title: Quantitative assessment of the switchability of generic products.
abstract: Generics are usually considered to exhibit comparable in vivo properties in terms of efficacy and safety and for this reason are intended to be interchangeable with the reference product. The aim of this study is to provide a quantitative picture of the switchability problem between two generics and to introduce the concept of conditional probability of bioequivalence (BE) acceptance. Monte Carlo simulations were performed to examine all possible relationships between the tested products. Four types of percent BE acceptances are defined and evaluated: (a) %BA1, when generic T₁ is compared to the R product, (b) %BA2, in cases of comparison of generic T₂ with the R product, (c) %BA21, when generic T₂ is compared to another generic T₁, and finally (d) %BA21C which is the conditional probability of percent bioequivalence acceptance of generic T₂versus another generic T₁ given that both T₁ and T₂ are declared bioequivalent to the same R formulation. The simulations were expanded to study concomitantly the performance of T₁ and T₂ when compared to the same R formulation. In each case, the 2 × 2 cross-over design was used and evaluation of BE was based on the classic BE limits (0.80-1.25) and the stricter BE limits (0.90-1.11) for narrow therapeutic index (NTI) drugs. A number of 24 and 48 subjects were assumed to participate in the simulated trials, while the coefficient of variation for the within-subject variability (CVw) was 20% and 40%. A number 40,000 BE trials were simulated under each condition. The T₁/R and T₂/R ratios ranged from 0.80 to 1.25 using a step of 0.05. Even though two generics (T₁ and T₂) can be declared bioequivalent to the same R product, this does not ensure that they are always mutually bioequivalent. On the contrary, two generic products which differ substantially from the R product can still have a high probability to be truly interchangeable. The two generics (T₁ and T₂) can be switched from one to another when the T₁/R and T₂/R ratios are close to the same value, the CVw of the drug is low, and each BE study of T₁-R and T₂-R was conducted using a relatively large number of subjects. In the same context, two generic NTI drugs which differ more than 10% from the R product can still be declared bioequivalent to one another depending on the relative T₁/R and T₂/R ratios. Switchability between generics assessed at the 0.90-1.11 interval is safer, but not always ensured.
authors: Laboratory of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, National and Kapodistrian University of Athens, 15771 Athens, Greece. Electronic address: vkaralis@pharm.uoa.gr.
authors: Vangelis
authors: V
authors: Karalis
authors: Meir
authors: M
authors: Bialer
authors: Panos
authors: P
authors: Macheras
mesh_terms: D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D016568:Drugs, Generic / Q000493:pharmacokinetics*; D006801:Humans; D009010:Monte Carlo Method; D013810:Therapeutic Equivalency
chemical_list: D016568:Drugs, Generic
keywords: BA1 (%); BA2 (%); BA21 (%); BA21C (%); BE; Bioequivalence; CI; CVw; Conditional probability; GMR; Generics; N; NTI; Narrow therapeutic index drugs; Pharmacokinetic simulations; R; Switchability; T; T(1); T(2); acceptance limit of bioequivalence imposed by the regulatory authorities; bioequivalence; coefficient of variation of the within-subject variability; confidence interval; generic assessed after the approval of the first generic; generic first approved; geometric mean ratio of the bioequivalence metric for the two products (T over R); narrow therapeutic index drug; percent bioequivalence acceptance of generic T(1) when compared to the reference product; percent bioequivalence acceptance of generic T(2) when compared to the reference product; percent bioequivalence acceptance of generic T(2)versus another generic T(1); percent bioequivalence acceptance of generic T(2)versus another generic T(1) given that both T(1) and T(2) are declared bioequivalent to the same reference formulation; reference product; sample size; test product (generic); θ