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A Lifecycle Approach to the Evaluation of FDA
Approval Methods and Regulatory Actions
Opportunities Provided by a New IOM Report
JAMA, Published online May 4, 2012
COMMENT: This article and the and the IOM report it reviews have particular relevance to several posts relating to the benefit-risk profile of several drugs we use to treat diabetes and its related cardiovascular risk factors. It proposes the regulatory agencies adopt a life cycle approach to drug approval and post-approval monitoring. The basis for this is both the discovery of serious side effects of medications that were not apparent during the approval process. The article cites a series of highly publicized drug withdrawals, including rofecoxib (Vioxx) in 2004. In 2006 the US Food and Drug Administration (FDA) invited the Institute of Medicine(IOM) to review the system of drug-safety assessment in the United States. The centerpiece of the 2007 IOM report was the recommendation that the FDA should monitor and evaluate the benefits and risks of drug therapies not only prior to their approval but throughout their entire market life. In some instances, post-market safety issues may not become apparent until several years after approval. In 1999, for instance, marketing authorization was granted both in the United States and Europe for rosiglitazone (Avandia) and pioglitazone(Actos) for the treatment of type 2 diabetes, a condition that substantially increases the risk of cardiovascular disease. The basis of regulatory approval for both these drugs was the beneficial effects seen on blood glucose levels and glycated hemoglobin levels, which, as surrogate markers, were assumed to predict clinical and cardiovascular benefit. In 2004, a World Health Organization report raised questions about an association of these agents with cardiac disease, and in 2007, new evidence of an increase in cardiovascular events associated with rosiglitazone became apparent. This experience stimulated new requirements for sponsors of drugs used to treat type 2 diabetes. The revised FDA guidance requires manufacturers to assess cardiovascular events in all phase 2 and phase 3 clinical trials and to submit these to meta-analysis. The upper 95% confidence level of the association with cardiovascular disease risk is considered in the regulatory decisions about drug approval and post-marketing requirements for additional trials. Although the current acceptable upper 95% confidence level for cardiovascular risk may require future revisions, the new guidance advanced approval methods; and the requirement for a preplanned meta-analysis of data from preapproval trials may spread to other drug classes such as anti-obesity agents. Concerns about the cardiovascular risks of rosiglitazone served in part as the impetus for a new IOM report on the ethical and scientific issues in studying the safety of approved drugs. Currently, FDA can mandate sponsors of new medicines to fulfill certain post-marketing study requirements and may also require the use of specific plans to mitigate known risks in a Risk Evaluation and Mitigation Strategy. The new IOM report acknowledges the advance in drug safety undertaken by the FDA in the last few years and recognizes the ethical and public health responsibility to ensure drug safety. These changes and others suggested in the report are heartening to those of use who treat diabetes and other chronic diseases. We have learned from harsh experience that surrogate end points are not necessarily indicative of long-term benefits. We and especially our patients welcome a life cycle approach to drug approval and the use of medically meaningful end points to determine the benefit-risk profile of new agents.