Requirements for generic anti-epileptic medicines: a regulatory perspective

Interchangeability of Gabapentin Generic Formulations in the Netherlands: A Comparative Bioavailability Study

“…It is possible that distrust of generic drugs makes adherence a problem, which means that it may not be possible to predict equivalence in clinical outcomes on the basis of equivalent pharmacokinetics alone when switching from an innovator to a generic drug. However, the comparable exposure demonstrated in this study, together with the publications from the Food and Drug Administration 11 and the regulatory authority in the Netherlands 10 on generic drugs, strongly suggests that there was no clinically relevant difference in exposure to gabapentin among the different formulations. Third, our findings cannot be simply extrapolated to other therapeutic agents because gabapentin is considered to have relatively simple pharmacokinetic properties, i.e., high solubility, active transport through cells, and renal excretion.…”

“…For instance, if the within‐subject variability in drug plasma levels is high, switching to another formulation (innovator or generic), which is usually accompanied by fluctuations in drug plasma levels, may lead to great variations in plasma levels and hence changes in efficacy and safety outcomes. Second, we did not address other factors that may determine effectiveness in clinical practice, such as adherence, which may be particularly relevant in patients with psychiatric disorders 6 , 10 , 21 , 22 . It is possible that distrust of generic drugs makes adherence a problem, which means that it may not be possible to predict equivalence in clinical outcomes on the basis of equivalent pharmacokinetics alone when switching from an innovator to a generic drug.…”

“…Patients and prescribers are often reluctant to switch from innovator to generic drugs or from generic to generic drugs 5 , 6 , 7 , 8 , 9 . From the regulatory authorities’ perspective, the bioequivalence requirements are strict so that generic drugs can be considered therapeutically equivalent to the branded drug 10 , 11 . In an evaluation of registered generic drugs, the US Food and Drug Administration reviewed 2,070 bioequivalence studies from 1996 to 2007 and found the average difference in the area under the plasma drug concentration–time curve (AUC) between generic and innovator drugs to be <5% 11 .…”

“…The Food and Drug Administration and the European Medicines Agency have been questioned about their guidances for generic medicinal products 12 , 13 because according to these guidances, generic drugs are only compared with innovator drugs in single‐dose bioequivalence studies applying the 80–125% criterion and not with other registered generic versions. Almost none of the publications reporting problems in generic drug substitution provide data on actual drug exposure, which makes it difficult to ascertain whether these and other concerns about the presumed higher risk of treatment failure with generic products are valid 4 , 6 , 10 , 14 , 15 . Theoretically, there may be so‐called “drift” when one generic drug is exchanged for another 1 , 16 such that although both generic drugs show bioequivalence with the innovator drug, they do not necessarily show bioequivalence with each other (the 90% confidence interval (CI) for this comparison may not meet the 80–125% criterion).…”

Methods, strengths, weaknesses, and limitations of bioequivalence tests with special regard to immunosuppressive drugs

“…There is no requirement to demonstrate bioequivalence with the other generic formulations, and all generics are considered interchangeable. It is argued that although the generic formulations have not been directly compared in a formal bioequivalence study, it would be unlikely that they would fail if directly compared . This is a shortcoming of the registration process.…”