BUILDING A
VISION
RESEARCH AT UC DAVIS
Conflicts of Interest
Lynne Chronister, MPA
Wendi Delmendo, JD
Mentored Clinical Research Training Program
K30 Summer RCR Course
September 10, 2008
OFFICE OF RESEARCH
Wisdom From Disney
– Elizabeth: Wait! You have to take me to shore. According
to the code of the order of the brethren…
– Barbossa: First, your return to shore was not part of our
negotiations nor our agreement so I must do nothing.
And secondly, you must be a pirate for the pirate’s code
to apply and you’re not. And thirdly, the code is more
what you'd call “guidelines” than actual rules. Welcome
aboard the Black Pearl, Miss Turner.
2
RESPONDS TO:
1. Culture of Compliance
2. Federal Regulations
3. State of California Political Reform Act
4. University of California, Davis, PPM 230-05
5. Organizational Recommendations from:
• AAMC
• AMA
• IOM
6. Gift or Grant
3
HISTORICAL CONTEXT
– 1980 Bayh Dole Act
– Congressional Mandate (1995)
– Increase in Industry Collaboration
– Notable Cases
– NIH/NSF Required Policies
– Federal Common Rule
4
RESPONSIBILITIES &
CHALLENGES
– Research integrity is the umbrella for
accountability
– Ensure the integrity of science and research
– Public accountability
– Delicate balance
– Culture of consciousness and promotion of
integrity
– Management does not ensure integrity/
equitable monitoring
5
COI Wants To Ensure:
– Research is appropriate to the University
– The teaching and research environment is
open
– Freedom to publish and disseminate
results is preserved
– University resources and facilities are not
benefiting private sponsors
6
Gelsinger Case
– Jesse Gelsinger was an 18-year old male
with a relatively mild form of OTC
deficiency, controlled with diet and drugs
– He had decreased liver function, but led a
relatively normal life
– Volunteered for a gene therapy study –
toxicity testing
7
Gelsinger Case, cont.
– Vector injected into liver 9/13, am
– That evening, developed high fever
– Next morning, disoriented and jaundiced
– That afternoon, became comatose
– Dialysis, ECMO begun
– Declared brain dead 9/17 am
8
Gelsinger Complaint
– Failed to tell NIH RAC of change in virus
delivery method
– Changed consent form from that approved
by FDA – omitted information on monkey
deaths
– Failed to report liver toxicity in prior subjects
– Failed to follow enrollment rules
– Poor handling of vectors, causing variance in
potency
9
Possible Reasons
– Studies designed to favor study drug
• e.g., inadequate comparator: drug or dose
– Publication bias (suppression negative
results)
– Discontinuation of studies in progress
– Publication in symposia without peer
review
10
BUILDING A
VISION
RESEARCH AT UC DAVIS
Federal Laws
OFFICE OF RESEARCH
POTENTIAL CONFLICT
– Individual
– Institutional
– Leadership/Administration
– Reviewer Bias (NIH, $10,000, 2004)
– Research Sponsors (Zerhouni, 2005)
– Legislature (Rep. Greenwood, R - PA)
• Biotechnology Industry Organization
12
DISCLOSURE
– University
– Sponsor
– Patients/Subjects
– Publications
– Presentations
13
UNIVERSITY RESPONSIBILITY
– To have a Conflict of Interest Policy and
Procedure, to disseminate the policy and to
provide review and oversight for any conflict of
interest situation.
– University must “manage, reduce or eliminate”
any conflict of interest.
– Must report to federal sponsor as appropriate.
(NIH prior to account activation)
14
DEFINITIONS:
CONFLICT OF INTEREST
– Any outside interest or activity that may
adversely affect, compromise or be
incompatible with obligations of the
employee to the University or professional
norms. Includes situations where
significant financial or other interests will
affect the approval, design, conduct or
reporting of research and other projects.
15
SIGNIFICANT
FINANCIAL INTEREST
– Anything of monetary value including (e.g.):
salary, consulting fees, equity interests and
IP rights. Does NOT include (e.g.): income
from public/nonprofit seminars/teaching,
equity interest of $10,000 or less or not
more than 5% ownership, salary, royalty
etc. of $10,000 or less aggregated over 12
months, mutual funds, physician
reimbursement.
16
CONFLICT OF COMMITMENT
– May occur when external activities demand
excessive time conflicting with a faculty or
other employee’s responsibility to the
University.
