The Food and Drug Administration has declined to approve insulin degludec, calling for more cardiovascular safety data on the long-acting basal insulin analogue, setting back the timeline for its availability by at least a year.
In a statement released on Feb. 11, the manufacturer, Novo Nordisk, said that in a complete response letter, the FDA has requested "additional cardiovascular data from a dedicated cardiovascular outcomes trial" before the review of insulin degludec (IDeg) and insulin degludec combined with insulin aspart can be completed. The decision applies to both IDeg alone and IDeg combined with the fast-acting insulin analogue insulin aspart. In September 2011, the company filed for approval of these products to improve glycemic control in adults with type 1 and type 2 diabetes.
The FDA issues complete response letters when a product is not ready to be approved, outlining deficiencies in the application, and, when possible, including recommendations on what is needed to complete the approval process. The FDA does not announce these letters publicly, but the companies are free to announce them.
"Novo Nordisk is evaluating the content of the Complete Response Letter and will work closely with the FDA to provide the requested data," according to the statement, which adds that the company does not expect to have the data available in 2013. Approval is also dependent on the resolution of violations in good manufacturing practice (CGMP) at manufacturing facility, outlined in a Dec. 12 warning letter from the FDA, the company said.
In November 2012, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee unanimously recommended that Novo Nordisk conduct a cardiovascular outcomes study to investigate a cardiovascular safety signal detected in a meta-analysis of clinical trials, an increase in a composite major cardiovascular event (MACE) endpoint of unstable angina pectoris, cardiovascular death, stroke, and acute coronary syndrome. But the panel was less united on whether the data should be required before or after approval, voting 8-4 to recommend approval.
Based on a 2008 guidance issued by the FDA on cardiovascular risk assessments of new drugs for type 2 diabetes, preapproval safety analyses should provide reassuring estimates of risk.
IDeg forms multihexamers after injection, resulting in a soluble depot from which there is a slow, continuous, and extended release of IDeg, and a flat stable profile, according to Novo Nordisk, which markets insulin aspart as Novolog. If approved, the company plans to market insulin degludec as Tresiba and the combination product as Ryzodeg. Both have been approved in the European Union, Mexico, and Japan.