The unusual way senior FDA officials handled last week's advisory committee meeting on Genelabs Technologies Inc.'s Aslera prasterone DHEA suggests that the agency is looking for ways to approve the NDA to treat women with systemic lupus erythematosus. To do so, the agency will have to stretch its approval criteria, and do so in a way that doesn't set a precedent for diluting its requirements for robust scientific data.

FDA has a variety of motives for smoothing the path for Aslera (GL701), not the least the desire to make a new therapy available for a debilitating disease for which no new therapies have been approved for decades. But of perhaps equal importance is an interest in using Aslera as a weapon in the agency's battle to regain control over the marketing of dietary supplements. DHEA is available as a nutraceutical (see "Wedge Against Dietary Supplements," A4).

NIH estimates there are 180,000 lupus patients in the U.S., a figure that has allowed GNLB to achieve Orphan Drug designation for Aslera. But systemic lupus erythematosus (SLE) is a valuable market in part because there may be many more patients - the Lupus Foundation of America contends NIH's estimate is off at least 10-fold - and because any agent that successfully treats the condition is a promising candidate for other autoimmune diseases.

SLE is a poorly understood, debilitating autoimmune disorder that primarily strikes women and displays an unpredictable pattern of flares and remissions. The principal treatment for SLE, long-term administration of low doses of corticosteroids, causes a wide range of adverse effects that for some patients are worse than the disease.

GL701 is a synthetic version of dehydroepiandrosterone (DHEA), a naturally occurring endogenous steroid that, along with its metabolite DHEA-S, is the most abundant circulating steroid hormone in humans. Women with SLE have dramatic reductions in DHEA and DHEA-S, and some symptoms of the disease suggest that it is caused by a hormonal imbalance. Androgens like DHEA are effective in treating lupus in a mouse model.

Researchers at Stanford University completed a pilot clinical trial in SLE in 1993. Based on the results, GNLB licensed the compound, and in 1993 it sought permission from FDA to run a Phase III trial. Because no FDA guidance documents had been issued for lupus, and few large-scale trials had been conducted, GNLB was "in uncharted waters," FDA medical reviewer Kent Johnson told the Arthritis Advisory Committee last week.

Indeed, there were no data to determine the appropriate number of patients to achieve statistical power. An FDA review provided to the advisory committee stated that a "key to any randomized trial design in lupus is use of credible instruments to assess efficacy, but this fundamental precondition is itself problematic in lupus. There is no simple, established disease assessment available. Also, there are virtually no design precedents in lupus to judge the performance of candidate instruments."

Clinical history

To measure effectiveness of therapy in a chronic disease that is characterized by unpredictable flares and quiescence, while acknowledging the practical impossibility of conducting a placebo-controlled trial, the company and FDA agreed on steroid sparing