Obesity Therapeutics Report in Response to Senate Report 112-073 Food and Drug Administration Marg?'ret A. Hamburg, M.D. Commissioner of Food and Drugs Report to Congress on Obesity Therapeutics I. Introduction The Senate report 112-073 to accompany the FY 2012 Agriculture, Rural Development, Food and Drug Administration and Related Agencies Appropriation Bill contained the following request: The Committee is concerned with the absence of novel medicines to treat obesity. the second leading cause of preventable deaths in the United States and a disease linked to cancer, high blood pressure, heart disease, diabetes, and stroke. With only diet, exercise, and gastric surgery as options, the lack of obesity medications is a signi?cant unmet medical need. The Committee directs FDA to report by March 30. 2012 on the steps it will take to support the development of new treatments for obesity, including the use of its Risk Evaluation and Mitigation Strategy and other post-marketing authorities, to mitigate risk and ensure rigorous post-market scrutiny while increasing access to novel medications. FDA submits this report in response to the request. II. Background Given the high rate of overweight and obese people in America, and the indisputable adverse health consequences of excess body weight, FDA readily acknowledges the need for new obesity drugs that are safe and effective. This unmet medical need is underscored by the increased risks of heart disease, stroke, and diabetes among individuals who are obese. However, as detailed below, the safety track record for obesity drugs has not been good, and FDA has been forced to remove multiple weightless treatments from the market over the past 15 years. Regulatogt Histogg of Products Used for Weight Loss In 1997, the prescription weight loss drugs fen?uramine and dexfen?uramine were removed from the market following evidence linking these two compounds to the development of valvular heart disease, which in some cases required open-heart surgery and valve replacement. In 2004, Ephedra, a dietary supplement used for weightless, was deemed adulterated under the Federal Food, Drug, and Cosmetic Act because it presented an unreasonable risk of illness or injury chie?y increases in blood pressure and adverse cardiovascular events under the conditions of use recommended or suggested in labeling. In a 2005 Proposed Rule, FDA stated that scienti?c evidence supports the conclusion that weight~control products containing over-the-counter (OTC) cannot be generally recognized as safe and should no longer be available for OTC use. The evidence included the results of a Yale University School of Medicine study suggesting 2 an association between and hemorrhagic stroke, previous and continuing adverse event reports, reports in the published literature, and biologically plausible capacity to cause increases in blood pressure. Sibutramine, a prescription weight loss drug originally approved in 1997, was removed from the market in October 2010 following review of a clinical trial indicating that overweight and obese subjects treated long-term with the drug had a higher rate of heart attacks and strokes compared with overweight and obese subjects treated with a placebo. These data were discussed at an advisory committee meeting, and half of the panel recommended that sibutramine be removed from the market. It is also worth noting that rimonabant, a prescription weight loss drug approved by the European Medicines Agency in 2006, but not approved by FDA, was withdrawn from the European market in 2009 due in large part to an increased risk of suicide. In all the above cases, it was ultimately determined that the bene?ts of the drugs did not outweigh their risks when used for weight loss. IV. Challenges with Latest Products There have been signi?cant safety issues involving three recently reviewed obesity drugs. These safety concerns include: elevations of blood pressure and potential risk for adverse cardiovascular events with the investigational drug Contrave 0 increased rates of breast and brain tumors in animal studies with the investigational drug Lorqess 0 increased rates of birth defects, speci?cally oral clefs, in animals and possibly humans treated with the investigational drug Qnexa. FDA continues to actively work with the sponsors of these drugs to obtain additional data to better de?ne their drugs? bene?t?risk pro?les. V. Recognition of Unmet Medical Need FDA has taken a very proactive stance in addressing this serious public health problem. The Agency established an Obesity Working Group which has recommended several actions including: a developing appropriate and effective consumer messages to aid consumers in making wise dietary choices 0 establishing educational strategies and partnerships to support appropriate messages and teach people, particularly children, how to lead healthier lives through better nutrition 0 developing initiatives to improve the labeling of packaged foods calorie and other nutrition information encouraging and enlisting restaurants in efforts to combat obesity and provide nutrition information to consumers, including information on calories, at the point of sale designing and conducting effective research in the fight against obesity continuing to involve and engage stakeholders in the effort to find new and improved strategies for managing and treating the disease. In February 2007, FDA issued a draft guidance entitled, Developing Products for Weight Management. This document was written following input from the Division of Metabolism and Endocrinology Products? advisory committee panel, pharmaceutical companies, and experts from the field of obesity research. The recommendations provided in the 2007 draft guidance document continue to guide the development of obesity drugs. As stated in the draft guidance, a drug will be considered effective for the treatment of obesity if either of the following two criteria are satisfied: 1) If after one year of treatment, the mean weight loss in the drug group is at least five percent greater than the mean weight loss in the placebo group and the difference is statistically significant. 2) If after one year of treatment, the proportion of subjects who lose at least five percent of baseline body weight is at least 35 percent and approximately double the proportion who lose at least five percent in the placebo group and the difference is statistically significant. When determining the approvability of a new weight-loss drug, FDA weighs the drug's effect on body weight and its effect on common weight-related comorbid conditions such as blood pressure, cholesterol, and blood sugar control in diabetic patients versus the drug's risks or potential harms. It is possible that a new weight-loss drug could satisfy the efficacy criteria set forth in the 2007 draft guidance but would not be approved by FDA because the potential risks or harms of the drug outweigh its benefits or efficacy, rendering the drug's overall benefit-risk profile unfavorable. VI. Path Forward FDA has begun a process to work with stakeholders such as patient and physician groups to explore the complex issues related to development and approval of drugs for obesity. These interactions will include an FDA public advisory committee meeting in early 2012 and participation in a series of roundtable meetings with key players in the obesity community spearheaded by George Washington University. These meetings will provide a forum to discuss clinical trial designs, endpoints, and indications for drugs to treat obesity. FDA is committed to working with pharmaceutical companies to bring new obesity drugs with favorable benefit-risk profiles to the market. We stand ready to assist any pharmaceutical sponsor in this effort. Moving forward, as FDA evaluates new drugs for the treatment of obesity; we will carefully consider how we can effectively apply our new safety authorities, such as requirements for REMS and post-marketing studies, to ensure that the benefits of the drug outweigh its risks for the group of patients in which the drug will be used.