Tougher tests for diabetes drugs?
clinical trials of diabetes drugs if it follows the advice of one
of its advisory committees.
The proposal would make it compulsory for trial sponsors to carry out testing on the cardiovascular safety of diabetes treatments ahead of approval, and perhaps also extensive post-marketing studies. The move comes after strict warning labels were added to drugs in the glitazone class of antidiabetic agents last year, as well as the results of large clinical trial, called ACCORD, which seemed to suggest that aggressive glucose lowering therapy in diabetics increased mortality. Last year GlaxoSmithKline added safety warnings for its Avandia (rosiglitazone) diabetes product, while Takeda took the same approach for Actos (pioglitazone) after a meta-analysis raised concerns about the cardiovascular risks associated with the drug class. In the latest development, the FDA's Endocrinologic and Metabolic Drugs Advisory Committee voted by 14 to two that drugmakers should have to carry out long-term studies of cardiovascular effects. However, the actual form of the additional testing remains up in the air, including the duration of the studies, the clinical endpoints that should be used in trials and the thresholds for acceptable risk. A lot will depend on whether a safety signal has been seen in mid-stage clinical testing, according to some panel members, including acting committee chair Kenneth Burman of Washington Hospital Center. Other panellists suggested the studies might need to last as long as five years if they were to reliably detect an elevated risk of heart attack, stroke or other cardiovascular events, but there were argument son both sides as to whether these should be conducted before or after approval. Steve Nissen of the Cleveland Clinic suggested one possible approach - a small-scale, pre-approval trial followed by long-term studies once a product is cleared for sale. The panel agreed that these safety trials should employ comparator drugs rather than placebo and should not have to show cardiovascular benefit, an issue the FDA had asked it to address ahead of the meeting. "A likely scenario would involve a 2 to 3 year screening trial completed pre-approval and a three to five year confirmatory trial post-approval," commented analysts at Dresdner Kleinwort. The FDA recently outlined a plan to beef up its post-marketing surveillance muscle after being criticised for not doing more to ensure companies fulfil their commitments to post-approval or Phase IV studies. Meanwhile, the panel also agreed that a non-inferiority margin should be pre-specified for both trials, and that the studies should use a composite endpoint including mortality, myocardial infarction and stroke. The trials should also be conducted in a 'real world' manner in diabetic patients with cardiovascular risks. Dresdner Kleinwort notes that the FDA has hinted that this methodology could be applied to other settings. "It is unclear if currently approved drugs will be re-tested, it will depend on what data is available," said the analysts, although an FDA spokesperson suggested that the agency may look back at the data filed in support of approved diabetes drugs to see if additional information is required. "However, it is likely to have a larger affect on those drugs in Phase II/III." They note that the new proposals, if accepted by the FDA, could affect Novo Nordisk, which recently filed for approval of diabetes drug liraglutide, as well as other drugs in development such as Roche/Ipsen's GLP-1.