Abstract
An unprecedented evolution in the development of novel technologies and therapies to treat human disease processes has occurred within the past 50 years. Initially, these strategies focused on identifying and developing small molecules or proteins (biologics) that were effective as curative or palliative pharmacologic monotherapies. Medical devices were designed and developed to provide physical, nonpharmacologic approaches to treating unmet medical needs. More recently, novel therapies that cross-engineer the therapeutic effectiveness of each of these treatment approaches into combination products have laid the foundation for another successful branch in the evolution of modern medicine.
As defined by the US Food and Drug Administration (FDA), a combination product is “a product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity.” The FDA has stated that it expects to receive increasingly large numbers of combination products for review as innovative technologies merge product types and blur the traditional lines of separation between FDA’s medical product centers, CDER (Center for Drug Evaluation and Research), CBER (Center for Biologics Evaluation and Research), and CDRH (Center for Devices and Radiologic Health). 1
Indeed, data provided by the FDA indicate that the number of combination products submitted for review in fiscal year (FY) 2007 increased significantly, reaching a 5-year high. After decreasing by 14% from FY 2005 to FY 2006, the number of combination products submitted for review increased by 42% from FY 2006 (n = 235) to FY 2007 (n = 333). All 3 FDA centers received increased applications for the review of combination products. 2
Combination products present a significant challenge to modern regulatory affairs professionals and the companies or governmental agencies they represent. Individual components of a combination product can significantly affect the regulatory processes associated with all aspects of the combination product life cycle, including requirements for preclinical testing, clinical investigation, marketing applications, manufacturing and quality control, adverse event reporting, promotion and advertising, and postapproval modifications. Additionally, combination products are often designed using state-of-the-art, innovative bioengineering and pharmacologic technologies that challenge the scientific knowledge and established regulatory paradigms of all parties involved in the product approval process. Finally, FDA statutory requirements and regulatory guidance documents essential to successful combination product approval are often written within the perspective of the individual review divisions of FDA (CDER, CBER, CDRH) and generally do not discuss an integrative approach to development of combination products. These factors combine to present significant challenges to the regulatory professional providing leadership in the processes leading to the successful approval of combination products for treating important human diseases.
Development and Approval of Combination Products: A Regulatory Perspective is a well-written, authoritative book that constitutes an important resource for regulatory professionals working with combination products. The authors provide an up-to-date and comprehensive compendium of drug/device, biologic/device, drug/drug, and biologic/biologic product development within the current FDA environment. Each chapter in the book goes beyond a simple regurgitation of FDA statutory requirements or guidance documents and provides readers with an insightful, integrative, and strategic discussion of successful combination product development regulatory strategies.
Topics covered in this book include modern regulatory strategies and combination product development; integrated approaches to chemistry manufacturing and control; design and importance of nonclinical studies, particularly as they relate to the complexities of combination products; and clinical development strategies. Individual chapters discuss the strategies and challenges associated with the development of specific, approved combination products. Each chapter is well written and logically designed and contains useful tables that effectively summarize the key points.
Chapter 1, written by Dr Siegel, provides a succinct, informative strategic overview that lays the foundation for the proceeding chapters, written by James Barquest, PhD, Chaline Brown, PharmD, Partick L. Devillier, MS, and Duane B. Lakings, PhD.
Chapter 2 provides a detailed overview of the regulatory approaches and processes inherent in the approval processes of combination products. This well-written and authoritative chapter is useful as a reference and strategic resource for regulatory professionals.
Chapter 3 details nonclinical recommendations for the characterization and development of combination products. Product design, safety considerations, and the specific disease process being targeted are usually the key considerations in the design of the nonclinical program needed to support approval of a combination product. Dr Lakings provides an informative, albeit generic discussion on nonclinical strategies for combination product development that I found to be useful and informative.
Chapter 4 provides an excellent overview of the clinical pharmacology and clinical development tenets important in combination product development. This well-written chapter is seeded with relevant case studies on approved products that successfully reinforce key suggestions and recommendations.
Chapter 5 covers the chemistry, manufacturing, and controls (CMC) of combination products. This chapter is limited in scope and could have benefited significantly from discussions of CMC issues associated with approved products and the strategies that were developed to address the uncertainties and risks. CMC issues associated with drug/device, biologic/device, drug/biologic, or drug/device/biologic are generally complex and require a great deal of technical expertise and integrative regulatory approaches. A more detailed discussion of these complexities and how to approach them would have made this chapter extremely powerful and important. Nonetheless, this chapter provides an excellent and useful listing of pertinent guidance documents that can be used by sponsors to develop and refine their CMC strategies for combination products.
Development and Approval of Combination Products: A Regulatory Perspective is a well-written resource that should be in the library of all regulatory professionals working with combination products.