Tearing Down The Goalposts: What’s Next For US FDA Diabetes Guidelines?
Executive Summary
Advisory committee discussion of cardiovascular safety standards for type 2 diabetes therapies was a friendly, collegial event with broad agreement on how FDA’s diabetes guidelines can be improved. Unfortunately, the panel split down the middle on the critical question for FDA.
The chair of the US FDA’s Endocrinologic & Metabolic Drugs Advisory Committee offered an especially apt summary of the panel’s Oct. 24-25 discussion of elements of FDA’s safety standards for diabetes drugs: "Everybody said they were saying the same thing, but you all said something different."
The chair, Emory University’s Peter Wilson, was attempting to summarize the specific points made in response to a question about whether safety findings related to an individual drug should or should not be applied to all drugs in the class. But he could just as easily have been commenting on the discussion and overall outcome of the meeting.
In one sense, the committee was essentially unanimous in advising FDA that it should change its current diabetes outcomes standards to get rid of the “goalposts”: the requirement, outlined in a 2008 guidance, that all new diabetes drugs rule out one-level of excess risk of CV events prior to approval (a hazard ratio of 1.8 compared to background therapy) and then conduct a post-marketing study to rule out a smaller risk (HR of 1.3).
On the other hand, the single voting question – whether FDA should continue to require drug developers to rule out an excess CV risk in the absence of a specific signal for a given product – was as divided as it could be: 10 “yes” and 9 “no.” (Also see "Diabetes Drugs: Longer, Broader Phase II/III Trials Could Replace CV Outcomes Trials, US Panel Says" - Pink Sheet, 25 Oct, 2018.)
George Grunberger said he agreed entirely with the immediate prior comments by National Institute of Allergy & Infectious Diseases statistician Martha Nason, who voted “yes,” even though he voted “no.”And yet, essentially every member of the panel agreed that the burden of large CV outcomes trials is too high, and that “something simpler” would be an improvement. Many members specifically advocated for shifting to a single pre-market standard of ruling out an excess risk of 1.5. Drug developers may not consider the idea of longer, larger pre-market trials to be “simpler,” but the committee clear supports streamlining the process somehow.
So many members repeated those points that the final of the 19 members to explain their vote, George Grunberger (Wayne State University), pointed to the slide showing the 10-9 result and joked, “if you turned off the screen, everybody said exactly the same thing.” He then said he agreed entirely with the immediate prior comments by National Institute of Allergy & Infectious Diseases statistician Martha Nason, who voted “yes,” even though he voted “no.”
However, in explaining his vote, Grunberger also pointed directly to the key point that divided the committee. Nason said she voted “yes” because the question was phrased to ask whether FDA should rule out “an unacceptable risk” of adverse CV effects. “I felt I had to vote yes,” she said.
Grunberger, however, focused on the rest of the voting question “regardless of the presence or absence of a signal” for the specific drug in development to explain his “no” vote.
That gets to the dilemma for FDA: 10 years after imposing the outcomes standard, there have been eight completed CVOTs with none showing an increased risk of atherosclerotic events. There have been studies in one class (the DPP4 inhibitors) suggesting potential increased risk of heart failure, while other classes (GLP1s and SGLT2s) have shown cardiovascular outcome benefits.
The agency cannot simply require trials because they are nice to have – the request has to be grounded in the FDAAA authority.However, as FDA Division of Metabolism and Endocrinology Products Acting Director William Chong repeatedly reminded the committee, FDA’s authority to mandate safety trials requires a formal determination under the 2007 FDA Amendments Act that there is a safety issue that requires further investigation. The agency cannot simply require trials because they are nice to have – the request has to be grounded in the FDAAA authority.
FDA has been invoking that authority for all newly approved type 2 diabetes therapies since 2008, including a boilerplate sentence in its approval letters: “There have been signals of a serious risk of cardiovascular events with some medications developed for the treatment of type 2 diabetes mellitus, and available data have not definitively excluded the potential for this serious risk with [drug name].”
FDA’s voting question, in essence, asked whether the premise that “available data have not definitely excluded” the risk is still true.
The split vote leaves FDA with no clear mandate to drop the requirement – especially since the committee technically voted in favor of retaining it, albeit by the narrowest of margins. On the other hand, the nature of the deliberations and committee discussion strongly suggest that the argument for a legally enforceable mandate is tenuous at best.
So, even though there was a strong consensus on the committee to get rid of the “goalposts,” it may still be a while before FDA actually moves to tear them down.
From the editors of the RPM Report