Regulatory Affairs for Combination Products

In the US, under the 510k process, it can be fairly straightforward on the submission side if you have a predicate that utilizes the same drug product at the same level. Adding an established drug that hasn’t been used in a device complicates the situation tremendously. It most likely will raise new questions of safety and performance leading to a de novo or PMA pathway. Adding a new chemical entity that functions as a drug will bring a consult from CDER on your device submission and all the testing to support the product just like a New Drug Application (NDA). In EU, the answer is that if the drug is ancillary to the device, you will leap all the way to a Class III device under Rule 14 and the drug substance dossier will be reviewed in addition to your full technical documentation package at the NB. Entering into the combination product world also means you will have to follow additional quality system regulations including 21 CFR 4 in the US.

While some combination products can rely on a single application to gain regulatory approval, the simple answer is this – it depends! There are two main factors that impact this decision:

1. The intended market – US and EU have key differences.
2. The type of combination product – there are regulatory differences for single-entity/integral products, co-packaged products, or cross-labeled products

In the US, combination products that are single-entity or co-packaged products are assigned to a single FDA Center that will have primary jurisdiction for its premarket review and regulation based on the most important therapeutic action. Typically, only a single marketing application is necessary for these types of combination products although inter-agency consults may be utilized during the review of the application. In an example where the most important therapeutic action is the drug, then the product will require a drug application and will be regulated by CDER. During the drug application review, a consult with CDRH may be requested for the device constituent of the product. Conversely, if the most important therapeutic action is the device, then the product will require a device submission to CDRH and may include a CDER consult during the review. Products where the drug and the device constituents would be sold separately and labeled to be used together are considered cross-labeled combination products. For these products, each constituent would typically be regulated separately, and each product would require their own marketing applications to the appropriate FDA Centers.

In the EU, Article 117 of the new EU MDR introduced new requirements for drugs with an integral medical device, which are equivalent to single-entity products in the US. Since 2021 the drug application will need to include a CE certificate for the device or include an opinion from a notified body on the conformity of the device if it is not CE marked. The notified body opinion could be obtained during the drug review if it is not separately CE Marked. Devices with an integral medicinal product are automatically classified as Class III medical devices and may require a drug review to achieve CE marking. Co-packaged products are treated differently in the EU and would typically require separate device and drug applications. Cross-labeled products align with the US in that CE marking is required separately from the drug application for these product types.

The Pre-RFD process is used to get informal and non-binding feedback from the FDA about your combination product, whereas the RFD process provides binding feedback through a formal process. The Pre-RFD is helpful early in the product development stages where you may want to understand how the agency is likely to designate the lead center for reviewing your combination product - CDER, CBER, or CDRH. The pre-RFD process provides a flexible and approachable way to obtain informal feedback from the Agency about the type of marketing application and the lead FDA Center that is most likely to be assigned for review and regulation of the product. If you are in later stages of development and the device does not have a clear primary mode of action, then the formal RFD process provides a binding decision to assign the lead center for review. This process can be used to avoid rejection or delays in a marketing application if the classification or assignment is determined to be unclear or in dispute during the review process. It is important to note that a Pre-RFD or an RFD are not always required for a product. If the product is very similar to an existing product, then it is possible to rely on capsular decisions that are posted on the FDA website to understand how similar products have been assigned.

Yes, your drug quality system will need be adjusted to comply with additional device quality system requirements under 21 CFR 820 for management responsibility, design controls, purchasing controls, corrective and preventive action, installation, and servicing. While many of these elements may be covered in Pharmaceutical Quality Systems, design controls is one element that typically poses the most significant challenge for drug manufacturers. Design controls are a systematic process to ensure the product design meets the user needs, the intended uses, and any specific regulatory requirements. The design process culminates in a design history file, or a DHF, that is maintained over the product lifecycle. Drug manufacturers often need to adjust their quality systems to meet these requirements and also perform DHF remediation to ensure that changes in the product are appropriately documented over the lifecycle.