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      Bioequivalence and other unresolved issues in generic drug substitution

      Clinical Therapeutics

      Elsevier BV

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          Abstract

          Substitution of generic drugs for brand-name products is highly controversial and often is met with suspicion by health care providers and patients. Historically, the debate has focused on the issue of bioequivalence, and clinical practice has identified a number of drug classes for which generic substitution should be approached with caution. Current bioequivalence requirements are based on a measure of average bioequivalence; however, there are fears that use of this measure may be inappropriate in the case of a drug with a narrow or wide therapeutic range or high intrasubject or intersubject variability. Under these circumstances, measures of individual and population bioequivalence are proposed to be more accurate than measures of average bioequivalence. This paper addresses issues of bioequivalence and other concerns with generic drug substitution. I conducted a MEDLINE search of the English-language literature containing the key terms generic, multisource, quality, and brand and published between 1973 and 2003. The names of branded pharmaceuticals whose patents had recently expired (eg, Ventolin HFA, Adalat, Capoten, Tagamet HB 200, and Valium) also were used to search for articles on generic substitution. Reference lists of relevant articles also were searched. Bioequivalence issues are presented together with more general concerns over generic drug substitution, such as consumer perception of risk, differences in product and packaging appearance, and differences in excipients. The literature reviewed act to highlight a number of different drug categories and patient subpopulations for which generic substitution can still prove to be problematic. I recommend that health care providers continue to exercise caution in the consideration of generic drug substitution under certain circumstances.

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          Most cited references 38

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          A physician survey on generic drugs and substitution of critical dose medications.

          Generic substitution has become a common practice since the late 1970s. Because of the increased use of generic alternatives and concerns about the Food and Drug Administration standards for bioequivalency, especially with respect to narrow therapeutic index drugs, the awareness and attitudes of prescribing physicians to generic drugs and generic substitution are important. A questionnaire designed to assess attitudes, beliefs, knowledge, and experiences with generic drugs and generic substitution was sent to 3639 physicians nationwide. Cluster analysis was used to identify attitudinal groups that were then analyzed with respect to differences in beliefs, knowledge, and experience with generic drugs. Perceptions of the therapeutic index for 15 branded drugs and comfort in substituting those products with generic alternatives were assessed. Physicians were classified into prosubstitution and antisubstitution groups, with a further division of antisubstitution physicians according to whether they felt influenced by outside pressures to substitute. Significant differences were found between the prosubstitution and antisubstitution groups with respect to beliefs about and experiences with generics and knowledge of the Food and Drug Administration bioequivalency standards. Of particular significance was the low percentage (17%) of physicians who correctly identified the Food and Drug Administration standards for bioequivalency. Prosubstitution physicians generally rated therapeutic indexes as wider than antisubstitution physicians. Physicians in all groups identified similar products they believed were not appropriate for substitution. Attitudes toward generic substitution are related to prescribing behaviors, beliefs about and experience with generic substitution, and perceptions of therapeutic index and comfort with substitution. Physicians need to understand the issues surrounding generic substitution and remain empowered to influence decisions to substitute.
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            Drug substitution in transplantation: a National Kidney Foundation White Paper.

            Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent substitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless the prescribing physician has granted approval. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.
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              The Clinical Importance of Proton Pump Inhibitor Pharmacokinetics

              Achieving the optimal clinical response for patients with upper gastrointestinal peptic disease is important. This response depends on the pathology treated as well as on the choice of proton pump inhibitor. Here, we identify factors in specific disease therapy and proton pump inhibitor (PPI) pharmacokinetic and pharmacodynamic characteristics that help us achieve this goal. These include differences in PPI bioavailability and acid-suppressive effects. Available data indicate that PPIs appear to have similar potency on a milligram basis, and that omeprazole and lansoprazole are more frequently double dosed than pantoprazole. The lower propensity for double dosing with pantoprazole may also result in lower medication acquisition costs and a reduction in physician visits due to ineffective therapy with the standard dosing of these other agents.
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                Author and article information

                Journal
                Clinical Therapeutics
                Clinical Therapeutics
                Elsevier BV
                01492918
                November 2003
                November 2003
                : 25
                : 11
                : 2875-2890
                Article
                10.1016/S0149-2918(03)80340-5
                14693311
                © 2003

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