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Executive Summary

Syntex will run remedial advertisements in 18 medical journals and on "Lifetime" Medical Television for its nonsteroidal anti- flammatory drug Naprosyn (naproxen) as part of a landmark consent decree with FDA filed in San Francisco federal court on Oct. 10. The remedial ads in medical journals and on cable TV are the first part of a package of corrective actions. The decree is the first judicially-enforceable corrective promotions agreement between FDA and a pharmaceutical firm. The decree is supposed to balance the effects of more than two years of promotions claiming that Naprosyn has arthroprotective abilities. FDA is asking again for what has become a standard penalty in repeat promotion cases: a two-year preclearance commitment from the firm for all promotional materials related to the product for which the violative materials were issued. That part of the agreement is similar to the Bristol-Myers Squibb oncology promotion settlement reached in May ("The Pink Sheet" June 3, p. 4). Syntex agreed to preclear all Naprosyn promotional and education materials and activities with FDA for two years; send out a quarter-million "Dear Doctor" letters; fund a year of remedial multimedia educational and advertising campaigns; and pay $ 131,000 for FDA's investigation costs plus all other costs of the agency's compliance surveillance activities. Syntex will pay for the campaigns from a $ 2 mil. escrow account. The consent decree says that Syntex suggested, on the basis only of preliminary animal and lab studies, that Naprosyn "is clinically effective in modifying the arthritis disease process in humans . . . including, but not limited to, halting the progression of the joint degeneration associated with any such disease." To counter these promotional or educational claims for Naprosyn, the decree requires Snytex to run remedial ads in "each of 18 medical journals in which Naprosyn has been advertised since Jan. 1, 1988" and to run "a video advertisement for repeated placement" on Lifetime Medical Television. The TV ad is to be run "each Sunday," and Syntex also may run one nonremedial Naprosyn ad per week "at a time approved by FDA, comparable to that of the remedial ad," the decree instructs. The journal ads are scheduled to begin running in November issues. The Lifetime ad is slated to begin airing in the latter part of April. The remedial journal ad is headlined: "Published to correct previous advertisements which the Food and Drug Administration considered to be misleading." The TV ad announces that the "following message is brought to you at the request of the FDA." The content of the print and TV ads is virtually identical. The corrective ads will state that FDA has determined that Syntex' promotional campaign for Naprosyn "was false or misleading. The campaign used terms such as "arthroprotective" and 'New Evidence of Positive Effects' and involved journal advertisements and activities of our sales representatives." Disease remission or protection claims in the treatment of arthritis have been a traditional concern of FDA's for almost a decade since the introduction of Oraflex. Lilly was chided by the agency at the time of that introduction for releasing press materials that indicated that benoxaprofen might have affect on the process of arthritis. The Naprosyn promotional activities in question have been under FDA investigation since mid-1988, when the agency and Syntex had a series of exchanges concerning the use of "arthroprotective" claims for Naprosyn. Syntex had initiated the joint degeneration prevention claims at around the time Ciba-Geigy's Voltaren (diclofenac) NSAID was launched into the arthritis market with such immediate success. In October 1988, Syntex agreed not to use the claims in future promotional material for Naprosyn; however, the company reportedly resumed the extensive use of these types of claims in 1989 just months after the agreement with FDA. The corrective ads will also declare that "FDA has determined that the campaign misrepresented that Naprosyn has disease- modifying effects in osteoarthritis, based on the results of in- vitro and animal studies. In fact," the proposed corrective ads state, "these in-vitro and animals studies are of unknown value as predictors of Naprosyn's effects in arthritic patients. No adequate and well-controlled clinical trials demonstrate that Naprosyn has any disease-modifying effects. Naprosyn has not been demonstrated to halt the progression of joint degeneration." Syntex also agrees to admit in corrective letters to 250,000 physicians that FDA has found Naprosyn promotions to be "false or misleading," that the drug "has not been demonstrated to protect patients from arthritic joint degeneration" and that ostensibly independent educational activities were, in fact, "promotional activities controlled by Syntex," the consent decree states. The "Dear Doctor" letters are signed by Syntex Labs President Virgil Thompson and began going out to