By: Brandon D. Burch, M.S., Ph.D. Senior Manager, Scientific Writing & Regulatory Affairs
In a previous post, we discussed how combination products are defined in the Code of Federal Regulations, introduced FDA’s Office of Combination Products, and touched on a few unique aspects of how these products are regulated. In this post, we delve into some important points to consider when developing combination products.
Considerations by Component
A combination product is comprised of two or more regulated components of different classes (i.e., drug, biologic, device) that are intended for use together. It might seem elementary, but it is not enough to understand how the constituent parts work by themselves, even if each component has been well-characterized previously. Because it is the combined product for which approval is ultimately sought and because there may be unique issues that arise in the combined product that were not observed for the individual components, it is of the utmost importance for the sponsor to have a thorough understanding of how the components interact and how these interactions could impact the safety or effectiveness of the combination product.
For products containing device components, new engineering, functional testing or additional safety and biocompatibility studies may be needed to determine the suitability of the device design. This is especially critical if the environment or location in the body in which the combination product will be used differs from that of the standalone device. Device design may also impact the stability, efficacy, or safety profile of the companion drug or biologic. The sponsor should also be cognizant of any potential impurities (e.g., leachables, extractables, or manufacturing residues) arising from the device that could impact patient safety or the companion product, as well as any effect of the companion product on the integrity or functioning of the device. In some cases, human factors studies may be appropriate to evaluate the device user interface and to determine any device modifications that need to be implemented to prevent negative impacts on safety or efficacy. Such evaluations should be performed early in development and prior to key studies intended to establish the safety or efficacy of the combination product.
For drug and biologic components, while understanding the components in the context of the combination product is critical, it may also be necessary to gather data on these components individually, especially in the case of a new molecular entity (NME). If a drug or biologic component has already been approved as a standalone product, then it is important to consider any potential changes in established safety, effectiveness, or dosing requirements once in combination. New nonclinical and/or clinical studies may be necessary if there is a change in formulation, strength, route of administration, or delivery method, or if the dosage changes (i.e., dose, duration, or regimen), if there is a new target patient population, if there is a change in indication, or if there is an increase in exposure locally or systemically.
From a manufacturing standpoint, combination products can present unique challenges that necessitate new or modified manufacturing techniques, in-process testing, specifications, and additional characterization methods to assess changes in both the constituent parts and the combination product itself. Additional in vitro, nonclinical, and/or clinical bridging studies may be appropriate for some products. Also, because combination products often undergo manufacturing changes during product development and even post-approval, it is important to consider these as early as possible, communicate with FDA about them, and potentially prepare post-approval change protocols for further discussion with FDA.
Manufacturing requirements for combination products are covered in 21 CFR 4. For combination products in which the components are manufactured separately and not packaged together, Current Good Manufacturing Practice (CGMP) and Quality System (QS) regulations apply as they would for non-combination products. For single entity and co-packaged combination products, there are two options:
- Full Compliance Approach: Demonstrate compliance with all CGMP and QS regulations applicable to each constituent, or
- Streamlined Approach: Demonstrate compliance with either the drug/biologic CGMP (21 CFR 211) or the device QS regulations (21 CFR 820) rather than full compliance with both
Importantly, under the streamlined approach the sponsor is not required to choose the compliance pathway associated with the lead center for their product at FDA, although the lead center is still responsible for ensuring compliance and conducting preapproval inspections regardless of the pathway chosen. For example, even if the drug constituent provides the primary mode of action and the Center for Drug Evaluation and Research (CDER) conducts the inspection, the manufacturer still may choose to comply with device QS regulations rather than demonstrate full compliance with drug CGMP. That being said, the streamlined approach still requires demonstrated compliance with specified provisions from the other set of requirements, as detailed in 21 CFR 4.4(b). Also, if a biological constituent is included, then CGMP requirements for biological products (21 CFR 600-680) apply; likewise, if human cells, tissues, and cellular and tissue-based products (HCT/P) are included, then regulations in 21 CFR 1271 apply, including current good tissue practice (CGTP) and donor eligibility requirements.
Developing combination products presents many unique challenges that often go beyond those associated with traditional drug development. Because of these inherent complexities, FDA strongly encourages sponsors developing combination products to engage with FDA early in the development process. Doing so allows FDA to provide feedback on the nonclinical and clinical testing strategy, may help identify critical product development issues before they become costly in both time and money, and will help ensure an efficient development and approval process.