Risk of Death From Vioxx In Clinical Trials May Have
Been Misrepresented By Merck
JAMA focuses on drug-maker Merck's apparent attempt
to manipulate data
April
15, 2008 - A comparison of internal company documents, data submitted by
the company to the FDA, and published clinical trial results indicates
that the risk-benefit profile of rofecoxib, marketed as Vioxx and Ceoxx,
in clinical trials involving patients with cognitive impairment may have
been misrepresented by study sponsor Merck, according to an article in
the April 16 issue of the Journal of the American Medical Association
(JAMA).
Watch Video
See Video on Vioxx
Litigation involving drug maker Merck has revealed new
information about safety concerns associated with the drug
Vioxx, pulled from the market in 2004. Legal documents recently
made public show the company found an increased risk in
mortality rates during clinical trials to treat patients with
Alzheimer’s disease but the dangers were never made clear to the
public. Jennifer Mitchell explains in this week’s JAMA Report.
“Sponsors have a marketing interest to represent
their products in the best light. This approach conflicts with
scientific standards that require the symmetric and comparable reporting
of safety and efficacy data. Selective reporting of the results of
clinical trials can misrepresent the risk-benefit profile of drugs,” the
authors write.
Bruce M. Psaty, M.D., Ph.D., and Richard A. Kronmal,
Ph.D., of the University of Washington, Seattle, conducted a review of
documents to summarize how the study sponsor represented findings
regarding the risk of death associated with rofecoxib in clinical trials
of patients with Alzheimer disease or cognitive impairment.
The documents became available during litigation
related to rofecoxib involving Merck, including internal company
analyses and information provided by the sponsor to the Food and Drug
Administration (FDA). The authors also evaluated information in two
published articles that reported results of these trials.
In one article (reporting results of protocol 091)
published in 2004, 11 “non-drug related deaths” were reported (9 deaths
among 346 rofecoxib patients and 2 deaths among 346 placebo patients).
In another article (reporting results of protocol
078) published in 2005, 39 deaths were reported among patients taking
study treatment or within 14 days of the last dose (24 among 725
rofecoxib patients and 15 among 732 placebo patients) and an additional
22 deaths in the off-drug period (17 in rofecoxib patients and 5 in
placebo patients).
More
About Rofecoxib (Vioxx)
Rofecoxib is a nonsteroidal
anti-inflammatory drug (NSAID) developed by Merck & Co. to treat
osteoarthritis, acute pain conditions, and dysmenorrhoea.
Rofecoxib was approved as safe and effective by the Food and
Drug Administration (FDA) on May 20, 1999 and was subsequently
marketed under the brand name Vioxx, Ceoxx and Ceeoxx.
Rofecoxib gained widespread
acceptance among physicians treating patients with arthritis and
other conditions causing chronic or acute pain. Worldwide, over
80 million people were prescribed rofecoxib at some time.
On September 30, 2004, Merck
voluntarily withdrew rofecoxib from the market because of
concerns about increased risk of heart attack and stroke
associated with long-term, high-dosage use. Rofecoxib was one of
the most widely used drugs ever to be withdrawn from the market.
In the year before withdrawal, Merck had sales revenue of $2.5
billion from Vioxx. From Reuters report on Wikipedia.
Click to read more…
“However, these articles did not include analyses
or statistical tests of the mortality data, and the two articles
concluded that regarding safety, rofecoxib is ‘well tolerated,’” the
authors write.
In contrast, in April 2001, the company’s internal
intention-to-treat analyses (data analysis technique based on evaluation
of patients in the study group to which they were randomly assigned) of
pooled data from these two trials identified a significant three-fold
increase in total mortality, with overall mortality of 34 deaths among
1,069 rofecoxib patients and 12 deaths among 1,078 placebo patients.
“These mortality analyses were neither provided to
the FDA nor made public in a timely fashion,” the authors write. The
data submitted by the sponsor to the FDA in a Safety Update Report in
July 2001 used on-treatment analysis (a data analysis technique based
only on evaluation of patients who were actually taking the drug or
placebo they were assigned to take) methods and reported 29 deaths (2.7
percent) among 1,067 rofecoxib patients and 17 deaths (1.6 percent)
among 1,075 placebo patients.
“This on-treatment approach to reporting minimized
the appearance of any mortality risk,” they add. Deaths that had
occurred more than 14 days after discontinuation of the trial drug
apparently were not included.
In December 2001, when the FDA raised safety
questions about the submitted safety data, the sponsor did not bring
these issues to an institutional review board for review and revealed
that there was no data and safety monitoring board (DSMB) for the
protocol 078 study.
During additional follow-up time for the 078 study,
there were approximately 8 excess deaths among those randomly assigned
to receive rofecoxib, which was also associated with an increased risk
of progression to Alzheimer disease, “a finding that was apparent early
in the trial. The mortality findings and the Alzheimer disease findings
would, in our judgment, have prompted a DSMB, if it had existed, to stop
the trial early,” the researchers write.
