Rosiglitazone Wrangling Continues
August 29, 2007 (Boston, MA) - Reaffirming its title as the most hotly disputed drug of the year, rosiglitazone was once again the focus of debate--this time in correspondence appearing in this week's print issue of the New England Journal of Medicine and in additional letters released early online the same day [ 1, 2, 3, 4, 5, 6, 7, 8, 9]. Most of the print issue letters quibble with the statistical methods used in Nissen and Wolski's original meta-analysis [ 10]--to which the authors respond--while the online letters trade barbs over a subsequent rosiglitazone Perspective [ 11].
In the print issue, Dr Michael B Bracken (Yale University, New Haven, CT); Drs Edoardo Mannucci, Matteo Monami, and NiccolòMarchionni (University of Florence, Italy); and Drs George Diamond and Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) all present criticisms of the methods used in the original meta-analysis and offer their own reanalyses to show that the ones chosen by Nissen and Wolski overestimate the degree of risk associated with rosiglitazone. In response, Nissen and Wolski write that they chose the Peto method for their meta-analysis because "it is widely viewed as the optimal approach" for the type of data they were analyzing. They also argue that they did not include other statistical methods in their analysis because they believed the issue needed to be approached "with the same rigor as that used in a randomized trial" and as such prospectively chose a single method and did not apply others in a post hoc manner. They also defend their inclusion of the DREAM and ADOPT trials and reject the Bayesian approach used by Diamond and Kaul as "controversial."
Yet another letter, this one by Dr Alan S Brett (University of South Carolina, Columbia), takes issue with points made in the Psaty and Furberg editorial that originally accompanied the Nissen-Wolski meta-analysis [ 12]. Psaty and Furberg, writes Brett, "disparage physicians who have prescribed rosiglitazone" because of its effect on glycemic control. "It is unreasonable to expect that practicing physicians would be more knowledgeable about fine distinctions between outcomes and surrogate end points than are the experts who guide clinical practice," Brett notes. In response, Psaty and Furberg counter that the rapid uptake of rosiglitazone happened in the absence of a trial examining hard events and that physicians chose rosiglitazone over other available antidiabetic drugs despite not having hard data showing health benefits of glucose-lowering. "Treatment decisions based on surrogate end points should be made with caution," they insist.
Debating FDA reform
This week's print issue also contains the Perspective by Dr Clifford J Rosen (St Joseph Hospital, Bangor, ME), published online August 8, 2007, as previously reported by heart wire. It, too, produced a minor squall of letters released online today. In one, FDA officials, led by Dr Hyton V Joffe, defend the use of surrogate end points in the approval of diabetes drugs but concede that postapproval studies looking at cardiovascular outcomes might be a "reasonable approach." A second letter, this one from rosiglitazone manufacturer GlaxoSmithKline (GSK), suggests that Rosen's Perspective "leaves readers with a misconception" about the FDA advisory committee's advice to the FDA. In his letter, senior VP of worldwide development, Dr Ronald Krall, clarifies that the advisory committee drew a distinction between rosiglitazone's MI risk as compared with placebo and as compared with other antidiabetic drugs, with the major signal of risk being seen when a placebo comparator was used. Rosen, in a third letter, replies that his primary intention had been to provide "an individual account of an extraordinary FDA advisory committee meeting."
But Rosen reiterates his views about important improvements he believes are needed to the FDA approval and oversight, insisting that the process of reporting adverse events needs an overhaul, including the creation of a "totally independent" data and safety monitoring board within the FDA.
The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
August 29, 2007 (Boston, MA) - Reaffirming its title as the most hotly disputed drug of the year, rosiglitazone was once again the focus of debate--this time in correspondence appearing in this week's print issue of the New England Journal of Medicine and in additional letters released early online the same day [ 1, 2, 3, 4, 5, 6, 7, 8, 9]. Most of the print issue letters quibble with the statistical methods used in Nissen and Wolski's original meta-analysis [ 10]--to which the authors respond--while the online letters trade barbs over a subsequent rosiglitazone Perspective [ 11].
