COMBINATION ANALGESIC/CAFFEINE STUDIES REVIEWED BY OTC ADVISORY COMMITTEE

COMBINATION ANALGESIC/CAFFEINE STUDIES REVIEWED BY OTC ADVISORY COMMITTEE at its April 8-9 meeting "suffer from one common deficiency: they did not utilize a factorial design," McNeil Consumer Products noted in a May 3 letter to FDA. The company observed that a factorial design "is required under the [FDA] guidelines for evaluating any combination analgesic." After reviewing studies submitted to FDA over the last ten years, the OTC Drugs Advisory Committee recommended that caffeine is an effective analgesic adjuvant in aspirin products and in aspirin/acetaminophen combinations ("The Tan Sheet" April 12, p. 3). The committee agreed, however, that the data did not support the efficacy of caffeine as an analgesic adjuvant to acetaminophen. Citing the recent analgesic guidelines, McNeil said they "expressly endorse factorial design for both combinations of two analgesics and combinations of an analgesic with a 'mood-altering' drug such as caffeine." Only where one of the components "has been documented to have little or no analgesic effect" is a factorial design unnecessary, the firm asserted, and "in such instances, the placebo may be eliminated and the less effective test treatment substituted in its place." Use of a factorial design is "all the more essential for a caffeine-containing combination to prevent potential unblinding of the study," McNeil argued. In a study that was not submitted for evaluation by the committee, for example, McNeil said that "there were no statistically significant differences between aspirin plus caffeine and aspirin alone in the relief of postoperative dental pain." "None of the studies on which the committee based its conclusions had a caffeine-only treatment cell, and thus all of these studies violate the guidelines," McNeil contended. "Had the committee been given an opportunity to study these guidelines prior to the meeting, it would have reached a different conclusion," the company asserted. Apart from lacking factorial designs, McNeil cited other problems with the studies reviewed by the OTC Drugs Advisory Committee. For its recommendations on aspirin, the committee evaluated three studies, including a placebo-controlled comparison of 1,000 mg aspirin plus 64 mg caffeine with 1,000 mg acetaminophen. "When it considered caffeine's potential effect on the combination of aspirin and acetaminophen, the committee properly disregarded analogous data which did not compare the relevant analgesic caffeine combination with the same analgesic base," McNeil said. However, "this critical design flaw was never raised in the committee's discussion of this study," the firm declared. The other two aspirin studies "also had problems," McNeil maintained, such as the placebo seeming to have "no effect whatsoever on the pain intensity or relief scores" in a single- investigator evaluation of aspirin plus caffeine, aspirin and placebo. "This atypical outcome for an analgesic study raises issues regarding the validity of the study results and their analysis and merits further evaluation," the J&J unit maintained. Also, "the analysis of this study covers only two hours," while "standard analgesic studies evaluate the efficacy of the test drugs over their usual time course -- four hours for a dose of aspirin," McNeil pointed out. The third aspirin study, a three-hour comparison of aspirin to aspirin plus caffeine and placebo in headache pain, "shares this deficiency," the firm noted. The third study also "improperly excluded patients who had ingested any caffeine in the four hours prior to entry evaluation," which McNeil asserted "suggested strongly that many of the patients who were enrolled in the study may have been suffering from caffeine withdrawal headache," which would make the aspirin/caffeine combo seem more effective. Regarding aspirin/acetaminophen combos, "the evidence of caffeine's adjuvant effect was even more slender," McNeil contended. The only study ultimately considered by the committee to support aspirin/acetaminophen combinations and caffeine was "designed originally as a relative potency assay" but subsequently "reanalyzed in order to show a head-to-head difference at one dose on one pain parameter." FDA typically requires two well-controlled studies to support a finding of effectiveness, McNeil said. McNeil concluded its letter to the agency by urging FDA to consider these arguments "as it decides whether to accept the committee's recommendation to reclassify caffeine to Category I [safe and effective] when combined with aspirin or a combination of aspirin and acetaminophen." Caffeine for use as an analgesic adjuvant was placed in Category III (safety and efficacy data insufficient to permit classification) in the 1988 tentative final monograph for OTC internal analgesics. McNeil has previously objected to caffeine as an analgesic adjuvant. The firm submitted data to FDA in 1989 showing no significant differences between acetaminophen and acetaminophen plus caffeine.