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• W1528483846 abstract "On September 9, 2005, the US Food and Drug Administration (FDA) conducted an advisory committee hearing1 on a new peroxisome proliferator-activated receptor (PPAR) agonist—muraglitazar—which is unique in comparison to approved PPAR agonists in that it possesses both α- and γ-receptor agonist properties.2 The hearing resulted in an eight-to-one vote recommending approval of muraglitazar for use in blood glucose control in type 2 diabetes. Subsequently, Nissen et al.3 reviewed phase 2 and phase 3 clinical trial documents for muraglitazar released under public disclosure laws for the FDA meeting and published an analysis concluding that “muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular [CV] events (MI [myocardial infarction], stroke, [transient ischemic attack]), and CHF [congestive heart failure].”3 An accompanying editorial4 discussed the analysis and concluded that the review of Nissen and colleagues brought out concerns about FDA safety evaluation. The present commentary focuses on the handling of the analysis of muraglitazar, but also on the more general concerns about safety issues with new drugs under investigation by the FDA and follow-up safety analysis of approved drugs. The FDA has an extensive process for approval of a new drug (Figure).5 FDA review requires initial short-term testing in animals, followed by long-term testing. On the basis of these studies, the drug company obtains FDA permission for trials in humans. These consist of phase 1 trials studying safety and toxic effects in healthy volunteers, phase 2 trials of safety and efficacy in patients with the condition to be treated, and phase 3 trials, consisting of at least two larger, randomized trials of efficacy and safety. Approximately 2000–5000 patients are usually exposed to the drug in clinical studies before FDA approval. After FDA approval, phase 4 studies are undertaken consisting of the FDA's monitoring of reported adverse reactions, although the FDA cannot mandate further safety studies after approval—unlike in Europe, where drug approvals are reviewed at 5-year intervals.5 Outline of the process of obtaining US Food and Drug Administration (FDA) approval for a new drug. Reprinted with permission from N Engl J Med. 2005;352:1173–1176.5 (c)2005 by the Massachusetts Medical Society. All rights reserved. There is considerable interest in the possible use of muraglitazar. The PPAR agonist agents appear to have multifold effects but currently they have specifically PPAR-α or -γ agonist actions. The PPAR-α agents, including the fibric acid derivatives gemfibrozil and fenofibrate, act primarily to lower triglycerides. The PPAR-γ agents include the thiazolidinediones (TZDs) rosiglitazone and pioglitazone, which increase insulin sensitivity. The combination of decreased insulin resistance and beneficial effect on lipids might, in combination, improve the CV risk profile. There is evidence, for example, that PPAR-γ activation decreases C-reactive protein in patients with diabetes.6 TZDs have been shown to rapidly reduce serum levels of the inflammatory markers C-reactive protein, serum amyloid A, and sE-selectin and increase flow-mediated endothelial-derived vasodilation in healthy subjects,7 and TZDs have been shown to normalize coronary vasomotor abnormalities associated with insulin resistance.8 In animal models, PPAR-γ activation reduces intimal hyperplasia9 and has an additive effect, with statins, of decreasing maximal vessel wall thickness due to atherosclerosis.10 In human studies, PPAR-γ activation blunts progression of carotid atherosclerosis in stable coronary artery disease.11 A large number of multicenter PPAR-γ trials are now being implemented, with results expected between 2006 and 2009. Thus, the possibility of a combined PPAR-α-γ agent may have considerable use in modifying CV risk. However, other preclinical studies have indicated potential CV toxicity from PPAR agonist agents.12–14 In regard to muraglitazar, the FDA advisory committee specifically recommended approval as monotherapy in type 2 diabetes and as combination therapy to control blood glucose in cases of inadequate control by metformin.1 Nissen et al. reviewed the two major documents considered at the meeting provided by the drug developers (Bristol-Myers Squibb, New York, NY and Merck & Co., Whitehouse Station, NJ) and by the FDA staff. There were a total of five studies of drug efficacy and safety. Efficacy specifically targeted glycemic control and effects on lipids. Safety evaluated major adverse outcomes. Of the studies, only one phase 2 trial and four phase 3 trials were evaluated. Because of adverse effects of drug dosage above 5 mg/d, doses at or below this level were requested by the manufacturers. The evaluation consisted of results from 2374 patients receiving muraglitazar in comparison with 528 receiving placebo and 823 receiving the TZD drug pioglitazone. Only one of these studies is available in the literature: a randomized, double-blind, placebo-controlled 24-week monotherapy trial in adult patients with type 2 diabetes, involving 340 patients.15 The primary end point was mean change in baseline glycosylated hemoglobin level. At 2.5 mg/d and 5 mg/d dosage, muraglitazar reduced glycosylated hemoglobin levels by −1.05% and −1.23%, respectively, compared with placebo change of −0.32% (p<0.001), associated with significant reductions in fasting glucose, plasma insulin levels, and free fatty acids. In this as well as the other four studies, the study exclusions are important in evaluating broad use of muraglitazar. These exclusions included: 1) CHF classes III and IV; and 2) within 6 months before enrollment, a history of MI, unstable angina, angioplasty or bypass surgery, or cerebrovascular disease, including transient ischemic attack or stroke.3 Nissen et al., in evaluating adverse event rates and mortality results in the five trials, found the following: 1) a primary outcome measure of all-cause mortality, nonfatal MI or nonfatal stroke, of 1.47% in drug-treated patients vs. 0.67% in controls (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07–4.66; p=0.03); 