Definition and Compliance for Combination Products
Combination products are medical devices that combine a drug, biological product, or device with another type of therapeutic agent to provide a single product that can be used to treat a disease or condition. The FDA defines combination products as products composed of two or more regulated components... such as drugs, devices, and/or biological products, including but not limited to:
Drugs and devices
Devices and biological products
Biological products and devices
Drugs, devices, and biological products
The complexity of combination products requires manufacturers to comply with multiple regulatory requirements, including those from the FDAs Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), and Center for Devices and Radiological Health (CDRH).
Regulatory Framework
To ensure compliance with regulations governing combination products, manufacturers must navigate a complex regulatory landscape. The FDAs framework for regulating combination products is outlined in the following categories:
Classification: Combination products are classified as either Class I, II, or III devices, depending on their intended use and level of risk.
Pre-market Approval (PMA): Devices with an implanted radioactive material, drug-eluting stents, and other high-risk combination products require a PMA from the FDA.
510(k) Clearance: Moderate-to-low-risk combination products can be cleared through the 510(k) process.
Manufacturers must also comply with relevant sections of the Federal Food, Drug, and Cosmetic Act (FDC Act), including:
Section 351(a): Biological products
Section 360(b): Devices
Section 505(j): Generic drugs
Device-Biological Product Combinations
Device-biological product combinations present unique regulatory challenges due to the overlap between device and biological product regulations. Manufacturers of these combination products must consider the following factors:
Biological component: Manufacturers must ensure compliance with CBERs regulations governing biological products, including licensure under Section 351(a) of the FDC Act.
Device component: Manufacturers must also comply with CDRHs regulations governing devices, including classification and clearance under Section 510(k) or PMA.
Key considerations for device-biological product combinations include:
Labeling: Clear labeling is essential to ensure safe use of the combination product. Labeling should address both the biological and device components.
Investigational New Drug (IND) Application: Manufacturers may need to submit an IND application if the biological component requires clinical trials.
Device-Drug Combinations
Device-drug combinations pose similar challenges due to the overlap between device and drug regulations. Manufacturers of these combination products must consider:
Drug component: Manufacturers must ensure compliance with CDERs regulations governing drugs, including licensure under Section 505(b) of the FDC Act.
Device component: Manufacturers must also comply with CDRHs regulations governing devices, including classification and clearance under Section 510(k) or PMA.
Key considerations for device-drug combinations include:
Labeling: Clear labeling is essential to ensure safe use of the combination product. Labeling should address both the drug and device components.
NDA (New Drug Application): Manufacturers may need to submit a NDA if the drug component requires clinical trials.
Examples of Combination Products
Examples of combination products include:
Insulin pumps: These devices deliver insulin in conjunction with the bodys natural insulin response. Insulin pumps are classified as Class II devices and require 510(k) clearance.
Stents: These small, wire mesh tubes expand to hold open narrow or blocked arteries. Some stents release medications to prevent clotting. Stents are classified as Class III devices and often require PMA.
QA Section
Q: What is the primary difference between a combination product and a device?
A: A combination product combines a drug, biological product, or device with another type of therapeutic agent to provide a single product that can be used to treat a disease or condition. A device, on the other hand, is a standalone medical device that does not contain a drug or biological product.
Q: What are the different types of regulatory categories for combination products?
A: Combination products can be classified as either Class I, II, or III devices, depending on their intended use and level of risk. They may also be regulated under Section 351(a) of the FDC Act for biological products or Section 360(b) of the FDC Act for devices.
Q: What is the role of the FDA in regulating combination products?
A: The FDA regulates combination products through its Centers, including CDER, CBER, and CDRH. Each Center has different areas of responsibility, with CDER focusing on drugs, CBER focusing on biological products, and CDRH focusing on devices.
Q: What is the difference between a PMA and 510(k) clearance?
A: A PMA (Pre-Market Approval) is required for high-risk combination products that require detailed scientific evidence of safety and effectiveness. 510(k) clearance, on the other hand, is granted to moderate-to-low-risk combination products after comparison with existing approved devices.
Q: What is an IND Application?
A: An IND Application is a document submitted by manufacturers for investigational new drugs, including biological products and device-biological product combinations that require clinical trials.
Q: Can I submit one application for both the device and drug components of a combination product?
A: In most cases, no. Combination products are subject to multiple regulatory requirements, each with its own set of rules and regulations. Manufacturers must submit separate applications or notifications to CBER, CDER, and/or CDRH.
Q: How do I determine the appropriate regulatory category for my combination product?
A: To determine the correct regulatory category for your combination product, you should consult with the FDAs guidance documents and Center-specific resources. You may also want to consider consulting with a regulatory expert or law firm experienced in combination products.
Q: What is labeling for combination products?
A: Clear labeling is essential for safe use of combination products. Labeling should address both the biological and device components, providing clear instructions on use, dosing, and potential side effects.
Q: Do I need to submit a NDA or PMA application for my combination product?
A: The type of application required will depend on the specific requirements for your combination product. If you have any questions about which application is necessary, consult with the FDAs guidance documents and Center-specific resources.
Q: What are some common mistakes that manufacturers make when developing combination products?
A: Some common mistakes include:
Insufficient labeling: Failure to provide clear instructions on use, dosing, and potential side effects can lead to adverse events.
Inadequate preclinical or clinical testing: Insufficient data can result in delayed approvals or even withdrawal of the product from the market.
Failing to address regulatory overlap: Combination products often require compliance with multiple regulations. Manufacturers must ensure they are meeting all relevant requirements.
This article provides a general overview of combination products, including their definition, regulatory framework, and key considerations for device-biological product and device-drug combinations. By understanding these factors and staying informed about the latest developments in regulatory guidance, manufacturers can better navigate the complex landscape of combination products and bring safe, effective therapies to market.
