Historia de la Biofarmacia
Breve acercamiento al desarrollo de la disciplina de la Biofarmacia.
2. Bioequivalencia
"Early in 1970, serum had been collected during an FDA-contracted bioavailability study from volunteers for the purpose of determining drug bioequivalence. Five different drugs were investigated, but equivalence/inequivalence was never determined as the methodology did not then exist to analyze the blood samples. As a result many of the generic as well as innovator companies requested waiver of the required BA studies on the basis that analytical methodology did not exist so as to permit them to do the study. To address this problem, we contracted Schools of Pharmacy to conduct a review of the literature to determine whether the analytical methodology existed for performing in vivo bioequivalence studies. The results were discouraging in that the required analytical methodology was largely non-existent. We then let contracts for methodology development, mostly to academic institutions, which could then be employed for the conduct of these studies.
Additionally, a Biopharmaceutics Laboratory was established under Dr. VK Prasad, which not only developed methodology for the conduct of these studies, but conducted surveys of marketed generic dosage forms. Following procedures developed under Professor Wagner’s contract, samples of innovator and generic dosage forms (e.g., digoxin 0.25 and 0.5 mg) were picked up by FDA Field Inspectors and analyzed by Dr. Prasad’s laboratory and FDA’s National Center for Drug Analysis (NCDA) in St. Louis. Those with varying dissolution results were tested in small panels of human subjects. Where possible, in vivo/in vitro correlations were developed. These would eventually be used to establish dissolution specifications for the product so as to provide lot-to-lot bioequivalence assurance, once the bioequivalence to the innovator’s product had been established.
Because methodology development for topical products proved to be especially difficult, a number (where one could observe clinical efficacy) were allowed to be marketed with “deferral” of the bioequivalence requirement. The thought was that when methodology was developed, in vivo studies would then be required. With the passage of the 1984 amendment, the granting of deferrals ceased, as the amendment required a demonstration of bioequivalence for approval.
The biopharmaceutic regulations (17) specified that blood level and/or urinary excretion studies must be conducted when possible. When such studies were not considered to be feasible, alternative pharmacodynamic studies could be employed to demonstrate BA/BE. Should neither blood level/urinary excretion studies nor pharmacodynamic studies be feasible, full clinical studies were required. As pharmacodynamic measurements proved to be difficult to interpret, the only bioequivalence-based approvals using a pharmacodynamic approach employed the Stoughton–McKenzie test (for the topical glucocorticoids) (18–21). Attempts to use skin-stripping to develop a pharmacokinetic curve did not pass muster."