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This article was originally published in The Tan Sheet

Executive Summary

SYNTEX OTC NAPROXEN EFFICACY DATA "MEET CURRENT STANDARDS" of approval for OTC analgesics in studies treating dental pain, dysmenorrhea, and aches and pain associated with minor arthritis, Syntex Executive Director-Regulatory Affairs Michael Perry told a joint FDA advisory committee on June 2. Syntex was given the opportunity to present naproxen efficacy data and to address several committee concerns during an unscheduled presentation on the second morning of the joint committee review of the Rx-to-OTC switch application after committee members postponed their vote on June 1. The presentation centered around six randomized, controlled clinical trials submitted as part of the switch NDA that were presented by Syntex VP-Clinical Affairs Bernadette DeArmond. Three studies (CRD 88-06, LAB 102 and LAB 982) looked at pain associated with dental extractions involving the removal of one to four wisdom teeth; one study (LAB 108) looked at musculoskeletal pain; and two studies (LAB 104 and LAB 105) looked at dysmenorrhea. All six studies found significant efficacy with naproxen at doses between 200 mg and 400 mg. The joint Arthritis and OTC Drugs Advisory Committees voted seven to four (with one abstention) against recommending approval of Syntex and marketing partner Procter & Gamble's switch application for naproxen sodium on June 2 ("The Tan Sheet" June 7, p. 1). However, the three areas where clear efficacy was demonstrated may present a starting point for negotiations between the company and FDA over a switch approval with different labeling from currently available OTC analgesics. The Syntex efficacy data initially were presented by FDA medical officers on June 1, the first day of the committee meeting. The presentations included data for headache, dysmenorrhea, dental pain, minor arthritis pain, minor aches and pains associated with colds, dental pain and fever indications, as well as usage studies of naproxen. Following the presentation, committee members expressed skepticism at the significance of cold and headache data and were uncertain how to read the efficacy data from the usage studies. When questioned by the committee about the appropriateness of approving naproxen sodium for the indications studied given the ambiguous study results, FDA Pilot Drug Evaluation Staff Director John Harter, MD, said the agency and the committee are "stuck with those indications and [have] to decide whether the data support them or not." He pointed that the "indications that we're using are the ones for the OTC monograph for aspirin, acetaminophen . . . and ibuprofen." He acknowledged: "If we were to start out fresh we might come out with a different set of indications." Responding to committee criticisms of trial designs, of studies using formulations of both naproxen and naproxen sodium, and of last-minute trial submissions by Syntex, Harter called the organization of the studies "typical" of an NDA. He said that the "vast majority of these [NDAs] haven't got the right dose [or the data] came out funny. There are only a handful of these where you can say: 'Boy, that's a good study! We can depend on that!'" Harter noted that "one of the reasons [FDA] presented the data rather than . . . the sponsor . . . is that if the sponsor presented the data it would look a lot better than [the FDA presentation(BRACKET)." Syntex organized its presentation to address committee concerns about the drug's clinical efficacy; dose selection; pharmacokinetics in the elderly; overdose toxicity; side-effect profile; and sodium content. The six studies featured in the Syntex presentation supported clinical efficacy for the 200 mg dosing interval of naproxen, according to DeArmond. "What we have learned throughout these studies is that the doses of naproxen in the range of 100 mg are not consistently effective; the doses of naproxen in the range of 200 mg generally are effective, but slow in onset; and that using the naproxen sodium at 220 mg [200 mg naproxen and 20 mg sodium] gives us the extra benefit of more rapid onset, because of the better absorption pattern; and that the doses of naproxen at 400 [mg] or naproxen sodium 440 [mg] are better for some patients in some pain models," DeArmond said. On the first day of the meeting, FDA Medical Officer Rudolph Widmark, MD/PhD, presented efficacy data on naproxen, naproxen sodium, ibuprofen and placebo for the relief of dysmenorrhea and dental pain. Widmark noted that Syntex has continued to submit efficacy data to FDA including one trial that "came in last night." He also commented on the relatively limited data available on naproxen sodium, the drug being examined for the switch. "The data are rather confusing," Widmark stated, "but we can conclude from these trials that [naproxen sodium] 220 mg had a faster onset of pain relief than naproxen 200 and even 400 mg," Widmark said. "We can conclude that Anaprox in the doses tested has an estimated onset of pain relief around 20-25 minutes and a duration of six-to-eight hours." Widmark noted that "this might be important" if "recommended for general OTC use." Widmark also was critical of two recently submitted Anaprox trials, which he suggested "should be shown to other sponsors [because of the poor design of these trials(BRACKET)." Citing some of the problems FDA had with the studies, Widmark noted that Anaprox was compared to an older ibuprofen formulation with a slower onset of action than the Advil product currently marketed by Whitehall. Also, he said, "in order to blind the trial, the sponsor put the tablet into a capsule, which made it even worse." Nevertheless, "we think that Anaprox 220 is a pretty effective analgesic for the majority of patients," Widmark noted, "although some of them might have to take a loading dose [of two tablets] for control of their pain." Presenting efficacy data on naproxen 100 mg and 200 mg for the treatment of minor arthritis pain, FDA Medical Officer Linda Katz, MD, noted that there were statistically significant differences in reducing pain intensity and granting pain relief between the two active dosage forms and placebo. However, there was no statistically significant difference between the two drug arms. Katz suggested in her presentation that the lack of dose response may be due to a faulty formulation of the 200 mg product used in the trial. Chairman of the OTC Drugs Advisory Committee Randy Juhl, PhD, University of Pittsburgh, said that "intuitively" Katz' interpretation of a faulty formulations "doesn't make sense." Juhl said, "I have some understanding of how there could be a difference in the pain response over the first two hours because of slow absorption. I am unable to theorize myself how those differences [in absorption] would affect a multiple dose, many-day trial." Katz also presented Syntex efficacy studies in four categories: cold, cold/compliance, 30-day home use and fever. Nearly all of the studies tested naproxen rather than naproxen sodium. Regarding fever trials, Katz noted that the "active treatment group performed better than placebo." The committee, however, was concerned with granting an antipyretic indication for NSAIDs. Katz reported that Syntex' headache trials did not show superior efficacy over placebo and, in the cold studies, Katz pointed to only one study that showed efficacy and then only for muscle aches associated with colds. OTC advisory committee member Louis Cantilena, MD/PhD, Uniformed Services University of Health Sciences, asked why the committee was examining an indication that was for the common cold when the only relief patients in the cold trials experienced was for headaches and minor aches and pains. Harter explained that these are the indications that other currently marketed NSAIDs carry. He added: "If we were to put out something labeled differently, it would be viewed as being very clinically significant and it would be promoted in the marketplace as a large difference." Juhl asked, "So we're stuck with those indications whether the data support them or not?" Harter replied that if the data do not support the claim then the indication would not be included in the labeling. Syntex also submitted three usage studies that were designed to "see how well patients could follow [label] instructions" and to assess safety and efficacy, Katz said. "The instructions the patients were supposed to read were the dosing instructions that would go into the label," Katz said, adding: "The majority [of the patients] took what they were supposed to take but there were clear outliers" -- or patients taking two additional doses per day. Patients were instructed not to exceed four naproxen or six ibuprofen in a calendar day. Designed to measure patient compliance and the drug's safety and efficacy under OTC use conditions, the usage trials' inability to show clear-cut efficacy frustrated the committee at times. For example, usage studies 685 and 90-01, which looked at naproxen and an ibuprofen control, showed a "trend . . . to be better than placebo but this did not reach statistical significance," Katz reported. In usage study 90-02 the active drug groups could not be distinguished from each other or from placebo.

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