FDA NewsPerspective

FDA draft guidance eliminates CV outcomes trial recommendation for diabetes drug approvals

The FDA on Monday issued a new draft guidance that no longer includes a recommendation that drug companies conduct cardiovascular outcomes trials demonstrating safety for all type 2 diabetes drugs, according to an agency press release.

The 2020 draft guidance will replace the FDA guidances for industry, “Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” published in December 2008, and “Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention,” published in February 2008. Guidance documents represent the agency's current thinking on a particular subject and “do not create or confer any rights for or on any person and do not operate to bind FDA or the public,” according to the FDA.

“The FDA continues to review new clinical trial evidence and update its recommendations for drug development to reflect emerging scientific information,” Lisa Yanoff, MD, acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the release. “By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications.”

As Healio previously reported, in October 2018, an FDA advisory committee narrowly supported continuing agency-recommended CV outcomes trials to demonstrate safety for all type 2 diabetes drugs, with most committee members recommending modifications to the 2008 guidance after a decade of data and no indication of increased CV risk.

Although nearly evenly split in their 10-9 vote on whether to require CV outcomes trials for all new type 2 diabetes therapies regardless of the presence or absence of a CV risk signal during development, the members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) seemed to express similar sentiments in a discussion after the vote. Most called for modifications to the 2008 FDA-issued guidance, including broadening the population recruited for such trials and the inclusion of endpoints beyond three-point major adverse cardiac events.

“FDA has reviewed the results of several cardiovascular outcome trials (CVOTs) conducted to meet the December 2008 guidance recommendations,” the agency wrote in the draft guidance. “None of the CVOTs to date have identified an increased risk of ischemic cardiovascular events; some of the CVOTs have instead demonstrated a reduced risk for cardiovascular events. In light of the CVOT results, FDA is revisiting the recommendations of the December 2008 guidance and is now proposing an updated approach to evaluating the safety of new drugs and biologics to improve glycemic control.”

Despite no observed increased ischemic risk in CV outcomes trials conducted since 2008, some trials have yielded surprising findings regarding CV benefits that have changed the course of type 2 diabetes management. In 2015, researchers with the landmark EMPA-REG trial announced that the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) significantly reduced the risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CVD. In 2016, researchers with the LEADER trial reported people with type 2 diabetes and a history of CVD assigned liraglutide (Victoza, Novo Nordisk) saw reduced risk for CV death, nonfatal myocardial infarction and stroke vs. those assigned a placebo.

The FDA is also is soliciting comments from stakeholders regarding several key questions, including expectations regarding the size of a trial population vs. the amount of exposure, important comorbid conditions to explore, necessary safety evaluations, and whether there are specific safety concerns for people with type 2 diabetes that should be rigorously evaluated.

The public can submit electronic comments via the federal eRulemaking portal, available at www.regulations.gov, on the draft guidance during the next 90 days. After that time, the agency will begin work on the final version of the guidance. – by Regina Schaffer

Reference:

FDA. Guidance: Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control. Available at: https://www.federalregister.gov/documents/2020/03/10/2020-04877/guidance-type-2-diabetes-mellitus-evaluating-the-safety-of-new-drugs-for-improving-glycemic-control. Accessed: March 9, 2020.

Disclosure: Yanoff is acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research.

The FDA on Monday issued a new draft guidance that no longer includes a recommendation that drug companies conduct cardiovascular outcomes trials demonstrating safety for all type 2 diabetes drugs, according to an agency press release.

The 2020 draft guidance will replace the FDA guidances for industry, “Diabetes Mellitus — Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes,” published in December 2008, and “Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention,” published in February 2008. Guidance documents represent the agency's current thinking on a particular subject and “do not create or confer any rights for or on any person and do not operate to bind FDA or the public,” according to the FDA.

“The FDA continues to review new clinical trial evidence and update its recommendations for drug development to reflect emerging scientific information,” Lisa Yanoff, MD, acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, said in the release. “By following previous FDA recommendations, sponsors have shown that new type 2 diabetes drugs do not have excess ischemic cardiovascular risk, which has provided reassuring cardiovascular safety information for millions of diabetes patients. Now, with this proposed approach, we will have broader, valuable safety information for these medications.”

As Healio previously reported, in October 2018, an FDA advisory committee narrowly supported continuing agency-recommended CV outcomes trials to demonstrate safety for all type 2 diabetes drugs, with most committee members recommending modifications to the 2008 guidance after a decade of data and no indication of increased CV risk.