17
INSTITUTIONAL
CONFLICT OF INTEREST
– Situations where the University’s beneficial
relationship with corporate entities may
place it in conflict with it’s responsibilities
as a public institution of higher education.
• Equity interest in companies
• Certain licensing situations
• Board or other leadership positions
18
IMPLICATIONS OF FEDERAL LAW
– Solicitation or receipt of a gift or other
compensation from a vendor.
– Confidentiality agreements that could affect a
students degree requirements or grade.
– Sponsor interference with publication or
suppression of data.
– Evaluation of faculty or students based on
participation in outside business activities by
an involved employee.
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BUILDING A
VISION
RESEARCH AT UC DAVIS
California State Laws
OFFICE OF RESEARCH
Government Code § 87100
– “No public official at any level of state or
local government shall make, participate in
making or in any way attempt to use his
official position to influence a governmental
decision in which he knows or has reason
to know he has a financial interest.”
21
Exception:
“Making or participating in making a
governmental decision shall not include:
...
(c) Academic Decisions
. . .”
(2 California Code of Regs., section 18702.4)
22
Academic Decisions:
– Teaching Decisions
• Example: Selection of books
– Research Decisions
• Example: Applying for funds to finance research,
allocating resources for research, manner or
methodology of research.
23
Disclosure Required
– Disclosure shall be required … in
connection with a decision made by a
person or persons at any institution of
higher education with principal
responsibility for a research project to
undertake such research, if it is to be
funded or supported in whole or in part
[with private funds] …,
(2 Cal. Code of Regs., section 18702.4(c)(2).)
24
Disclosure Categories
– Management positions/employment
– Equity ($2,000 or more)
– Income ($500 or more in last year)
– Loans ($500 or more in last year)
– Gifts ($50 or more in last year)
– Travel payments ($50/$500 – outside CA)
25
Disclosure Form
– California Form 700-U
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CAUTION: Travel Payments
– Complex rules for travel payments
– If gift, limited to $390/year
27
Buying Advice in Biopolis
A drug company has established a large
biotech research and development campus
in the Biopolis section of Singapore. In
anticipation of receiving a proposal from a
faculty researcher, it invites him to visit its
facilities to review and comment on a
product, to discuss their independent
research projects, and to explore the
potential for collaborative research.
The company offers to pay all of the travel
expenses for the Singapore trip.
28
Buying Advice in Biopolis
If the company decides to fund the
investigator’s proposal, will he need to
disclose the travel expenses on the Form
700U?
– The best answer is
A. The travel expenses are reasonable
compensation for the time and
inconvenience of the travel. No disclosure
is required.
B. The travel expenses are a gift and must
be disclosed.
29
Buying Advice in Biopolis
– Explanation of the answer
Transportation outside of California is
considered a gift, so the travel to and
lodging in Singapore should be reported
as gifts. Token advisory or consulting
arrangements cannot be used to justify
compensation, so the gift thresholds
would apply. To avoid receiving a gift, the
researcher’s department could pay for the
transportation expenses.
30
Substantive Review Required
– … disqualification may not be required …
if the decision is substantively reviewed by
an independent committee established
within the institution.”
(Section 18702.4(c)(2))
31
BUILDING A
VISION
RESEARCH AT UC DAVIS
University Policies and
Procedures
OFFICE OF RESEARCH
COI Policies
– UC Compendium of COI Policies
– UCD
•
•
•
•
PPSM 82, Conflict of Interest
PPM 380-16, Conflict of Interest
PPM 230-05, Conflicts of Interest in Research
APM 025, Conflict of Commitment
– UCDHS
• Section 1705, Conflict of Interest
• Section 2204, Vendor Relationships
33
PPM 230-05: Prohibitions
– Academic Freedom Restrictions
• Can’t require others to participate in outside activities
• Can’t enter into agreements that
 Impact evaluation of others
 Allow sponsor to interfere with analysis/publication
 Delay protection of IP, fulfillment of degree req’s or publication
– Human Subjects Research
• Can’t accept gifts from sponsors
• Can’t buy/sell sponsor stock until results made public
• Can’t accept payments from sponsor unless commensurate
w/effort
– Licensing
• Can’t be involved w/licensing if have interest in entity
• Can’t be on board of licensee if University holds equity
34
PPM 230-05: Disclosure
– When a research project is sponsored by private
funds, PI must disclose any financial interest in
sponsor of the research
– When research project is sponsored by public
funds, PI and key personnel must disclose any
significant financial interest related to the project
or that could reasonably appear to be affected by
the project
– When privately funded project involves human
subjects research, key personnel must disclose
any significant financial interest in the sponsor of
the research
35
Disclosure Process –
Private Sponsor
• PI completes California Form 700U – let
the form and instructions be your guide
• PI and key personnel complete Form 800
• If answer “yes” to any question,
complete supplemental form
• Confidentiality
36
Disclosure Process –
Public Sponsor
– PI and key personnel complete Form 800
Statement of Economic Interests
– What constitutes a “financial interest
related to the work to be conducted under
the project”?
