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Executive Summary

Bioequivalence study results for each formulation of a multisource drug should be included on the labeling as an FDA regulatory requirement, Searle said in written comments submitted to the agency as part of FDA's bioequivalence hearing. Searle Regulatory Affairs VP Douglass Given, MD/PhD, maintained that the agency's current regulations provide inadequate information on bioequivalence of different formulations of the same active ingredient to health care professionals. He wrote that "a potential solution to the lack of information would be for FDA, by regulation, to require that in the clinical pharmacology section of the labeling for all drugs the actual results of bioequivalence studies be provided." Given said that the description "should include information such as the study population, study design, the results and methods of analysis." The firm maintained that the added labeling requirement is necessary because: "The mere categorization of a drug as bioequivalent in the FDA list entitled "Approved Prescription Drug Products with Therapeutic Equivalence Evaluations" does not tell a professional whether a drug is more or less bioavailable to the reference or how the various drugs listed as bioequivalent to a reference relate to one another," Given stated. Given maintained that "the lack of meaningful information is compounded by substitution laws that may mandate or permit substitution based on the determinations made and published by FDA." Searle noted that it was filing its comments to supplement those prepared by PMA, and the firm added that it has reviewed and supports the association's views. PMA itself will make five separate presentations at the FDA bioequivalence hearing. Among the points the association is expected to make are that testing guidelines should be established for each drug to account for unique characteristics, that the agency should eliminate the +/-20% rule in favor of drug-of-drug standards, and that in vitro tests can never by used to establish bioequivalence. Searle maintained "FDA's position that pharmaceutical bioequivalence under specified study conditions predicts therapeutic equivalence is based on assumption and not scientific fact." Given asserted that for drugs "for which there is a narrow therapeutic/toxic range, or for which blood levels in healthy volunteers may not be predictive of safety or efficacy, reliance on FDA's assumption may be dangerous to patients who use the drugs under a variety of different conditions." The company said FDA "should require that bioequivalence be determined by studies designed with reference to the use and pharmacological characteristics of the drug." For instance, Searle said the use of healthy volunteers in a fasting state may be appropriate for some drugs. Searle concluded that FDA should promulgate testing regulations "specifying the necessary studies and evaluations needed to determine bioequivalence for the various classes of drugs or for specific drugs as needed." The firm also maintained that "the number of subjects or patients should vary depending on the nature of the drug and the intended patient population. Studies should be of sufficient size to show that blood levels of the tested drug are statistically equivalent to the reference drug for the intended patient population." Also, Searle added that "the requirement for single or multiple dose studies should be dependent on the pharmacokinetic characteristics of the drug. Clearly, when steady state blood levels cannot be reliably predicted from a single dose study, multiple dose studies must be conducted."

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