data will be carried
  out by an independent company, with access to
  randomization codes only after the database is
  locked.
• If needed for patient safety, unblinded
  statistician will provide code only to the Data
  Safety Monitoring Board.
• Medical Director of pharmaceutical company (the
  inventor) is blinded to randomization code until
  final analysis is performed by independent
  contractor.

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NATIONAL DESK August 3, 2003,
Sunday Undisclosed Financial Ties Prompt Reproval
of Doctor By MELODY PETERSEN (NYT) 979
words Late Edition - Final , Section 1 , Page 18
, Column 5 ABSTRACT - Two doctors raise concerns
about article in journal Nature Neuroscience that
described experimental treatments for depression
because lead author, Dr Charles B Nemeroff, did
not disclose his significant financial ties to
three therapies that he mentioned favorably
journal says it has not required disclosure of
potential conflicts for articles that do not
describe original research, but is considering
changing its policy in light of criticism
Nemeroff says he would have reported conflicts if
journal had asked him to.