Interview with FDA Panelist (Continued)

CARDIOVASCULAR RISK AND CARDIOVASCULAR OUTCOMES TRIALS

Sanjay:: We would love to talk more about cardiovascular outcomes trials. To start, how do you think one can assess the risk of cardiovascular outcomes for an obesity drug, given that the benefits of modest weight loss may accrue over time, and the target population may not be at a high enough short-term risk to make what a traditional outcomes study, at least in diabetes, feasible?

Dr. Kaul: Most obesity trials have been conducted in women in their 40s, and the risk level in this demographic is lower than what would typically be seen in diabetes trials. In general, cardiovascular risk is higher for men than women. So this poses a challenge in trial design. What I've seen so far with pre-approval trials of obesity drugs in general is the opposite – a "sanitized" population that is not representative of the real-world patients, and a follow-up limited to about one to two years. One of the major shortcomings of randomized controlled trials (RCTs) is their limited external generalize ability. These trials enroll highly selective and homogeneous populations who receive standardized optimal care. The real-world scenario is quite different. The population is heterogeneous (in terms of underlying risk and treatment response), and there is substantial variability in the quality of care the patients receive. I am a strong believer in large and simple, so-called "pragmatic" RCTs that minimize exclusionary criteria and faithfully capture the real-world efficacy and safety of therapeutic interventions. In such trials, the most reliable estimate of a treatment effect within a particular subgroup is the overall treatment effect in the trial.

Kelly: That's unsettling and points to a different problem, a REMS issue. Why would the FDA even approve any drugs indicated for specific populations, if the view is that the indications will be ignored?

Dr. Kaul: Well, that's the reality. There's a regulatory world, and then there's a real world. Regulators are responsible for approving drugs. They are not in the business of mandating the practice of medicine. Physicians are free to use approved drugs in any fashion they deem safe. And, in some instances, the art-of-medicine philosophy might even encourage off-label use as proper exercise of clinical judgment. Controlling the use of drugs beyond the label indication is a challenge. The FDA always worries that diet drugs will not be used or prescribed appropriately. None of this should come as a surprise. Let us not forget the diet clinics ("pill mills") that popped up during the fenphen years. It is very difficult to prevent widespread usage of weight-loss drugs in inappropriate populations. One of the biggest concerns is that since obesity drugs are not typically reimbursed, claims data are not typically available to conduct observational studies post-launch and to monitor outcomes, making surveillance all the more difficult. These challenges are further compounded by lack of a reliable REMS program to mitigate anticipated risks. So, while limited approval might sound intuitively appealing, the difficulty lies in implementing these programs, controlling use, and restricting access.

Sanjay: For diabetes medications, do you think the pre-approval cardiovascular outcomes requirement has been constructive thus far? It seems as if we've completely reversed where the regulators stand in terms of the information they receive.

Dr. Kaul: There is a cloud over new diabetes drugs as a result of the new guidance, which has discouraged and will continue to discourage the pharmaceutical industry from venturing into this area. Some have remarked that in our great concern about safety, we may be standing in the way of developing even better drugs in the future. I personally believe that the guidance should be refined in that it should be more anchored in both the science and in the art-of-medicine philosophy. The safety concerns should be balanced against the treatment benefit. In my opinion, ruling out the same degree of fixed cardiovascular harm for drugs that provide varying degrees of efficacy is not appropriate. The guidance should be flexible, thereby allowing tolerability of a greater degree of harm in return for a greater degree of benefit. For example, drugs that improve hemoglobin A1C by 1% or more should not be expected to rule out 30% harm post-approval. I would argue that ruling out perhaps 50% harm is quite acceptable. On the other hand, drugs that only offer less than half a percent improvement in hemoglobin A1C should require more stringent criteria for approval.

Sanjay: What are your thoughts on the existing obesity guidance?

Dr. Kaul: I think it is in the best interest of the FDA and the sponsors to come up with a more comprehensive guidance that captures the true benefit-risk of weight-loss intervention in its intended real-world environment. Our committee felt it had enough criteria to work with efficacy, but lacked sufficient guidance from FDA on safety of weight-loss drugs. Changing the goal posts in the middle of the game is obviously not fair to the sponsors. On the other hand, I can't necessarily fault the FDA for being risk-averse, given their goal to protect the public, and especially given the dubious past track record of weight-loss drugs. So I think a standardized guidance document that clearly outlines the metrics for a favorable benefit-risk assessment, including weight loss, cardio-metabolic profile, and morbidity and mortality outcomes a priori, would help the sponsors navigate the stormy waters of drug development and approval.

FINAL THOUGHTS

Kelly: Cardiovascular outcomes in the overall population may look better if the 27 million people with diabetes in the U.S. and hundreds of millions more all over the globe could start doing better earlier on in their disease progression. It's likely that diabetes rates would drop dramatically if obesity could be better addressed. Are there any final thoughts on the obesity epidemic and implications for diabetes outcomes overall? The diabetes community is concerned about macrovascular disease, and they're also worried about people going blind, losing limbs, and developing other microvascular complications. What I'm most worried about is that we're creating an increasingly "elderly unwell" population that is growing dramatically, driven in large part by obesity that is so challenging to address.

Dr. Kaul: I agree that minimizing the risks of both microvascular and macrovascular disease is a critical clinical goal in the management of patients with diabetes. And lifestyle modification, including eating healthier, getting more physically active, and losing weight (aided by pharmacologic and non-pharmacologic interventions wherever appropriate), together with adequate control of risk factors such as blood pressure, lipid, and blood glucose, should be the major focus of our efforts to stem the rising tide of the obesity epidemic.

Kelly: Thank you so much for all of your insights, Dr. Kaul. It has been an incredible privilege to spend time better understanding your thinking about obesity, cardiovascular disease, and the U.S. regulatory environment.

Dr. Kaul: It has been a pleasure speaking with you and Sanjay. Thank you.

diaTribe is an independent, advertising-free e-newsletter for everyone eager to learn about the latest advances in diabetes management. diaTribe is your inside track on diabetes research and products — sign up here for your complimentary lifetime subscription!

NOTE: This information is not intended to be a replacement or substitute for consultation with a qualified medical professional or for professional advice related to diabetes or another medical condition. Please contact your physician or medical professional with any questions and concerns about your medical condition.

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Last Modified Date: April 23, 2013

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