Download Human Research and Regulatory Requirements

Conflicts of Interest in
Research
Delia Y. Wolf, MD, JD, MSCI
Assiociate Dean,
Regulatory Affairs & Research Compliance
Email:
[email protected]
October 24, 2014
What is a Conflict of Interest
 Many definitions, only some consensus
 One possible working definition: an
individual or institution has a primary
interest or duty (e.g., scientific
integrity and objectivity, protection of
subjects) that may be affected or
undermined by a competing interest
(e.g., financial reward, professional
advancement, etc.)
2
Types of Potential Conflicts
 Individual financial interest, examples
 Equity interests: ownership of stock and stock options in
a company sponsoring research
 Royalty: when an investigator is conducting a research
project for a company that is developing the technology,
of which the investigator is also the inventor
 Consulting fees, over-scale honoraria and gifts, or other
monetary compensation from companies whose products
are affected by investigators’ research results
 Recruitment bonus or milestone payments from
sponsoring company to investigators in order to
“accelerate” research process
 Finder’s fees
3
Significant Financial Interest (SFI)
 Significant Financial Interest according to PHS
include:
 An equity interest which when aggregated for
the investigator and his/her spouse and
dependent children (a) exceed $5,000 in value
and/or (b) represents more than five percent
(5%) ownership in any single entity
 Salary, royalties or other payments for service
that when aggregated, investigator and his/her
spouse and dependent children, over twelve
months period, is reasonably expected to
exceed $5,000
4
Financial Interests Disclosure
 Financial interests meet De minimis
threshold of $5000 (SFI)
 ALL SFI related to the investigator's
institutional responsibilities (note: the 1995
regulations required “only those SFI the
investigator deems related to the PHSfunded research”)
 Travel reimbursements and sponsored
travel (De minimis threshold does not
apply)
5
Excluded from Disclosure
 Income from lectures, seminars, or teaching
engagements sponsored by public or nonprofit
entities; a federal, state, or local government
agency, an Institution of higher education, an
academic teaching hospital, a medical center,
or a research institute that is affiliated with an
Institution of higher education.
 Income from investment vehicles, such as
mutual funds and retirement accounts, as long
as the investigator does not directly control the
investment decisions
6
Conflicts of Commitment
 Competing demands on researchers’ time




Working on one or more funded projects
Teaching and advising students
Attending professional meetings and giving lectures
Serving as a peer reviewer
 Allocation of time
 Time and effort reporting – seek advice if unsure
whether a particular commitment of time is allowed
under an institution's or funding agency’s policy
 Use of resource
 Equipment purchased with public funds cannot be
used for private research
7
Examples of potential COI
 An academic researcher in a NIH study
section reviews a grant application from
a competitor in the same field
 A clinical investigator receives $3,000
for each patient she recruits into a
clinical trial
 A university’s IRB reviews a research
proposal sponsored by a company that
has recently given $10 million to the
university
8
Examples of potential COI
(cont.)
 A university holds stock in a chemical
plant but also hires employees to
monitor its emissions.
 A university president owns stock in a
company that sponsors research on
campus and has made large gifts to the
campus
9
Impact of Financial Interests
 Existing evidence suggests an impact on
science doe to financial relationships:
 Industry-sponsored studies that are published
are more likely to reach pro-industry
conclusions (Bekelman et al., 2003)
 Gifts change physicians’ prescribing behaviors (to
the benefit of the gift-giver)
 In one survey, 15.5% of 3,247 scientists surveyed
reported that they had changed the design,
methodology or results of a study in response to
pressure from a funding source (Martinson et al.,
2005)
10
How COI is identified/judged
 Conflicts usually judged in retrospect
 Hard to “prove” causative effect
(conflict  bias)
 Often only an issue in the wake of an
adverse event and compounds the
problem for investigators and/or
institutions
 Public perception/media focus
11
Regulatory Requirements
 FDA Regulations (21 CFR Parts 54; 312.53; 812.43)
 Investigators must disclose certain financial
interests to sponsors; sponsors then
disclose to FDA
 FDA may take action if it determines that
the financial interests of an investigator
raise a serious question about data integrity
 PHS Regulations
 42 CFR Parts 50 and 94 (1995)
 Revised final rule public August 2011
12
University-wide Policy
 Harvard University policy on individual
financial conflicts of interest policy can
be found at:
http://vpr.harvard.edu/content/conflicts
-interest
 Approved by the President and Fellows
of Harvard College on May 26, 2010
 Applies to holders of faculty and
teaching appointments at the Schools
13
Responses to COI Concerns
 Common themes in existing responses:
 DISCLOSURE
 Information gathering
 IDENTIFICATION
 Defining what constitutes a COI
 MANAGEMENT
 Disclosure component (transparency)
 Reducing impact of conflicted investigator
14
Managing Financial COI
 Disclosure to the IRB
 Protocol-specific
 $1 threshold at Harvard Catalyst institutions
 Following management plan such as:




