Biopharma companies hoping to develop drugs to compete in the type 2 diabetes market can breathe a bit easier with the approval of Bristol-Myers Squibb/AstraZeneca’s Onglyza (saxagliptin): the final go ahead from the Food & Drug Administration July 31 unequivocally shows that it is indeed possible to meet FDA’s new cardiovascular safety guidelines for the class.The outcome is not surprising, after an advisory committee overwhelmingly supported approval of the drug earlier this year—but given the delays and uncertainty, sponsors may be forgiven if they weren’t going to believe it until they saw it.
And now that FDA has posted the approval letter for the drug, sponsors can get to work on figuring out exactly what it will take in terms of post-marketing requirements in the type 2 market of the future.
The letter makes one thing clear: a mandatory Risk Evaluation & Mitigation Strategy will not be an inevitable price for entering the class. Onglyza was approved with a host of post-marketing study commitments, but no REMS.
As for those post-marketing studies themselves, the key commitment is exactly what sponsors would have expected: a prospective clinical trial to assess cardiovascular outcomes. That section is bound to be read carefully by sponsors eager for more clues about how onerous post-marketing trials will be in the class. But they probably won’t learn much that they don’t already know.
Recall that during the advisory committee, Bristol declared its intention to run a study to demonstrate a superior cardiovascular safety profile for saxagliptin. The approval letter (in keeping with the safety focus of the new post-marketing authorities) frames the trial differently, with the goal of showing a relative risk of 1.3 or less versus the control population.
The letter also does not include any details about numbers of patients, duration of therapy or other key trial design elements. However, FDA has made clear its preference for an event-driven trial design, which (assuming Bristol agrees) would make some of the those elements irrelevant.
The letter does detail a number of other specific risks to test for (most triggered by signals in the NDA for Onglyza, but some clearly of a classwide concern.)
And it does set some deadlines. Bristol must finish designing the trial in November, and then complete the study in less than five years.
But beyond that, there’s not much to learn.
Still, the Onglyza letter is certain to be a template for future approvals in the type 2 diabetes class, so here is how FDA describes the pivotal post-marketing trial:
As for those post-marketing studies themselves, the key commitment is exactly what sponsors would have expected: a prospective clinical trial to assess cardiovascular outcomes. That section is bound to be read carefully by sponsors eager for more clues about how onerous post-marketing trials will be in the class. But they probably won’t learn much that they don’t already know.
Recall that during the advisory committee, Bristol declared its intention to run a study to demonstrate a superior cardiovascular safety profile for saxagliptin. The approval letter (in keeping with the safety focus of the new post-marketing authorities) frames the trial differently, with the goal of showing a relative risk of 1.3 or less versus the control population.
The letter also does not include any details about numbers of patients, duration of therapy or other key trial design elements. However, FDA has made clear its preference for an event-driven trial design, which (assuming Bristol agrees) would make some of the those elements irrelevant.
The letter does detail a number of other specific risks to test for (most triggered by signals in the NDA for Onglyza, but some clearly of a classwide concern.)
And it does set some deadlines. Bristol must finish designing the trial in November, and then complete the study in less than five years.
But beyond that, there’s not much to learn.
Still, the Onglyza letter is certain to be a template for future approvals in the type 2 diabetes class, so here is how FDA describes the pivotal post-marketing trial:
"A randomized, double-blind, controlled trial evaluating the effect of saxagliptin on the incidence of major adverse cardiovascular events in patients with type 2 diabetes mellitus.
The primary objective of this trial is to establish that the upper bound of the 2-sided 95% confidence interval for the estimated risk ratio comparing the incidence of major adverse cardiovascular events observed with saxagliptin to that observed in the control group is less than 1.3.
Secondary objectives must include an assessment of the long-term effects of saxagliptin on lymphocyte counts, infections, hypersensitivity reactions, liver, bone fracture, pancreatitis, skin reactions, and renal safety. For hypersensitivity reactions, especially angioedema, reports should include detailed information on concomitant use of an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker. For cases of pancreatitis, serum amylase and/or lipase concentrations with accompanying normal ranges and any imaging study reports should be included in the narratives.
Because renal impairment is an important complication of diabetes, you must ensure that there is a minimum of 1 year of exposure for at least 200 saxagliptin-treated patients with moderate renal impairment and at least 100 saxagliptin-treated patients with severe renal impairment.
The timetable you submitted on July 15, 2009, states that you will conduct this trial according to the following timetable:
Final Protocol Submission: by November 30, 2009
Study Completion: by July 31, 2015
Final Report Submission: by January 31, 2016.”
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