Dispute highlights pitfalls in drug review process

Two months have lapsed since the FDA warned that the antifibrinolytic drug aprotinin (Trasylol) could cause renal failure, congestive heart failure, stroke and death. Yet significant questions about the drug's safety profile continue to swirl, stoked in part by one researcher's alleged failure to provide full access to his data and looming questions about Bayer HealthCare's admitted blunder in not immediately sharing data from a retrospective study.The aprotinin flap plays out in a provocative collection of writings published in the Nov. 23 issue of the New England Journal of Medicine. Taken together, the two "Perspective" pieces, two letters to the editor and editorial highlight continuing difficulties in assuring that data from relevant drug studies are fully disclosed to the FDA and that methods used to obtain those findings are made transparent."This is yet another example of why there has to be full clinical trial registry and full releases of data at appropriate times and after appropriate cleaning up of the data," said Steven Findlay, managing editor of Consumer Reports Best Buy Drugs at Consumers Union in Washington, D.C. Findlay is a consumer representative on the FDA's Cardiovascular and Renal Drugs Advisory Committee. The panel convened Sept. 21 to review aprotinin in the wake of serious safety concerns raised by a pair of observational studies published in early 2006, including one led by Dennis T. Mangano, principal scientist, founder and CEO of the Ischemia Research and Education Foundation in San Bruno, Calif. Writing in the NEJM, William R. Hiatt, chairman of the advisory committee, alleges that Mangano gave neither the agency nor the panel full access to his data, a contention corroborated by the FDA's R. Dwaine Rieves and Karen D. Weiss. The FDA officials assert that Mangano "imposed restrictions, including his physical presence at the FDA while the FDA representatives inspected and analyzed the data, and limitations on the nature of the analyses the agency could perform." In addition, he "required the FDA to make a determination of the validity of the published findings and conclusions rather than assess the methods alone," they noted in a letter to the editor concluding that his terms prevented an independent evaluation of the study methods."We ultimately were presented the data very similar to how they were reported in the publication, and we did not have any FDA independent confirmation of those analyses for our review," Hiatt told The Scientist. "And that's an unusual situation to be in, particularly when that article was the subject of the meeting."Defending his actions, Mangano insisted in his own letter to the editor that he and his colleagues "made every effort to have the FDA review in detail" all of the data, documentation and operating procedures used in the study. He acknowledged making certain requests of the FDA, including assurances of patient privacy. But as the committee meeting drew closer and the FDA had not acted, Mangano said that he abandoned those requests and offered to provide the data without strings attached. "However, the FDA refused, and we were told that a review was not necessary," he wrote.Jerry Avorn, professor of medicine at Harvard Medical School and chief of pharmacoepidemiology and pharmacoeconomics at Brigham and Women's Hospital, both in Boston, highlights another troubling wrinkle in the aprotinin safety review: Bayer's failure to turn over data from a large observational study of postoperative complications in patients given the drug. The study showed that these patients "had higher mortality rates and substantially more renal damage than those given other treatments," he wrote. "But neither Bayer nor its contractor had provided the report to the FDA or even acknowledged its existence before the meeting."Bayer "regrets the error it made" in not sharing the data prior to the advisory committee meeting, a spokeswoman said. Among other actions, the company has now provided the FDA with a copy of the preliminary report, the draft study protocol and a preliminary evaluation of the study methodology and findings conducted by an outside expert. It also suspended the two individuals who received the preliminary report from their current responsibilities and initiated an internal independent investigation."Bayer's failure to submit the data, or to even make it known that they were doing the study, is simply inexcusable," said Keyvan Karkouti, a researcher with the Toronto-based University Health Network who led one of the two aprotinin studies that raised concerns about the drug's safety."It just doesn't make any sense that Bayer would do that willfully," Findlay added, "and if they did it willfully, then there ought to be consequences."While the advisory committee concluded that no labeling changes were needed, the absence of key data leaves open questions about the overall safety of the drug, Hiatt acknowledged. "My conclusion in that Perspective piece was that today we cannot form a judgment on the safety of aprotinin -- either for or against."Karen Pallarito mail@the-scientist.comLinks within this article:FDA Issues Public Health Advisory for Trasylol http://www.fda.gov/bbs/topics/NEWS/2006/NEW01472.htmlI. Ganguli, "A Question of Quality," The Scientist, March 1, 2006 http://www.the-scientist.com/article/display/23178A. Bouchie, "New drug safety bill in U.S. Senate," The Scientist, Aug. 8, 2006 http://www.the-scientist.com/news/display/24266Consumer Reports Best Buy Drugs http://www.crbestbuydrugs.orgFDA Cardiovascular and Renal Drugs Advisory Committee http://www.fda.gov/ohrms/dockets/ac/cder06.html#CardiovascularRenalDennis T. Mangano http://www.iref.org/intro.htmlWilliam R. Hiatt http://www.cpcmed.org/About/Hiatt.aspxW. Hiatt, "Observational Studies of Drug Safety - Aprotinin and the Absence of Transparency," NEJM, Nov. 23, 2006 http://content.nejm.org/cgi/content/full/355/21/2171R. Dwaine Rieves and Karen D. Weiss letter to the editor http://content.nejm.org/cgi/content/full/355/21/2261Mangano letter to the editor http://content.nejm.org/cgi/content/full/355/21/2261J. Avorn, "Dangerous Deception - Hiding the Evidence of Adverse Drug Effects," NEJM, Nov. 23, 2006 http://content.nejm.org/cgi/content/full/355/21/2169

Dispute highlights pitfalls in drug review process

Aprotinin's safety profile remains in question in absence of full data disclosure

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