[e-drug] WHO: the findings of all clinical trials must be made publicly available

[e-drug@healthnet.org]

E-DRUG: WHO: the findings of all clinical trials must be made publicly available
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[Interesting piece in WHO Bulletin, which opens the debate on the need for transparency of and accessibility to the findings of ALL clinical trials. Cross posted from DRUGINFO - thanks to Andy for spotting. Copied as fair use. WB]

http://www.who.int/bulletin/volumes/86/6/08-053769/en/index.html 
(Volume 86, Number 6, June 2008, 417-496)

Reporting the findings of clinical trials: a discussion paper

D Ghersi a, M Clarke b, J Berlin c, AM Glmezoglu a, R Kush d, P
Lumbiganon e, D Moher f, F Rockhold g, I Sim h, E Wager i

Background

When researchers embark on a clinical trial, they make a commitment to
conduct the trial and to report the findings in accordance with basic
ethical principles. This includes preserving the accuracy of the results
and making both positive and negative results publicly available.1
However, a significant proportion of health-care research remains
unpublished and, even when it is published, some researchers do not make
all of their results available.2 Selective reporting, regardless of the
reason for it, leads to an incomplete and potentially biased view of a
trial and its results.3

The consequences of publication bias and selective reporting have
gained the attention of health-care consumers, the media and
politicians. All have recognized the impact that undisclosed results can
have on the ability of patients, practitioners and policy-makers to make
well-informed decisions about health care. Concern over the
underreporting of adverse events, in particular, has increased the
demand for more transparent processes for registering clinical trials
and reporting their findings. In recent years, trial registration has
become increasingly widely accepted and implemented. There are now
well-established mechanisms to register trials, assign unique
identifiers and make this information publicly available. WHOs
International Clinical Trials Registry Platform Search Portal helps
bring the data from these registers together, making it much easier to
search for the existence of a trial (available at:
http://www.who.int/trialsearch).

The value of registration goes far beyond the administrative benefits
of having a complete collection of all trials. Trial registers may
facilitate recruitment into clinical trials by raising awareness of
their existence among potential participants and health-care
practitioners. They may also lead to more ethical and successful
research by avoiding the unintentional duplication of research already
under way elsewhere. From the perspective of this paper, however, the
greatest benefit of trial registration is enhanced transparency; that
is, making it clear which trials are being conducted so that people can
anticipate their results.

The next step to informed decision-making is to make the findings of
clinical trials available, since it is knowledge of the findings, rather
than of the existence of a trial, that is likely to have the greatest
impact on people trying to choose between alternative interventions. The
arrival and growth of electronic publishing and the Internet as
dissemination tools without page or length restrictions has greatly
expanded the ability of people to make findings available and accessible
in full. The recognition of the need for reliable evidence to improve
health care and to facilitate the synthesis of the results of research
into systematic reviews has fuelled the demand for access to the
findings of all research, as have the needs of the numerous other
stakeholders in clinical research.

A proposed position

The position proposed by the members of the WHO Registry Platform
Working Group on the Reporting of Findings of Clinical Trials is that
the findings of all clinical trials must be made publicly
available. This paper discusses the principles underlying this
position. Our goal is to contribute to the ongoing debate and to foster
the collaboration that is necessary to ensure that the findings of
clinical trials do not remain hidden from the people who need access to
them.

What is a finding?

The language used to discuss the reporting of clinical trials usually
focuses on results - often taken to mean the numerical results of
an analysis for a specific outcome. For example, a summary estimate such
as a relative risk. However, the reader or user of research also needs
background information that will allow them to correctly interpret the
results for specific outcomes. The type and amount of information
required will depend on the nature of the audience and how it will use
the information received but will have four key elements:

1. Methodological context

The user needs to know what the original plans for the trial were and
how it was actually conducted. Some of the original plans will be
available if the trial was registered, but more complete information
should be in the full trial protocol. The actual conduct of the trial
might, however, differ from that planned. Such differences may be valid
but should be traceable, preferably via a clinical trial registry. The
methodological context for a trial might also include information on the
primary question that the researchers set out to answer; the hypothesis
they were seeking to test; the methods they used to allocate or select
participants for the interventions; whether any blinding or masking was
done; and a description of the statistical methods planned and used,
including a justification of the sample size.

2. Population context

The user needs to consider to whom the results of the trial can be
applied. They need to know the characteristics of the population it was
initially intended to recruit, as well as the characteristics of the
population who were recruited. In reporting their findings, the
researchers should therefore refer to the original inclusion and
exclusion criteria and provide information on the population that
actually took part, describing the extent to which participants left the
trial early (with reasons for doing so) and whether interventions were
delivered as planned.

