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Avandia Meta-Analysis Problems Metastasize For FDA After JAMA Studies
Avandia Meta-Analysis Problems Metastasize For FDA After JAMA Studies
By Petter pitts
September 9,2007
GlaxoSmithKline's Avandia (rosiglitazone) has become the chorus line to discussions of FDA's drug approval and oversight systems.
Whereas much of the original discussion of concerns about the product and attendant issues has occurred in the pages of the New England Journal of Medicine, the torch has now been taken up by the Journal of the American Medical Association.
In the Sept. 12 issue, JAMA published two meta-analyses that found while Avandia is associated with a significantly increased risk of myocardial infarction and heart failure, its rival thiazolidinedione Actos (Takeda's pioglitazone) is associated with a significantly lower risk of MI or stroke.
The studies, and an accompanying editorial, add to the pressure on FDA to limit use of Avandia either through labeling changes or a restricted access program.
The agency said it is examining all available data and information with "great interest" as it continues to conduct a "careful and thorough review" of CV risks related to Avandia and Actos. "It is of high public health importance to characterize the risk of heart attacks with the use of these drugs."
Cleveland Clinic's Steve Nissen, one of the authors of the original NEJM piece on Avandia that sparked the controversy as well as the most recent JAMA study on Actos, said in an interview that it was difficult to predict what FDA will do in light of this new information.
"FDA is in an awkward position. They had the same data for about two years, but failed to take action. If they act decisively now, they look bad; if they don't act, they look bad," Nissen said.
Meanwhile, the Center for Medicine in the Public Interest released a statement entitled "Who Is Doing Peer Review at JAMA?" which questioned the methodology used for the new meta-analysis of the Avandia studies.
"The publication of these articles by JAMA is an exercise in fear mongering," Center President Peter Pitts, former FDA Associate Commissioner for External Affairs, said. "It's a blatant attempt to usurp the FDA's authority - and to undo a careful consensus on drug safety evaluation."
An editorial in JAMA by Harvard Medical School professors Daniel Solomon and Wolfgang Winkelmayer makes the case for five regulatory reforms in light of the Avandia events.
First, the authors state, early safety concerns about a drug "must prompt strong and clear regulatory action," preferably beyond labeling changes, which are often considered ineffective.
Second, a drug's approval should be conditioned on "systematic and targeted postmarketing surveillance or randomized trials in high-risk patient groups."
Like a similar NEJM piece, the JAMA editorial also argues that "after several drugs are available for a given indication, new drug approval should be based on improvement in clinical outcomes, not surrogate measures."
Solomon and Winkelmayer also argue that the same standards should apply to drugs that are on the market and those that are up for initial review. Describing the recent advisory committee meeting on Avandia, the editorial notes although "there was almost unanimous agreement that the drug was associated with cardiovascular risk," the panel voted "to allow for its continued marketing. It would be unlikely for the drug to be initially approved for marketing with such agreement about its cardiovascular risk."
Lastly, the editorial argues that "While there are rigorous methods for weighing benefits and risk, these analyses are not often considered in FDA advisory committee meetings. The FDA could develop or codify methods for such calculations and require them as part of New Drug Applications or for continued marketing of drugs."
Such an effort appears to be underway. Among the pilot programs that FDA will undertake in the new user fee cycle is to "explore new approaches to a structured model for benefit/risk assessment," which will likely create another forum for debates over approval standards (1"The Pink Sheet" Jan. 29, 2007, p. 15).
The Avandia drumbeat may lead to some strengthening of the FDA reform bill Congress is rushing to finalize. The legislation, however, will not overhaul the agency's approval standards as the editorial recommends.
But the real risk for companies from the Avandia saga may be an agency that demands considerably more pre-approval data, despite FDA's statements in support of surrogate endpoints (2"The Pink Sheet" Sept. 3, 2007, p. 9).
Overall, the two studies in JAMA paint a now-familiar picture of the diabetes drugs, but one that sponsors see in different lights.
A meta-analysis led by Wake Forest University's Sonal Singh concluded that among patients with impaired glucose tolerance or type 2 diabetes, Avandia use for at least 12 months is associated with a significantly increased risk of myocardial infarction and heart failure, but without a significantly increased risk of cardiovascular mortality.
The Wake Forest meta-analysis differs from Nissen's original meta-analysis in that it included only studies of at least 12 months' duration that prospectively collected information on CV events. Data from the study revealed a 42 percent increase in risk of myocardial infarction and more than doubling of the risk of heart failure with Avandia.
Commenting on the new Avandia study, Nissen said, "It's quite striking that they get nearly exactly the same hazard 1.42 that we reported."
In the Actos study, researchers at the Cleveland Clinic led by Michael Lincoff concluded that pioglitazone is associated with a significantly lower risk of death, MI or stroke among a diverse population of patients with diabetes. In addition, they found that serious HF is increased by Actos, although without an associated increase in mortality.
In contrast to Nissen's original Avandia study, which relied on study-level data, the Actos study used patient-level data provided by Takeda, which enabled "time to event" analysis. The examination of 19 randomized, double-blinded trials found that among patients randomized to receive Actos, the rate of death, MI or stroke was reduced by 18 percent.
In a statement, GlaxoSmithKline said that the conclusions drawn from the most recent meta-analysis do not confirm a difference in the safety profiles of Avandia and Actos. "These analyses reflect limitations that are common to all meta-analysis, by the authors' own admission. These analyses do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments for their patients. Comparisons between different meta-analyses with different endpoints and patient populations are even more unreliable."
GSK said that the new meta-analysis on Avandia is yet another iteration of previously analyzed data, and offers no new information on the safety of Avandia. "The suggested increase in heart attack cited comes from selective re-analyses of previously published and highly selective data from only four of 166 available studies, and reflects a difference of only 11 events in 14,291 patients between Avandia and control."
GSK said that "in this limited meta-analysis, in the context of all the other evidence, we believe it is inappropriate for the author to advise doctors to disregard the FDA's advice which is to keep patients who are effectively controlling their diabetes on Avandia."
Executives at Takeda were more upbeat about the results of the Cleveland Clinic study. Robert Spanheimer, Takeda's Senior Director of Diabetes and Metabolism, said that the meta-analysis builds on information that Takeda already has. "It expands that information to different patient populations but it also is consistent with the PROACTIVE, prospective study, and I think that consistency really is added confidence for patients and physicians."
While FDA action on Avandia could come in the near term, researchers continue to develop data on the drug.
Singh, lead author on the JAMA Avandia study, said that in the future, the team at Wake Forest is looking into other side effects of thiazolidinediones including fractures in women and the risk of blindness due to fluid accumulation apart from the risk of heart attacks and heart failure.
Nissen said that he has no immediate plans for additional research in the area of cardiovascular events and thiazolidinediones but he didn't rule out further studies. "You can never predict," he said.
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