Reevaluation of RECORD trial data fails to uncover elevated cardiovascular risk.
FDA has eased restrictions on patient access to the controversial diabetes drug rosiglitazone (Avandia, GlaxoSmithKline). The agency made its determination after an FDA Advisory Committee reviewed the drug in June 2013 and voted to lift its restrictions, and new information was released indicating that the drug carries no heightened cardiovascular risk.
Among its new actions, FDA is calling for modifications to cardiovascular-safety labels and the easing of restrictions connected with the Risk Evaluation and Mitigation Strategy (REMS) program, as well as provision of information updates for prescribers as changes arise in knowledge of cardiovascular risk connected with the drug. GSK will work with FDA to update labeling and to implement its decisions on easing access restrictions to the drug.
“The recent FDA decision to remove certain restrictions with regard to the prescribing to Avandia demonstrates the power of clinical trials to provide valuable information. This also has the potential to alter clinical decision-making processes in an effort to improve patient care,” said Abimbola Farinde, PharmD, MS, who serves on the faculty at Columbia Southern University, Orange Beach, Ala.
Results from the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) clinical trial showed no elevated risk of heart attack or death in patients treated with Avandia when it was compared to standard-of-care diabetes drugs. These data do not confirm the signal of increased risk of heart attacks that was found in a meta-analysis of clinical trials first reported in 2007.
Once the changes are final, rosiglitazone’s indication for use will no longer be limited to certain patients. FDA expects the new indication to state that the drug may be used along with diet and exercise to improve control of blood sugar in patients with type 2 diabetes mellitus. This is similar to indications for other diabetes drugs currently available.
Once the changes to the REMS are finalized, healthcare professionals, pharmacists, and patients will no longer be required to enroll in the rosiglitazone REMS program to prescribe, dispense, or receive rosiglitazone medicines. Patients will also be able to receive rosiglitazone through regular retail pharmacies and mail-order pharmacies.
The manufacturers of rosiglitazone drugs will be required to ensure that healthcare providers who are likely to prescribe rosiglitazone-containing medicines be provided training based on the current state of knowledge concerning the cardiovascular risk of these medicines.
FDA is also releasing GlaxoSmithKline from the postmarket requirement to conduct a clinical trial, known as Thiazolidinedione Intervention with Vitamin D Evaluation (TIDE), comparing Avandia to Actos (pioglitazone), the only other approved drug in the thiazolidinedione class, and to standard diabetes drugs. FDA has concluded that this trial is no longer necessary or feasible.
In 2010, in response to data from a meta-analysis of placebo-controlled randomized trials that suggested an elevated risk of cardiovascular events in association with rosiglitazone use, FDA announced it would restrict use of the drug to patients with type 2 diabetes who could not control their diabetes on other medications. FDA also required GSK to convene an independent group of scientists to reevaluate key aspects of RECORD, which studied the cardiovascular safety of Avandia compared to that of standard diabetes drugs, in order to provide clarity about the integrity of the study findings.
On June 5 and 6, 2013, the readjudicated results of RECORD, which were consistent with the original findings of the trial, were discussed at a joint meeting of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee. Committee members generally agreed that the readjudication was conducted appropriately and provided reassurance that the original study findings were accurate. A majority of the committee members, 13 of the 26, voted to recommend that the REMS for rosiglitazone be eliminated or modified to lessen restrictions to use.
Rosiglitazone is available in the form of Avandia and in combination with other diabetes medications, including metformin under the brand name Avandamet and glimepiride under the brand name Avandaryl.