September 13, 2007

Bayer apologizes to FDA panel on Trasylol data

GAITHERSBURG, Md. -- Bayer AG apologized on Wednesday to a U.S. health advisory panel for failing to present troubling hospital data one year ago when the panel recommended continued use of its heart surgery drug Trasylol. The U.S. Food and Drug Administration panel of health experts is expected to vote later in the day on whether Trasylol, a drug used to stem bleeding during heart bypass surgery, should remain on the market.
The FDA advisory group was asked to again review the safety of Trasylol because days after an advisory panel concluded in September 2006 that the drug was safe for some patients, new data emerged from Bayer that suggested an increased risk of death. German drugmaker Bayer says it mistakenly withheld a study of 67,000 hospital records suggesting that the drug might boost the risk of death, serious kidney damage, congestive heart failure and stroke.

FDAnews Drug Daily Bulletin, Sept. 14, 2007 | Vol. 4 No. 181

FDA Advisory Committee Recommends Trasylol Stay on the Market

A joint FDA advisory committee voted 14-1, with one abstention, recommending Bayer Healthcare’s antifibrinolytic drug Trasylol remain on the market despite safety concerns committee members have with the product.
The Cardiovascular and Renal Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee convened to discuss safety issues associated with Trasylol (aprotinin), including the risk of renal failure/dysfunction, death, heart attack and stroke.
Despite the good news for Bayer, committee members wanted labeling updated to highlight the risk of using the product off label. A physician education program and restrictive-use program also were recommended, although not voted on, and members wanted more emphasis on physician labeling limiting Trasylol’s use to high-risk patients.
Labeling for the product was updated last year to limit its indication to patients with an increased risk of blood loss or transfusion. At the time, the labeling changes also reflected an increase risk of kidney damage associated with the drug.
An FDA analysis of data from a large observational study presented during the meeting showed the relative risks of kidney failure associated with the use of Trasylol were significant. In addition, the FDA said the product increases the risk of death, heart failure and stroke, but the agency conceded that the data had limitations.
During the meeting, Bayer said the data sources for the study were unreliable as treatment selection criteria varied across clinical trial sites. The company also said the product was associated with renal dysfunction, not renal failure.

September 18, 2007, Seattle Post Intelligencer

Timely disclosure critical in drug trials

Largely as a result of high-profile drug safety problems such as Vioxx and Avandia, House and Senate versions of the reauthorization of the Prescription Drug Fee Users Act contain key provisions about post-market studies, the registration of clinical trials and the public release of clinical trial results.
Between 1998 and 2003, only a quarter of the post-market studies agreed to at approval by sponsors were completed. Currently, 899 are listed as "pending." If a post-market study is agreed to, it should be completed in a timely fashion. If it is not, there should be consequences.
Completing clinical trials is not enough; results must be publicly disclosed to be useful. It is not now possible to know how many studies remain unpublished. Unpublished studies come to light only sporadically.
In August 1999, Bayer decided not to publish findings from a high-dose randomized trial of Baycol, a lipid-lowering statin drug, largely because of a "high incidence" of serious adverse effects. In 2000, Pfizer completed a randomized trial of Celebrex, a COX-2 inhibitor, in patients with Alzheimer's disease but never published the unfavorable cardiovascular findings and did not post them on a Web site until January 2005. In September 2006, Bayer did not disclose to the FDA or its advisory committee the risks of kidney damage seen in an observational study of Trasylol, a drug used to limit post-operative bleeding.
In each case, the sponsor failed to reveal a serious safety problem with its product. If a study puts a drug in an unfavorable light, the results should not be buried. The public needs information about risks and benefits. Both the failure to publish study results and the incomplete reporting of safety findings in published studies form part of a recurring pattern that distorts the publicly available knowledge base in medicine.
The standard in medical science is simple -- the complete and accurate reporting of the efficacy and safety findings. Selective reporting of the results of randomized trials not only misrepresents the evidence, but also undermines efforts to establish a clear picture of the drug's overall risk-benefit profile.
Had clinical trial findings favored the sponsor's drug, marketing teams would have spread the word rapidly. Although an asymmetric approach to disclosing scientific findings, promoting the good and suppressing the bad, may seem natural from a business perspective, selectively concealing results represents a type of falsification, and this common form of corporate behavior would, if practiced by a scientist, amount to scientific misconduct.
In 1997, Congress first required registration of clinical trials evaluating treatments for serious illnesses, a requirement frequently ignored by drug companies. In part because the International Committee of Medical Journal Editors required registration as a condition of publication by September 2005, registration at the Web site clinicaltrials.govexpanded rapidly to more than 23,000 trials and has become standard.
Registration of trials, which simply provides information about the existence of a clinical trial, does not guarantee the publication of results. The timely public disclosure of clinical-trial results, good and bad, is essential. The House and Senate bills would expand the requirements for trial registration and create a new publicly accessible results database. To be effective, the results database must contain a scientifically rigorous and standardized summary of key findings about risks and benefits presented in a non-promotional manner.
A sound knowledge base in medicine is so critical to the health of the public that the provisions for new authorities in the post-market setting, for clinical trials registration and for the clinical trials results database, if passed and signed into law, will be the major legacy of the drug safety legislation of 2007.
Bruce M. Psaty, M.D., Ph.D., is a professor of medicine and epidemiology at the University of Washington, an investigator at the Center for Health Studies, Group Health, and was a member of the Institute of Medicine's Committee on the Assessment of the U.S. Drug Safety System.

