Monday, November 4, 2013

Fwd: qotd: Drug and device studies being withheld illegally

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Subject: qotd: Drug and device studies being withheld illegally
Date: Mon, 4 Nov 2013 14:28:36 -0800
From: Don McCanne <>
To: Quote-of-the-Day <>

October 29, 2013
Non-publication of large randomized clinical trials: cross sectional
By Christopher W Jones, Lara Handler, Karen E Crowell, Lukas G Keil,
Mark A Weaver, Timothy F Platts-Mills

Randomized clinical trials are a critical means of advancing medical
knowledge. Clinical trials depend on the willingness of participants to
expose themselves to the risks of randomization, blinding, and unproven
interventions. The ethical justification for these risks is that society
will eventually benefit from the knowledge gained from the trial.
Because the risks involved in trial participation may be significant,
and because individual trial participants often do not benefit directly
from trial participation, substantial safeguards have been implemented
to protect the interests of study participants both prior to and during
the trial. These safeguards take multiple forms, including oversight by
institutional review boards, the informed consent process, and data and
safety monitoring boards. Until recently, the protection of the
interests of study participants after trial completion has received
significantly less emphasis. This began to change in 1997 with the
signing of the Food and Drug Administration Modernization Act in the
United States, which mandated that the US Department of Health and Human
Services establish a registry of clinical trials, thereby providing
permanent, public access to information on the conduct of both publicly
and privately funded clinical trials.

In 2005 the International Committee of Medical Journal Editors (ICMJE)
required that prospective trials involving human participants be
registered prior to the beginning of study enrollment in order to be
considered for publication in member journals. This requirement was
later incorporated into the ICMJE's "uniform requirements for
manuscripts submitted to biomedical journals," along with the updated
CONSORT 2010 statement for the reporting of randomized controlled
trials. The prospective registration of phase II-IV clinical trials
subsequently became federal law in the United States in 2007 with the
passage of the Food and Drug Administration Amendments Act. This
legislation also expanded the scope of to include a
database of trial results. Results from all registered studies may be
posted to, including studies completed prior to
enactment of the Food and Drug Administration Amendments Act. In
addition, reporting results is now mandatory for many trials. Failure to
comply with this mandate can result in substantial penalties, including
civil fines of up to $10 000 (£6200; €7400) per day and withholding of
funds from investigators sponsored by the National Institutes of Health.

The registration of clinical trials serves an important role in
protecting the interests of study participants after trial completion.
In addition to discouraging investigators from preferentially choosing
to report statistically significant positive outcomes, trial
registration can increase awareness of possible publication bias within
the medical literature by allowing the public to compare the subset of
trials with published results to the total number of trials that were
registered and conducted. Publication bias can distort the apparent
efficacy of interventions, which complicates the interpretation of the
medical literature. The non-publication of trial data also violates an
ethical obligation that investigators have towards study participants.
When trial data remain unpublished, the societal benefit that may have
motivated someone to enroll in a study remains unrealized. Systematic
trial registration provides a tool that can help to assess both the
magnitude and the causes of these problems.

Data sources

PubMed, Google Scholar, and Embase were searched to identify published
manuscripts containing trial results. The final literature search
occurred in November 2012. Registry entries for unpublished trials were
reviewed to determine whether results for these studies were available
in the results database.


Of 585 registered trials, 171 (29%) remained unpublished. These 171
unpublished trials had an estimated total enrollment of 299 763 study
participants. The median time between study completion and the final
literature search was 60 months for unpublished trials. Non-publication
was more common among trials that received industry funding (150/468,
32%) than those that did not (21/117, 18%), P=0.003. Of the 171
unpublished trials, 133 (78%) had no results available in

From the Discussion

Trial investigators and sponsors have an ethical obligation to study
participants to publish trial results. This principle is implicit in the
US Federal Policy for the Protection of Human Subjects, also known as
the "Common Rule," which outlines the scope and responsibilities of
institutional review boards for overseeing research using human
participants. The Common Rule states that institutional review board
approval requires demonstration that "risks to subjects are reasonable
in relation to anticipated benefits, if any, to subjects, and the
importance of the knowledge that may reasonably be expected to result."
Similarly, the Declaration of Helsinki, which was instrumental in
developing the modern system of oversight by institutional review
boards, also acknowledges the importance of disseminating research
results, stating "Authors have a duty to make publicly available the
results of their research on human subjects and are accountable for the
completeness and accuracy of their reports." By directing institutional
review boards to assess the societal importance of resulting knowledge
in addition to the possible risks and harms to individual research
participants, the Common Rule provides justification for institutional
review board oversight of results reporting, including trial
registration and publication. Because the involvement of institutional
review boards with clinical trial oversight begins prior to participant
enrollment, these institutions are uniquely positioned to protect the
rights of study participants throughout all stages of trial conduct,
from study planning to reporting results. Given the persistent problem
of unpublished trial results despite continued emphasis on trial
registration from governmental agencies, funding organizations, and the
editorial community, increased institutional review board attention
toward this issue may be needed.


We observed that non-publication is common among large randomized
clinical trials. Furthermore, the sponsors and investigators of these
unpublished trials infrequently utilize the results
database. The lack of availability of results from these trials
contributes to publication bias and also constitutes a failure to honor
the ethical contract that is the basis for exposing study participants
to the risks inherent in trial participation. Additional safeguards are
needed to ensure timely public dissemination of trial data.


Comment: Publication bias of drug and device studies has bordered on
the criminal. Industry funded studies in particular were often withheld
from publication if the results were not favorable for the future
marketing of the product; that is, if the studies showed no benefit or,
worse, if they showed that the products were harmful.

Recognizing the problem, in 2005 medical journal editors began to
require that studies be registered before clinical trials began or the
studies would not be published in peer reviewed journals. In 2007 the
federal government began to mandate the reporting of studies with the
threat of civil fines for failing to comply. Many of us recognized that
this failure of the private sector required government intervention, and
we were relieved to finally see it.

Alas, this study shows that non-compliance is still common, especially
with industry funded studies. Not only does this corrupt the data bases
on which our knowledge of new drugs and devices relies, it is also a
failure of ethics by withholding results of human experimentation
consented to by individuals who placed their health at stake to advance
our understanding of the benefits and potential harms of these products.
That ethical failure extends to future individuals who might be exposed
to ineffective or harmful interventions merely because this adverse
information was withheld from the medical community.

There is an analogy with single payer. Private sector enthusiasts insist
on exposing us to the waste, inefficiencies, and sometimes harm
inflicted on us by the private insurance industry and its marketplace
applications. The administrators of a government single payer program do
not experiment with patients in order to expand the market for health
care. However, they do collect generic data, rather than hiding it, to
help advance our understanding of beneficial health care interventions.

Whether it's drug and device research or health care financing, we need
more government involvement, not less.

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