CHRONIC PAIN DRUGS: FDA ENCOURAGING INCREASED SUBMISSIONS

CHRONIC PAIN DRUGS: FDA ENCOURAGING INCREASED SUBMISSIONS with the understanding that agency reviewers are well versed in the problems posed by conducting trials for the indication, FDA Pilot Drug Evaluation Staff Narcotics Team Medical Review Officer Curtis Wright, MD, said at a May 6 meeting in Philadelphia sponsored by the Cambridge Healthtech Institute.

Calling chronic pain an "underserved area," Wright said: "All I can assure you is that the people who are reviewing today know about the problem, know about the difficulties and know about the need and are going to do everything that is humanly possible to make it as easy as possible to get these products to market," Wright said. He added: "you need to know what you need to know, but if you do a good job on the science, [FDA] will adapt to new science and we will catch up."

National Institute of Dental Research Neurobiology and Anesthesiology Branch Clinical Trials Unit Chief Mitchell Max, MD, estimated that there are 10-20 mil. people in the U.S. with neuropathic pain. Wright noted that about three quarters of the approximately $823 mil. non-parenteral, non-arthritis prescription analgesic market consists of combinations of acetaminophen or aspirin with weak or small amounts of strong opioids, and these "aren't very impressive drugs."

Wright discussed a number of possible trial designs, with the caveat that the designs "are neither the only choices nor the best choices in all situations." He urged the companies to "keep the amount of information that you're trying to squeeze out of [a] trial down to one or two good questions, but answer those questions."

One type of study Wright highlighted was the large simple trial. The agency recently has begun suggesting this means of gathering in-use data on drugs to treat AIDS patients (see related item, T&G-6).

The agency "went through a period where if it wasn't double- blind and parallel...it wasn't science...and that just couldn't be further from the case," Wright explained. "Not all doctors are careful, thoughtful people who read everything available about a new agent before they put it in clinical use... Some of them use doses that scare the stink out of me and unfortunately our usual Phase III...studies don't gather that information."

Similarly, in his discussion of dose titration/escalation studies, Wright commented that FDA many times does not have data on the "toxicodynamic curve" of a drug, because "a common mistake ...in applications is a failure to run the dose of the new agent high enough to get a handle on the emerging toxicity. There is a need to know the toxicodynamic curve of a drug...so we know where you don't want it."

The agency has developed a "red triangle" warning for the package of high-dose opioids or medications with risks "that non- tolerant individuals cannot bear." The warning, which is voluntary, is the "evolving standard" for the drug group, Wright said.

The triangle was first used by Janssen when it launched Duragesic in 1990 for the higher doses of its transdermal fentanyl patch. Wright explained that because Janssen got "such a good adverse event profile" for such a potent narcotic, other firms are now preparing to use the warning with their products. The triangle bears the words "for use in opioid-tolerant patients" and is meant to alert the physician, pharmacist and patient that "this is not something you hand out for headaches," Wright added.