2) borderline increase in CV death occurred in 1.14% of drug-treated patients and 0.52% of controls (RR, 2.21; 95% CI, 0.956–5.08; p=0.06); and 3) if CHF and transient ischemic attack events were included in composite end points (primary outcome measure), the results indicated a 2.11% incidence for muraglitazar and 0.81% for control patients (RR, 2.62; 95% CI, 1.36–5.05; p=0.04). It should be emphasized that drug exposure was limited to a period from 24 weeks to 2 years. Nissen et al. indicated an “unacceptable patient hazard” if the drug were approved by the FDA, and that the agent “appears to increase the risk for morbidity and mortality in diabetic patients during relatively short-term treatment.” Possible reasons for adverse effects with muraglitazar include drug interactions (most adverse CV effects were in studies in combination with other glycemic control agents, glyburide and metformin),3 and a possible paradoxical response that may produce compensatory increases in levels of inflammation.16 The sponsor's presentation to the advisory committee concluded that there was no excessive risk of deaths or CV events.1,4 The accompanying editorial by Brophy4 pointed out that the sponsor utilized three groups (placebo, pioglitazone, and muraglitazar) rather than the two groups evaluated by Nissen et al. (muraglitazar vs. other agents or placebo), and although the three-group analysis suggested the relative safety of muraglitazar, Brophy indicated that smaller doses of muraglitazar for which approval was not sought were included in the denominator. Other concerns in the editorial included the following: first, very few patients with class I and II CHF were recruited, although their CHF risk was increased 10-fold, and baseline left ventricular ejection fractions were 40% or above, limiting generalizability to many patients who would be included in the population receiving the drug. It is possible that increased circulating blood volume, seen with other PPAR-γ agents, may have been responsible. Edema was prominent in muraglitazar use, especially at higher doses. Second, cancer was reported in drug users at a rate of 9.8/1000 patient years, vs. 3.0/1000 patient years in placebo users (95% CI, 6.7–13.3 vs. 0.1–21.3).4 Several methodologic issues of concern in the application were observed by Brophy, including: 1) selecting a study population unlikely to have adverse outcomes but unrepresentative of potential future users (e.g., limited older age groups); 2) underpowering studies, thus maximizing type II errors; 3) reporting individual rather than composite safety outcomes to decrease statistical significance; 4) limiting peer review of preapproval publications; 5) using surrogate measures such as reduction of C-reactive protein and glycosylated hemoglobin to assess safety rather than clinical outcome events; and 6) excluding from analyses those subjects not fully compliant with medication. There are several concerns devolving from this analysis that lead to broader issues: 1) the ability of drug databases to predict adverse events after drug approval; 2) the effectiveness of information on adverse effects after approval; 3) the effective reporting of adverse effects in clinical trial reports; and 4) the objectivity of advisory panel members who may have ties with the pharmaceutical industry. An example of the problems of database issues was the use of antiarrhythmic agents in the Cardiac Arrhythmia Suppression Trial (CAST) conducted between 1987 and 1991. Although encainide, flecainide, and moricizine—the agents used—effectively decreased arrhythmias in the post-MI patients before randomization, mortality was increased during the trial with these agents compared with placebo. The database on 908 patients given moricizine demonstrated a low proarrhythmic potential,17 yet significantly greater mortality developed in the moricizine group during the first 14-day exposure phase of treatment, an initial blinded, randomized phase involving 1325 patients—well above the number in the drug database.18 Thus, databases alone, based on small clinical studies, may not elucidate possible adverse effects because of inadequate power to detect these outcomes (type II errors). A second issue is the reporting of adverse effects after drug approval. In this situation, we are dealing with a drug that was previously evaluated for efficacy and adverse effects in a few thousand people and would now be administered to, possibly, millions.5 At present, about 50% of drugs entering the market have serious adverse effects detected only after approval.5,19 The problem with post-approval monitoring is that the FDA relies on drug companies, health care providers, and consumers to provide information about side effects and thus is not proactive in this regard. Put in other terms, the FDA cannot legally mandate safety studies after drug approval. Ways to circumvent these problems, as recommended by policy experts with backgrounds in the field of pharmacology and medicine, include: 1) collections of databases from managed care networks and the use of electronic medical records; 2) a time limitation on FDA approval of new drugs, with the manufacturer responsible to collect extensive safety data over the next few years as a condition for retaining patent exclusivity; and 3) prohibition of marketing to consumers until observational data have been collected on a large number of users of the drug.5 A third issue, completeness of reporting of safety information in randomized trials, was evaluated by Ionannidis et al.20 in an analysis of 192 randomized drug trials, comprising over 130,000 patients. Severity of clinical adverse effects was defined in only 39% of the trials, and laboratory-determined toxicity was provided in only 29%. Moreover, half the reports did not mention laboratory-determined toxicity. Fewer than 50% of reports stated the frequency of specific reasons for discontinuance of treatment due to toxicity. Less than one third of a page, on average, was devoted to safety results. Considering that these trials utilized at least 50 patients per study arm, it is unlikely that