“The only human-subjects protections available to
the study participants were those provided by the investigators who were
blind not only to the treatment allocation but also to the findings for
study-wide adverse events, and by the unblinded Merck investigators, who
did not discern a safety issue. The sponsor’s submission of individual
adverse event reports over time to the FDA is not adequate for active
trial monitoring.
"The FDA depends on the sponsor and the DSMB to
alert the agency about any evidence of harm that may be associated with
the drug.” They add that all large clinical trials, especially for drugs
with known serious risks, should have a DSMB.
“Sponsors have a direct financial interest in their
products and a fiduciary duty to shareholders to provide a return on
their investment. These interests disqualify sponsors from other
important duties, including those normally accorded to DSMBs and
institutional review boards (IRBs). Failure of the sponsor to inform
IRBs of a safety issue violates the trust of those human participants
who volunteered to advance science, medicine, and public health.”
“For sponsors that conduct their own studies or use
contract research organizations to conduct studies, it is not clear how
transparency in the reporting of results can be achieved if a sponsor
chooses to represent its products in the best possible light.
"The commercialization of clinical trials has
neither improved the quality of the science nor enhanced the protection
of human research participants. The findings from this case study
suggest that additional protections for human research participants,
including new approaches for the conduct, oversight, and reporting of
industry-sponsored trials, are necessary. A clinical trials system in
which sponsors fund the trials that are conducted by independent
investigators would provide additional protections,” the authors
conclude.
Use of Ghostwriters, Guest Authors Appears
Frequent For Studies Involving Rofecoxib
An examination of medical articles about rofecoxib
(a nonsteroidal anti-inflammatory drug marketed as Vioxx) and court
documents from litigation related to this product indicates that company
employees or other unacknowledged authors were frequently involved in
writing clinical trial articles and review articles, but that primary
authorship was often attributed to academically affiliated investigators
who may have had little to do with the study, or who did not always
disclose financial support from the sponsor of the study, according to
another article in the same issue of JAMA.
Authorship in biomedical publication provides
recognition while establishing accountability and responsibility. Guest
authorship has been defined as the designation of an individual who does
not meet authorship criteria, according to background information in the
article. Ghostwriting has been defined as the failure to designate an
individual (as an author) who has made a substantial contribution to the
research or writing of a manuscript.
“Recent litigation related to rofecoxib provided a
unique opportunity to examine guest authorship and ghostwriting,
practices that have been suspected in biomedical publication but for
which there is little documentation,” the authors write.
Joseph S. Ross, M.D., M.H.S., of Mount Sinai School
of Medicine, New York, and colleagues conducted a case-study review of
court documents, in combination with a review of the relevant medical
literature, to describe the practice of guest authorship and
ghostwriting related to rofecoxib. The researchers used court documents,
created predominantly between 1996 and 2004, originally obtained during
litigation related to rofecoxib against Merck & Co. Inc. In addition,
publicly available articles related to rofecoxib were identified via
MEDLINE. Approximately 250 documents were relevant for the review.
When publishing their own clinical trials
(designed, conducted, and sponsored by Merck), documents were found
describing Merck scientists often working to prepare manuscripts and
subsequently recruiting external, academically affiliated investigators
to collaborate on the manuscript as guest authors. “Recruited authors
were frequently placed in the first and second positions of the
authorship list. For the publication of scientific review papers,
documents were found describing Merck marketing employees developing
plans for manuscripts, contracting with medical publishing companies to
ghostwrite manuscripts, and recruiting external, academically affiliated
investigators to be authors,” the researchers write. Documents indicated
that medical publishing companies provided near complete drafts of
review manuscripts to authors for editing, in addition to managing
submissions and revisions.
Documents were also found describing Merck
compensating investigators with honorarium for agreeing to serve as
authors on review manuscripts ghostwritten on their behalf by medical
publishing companies. “Among 96 relevant published articles, we found
that 92 percent (22 of 24) of clinical trial articles published a
disclosure of Merck’s financial support, but only 50 percent (36 of 72)
of review articles published either a disclosure of Merck sponsorship or
a disclosure of whether the author had received any financial
compensation from the company.”
“This case-study review of industry documents
related to rofecoxib demonstrates that Merck used a systematic strategy
to facilitate the publication of guest authored and ghost written
medical literature,” the authors write. “We are hopeful that our
findings encourage discussion of ways in which to improve the integrity
of research. The medical profession and the pharmaceutical industry
should agree that collaborations must be conducted with the highest
standards. We suggest that academic researchers consistently provide to
the journals the author contributions for all manuscripts, including
original research, meta-analyses, reviews, and commentaries, and
disclose relationships and support from all industry sources, regardless
of the journal’s requirements.”
