Combination products under US FDA regulations and comparison with European regulation

The global market for combination products (i.e., drug-eluting stents, transdermal patches, infusion pumps, inhalers) has been unstoppably growing over the last decade. This tendency is forecasted to keep boosting due to the increasing prevalence of chronic diseases, the rising number of the geriatric population and the improvement in the medical technology sector. However, the legislation around combination products substantially varies according to geography, which can hinder the way medical device manufacturers strategically prepare to market their products. Here in this article, we aim to support manufacturers in understanding the main regulatory aspects when placing combination products in the US and the European market while comparing both legislations.

Combination products in the US

Beginning with the FDA, this agency defines combination products as “therapeutic and diagnostic products that combine drugs, devices, and/or biological products” (21 CFR 3.2(e)). Importantly, the combination of medical devices only, or drugs only, are not considered combination products. Thus, the term combination product includes:

A product comprised of two or more regulated components that are physically, chemically, or otherwise combined or mixed and produced as a single entity;
Two or more separate products packaged together and comprised of drug and device products, device and biological products, or biological and drug products;
Any (investigational) drug, device, or biological product packaged separately that according to its investigational plan or proposed labelling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect;

*Combinations of medical devices only, or drugs only, are not considered combination products.

Types of combination products in the US

The FDA has categorized combination products into 9 different types:

Convenience Kit or Co-Package: Drugs and devices are provided as individual constituent parts within the same package.
Prefilled Drug Delivery Device/System: The drug is filled into or otherwise combined with the device, AND the device’s sole purpose is to deliver the drug.
Prefilled Biologic Delivery Device/System: The biological product is filled into or otherwise combined with the device, AND the device’s sole purpose is to deliver the biological product.
Device Coated/Impregnated/ Otherwise Combined with Drug: The device has an additional function in addition to delivering the drug.
Device Coated or Otherwise Combined with Biologic: The device has an additional function in addition to delivering the biological product.
Drug/Biologic Combination.
Separate Products Requiring Cross Labeling: Products not co-packaged but labelled to be used in combination.
Possible Combination Based on Cross Labeling of Separate Products: I,e., drug/biological product under development utilizes a device, but unclear whether the final product will require that the two be cross-labelled.
Other Type of Part 3 Combination Product (e.g., Drug/Device/ Biological Product): Combination product not otherwise described.

Common examples of combination products include a drug-eluting stent, monoclonal antibody combined with a therapeutic drug, drug or vaccine vial packaged with a delivery device, a single-dose prefilled syringe, a pen and injector, or an implant containing a medicinal product whose primary purpose is to release the medicinal product.

Regulatory framework for combination products in the US

Since combination products include components that follow different regulatory pathways, their regulatory roadmap may raise uncertainty. To provide clear guidelines on this process, the Office of Combination Products (OCP) develops FDA guidance for product classification and jurisdiction. The classification of a product determines the type of a product (drug, device, biological product, or combination product). In contrast, jurisdiction determines the FDA Center or Lead Center that will review the product: the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH). Additionally, these three FDA Centers also provide product-specific guidance.

These entities and all stakeholders shall comply with the combination product regulatory framework. The following documents lay down the requirements for combination products:

21 CFR 3.2(e) – Combination product definition
21 CFR Part 4 – Good manufacturing practices (2013) and postmarket safety reporting requirements (2016) for combination products
21 CFR 3.7 – Request For Designation (RFD) submissions
Final rule to define “mode of action” (MOA) and “primary mode of action” (PMOA) – new definitions
Proposed rule to amend regulations concerning the classification of products as biological products, devices, drugs, or combination products, and their assignment to Agency components for premarket review and regulation – Amendment to clarify jurisdiction scope (2018).

Furthermore, although not legally binding, several guidance documents have been developed to support manufacturers to comply with the abovementioned regulations. The latest guidance document, “Requesting FDA Feedback on Combination Products”, was released in December 2020 to discuss possibilities for manufacturers to obtain feedback from FDA on scientific and regulatory questions and to describe best practices for FDA and manufacturers when interacting on these topics.

Another draft guidance document describes the submission pathways for combination products (“Principles of Premarket Pathways for Combination Products”, February 2019). Currently, a single application is generally accepted, and the application type submitted should be chosen depending on the constituent part which provides the primary mode of action (e.g., a Premarket Approval Application (PMA), De Novo, or 510(k) for a device-led combination product, a New Drug Application (NDA) or Abbreviated New Drug Application (ANDA) for a drug led combination product or a Biologics License Applications (BLA) for a biologic-led combination product).

