Could Enrichment Cloud CV Signal For Weight-Loss Drugs?

FDA’s Robert Temple says the trend in risk indicators is the important element when interpreting data from high-risk patients for low-risk patients, after some advisory panel members question the relevance of data from older, sicker participants to the younger patients who take obesity products.

Whether a cardiovascular safety study can be enriched with patients with cardiovascular risk – not the primary users of the test drug – was called into question during the March 28-29 meeting of FDA’s Endocrinologic and Metabolic Drugs Advisory Committee.

FDA convened the session to gather input on how to collect cardiovascular safety data for obesity drugs, with a focus on CV outcomes trials (Also see "Potential Cardiovascular Benefit Colors CV Safety Expectations For Obesity Drugs" - Pink Sheet, 9 Apr, 2012.).

But the agency also asked if strengthening the signal for CV events during the clinical trial development program by enrolling patients with a higher risk for cardiovascular events would be beneficial in performing a meta-analysis of prospectively adjudicated major adverse cardiovascular events. As an example of such patients, FDA suggested those with a history of myocardial infarction, stroke and multiple risk factors.

Panel members generally accepted the need for enrichment to ensure that enough adverse cardiovascular events will occur to detect a signal. But some members questioned this tactic in the obesity space, where enrichment means enrolling participants who are older and sicker than those who typically take weight-loss drugs.

“We’re putting ourselves in a position of using the older population as a sentinel for whether these drugs cause excess risk in the using population. … To the extent that these drugs cause excess risk, can we expect that the younger population will reflect that in the same way that the older population does?” Edward Gregg, Centers for Disease Control and Prevention, asked.

In diabetes, essentially half the target population is 60 and older and enrichment with this group is moving closer to those who need the drugs, he pointed out (Also see "FDA Diabetes Guidance Encourages Enrollment Of Sicker Patients" - Pink Sheet, 17 Dec, 2008.). In obesity, “it’s actually the opposite situation.”

The response from FDA presented two sides of the issue. “The presumption in all this is that if you show adverse effect in a selected higher risk population, it’s reasonable to assume that the direction of the effects would be similar in the lower risk population,” CDER Director for Clinical Science Robert Temple explained. “It may be less common in a lower risk population, but it’s still potentially there.”

Mary Parks, director of the Division of Metabolism and Endocrinology Drug Products, suggested the state of patients’ health could be a factor in the trial results. “I don’t know if I feel the same way,” she told Temple. “I think one thing here is, you may see a risk in a higher-risk patient population and could it be that the horse is already out of the barn?”

Questions were raised about the benefit of statins for patients on dialysis “because they were already too far along in their disease process,” she noted. “That may be the case here with obesity drugs.”

That is part of the discussion, Temple responded. “But in heart failure, in lipid lowering, in blood pressure, it’s always been true, every time, that we go to a less sick population and increase the study sample size appropriately and you see the same direction of effect.”