E-DRUG: Maintaining the integrity of the clinical evidence base
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[This text was published as an editorial in the WHO Bulletin,
December 2001. Because of its importance, an integral copy.
Copied as fair use.
Best wishes to all E-druggers for 2002, which also happens
to be the 25th year of the concept of essential drugs, as the
first Essential Drug List was published by WHO on 21 Oct 1977.
WB]
Maintaining the integrity of the clinical evidence base
by Jonathan Quick, Director, Essential Drugs and Medicines Policy,
World Health Organization, 1211 Geneva 27, Switzerland.
In this issue of the Bulletin Jos� Esparza highlights the promise of
modern clinical research in combating a major killer disease (pp
1133-1137). During the last decade, at least 15 antiretroviral drugs
have come onto the market, bringing longer life and vastly improved
quality of life to AIDS patients. In recent months there has been
vigorous debate about making those medicines affordable in the South,
and about the procurement of ciprofloxacin for the treatment of
anthrax in the North. The technical and moral challenge of both
ensuring access to existing medicines today and providing incentives
for the discovery of new ones for tomorrow has never been more
intense.
Clinical trials form the basis of effective research and development,
but their reliability is currently imperilled by three major flaws:
conflicts of interest on the part of the investigators; inappropriate
involvement of research sponsors in their design and management; and
publication bias in disseminating their results.
On financial conflicts of interest, Bodenheimer has reviewed studies
showing that authors who supported use of certain cardiovascular
treatments were significantly more likely to have a financial
relationship with the drug's makers than those who did not; that
studies funded by the manufacturer of a new therapy were more likely
than others to find in favour of that therapy; and that independently
funded pharmacoeconomic studies of cancer drugs were seven times more
likely than industry-sponsored studies to reach unfavourable
conclusions about a product (1).
On inappropriate involvement, recent reviews have documented how
industry sponsors influence clinical trials to produce desired results
(2). Investigators may have little or no input into trial design, no
access to the raw data, and limited participation in data
interpretation. This may result in flawed design or invalid practices
such as "data dredging" (performing multiple post hoc analyses until
some positive results show up). A major cardiovascular trial used
eight combinations of drug versus placebo, ensuring a 23% probability
of at least one good outcome by chance alone. Contract research grew
dramatically during the 1990s, making it easier for commercial
sponsors to directly influence clinical trials (3).
Bias in publicizing positive results and underreporting negative ones
is the third threat to the clinical evidence base (4). One study of
university-industry research centres found that 35% of signed
agreements allowed the sponsor to delete information from publication,
53% allowed delay of publication, and 30% allowed both (5). A series
of high profile cases have shown how investigators who publish or
otherwise communicate results contrary to the wishes of the sponsor
face intimidation, efforts to discredit them professionally, and
threats of legal action to recover the value of "lost sales"(1).
What can be done? Most clinical research is still conducted to highly
exacting standards of objectivity. Yet concern over current trends led
the editors of 13 leading medical journals to publish a joint
editorial about it in September 2001 (6). Their statement is
unequivocal: "[Research] contracts should give the researchers a
substantial say in trial design, access to the raw data,
responsibility for data analysis and interpretation, and the right to
publish." The former editor of the New England Journal of Medicine
argues in a separate piece that the editors did not go far enough.
"The entire system of clinical investigation is driven by profit," he
writes:."we are seeing the corruption of a system of research that
used to have high ideals and be clearly in the public interest. (7)"
Lo and colleagues propose that university-based investigators and
researcher staff should be prohibited from holding stock, stock
options or decision-making positions in a company that may be affected
by the results of their clinical research (8). The World Health
Organization is tightening its rules for staff and expert advises on
conflicts of interest, and has established procedures to maintain a
"firewall" between commercial interests and normative, regulatory and
research decisions.
In a highly competitive world, the pressures may be simply too great
for individual researchers, universities, medical journals, or public
agencies to stem the tide of commercial influence. Decades ago, when
too many clinical trials were putting patients unacceptably at risk,
the Helsinki Declaration was drawn up to protect trial subjects.
Perhaps it is time for a similar declaration on the rights and
obligations of clinical investigators and on how to manage the entire
clinical trials evidence base. In addition to the measures proposed
by journal editors in September, such a declaration could stipulate:
certification by sponsors that specified rules have been kept to
ensure the intellectual independence of investigators; inclusion of
all details of all trials in a registry which is accessible to third
parties such as the Cochrane Collaboration (9); prohibition of legal
action by sponsors against investigators except in the case of fraud;
and protection of whistle-blowers who report unscientific and
unethical research practices (10).
Investment always involves risk, and in clinical research unfavourable
results are part of that risk. If clinical trials become a commercial
venture in which self-interest overrules public interest and desire
overrules science, then the social contract which allows research on
human subjects in return for medical advances is broken.
In the last 50 years the world has seen a stunning output of new
medicines and vaccines. Continued progress depends critically on the
quality of clinical trials. It is in the interest of all stakeholders,
including pharmaceutical firms, that the evidence on which clinical
and policy decisions are based meets the highest standards of
scientific and ethical integrity.
1. Bodenheimer T. Uneasy alliance: Clinical investigators and the
pharmaceutical industry. New England Journal of Medicine, 2000, 342:
1539-1544.
2. Bero LA, Rennie D. Influences on the quality of published drug
studies. International Journal of Technology Assessment in Health
Care, 1996, 12: 209-237.
3. Rettig RA. The industrialization of clinical research. Health
Affairs, 2000, 19: 129-146.
4. Chalmers I. Underreporting research is scientific misconduct.
JAMA, 1990, 263: 1405-1408.
5. Cohen W, Florida R, Goe WR. University-industry research centers
in the United States. Pittsburgh, Carnegie-Mellon University Press,
1994.
6. Davidoff F et al. Sponsorship, authorship, and accountability.
Lancet, 2001, 325: 854-856 (Published simultaneously in 12 other
medical journals.)
7. Relman A. Trust me, I'm a scientist. New Scientist, 22 September
2001, 46-47.
8. Lo B, Wolf LE, Berkeley A. Conflict-of-interest policies for
investigators in clinical trials. New England Journal of Medicines,
2000, 343: 1616-1620.
9. Maynard A, Bloor K. Regulating the pharmaceutical
industry. BMJ, 1997, 315: 200-201.
10. Shuchman M. Consequences of blowing the whistle in
medical research. Annals of Internal Medicine, 2000, 132: 1013-1014.
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