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Executive Summary

The review of Syntex' NDA for injectable ketorolac (Toradol) appears to be near completion at FDA based on comments by FDA Anti-inflammatory Drug Group Leader John Harter, MD, at the agency's Arthritis Drugs Advisory Committee meeting April 24. In a discussion of proposed class labeling for analgesics, Harter told the advisory committee that ketorolac has been "given a 'B' categorization [moderate therapeutic advantage over existing therapies]." He added: "We hope it won't be too much longer" before approval. The ketorolac NDA, Harter noted, "has sort of stimulated us" to consider new approaches to labeling analgesics. "Ketorolac, a parenteral drug that you can use in place of morphine and Demerol post-operative, has got to be something that ought to excite the surgeons, and we'd like to write a label that gives you a fighting chance to use it constructively and get started with it properly when it is introduced," he explained. Syntex submitted NDAs for both injectable and oral ketorolac in the spring of 1987. The Indications section in most current analgesic labeling describes the appropriate use of the drugs in terms of "mild," "moderate," "moderately severe," or "severe" levels of pain. FDA is now proposing that labeling for analgesics instead state that the drugs are indicated for the relief of pain, and then specify in other sections of labeling how the drug compared to standard analgesics in clinical trials. In a handout to the committee, the agency explained that the Indications section could reference the Clinical Pharmacology and Dosage and Administration sections of labeling "and then in those sections of the insert try to distill information from the trials actually done and to make statements as to what doses were/are comparable to what doses of other analgesics." FDA invited representatives from the analgesiology section of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) to present their views on analgesic labeling. Like FDA, the group suggested that the "mild/moderate/severe" classification system be discontinued. How- ever, the society differed with FDA on how to replace the current pain classification system, recommending, instead, that a new ranking system, based on standard analgesic therapies, be used in the indications section of labeling. Under the society's proposal, labeling would state that the analgesics are "indicated for the relief of (acute/chronic) pain as a substitute" for one of four standard analgesic drug classes: aspirin or acetaminophen; aspirin with codeine, acetaminophen with codeine, or ibuprofen; intramuscular morphine (for drugs without a ceiling effect, such as opioids); and intramuscular morphine or ibuprofen (for drugs with a ceiling effect, such as nonsteroidal anti-inflammatories). ASCPT representative William Beaver, MD, suggested that using a ranking system based on equivalent standard analgesics would provide the physician with more useful information about new agents. The current system, Beaver asserted, "is inconsistent. For example . . . there are agents that are labeled for moderate and severe pain which, on the basis of all controlled clinical studies, are clearly no more effective than aspirin or acetaminophen." In "the opposite direction," he continued, "some of the NSAIDs are clearly more effective than aspirin/acetaminophen, and even comparable or better than some of the opioids, and some of these are [labeled only for] mild to moderate pain." Most of the advisory committee members favored changing labeling from the "mild/moderate/severe" categories to a comparison against standard analgesics, with the caveat that labeling distinguish between acute and chronic pain. Summarizing the views of the committee, Chairman Frederic McDuffie, MD, Piedmont Hospital Arthritis Center, said: "I think we are pretty much agreed that if you restrict yourself to an acute model, then most people feel that the substitution of standards such as aspirin . . . narcotics . . . and ibuprofen, may be useful and may be better than the 'mild, moderate and severe' [classifications], particularly because there are data in the literature in which drugs are compared that way." The committee was somewhat divided on whether comparative clinical trial data should be included in analgesic labeling. Several members raised the point that physicians might not read extensive clinical trial reports. "On the issue of whether the actual data should be included in the labeling, we're of a mixed mind," McDuffie said. "On the one hand, we do like the idea of including some data, at least in summary form . . . [but] on the other hand, since we want it to be simple, we don't want too much data or it will be hard for physicians to understand." Several committee members also pointed out that labeling should indicate the types of pain the drug had been shown to be effective in treating. FDA views its relabeling proposal as a way to give the physician more useful information about drugs, while encouraging more accurate analgesic advertising. The agency noted the potential positive effect on advertising in its handout to the committee. "In addition to being more helpful to the physician," FDA said, "we wonder if it might not encourage advertising to be less misleading and superficial and instead make it more useful in supplying information about the drug and how to use it as an analgesic."

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