physicians by certified restricted mail delivery on Oct. 11. All the letters will go out over a one- to-two week period after that date. Syntex will have to continue the remedial campaign, as outlined in the consent decree, for one year, unless the company can document that certain levels of physician awareness have been reached. The higher and quicker those specified levels are reached, the sooner Syntex can stop the remedial campaign. Specifically, if Syntex can demonstrate satisfactorily that "any time after 45 days" of the decree's filing that 80% of the 250,000 targeted physicians "have been made aware of the agency's findings" about the Naprosyn campaign, the remedial program can stop after three months; if 70% of the 250,000 physicians are made aware after four-and-one-half months, the program can be terminated in six months; and if 60% of the targeted physicians are aware of the remedial campaign seven-and-one-half months after the consent agreement, then Syntex can halt the campaign after nine months. Beyond corrective print and TV ads and "Dear Doctor" letters the consent decree compels Syntex to submit to a comprehensive program of FDA preclearance of all promotional and educational materials for the next two years. Syntex also has agreed to call back from the public and its sales forces all promotional materials relating to the "arthroprotective" and/or "bone and cartilege campaign" or any materials suggesting a disease-modifying effect by Naprosyn and to destroy those materials. The decree requires that Syntex "provide FDA with a written certification that (a) all materials (including detail pieces, mailers, other printed pieces, display panels, video tapes, and audio tapes) disseminated by or on behalf of the defendants" have been returned to Syntex and that "defendants have destroyed the returned materials." Additionally, the consent decree grants FDA inspectors the explicit authority to inspect all Naprosyn product and promotional materials and records. The consent decree states that FDA will have "access at reasonable times to all plants, offices, and other facilities" of Syntex "manufacture, distribute or hold" Naprosyn product or "distribute or hold any promotional materials" pertaining to Naprosyn. Inspectors still have to provide written notice of the inspection, but their authority extends to "all equipment used in manufacturing and processing such drugs and all such drugs and components therein, all promotional materials and all records relating to the manufacturer, processing, packing, holding, labeling, promotion, receipt and distribution" of Naprosyn," the consent decree states. The comprehensive scope and breadth of FDA scrutiny set out in the consent agreement are unprecedented, but the agency appears to have been promoted to seek a more enforceable guarantee of Syntex' cooperation because of the company's past history of Naprosyn promotions. While the Syntex agreement marks the first use of a consent decree mechanism to enforce a pharmaceutical firm's promotional compliance, FDA indicated that it is now willing to take similar measures against other pharmaceutical promotional abuses. In an Oct. 10 press release announcing the consent agreement, FDA Commissioner Kessler said Syntex is a "landmark case that delivers a strong message to other firms." Calling the agreement "an important and innovative approach to remedying promotional abuses by drug companies," he said the consent decree is "a precedent for dealing with those [firms] who would mislead physicians or patients on matters affecting the public health." To get the Syntex agreement, FDA is understood to have threatened to seize of all the company's stocks of Naprosyn. FDA said it began negotiations with Syntex to settle the false or misleading Naprosyn promotional campaign in May. A seizure action would have been a major blow to Syntex' revenues. The company's flagship product line, Naprosyn sales in the U.S. were $ 665.4 mil. in FY 1991 (ended July 31) and $ 910.8 mil. worldwide. U.S. sales of Naprosyn generated nearly 37% of Syntex' consolidated sales for the fiscal year. Syntex Chairman Paul Freiman said Oct. 7 in a preliminary announcement of the consent agreement only that Syntex "decided to sign this consent agreement because we felt that it was in the best interests of our customers, physicians, patients, employees and shareholders to put this incident behind us and to move forward on a positive note." Freiman added: "We cooperated fully with the FDA in reaching this agreement," and said, "we intend to comply fully with the terms of the decree." FDA's action against Naprosyn marks the second time in six months that Syntex has been reprimanded for false or misleading ad and promotional claims. In May, Syntex halted superiority claims for its calcium channel blocker Cardene in the treatment of angina and hypertension. Syntex previously had agreed to drop Cardene "cardiac protection" claims after being cited by FDA in September 1989.

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