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FDA committee debates merit of CV outcomes trials for diabetes drugs
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An FDA advisory committee is examining the merit of agency-mandated cardiovascular outcomes trials to demonstrate safety for type 2 diabetes drugs, with several experts speaking about the benefits and drawbacks of such trials after a decade of data and no indication of increased CV risk.
The FDA issued guidance in 2008 to ensure that new antidiabetes therapies were not associated with an unacceptable increase in CV risk. The recommendations in the guidance were applied to all new drug products intended to treat type 2 diabetes, irrespective of whether a signal of concern was identified in the development program.
A decade after that guidance was issued — with no excess CV risk demonstrated in any study — the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) convened a 2-day meeting to ask members whether every new diabetes drug should continue to go through the rigorous process of a formal CV outcomes trial.
“We are now up to 26 cardiovascular outcomes trials in a variety of different drug classes utilizing over 190,000 patients, randomized to placebo by design,” Robert Ratner, MD, professor of medicine in the division of endocrinology at Georgetown University School of Medicine, said during a presentation. “We really need to stop and think whether or not this is working. Is this the direction we will continue going?”
Important lessons
Ratner, who participated in the original meetings to design the draft guidance in 2008, said much has been learned from well-designed CV outcomes trials — all studies since 2008 have demonstrated CV neutral or reduced CV risk in certain populations. Researchers have also gleaned valuable information on adverse events, including a signal for congestive heart failure with DPP-IV inhibitors and an observed increased risk for lower limb amputations with SGLT2 inhibitors, although that association remains a matter of debate, according to Ratner.
“Those have been important learning lessons,” he said.
More than 70% of adults with diabetes do not have CVD. The trials, Ratner said, have demonstrated an effect on secondary prevention, not primary prevention.
The FDA, he said, should not mandate that industry conduct a study that will demonstrate a neutral effect. Different trial designs, including registry-based randomized controlled trials or observational studies, are cheaper and easier to do, and can produce similar results, according to Ratner.
“There are choices in terms of study design that get you to the same point without the need for doing a large randomized controlled trial,” he said. “One of these is an adaptable study design — predefined points where you can make changes in the protocol based upon information that comes out.”
CV outcomes trials ‘critically important’
In a presentation during the meeting, Jennifer Green, MD, associate professor of medicine in the division of endocrinology at Duke University School of Medicine, said the CV outcomes trials remain “critically important,” although a decade later, there is room for modifications.
“Just because we have a better handle on what 10 or so drugs do to people, I don’t want to make an enduring decision to do otherwise,” Green said during a Q&A session after her presentation.
The guidance requirements, Green said, do not come without cost. Large CV outcomes trials, as traditionally conducted, can cost upward of $500 million, and that cost could ultimately be passed on to patients. But despite that cost, 15 CV outcomes trials for agents in three new classes, plus one insulin therapy have been completed since 2008, according to Green.
“That’s a nontrivial number of new therapies available to our patients,” she said.
Even trial results that demonstrate CV neutral benefits, Green said, are clinically relevant.
“We rarely have the luxury of managing diabetes adequately with one or two drugs,” she said. “People end up requiring complex medication regimens, oftentimes changing medications, and it’s important to understand the safety as best we can.”
However, the previously used CV outcomes trial model designed to satisfy FDA requirements should not be the only path forward, according to Green.
“We need to find new ways to design these trials, so they are less costly and can give answers more quickly,” she said.
‘Trials can be simpler’
In a presentation on the design and conduct of CV outcomes trials, Marc Sabatine, MD, MPH, the Lewis Dexter, MD, Distinguished Chair in Cardiovascular Medicine and professor of medicine at Brigham and Women’s Hospital and chairman of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, said there is no substitute for dedicated CV outcomes trials to definitively answer questions of safety and efficacy, although “certainly trials can be simpler.”
“As robust, validated treatment benefits consistently emerge for a class, equipoise for ongoing trials needs to be considered,” Sabatine said, adding that when designing a new trial, careful attention must be paid to existing data to guide the selection of patients to be studied, comparator and endpoints.
“Think about the comparator and the endpoints that make the most sense,” Sabatine said.
After several recent CV outcomes trials demonstrated CV superiority, Sabatine said they have “paid huge dividends.”
“Let’s think creatively,” he said. “What are the outcomes that we care about? There may need to be more adaptations as the data comes in, so that the trials give us useful information. Some of those data on heart failure and renal outcomes wouldn’t be highlighted [without this trial data].”
The EMDAC meeting will continue Thursday. The committee is expected to vote on whether an unexpected increase in CV risk should be excluded for all new drugs to improve glycemic control in type 2 diabetes, regardless of the presence or absence of a signal for CV risk in the development program. – by Regina Schaffer
For more information:
FDA briefing materials. Available at: www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM623913.pdf.
Disclosures: Green reports she has received research grants or consultant fees from AstraZeneca, Bioscientifica, Boehringer Ingelheim, Diachi Sankyo, Intarcia, Merck, Novo Nordisk and Sanofi. Ratner reports financial relationships with Adocia, Novo Nordisk and Virta Health. Sabatine reports he receives honoraria for consulting from Alnylam, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, Intarcia, Ionis, Janssen Research and Development, MedImmune, Merck, MyoKardia, Novartis and The Medicines Company.