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Executive Summary

POTASSIUM CHLORIDE CONTROLLED RELEASE ANDAs SHOULD NOT BE APPROVED until FDA issues guidance defining the conditions a manufacturer must meet to obtain approval of such products, D.C. law firm Hyman, Phelps & McNamara stated in an Oct. 23 petition to FDA. The firm requested that FDA issue an advisory opinion or a guideline "defining the circumstances under which a manufacturer may submit an application to market potassium chloride controlled-release tablets or capsules in 8 mEq, 10 mEq, and 20 mEq strengths." Specifically, the law firm asked FDA to state whether manufacturers are "required to conduct ulcerogenicity studies in cats, pigs, or monkeys and endoscopic studies in healthy volunteers in order to secure approval" for the products. Hyman & Phelps said approval of potassium chloride controlled release ANDAs before FDA issues some guidance "could effectively discriminate against those manufacturers who have been requested by the agency in the past to submit human endoscopic and animal ulcerogenicity study data in order to demonstrate the safety of their products" for NDA approvals. The law firm said it "questions whether potassium chloride controlled-release products are suitable for ANDAs." But, the firm stated, "if FDA decides to allow ANDAs for the products, human endoscopic and animal ulcerogenicity data should be required as a condition of approval." The law firm noted that Key (K-Dur 10 and 20 mEq dosage forms) and Upshur-Smith (Klor-Con 8 and 10 mEq) received NDA approvals for potassium chloride controlled-release oral dosages in 1986. Hyman & Phelps stated that "in light of different types of controlled-release dosage formulations (e.g. wax matrix, microencapsulated, and explo-tablet), bioequivalence studies are unable to provide useful data on the rate and extent of absorption and the safety of the controlled-release formulations." In addition, the firm said bioequivalence studies "do not resolve the issue of gastrointestinal ulceration, which is the major safety concern related to these products." The law firm attached FDA Cardio-Renal Div. Director Raymond Lipicky's review of NDAs for Klor-Con and K-Dur to its petition. In his review of Klor-Con, Lipicky stated that "under the best of conditions a KCl bioavailability study cannot measure the rate and extent of absorption" which are the "two parameters that judgments with respect to bioequivalence are made from." However, he said that by comparing the time of peak urinary excretion rates, "one can determine that the formulation in vivo has slow release characteristics." In his review of K-Dur, Lipicky outlined arguments for and against approval of a 20 mEq dosage strength and then concluded that it should be approved. He added: "At a time that the division is proposing approval by the ANDA route, I certainly hesitate to recommend approval of a 20 mEq unit dose and concomitantly say that 20 mEq wax matrix unit dose forms need a full NDA. We will once more be swamped by KCl NDAs."

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