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Citation: The PLoS Medicine Editors
(2011) Why Drug Safety Should Not Take a Back Seat to Efficacy. PLoS
Med 8(9): e1001097. doi:10.1371/journal.pmed.1001097
Published: September 27, 2011
Copyright: © 2011 PLoS Medicine Editors.
This is an open-access article distributed under the terms of the
Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original
author and source are credited.
Funding: The authors are each paid a salary by the Public Library of Science, and they wrote this editorial during their salaried time.
Competing interests: The authors' individual competing interests are athttp://www.plosmedicine.org/static/editorsInterests.action. PLoS is funded partly through manuscript publication charges, but the PLoS Medicine Editors are paid a fixed salary (their salary is not linked to the number of papers published in the journal).
* E-mail: medicine_editors@plos.org
The PLoS Medicine Editors are Virginia Barbour, Jocalyn Clark, Susan Jones, Melissa Norton, Paul Simpson, and Emma Veitch.
Provenance: Written by editorial staff; not externally peer reviewed.
Historically,
the evaluation of harmful effects resulting from prescription drug use
has been considered less important than demonstrating drug efficacy, yet
the harms caused by specific adverse drug reactions are a major, and
avoidable, contributor to hospitalizations and deaths [1].
There are many reasons (both scientific and social) why reliable data
on harmful effects may only emerge well after drug approval and
marketing [2].
Some evidence suggests that drugs approved under a rapid regulatory
review process may be more likely to show problems with safety
post-marketing than drugs that go through a slower evaluation process [3].
And debates continue about the best ways to meaningfully synthesize and
interpret data on the possible harmful effects of drugs—for example,
how passive surveillance systems (spontaneous reports of suspected
adverse reactions) should be improved, whether new drugs should go
through a phased launch process with enhanced safety evaluations, and
whether risk mitigation strategies are appropriate for drugs with safety
concerns.
One
such debate—whether systematic reviews estimating the risk of harmful
effects should use evidence from randomized trials or observational
studies—seems finally to have been laid to rest. In a systematic
overview published earlier this year in PLoS Medicine [4],
Su Golder, Yoon Loke, and Martin Bland demonstrate that, for 19
specific drug–harm relationships, the evidence on magnitude of risk for
each particular harm discovered through systematic reviews of randomized
trials was, on average, no different from the evidence assembled via
systematic reviews of observational studies. This is an important
finding, although perhaps counterintuitive: it is easy to imagine that
observational studies would be so plagued by confounding that the
estimates of risk of harm they generate could be biased away from true
effects. The implications of this study for future evaluations of drug
safety are clear: systematic reviewers should consider all types of
evidence in trying to build a complete picture of harms associated with
drug treatments.
In another study published this week in PLoS Medicine [5],
Patricia McGettigan and David Henry report their re-evaluation of one
specific and much-studied harmful effect—that of cardiovascular risk
associated with use of nonsteroidal anti-inflammatory drugs (NSAIDs).
Many previous systematic reviews have been conducted, largely using
evidence from randomized trials, but these trials have generally
captured only small numbers of cardiovascular events and have focused
mainly on a small range of specific NSAIDs. By revisiting observational
data in their systematic review, Henry and colleagues were able to form a
fuller profile of the cardiovascular risks associated with use of a
much wider group of NSAIDs, across dose ranges and in population
settings, than had previously been the case. Broadly, their findings
correlate closely with those of systematic reviews of trial data, but
also show that there seems to be no “safe” lower dose for cardiovascular
risk associated with certain NSAIDs, such as rofecoxib and diclofenac.
These
studies together highlight the importance of data from high-quality
observational studies in enabling estimation of the risk of harms
associated with specific drug treatments. Passive surveillance is still
crucial for providing early warning signals and generating new
hypotheses about possible harms associated with specific approved drugs.
However, new hypotheses emerging from such surveillance must
subsequently be explicitly tested, preferably using study designs that
can incorporate data on the size of the exposed population (such as
cohort or record linkage studies). Such studies can therefore estimate
the relative increase in risk associated with exposure, which is
difficult or impossible to calculate from passive surveillance data.
A
new initiative established by the European Medicines Agency (ENCEPP,
the European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance [6],[7])
seeks to promote the conduct of such studies and establish standards
for post-marketing safety evaluations. Given the diversity of designs
and multiple possible sources of bias in pharmacoepidemiology, this will
not be an easy job. But the initiative is already showing signs of
setting high standards in some areas. Studies conducted solely by
industry will not be eligible to qualify for ENCEPP approval; studies
must be publicly registered before collection of data, and protocols and
datasets must be released (with some restrictions relating to data
privacy) in a timely way after completion. Some vague wording in the
ENCEPP code of conduct remains, however: “datasets” can be interpreted
to mean analyzed, not raw, data, meaning that other investigators may
not be able to exploit the full potential of the data in conducting
reanalyses. Critically, ENCEPP can still potentially approve studies
funded by the pharmaceutical industry, with involvement of industry
partners in design and analysis, providing the study's lead investigator
is based within an ENCEPP-approved center. More worryingly, the code
allows for industry sponsors to retain control of datasets; this, and
other provisions, may enable conflicts of interest to creep in during
study design or data analysis.
Clearly,
for post-approval safety studies, one size will not fit all. Conduct
and reporting are unlikely to be standardizable in the same way as has
been possible for randomized trials, in which there is agreement on what
information needs to be registered about the study and when [8], and specific standards for the reporting of studies, such as CONSORT [9],
are widely accepted. The ENCEPP guidance avoids normative statements
about study design, instead preferring to highlight the methodological
challenges and multiple sources of bias that plague analysis and
interpretation of data. However, these challenges should not discourage
investigators, regulators, and patients from demanding a higher safety
standard for approved drugs. Higher standards will require both greater
transparency—in revealing what studies are being conducted and what data
that have been generated—and greater willingness of funders to support
new studies specifically addressing drug safety.
Author Contributions Top
Wrote the first draft: EV. Contributed to the writing of the paper: VB JC SJ MN PS.
References Top
- (2004) Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18,820 patients. BMJ 329: 15–19. FIND THIS ARTICLE ONLINE
- (2004) Potential for conflict of interest in the evaluation of suspected adverse drug reactions. JAMA 292: 2643–2646. FIND THIS ARTICLE ONLINE
- (2008) Drug-review deadlines and safety problems. N Engl J Med 358: 1354–1361. FIND THIS ARTICLE ONLINE
- (2011) Meta-analyses of adverse effects data derived from randomised controlled trials as compared to observational studies: Methodological overview. PLoS Med 8(5): e1001026. doi:10.1371/journal.pmed.1001026.
- (2011) Cardiovascular Risk with non-steroidal anti-inflammatory drugs: Systematic review of population-based controlled observational studies. PLoS Med 8(9): e1001098. doi:10.1371/journal.pmed.1001098.
- European Network of Centres for Pharmacoepidemiology and Pharmacovigilance. Home page. Available: http://www.encepp.eu/.
- (2011) Postmarketing studies of drug safety. BMJ 342: d342. FIND THIS ARTICLE ONLINE
- (2007) Clinical trial registration — Looking back and moving ahead. N Engl J Med 356: 2734–2736. FIND THIS ARTICLE ONLINE
- CONSORT: Transparent Reporting of Trials. Home page. Available: http://www.consort-statement.org/.
