Interview with FDA Panelist (Continued)
OBESITY DRUG DEVELOPMENT AND THE REGULATORY LANDSCAPE
Kelly: Some of the panelists on the Contrave advisory committee expressed concern that obesity drug development would slow dramatically or come to a halt if a pre-approval cardiovascular outcomes trial was required of Contrave. Can you share your thoughts on this with us?
Dr. Kaul: In my assessment, a pre-approval cardiovascular trial is warranted, and the FDA made the right call, and not a very surprising one in my opinion.
Kelly: I think what surprised some of us was that panelists voted that a pre-approval trial was not needed and that Contrave should be approved; in effect, the FDA voted against the panel, which we're certainly aware can happen, but we don't view as common – we didn't realize as you just said that this happened up to one-third of the time! On a related note, can you discuss your view on the need for obesity drug development broadly speaking? And specifically, what is your thought on what will happen with Contrave?
Dr. Kaul Yes, I do think that obesity drugs need to be developed, but rather than repackaging old ones, I also feel that the whole field would be better served by focusing on innovative, safe, and effective therapies. Perhaps the recent negative decisions by the FDA regarding the obesity drugs will help spur this innovation. With regards to Contrave, it all depends on whether the company has the fortitude and the fiscal health to carry out the evaluation that that FDA has asked for. Obviously it will take time, effort, and money. The critics lament that the FDA is setting up a very high bar requiring the sponsors to prove their drugs are "whiter than white" in terms of safety. However, given the checkered history of weight-loss drugs, I believe extra caution is warranted. Otherwise, there is a price to pay every time the FDA pulls a weight-loss drug off the market because of anticipated or unanticipated risks — erosion of public trust. No one likes to be second-guessed. The FDA often walks a tightrope reconciling the dual goals of protecting and promoting public health.
Kelly: Another view is that since there are fewer options for people who are obese and since the epidemic is arguably worse [than the diabetes epidemic], it's reasonable for the standards to differ [from the standards for diabetes drugs].
Dr. Kaul: I am sensitive to that argument. However, if there are already signals for cardiovascular risk in early phase development, and an identified plausible mechanism, then it is incumbent upon us to make sure that we are not increasing the cardiovascular risk of those exposed. I am aware of the criticisms that the Qnexa panel was sensitized by the Avandia hearings that immediately preceded it, and that the FDA is risk-averse and not approving the drug is a sure way to limit exposure and risk. Frankly, such criticisms are off target. Each panel member does his or her best to adjudicate benefit-risk based on the specific evidence at hand. And the FDA, to the best of my knowledge, takes its job of protecting and promoting public health very seriously. Obesity drugs should be required to rule out some degree of unacceptable cardiovascular harm pre-approval, wherever appropriate, i.e., depending on the mechanism of action and the signal for increased cardiovascular risk (such as elevated heart rate, blood pressure, or valvular side effects) identified during early phase development. I also generally agree with the current guidance that requires all diabetes drugs to exclude cardiovascular harm pre-approval. However, rather than fixing the boundary of unacceptable harm, it should be flexible based on the individualized benefit-risk tradeoffs. Ideally, pre-approval trials should assess durability of weight-loss efficacy by extending the follow-up to at least two years. However, whether the weight loss translates into meaningful health benefits should be assessed post-approval.
Kelly: We will certainly be eager to see more on this, if drug development can continue. Can you give us your thoughts on conditional approval for weight-loss medications?
Dr. Kaul Conditional or accelerated approvals are granted by the FDA under Subpart H regulations for a new drug product on the basis of adequate and well-controlled clinical trials establishing that the drug product has an effect on a surrogate endpoint that is reasonably likely, based on different sources of evidence to predict clinical benefit. Approval under this section is subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit. This could be potentially implemented for weight-loss medications. However, the FDA currently lacks the legislative authority to enforce withdrawal of conditional approval if post-marketing clinical studies fail to verify clinical benefit (two recent examples that come to mind include midodrine and Avastin). At what cost? The advisory members and the FDA reviewers (who are loath to be second guessed) are going to be hesitant to consider conditional approval in the future, thereby denying patients timely access to potentially life-saving therapies. It's a double-edged sword. Thus, it is vitally important to allow the regulatory process to take its due course of action.
Sanjay: Another broad question. Do you think a formal structure to give the FDA that legislative authority would be helpful?
Dr. Kaul: Absolutely. They already have that for safety assessment under the FDA Amendment Act of 2007, which provides a mandate to require drug sponsors to implement specific measures to reduce safety risks through REMS (Risk Evaluation and Mitigation Strategy) programs. I believe it should also be extended to assessment of clinical efficacy of drugs that are approved based on surrogate measures of efficacy. Ideally, the FDA should grant only "provisional approval" when surrogate endpoints are used. The conditions for full approval should be timely demonstration of efficacy and safety in large, well-designed clinical-outcomes trials that examine cardiovascular endpoints. Furthermore, Congress should empower the FDA to enforce post-marketing commitments, including withdrawal of approval if these post-marketing studies fail to confirm clinical benefits. Only then can we hope to avoid potential controversies.
Kelly Dr. Kaul, we are also really interested in your opinion of warnings and restricted access programs.
Dr. Kaul: Labeling changes do not reliably mitigate risk. Elevating warnings to contraindications has a poor track record of improving inappropriate patient selection.
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As I mentioned in an earlier post, one of the benefits that made it cost-effective for me to go with the real healthcare (HSA) plan rather than the phony (HRA) plan is that my company is now covering "preventative" medicines at $0 copay. The formulary for these, as stated by CVS/Caremark (my pharmacy benefits provider), covers all test strips, lancets, and control solutions. I dutifully get my doctor to write up prescriptions for all of my testing needs, submit...