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Executive Summary

Ciba-Geigy's Accutrim will need an approved NDA for marketing because Alza's OROS timed-release dosage system is a "new and unique" drug delivery mechanism, FDA told the firm in a May 24 regulatory letter. "We regard Accutrim to be a new drug because it utilizes a sustained-release mechanism which is new and unique in the United States," FDA Center for Drugs & Biologics Office of Compliance Director Daniel Michaels stated. "Such drug when incorporating the OROS delivery system is not generally recognized, among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use" as stated in Accutrim labeling. In a May 18 letter to FDA General Counsel Tom Scarlett, Ciba-Geigy argued that "innovation per se in drug delivery technology does not automatically result in a 'new drug.'" "Improvements to existing dosage forms and development of new dosage forms or routes of administration are common," Ciba-Geigy atty. Dorothy Watson asserted. "In those instances where the drug active ingredient is itself subject to the new drug provisions, such changes may require an NDA or a supplementary NDA." Watson stated that "active drug ingredients that are not subject to the new drug provisions may undergo similar changes; however, those changes are themselves generally not subject to the NDA requirements, with the possible exception of timed-release dosage forms." Ciba-Geigy Cites Cremacoat, Oxy-5 As "Innovative Formulations" Without Approved NDAs Ciba-Geigy cited several OTC drugs with "innovative" formulations that do not have approved NDAs. The products include Rich-Vicks Vicks Cremacoat products "that combine an antitussive, decongestant and antihistamine in a novel throat-coating liquid base;" Reed & Carnrick's Phazyme-95 antiflatulent "that combines an outer coating of immediate-release simethicone with a timed-release core of simethicone and various enzymes;" and Norcliff Thayer's Oxy-5 topical antiacne medication that contains Sonboxyl. The company also compared Alza's OROS timed-release system to bead technology. Noting one type of bead "absorbs water through an insoluble film by osmosis, until the bead breaks open," Ciba-Geigy said "this is the same basic technology used in the Accutrim tablet, except that the insoluble film tablet coating contains a tiny laser-drilled hole." The firm cited Dexatrim Extra Strength, Dietac, PVM, Dex-A-Diet and Vita Slim as timed-release appetite suppressants using various bead technologies which have not "incurred an FDA regulatory response." Verex Labs' Verin, Boots' Zorprin, and Sterling's Bayer Timed Release Aspirin were also cited as timed-release products utilizing innovative technology without NDAs. "We do not disagree with the notion that, until the agency develops standards for timed-release dosage forms, individual timed-release products should have NDAs," the firm declared. "We do contest, however, FDA's subjective interpretation that the technology employed in the Accutrim timed-release system is so substantially different from timed-release products now in the market place as to invoke" regulatory action in advance of the final monograph. FDA's preamble to the Miscellaneous Internal panel report on OTC weight control products stated that NDAs will be required for sustained-release products containing the maximum 75 mg daily dosage of phenylpropanolamine upon publication of a final monograph. Ciba-Geigy said the preamble "makes no distinctions among timed-release technologies or systems." The company further asserted that "the Accutrim technology offers an improvement in timed-release technology resulting from the innovative use of compendial inactive ingredients and existing technologies." As the panel report "does not purport to cover inactive ingredients or timed-release technology," Ciba-Geigy continued, "Accutrim is comprehended by the [panel report]." FDA took a similar "new drug" position last summer with Block's Sensodyne F and Promise toothpaste combination products. In April, FDA sent a policy guide to its field staff to remind them that OTC non-monograph combinations marketed after the OTC review in May 1972, are new drugs if the product has not been cleared by the agency ("The Pink Sheet" May 7, T&G-6). The agency also used the fact that ibuprofen 200 mg had never before been marketed as the rationale for requiring an NDA to move the drug from Rx-to-OTC status. In its letter, Ciba-Geigy differentiated between the OTC Review and the DESI (Drug Efficacy Study Implementation) Review. "Unlike the DESI Review, which was intended to be a market 'snapshot,' the OTC Review was envisioned as a lasting regulatory framework, dependent on the flexibility of the therapeutic category approach," the firm stated. The company said a snapshot view of the OTC Review would preclude "the introduction of better products otherwise encompassed by such monograph."

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