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Executive Summary

Rx ANALGESIC DRUG GUIDELINES OFFER CLUES FOR OTC SWITCH studies, Whitehall Labs VP Medical & Clinical Affairs Bernard Schachtel, MD, told the Nonprescription Drug Manufacturers Association Research & Scientific Development Conference Nov. 15. The guidelines "are primarily geared towards prescription internal analgesics," Schachtel noted, but "there is much room here for interpretation of these guidelines as they relate to OTC analgesics." FDA "welcome[s] newer, more-OTC oriented models, real life conditions if you will, [because] the eventual OTC consumer will be using the product," Schachtel remarked. "That kind of innovation in study design is very welcome and intuitively is quite appropriate to the kinds of drugs we are studying, which are not opiates, which are not potent strong analgesics," Schachtel noted. FDA's Arthritis Drugs Advisory Committee on Dec. 6 will discuss revisions to the 1979 Guidelines for the Clinical Development of Analgesic Drugs that have been developed by the American Society for Clinical Pharmacology and Therapeutics. ASCPT submitted its revisions to FDA in May, and has been notified that FDA will soon respond to the proposed revisions and accept them without substantive changes. At the Arthritis Drugs Advisory Committee's meeting last February, possible Rx-to-OTC switch guidelines for nonsteroidal anti-inflammatory drugs were discussed ("The Pink Sheet" Feb. 26, p. 3). However, the idea of switch guidelines was generally opposed by industry, particularly NDMA which urged FDA to rely on the existing NDA database for NSAID switches. Study models suggested by the revised guidelines for prescription analgesics include post-operative pain, cancer pain, postpartum pain, sore throat pain, headache, and musculoskeletal pain. Also addressing the NDMA meeting, ASCPT guideline committee member Abraham Sunshine, MD, New York University Medical Center, emphasized that "the model and the patient population selected should be a population that would normally use the test drug for the relief of that pain." For OTC use, Sunshine noted, "models that have been mentioned although not in the guidelines, as such, are dental pain, sore throat, headache, dysmenorrhea, and pain of musculoskeletal origin." Panel member Stephen Cooper, DMD, Temple University School of Dentistry, suggested that inpatient pain models such as postpartum and episiotomy pain might be appropriate for OTC testing. "It is okay to use those models some of the time for testing, but not to develop the drug exclusively for inpatient models when you are going to have its main proposed use in outpatient environments," he added. Formerly only two pain models were required to demonstrate efficacy for a new oral analgesic. However, the revised guidelines advise that "it is desirable to explore the use of the test drug in as many appropriate models as possible." In addition, the guidelines state that "to assess the efficacy fully, all available studies will be considered." Sunshine pointed out that one cannot "do a 100 trials and select two that prove your point and disregard the other 98 that do not." He added: "Apparently FDA has had this experience, so they asked us to add the sentence." During development of a drug, data should be collected on onset of effect, peak effect, total effect and duration of effect, the proposed revisions state. "Onset of analgesia is now a key factor especially important with OTC drugs because one of the issues FDA has shown some concern about is how rapidly a drug will work to satisfy the patient," Cooper said. The study design most useful for OTC analgesics, committee member William Beaver, MD, Georgetown University School of Medicine, told NDMA, is one that incorporates "a placebo, a standard, and one and usually more than one dose of the test drug." The revised guidelines also suggest the use of multiple standards -- a low standard such as aspirin and a high standard such as ibuprofen -- "to be able to look at the upside assay sensitivity in the study," Beaver noted. "The relevance in the OTC situation here has to do with the appearance of the 400 mg dose of ibuprofen OTC," (Upjohn's Motrin IB) he said. Phase II studies should explore doses above and below the recommended dose, the guidelines note. "You need to find a dose that is in the ball park of the usual doses of acetaminophen or aspirin ... and then a dose that is clearly lower than that," Beaver commented. "FDA wants the lower part of the dose response curve thoroughly explored, because presumably if you are contemplating a switch with a prescription NSAID, you already have the upper part of the curve fairly well explored," he said. The revised guidelines also contain a completely new section on pharmacokinetic/pharmacodynamic (PK/PD) studies as an aid to selecting appropriate doses. While "the jury is out on the value of these studies," Cooper noted, "for now they are here, and I doubt anyone is going to go through a development without PK/PD studies." "If I can interpret for the FDA, I think the bottom line is [that] they would like to predict what blood levels of the drug you need to establish to get efficacy [and] they want to see this in a dynamic environment," Cooper said. FDA Center for Drug Evaluation and Research Director Carl Peck, MD, has been a major proponent for PK/PD studies and has frequently suggested that they be used throughout clinical drug development.

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