The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure The Harvard community has made this article openly available. Please share how this access benefits you. Your story matters Citation Allison Nina Canton, The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure (March 2011). Citable link http://nrs.harvard.edu/urn-3:HUL.InstRepos:8789607 Terms of Use This article was downloaded from Harvard University’s DASH repository, and is made available under the terms and conditions applicable to Other Posted Material, as set forth at http:// nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of- use#LAA The Elusive Silver Bullet: FDA Failures, Rejected New Drug Applications, and the Search for an Obesity Cure Allison N. Canton Class of 2012 March 2011 This paper is submitted in satisfaction of the course requirement for: Food and Drug Law Professor Peter Barton Hutt Winter 2011 Abstract: Over the past forty-five years, America has fallen victim to an obesity epidemic, affecting more than thirty percent of American adults. If the incidence of obesity continues at current rates, an estimated forty-percent of Americans will be obese by 2018. Despite its widespread prevalence, treatment is limited to lifestyle modification, surgery, and pharmacotherapy. With lifestyle modification proven to be largely ineffective, surgical options reserved only for the severely obese, and only one long-term drug on the market, there is a vacuum in obesity treatment options. Moreover, the Food and Drug Administration recently rejected three promising drugs. In this paper, I review the obesity problem facing America and describe the history of anti-obesity pharmaceuticals. After examining the three recently rejected drug applications, I bring to light FDA’s new priorities and offer an alternative framework for thinking about pharmacology to guide anti-obesity drug development and review. TABLE OF CONTENTS I. INTRODUCTION ................................................................................................................................ 1 II. OVERVIEW OF THE OBESITY PROBLEM IN THE US ........................................................... 1 A. DEMOGRAPHICS AND PREVALENCE .................................................................................................. 1 B. THEORIES BEHIND THE GROWING OBESITY RATES .......................................................................... 3 C. OBESITY’S TOLL: INCREASED MORBIDITY & MORTALITY AND INDIRECT COSTS ........................... 3 III. OVERVIEW OF THE CURRENT ANTI-OBESITY DRUG MARKET .................................... 4 A. THE CURRENT MARKET .................................................................................................................... 5 i. Phentermine ................................................................................................................................... 5 ii. Diethylpropion (Tenuate).............................................................................................................. 6 iii. Orlistat (Xenical/Alli)................................................................................................................... 7 B. FDA FAILURES .................................................................................................................................. 8 i. Fen-Phen (1997) and Dexfenfluramine (Redux) (1997) ................................................................ 9 ii. Sibutramine (Meridia) (2010) ..................................................................................................... 13 IV. AN EXAMINATION OF THREE RECENTLY-REJECTED WEIGHT LOSS NDAS .......... 16 A. THE LONG ROAD FROM DRUG DEVELOPMENT TO APPROVAL ....................................................... 16 B. GUIDELINES FOR APPROVAL OF A WEIGHT LOSS DRUG ................................................................. 17 C. RECENT REJECTED NEW DRUG APPLICATIONS............................................................................... 19 i. Qnexa (July 2010) ........................................................................................................................ 19 ii. Lorcaserin (September 2010)...................................................................................................... 24 iii. Contrave (December 2010)........................................................................................................ 28 V. THE IMPACT OF NON-APPROVAL ........................................................................................... 31 VI. LOOKING AHEAD......................................................................................................................... 33 VII. CONCLUSION ............................................................................................................................... 37 I. INTRODUCTION With FDA’s rejection of Contrave’s new drug application (NDA), the third anti-obesity drug rejected in the past nine months, the Internet was ablaze with predictions that the anti- obesity pharmaceutical market was effectively dead. Some incensed critics alleged that FDA didn’t care enough about obese Americans to let innovative new drugs come to the market. An exploration of the history of the anti-obesity pharmaceutical market in the US, however, leads one to the opposite conclusion. FDA’s hesitancy to approve a new drug is a manifestation of the agency’s deep concern over patient safety. And given the history of FDA-approved anti-obesity drugs that turned out to be harmful, including Meridia, which was withdrawn from the market in October 2010, it’s hard to say that their concern is not well founded. In this paper, I will provide an overview of the obesity problem today in order to illustrate why a solution is urgently needed. Then, I will describe the history of anti-obesity pharmaceuticals in the US, paying particular attention to instances where FDA ultimately turned out to be wrong about the safety and efficacy of an approved drug. Next, I will chronicle three promising anti-obesity pharmaceuticals whose new drug applications (NDAs) were rejected in rapid succession over the past nine months. Finally, I will discuss the aftermath of non-approval of these NDAs and forecast an alternative framework to guide anti-obesity drug development and review. II. OVERVIEW OF THE OBESITY PROBLEM IN THE US a. DEMOGRAPHICS AND PREVALENCE According to the 2008 National Health and Nutrition Examination Survey (NHANES), seventy-four percent of Americans aged twenty and older are overweight or obese.1 Of these, 1 Cynthia L. Ogden and Margaret D. Carroll, Prevalence of Overweight, Obesity, and Extreme Obesity Among Adults: United States, Trends 1976-1980 Through 2007-2008 (2010). 1 almost half were considered obese (body mass index [BMI]2 of thirty or higher).3 These rates are alarming not only for their extreme prevalence among the American population, but also for their rapid growth over the past forty-five years. Specifically, while the percentage of overweight Americans has not significantly changed since 1976, the prevalence of obesity among adults between ages twenty and seventy-four more than doubled between 1976 and 2008.4 If the current obesity trend continues, some studies have estimated that 43% of the U.S. population will be obese by 2018.5 Public health professionals have characterized the situation to be of “epidemic” proportions.6 The obesity epidemic has a disparate impact on minority communities, especially among women. Non-Hispanic black women and Mexican-American women are far more likely (50% and 45%, respectively) to be obese than non-Hispanic white women (33%).7 Evidence also suggests disparities along class lines; 15% of children aged two to four year old from low- income households are obese.8 The prevalence of obesity varies across the nation. While none of the states in 2009 met the 15% obesity target set forth in Healthy People 2010, 9 obesity rates 2 BMI is a measure of body fat based on height and weight. An adult’s BMI is calculated by dividing her weight in kilograms by the square of her height in meters. A normal BMI is between 18.5 and 24.9. An individual is considered overweight if her BMI is between 25 and 29.9 and is clinically obese if her BMI is over 30. See Centers for Disease Control and Prevention, Healthy Weight: Assessing Your Weight: About BMI for Adults (2009), available at http://www.cdc.gov/healthyweight/assessing/bmi/adult_bmi/index.html. 3 Ogden, supra note 1. 4 Id. 5 United Health Foundation et al., The Future Costs of Obesity: National and State Estimates of the Impact of Obesity on Direct Health Care Expense 9 (2009), available at http://www.fightchronicdisease.org/pdfs/costofobesityreport-final.pdf. 6 See, e.g., Youfa Wang and May A. Beydoun, The Obesity Epidemic in the United States—Gender, Age, Socioeconomic, Racial/Ethnic, and Geographic Characteristics: A Systematic Review and Meta-Regression Analysis, 29 Epidemiological Reviews 6-28 (2007). 7 Ogden, supra note 1. 8 National Center for Chronic Disease Prevention and Health Promotion, Obesity: Halting the Epidemic by Making Health Easier (2010). 9 U.S. Dep’t of Health and Human Services, Healthy People 2010: Nutrition and Overweight 19-11, available at http://www.healthypeople.gov/2010/Document/pdf/Volume2/19Nutrition.pdf 2 across the country ranged from 19% in Colorado to 34% in Mississippi.10 At least thirty percent of people were obese in