At the April 1st hearing of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, the panel was asked to evaluate Bristol-Myers Squibb’s cardiovascular safety data for its candidate diabetes drug saxagliptin. This was the first diabetes drug to be reviewed by the committee since the FDA issued new guidance in December 2008 requiring companies to perform more extensive premarketing evaluations of CVD safety than they have done in the past.
As the panel struggled with the statistical uncertainty arising from the low rate of major adverse cardiac events (MACE) in the phase 2/3 clinical trials—a total of just 40 among 4,607 subjects over a mean of 62 weeks—a larger question emerged: Why was the MACE rate so low? The answer, several panel members noted, is that the study population was relatively low-risk: They had a mean age of 54 years and mean diabetes duration of just 4 years. Exclusion criteria for the trials included significant CV events within the past 6 months and congestive heart failure.
“I’m actually feeling quite comfortable giving this drug to a patient who doesn’t have underlying cardiac disease. I just have no idea what happens when you give this to someone who actually has coronary disease or who has had diabetes for a longer time and actually has these underlying risk factors that tend to predispose someone to having a myocardial infarction,” said Dr. John R. Teerlink, a San Francisco cardiologist who served as a temporary voting member of the panel.
Indeed, as a March 30th New York Times article pointed out, multiple chronic conditions are the rule, not the exception: Two-thirds of people over age 65 have more than one chronic condition, and people with five or more conditions comprise 68% of Medicare spending.
Yet patients with multiple diseases are routinely shut out of drug trials. A 2007 study found that 81% of the randomized trials published in the most prestigious medical journals excluded patients because of coexisting medical problems, Times reporter Siri Carpenter wrote, adding, “Because so little research includes complicated patients, physicians have little scientific evidence on which to base their care.”
At the end of the saxagliptin hearing, the advisory panel voted 10-2 to support the drug’s CV safety data for the patient population studied, but voted unanimously, 12-0, to require BMS to conduct a long-term postmarketing study in higher-risk patients with type 2 diabetes who better represent the range of those that physicians see every day. Might this decision signal the start of more such “real-world” pre-marketing drug studies in the future? If so, it would seem that the aging Baby Boomer generation will be the first to gain.