September 10, 2007 , Wall Street Journal

Antibleeding Heart Bypass Drug Faces Another FDA Safety Review

WASHINGTON -- A Bayer Pharmaceuticals drug used to control bleeding in patients undergoing heart bypass surgery will face a second safety review by a Food and Drug Administration panel Wednesday.
The drug, Trasylol, has been the subject of an ongoing FDA safety review since two studies published in 2006 suggested the drug doubled the risk of kidney failure. Since then, two additional studies have suggested the drug also could increase the risk of death.
Last December, the FDA updated its strictest black-box warning on Trasylol, stating that it could increase risk of kidney damage and that it should be used only in certain situations in which patients are at an increased risk for blood loss during heart bypass surgery. That decision followed a FDA panel meeting in September 2006.
One of the newer studies, known as the I3 drug report, had been given to Bayer shortly before last September's meeting, but the company didn't submit the findings until after the panel meeting. Bayer has said that it didn't intentionally keep the results from the panel and that senior management wasn't told the report was in until after the FDA panel met.
The FDA said in documents posted to its Web site Monday that the major purpose of this September's advisory committee meeting is "to provide recommendations about the overall risk-benefit assessment for Trasylol, especially when considering the information that was not provided to the 2006 advisory committee."
The agency didn't release the specific list of questions it would ask the advisory committee.
Preliminary results from the I3 drug study found that Trasylol increased the risk of death by 54%, the FDA said. However, the FDA said the study alone shouldn't be used to determine if the use of Trasylol is safe.
The agency said Bayer recently submitted final results of the I3 study, and an agency review of those results is continuing. Earlier this year, another study published in the Journal of the American Association, suggested the drug also increased the risk of death by about 50% for a certain group of patients. That study was a follow-up to one of the 2006 studies that showed a doubling of kidney failure among patients receiving Trasylol.
The FDA said it would ask the panel about the strengths and limitations of the new studies, which are considered observational and not controlled clinical trials, when considering the overall risks and benefits of the drug.
Bayer, in documents also posted to the FDA's Web site, said it did appear the drug was associated with "renal dysfunction," or kidney problems, but said the product did not appear to be associated with an increased risk of death. By JENNIFER CORBETT DOOREN

ZymoGenetics Suffers FDA Setback

By Elizabeth Trotta, 8/22/2007

ZymoGenetics on late Wednesday said the Food and Drug Administration will take longer to complete a review of a new blood-clotting agent, a setback as the company embarks on a lucrative sales and marketing deal with a Bayer subsidiary.
ZymoGenetics said in a conference call Wednesday that the Food and Drug Administration is considering the submission of additional manufacturing-related information a major amendment to its application for rThrombin, a product used to help control bleeding during surgery. The company in June signed a deal -- potentially worth up to $198 million -- with Bayer HealthCare to help market and sell the drug.
The FDA review, originally expected to be completed by Oct. 18, now is not expected to be done until Jan. 17. The delay means the company cannot earn any of the $40 million in milestone payments expected through the Bayer HealthCare deal this year, impacting 2007 revenue.
"This delay simply reflects that they need more time to complete the review," said ZymoGenetics CEO Bruce Carter during a conference call. "We have no reason to believe the filing package is deficient in any way." The company said the additional information was in response to questions that arose in a mid-cycle review.
ZymoGenetics had expected to launch rThrombin in October, but now anticipates a launch 10 days after the expected end of the FDA review in January.

more information:
NYT article "Bayer failed to report risks of drug"
Trasylol: Bayer Drug Shows Flaw in Studying Safety
Bayer drug Trasylol carries tougher kidney warning - FDA
Bayer´s Trasylol: Multiple Risks of Surgery Drug Seen