Chapter 27: Evolving Regulatory Landscape for Combination Products: US Perspective

This chapter tracks the relatively short, but fairly robust, history of combination product regulation in the USA. It starts with an overview of the legislation, regulations, and key policy events that have shaped the regulatory environment for combination products since the 1970s, when these products first started coming on the scene. It covers events such as the enactment of the Safe Medical Devices Act in 1990, which expressly recognized the existence of combination products and created an avenue for FDA to develop a framework for assigning these products for regulatory review, as well as the creation of the Office of Combination Products in 2002. Additionally, the chapter outlines the Agency’s combination product initiatives leading up to the enactment of the 21st Century Cures Act (“Cures Act”) in 2016, an overview of the impact of the Cures Act on combination products and a summary of the Agency activities that have occurred following the enactment of the Cures Act. The middle portion of the chapter provides an overview of the increasing technical and regulatory expectations for combination products. This includes an in-depth discussion of 21 CFR 4 and how these requirements affect product development. Additionally, this portion of the chapter focuses on the technical considerations relating to container closure systems, injection products, inhalation products, human factors, and bridging. The final portion of the chapter provides regulatory submission and life cycle management considerations, including eCTD structure, use of master files, postapproval changes, and postmarket safety reporting. The chapter concludes with perspectives for the future of combination product regulation in the USA.