JAMA news releases are made available to the public after 3 pm US Central time on the first 4 Tuesdays of each month. The Archives Journals news releases are made available to the public after 3 pm Central time on Mondays. We also provide a list of previous news releases.
THIS WEEK'S CONTENT
JAMA NEWS RELEASES
(Embargoed for Release: 3:00 p.m. CT, Tuesday, April 15, 2008)
JAMA NEWS RELEASES
USE OF GHOSTWRITERS, GUEST AUTHORS APPEARS FREQUENT FOR STUDIES INVOLVING ROFECOXIB
RISK OF DEATH FROM ROFECOXIB IN SOME TRIALS MAY HAVE BEEN MISREPRESENTED BY STUDY SPONSOR
EDITORIAL: IMPUGNING THE INTEGRITY OF MEDICAL SCIENCE - THE ADVERSE EFFECTS OF INDUSTRY INFLUENCE
JAMA REPORT (VIDEO SCRIPT)
VIDEO: Windows Media | Quicktime
MERCK FAILS TO DISCLOSE MORTALITY RISK ASSOCIATED WITH VIOXX
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TV Note: This week's JAMA Video News Report is on the reporting of the risk of death findings in the trials of rofecoxib for Alzheimer disease or cognitive impairment. The report will be fed Tuesday, April 15, from 9:00 - 9:30 a.m. ET and 2:00 - 2:30 p.m. ET, on Galaxy 26 (formerly Intelsat America 6) C-Band, Transponder 14, downlink frequency: 3880 vertical, audio 6.2/6.8. For more information, call 312/464-JAMA.
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Embargoed for Release: 3:00 p.m. CT, Tuesday, April 15, 2008
Media Advisory: To contact Joseph S. Ross, M.D., M.H.S., call the Mount Sinai Newsroom at 212-241-9200.
USE OF GHOSTWRITERS, GUEST AUTHORS APPEARS FREQUENT FOR STUDIES INVOLVING ROFECOXIB
CHICAGO—An examination of medical articles about rofecoxib (a nonsteroidal anti-inflammatory drug) 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 an article in the April 16 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.
(JAMA. 2008;299[15]:1800-1812. Available pre-embargo to the media at www.jamamedia.org)
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. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.
For More Information: Contact the JAMA/Archives Media Relations Department at 312/464-JAMA (5262) or email: mediarelations{at}jama-archives.org.
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Embargoed for Release: 3:00 p.m. CT, Tuesday, April 15, 2008
Media Advisory: To contact Bruce M. Psaty, M.D., Ph.D., call Clare Hagerty at 206-685-1323.
RISK OF DEATH FROM ROFECOXIB IN SOME TRIALS MAY HAVE BEEN MISREPRESENTED BY STUDY SPONSOR
CHICAGO—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 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 JAMA.
“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). “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.
(JAMA. 2008;299[15]:1813-1817. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Please see the article for additional information, including author contributions and affiliations, financial disclosures, funding and support, etc.
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Embargoed for Release: 3:00 p.m. CT, Tuesday, April 15, 2008
Media Advisory: To contact Catherine D. DeAngelis, M.D., M.P.H., call Jann Ingmire at 312-464-2499.
EDITORIAL: IMPUGNING THE INTEGRITY OF MEDICAL SCIENCE — THE ADVERSE EFFECTS OF INDUSTRY INFLUENCE
CHICAGO—In an editorial in the April 16 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:
- 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.
- 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.
- All journals must disclose all pertinent relationships of all authors with any for-profit companies, and must publish all funding sources for each article.
- 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.
- 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.
- ll journals must require a statistical analysis of clinical trial data conducted by a statistician who is not an employee of a for-profit company.
- 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.
- 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.
- 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.
- 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.
- 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.
(JAMA. 2008;299[15]:1833-1835. Available pre-embargo to the media at www.jamamedia.org)
Editor's Note: Please see the article for additional information, including financial disclosures, funding and support, etc.
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JAMA REPORTS
VIDEO: Windows Media | Quicktime
MERCK FAILS TO DISCLOSE MORTALITY RISK ASSOCIATED WITH VIOXX
INTRO:
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.