Disclosure to potential research participants
Refrain from recruitment activities
Refrain from interpretation of data
Appoint another investigator to be the
principal investigator (PI)
15
Managing Financial COI (cont.)
 Limitations of disclosure to subjects:
 Can subjects make meaningful use of that
information?
 Evidence that some patients view their
doctors’ financial interests positively:
 Demonstrates knowledge and that they are on
cutting edge
 If physicians are more vested they will work
harder
16
COI in International Research
 Globalization of research/clinical trials
 Increased outsourcing of research by
industry
 This has resulted in the outsourcing of COIs as
well (Gatter, R.)
 Drug company payments to health
professionals in resource-poor countries can
double or triple their annual incomes
(Washington Post, Dec. 2000)
17
COI in International Research
(cont.)
 Reliance on industry funding
 Many countries want to be viewed positively
to industry as a good place to site trials
 Trials bring funding for research as well as
access to investigational therapies and, for
resource-poor countries, often additional
capacity-building for the institution and/or
nation that goes beyond the research study
(e.g., access to standard of care therapy for
all patients, funds to improve facilities, etc.)
18
COI in International Research
(cont.)
 Government involvement
 In many countries, regional and/or national
approval of research is required
 Governments may have incentives either to
ensure research happens (reflects positively
on country, financing is dependent on it) or
block it (if anticipated results may damage
country’s reputation)
19
CASE STUDY
 A U.S.-based pharmaceutical company is conducting a drug trial in a
resource-poor country; the protocol involves studying the safety and
effectiveness of a new drug for hypertension.
 In addition to the research budget, the local investigators are being
paid through consulting agreements to advise the company on
research and political strategy and to liaison with local officials (the
amounts, while modest by US standards, are 3 times what the
investigators make in annual salary at their institutions).
 The consulting agreements give the company the rights to control
access to data and approval any publications.
 The local institution’s Ethics Committee is comprised primarily of
hospital management and prominent community members.
 In addition to the institutional EC, the protocol must be reviewed by
a regional Ethics Committee, the Chair of which holds a prominent
position in the local government.
20
CASE STUDY
 Local government officials have repeatedly expressed a desire to
improve their reputation as a “research-friendly” locale.
 The local health system, including the site, desperately needs
investment in infrastructure.
 The standard of care for hypertension in the US is currently
prohibitively expensive for the site’s patient population.
 The company has offered to invest a significant amount of resources
in improving the site, building local health clinics, as well as
providing infrastructure and resources for the EC.
 The company has also offered to ensure that all patients at the site
(whether on protocol or not) receive the standard of care for
hypertension during the course of the trial and for 3 years following;
additionally, if benefits are shown, the company has offered to make
the new drug available to all patients at the site for the same timeframe.
21
CASE STUDY: Q & A
 What conflicts do you see with this
arrangement?
 Whose responsibility is it to question the
validity of the regional EC approval?
 How should the reviewing ECs balance just
reward to the site for participating against
the potential to create conflicts?
 What management techniques might work
in this context?
22
Collaborative Research
 Types of collaborative research
 Points to consider before, during and
after collaboration
 Case studies
23
Types of Collaborative Research
 Within institution
 With institutions/hospitals
 Multicenter – within the US
 Multicenter – transnational
 Collaborations with industry
24
Points to Consider
 Before any work is undertaken
 Clear understanding of the nature of the collaboration
 Roles and responsibilities
 Sufficient resources

Time, space
 Written agreement (between/among collaborators)
 Who does what
 Who owns what
 Criteria to identify and rank contributing authors
 Necessary review and approval from institution
 Grants/contracts
 Technology transfer
 IRB/IACUC
25
Points to Consider (cont.)
 During the course of collaboration
 Following research plan/study protocol
 Communication
 Report Progress
 Share findings
 Discuss problems
 Documentation
 If it is not documented, it is not done!
 Training and supervision
 Verification
 Good record keeping
 Time and effort
26
Points to Consider (cont.)
 After the completion of a collaborative
research project
 Submit final report/closure to relevant
offices at researcher’s institution
 IRB office
 Be aware if record keeping requirements
 Institutional requirements
 Sponsor requirements
 Government agency requirements
27
Case A



Amber, Ben and Carol have just received funding from a small
pharmaceutical company to test one of its imaging agent.
Amber is a neuro-radiologist at BIDMC, who will be the PI, as
well as the IND holder, Ben is a psychiatrist at MGH, and Carol
is a biostatistician at HSPH. All three will serve as coinvestigators.
Study is going to be conducted at BIDMC. Both Amber and
Ben will be interact with research participants; Carol will not
have direct contact with participants, but will have access to
participants’ identifiable information.



Which office(s) will they have to deal with
Do all three need to get IRB approval from each of his/her
institution
Do they need an agreement among themselves? If so, what should
be included in the agreement?
28
Case B
 Dr. D is a biostatistician from HSPH. He is the
PI for a data coordinating center that oversees
and analyzes all data collected from a multicanter clinical trial involving 12 sites in the US
and 10 sites outside of the US.
 What are Dr. D’s responsibilities in terms of meeting
regulatory requirement?
 Obtaining IRB approval
 Oversight of research conduct
 Reporting obligations
29
Case C
 Dr. M is the overall PI for a multi-center
Vitamin A supplementation clinical trial that is
sponsored by NIH. She is a faculty member at
HSPH, but no study activities will be conducted
in the US. There are a total of three sites in
India, Tanzania and Botswana.
 Does Dr. M need to get HSPH IRB approval to work
on the study?
 Which country’s rules should be followed for
regulatory oversight?
 Since she only visits each site once a year, how can
she fulfill her responsibility as a PI?
30