Elias A. Zerhouni, M.D., Director
National Institutes of Health
9000 Rockville Pike
Bethesda, MD 20892-2152
Dear Dr. Zerhouni,
A senior scientist/physician from the NIH (National Heart, Lung, and Blood Institute – NHLBI), who has been a consultant to AstraZeneca, was the editor of the proceedings of a symposium and the author of an article in the proceedings containing an incomplete, inaccurate analysis understating the serious risks of AstraZeneca’s cholesterol-lowering drug, rosuvastatin (Crestor). According to the article, this analysis of Crestor’s safety was based on information provided to the NIH physician, Dr. H. Brian Brewer, by AstraZeneca as of April, 2003. The symposium, at the American Heart Association meeting in November, 2002, and the costs of publishing this Supplement to the American Journal of Cardiology containing these proceedings (conveniently published August 21, 2003, the week after FDA approved Crestor), were “supported by an unrestricted educational grant from AstraZeneca.”
Incomplete or inaccurate information in the article by Dr. Brewer includes the following:
- The article inexplicably is limited to results with the 10 to 40 milligram doses and mentions none of the serious adverse reactions that occurred at the 80 milligram dose of rosuvastatin. That dose was widely studied but dropped before marketing because of its toxicity. These results include: 7 cases of life-threatening rhabdomyolysis – destruction of muscle (no cases at any dose had occurred in pre-approval trials with any other statin, including the banned Baycol). Also missing from Dr. Brewer’s article is the information, discussed in FDA briefing documents, that: “there is a higher incidence of myopathy (1·0%) and rhabdomyolysis (0·4%) observed in the clinical trials with 80 mg of rosuvastatin than reported in the original NDA or current labels for any of the currently approved statins.”
- The FDA briefing documents also refer to one case of rhabdomyolysis at the much lower dose of 10 milligrams whereas Dr. Brewer’s article clearly states that “No cases of rhabdomyolysis occurred in patients receiving rosuvastatin 10 to 40 mg.”
- FDA briefing documents state, but Dr. Brewer’s article does not mention, that “… rosuvastatin was also associated with renal findings not previously reported with other statins.”
- Not mentioned by Dr. Brewer were three cases of renal insufficiency or renal failure during the trials in people using 80 mg, cases that, according to the FDA briefing documents, were “of concern because they present with a clinical pattern, which is similar to the renal disease seen with rosuvastatin in these clinical trials. There is mild proteinuria associated with hematuria and the suggestion of tubular inflammation or necrosis… However, if they [proteinuria and hematuria] are the signals for the potential progression to renal failure in a small number of patients, this may represent an unacceptable risk since currently approved statins do not have similar renal effects.”
This journal supplement, like many supplements to some medical journals, are a means of greatly increasing revenues for publications by printing information often quite favorable to a particular drug. The drug’s manufacturer then pays the journal to print and distribute of massive numbers of the supplement containing these articles to subscribers to the “real” version of the journal and to others. One study found that “articles published as journal supplements are of lesser quality than articles published in the parent journal.”
On its web site, Elsevier, publisher of the American Journal of Cardiology, emphasizes the benefits of such supplements to pharmaceutical companies: “Scientific Sponsors and pharmaceutical companies regard them [supplements] as an ideal method for rapid and powerful dissemination of their conference material or scientific findings to as wide or narrow an audience as required… Elsevier publishes many of the leading health science journals; a fully reviewed supplement to an Elsevier journal will carry the prestige of the journal and its editorial board.”
Dr. Brewer’s article, from the supplement financed by AstraZeneca, has repeatedly been cited by AstraZeneca to promote Crestor’s alleged superiority to other statins (based on higher cholesterol-lowering potency, milligram for milligram). A recent Crestor slide show, created by AstraZeneca, contains slides taken from and attributed to Dr. Brewer’s article.
Serious questions, especially important in the light of the multiplicity of recent scandals involving relationships between NIH scientists and the pharmaceutical industry, must be asked:
- Has Dr. Brewer been a paid consultant to AstraZeneca while working at the NIH, and has he received any other compensation from the company?
- What is the NIH policy on allowing its employees to participate in drug industry-sponsored symposia and to edit or write articles in drug industry-sponsored journal supplements, which are clearly, as in this case, tilted favorably toward the company’s drug?
- The National Library of Medicine’s website for medical journal articles, Medline, lists the abstract of Dr. Brewer’s article, and the full article can be obtained separately for a fee for those who are not subscribers to the American Journal of Cardiology or who have not received the article free from AstraZeneca. The article itself fails to mention that Dr. Brewer has been a consultant to AstraZeneca, or that AstraZeneca paid for the supplement. Is this consistent with NIH policies?
I look forward to a quick response to these questions about what appears to be another drug industry-NIH outrage.
Sidney M. Wolfe, M.D.
Public Citizen’s Health Research Group
cc: Congressmen James Greenwood, Henry Waxman, and John Dingell
 On the medical web site Medscape, under the topic “Sculpting New Treatments Strategies for High-Risk Patients With Dyslipidemia”, Dr. Brewer, one of the authors, is said to be a consultant for AstraZeneca. http://www.medscape.com/viewprogram/3091_authors (accessed 7/1/04)
 Brewer HB Jr. Benefit-risk assessment of Rosuvastatin 10 to 40 milligrams. Am J Cardiol. 2003 Aug 21;92(4B):23K-29K
 The above article appears in a supplement to the Am. J Cardiol entitled “A Symposium: Charting the Universe in Dyslipidemi Management” stating, on the cover of the supplement, “the Symposium and publication of these proceeding were supported by an unrestricted educational grant from AstraZeneca.”
 Food and Drug Administration Center for Drug Evaluation and Research (CDER). Endocrinologic and Metabolic Drugs Advisory Committee Meeting, July 9, 2003. Briefing information: Crestor: indicated for the treatment of hypercholesterolemia and mixed dyslipidemia. (Based on a review of AstraZeneca data) http://www.fda.gov/ohrms/dockets/ac/03/briefing/3968b1.htm (accessed June 1, 2004).
 Rochon PA, Gurwitz JH, Cheung CM, Hayes JA, Chalmers TC. Evaluating the quality of articles published in journal supplements compared with the quality of those published in the parent journal. JAMA. 1994 Jul 13;272(2):108-13.
 Many journalists, especially the Los Angeles Times’ David Willman, have written extensively about this serious problem of conflict of interest involving the NIH and the pharmaceutical industry.