FDA Issues New Rules for Evaluating Diabetic Drugs

Every day, Americans come in contact with a host of products regulated by the Food and Drug Administration (FDA); everything from common food ingredients to lifesaving drugs. The FDA’s regulatory approaches are dictated by laws and the relative risks that a product poses to consumers. For instance, some products, such as cosmetics and dietary supplements, can be marketed with no prior approval, where others, such as medical devices and new drugs, must be proven safe and effective before companies can put them on the market. The FDA has on occasion drawn criticism when drugs approved by the agency are later found to have health risks, as is the case with an agent used to treat type 2 diabetes—Avandia. Problems with the drug, approved by the FDA in 1999, gained national attention in May 2007 when a study conducted by the Cleveland Clinic showed that patients taking Avandia had a 43 percent higher risk of having a heart attack, and a 64 percent higher chance of sudden cardiac death. The study prompted the FDA to convene a hearing of an advisory panel to discuss the heart attack risks. The panel agreed that patients using Avandia face a greater risk of heart attack, and that the drug should bear the strictest FDA warnings, but stopped short of recommending Avandia be removed from the market entirely.

Another study conducted by researchers at the Lahey Medical Center in Massachusetts and published in the journal Lancet on September 29, 2007 cast further doubts about the safety of Avandia and fueled the debate about whether or not the drug should still be available for diabetes patients. The Lahey study took data from seven trials where more than 20,000 patients with type 2 diabetes or pre-diabetes were given Avandia or Actos, another drug in the thiazolidinediones group. Patients with a history of heart disease and heart failure were found to have as high as a 72 percent increased risk of heart failure while taking the drug. An editorial accompanying the Lahey findings criticized researchers for using reduced glucose levels as evidence of a drug’s success, and said they should focus more on patient outcomes such as quality of life and survival. The editorial recommended that drug companies be required to conduct further clinical trials of their medications after they are on the market. “Regulatory agencies must hold manufacturers’ feet to the fire to ensure that these are performed,” the editorial says. “Unless limitations on the understanding, analysis, and communication of drug safety issues are addressed, the TZDs (thiazolidinediones) will simply become the latest in a series of preventable drug disasters.”

Apparently, the FDA agrees that a better understanding of an anti-diabetic drugs’ cardiovascular risk is needed, evident in their issuance of new recommendations for the evaluation of such medications. Until now, companies generally needed only show their anti-diabetic medications lowered blood sugar levels in order to gain approval. However, that will no longer be enough. Beginning immediately, manufacturers developing new drugs and biologics intended to treat type 2 diabetes will need to provide evidence that the therapies do not increase the risk of cardiovascular events, such as heart attack, in comparison with existing therapies before FDA approval. The FDA also recommends that phase II and III clinical trials recruit older patients, with more cardiovascular risk factors or with renal damage, or both, and prospectively study them for up to two years, rather than the three to six months that has been typical. Manufacturers are also urged to have any cardiovascular events in their clinical trials analyzed by committees of outside cardiologists who are unaware of which patients received the tested products and which were on the placebo.

Cardiologist Steven Nissen, who warned about the heart attack risks of Avandia and proposed more safety data before FDA approval with additional study once a drug reaches the market, thinks with their new policy, “the FDA got this one right.” In an interview, Nissen said “it’s setting the bar at an appropriate level that will give us the information we need to make good treatment decisions.” But industry analysts say the new recommendations will make it more costly and time-consuming for companies to develop drugs that lower blood glucose levels, over 100 of which are in some stage of development. 

Mary Parks, M.D., director of the Division of Metabolism and Endocrinology Products at the Center for Drug Evaluation and Research (CDER) of the FDA says letters have been sent to the drug companies to inform them of the new guidelines, which will apply to future applications as well as those currently pending FDA approval. Pending applications include one from Bristol-Myers Squibb Co. and AstraZeneca for saxagliptin, and one from Eli Lilly and co. and Amylin Pharmaceuticals Inc. for Byetta as a stand-alone treatment. Dr. Parks said she couldn’t comment specifically on pending drug applications, but said some companies may only have to make “very minimal” alterations to their new drug applications.

The agency is also continuing to evaluate how these recommendations will be applied to anti-diabetic drugs that have already been approved and expects to release further guidance in the future. And, although these recommendations to companies aren’t binding, they do have the effect of being a requirement as the agency can refuse approval of drugs that don’t meet their recommendations.

Avandia’s maker, Glaxo, has said the drugs’ safety is comparable to similar pills and agreed to add a strong warning that the drug might increase heart attack risk, with a note that the data was inconclusive. Studies of its heart effects are continuing.

Currently in the United States, there are an estimated 23.6 million people who have type 2 diabetes. Of those cases, 17.9 million have been diagnosed, but 5.7 million people don’t even know they have the condition. Over time, diabetes can lead to blindness, kidney failure and nerve damage. Diabetes is also an important factor in accelerating the hardening and narrowing of the arteries, leading to strokes, coronary heart disease, and other large blood vessel diseases.