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ALLERGAN BETAGAN "DEAR DOCTOR" LETTER SOUGHT BY FDA: AGENCY OBJECTS TO MONOGRAPH CITING UNSUPPORTED COMPARATIVE CLAIMS AND UNAPPROVED INDICATIONS

Executive Summary

Allergan is being pressed by FDA to send a "Dear Doctor" letter to all physicians who received a product monograph for Betagan Liquifilm ophthalmic solution. The agency issued a July 10 warning letter to the company objecting to alleged continuing promotional violations for the glaucoma treatment. Citing a recent monograph on the product as the catalyst for the warning letter, FDA said: "We find that the monograph is misleading because it promotes unapproved uses, makes comparisons without adequate data, implies the significance of differences which are not of clinical significance, makes unsupported claims for an inactive ingredient and compares the product to strengths of other products which are not marketed in the United States." The tough admonition against alleged unapproved indications and unsupported comparative claims is not unusual during this period of renewed FDA surveillance of drug promotions. However, the form of FDA complaint apparently does set a precedent. The agency used its newest regulatory tool, a "warning letter," to convey its objections to Allergan. FDA's corrective action program for Allergan calls for: "a 'Dear Doctor' letter, approved by this office, to [be sent to] all physicians who received the subject monograph." The agency specifies that the corrective letter "should address the fact that Betagan has not been proven to be superior to other beta-blockers in either safety or efficacy, and that polyvinyl alcohol is not an active ingredient and has not been demonstrated to exert a contributory effect on efficacy or safety." The agency's comments on the inactive ingredient indicate the type of correction that FDA is seeking. FDA complains that, by identifying 1.4% polyvinyl alcohol as a viscosity agent used in the treatment of dry eye, the monograph attempts to establish that ingredient "as an active ingredient and creates a new indication for which Liquifilm sterile ophthalmic solution is not approved." FDA argues that Allergan would have to "establish polyvinyl alcohol as an active ingredient or establish that your formulation of levobunolol with PVA is superior to a formulation without PVA." In the interim before the issuance of the "Dear Doctor" letter, the agency wants Allergan Chairman and CEO Gavin Herbert to provide a written statement "describing the steps you will take to discontinue the use of this particular brochure [and] other promotional pieces containing such comparative claims of efficacy and safety." An Allergan spokesperson said the company intends to "fully cooperate with the FDA"; however he went on to say that FDA's demand for a "Dear Doctor" letter "is based on an assumption; we haven't concluded that a letter is required." The warning letter requests a response from Allergan within 15 days of its receipt by the company. FDA is also using a preclearance requirement again as in the agreement with Bristol-Myers Squibb over oncology drug promotions. Allergan is being asked to agree to preclear with the agency "the campaign intended to replace the current violative material" and "future Betagan promotional material for a period of one year." Among the alleged misleading claims for Betagan in the monograph was a comparison to the beta-blocker timolol that "implies that because levobunolol has a metabolite which has beta- blocking activity in animals, it is superior to timolol which has no active metabolite." FDA's warning letter adds that "presentation of this hypothetical advantage of your product is misleading in the absence of clinical data establishing that your product is therapeutically superior to timolol, and that superiority is attributable (at least in part) to the therapeutic contribution of levobunolol's active metabolites." The warning letter also states that "the claimed differences in efficacy between betaxolol and levobunolol have not been shown to be clinically significant." FDA noted that "the issue of statistical versus clinical significance as related to comparative promotional claims has been discussed in previous correspondence with your firm." FDA's correspondence with Allergan over claims for Betagan began a year and a half ago with a February 12, 1990 letter, which asked the company to stop use of "all materials comparing Betagan to Betoptic [betaxolol] 0.5%." FDA says it found Allergan's response to the first letter inadequate; and, in a March letter, the agency repeated its request for cancellation of all materials comparing the effectiveness of Betagan and Betoptic. Subsequently, in an April letter, Allergan stated that it would discontinue use of promotional materials containing comparative claims. FDA views the recent monograph as a violation of that commitment by Allergan. "As we have detailed, however, the same material appears in this monograph. Thus, even though your firm has been advised of the violative nature of this type of promotion, any you have declared an intent to discontinue such advertisements, the violations presented in the Betagan brochure constitute repeated violations of the [FD&C Act(BRACKET)." FDA declared that "such a pattern of repeated violations by your firm indicates a willful and flagrant disregard for compliance in your promotional activities." The warning also contends that a section in the monograph on "'Prophylactic Use in Surgical and Laser Procedures' improperly promotes an unapproved use of the product." FDA pointed out that "levobunolol is approved for the reduction of intraocular pressure, not for prophylactic use in preventing elevations in IOP under any circumstances."

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