by Dennis T. Mangano, Ph.D., M.D.
I was troubled by the recent, near-unanimous decision of the Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee publicly advocating the safety of aprotinin1 — despite considerable evidence to the contrary,2,3,4 including our recent study2 and the FDA's own initial 1993 warning regarding "kidney toxicity."5 We learned after the Advisory Committee's meeting of newly disclosed records of 67,000 patients, yielding data that were consistent with our warnings (renal failure, stroke, and heart failure)2 and that were inconsistent with the positions of the committee and Bayer.1,6
In defending the committee's decision, Dr. Hiatt makes allegations in this issue of the Journal regarding our "transparency" (FDA access to our data).7 In fact, there is no question that our independent, nonprofit research groups (the Ischemia Research and Education Foundation [IREF] and the Multicenter Study of Perioperative Ischemia [McSPI] reseasrch group) made every effort to have the FDA review in detail all of the source and derivative data from our study2 and all associated documentation and operating procedures.
In February 2006, after publication of our article,2 the FDA asked that we present our data to them. We agreed and sent a team of IREF scientists to the FDA. The FDA and Bayer then asked that we send them our database, because they each wanted to combine our data with Bayer's data and then perform a number of unspecified analyses. We agreed to the FDA proposal, making three requests: that patient privacy and legal trust be preserved, that the methods used to mix our patient data with the Bayer patient data be specified, and that in addition to their analyses, the FDA independently analyze our data, comment on each finding of our study published in the Journal,2 and make the results known to the public. In May (4 months before the Advisory Committee meeting), frustrated by the delay and concerned that our data would not be reviewed, I abandoned all three requests and informed the FDA that we would provide our database and any and all source data for its review. Hearing no response, after several weeks, I wrote to the FDA and again asked for a review of our data. However, the FDA refused, and we were told that a review was not necessary. As I publicly stated to the Advisory Committee on September 21, 2006, we stand by our offer to the FDA to provide for review any and all data regarding our publication without constraint or condition.
The FDA and its Advisory Committee should take a conservative, protective stance when independent evidence regarding drug safety presents itself. Instead, they appear to be protecting the drug rather than the patient.
- FDA advisory committee strongly endorses use of Trasylol in CABG surgery patients. Medical News Today. September 25, 2006. (Accessed November 7, 2006, at http://www.medicalnewstoday.com/medicalnews.php?newsid=52568.)
- Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-365. [Abstract/Full Text]
- Hunter D. First, gather the data. N Engl J Med 2006;354:329-331. [Full Text]
- Vlahakes GJ. The value of phase 4 clinical testing. N Engl J Med 2006;354:413-415. [Full Text]
- Approval of aprotinin. Press release of the Food and Drug Administration, December 30, 1993. (Accessed November 7, 2006, at http://www.fda.gov/bbs/topics/NEWS/NEW00453.html.)
- Harris G. FDA says Bayer failed to reveal drug risk study. New York Times. September 29, 2006.
- Hiatt WR. Observational studies of drug safety -- aprotinin and the absence of transparency. N Engl J Med 2006;355:2171-2173. [Full Text]
source - NEJM