1. Has FDA provided ‘sufficient guidance’ to guide development and registration of prescription diet medications? If you agree, provide examples of what you consider ‘sufficient advice’ (including date of publication).
I believe the FDA does provide sufficient guidance on the development and registration of prescription diet medications. In 2007, FDA issued draft guidance that clearly defines their expectations to judge effectiveness (weight reduction and maintenance of weight loss after 1 year’s treatment). It also indicates an effective product should provide improvements in blood pressure, lipids, and glycaemia therefore changes in common weight-related comorbidities need factored into clinical trial to assess efficacy. FDA also states it expects to see drug-mediated weight reduction demonstrated to result from a loss of body fat verified through advance screening tools. From a safety perspective, the FDA states the drug should not adversely affect cardiovascular function particularly highlighting cardiac valvulopathy.
2. Has FDA’s grounds for rejecting the NDAs of prescription diet pills in the last 10 years been based on safety/efficacy concerns?
In 2010 alone, three drugs reviewed by the Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) have failed to gain approval. EMDAC felt each drug (naltrexone/bupriopion, lorcaserin and phentermine/topiratate) had unacceptable safety issues (particularly cardiovascular risk profiles). The committee also concluded that lorcaserin did not provide enough convincing evidence of efficacy and safety to gain approval. EMDAC cite lack of diversity in the phase 3 trial population might result in efficacy of the drug being overstated while potential safety risks understated. While lorcaserin did meet the FDA efficacy criteria minimally, those merits were dulled by the lack of real-world information on patients with significant comorbid conditions (e.g. diabetes, CV disease). Another safety concern specifically for naltrexone and lorcaserin was the lack of data regarding use of the drug in combination with other drugs (concomitant) known or suspected to carry risk for valvular heart disease.
3. Has FDA considered any ‘potentially alarming’ safety signals from nonclinical toxicology studies in animals or in vitro studies when making their decision on an NDA?
When reviewing the NDA for lorcaserin the EMDAC noted safety concerns when reviewing the animal data submitted. They felt the animal data on cancer risk did not correlate well with that potential in humans. In the complete response letter, the FDA asked the Sponsor (Arena) to conduct additional preclinical studies to assess a cancer signal in rodents (there were statistically significant increases in mammary tumors in female rats and brain tumors in male rats). They also requested a repeat of two nonclinical studies to assess abuse potential and consider a 12-month rodent toxicity test in addition to the planned three-month studies to...