FDA Panel: Keep CV Outcomes Trials for Diabetes but Tweak Them

Miriam E. Tucker

October 26, 2018

An advisory panel split nearly down the middle when voting on whether the US Food and Drug Administration (FDA) should continue to require manufacturers of drugs for treating type 2 diabetes to perform dedicated randomized cardiovascular safety outcomes trials as a condition of US marketing. The vote was, narrowly, to keep the trials, but most panel members recommended some changes to them.

In response to the question, "Should an unacceptable increase in cardiovascular risk be excluded for all new drugs to improve glycemic control in patients with type 2 diabetes, regardless of the presence or absence of a signal for cardiovascular risk in the development program?" the official vote of the FDA's Endocrinologic and Metabolic Drugs Advisory Committee was 10 "yes" versus 9 "no."

Despite the split vote, all panel members agreed that lessons learned from the mandated cardiovascular outcomes trials (CVOTs) completed over the past few years point to the need for revisions of the 2008 Guidance for Industry: Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes, which set the original mandate.  

Some panel members who voted for continuation of the CVOTs suggested various ways that they could be streamlined such as using remote monitoring technology or data from electronic health records to minimize the costs involved.

On the other hand, most who voted to discontinue the trials advised that premarketing phase 2 and 3 trials be better designed with larger and more diverse populations and for longer durations to increase detection of cardiovascular endpoints and other outcomes, including heart failure, chronic kidney disease, and peripheral vascular disease.

There was also unanimous agreement that dedicated randomized trials would be necessary if any safety signals were detected. 

The 2008 guidance arose out of concerns about cardiovascular harm arising from older studies of type 2 diabetes medications. The immediate trigger was a meta-analysis of 42 trials of rosiglitazone (Avandia, GlaxoSmithKline) that suggested increased risks of both myocardial infarction and cardiovascular mortality with the drug. But those risks weren't seen in a subsequent trial and FDA's prior regulatory restrictions were later lifted.

And thus far, none of the eight completed mandated CVOTs have identified excess cardiovascular risk from the drugs in question, while three have actually shown benefit.

In public comments, representatives from several stakeholder pharmaceutical companies argued that today the high cost and complexity of the CVOTs as currently mandated represent an unnecessary financial burden and pose a barrier to innovation.

Time to Revise the Design of CVOTs

In remarks on the first day of the 2-day advisory panel meeting, Robert E. Ratner, MD, formerly chief scientific and medical officer of the American Diabetes Association (ADA) and now with Georgetown University, Washington, DC, pointed out that the CVOTs have provided extremely useful information leading to major changes in clinical practice guidelines.

Earlier this month, for example, the ADA and European Association for the Study of Diabetes issued a joint statement on type 2 diabetes treatment that incorporates information gleaned from those trials, advising use of drugs with proven cardiovascular benefit in patients with established cardiovascular disease.

He also noted that the CVOTs have identified unanticipated safety signals, including amputations with canagliflozin (Invokana, Janssen) and heart failure hospitalizations with saxagliptin (Onglyza, AstraZeneca).

Still, Ratner said and the panel agreed that it's time to revise the FDA guidance.  

"The 2008 guidance was created at a time when uncertainty was great and there was a desire to gain more information. We've learned enormously from that endeavor. We've changed the paradigms for how to treat diabetes...The question is how do we move forward much more efficiently to ensure new drug development to improve the lives of people with diabetes at a cost that's reasonable to both the pharmaceutical company and patients without putting anyone at risk?" Ratner commented to Medscape Medical News in an interview.

Panel member Kenneth D. Burman, MD, chief of endocrinology at MedStar Washington Hospital Center, DC, voted yes to the question to maintain the CVOTs, noting, "A standard phase 2-3 trial for efficacy and safety is not generally adequate to detect sensitivity and specificity and to detect a relevant cardiovascular signal. I think the next issue is whether a CVOT can be appropriately modified to improve efficiency."

Thomas J. Wang, MD, director of cardiology and chief of the Vanderbilt Heart and Vascular Institute, Nashville, Tennessee, also voted yes.

"Given the current state of knowledge, I don't think we have an appropriate substitute to the CVOT for generating information on the cardiovascular effects of new diabetes medications...Rather than addressing the imperfections of the process by eliminating guidance and returning to the pre-2008 situation, it seems preferable to focus our efforts on considering how the design of these trials and the endpoints might be improved. This might include considering more cost-effective or flexible designs, thinking about the incorporation of heart failure and renal endpoints, and considering alternatives to the placebo control."

The mention of alternatives to placebo controls refers to a point made by several other panel members. Because of recent guidelines advising use of a medication with proven cardiovascular benefit in patients with type 2 diabetes who have established cardiovascular disease, conducting trials of drugs against a placebo among such patients may no longer be ethical.

'No' Voters Explain Themselves

Judith Fradkin, MD, director of the Division of Diabetes, Endocrinology, and Metabolic Diseases at the National Institute of Diabetes, Digestive, and Kidney Diseases, Bethesda, Maryland, voted no to the question given to the panel, explaining, "I was impressed by the number of trials performed over the last 10 years and what we've learned from them, but also the fact that we haven't seen a significant cardiovascular risk and that the rosiglitazone meta-analysis, which precipitated this decision, has really subsequently been called into question."

Fradkin added that she was also "influenced by the opportunity costs of these postmarketing studies, not just the economic costs to pharma so much, but actually more the lack of attention to components of diabetes other than major adverse cardiovascular events (MACE)...and to the lack of diversity that this focus on reaching a power for MACE has engendered," she said. Fradkin was referring the fact that in order to obtain sufficient numbers of cardiovascular events for statistical power, the CVOTs have enrolled mostly high-risk patients with established cardiovascular disease, rather than a group representing the spectrum of diabetes patients who receive the drugs in clinical practice.

Endocrinologist George Grunberger, MD, chair of the Grunberger Diabetes Institute, Bloomfield Hills, Michigan, also voted no. "To me, it makes sense to broaden the phase 2 and 3 trials to include heart failure, kidneys, peripheral vascular disease, to make them more robust." That way, he said, better data are gathered earlier and a CVOT would only be done if a safety signal were detected.  

He also made the new ethics point, a byproduct of the CVOTs. "I don't think we can justify now doing trials against placebo. I think now all the trials need to have an arm which has in it a medication that has been shown to have cardiovascular benefit."

Members of FDA advisory panels are vetted for conflicts of interest and waivers are granted for participation if necessary. No waivers were granted for this meeting. Ratner is a consultant to Adocia, Novo Nordisk, and Virta, and he holds stock in Johnson & Johnson, Abbott, and AbbVie. 

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