The European Medicines Agency (EMA) released on 4th April 2017 a consultation paper on the requirements to enable waivers to be granted for clinical trials to demonstrate therapeutic equivalence for locally applied, locally acting gastrointestinal products to be registered as either a generic/hybrid product under Article 10 or as a reformulation of an existing product.
This consultation paper discusses the choice and design of both PK bioequivalence studies and in vitro equivalence tests for immediate release and modified release chemical entities. Biologics are excluded from the scope.
A current guideline (CPMP/EWP/239/95) already exists which covers the requirements for known active substances in this context, and it is that guideline which lays out the principle that although clinical trials are generally required, there may be other models that can be used or developed for the purposes of showing therapeutic equivalence. Indeed, as also mentioned by the FDA in their note for industry on Locally-Acting Gastrointestinal Drugs, in many cases clinical studies are not only insensitive to detect differences between two products that are locally acting but also require high numbers of patients and are prohibitively expensive to run. It is known that in vitro and in vivo methods may be more sensitive than clinical or pharmacodynamics endpoints usually seen in clinical studies to differences between two products. This draft guideline takes into account the generally accepted principle that a similar drug release profile and bioavailability in themselves are able to demonstrate a similar effect of the drug where a product is both locally applied and acts locally.
The drugs covered by this guideline are classified into site of action, mechanism of action, biopharmaceutical and PK properties, and pharmaceutical form. It covers those that act locally in the GI system i.e. in the mouth, throat, stomach or intestine; various mechanisms of action including antacids, those that bind to receptors in the intestinal wall and endogenous compounds such as pancreatin; absorbable and non-absorbable drugs and liquid and solid oral dosage forms. Suppositories and enemas are also included.
The draft guideline lays out a hierarchy which should be considered by companies when establishing what data will be sufficient depending upon the complexity of the reference product. All choices of approach must be justified and validated in the presented dossier:
Furthermore, in Section 4.3.1 to 4.3.4, the guideline lays out in vitro models that can be considered in order to generate the required evidence for certain products that act locally in the mouth and/or throat, in the stomach, in the intestine and in the rectum. Finally, the considerations for showing equivalence between other strengths of the test product and the reference product are discussed.
The consultation paper should be read in conjunction with the existing guideline on bioequivalence and the guideline on pharmacokinetic and clinical evaluation of modified release dosage forms. The consultation is open until 30th September 2017 and submission of comments can be made to the following email address: firstname.lastname@example.org
To access the consultation paper, click here.