Europe – Guideline on equivalence studies for the demonstration of therapeutic equivalence for locally applied, locally acting products in the gastrointestinal tract

This guideline refers to medicinal products that are applied locally and intended to exert their effect locally at specific sites(s) in the gastrointestinal (GI) tract. The assumption is that systemic action, if any, would be considered as an undesired effect.
The ‘Note for guidance on the clinical requirements for locally applied, locally acting products containing known constituents (CPMP/EWP/239/95)’ provides general recommendations on the clinical requirements for medicinal products with known active substances. According to this guideline, in order to demonstrate therapeutic equivalence, clinical trials are in principle considered necessary, but other models may be used or developed. Depending on the situation, human pharmacodynamic (PD) studies,
local availability studies or, where appropriate, even animal or in vitro studies may be considered, provided that the respective methods/models are adequately qualified.
During recent years the assessment of locally applied and locally acting products has evolved. It has been shown that alternative models (including in vitro and in vivo methods) may have a higher sensitivity than traditional clinical and PD endpoints to detect possible differences between medicinal products containing the same active substances. Also, based on the experience with some of these alternative models, either individually or in combination, it is possible to compare, directly or indirectly, concentrations at the specific sites of action. Therefore, therapeutic equivalence of locally applied, locally acting GI products could be demonstrated using these alternative models, provided they have
been proven to be able to accurately reflect in vivo drug release and availability at the sites of action.
Furthermore, it has been recognised that the similarity of drug release and availability at the sites of action are the major factors determining similar clinical responses for locally applied, locally acting medicinal products containing the same active substance. Therefore, in those cases where the in vitro tests or pharmacokinetic (PK) studies reflect in vivo drug release and local availability at the sites of action, clinical trials could be waived…