The Wider Use of Fixed-Dose Combinations Emphasizes the Need for a Global Approach to Regulatory Guideline Development

Abstract

A fixed-dose combination (FDC) is a drug product in which two or more separate drug components (active pharmaceutical ingredients) are combined in a single-dosage form. Interest in developing FDCs is increasing in a range of diseases. This project investigated the regulatory environment for FDCs in the EU and US. A review of the FDC guidelines set forth by the EMA, FDA, and ICH, followed by interviews of key informants in industry, identified 5 main industry concerns related to development of FDCs. These concerns were presented to key informants from both the EU and US regulatory authorities. It was clear from the results that the current regulatory environment for FDCs lacks consistency. This may create a barrier to innovation moving from the laboratory to the clinic, as companies cannot clearly see the development path requirements. This project also highlighted certain challenges that currently face the regulatory world: how to improve the role of regulatory science and provide clear quantification in assessment decisions; the role of guidelines and their impact on innovation; and, most important, the question of globalization and how to move toward a more harmonized regulatory system.

Analysis of Fixed-Dose Combination Products Approved by the US Food and Drug Administration, 2010–2015: Implications for Designing a Regulatory Shortcut to New Drug Application

“…6 However, it was found that there are several gaps and a lack of harmonization of FDC regulations between the US Food and Drug Administration (FDA) and the EMA. 7 In the US, a fixed-dose combination drug is defined as “a drug product in which two or more separate drug components are combined in a single dosage form,” which is similar to the EMA’s definition, but the definition of a second term, the combination product , is a distinct and unique concept of the US FDA, and it is defined as a product composed of two or more components (ie, drug/device, biologic/device, drug/biologic, or drug/device/biologic). 7 –9 In the US, there are some regulations concerning the development of FDCs, but specific guidance that directs the required clinical programs of the FDCs is not currently available.…”

“…7 In the US, a fixed-dose combination drug is defined as “a drug product in which two or more separate drug components are combined in a single dosage form,” which is similar to the EMA’s definition, but the definition of a second term, the combination product , is a distinct and unique concept of the US FDA, and it is defined as a product composed of two or more components (ie, drug/device, biologic/device, drug/biologic, or drug/device/biologic). 7 –9 In the US, there are some regulations concerning the development of FDCs, but specific guidance that directs the required clinical programs of the FDCs is not currently available. 8,10 –12 Therefore, if a pharmaceutical company wishes to develop a unique FDC product for the US market, the company should also refer to applicable precedent cases and other health agencies’ regulations to prepare the clinical studies.…”

An Analysis of the Fixed-Dose Combinations Authorized by the European Union, 2009–2014: A Focus on Benefit-Risk and Clinical Development Conditions

“…In particular, the EMA guidelines are written and directed for combinations of 2 or more drugs that are already approved for the indication of the FDC or where 1 substance is a new active substance. 14 Yet, the FDA also focuses on combinations containing devices. 14 This article focuses on only the perspective from EMA, although for future studies, it may be of interest to analyze the FDCs being authorized by the FDA.…”

“…14 Yet, the FDA also focuses on combinations containing devices. 14 This article focuses on only the perspective from EMA, although for future studies, it may be of interest to analyze the FDCs being authorized by the FDA. Gautam et al 14 surveyed European regulators concerning EMA and FDC guidelines.…”

“…14 This article focuses on only the perspective from EMA, although for future studies, it may be of interest to analyze the FDCs being authorized by the FDA. Gautam et al 14 surveyed European regulators concerning EMA and FDC guidelines. They concluded that there is an importance in developing ICH definitions, obtaining clearer information regarding the importance of the various justifications used in the authorizations and rejections of FDCs, as well as acquiring more information on FDCs in more disease areas.…”