Although nearly evenly split in their 10-9 vote on whether to require CV outcomes trials for all new type 2 diabetes therapies regardless of the presence or absence of a CV risk signal during development, the members of the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) seemed to express similar sentiments in a discussion after the vote. Most called for modifications to the 2008 FDA-issued guidance, including broadening the population recruited for such trials and the inclusion of endpoints beyond three-point major adverse cardiac events.

“FDA has reviewed the results of several cardiovascular outcome trials (CVOTs) conducted to meet the December 2008 guidance recommendations,” the agency wrote in the draft guidance. “None of the CVOTs to date have identified an increased risk of ischemic cardiovascular events; some of the CVOTs have instead demonstrated a reduced risk for cardiovascular events. In light of the CVOT results, FDA is revisiting the recommendations of the December 2008 guidance and is now proposing an updated approach to evaluating the safety of new drugs and biologics to improve glycemic control.”

PAGE BREAK

Despite no observed increased ischemic risk in CV outcomes trials conducted since 2008, some trials have yielded surprising findings regarding CV benefits that have changed the course of type 2 diabetes management. In 2015, researchers with the landmark EMPA-REG trial announced that the SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) significantly reduced the risk for CV death and all-cause mortality in adults with type 2 diabetes and an established history of CVD. In 2016, researchers with the LEADER trial reported people with type 2 diabetes and a history of CVD assigned liraglutide (Victoza, Novo Nordisk) saw reduced risk for CV death, nonfatal myocardial infarction and stroke vs. those assigned a placebo.

The FDA is also is soliciting comments from stakeholders regarding several key questions, including expectations regarding the size of a trial population vs. the amount of exposure, important comorbid conditions to explore, necessary safety evaluations, and whether there are specific safety concerns for people with type 2 diabetes that should be rigorously evaluated.

The public can submit electronic comments via the federal eRulemaking portal, available at www.regulations.gov, on the draft guidance during the next 90 days. After that time, the agency will begin work on the final version of the guidance. – by Regina Schaffer

Reference:

FDA. Guidance: Type 2 Diabetes Mellitus: Evaluating the Safety of New Drugs for Improving Glycemic Control. Available at: https://www.federalregister.gov/documents/2020/03/10/2020-04877/guidance-type-2-diabetes-mellitus-evaluating-the-safety-of-new-drugs-for-improving-glycemic-control. Accessed: March 9, 2020.

Disclosure: Yanoff is acting director of the Division for Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research.

    Perspective
    Helena W. Rodbard

    Helena W. Rodbard

    I applaud the FDA for thinking beyond ischemic CV safety. It has been more than 11 years since the original draft guidance was published, and it is time to reevaluate.

    When the original guidance for industry was first published in 2008, we could have never imagined that we would acquire so much information, well beyond ischemic CV safety. Today, we know many of these drugs offer benefits that go beyond ischemic heart disease, with trials demonstrating heart failure benefits, renal benefits, glycemic benefits and decreased CV mortality with some agents. These findings have been responsible for major guideline changes, not just for endocrinologists, but for cardiologists and nephrologists.

    Yes, these studies come with a cost. One thing we must be cautious about is that cost should not be an inhibitor for the development of new medications. That of course will depend on what variables are being evaluated. I do like the new proposed draft guidance, because it states that FDA is looking for specific degrees of risk over and above ischemic CV adverse outcomes.

    We already know that the drugs currently on the market, at least, have been extensively evaluated and are safe from a CV standpoint. Broad safety evaluations, before the drug approval, are important, as well as the inclusion, as FDA is proposing, of a broader scope of human participants, such as older people, people with chronic kidney disease, and more gender and racial diversity. Different populations may respond differently to different drugs. Hepatic safety may be another endpoint of interest, so long as excessive regulations do not inhibit the development of these drugs. There needs to be a balance between safety and examining the appropriateness of including different populations and endpoints.

    • Helena W. Rodbard, MD, FACP, MACE
    • Medical Director, Endocrine and Metabolic Consultants, Rockville, Maryland

    Disclosures: Rodbard reports she has received grant support and consultant fees from AstraZeneca, Boehringer Ingelheim, Janssen, Lexicon, Lilly, Novo Nordisk and Sanofi.