Bioequivalence

Bioequivalence is the demonstration that two medicinal products containing the same active substance, administered at the same molar dose, have a bioavailability, that is to say a rate and extent of absorption, close enough for their effects to be essentially the same. It is the central condition in the definition of a generic medicinal product laid down by Directive 2001/83/EC and by Article L. 5121-1 of the French Public Health Code. It relieves the generic of the need to repeat clinical efficacy and safety trials.

Demonstrating bioequivalence

The demonstration generally rests on a pharmacokinetic study in healthy volunteers comparing the generic with the reference medicinal product. Under the European Medicines Agency’s guidelines, the 90% confidence interval for the ratio of the means of the area under the curve and of the maximum concentration should in principle lie between 80.00% and 125.00%. This interval is narrowed for substances with a narrow therapeutic index and may be widened, for the maximum concentration, where the substance is highly variable. Certain forms and certain highly soluble substances may qualify for a waiver of in vivo studies based on the Biopharmaceutics Classification System.

Bioequivalence and the composition of the generic

Bioequivalence does not require an identical formula. The generic must have the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference, but it may use different excipients. Salts, esters, ethers, isomers and derivatives of the same active substance are regarded as the same substance unless they differ significantly in safety or efficacy, and immediate-release oral forms are regarded as the same form. Where bioequivalence cannot be established, the applicant switches to the hybrid procedure and provides additional data.

Bioequivalence in patent litigation

Bioequivalence studies fall within the scope of the Bolar exemption and may be carried out during the term of the patent without constituting infringement. They are, however, a valuable source of evidence. Where the patent claims a formulation, a release profile or a pharmacokinetic parameter, the generic’s bioequivalence dossier and summary of product characteristics shed light on whether the claimed features are reproduced, and a saisie-contrefaçon often makes it possible to obtain a copy. Conversely, a generic manufacturer that has opted for a different formula argues that equivalence of effects is not enough to establish infringement of a formulation claim.

Key points

Bioequivalence guarantees the therapeutic equivalence of the generic without requiring its formula to be identical. Patent holders should analyse the competitor’s bioequivalence dossier as early as possible, as it sheds light on infringement of formulation or pharmacokinetic profile claims. For the generic manufacturer, the choice of different excipients and a different process should be documented before the application is filed, in order to prepare the non-infringement case.

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This glossary entry is general in scope and does not constitute legal advice.

Dhenne Avocats acts in pharmaceutical patent disputes and on the medicines regulatory questions that accompany them, from the marketing authorisation to the supplementary protection certificate.

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