by Sanjay Kaul, MD

 

 

Obesity is the second leading cause of preventable deaths in the United States, often being linked to high blood pressure, diabetes, cardiovascular disease (CVD), and cancer. Approximately one-third of US adults are obese, and the number keeps on growing every year. Given the public health and economic impact of obesity, several biopharmaceutical companies are attempting to develop new drugs to target obesity. However, it has been claimed that the regulatory environment is not conducive to development and approval of new obesity drugs. Is this assertion supported by facts?

While there is emerging evidence of health benefits with lifestyle intervention and gastric surgery, supportive evidence for clinical benefit beyond cosmetic weight loss is currently lacking with pharmacologic interventions. To compound matters further, four obesity agents (Ephedra, Fen-phen, phenylpropanolamine, and sibutramine) were withdrawn from the market as a consequence of cardiovascular toxicity. Rimonabant was approved for marketing in Europe, but was never FDA-approved because of severe psychiatric side effects. At this time, Xenical is the only drug that is FDA-approved for chronic treatment of obesity, and its use is limited by abdominal discomfort and steatorrhea. Given the checkered history of obesity drugs, these agents continue to come under close scrutiny by the regulatory agencies with no new drugs approved in the past 13 years until the recent approval of lorcaserin on June 27, 2012.

Too Strict, or Not Strict Enough?

In 2010, three new agents: phentiramine/topiramate (Qnexa), naltrexone/bupropion (Contrave), and lorcaserin (Belviq, formerly given the brand name Lorquess) failed to gain FDA approval primarily due to safety concerns. This led the critics to lament that the FDA is setting too high a bar in terms of safety, thus stifling innovation and public access to sorely needed new cures that have the potential to improve and/or save patients’ lives. They claim that as errors of commission trump errors of omission, the FDA has become risk-averse and not approving the drug is a sure way to limit exposure and risk. Last September, the Senate Appropriations Committee declared the lack of obesity medications as a “significant unmet need” and directed the FDA to take the necessary steps to support the development of new treatments for obesity.

In contrast, others note that the current FDA guidance for obesity drugs, primarily driven by weight-loss efficacy criteria without requiring assessment of health-related outcomes, does not go far enough to ensure public safety. They argue that every time the FDA pulls a weight-loss drug off the market because of anticipated or unanticipated risks, there is a price to pay: erosion of public trust. As a consequence, some have called for a stringent regulatory standard that shifts from an emphasis on surrogate endpoint of weight loss to one on demonstration of clinically meaningful health benefits. Given these contrasting perspectives, how can the FDA reconcile its mission of promoting innovation and protecting public health?

How to Solve the Problem

Two potential solutions merit consideration: 1) “rule out excessive risk” approach; and 2) “conditional approval” approach. The first approach includes an efficient trial design strategy where the principal objective is not to prove clinical benefit in a phase III superiority trial (which would require a prohibitively large sample size) but to rule out a prespecified ‘unacceptable’ level of excess risk (primarily cardiovascular risk) using a noninferiority trial design similar to the FDA draft guidance for new oral agents to treat type 2 diabetes. The level of unacceptable risk should be based on the overall benefit-risk balance of the drug; tolerating greater degree of risk for greater weight loss and ancillary benefits in cardiometabolic profile. Because low-risk patients are typically enrolled in pre-market registration trials (as reflected in accrual of only 27 MACE in nearly 18,000 patients enrolled in the three weight loss submissions in 2010), strategies for amplifying event rate in an attempt to reduce sample size requirements should include:

• enriching study populations to include high-risk patients with diabetes, a prior history of CVD, or those with multiple cardiovascular risk factors;
• broadening the MACE endpoint (CV death, nonfatal MI, or nonfatal stroke) to include other endpoints such as unstable angina requiring hospitalization or ischemia-driven revascularization;
• and pooling the safety databases across all phase II and III trials and performing a meta-analysis of all CV events with prospective adjudication by an independent, blinded clinical events committee.

For drugs with an identifiable signal of potential CV harm, a dedicated CV outcomes trial should be required prior to approval. Although such trials are likely to be time- and resource-intensive, an extended drug patent would potentially mitigate financial risk to the manufacturers. By doing so, pharmaceutical companies could be incentivized to fulfill the preapproval outcome-trial requirement yet still have sufficient time to market the drug and earn a return on their investments. For drugs without an identifiable signal, a two-staged approach should be considered: first, rule out a higher degree of excessive risk as a required condition for approval, and then rule out a smaller excess risk in the post-approval final analysis (analogous to the FDA draft guidance for diabetes drugs).

An alternative approach to consider is “conditional approval” modeled after the accelerated approval granted by the FDA under Subpart H regulations in 1992 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 in a timely manner. This could be potentially implemented for obesity agents endowed with sufficient weight loss efficacy proven to be associated with tangible clinical benefits (placebo-subtracted mean weight loss of 7-10% baseline weight) and without identifiable harmful signal. Under this approach a limited marketing authorization would be granted by the FDA after successful phase II trials. The FDA would require empowerment by the Congress to revoke the approval if post-marketing studies are not completed in a timely manner or if they fail to confirm clinical benefits or if unexpected safety concerns come to light.

To avoid recent controversies surrounding obesity drugs, the FDA must come up with a more streamlined process to make obesity drug approval not just scientifically rigorous, but clear, consistent, and predictable, and one that facilitates accelerated access to patients without unduly burdening drug development or compromising safety. A standardized guidance document that clearly outlines these principles would help the FDA navigate the stormy waters between Scylla (promoting innovation) and Charybdis (protecting public health). In this regard, on March 28 and 29 the expert panel convened by the FDA for advice to evaluate cardiovascular safety considerations in the approval of new obesity drugs is a step in the right direction.

Sanjay Kaul, MD, is director of the Vascular Physiology and Thrombosis Research Laboratory at the Burns and Allen Research Institute at Cedars-Sinai Medical Center in Los Angeles. Dr. Kaul also directs the Cardiology Fellowship Training Program and the Cardiology Consult Service.

Keywords: Phentermine, Diabetes Mellitus, Type 2, Risk Factors, Cyclobutanes, Benzazepines, Piperidines, Biomarkers, Thrombosis, Cardiovascular Diseases, Obesity, Anti-Obesity Agents, Fructose, Hypertension, United States, Stroke, Neoplasms, Weight Loss, Steatorrhea, Pyrazoles, Burns, Drug Combinations, Drug Approval, Naltrexone, Lactones, Ephedra, Hospitalization, Phenylpropanolamine, Bupropion

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