VIDEO:
B-ROLL
Wide shot documents on table
Tight to papers
Vioxx name
Elderly patients
AUDIO:
THESE LEGAL DOCUMENTS SPELL OUT WHAT MERCK KNEW AND WHEN THEY KNEW IT. IN CLINICAL TRIALS DURING THE LATE NINETIES THE COMPANY TESTED WHETHER THEIR ANTI-INFLAMMATORY DRUG VIOXX COULD PREVENT COGNITIVE DECLINE IN PATIENTS WITH ALZHEIMER’S DISEASE. LIFE THREATENING RISKS WERE DOCUMENTED BUT WERE NEVER REPORTED TO THE F-D-A OR THE PUBLIC.
VIDEO:
SOT/FULL
Super @: 21
Bruce Psaty, M.D., Ph.D.
University of Washington
Runs :11
AUDIO:
“The company found a threefold increase risk in mortality and failed to see a safety signal. By scientific standards this is a major safety issue.”
VIDEO:
B-ROLL
Researcher looking at documents
Wide shot report on table
Tight shot –“Neurology 2004”
FULL SCREEN GRAPHIC:
“Generally well tolerated by the elderly patients in our study...”
Internal company document
FULL SCREEN GRAPHIC:
“Hazard Ratio... 2.99” “April 8, 2001”
AUDIO:
DOCTOR BRUCE PSATY (Pa-sade-E) AND COLLEAGUES AT THE UNIVERSITY OF WASHINGTON REVIEWED NUMEROUS LEGAL DOCUMENTS FROM LITIGATION INVOLVING MERCK AND VIOXX. IN A PUBLISHED REPORT IN 2004 MERCK REPORTED THAT VIOXX IS QUOTE “GENERALLY WELL TOLERATED BY THE ELDERLY PATIENTS IN OUR STUDY”. BUT THIS INTERNAL COMPANY DOCUMENT TELLS A DIFFERENT STORY. IT REVEALS MERCK KNEW ABOUT AN INCREASED RISK IN MORTALITY ASSOCIATED WITH VIOXX AND THEY KNEW THIS IN 2001.
VIDEO:
SOT/FULL
Bruce Psaty, M.D., Ph.D.
University of Washington
Runs: 16
AUDIO:
“If these findings had been made public back in 2001 many fewer people would have taken Vioxx and because it is associated with an increased risk of mortality and of heart attacks many fewer people would have been harmed.”
VIDEO:
B-ROLL
Vioxx ad here
AUDIO:
IN 2002, DESPITE KNOWING THE RISK, MERCK EXTENDED ONE OF THE CLINICAL TRIALS AND EVEN RE-ENROLLED PATIENTS. DURING THIS TIME EIGHT DEATHS WERE ASSOCIATED WITH THE USE OF VIOXX.
VIDEO:
SOT/FULL
Bruce Psaty, M.D., Ph.D.
University of Washington
Runs:06
AUDIO:
“Large clinical trials like these clearly need independent data and safety monitoring committees to protect the patients.”
VIDEO:
B-ROLL
GFX/ JAMA COVER
AUDIO:
DOCTOR PSATY’S REVIEW APPEARS THIS WEEK IN JAMA, JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION.
VIDEO:
SOT/FULL
Bruce Psaty, M.D., Ph.D.
University of Washington
Runs: 12
AUDIO:
“The wisdom of allowing companies to control and analyze the data from their studies really comes under question when we have mortality findings that are concealed in this way.”
VIDEO:
B-ROLL
Person working in lab
Person taking a pill
AUDIO:
PSATY SAYS STRICTER REGULATIONS ARE NECESSARY NOT ONLY TO AVOID SELECTIVE REPORTING OF RESULTS, BUT TO HELP RESTORE PUBLIC TRUST. JENNIFER MITCHELL, THE JAMA REPORT.
TAG:
Some new safeguards are already in place. The Food and Drug Administration Amendments Act went into effect in October 2007 requiring companies to submit clinical trial findings to a public results database. This is meant to help prevent selective reporting of results from clinical trials. For more information about this study you can log on to www.jama.com.
