FDA discusses revised draft guidance for drug development for RA

by Deborah Toscano 25 Jul 2013
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This morning, the FDA held a webinar to discuss and summarize the revised draft guidance for industry for development of drugs for rheumatoid arthritis. Since the last guidance document published back in 1999, a lot has happened in the way of medical advancements, the agency felt the time was right to update their recommendations for industry to account for these changes as well as address some concerns of the regulatory and rheumatology communities that have arisen. Draft guidance was published May 31, 2013, and public commentary is open until July 31, 2013. One of the main issues of concern for RA trials, which is also applicable across several other disease areas as noted by the FDA, is the use of placebo. The agency acknowledges that comparison to placebo is sometimes necessary, but recommends that for ethical reasons, exposure to placebo be limited to 12 weeks maximum. In addition, ethical concerns around keeping patients with uncontrolled disease on either placebo or an ineffective therapy have arisen, and the FDA recommends that trial designs need to incorporate provisions for escape to rescue therapy without compromising the integrity of the data, suggesting that measurement of primary and some secondary endpoints coincide with conversion to rescue therapy. Measurement of efficacy was also a main issue. Minimal expectations are that efficacy needs to be demonstrated for both clinical response (i.e. ACR 20) and physical function, with 12-week data for both points considered acceptable. The agency noted that additional relevant secondary endpoints such as radiographic evidence of disease progression are becoming increasingly difficult to measure, and that other methods of evaluating disease progression need to be validated to enable shorter trials. Pursuit of clinical remission as an endpoint, which was unrealistic at the time of the last guidance, is highly encouraged by the FDA. However, it was noted that a Disease Activity Score (DAS)28 of less than 2.6, which is considered by many to define clinical remission, is considered by the FDA as low disease activity, but not remission. The agency's position is that they would consider claims of remission with scores somewhere between zero and less than 2.6 to be remission; for example, only one joint still active could probably be considered remission. Regarding durable remission, the FDA would consider on a case by case basis, and does not have any particular time frame in mind, but noted that, at a minimum, remission at more than one time point was needed. It was also noted that an acceptable timeframe for remission would be highly dependent on the risk/benefit profile of the drug, with longer duration of remission needed for more toxic drugs, and shorter durations acceptable for more benign drugs. Sponsors should plan to discuss this endpoint with the FDA. A couple of issues regarding drug dosing were noted. The agency recommends that dose selection evaluation extend well beyond a single dose ranging trial, and be fully explored in preclinical and early clinical work as well as extend into Phase 3 confirmatory studies, with at least two doses tested in late development. It was noted that dose finding studies are often of shorter duration and size and not really adequate for fully assessing the safety of each dose, leaving the door open later for questions if safety issues arise down the road that perhaps could have been avoided with a lower dose. The FDA would like to see solid data for the minimal effective dose as well as the efficacy plateau. The use of drug-device combination products is acknowledged in the revised guidance, in light of the numerous biologic and other injectable drugs introduced to the market. The FDA recommends that the combination product be used in the Phase 3 confirmatory studies. Finally, safety of RA drugs is a critical issue, in light of the inherent risks of chronic immunosuppressive therapy and the latency period of safety issues such as opportunistic infections, malignancy, etc. The minimum requirement for a safety database is 1,000 to 1,500 patients with at least one year of data.

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