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Executive Summary

Warner-Lambert's Lopid SR and Estrostep NDA reviews will be delayed until the company has addressed discrepancies discovered by FDA in applications for products being manufactured at the firm's Puerto Rico facilities. "FDA has informed the company that the agency has found some discrepancies in data the company submitted on products manufactured at its Vega Baja and Fajardo, Puerto Rico plants," Warner-Lambert reported in a 10Q filing with the Securities & Exchange Commission on Nov. 9. In late September, FDA notified the company that it would "defer substantive scientific reviews of pending [NDAs] and [ANDAs] for products to be manufactured at these facilities," including the Lopid SR and Estrostep NDAs. Warner-Lambert must conduct a revalidation review of all of its NDAs and ANDAs for products to be produced at the Vega Baja and Fajardo plants. Following the company's verification of the data, "the agency will be conducting validity assessments on all drug applications associated with these two facilities," Warner- Lambert said. The company noted that "it is not possible to predict when the validity assessments will be completed or whether the FDA will take any additional action." However, the firm estimated that the process could take up to three months. "The company has pledged its full cooperation to resolve all issues and is actively working with the FDA's San Juan [district] office to complete the validity assessments," the 10Q states. Warner-Lambert said that it "does not presently believe that this matter will have a materially adverse effect upon the financial position of the company." * The FDA decision to defer pending reviews is one of the first implementations of the "integrity policy" to surface involving a major brandname pharmaceutical manufacturer. The "Fraud, Untrue Statements of Material Fact, Bribery and Illegal Gratuities" policy, published in September 1991, allows FDA to suspend review of applications not directly associated with questionable data submitted by a company ("The Pink Sheet" Sept. 16, 1991, T&G-4). At the same time, the policy gives FDA staff the flexibility to continue scientific reviews of important new therapies. The agency has told Warner-Lambert that it will not defer reviews of the Cognex (tacrine) and Neurontin (gabapentin) because they are "critically needed new products." The FDA move is another setback for Lopid SR, which now is not anticipated to receive any form of approval before the patent for immediate-release Lopid (gemfibrozil) expires on Jan. 4, 1993. Warner-Lambert had hoped to gain approval of the sustained- release lipid-lowering product with at least a triglyceride reduction claim by the end of 1992. In February of this year, the agency informed the company that the Lopid SR NDA lacked sufficient data to support the sustained-release product's approval for the additional claim of chronic heart disease ("The Pink Sheet" March 2, p. 11). FDA's suspension of application reviews of products produced by the Puerto Rico plant may also delay the company's planned launch of a generic Lopid depending on whether the product is manufactured at the Puerto Rico facilities or the company's Morris Plains, N.J. plant. Warner-Lambert said in April that it plans to market a generic version of gemfibrozil immediately after the patent expires. Warner-Lambert is awaiting the results of a large, long-term controlled trial of Cognex to supplement two pivotal clinical trials. Meanwhile, the drug has been distributed to about 4,000 Alzheimer's patients under a Treatment IND protocol that will ultimately enroll approximately 15,000 patients. Neurontin, a gamma-amino butyric acid analog to be used as an adjunct to anticonvulsive drug therapy, is coming up for review as an epilepsy treatment before FDA's Peripheral & Central Nervous System Advisory Committee on Dec. 15 (see related brief). Warner- Lambert filed the Neurontin NDA in January. In addition to Lopid SR and Estrostep, a triphasic contraceptive formulated to reduce side effects that entered NDA review in December 1990, other Warner-Lambert NDAs that could face delays include: Pro-Air (procaterol), a beta agonist bronchodilator, and Amsidyl (amsacrine), an orphan treatment for acute adult nonlymphocytic leukemia. FDA's decision to suspend reviews of all applications of products manufactured at the Puerto Rico facilities apparently followed an inspection conducted by the agency earlier this year. Some of the discrepancies said to have been noted by the agency involved batch production numbers that did not match claimed batch numbers recorded in certain of the firm's applications. The 1992 inspection and its fallout mark the second time within a year that FDA has issued adverse inspectional findings on the Puerto Rican facilities. According to FDA inspection records, a multiple NDA pre- approval inspection conducted in the Vega Baja plant between May and November of 1991 resulted in an FD-483 list of 58 violations of current Good Manufacturing Practice (CGMP) regulations and other violations. The EIR notes that the inspection focused on: "retesting of stability lots"; "reporting [only] those tests which rendered within specification results"; failure to conduct "adequate investigations"; and "not reporting product stability problems to FDA until confronted during the inspection." Stability assays for the approved thyroid hormone products Euthroid and Proloid were also inspected. The EIR states that "numerous other GMP problems were reported" and the inspection was given an "Official Action Indicated" (significant deviations found) classification. The issuance of a warning letter was recommended. There is no evidence, however, that a warning letter was sent to the company. FDA also conducted a "limited" inspection from Nov. 21 through Dec. 2, 1991 of the Vega Baja facility specifically looking at stability data for an unnamed drug for a "serious life-threatening disease." While there were some questions about stability retesting, the inspection resulted in no adverse observations beyond those previously cited. A Treatment IND for Cognex was approved on Dec. 2. An EIR on Warner-Lambert's Fajardo plant discusses several GMP deviations observed during a May 2-Sept. 5, 1991 inspection of the facility. The pre-approval inspection involved five ANDAs and two NDAs. FDA inspectors documented evidence that "the firm is not adhering to the ANDA commitments," the EIR states. In addition, the inspection found that the "firm is not following its own written procedures in relation to their equipment cleaning operation."

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