studies using fewer patients would be able to identify—much less feel compelled to report—important safety information. There also appears to be less interest in reporting safety information in studies of drugs with prior established indications.20 The study utilized seven trial parameters that could be useful in gauging safety information in future clinical trials (Table). A fourth issue, a possible lack of objectivity in advisory panel members' evaluation of information on adverse effects after approval, can be seen in the way rofecoxib was handled.21 Based on information received, an advisory panel of the FDA in February 2005 agreed that the three available cyclooxygenase (COX)-2 inhibitors used for pain and arthritis seriously increased the risk for CV events, but voted to continue marketing the drugs, although adding a “black box” label that severely limits use. Merck voluntarily withdrew rofecoxib from the market but has indicated that the product may be brought back.21 This was probably one of the first times that the FDA had to deal with an adverse effect that could involve a large segment of the population. Of interest was the lack of evidence that the newer COX-2 inhibitors had been shown to be superior to the older, nonsteroidal anti-inflammatory agents (NSAIDs) and, in fact, there was a paucity of long-term studies on CV risk with the older NSAIDs. It is also interesting that in one trial submitted to the FDA in 2000, in which rofecoxib was compared with naproxen, an increasing frequency of CV events in the rofecoxib group was interpreted by the study's investigators as indicating a protective effect of naproxen rather than an adverse effect of rofecoxib.22 During the FDA meeting, officials from the COX-2 drug companies omitted information regarding adverse events, including a study released the previous day on increased risk of heart failure in users of celecoxib. The advisory committee voted 31 to 1 to keep celecoxib on the market, and 17 to 13 in favor of rofecoxib. Of those who voted in favor of keeping COX-2 drugs on the market, 10 had financial ties to the manufacturers of these drugs.23 The FDA is aware of these problems. Reforms are being implemented in the FDA to improve oversight and openness.24 These will include: 1) earlier sharing of safety information, more broadly and more conveniently; 2) a Drug Safety Oversight Board to oversee the management of important safety issues; and 3) constitution of the board with FDA members and medical experts from other US Department of Health and Human Services agencies and government departments. As previously indicated, however, the FDA can request postmarketing studies, but these are not mandated. Last year, over 65% of open postmarketing commitments requested for approved drugs were still pending.25 Over 7 years ago, it was recommended in a leading medical journal that an independent drug safety board be established for assessment of drug safety.26 Independent of both the FDA and the manufacturers, the board would provide formal postmarketing mandatory and routine drug surveillance. Before approval for marketing of a new drug would be considered, safety data would be collected from manufacturers, provided electronically on an ongoing basis. The board would have sufficient funds to initiate its own studies, if necessary, or hold open hearings on drug safety. The board would also make recommendations to the FDA for changes in a drug's approval status. Being cognizant of protection needed for manufacturers in developing and implementing new drug activities, this system would include protection from baseless liability suits based on data that do not support liability claims. Recommendations have also been made regarding the composition of advisory panels to the FDA, to minimize actual conflicts of interest.27 These could include the publication of names and background information on potential committee members for public comment prior to finalizing such committees, and publication of more financial disclosure with respect to the FDA's outside advisors. Congress is acting on some of these FDA safety issues. In October 2005, Public Law 109–97 was passed with an amendment (approved by a 218-to-210 House of Representatives vote) that prohibits the FDA from using appropriated funds to grant waivers of its financial conflict of interest requirements to voting members of its advisory committees. Presumably, industry-connected scientists would be unable to serve on advisory committees during the life of the law (until September 30, 2006).27 Another bill (HR 2090), now sent back to committee, would, among other measures: 1) prohibit the FDA from collecting fees paid by companies; 2) create mandatory funding levels to cover the cost of the functions previously paid directly by drug companies; 3) require the FDA to post on its Web site the membership of all advisory board members at least 30 days before the panel's meeting and provide the public with adequate time to comment; 4) create an independent Center for Post-Market Drug Safety and Effectiveness responsible for regulating all approved drugs as well as all advertisements and promotions associated with these products; and 5) provide the FDA with the legal authority to require companies to conduct postmarketing studies of FDA-approved drugs. The fundamental precept of the practice of medicine, primum non nocere, requires vigilance in the treatments prescribed. If we are to see that we treat patients safely, every health care professional who deals with a patient should have at his or her fingertips the appropriate information needed to ensure standards of safety—and be prepared to support measures that will strengthen the appropriate agencies to supervise drug safety and truly minimize conflicts of interests in judging drug efficacy and safety." @default.
• W1528483846 created "2016-06-24" @default.
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• W1528483846 date "2006-03-01" @default.
• W1528483846 modified "2023-10-16" @default.
• W1528483846 title "Muraglitazar and the FDA: What Constitutes Drug Safety?" @default.
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