As I am delivering a guest lecture on combination Medicine-Device product this week, I decided it would be a good idea to also talk about this in our regular deep-dive! 

The regulation of combination products, those that integrate medicinal products with medical devices, is a complex area within medical products regulation. Due to their hybrid nature, combination products challenge conventional regulatory pathways, demanding a nuanced approach to ensure their safety, efficacy, and quality. This article delves into the regulatory frameworks governing combination products in the European Union (EU) and the United States (US), highlighting key similarities, differences, and unique challenges.

Definition and Classification of Combination Products

Combination products can range from drug-coated stents and prefilled syringes to inhalers containing medicinal substances. The classification hinges on whether the primary mode of action is pharmacological, immunological, metabolic, or based on a physical device function. In both the EU and US, regulatory authorities have established guidelines for determining the nature and oversight of combination products.

In the EU, combination products are governed under the framework established by Regulation (EU) 2017/745 on medical devices (MDR) and Directive 2001/83/EC on medicinal products. The determination of whether a product falls under the medicinal or device category depends on its principal mode of action. The European Medicines Agency (EMA) and national competent authorities share regulatory responsibilities, depending on the product's nature.

In the US, combination products are regulated by the Food and Drug Administration (FDA). The FDA’s Office of Combination Products (OCP) was established to streamline the process and provide guidance on jurisdictional issues. The classification depends on the primary mode of action, and the FDA uses an inter-center consultative process involving the Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), and Center for Biologics Evaluation and Research (CBER).

The EU Regulatory Pathway

In the EU, combination products are subject to dual oversight if they incorporate both a medicinal and device component. Key aspects include:

• Single Integral Products: These products, such as prefilled syringes, are regulated as medicinal products. The device part must comply with the General Safety and Performance Requirements (GSPR) under the MDR.
• Co-packaged Products: When medicinal products and medical devices are sold together but not integrated, they must adhere to their respective regulatory requirements. The marketing authorization for the medicinal product must demonstrate the safety and compatibility of the device used.
• Device-led Products with Ancillary Drug Function: If a device has an ancillary medicinal function, the device must meet MDR requirements and receive a scientific opinion from the EMA or a national authority regarding the medicinal component.

Compliance with both the MDR and pharmaceutical regulations can involve coordination between the EMA and Notified Bodies, which assess device conformity. This dual assessment ensures that both components meet safety and performance standards.

The US Regulatory Pathway

In the US, the FDA’s OCP plays a central role in determining the lead centre for regulatory review based on the product’s primary mode of action (PMOA). The pathways include:

• Drug-led Combination Products: These are primarily reviewed by CDER, with input from CDRH or CBER for the device aspect.
• Device-led Combination Products: CDRH takes the lead, consulting CDER or CBER as needed for the drug component.
• Biologic-led Combination Products: CBER reviews biologic-led products with ancillary device functions.

The FDA’s premarket approval (PMA), De Novo classification, and 510(k) pathways may apply, depending on the complexity and risk class of the device involved. Drug-led products typically require a New Drug Application (NDA) or Biologics License Application (BLA).

Pre-Market Review and Approval Processes

The pre-market approval processes for combination products vary between the EU and US, reflecting differences in regulatory philosophy.

EU Process: For drug-led combination products, the marketing authorization application (MAA) is the primary submission. The relevant Notified Body evaluates the device component's compliance with MDR standards. Coordinated assessments between EMA and Notified Bodies can extend timelines due to the need for comprehensive reviews.

US Process: The FDA follows a “primary center” model to manage combination product reviews. The agency may issue a Request for Designation (RFD) to determine the appropriate center. The review process incorporates guidance documents specific to combination products, ensuring that both drug and device components are assessed under relevant statutory provisions. This integrated approach can expedite the timeline if coordination between CDER, CDRH, and CBER is efficient.

Post-Market Surveillance and Compliance

Post-market requirements are crucial for maintaining safety and effectiveness over the product’s lifecycle. In the EU, products must adhere to post-market surveillance obligations as per the MDR and pharmacovigilance rules under Directive 2001/83/EC. This includes periodic safety update reports (PSURs) and vigilance reporting for both medicinal and device aspects.

In the US, the FDA enforces post-market requirements, including adverse event reporting and compliance with Good Manufacturing Practices (GMPs). Drug-led products must comply with pharmacovigilance requirements, while device-led products adhere to Quality System Regulations (QSRs). The FDA’s OCP oversees coordination to ensure consistent post-market oversight.

Key Challenges in Regulation

Inter-Agency Coordination: One of the primary challenges in both the EU and US is ensuring seamless coordination between drug and device regulatory bodies. Differences in regulatory expectations, timelines, and review processes can complicate the approval of combination products.

Harmonization Issues: Although international regulatory bodies, such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), aim to promote convergence, significant differences remain between the EU and US in terms of data requirements and review procedures.

Technical and Scientific Complexity: Advances in technology have led to increasingly complex combination products that challenge existing frameworks. Innovations like digital health applications integrated with drug delivery systems require updated regulatory approaches.

Regulatory Burden for Manufacturers: The need for multiple regulatory submissions and the complexity of complying with both drug and device regulations can lead to increased costs and extended development timelines. Harmonized guidance documents can alleviate some of these challenges but are not always comprehensive.

Future Outlook

The landscape for combination product regulation continues to evolve. Both the EU and US are exploring measures to streamline the review processes and enhance inter-agency collaboration. The EU’s implementation of the MDR and ongoing revisions in the US’s FDA guidance reflect efforts to better align regulatory practices with technological advancements.

Regulatory science initiatives and stakeholder engagement are essential to anticipate emerging trends and refine the frameworks that govern combination products. Greater global collaboration and alignment could help address discrepancies and reduce the regulatory burden on manufacturers while maintaining high safety and efficacy standards for patients.

While the EU and US share similar overarching goals for the regulation of combination products, notable differences persist in their approaches. Ongoing dialogue and coordinated efforts among regulatory authorities, manufacturers, and stakeholders will be crucial for optimizing the regulation of these multifaceted healthcare products.

Orion GXP Consulting has a team of GMP and MDR subject matter experts with in-depth expert knowledge in the area of combination devices. We would be happy to assist with assessing compliance and ensure your combination device is compliant.

Please feel free to contact us if you would like to discuss: admin@oriongxp.com or +353(0)71 98 10101 (IRL) or +44 203 475 0375 (UK).