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Postsurveillance data should be systematically collected, timely, and publicly available
On 21 May 2007, the New England Journal of Medicine published a meta-analysis of 42 trials of rosiglitazone (Avandia, GlaxoSmithKline) for treating type 2 diabetes mellitus. It found that the drug was associated with an increased risk of myocardial infarction (odds ratio 1.43; 95% confidence interval 1.03 to 1.98; P=0.03) and death from cardiovascular causes (1.64; 0.98 to 2.74; P=0.06).1
Rosiglitazone, a thiazolidinedione, is an agonist at the peroxisome-proliferator activated receptors in cell nuclei. These receptors modulate the expression of a host of genes, and glycaemic control is achieved primarily through increased insulin sensitivity in peripheral tissues. Rosiglitazone was approved by the US Food and Drug Administration (FDA) in 1999 and by the centralised process of the European Medicines Agency (EMEA) in 2000. Its popularity has increased steadily, with more than one million prescriptions written in the one year period ending March 2006 in England alone—a 22% increase over the previous year.2 However, the recently published meta-analysis raises serious questions about the drug's safety.
Meta-analyses have unique strengths and weaknesses and this one is no exception.3 Its singular strength is the statistical power generated by data on 15560 patients from published and unpublished trials. However, it includes clinically heterogeneous trials and criteria used by individual trials to classify adverse events are somewhat unclear. Only summary data are available in the public domain—for example, whether or not a person had a myocardial infarction, not when it occurred—which makes time to event analyses impossible. Also, the total number of adverse events was small, so that misclassification of a few events could alter the conclusions.
In response to the concerns raised by this meta-analysis, an unplanned interim analysis of a large, manufacture sponsored, randomised, open label, non-inferiority trial specifically designed to investigate the cardiovascular safety of rosiglitazone was recently released.4 Compared with patients taking metformin and a sulphonylurea, people taking a regimen that included rosiglitazone had no significant increase in the risk of myocardial infarction (hazard ratio 1.16, 0.75 to 1.81), although they had a significantly increased risk of heart failure (2.24, 1.27 to 3.97). When these new data are added to the trials in the previous meta-analysis, rosiglitazone is associated with an increased risk of myocardial infarction (odds ratio, 1.33; 1.02 to 1.72).5
To summarise, the meta-analyses show a significantly increased risk for myocardial infarction, whereas several individual prospective trials do not. More data would certainly help to clarify the matter, but the emerging safety concerns question the prudence of continuing ongoing trials. Notwithstanding the ethical concerns, it may be impossible to prevent an exodus of patients from these trials in light of the ongoing “trial by media” of the drug.
The broader question is how this reflects on regulatory processes used to monitor drug safety. Postmarketing surveillance, or pharmacovigilance, remains the weakest link in the regulatory process on both sides of the Atlantic. The current approach—the FDA's adverse event reporting system and the European EudraVigilance programme—relies heavily on passive surveillance, and it is based on reports of unusual adverse events from consumers, practitioners, manufacturers, and national regulatory authorities. At best, this creates a case series, one of the weakest forms of epidemiological evidence,6 that would be insensitive to an increase in common events like myocardial infarcts in diabetics.
Alternatively, the regulatory authorities may require systematic phase IV trials after market authorisation, but these are often not completed in a timely manner. In the United States, completion dropped from 62% in the 1970s to 24% in recent years,6 and the FDA is ill equipped to act against defaulters. As of September 2006, 930 (74%) of the 1259 postmarket studies were pending or delayed.7
This results in a fractured regulatory process, where the preapproval phase is marked by stringent requirements for safety and efficacy data, but performance in postmarketing surveillance falls short of the standards the agencies set for themselves. This is exemplified by the case of rosiglitazone. Rosiglitazone comes from a family of drugs with well documented side effects,8 9 and itself is associated with increased heart failure, anaemia, and raised low density lipoprotein concentration. However, postmarketing safety data seven years after regulatory approval consist of a patchwork of heterogeneous manufacturer sponsored trials, many of which are unpublished. Of note, a similar meta-analysis submitted by the manufacturer to the EMEA and the FDA in August 2006 showed an increased risk in ischaemic events (hazard ratio, 1.31, 1.01 to 1.70).10 The EMEA updated the product label of the drug,11 but no specific communication to healthcare professionals was issued. The FDA did neither.
The system needs to be fixed. The Institute of Medicine recommends a life cycle approach to drug evaluation.12 This would involve a systematic effort to monitor the safety and efficacy of a drug before and after approval using data from well designed clinical trials to inform ongoing risk-benefit analyses. This process could be made more systematic by requiring regulatory authorities to periodically and independently re-evaluate all data gathered after approval for all new molecular entities—particularly drugs with high sales.
In addition, the lack of transparency in the current system needs to be dealt with. There should be a legal requirement for all phase II-IV trials to be registered in a centralised database, such as the National Library of Medicine's clinicaltrials.gov or an equivalent. Complete datasets from these trials, systematic analyses of the results, and reports of periodic evaluations by the regulatory agencies must be publicly available.
A radical change is needed in the culture of existing regulatory institutions that regard postmarketing surveillance as their secondary mandate. This will require systematic rethinking of the existing regulatory and funding processes, and expediting changes currently in the pipeline.13 Progress will entail empowering the regulatory agencies with additional authority and resources.
The manufacturer and the FDA will share the spotlight as congressional investigation into the matter starts. In the meantime, what are the implications for patients currently on rosiglitazone? Doctors will need to revisit the indication for the drug on a case by case basis, bearing in mind that several alternatives are cheaper, supported by robust evidence, and now perhaps safer.14 The decision to switch drugs must be tempered by the fragility of the available evidence and the risks associated with altering patients' medical regimens. Needless to say, the ongoing use of rosiglitazone merits careful deliberation.
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.