Volume 1, December 2001
Conflict of Interest and Medical Research:
the Medical-Industrial Complex
It has been a
generation since the foundations of medical research in the United States have
been shaken to the point of necessitating reform in the system of
oversight. The sentinel event at that
time was the Tuskegee Syphilis Study; the ethical lapses threatened the system
of trust between patients, their physicians, and the medical research
system. In response to the egregious
actions of the Tuskegee scientists, Congress passed the National Research Act,
which requires the establishment of Institutional Review Boards (IRBs) to
review federally-funded research. The
Act also created the National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research.
This commission subsequently issued the Belmont
Report, which detailed the ethical principles upon which the systematic
protection of research participants is based.
Although the same ethical principles pertaining to the
protection of research subjects apply, new challenges have also arisen. While
fortunately there has been no recent event that is comparable to Tuskegee,
there are increasing concerns that the current system of human subject
protection is inadequate. What
happened? Research has become a for-profit
industry, and the resulting financial conflicts of interest jeopardize human
subjects, patients, and the future role of academic medical institutions. It is
time to reconsider the clinical research system.
Medicine, and the
medical research endeavor, has changed considerably over the past 25
years. Although the NIH budget has
increased substantially, there has been an even greater increase in industry
sponsorship of clinical research.
This increase in research funding, in combination with pressures to ensure that
clinical trials are efficient and organized, has produced a new, for profit
research industry. This industry consists of contract research
organizations, which perform nearly every aspect of the research process, and
do so at rates that are competitive with academic institutions. Unfortunately for academic institutions,
this new competition for research funding comes at a horrible time – when
clinical revenues have fallen substantially in the setting of managed
care. Clinician-scientists need
industry sponsorship more than ever.
Institutions themselves, in a similar position – since the passage of
act in 1980, have stood to yield substantial financial gains from the
discoveries of their faculty members.
work has demonstrated that investigators can be unduly influenced by a
financial connection to an industry sponsor, resulting in biased science. In a prior review of 107 controlled clinical
trials, Davidson reported that 89% of the industry supported trials had a
positive outcome, in comparison to only 61% of the non-industry supported
More recently, another review of 136 randomized trials found that industry
sponsored trials were not only more likely to yield positive results (74% vs.
47% for non-industry studies), but also more likely to use placebo rather than
active agent as the treatment for the comparison group.
A similar analysis found that industry-sponsored cost effective studies were
significantly more likely than non-industry funded studies to yield positive
Academic scientists who were supported by industry reported that they were more
likely to have their areas of inquiry influenced by the interests of their
conflicts need to be addressed. In the
most recent update to the federal human protections system, the DHHS
regulations for IRB participation and function were modified and eventually
adopted by 17 other federal agencies.
Financial conflicts of interest received scant attention. The section on IRB membership states that “No IRB may have a member participate in the
IRB's initial or continuing review of any project in which the member has a
conflicting interest, except to provide information requested by the IRB.”
The threshold for disclosure of financial conflicts set by regulations is quite
specific - investigators are required to disclose “significant” (>$10,000 in
equity, $10,000/year in fees, or >5% ownership in the company) financial
interests in companies that might be affected by their research.
These interests are disclosed to the scientists’ own institutions, which are
then required to “manage, reduce, or eliminate them”.
The approach to this problem is highly variable across institutions, however.
Disclosure alone is
inadequate. This is not only because
the response to the disclosed information can vary dramatically between
institutions, but also because it is difficult to assess the nature of complex
relations between scientists and their sponsors based on financial data alone. Further guidance regarding managing
financial conflicts and ensuring subject safety and research integrity are
warranted. A recent joint
editorial co-authored by the editors of a dozen of the highest impact
general medical journals, represents an important first step in this direction.
The editors acknowledge that industry sponsors have a powerful position, but
that scientists must be accountable for key aspects of the investigations over
which they reportedly preside.
As such, the joint editorial states “we strongly oppose contractual agreements
that deny investigators the right to examine the data independently.”
For instance, JAMA will require authors to sign a statement attesting that they
“…had full access to all of the data in the study and take responsibility for
the integrity of the data and accuracy of the data analysis.”
Other journals are expected to follow suit.
The editors also addressed concerns about squelching negative studies by
stating that the “sponsor must impose no impediment, direct or indirect, on the
publication of the study’s full results, including data perceived to be
detrimental to the product.”
This action by the
journal editors is a welcome and essential first step in addressing
investigator conflicts. But what about
institutional conflicts? If a
university holds equity stake in a “start-up company”, the existence of which
depends on a successful clinical trial, can institutional officials evaluate
the financial conflicts presented by that trial objectively? They should not be in that position in the
first place. Institutional officials
cannot evaluate themselves; they need external guidance just like individual
investigators do. It is time to create
an external oversight system for institutional conflicts. The American Association of Medical Colleges
is currently drafting a proposal to address financial conflicts of interest;
whether institutional conflicts receive their due notice remains to be
seen. Not only can financial conflicts
jeopardize those who participate in the studies, but they can affect the
validity of the scientific research enterprise as well. It is time to take action to ensure that the
public’s trust in medicine and medicine research is not further eroded.
 R. Rettig,
“The industrialization of clinical research,” Health Affairs, 2000;19:129-146.
 R. Davidson,
“Source of funding and outcome of clinical trials,” J Gen Int Med, 1986;1:155-58.
 B. Djulbegovic, M. Lacevic, A. Cantor, K. Fields, C. Bennett, and R.
Adams, “The uncertainty principle and industry-sponsored research,” Lancet, 2001;356:635-8.
Friedberg, B. Saffran, T. Stinson, W. Nelson, and C. Bennett, “Evaluation of
conflict of interest in economic analyses of new drugs used in oncology,” JAMA, 1999;282:1453-7.
Blumenthal, “University-industry research relationships in biotechnology:
implications for the university,” Science,
 Code of
Federal Regulations, Title 45: Public Welfare, Part 46: Protection of Human
Subjects, June 18, 1991.
Responsibility of applicants for promoting objectivity in research for which
PHS funding is sought, 1999.
 B. Lo, L.
Wolf, and A. Berkeley, “Conflict of interest policies for investigators in
clinical trials,” N Engl J Med.
Davidoff, C. DeAngelis, and J. Drazen, “Sponsorship, authorship, and
accountability,” Ann Int Med.
“Instructions for authors,” JAMA,
2001;286:101-8; C. DeAngelis, P. Fontanarosa, and A. Flanagin, “Reporting
financial conflicts of interest and relationships between investigators and
research sponsors,” JAMA,
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