Regulatory Action on Rosiglitazone

There have been ongoing concerns about the safety of the diabetes drugs containing rosiglitazone (Avandia, Avandaryl, and Avandamet) — a thiazolidinedione antidiabetic agent indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

In 2007, a meta-analysis of controlled clinical trials found increases in the risk of myocardial infarction and a near-significant increased risk of death from cardiovascular causes when rosiglitazone was compared with placebo or with standard diabetes drugs. Following an advisory committee meeting held in July 2007, the U.S. Food and Drug Administration (FDA) added information about the possibility of ischemic cardiovascular risk to the drug’s existing boxed warning. At the same time, the FDA also required the sponsors to conduct a head-to-head cardiovascular safety trial of rosiglitazone versus pioglitazone — the other antidiabetic drug in this class available in the United States. After new data became available, the FDA held a second advisory committee meeting on rosiglitazone safety on July 13 and 14, 2010. On September 23, 2010, the FDA announced regulatory actions stemming from these deliberations.

The FDA is restricting access to rosiglitazone by requiring the drug sponsor to submit a Risk Evaluation and Mitigation Strategy, or REMS. Under the Food and Drug Administration Amendments Act of 2007, the FDA can require a drug sponsor to issue a REMS to impose certain restrictions so that the benefits of a drug continue to outweigh its risks. When the REMS for rosiglitazone is implemented, the drug will be available to patients not already taking it only if they are unable to achieve glycemic control using other medications and, in consultation with their health care professional, decide not to take pioglitazone for medical reasons. Current users of rosiglitazone will be able to continue using the medication if they appear to be benefiting from it and they acknowledge that they understand these risks. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns. The agency anticipates that the REMS will limit use of rosiglitazone significantly.

The FDA is taking this step on the basis of its assessment of all available data on the cardiovascular ischemic risk of rosiglitazone. At the recent advisory committee meeting, FDA scientists and external experts presented new signals of risk from observational studies and meta-analyses. Each of these data sources has its limitations, including the potential for bias in observational studies and the fact that pooling the results of the studies that were not designed to assess cardiovascular risk can lead to invalid conclusions. But there was no reliable evidence to refute these cardiovascular safety concerns.

After considering the data, 18 members of the advisory committee found significant cause for concern about an increase in ischemic cardiovascular events with rosiglitazone relative to other non-thiazolidinedione antidiabetic agents, whereas 6 committee members did not. Twenty-one members believed that the cardiovascular risk with rosiglitazone was significant as compared with pioglitazone. Three members did not reach this conclusion. This 21-to-3 vote also reflected recognition that available evidence on pioglitazone, including the results of a well-designed trial in high-risk patients, does not show a signal of a cardiovascular ischemic risk.

The rosiglitazone controversy is remarkable because there are strongly held, differing positions on how the agency should respond to emerging safety data, both inside the FDA and in the biomedical community. The 2010 advisory committee was split in advising the agency about what to do. Moving from the least to most restrictive options, 3 members voted to allow continued marketing with no changes to the label; 7 voted that the FDA should adjust the label to account for the new concerns but take no additional action; 10 members voted for the FDA to both increase warnings and limit access to rosiglitazone; and 12 voted that the medication should be removed from the market altogether. The FDA decided to increase warnings and limit access to rosiglitazone substantially.

The FDA anticipates questions on whether the agency has gone too far, or not far enough.

Some may note the limitations of available data and argue that the FDA should provide more information to clinicians but not impose additional restrictions. The FDA’s response is that a label change alone does not provide adequate assurance that use of rosiglitazone will be limited to appropriate patients. New label warnings are not always read. The significant questions about the drug’s cardiovascular safety justify stronger measures to support good clinical decision making and protect patients.

Others may argue that rosiglitazone should be removed from the market because there is no predefined patient population for whom it is known that it will be more advantageous than pioglitazone. Our response starts with the fact that rosiglitazone does have benefits in glycemic control. These benefits include reductions in short-term complications of hyperglycemia. There is also a broad range of evidence supporting glycemic control as a reliable surrogate marker for decreasing the rate of progression of the microvascular complications of diabetes, including retinopathy and kidney disease.

Against these benefits, we must assess the evidence of rosiglitazone’s cardiovascular risks. This evidence is concerning, but it is not definitive. There are patients with severe type 2 diabetes whose disease may not be controlled on other medications and either may not tolerate pioglitazone or, in consultation with their health care professional, decide not to take pioglitazone for other medical reasons. If well informed, these patients may be willing to accept the concern about cardiovascular safety in exchange for the known benefits of glycemic control. The FDA recently announced that the agency is investigating further signals of a possible increase in the risk of bladder cancer with long-term use of pioglitazone. Although the absolute risk to all patients appears to be small, some patients with a history of bladder cancer, in consultation with their doctors, may decide not to take pioglitazone. When there are just two drugs in a class, and many outstanding uncertainties, maintaining some flexibility may have value for patient care.

The FDA will continue to review emerging data on rosiglitazone. The agency is requiring an independent readjudication of end points at the patient level of an important trial of rosiglitazone’s safety — the Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes, or RECORD, trial. As published, RECORD demonstrated the noninferiority of rosiglitazone when compared with sulfonylureas and metformin with respect to a composite end point of multiple cardiovascular events and death, but it did not rule out an elevated risk of myocardial infarction. However, during the course of the FDA’s review of the RECORD study, serious questions arose about potential bias in identification of cardiovascular events arising from the study’s open-label design. The FDA is requiring the readjudication of end points to provide additional clarity about the findings.

Other actions taken by the agency include the discontinuation of the trial known as TIDE (Thiazolidinedione Intervention with Vitamin D Evaluation) — the head-to-head cardiovascular safety trial of rosiglitazone versus pioglitazone. Given the current state of the evidence and the FDA’s recent actions, participants would need to be informed of significant concerns that rosiglitazone may cause more cardiovascular disease than pioglitazone, the restrictions on the use of rosiglitazone that will be imposed through the REMS, and that it is unlikely that, outside the study, the patient would receive rosiglitazone. According to recent recommendations from an Institute of Medicine committee, such an informed consent process might be justified if the study’s outcome could realistically yield a significant benefit to public health. At this point, however, the FDA does not consider TIDE such a study. It is possible that additional data, including information from the readjudication of RECORD, could support additional clinical trials of rosiglitazone safety.

How can the FDA prevent such uncertainty about a major risk from happening again? In 2008, the FDA issued draft guidance on the assessment of cardiovascular risk for new antidiabetic drugs. In this guidance, the FDA proposed upper boundaries for the risk of major cardiovascular events in a meta-analysis or a noninferiority study that compares the new drug with standard therapy. The FDA also recommends that the data for these comparisons come from longer-term trials — that is, trials of at least 2 years’ duration. Guidance represents the FDA’s current thinking on how to meet a specific requirement — in this case, demonstration of the safety of a new drug for this indication. Drug sponsors are free to use other methods to show safety, but such methods need to be equally robust. The expectation of longer-term evidence on the cardiovascular risks of new antidiabetic drugs will assure that such evaluations are routinely conducted and that longer-term data on multiple safety parameters are also available.

The case of rosiglitazone underscores the need for a robust evidence base to demonstrate the safety of medicines administered long-term. The FDA is committed to advancing the science of drug safety evaluation, during both drug development and in the postmarketing period.