– If answer “yes” to any question, complete
supplemental form
37
Supplemental Form
– Purpose
– Let the form be your guide
– Fill out the form yourself
– “How are you keeping your interests
separate?”
38
PPM 230-05: Review Process
– Conflict of Interest Committee undertakes
independent substantive review
– Committee recommends whether there is a real
or potential conflict of interest and, if so,
whether any modifications or conditions
should be imposed.
– Recommendations go to Vice Chancellor –
Research for final decision
39
COI Management Strategies
– Public disclosure
•
•
•
•
•
•
40
Departments
Sponsors
Students/research personnel
Publications
Conferences
Research subjects
41
Management Strategies, cont’d
– Independent monitoring
– Modification of research plan
– Disqualification from participation in
research
– Divestiture of financial interest
– Severance of conflicting relationship
42
UCDHS 2204 – Vendor
Relationships
– Policy is based on research showing that providing
gifts of nominal value may affect provider behavior
and give the appearance of favoritism
– Gifts from vendors to an individual are prohibited
– Vendors can make gifts to a department/division
– Policy regulates vendor visits
43
APM 025 – Conflict of Commitment
– Time limits for outside compensated activities
• Academic year appointment – 39 days
• Fiscal year appointment – 48 days
– Categories of activities
• Category I – approval required
• Category II – disclosure required
• Category III – no disclosure, no time limit
44
BUILDING A
VISION
RESEARCH AT UC DAVIS
Medical Issues
OFFICE OF RESEARCH
CLINICAL INVESTIGATIONS
– Any financial interest must be disclosed to
the IRB and possibly research subjects.
– Employee with conflict can be a PI or Co-PI
only under exceptional circumstances.
– NOT a Good Idea: incentive payments to
individuals from sponsors — these should
go into a Dept. account.
– NOT a Good Idea: Consent of subjects by an
employee with a conflict.
46
Funding Affects Publications
– Experimental drug recommended as
treatment of choice more often (5.3X)
– Unfavorable economic analysis 8X less likely
– Second hand smoke
• Industry sponsored 94% pro-industry
• Non-industry sponsored 13%
– Calcium channel blocker safety
• 51% vs. 0% supportive
47
Outline
– AMA code of ethics
– AAMC guidelines
– DHHS-OIG concerns
48
AMA Code Of Ethics
– All members of UCDMC Medical Staff agree
to abide by the principles of the AMA code
of ethics
– “Avoidance of real or perceived conflicts of
interest in clinical research is imperative if
the medical community is to ensure
objectivity and maintain individual and
institutional integrity.”
– Two parts
• General guidelines
• Clinical trials
49
General Guidelines
For Research
– Once a clinical investigator becomes
involved in a research project for a company
or knows that he or she might become
involved, she or he, as an individual, cannot
ethically buy or sell the company’s stock until
the involvement ends and the results of the
research are published or otherwise
disseminated to the public.
– Any remuneration received by the researcher
from the company whose product is being
studied must be commensurate with the
efforts of the researcher on behalf of the
company.
50
General Guidelines, cont.
– Clinical investigators should disclose any
material ties to companies whose products
they are investigating including: financial
ties, participation in educational activities
supported by the companies, participation in
other research projects funded by the
companies, consulting arrangements and
any other ties.
– What is material?
51
Who To Disclose To?
– The medical center
– Organizations funding your research
– Journals when publishing results
• Include statement in publication disclosing the conflicts
– Any other publication (e.g., letter to the editor)
52
Specific Guidelines For
Clinical Trials
– “Safeguards against conflicts of interest
are needed to ensure the integrity of the
research and to protect the welfare of
human subjects. Physicians should be
mindful of the conflicting roles of
investigator and clinician and of the
financial conflicts of interest that
arise from incentives to conduct trials and
to recruit subjects.”
