Regulatory Consultancy for Drug-Device Combination Products

Combination products stall in review because two regulatory systems judge the same product against different evidence. A device reviewer checks conformity with MDR Annex I; a medicines reviewer weighs quality, safety, and efficacy. When required device documentation is missing, EMA Q&A on medicines used in combination with medical devices (Rev. 6, Dec 2025), section 2.3 notes that the procedure can pick up additional clock stops.

Teams usually feel the strain well before submission. Without a settled view of who regulates what, the device team plans for one authority and the pharma team for another, and the Notified Body and marketing authorization timelines drift apart. Documentation written for one reviewer then lacks the component-specific justification the other expects. Cost rises, launch slips, and the risk of non-compliance findings at review grows. Interpretations also move, so a position that held at the start of development may need a fresh justification by the time of filing.

What does a combination product regulatory consultancy do?

A combination product regulatory consultancy determines which framework governs a drug-device product, then prepares the documentation and authority interactions that framework requires. Qserve does this across EU MDR, EU medicines law, and FDA requirements, with regulatory, quality, and clinical specialists from both the device and the pharmaceutical side working on one file.

The difference shows in the handoffs. A pharma-only team can write a strong dossier and still miss what a Notified Body needs to see for the device part. A device-only team can build a clean technical file that does not connect to the quality module of the marketing authorization application. One coordinated team keeps the two files consistent and gives both sides a single regulatory position to work from. Projects without a medicinal component are covered by our medical device regulatory consultancy.

What is a drug-device combination product?

A drug-device combination product joins a drug or biologic with a medical device so the two work as one therapy, whether as a single integral product, co-packaged in the same pack, or cross-labeled for use together. Mode of action decides which rules apply, and the EU and the US apply different tests.

How the EU and the US treat each type:

In the US, FDA assigns a lead center for every type by primary mode of action. 

How do you determine the regulatory pathway for a combination product?

The pathway follows the product's mode of action: which component delivers the principal intended effect. In the EU, the principal mode of action decides whether the product is regulated as a medical device or as a medicinal product. In the US, FDA's primary mode of action (PMOA) assigns the lead center, CDER, CDRH, or CBER.

The two terms are not interchangeable. PMOA is a US concept, defined in 21 CFR 3.2 as the single mode of action that provides the most important therapeutic action of the combination product. The EU test is principal mode of action, applied through Articles 1(8) and 1(9) of the EU MDR and the borderline guidance in MDCG 2022-5 rev.1. Because the tests differ, Qserve assesses both positions together before a strategy is fixed.

When classification is genuinely unclear, each system has a route to an answer. In the EU, qualification of a borderline product rests with the national competent authorities, and EMA's Innovation Task Force can give informal input. In the US, a Request for Designation (RFD) gives a formal determination from FDA's Office of Combination Products, and a Pre-RFD gives informal, non-binding feedback first. Qserve builds the mode-of-action argument those routes rest on and prepares the request.

When do you need combination product regulatory support?

A manufacturer needs combination product regulatory support when the mode of action is unsettled, when a marketing authorization application needs device evidence it does not yet hold, or when one product must satisfy both EU and US authorities. The situations below are typical triggers.

• You are unsure whether your product qualifies as a medicinal product or a medical device, or which mode of action is principal.
• You are preparing a marketing authorization application for a pre-filled syringe, pen, or inhaler and need an NBOp or other device conformity evidence.
• You are developing a device that incorporates a medicinal substance and need the Notified Body's consultation with EMA or a national authority.
• You are planning US and EU filings and need one consistent mode-of-action position, possibly backed by an FDA RFD or Pre-RFD.
• You have changed the device, formulation, or route of administration of an authorized product and need to know whether a new or updated opinion is expected.

A Notified Body Opinion (NBOp) states whether the device part of an integral drug-device combination meets the general safety and performance requirements (GSPRs) in MDR Annex I. For marketing authorization applications submitted since 26 May 2021, MDR Article 117 requires proof of that conformity: an EU certificate or declaration of conformity where available, otherwise an NBOp.

The opinion has to confirm full compliance. EMA does not accept an opinion concluding partial compliance, and its scope must match the device's intended purpose in that application. For class I devices (excluding Is and Im) without a declaration of conformity, a statement of compliance from the marketing authorization holder can be acceptable instead. 

Timing matters as much as content. EMA and the national authorities strongly recommend submitting the opinion with the initial marketing authorization application, and discussing the plan at the pre-submission meeting if it cannot be ready in time.

Qserve prepares the device documentation and GSPR mapping the Notified Body assesses, supports the choice of a Notified Body whose designation covers your device, and manages the exchange until the opinion is in hand.

How does EU consultation work for a device with an ancillary medicinal substance?

When a medical device incorporates a medicinal substance whose action is ancillary to the device, MDR Article 1(8) keeps the product under device rules and requires CE marking. Before the Notified Body can issue an EU certificate, it must obtain a scientific opinion on the substance from EMA or a national competent authority.

The choice of authority is not always open. The Notified Body must seek EMA's opinion where the medicinal product falls exclusively within the scope of the centralized procedure or incorporates human blood or plasma derivatives. Otherwise it may go to a national competent authority or to EMA. The opinion covers the quality and safety of the substance and the benefit-risk of incorporating it into the device. It rests on a dossier that describes the manufacturing process and the data showing why the substance is useful in the device.

Substances consulted under the old Directives need a fresh consultation under the MDR, either a full initial consultation or a follow-up, depending on the case. Qserve prepares the substance dossier and manages the consultation with the Notified Body and the medicines authority. Companion diagnostics are a separate case: they fall under the IVDR, where the Notified Body also consults a medicines authority. Our companion diagnostics page covers that route.

How does the FDA decide which center leads a combination product?

FDA assigns every combination product to a lead center, CDER, CDRH, or CBER, based on its primary mode of action (PMOA): the single mode of action that provides the product's most important therapeutic action. Sponsors who cannot tell which center applies can request a formal determination from FDA's Office of Combination Products through a Request for Designation (RFD).

The choice between an RFD and a Pre-RFD depends on how settled the mode of action is and how much of the development plan hangs on the answer. Once the lead center is set, it holds primary jurisdiction for premarket review and regulation of the whole product. 

Qserve prepares the RFD or Pre-RFD, supports FDA meetings, and builds the submission strategy for the lead center. Our US FDA consulting page covers the wider US pathway.

What documentation does a combination product need?

The device part of a combination product needs technical documentation that maps each applicable MDR Annex I requirement to evidence, while the drug part needs quality, safety, and efficacy data in the electronic Common Technical Document (eCTD). Where the device is integral, the two files must agree on shared points such as dose delivery and performance over shelf life.

EMA's guideline on quality documentation for medicinal products used with a medical device EMA quality guideline describes what belongs in the quality part of the dossier. It focuses on the product-specific device aspects that can affect the quality, safety, or efficacy of the medicine. Qserve aligns the device documentation with the eCTD so a reviewer on either side finds consistent evidence, and can test the combined file first through a gap assessment.

How does Qserve reduce risk on a combination product project?

Qserve reduces risk on a combination product project by fixing the regulatory position first: one team agrees the mode of action, the lead authority, and the route in each market before documents are written. Device documentation, drug dossier sections, and authority interactions then run from that shared plan.

Integrating regulatory, clinical, and quality expertise across the device and pharmaceutical domains reduces internal complexity and aligns the documentation with what authorities expect. It also keeps strategic decisions open to revision at each phase: when an authority asks for a component-specific justification, or an interpretation shifts, the plan can be adjusted without rebuilding the file. The aim is faster development and a stronger case at review.