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Executive Summary

PANCREATIC ENZYME DEFICIENCY PRODUCTS NOT SAFE FOR OTC USE, FDA declares in a notice published in the July 15 Federal Register. The notice of proposed rulemaking reverses FDA's 1985 Tentative Final Monograph for OTC exocrine pancreatic insufficiency drug products, which would have established conditions under which the products could have been deemed Category I (safe and effective) for use without a prescription. FDA's notice further declares all exocrine pancreatic insufficency drug products currently marketed, whether prescription or OTC, to be new drug products requiring an NDA for continued marketing. All OTC products must move to prescription status, while prescription products must obtain agency NDA approval. Because of the marketing history and "well-established use" of the enzymes, NDAs for the products in most cases "would not need preclinical data but, instead, could refer to the Panel's report [the 1979 report of the FDA Advisory Review Panel on OTC Miscellaneous Internal Drug Products, which would have okayed OTC use] as a basis for the safety of the enzymes," the notice states. However, because of the variation in the formulation and dosage form of some currently available products, "e.g., encapsulated enteric coated microsphere dosage forms," preclinical and clinical data to establish the safety of the final formulation may be needed "in some cases," the notice advises. Products marketed for this indication are made from either of two pancreatic extracts, pancreatin or pancrelipase, which contain digestive enzymes that patients with pancreatic insufficiency do not produce in sufficient quantities for normal digestion. Cystic fibrosis patients form a large part of the population which require the products. The products have a confused regulatory history: various versions of the extracts have been marketed for decades both OTC and by prescription, but there has never been an NDA submitted for any product in the category. Because there are no previously approved pancreatic products, companies are blocked from submitting ANDAs until one or more company gets an NDA approved. Hoechst-Roussel markets one OTC pancreatic enzyme replacement, Festall II. Prescription products include A. H. Robins' Donnazyme, Entozyme, Entolase and Viokase; Organon's Cotazym and Zymase; Solvay Pharmaceuticals' (formerly Reid-Rowell's) Creon Capsules; McNeil's Pancrease; and Vitaline's Pancreatin. One principle factor swaying FDA's decision, the notice indicates, is data submitted since the 1985 TFM suggesting that continuous physician monitoring of patients taking the drugs is necessary for adequate safety. Data submitted to the agency by cystic fibrosis researchers argued that physician adjustment of enzyme intake is needed to maximize the benefit and safety of the replacement therapy. However, the need for a physician's care for an indication does not by itself prohibit a product from being sold OTC for that indication, FDA notes. The deciding factor in the agency's decision to take the pancreatic products off OTC shelves was test findings indicating that the products currently on the market, both Rx and OTC, exhibit significant differences in bioavailability. While the notice states that "when properly formulated, these products are effective for treatment of exocrine pancreatic insufficiency," there is a lack of data establishing which existing products are properly formulated. Marketed products vary in the amounts of enzyme they contain, with some providing higher levels of enzyme than stated in their labeling, FDA tests show. The effectiveness of various forms of enteric coatings on products in use, which also influence the bioavailability of the enzymes, has not been adequately studied, the agency said. Too little or too much enzyme supplementation can cause patients to suffer abdominal problems ranging from mild cramps to overt intestinal blockage. The agency is eager "to avoid a disruption of the market" for the products, which are a daily necessity for some patients: "Because the final rule for this class of OTC drug products will be effective six months after its publication in the Federal Register, FDA strongly recommends that manufacturers . . . consult with the agency as soon as possible concerning the content of these applications." Because the proposal is significantly different from the previously proposed rule, the period for comments will be 120 days from the notice's publication instead of the normal 60 days.

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