“Authors who ‘sign-off’ on or ‘edit’ original
manuscripts or reviews written explicitly by pharmaceutical industry
employees or by medical publishing companies should offer full
authorship disclosure, such as, ‘drafting of the manuscript was done by
representatives from XYZ, Inc.; the authors were responsible for
critical revisions of the manuscript for important intellectual
content.’ A coordinated oversight strategy involving academic
physicians, journal editors, and industry representatives is necessary
to discourage both guest authorship and ghostwriting and improve the
integrity of the biomedical authorship system,” the authors conclude.
Editor's Note: All of the authors have been
compensated for their work as consultants at the request of plaintiffs
in litigation against Merck & Co. Inc. related to rofecoxib. Co-author
Dr. Krumholz reported serving on the advisory boards of Amgen and
UnitedHealthcare and being a subject expert for VHA Inc.
Editorial: Impugning the integrity of medical
science — the adverse effects of industry influence
In an editorial in the same issue of JAMA,
Catherine D. DeAngelis, M.D., M.P.H., Editor in Chief, and Phil B.
Fontanarosa, M.D., M.B.A., Executive Deputy Editor, JAMA, comment on the
studies in this week’s JAMA documenting the apparent misrepresentation
of research data by one company and its manipulation of clinical
research articles and clinical reviews.
“What are the lessons from the 2 articles in this
issue of JAMA, from other publications that have examined related
issues, and from extensive experience with how clinical research has
been manipulated by for-profit companies? First, manipulation of studies
and misrepresentation of study results could not occur without the
cooperation (active and tacit) of clinical researchers, other authors,
journal editors, peer reviewers, and the Food and Drug Administration
(FDA).”
“Second, public trust for clinical research is in
great jeopardy especially when the extent of how widespread such
practices have become is unknown. Although we truly believe that the
vast majority of researchers and other authors are honest and have the
highest scientific integrity, manipulation of studies and publications
by the pharmaceutical and medical device industries is either increasing
or there has been more exposure of these practices.”
“Third, in addition to clinical research, clinical
practice and medical education also are greatly influenced by for-profit
companies. Drastic action is essential, and cooperation of everyone
involved in medical research, medical editing, medical education, and
clinical practice is required for meaningful change to occur.”
Drs. DeAngelis and Fontanarosa propose the
following:
1. All clinical trials must be prospectively
listed in registries accepted by the International Committee of Medical
Journal Editors (ICMJE) prior to patient enrollment, and the name(s) of
the principal investigator(s) should be included as a required data
element in the trial registration record.
2. All individuals named as authors on articles
must fulfill authorship criteria. Journals should require each author to
report his or her specific contributions to the article, and should
consider publishing these contributions.
3. All journals must disclose all pertinent
relationships of all authors with any for-profit companies, and must
publish all funding sources for each article.
4. Journal editors must seriously consider funding
sources and authors’ disclosed financial conflicts of interest and
financial relationships when deciding whether to publish a study or
review.
5. For-profit companies that sponsor biomedical
research studies should not be solely or primarily involved in
collecting and monitoring of data, in conducting the data analysis, and
in preparing the manuscript reporting study results.
6. All journals must require a statistical
analysis of clinical trial data conducted by a statistician who is not
an employee of a for-profit company.
7. Any author who fails to disclose financial
relationships or other conflicts of interest, or who allows his or her
name to be used for work that he or she did not actually perform, must
be reported to the appropriate authority (i.e., medical school dean or
department chair) or appropriate oversight body.
8. Any peer reviewer who provides any confidential
information, such as a manuscript under review, to any third parties,
such as for-profit companies, or who engages in other similar unethical
behavior, also should be reported to the appropriate authority (e.g.,
medical school dean) or oversight body, and should be banned from
reviewing and publishing articles in that journal.
9. Any editor who knowingly allows (or is party to
allowing) for-profit companies to manipulate his or her journal must be
relieved of the editorship.
10. To maintain a healthy distance from industry
influence, professional organizations and providers of continuing
medical education courses should not condone or tolerate for-profit
companies having any input into the content of educational materials or
providing funding or sponsorship for medical education programs.
11. Individual physicians must be free of financial
influences of pharmaceutical and medical device companies including
serving on speaker’s bureaus or accepting gifts.
“When integrity in medical science or practice is impugned or
threatened—such as by the influence of industry—patients, clinicians,
and researchers are all at risk for harm, and public trust in research
is jeopardized. Ensuring, maintaining, and strengthening the integrity
of medical science must be a priority for everyone,” they conclude.
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April
15, 2008 - A comparison of internal company documents, data submitted by
the company to the FDA, and published clinical trial results indicates
that the risk-benefit profile of rofecoxib, marketed as Vioxx and Ceoxx,
in clinical trials involving patients with cognitive impairment may have
been misrepresented by study sponsor Merck, according to an article in
the April 16 issue of the Journal of the American Medical Association
(JAMA). 