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Executive Summary

References to the Clozaril Patient Management System in the drug's approved labeling should be deleted, FDA told the firm in a July 13 letter. "In order to reduce misunderstanding among patients, prescribers and health care providers, we ask that you expeditiously modify Clozaril's labeling by replacing references to CPMS [Clozaril Patient Management System] with more general descriptions of the essential elements of an acceptable system," FDA Neuropharmacological Drugs Division Director Paul Leber, MD, wrote. The letter asks that the changes be made "immediately." FDA's requirement that Clozaril labeling be changed undermines Sandoz' position that the CPMS distribution system, which has been contracted solely to Caremark, was a prerequisite for approval of the antischizophrenia drug. Sandoz has been under pressure from third party payors, the Veterans Affairs Department and Congress to broaden its distribution of Clozaril due to the high costs of the CPMS program. Pharmacy also opposes the CPMS system as a threat to the profession. Sandoz has contracted exclusively with Baxter subsidiary Caremark and with Roche Labs, respectively, to provide blood drawing and analysis services for patients receiving the antischizophrenia drug (clozapine). The company's price for Clozaril is based on the delivery and testing services; Sandoz has refused to itemize the cost of the drug treatment. Leber said the changes in the Clozaril package insert "are essential if the labeling is to describe the nature of the approved distribution system or systems accurately." FDA's approval of Clozaril was dependent on the drug's distribution "under a system that limits the actual delivery of Clozaril to those patients who have weekly white blood cell counts performed," Leber noted. However, approval of the drug and its labeling "did not constitute an approval of a specific vendor for the system of services referred to as the 'CPMS.'" CPMS describes the blood collection and drug distribution services provided by Caremark and the blood analysis provided by Roche under contract with Sandoz. However, the letter asserts, in approving current Clozaril labeling, that FDA officials considered and still "view the term 'CPMS' as a notation for any distribution system that reliably links the actual delivery of Clozaril to the patient to his or her compliance with a blood testing program." FDA contended that Sandoz' "use of a single-source vendor for the distribution of Clozaril has contributed to the confusion created by the somewhat ambiguous description of the CPMS in current labeling, which allows the inference that the distribution systems identified is a specific entity." There are four references to CPMS in Clozaril labeling, according to the letter. FDA requested the following replacement language: "Clozaril is available only through distribution systems that ensure weekly WBC [white blood cell] testing prior to delivery of the next week's supply of medication." The agency requires the blood monitoring to avoid agranulocytosis, an often fatal adverse effect of clozapine. Sandoz has not responded to the labeling request but expects to reply to the agency shortly. In a July 20 statement, Sandoz maintained that it was continuing negotiations with the Veterans Affairs Department over a plan to allow V-A to distribute Clozaril and to monitor its own beneficiaries in V-A health facilities. The company was responding to a July 19 announcement that the department had halted the negotiations due to Sandoz' intransigence. The company said any agreement to allow V-A to dispense Clozaril and conduct its own blood monitoring would have to include the assumption from Sandoz of any liability for adverse effects ("The Pink Sheet" July 23, T&G-12). In a July 24 statement, American Pharmaceutical Association Exec VP John Gans said FDA's decision to delete from official labeling any references to a commercial distribution arrangement "is welcome insofar as it represents an important clarification of Sandoz' representations as to what FDA required when it approved Clozaril." Gans added that the decision "once again raises questions regarding the appropriateness of the manufacturer's closed and costly commercial distribution system." In a July 20 statement on the status of negotiations between V-A and Sandoz, APhA asserted: "It is clear that the [V-A] had to weigh the benefits of clozapine against the extraordinarily high cost of the drug's 'monitoring program' and the many problems associated with closed distribution systems." Gans maintained: "The department should not be expected to pay for an inferior system that fragments patient care." In a July 19 press statement, Sen. Pryor (D-Ark.), who expressed "regret" at the reported "breakdown in negotiations," said "Sandoz is charging its U.S. customers about $9,000 annually, over five times as much as the firm is charging its European customers." The senator included a provision in his Medicaid drug price discount legislation (S 2605) to allow the federal government to contract with another manufacturer to make clozapine and supply its own distribution/monitoring services.

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