53
Clinical Trials
– Physicians should agree to participate as
investigators in clinical trials only when it
relates to their scope of practice and area
of medical expertise.
– When a physician has treated or
continues to treat a patient who is eligible
to enroll as a subject in a clinical trial that
the physician is conducting, the informed
consent process must differentiate
between the physician’s roles as clinician
and investigator.
54
Clinical Trials (2)
– Financial compensation should be at fair
market value and the rate of compensation per
patient should not vary according to the volume
of subjects enrolled by the physician and
should meet other existing legal requirements.
– It is unethical for physicians to accept payment
solely for referring patients to research studies.
– Physicians should ensure that protocols
include provisions for the funding of subjects’
medical care in the event of complications
associated with the research.
55
Clinical Trials (3)
– The nature and source of funding and
financial incentives offered to the
investigators must be disclosed to a
potential participant as part of the informed
consent process.
56
AAMC
– 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.
– In the event of compelling circumstances,
an individual holding significant financial
interests in human subjects research may
be permitted to conduct the research.
57
AAMC
– 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.
58
What Are
“Compelling Circumstances”
– Early trial of device for which the
investigator has special skills others do not
– Definitely not a late phase drug trial
59
Significant Financial Interest
– Consulting fees, honoraria, etc. over
$10,000/year
– Equity interest in non-publicly traded company
– Equity interest over $10,000 (unless < 5% of
value of company)
– Royalty income or right to receive patent or
copyright royalties from source other than
University
– Payments not related to costs of research (e.g.,
bonuses, milestone payments)
– Officer or other fiduciary role in company
60
Implications of AAMC rule
– Conflicts are inherently bad and disclosure
doesn’t help much
• Disclosure to University
• Disclosure to subject
– Active monitoring of study required
– Conflicted persons should not participate if
at all possible
61
DHHS – OIG
– Indications of questionable research include:
• Research initiated or directed by marketers or sales
agents
• Research that is unnecessary
– Prudent manufacturers should separate the
awarding of research contracts from
marketing or promotion of their products
– Grants must not be funded based, in any way,
expressly or implicitly, on the physician’s use
of the manufacturer’s product
62
Why?
– Research funds being distributed as
kickbacks
• TAP pharmaceuticals: $875M fine
• Whistleblower offered research grants and
educational grants to switch to Lupron
– Switching patients to manufacturer’s drug
under guise of research
• Phase IV studies
63
WHEN IS A GIFT A GIFT
AND
WHY DO I NEED TO TURN DOWN THE
LUNCH, THE DONUTS AND THE
PENS?
64
GIFTS AND BONUSES
– Recruitment Bonuses
– Gifts from Sponsors
– Definitions
• Primary Beneficiary
• Quid Pro Quo
65
DEFINITIONS
– Grant/Contract/Other: Depends on the
intent of the awarding agency and the
legal obligations of the awardee in
accepting the award. A grant may be
donative in nature, bestowed voluntarily
and without expectation of tangible
compensation. A contract always carries
explicit quid pro quo between the source
and the institution.
66
CONFLICTS OF INTEREST
– Federal rules (PHS, NSF) apply only to
research supported by Federal funds
(American Heart Association)
– University conflict of interest rules should
apply regardless of whether research is
funded by a gift or a grant
– Gift classification should not allow “bypass”
of conflict of interest review process
67
GIFT, GRANT OR GREY?
– Dr. Green owns 25% equity in a start up
company that is developing a new medical
device. He gifts the university $50,000 to
carry out research in his laboratory. He
states that there are no strings attached.
68
GIFT, GRANT OR GREY?
– Dr. Harris accepts $100,000 from ATV
Pharmaceutical company for a clinical
investigation. She signs the contract and
puts the money into her Development
account. The study cost $40,000 to
complete. The other funds are used for her
independent research.
69
GREY?
– Dr. Appleby consulted for Regis Inc., a
pharmaceutical and received a check for
$15,000. She donated the check to the
University for her laboratory. Who is the
donor and can she deduct the funds from
her federal income taxes?
70
Hypothetical
– The Case of the Sick Cows
71