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Executive Summary

Upjohn pharmacist programs that encourage diabetic patients to switch from other oral hypoglycemic agents to the company's Glynase Prestab tablets lack "fair balance" and provide "misleading" information, FDA alleges in a Nov. 25 warning letter. Materials disseminated by Upjohn and the pharmacists in these programs "contain inaccurate and unsupported statements in regard to the safety and efficacy of Glynase [micronized glyburide] and fail to disclose significant risks to patients who switch from other oral hypoglycemic agents to Glynase," FDA contends. The letter, signed by FDA Marketing, Advertising and Communications Division Acting Director Cheryl Graham, MD, requests that Upjohn cease two programs initiated by the company in September, send "Dear Doctor" and "Dear Pharmacist" letters, place corrective ads in medical and pharmacy journals and develop a plan to communicate to all patients who were contacted by pharmacists or physicians under the programs. Upjohn said that it is reviewing the issues raised by the agency letter and will work with FDA to come to a mutually satisfactory resolution. The Upjohn programs enlist pharmacists to encourage patients to switch from the company's older glyburide product, Micronase, Hoechst-Roussel's Diabeta and other oral hypoglycemics to the newer Glynase Prestab for the lowering of glucose in patients with non-insulin-dependent diabetes mellitus type II. Micronase loses patent protection and will face generic competition beginning in May 1994. By contrast, marketing exclusivity for Glynase, which was approved in March 1992, extends to March 1995. Upjohn's "Diabetes Cognitive Services Reimbursement Program," FDA explained, "provides for pharmacists to be compensated for the successful solicitation of physicians that results in patients being switched from Micronase or Diabeta to Glynase." A second program "provides for pharmacists or pharmacies to be compensated for soliciting patients to be switched from Micronase or Diabeta [to Glynase] by sending letters (on their own letterhead) to customers," the agency said. FDA's warning letter does not address the direct compensation of physicians and pharmacists by drug companies. However, the agency does routinely refer such cases to state licensing bodies and has given information about the Upjohn case to the National Association of States Attorneys General. In the past, some company promotional activities involving monetary compensation have been referred to the HHS Office of the Inspector General. The warning letter to Upjohn focuses on the medical implications of a direct switch from Micronase or Diabeta to Glyconase. The agency notes that the Precautions section for Glynase labeling states that "the serum glyburide concentration levels of Glynase are not bioequivalent to Micronase." In addition, labeling states that "no exact dosage relationship exists between Glynase Prestab and other oral hypoglycemic agents, including Micronase or Diabeta." Therefore, labeling adds, patients should be retitrated when being transferred from an oral hypoglycemic to Glynase. The letter mentions the potential for higher patient costs from a switch. Retitration, FDA pointed out, requires not only the usual monitoring of urinary glucose but measurements of blood glucose levels and other tests "to detect primary and secondary failure." The warning letter notes that "an inappropriate dosing regimen may also precipitate hypoglycemia." Therefore, "switching a clinically stable patient from Micronase or Diabeta to Glynase may cause the patient to incur significant safety risks, as well as additional expense and inconvenience." The agency is aware of "at least one pharmacy firm" that was contacted by Upjohn to enter into a contract to promote Glynase, the letter notes. The terms of the contract "required that the pharmacy send letters, on its letterhead, to consumers in its database that currently were taking Micronase or Diabeta." FDA said the letter "would announce the availability of Glynase, describe its advantages, and encourage patients to contact their physician or pharmacist to have their oral hypoglycemic agent switched to Glynase." The letters also contained coupons for a Glynase prescription that were redeemable at the pharmacy. Under the questioned contract, Upjohn "was to compensate the pharmacy for the mailings and the face value of coupons redeemed, and provide a marketshare based performance rebate on purchases of Glynase," FDA noted. FDA maintained that the contract program "directs pharmacists to promote the advantages of Glynase without disclosing the risks of Glynase therapy or the risks and costs of switching to Glynase therapy." By switching from Micronase or Diabeta to Glynase, patients "may incur serious medical risks because of the necessity for retitration and the possibility of loss of diabetic control," the letter maintains. The warning letter also objects to language used by Upjohn in the agreement form for the cognitive services program stating that Upjohn developed Glynase "to improve the bioavailability, dosagetitration flexibility, ease of administration and overall management of the diabetic patient." The agency contends that it is "not aware of substantial evidence or substantial clinical experience that the control and management of these patients is in any way enhanced or improved by Upjohn's new formulation of glyburide." The cognitive services agreement form also refers to Glynase's therapeutic effect as "the best possible outcome for this diabetic patient" and encourages the use of the product "to assure optimal utilization and therapeutic outcome," the warning letter notes. FDA reminded the company that "this is not the first time Upjohn has been informed of the agency's views on this matter." In an April letter to the company, FDA objected to the statement "designed for better management" in Glynase promotional materials. Furthermore, the warning letter states that "neither of these programs were submitted in a timely manner as required by the regulations." Upjohn began disseminating materials for the programs in August; the company submitted information to FDA on Oct. 29, the agency said. FDA has yet to receive details on the contract program from Upjohn, the warning letter notes. Upjohn must submit its plans for corrective action to FDA, including "instructions to the sales force, and a complete listing with sample copies of each piece of advertising and promotional labeling that will remain in use and those materials which will be discontinued," the letter states. In addition to letters to physicians and pharmacists, and corrective ads in eight medical and four pharmacy journals, Upjohn should "establish a quality control mechanism to assure that the 'Dear Pharmacist' letter is received by all pharmacists who are participating in, or who were solicited to participate in" the programs, FDA said. The corrective action directed at the diabetic patients who were contacted by the pharmacists or physicians "should include a mechanism for fully informing consumers about the serious issues in regard to the risks and additional cost that they may incur when being transferred to Glynase from another oral hypoglycemic agent." This plan must also be submitted to FDA's division of advertising.

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