Early Development Considerations for Combination Products
This guidance provides recommendations for the development of innovative combination products that combine devices, drugs, and/or biological products. It focuses on early development considerations and aims to provide context for initial discussions on the scientific and technical information needed for investigational or marketing applications. The guidance applies to combination products as defined under 21 CFR 3.2(e) and may also be useful for co-development of devices, drugs, and biological products used together but not meeting the regulatory definition of a combination product.
What You Need to Know? 👇
What is the FDA definition of a combination product?
A combination product is any combination of a drug and device, biological product and device, drug and biological product, or drug, device, and biological product. This includes products physically combined, separately packaged together, or requiring each other for intended use.
How does FDA determine which center reviews a combination product?
FDA assigns combination products to a lead center (CBER, CDER, or CDRH) based on the Primary Mode of Action (PMOA) - the single mode that provides the most important therapeutic action of the combination product.
What additional studies are needed when combining already-approved constituents?
Even with approved constituents, new studies may be required to address drug-device interactions, changes in formulation, new routes of administration, different exposure profiles, or novel indications not covered by existing approvals.
When should developers engage with FDA during combination product development?
FDA strongly encourages early communication through pre-IND/pre-IDE meetings. Early dialogue helps identify critical development issues, ensures efficient review processes, and allows FDA to establish appropriate intercenter review teams.
What manufacturing considerations are unique to combination products?
Developers must consider how manufacturing affects constituent interactions, stability of the combined product, sterilization compatibility, aseptic techniques, and potential changes during development that could impact safety or effectiveness.
Can combination product developers reference existing FDA submissions?
Yes, developers can use letters of authorized cross-reference to access information from existing applications or master files, allowing consideration of confidential data while maintaining intellectual property protection.
What You Need to Do 👇
Recommended Actions
- Engage in early communication with FDA review components and Office of Combination Products
- Consider what existing information is available for constituent parts to avoid duplication
- Evaluate potential interactions between constituent parts and need for new testing methodologies
- Develop appropriate preclinical testing plan considering both constituents and combination product
- Plan human factors evaluations early in development process
- Consider manufacturing and quality management aspects throughout development
- Establish arrangements with constituent part manufacturers regarding manufacturing changes
- Request participation from relevant review components from both lead and consulting Centers in development meetings
- Maintain awareness of applicable guidance documents and regulatory requirements
- Document scientific rationale for development approach and testing strategies
Key Considerations
Clinical testing
- Clinical investigation typically requires one investigational application (IND or IDE) for the combination product as a whole
- Consider trial design, sample size, statistical methods, clinical endpoints, number of studies needed
- Human factors evaluation may be needed to assess device usability under realistic conditions
- Early consideration of human factors to identify design features needing modification
Non-clinical testing
- Consider what preclinical testing is needed for device constituent alone vs combination product
- Evaluate potential interactions between device and drug/biologic constituents
- May need to adapt existing test methods or develop new methodologies
- Consider pharmacology and toxicology studies to establish safety profile
Human Factors
- Evaluate how users operate the system under realistic, stressful conditions
- Assess components, controls, displays, software, logic of operation, labels, instructions
- Analyze critical tasks, use error hazards and risks
- Conduct evaluations early in development process
Biocompatibility
- New biocompatibility studies may be needed for new uses/placement of device materials
- Consider local tissue response and long-term effects
Safety
- Evaluate changes in safety profile with new routes of administration or exposure
- Consider need for special safety studies in certain populations
- Assess local and systemic toxicity
- Monitor safety aspects unique to the combination product
Other considerations
- Manufacturing methods and quality management are important
- Consider stability of combination product vs individual constituents
- Early consideration of anticipated post-market manufacturing changes
- May need to develop new manufacturing techniques and testing methods
- Consider arrangements with manufacturers of constituent parts to maintain awareness of changes
Relevant Guidances 🔗
- Human Factors Studies and Related Analyses for Combination Products
- Current Good Manufacturing Practice Requirements for Combination Products
- Premarket Review Pathways for Combination Products
- Postmarketing Safety Reporting Requirements for Combination Products
- Obtaining FDA Feedback for Combination Products: Best Practices and Meeting Procedures
- Dispute Resolution Process for Combination Product Review Timelines
- User Fees for Combination Products and Associated Waivers
- Compliance Policy for Combination Product Postmarketing Safety Reporting Requirements
Related references and norms 📂
- 21 CFR 3.2(e): Definition of combination products
- 21 CFR 314.420: Drug master files
- 21 CFR Part 4: Current Good Manufacturing Practice Requirements for Combination Products