The Pharmaceutical Research & Manufacturers of America is asking FDA to change its guidance on the development of weight loss drugs to allow shorter trials.

"A one-year trial for efficacy is consistent with guidelines for other drugs used to treat metabolic disorders," ¹ PhRMA's comments argue. "Further, studies have shown maximal effect of weight loss drugs are evident within 6-12 months."

² FDA's 1996 guidance says trials should generally run for two years, with year one being a double-blinded study for efficacy and year two an open label safety continuation for a smaller cohort.

PhRMA wants FDA to allow approval based on one-year data with a commitment for longer safety studies.

"As it is adequate for a one-year exposure for drugs used to treat" type 2 diabetes, hypertension, and dyslipidemia, "it is not clear why agents used to treat obesity should be required to be studied for two years."

"Given the desire to ensure safety in a drug that would be used chronically and make this consistent with the other guidances, the duration of study should be one year for approval with a need to develop longer term (two year) safety data if approved," PhRMA said.

Johnson & Johnson submitted comments objecting to a recommendation in the guidance to follow up on drop-outs at 24 months.

"Such telephone follow-up requirements should be tailored for off-treatment monitoring of specific predefined safety concerns and not be used to assess post-treatment weight or other efficacy parameters due to the potentially unreliable nature of data captured in this format," ³ J&J's comments state.

FDA is reissuing the obesity drugs guidance as part of an effort to encourage research on new products in the category. The agency anticipates holding an advisory committee on the topic later this year.

PhRMA may have difficulty getting the agency to act on its request. Recent FDA discussion of obesity drugs has emphasized the need for long-term studies (⁴ Also see "FDA Seeks Comparative Trials, Public Relations Makeover For Obesity Drugs" - Pink Sheet, 3 May, 2004., p. 19).

The trade association's comments focus on expanding the eligible population for such drugs and the claims for which they can be approved.

The association offers three "treatment paradigms" for a weight maintenance indication: "(1) weight maintenance after drug-induced weight loss, (2) weight maintenance after diet-induced weight loss (e.g. six weeks of a very low calorie diet) or (3) prevention of weight gain associated with use of certain medications (e.g., sulfonylurea, antipsychotics, anti-epileptics, corticosteroids, etc.) or therapies (e.g., smoking cessation)."

The guidance should also "delineate a path toward an indication for the metabolic syndrome," PhRMA said, given "the clear link to increased cardiovascular morbidity and mortality."

⁵ Pfizer's comments offer several other possible indications: treatment or prevention of type 2 diabetes and other obesity-related co-morbidities.

PhRMA proposed a less stringent endpoint for a weight loss indication in addition to the two offered in FDA's guidance (placebo adjusted weight loss >5% at 12 months and significantly greater proportion of patients losing >5%).

The additional endpoint option would base approval on "total weight loss from baseline >5% at 12 months and statistically significant difference between the treatment and placebo arms."

The comments also suggest adding a significantly greater proportion losing >10% as an endpoint.

[Editor's note: A version of this story first appeared in ⁶ "The Pink Sheet" DAILY May 10. Visit our website, www.ThePinkSheetDAILY.com to sign up for a free trial.]

PhRMA also offered broader enrollment criteria for trials. The current guidance "identifies individuals who are overweight ([body mass index]>27) with comorbidities or who are obese (BMI>30) as relevant subjects for study."

"This unnecessarily limits the addressable population," PhRMA said.

"The description of relevant subjects for inclusion should be changed to incorporate the definition of excess weight" from the World Health Organization and National Heart, Lung & Blood Institute.

Trial enrollment requirements should be a BMI of 25-30 (overweight) with an associated comorbidity (insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, cancer, arthritis, respiratory and sleep disorders), or a BMI>30 with or without an associated comorbidity, PhRMA suggested.

PhRMA also wants FDA to remove the run-in requirements for enrollment of obesity drug studies.

The guidance currently requires that subject selection screen out patients who can lose weight without pharmaceutical assistance. "The subject selection process as described is not feasible," PhRMA said. "A vast majority of subjects have had multiple attempts to reduce their weight and have not been successful."

The criteria "should be modified to allow subjects who have attempted and failed to lose weight historically to enroll without the further hurdle of weight-loss criteria during a lead-in."

Another requirement that should be lifted is a hypocaloric lead-in phase. "Since data for long-term (one year) trials are required for efficacy, and changes of weight after one year are not affected by the lead-in weight-loss phase, it should be feasible to remove this requirement."

Such a lead-in "is perhaps more relevant for short-term studies (up to six months)," PhRMA said.

Weight-loss drugs should be "eligible for accelerated approval and fast track designation," PhRMA said, because "obesity is now recognized in the U.S. as a serious and life-threatening disease."

The comments also stated, "a distinction should be made in the future guidance between misuse (e.g., weight loss in non-obese subjects) and abuse (e.g., unintended use of product)."

"FDA could clarify this by issuing the pending guidance on assessment of abuse potential of drugs or provide specific direction to sponsors on the preclinical/clinical studies required to assess abuse liability."

Obesity Drug Trials Should Be Shorter, Have Broader Endpoints, PhRMA Says

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