E-drug: Integrity of the clinical evidence base
-------------------------------------------------------------------------
[Editorial. Bulletin of the World Health Organization, 2001, 79 (12).
Copied as fair use. HH]
Maintaining the integrity of the clinical evidence base
Jonathan Quick
In this issue of the Bulletin Jose 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. The
share of contract research grew from 40% to 80% 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
advisers 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 Medicine,
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.
--
To send a message to E-Drug, write to: e-drug@usa.healthnet.org
To subscribe or unsubscribe, write to: majordomo@usa.healthnet.org
in the body of the message type: subscribe e-drug OR unsubscribe e-drug
To contact a person, send a message to: owner-e-drug@usa.healthnet.org
Information and archives: http://www.healthnet.org/programs/edrug.html