Finally, due to the relevance of safety surveillance and reporting, the “Postmarketing Safety Reporting for Combination Products” was released in July 2019. This document discusses compliance with postmarketing safety reporting requirements for combination products in 21 CFR Part 4, Subpart B. Although these regulations are similar to those for drugs, devices, and biological products, each set of regulations establishes distinct reporting requirements, triggers and timelines.

Combination products and regulatory framework in EU

In contrast with the US framework, the EU regulatory landscape does not define precise requirements or guidelines for combination products. Moreover, the term “combination product” does not exist in the EU regulations. Such products are regulated as either medicinal products or medical devices, depending on which component has the principal mode of action and which one has an ancillary (secondary) function.

Accordingly, the Medical Device Regulation (EU 2017/745) (MDR) states that devices incorporating medicinal or biological products with an ancillary action to the whole device are governed by the MDR. In contrast, those products where the incorporated substance is responsible for the principal mode of action of the product are governed by the EU Directive 2001/83/EC or Regulation (EC) 726/2004, for medicinal products, and Directive 2004/23/EC, for non-viable tissues or cells of human origins. Nevertheless, note that the EU MDR’s general safety and performance requirements (GSPRs) still apply to the device part.

Combination product	EU Regulation
Medicinal product integrated into a medical device	Principal action? If yes, Directive 2001/83/EC or Regulation (EC) No 726/2004*	Ancillary action? If yes, EU MDR 2017/745
A device intended to administer a medicinal product	Single integral product, exclusively intended for administering the medicinal product, and not reusable? If yes, Directive 2001/83/EC or Regulation (EC) No 726/2004*	Other cases: EU MDR 2017/745
Non-viable tissues or cells of human origin or their derivatives integrated into a medical device	Principal action? If yes, is it covered by Regulation (EC) No 1394/2007?* If not, Directive 2004/23/EC*	Ancillary action? If yes, EU MDR 2017/745

* The EU MDR’s GSPRs still apply to the medical device part.

Additionally, the European Medicines Agency (EMA) classify combination products under the following groups:

Integral: the medicinal product and the device form a single integrated product (i.e., pre-filled syringes and pens, patches for transdermal drug delivery and pre-filled inhalers);
Non-integral:
1. Co-packaged: the medicinal product and the device are separate items contained in the same pack (i.e.: reusable pen for insulin cartridges, tablet delivery system with controller for pain management) or;
1. Referenced Devices: the medicinal product and the device are obtained separately, where a medical device is referenced in the product information of the medicinal product.

When in doubt about the proposed qualification of the device according to the EU MDR or the medicinal product Directive or Regulation, an opinion can be requested from a Competent Authority (CA). While the CA evaluates the safety and performance of the combined product, the Notified Body (NB) assesses the EU MDR’s applicable GSPRs for the medical device part.

To support drug-device combinations, the EMA released in 2019 a draft guidance: “Guidance on the quality requirement for drug-device combinations (DDCs)”. Recently, however, the first updated version of the guideline has been released, which will come into effect on the 1^st of January of 2022 (“Guideline on quality documentation for medicinal products when used with a medical device”). This guideline covers the expected documentation for the quality part of a medicinal product’s marketing authorization dossier when used in combination with a medical device, or device part, and submitted in accordance to Directive 2001/83/EC or Regulation (EC) No 726/2004. This includes the quality, safety and/or efficacy of the combined product. Manufacturers may note that the guideline is recommended to be read in conjunction with the Q&A document associated with the MDR and the In Vitro Diagnostics Medical Device Regulation (EU 2017/746) (IVDR).

Summarized comparison: US vs. EU

US	EU
Regulation and requirements	Well-established	Under development
Available guidance	Thorough	Only partial
Regulatory framework	Unique (21 CFR)	Medicinal products, MDR or IVDR, depending on the combined product’s nature
Regulatory pathways	Multiple (e.g., PMA, 510(k), NDA, etc.)	Multiple conformity assessment routes

The increasing number of combination products has resulted in improvement in healthcare but has also added an extra layer of complexity to the ever-changing regulatory landscape. While in the US the regulatory framework is well established and manufacturers of combination products have thorough guidance available, in Europe this framework is still under development and available guidance is insufficient. This represents a challenge for manufacturers, competent authorities and notified bodies and requires a multidisciplinary collaboration to achieve the product CE-marking.

Do you need help with your combination product in Europe?

At AKRN Scientific Consulting SL, we are experts in combination products. Our expert regulatory team can help manufacturers with the qualification and classification of their devices and can provide guidance regarding the applicable conformity assessment routes.