3. A result for each outcome

A clinical trial will usually consider several outcomes, each of which
might be measured in multiple ways or at multiple time points, and there
might be more than one way to analyse each of these measures. The
findings should contain the results for every outcome measure and
analysis specified in the register entry for the trial, and set out in
the protocol or statistical analysis plan. If any of these results are
not reported, a reason should be provided for their absence. Any
findings from analyses that were not pre-specified should be clearly
identified as such.

4. Interpretation

The most contentious aspect of reporting the findings of a clinical
trial may be whether the report should include the researchers
opinions and conclusions. It is in this section of a report where the
objectivity of the research is confronted by the subjectivity of authors
who use their power as owners of their writing to emphasize one point
of view more than another.4 Alternatively, linguistic spin is
considered by some to be essential to scientific communication, being
the opportunity for scientists to speculate and formulate new
hypotheses.5 Distinguishing opinions and conclusions from advocacy or
promotion can be difficult, and it may be preferable to leave the users
of the findings to draw their own conclusions and form their own
opinions of what the findings of a trial mean for them and their
decision-making.

Public availability

Clinical trial results should be available to everyone, regardless of
where they live. If the results are not made available within a
reasonable period, the reasons for delay and a date by which the
findings will be available should be submitted to the relevant clinical
trials registry. It should be the responsibility of researchers to
produce their findings in a format that can be accessed by potential
users, and it should be the responsibility of the user to seek these
results. The Internet could provide the main means by which this shared
responsibility can be satisfied. Access also needs to be considered in
terms of the end users ability to both view and understand the
information obtained.

Historically, access to the results of a trial has usually been
achieved through publication in a peer-reviewed journal. This
traditional publication model has its limitations, particularly in an
environment where the end users of research information now include
health-care policy-makers, consumers, regulators and legislators who
want rapid access to high quality information in a user-friendly
format. In future, researchers may be legally required to make their
findings publicly available within a specific timeframe (assuming any
legislation created does not have escape clauses built in). In the
United States of America, such legislation is already in place
(available at; http://www.fda.gov/oc/initiatives/HR3580.pdf). This may
compromise the ability of researchers to publish trial findings in a
peer-reviewed journal. Although some journal editors have acknowledged
the changing climate around results registration and reporting
(available at: http://www.icmje.org/clin_trial07.pdf), they may have a
conflict of interest in that they will probably want the key (and
potentially most exciting) messages from a trial to appear first, and
perhaps exclusively, in their publication.

Conclusion

People making decisions about health care need access to knowledge
derived from the findings of clinical trial research. Following on from
WHOs position that all clinical trials must be registered,6 it is
proposed that the findings of all clinical trials must be made publicly
available. This report is the start of a consultation process on how
this goal of transparency can be achieved, with the intention that
greater accessibility to the findings of all clinical trials will lead
to improvements in health and health care. To contribute to the first
phase of the consultation, please visit:
http://www.who.int/ictrp/results/consultation 

Competing interests: None declared.

References
1. Declaration of Helsinki. ethical principles for medical research
involving humans. Ferney-Voltaire, France: World Medical Association;
2000. Available from: http://www.wma.net/e/policy/b3.htm [accessed on 9
April 2008]. 
2. Song F, Eastwood AJ, Gilbody S, Duley L, Sutton AJ. Publication and
related biases. Health Technol Assess 2000; 4: . 
3. Chan AW, Hrobjartsson A, Haahr MT, Gotzsche PC, Altman DG. Empirical
evidence for selective reporting of outcomes in randomized trials:
comparison of protocols to published articles. JAMA 2004; 291: 2457-65
doi: 10.1001/jama.291.20.2457 pmid: 15161896. 
4. Horton R. The rhetoric of research. BMJ 1995; 310: 985-7 pmid:
7728037. 
5. Greenhalgh T. Commentary: scientific heads are not turned by
rhetoric. BMJ 1995; 310: 987-8 pmid: 7728038. 
6. Sim I, Chan AW, Gulmezoglu M, Evans T, Pang T. Clinical trial
registration: transparency is the watchword. Lancet 2006; 367: 1631-3
doi: 10.1016/S0140-6736(06)68708-4 pmid: 16714166. 

Affiliations
a. World Health Organization, Geneva, Switzerland. 
b. UK Cochrane Centre, Oxford, England. 
c. Johnson & Johnson, Titusville, NJ, United States of America. 
d. Clinical Data Interchange Standards Consortium (CDISC), Austin, TX,
USA. 
e. Khon Kaen University, Khon Kaen, Thailand. 
f. Childrens Hospital of Eastern Ontario, Ottawa, ON, Canada. 
g. GlaxoSmithKline, Philadelphia, PA, USA. 
h. University of California, San Francisco, CA, USA. 
i. Sideview, Princes Risborough, Buckinghamshire, England.