In the print issue, Dr Michael B Bracken (Yale University, New Haven, CT); Drs Edoardo Mannucci, Matteo Monami, and NiccolòMarchionni (University of Florence, Italy); and Drs George Diamond and Sanjay Kaul (Cedars-Sinai Medical Center, Los Angeles, CA) all present criticisms of the methods used in the original meta-analysis and offer their own reanalyses to show that the ones chosen by Nissen and Wolski overestimate the degree of risk associated with rosiglitazone. In response, Nissen and Wolski write that they chose the Peto method for their meta-analysis because "it is widely viewed as the optimal approach" for the type of data they were analyzing. They also argue that they did not include other statistical methods in their analysis because they believed the issue needed to be approached "with the same rigor as that used in a randomized trial" and as such prospectively chose a single method and did not apply others in a post hoc manner. They also defend their inclusion of the DREAM and ADOPT trials and reject the Bayesian approach used by Diamond and Kaul as "controversial."
Yet another letter, this one by Dr Alan S Brett (University of South Carolina, Columbia), takes issue with points made in the Psaty and Furberg editorial that originally accompanied the Nissen-Wolski meta-analysis [ 12]. Psaty and Furberg, writes Brett, "disparage physicians who have prescribed rosiglitazone" because of its effect on glycemic control. "It is unreasonable to expect that practicing physicians would be more knowledgeable about fine distinctions between outcomes and surrogate end points than are the experts who guide clinical practice," Brett notes. In response, Psaty and Furberg counter that the rapid uptake of rosiglitazone happened in the absence of a trial examining hard events and that physicians chose rosiglitazone over other available antidiabetic drugs despite not having hard data showing health benefits of glucose-lowering. "Treatment decisions based on surrogate end points should be made with caution," they insist.
Debating FDA reform
This week's print issue also contains the Perspective by Dr Clifford J Rosen (St Joseph Hospital, Bangor, ME), published online August 8, 2007, as previously reported by heart wire. It, too, produced a minor squall of letters released online today. In one, FDA officials, led by Dr Hyton V Joffe, defend the use of surrogate end points in the approval of diabetes drugs but concede that postapproval studies looking at cardiovascular outcomes might be a "reasonable approach." A second letter, this one from rosiglitazone manufacturer GlaxoSmithKline (GSK), suggests that Rosen's Perspective "leaves readers with a misconception" about the FDA advisory committee's advice to the FDA. In his letter, senior VP of worldwide development, Dr Ronald Krall, clarifies that the advisory committee drew a distinction between rosiglitazone's MI risk as compared with placebo and as compared with other antidiabetic drugs, with the major signal of risk being seen when a placebo comparator was used. Rosen, in a third letter, replies that his primary intention had been to provide "an individual account of an extraordinary FDA advisory committee meeting."
But Rosen reiterates his views about important improvements he believes are needed to the FDA approval and oversight, insisting that the process of reporting adverse events needs an overhaul, including the creation of a "totally independent" data and safety monitoring board within the FDA.
Bracken MB. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:937-938.
Mannucci E, Monami M, Marchionni N. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:938li>
Diamond GA, Kaul S. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:938-939.
Brett AS. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:939.
Nissen SE, Wolski K. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:939-940.
Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 357:940.
Joffe HV, Parks MH, Meyer RJ, et al. Rosiglitazone and the FDA. N Engl J Med 2007; DOI: 10.1056/NEJMc076347. Available at: http://www.nejm.org .
Krall RL. Rosiglitazone and the FDA. N Engl J Med 2007; DOI: 10.1056/NEJMc076347. Available at: http://www.nejm.org .
Rosen CJ. Rosiglitazone and the FDA. N Engl J Med 2007; DOI: 10.1056/NEJMc076347. Available at: http://www.nejm.org .
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular disease. N Engl J Med 2007; 356:2457-2471. Abstract
Rosen C. The rosiglitazone story. Lessons from an FDA advisory committee meeting. N Engl J Med 2007; 357: 844-846. Abstract
Psaty B and Furberg C. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 356:2522-2524. Abstract
The complete contents of Heart wire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.
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