Closing in, maybe By Rosy Guerra
Senior Editor

From appearances, biologic therapies for rheumatoid arthritis (RA) stand within sight of regulatory review: of the 12 biotech companies with therapies in the clinic profiled here, four are in Phase III, one has a pivotal trial, another has completed Phase II, and a few companies - such as Immunex Inc. (IMNX) and Centocor Inc. (CNTO) - recently reported encouraging trial results and hope to file BLAs with the FDA as early as 1998.

But for most companies, moving a late-stage therapy to an NDA or BLA submission can be challenged by several factors, not the least of which is that the FDA still is developing concrete clinical development guidelines for RA. The current FDA recommendation is that trials for biologic therapies be conducted a minimum of six months. But, according to Alan Solinger, director of clinical therapeutics at Idec Pharmaceuticals Corp. (IDPH), depending on the product, companies "negotiate" terms individually with the FDA,

"There's a growing consensus for RA trials that there be a certain duration of therapy and a certain duration of follow-up," Solinger said. "But it has not been formalized and it just depends a great deal on the product - different biologics are designed differently and need to have individually defined periods of time for both trials and follow-up. In addition - and it is something we still struggle with - defining end points in RA is a cloudy area."

In addition, Solinger said, a lengthy debate leading to the American College of Rheumatology's definition of a clinical responder also forced companies to "wait and see" what standards would finally evolve. The ACR published its definition of improvement in RA in 1996, so a standard for end points has been relatively recent (see A3).

In January the FDA released draft guidelines for clinical development programs for RA. They recommend that claims of improved functional ability/quality of life should be based on trials of at least 6 to 12 months and all other claims should be demonstrated in trials of at least one year.

Since remission does not imply a cure, the agency also suggested that trials intending to evaluate remission be at least one year in duration. A few companies told BioCentury that the FDA also can request that a company conduct post-trial follow up for six months or more to determine that patients remain symptom-free.

An FDA spokesperson said the agency expects to finalize the guidelines by year-end.

In getting to and through trials, companies also have wrestled with other issues: an incomplete understanding of the central pathogenic pathway of the disease; the lack of a standard for assessing symptoms; and toxicity issues.

Tackling uncertainties

RA is difficult to diagnose because the symptoms - of which there are many - usually start gradually and the course of the disease varies from person to person. Some 3 million Americans are estimated to have the disease. According to the Arthritis Foundation, a virus may trigger RA in people who have a genetic tendency for the disease.