FIX-DOSED COMBINATION: Global Development Strategy for Value Added Medicine

 The development of generic fixed-dose combination (FDC) has seized increasing industry interest due to its advantages in disease management, patient compliance, and market benefits. Adapting to the growth of novel and generic fixed-dose combination development, many regulatory authorities are providing regulated frameworks for these products. 

However, there are still gaps or controversies on the assessment method for these products. Assessing the bioequivalence of the combination of immediate-release (IR) and a modified-release (MR) formulated compounds (IR-MR combo) is one of the common challenges for the manufacturers.

Regulatory requirement – Advantage or Obstacle?

All three agencies outline requirements for modified-release drug products in addition to the general requirements of IR products, however, with different extensiveness. The FDA requires the fixed-dose combination and modified-release drug products to be similar to the standard IR products discussed in the BA/BE studies with PK endpoints. The EMA requires fixed-dose combination to prove the contribution of each active pharmaceutical ingredient (API) and the lack of drug-drug interaction.

 Studies required for modified-release also differ notably from IR (i.e., more studies are required). For the TPD, each API in the fixed-dose combination should be considered as a single entity, and there are only minor differences between the requirements for MR and IR. Presenting at the annual 2022 CRS conference in Montreal, the requirement of major agencies for both IR and MR formulations for comparative bioequivalence (BE) and bioavailability (BA) assessment was summarized.

Some researchers propose to follow stricter requirements among APIs for each API. An IR-MR combo can be considered as a modified-release formulation. Our approach, which we have confirmed is supported by most agencies, is to consider each API as a single entity. In most cases, a single-dose study on the most sensitive strength under the label-recommended condition should be performed.

IR-MR Combination 

For the IR-MR combo, there is leeway to interpret basic requirements as long as studies can characterize all APIs. In cases where multiple ascending dose studies are applicable, only the modified-release drug product is required to be assessed. Regardless of which guideline is being followed, clinical safety must be assessed for all APIs. To better demonstrating the concept, Table 1 is an example of the sitagliptin IR/ metformin modified-release combo required studies for three major agencies.

Table 1. Total bioequivalence and bioavailability studies required for Sitagliptin IR/Metformin MR combo following three agencies’ requirements 1–5

This strategic approach considering each API as a single entity in any fixed-dose combination, especially for the IR-MR combo, is consistent with the various agencies’ recommendations and provides a scientific and effective pathway for fixed-dose combination product development.

How BioPharma can help your next FDC submission?

BioPharma Services has diverse experience with novel and generic FDC products submitted to different regulatory such as FDA, EMA, TPD, GCC, TGA, ANVISA, NMPA, and more. Our Scientific group collaborating with other core teams in the Clinic and Bio-Laboratory can support you from the beginning of product development plan and study design, study conducting, bioanalysis, data analysis, until report writing.

Written by Sunny Le

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BioPharma Services, Inc., a Think Research Corporation and clinical trial services company, is a full-service Contract Clinical Research Organization (CRO) based in Toronto, Canada, specializing in Phase 1 clinical trials 1/2a and Bioequivalence clinical trials for international pharmaceutical companies worldwide. BioPharma has clinical facilities both in the USA and Canada with access to healthy volunteers and special populations.