Post

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.

  1. Engage in early communication with FDA review components and Office of Combination Products
  2. Consider what existing information is available for constituent parts to avoid duplication
  3. Evaluate potential interactions between constituent parts and need for new testing methodologies
  4. Develop appropriate preclinical testing plan considering both constituents and combination product
  5. Plan human factors evaluations early in development process
  6. Consider manufacturing and quality management aspects throughout development
  7. Establish arrangements with constituent part manufacturers regarding manufacturing changes
  8. Request participation from relevant review components from both lead and consulting Centers in development meetings
  9. Maintain awareness of applicable guidance documents and regulatory requirements
  10. 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

  • 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

Original guidance

  • Early Development Considerations for Combination Products
  • HTML / PDF
  • Issue date: 2006-09-01
  • Last changed date: 2021-05-13
  • Status: FINAL
  • Official FDA topics: Medical Devices, Combination Products, Drugs, Biologics
  • ReguVirta summary file ID: 08b814fcc6669b8e4a3d5616ef494a9a
This post is licensed under CC BY 4.0 by the author.