For drug-device and biologic-device combination products regulated as devices under MDR, the Clinical Evaluation Report must cover both the device and the ancillary substance. The usefulness, safety, and benefit-risk of the substance incorporated in the device are assessed by a medicines authority or EMA under the Article 52(9) consultation route, while the device's clinical performance and safety are assessed by the Notified Body against Article 61 and Annex XIV.

By Tibor Zechmeister and Felix Lenhard. Last updated 2026-04-10.

TL;DR

  • Combination products where the device is the principal mode of action and the substance is ancillary fall under MDR Article 1(8); the device is classified Class III under Annex VIII Rule 14.
  • Devices incorporating substances derived from human blood or plasma fall under Article 1(9) and are also Class III under Rule 14.
  • The Clinical Evaluation Report (CER) must address the device and the ancillary substance as a single product — you cannot split them.
  • Under Article 52(9), the Notified Body seeks a scientific opinion from a national competent authority for medicinal products, or from the EMA when the substance is blood- or plasma-derived.
  • Equivalence claims for combination products are much harder than for simple devices — MDCG 2020-5 still applies, but the substance's identity, dose, release kinetics, and mode of action must all match.
  • Plan the CER scope, the clinical investigation strategy, and the substance dossier together from day one — not in sequence.

Why this matters for your startup

A founder walked into a review with a bioresorbable wound matrix that released a growth factor. Reasonable device dossier. Small first-in-human study. Benchmarked against two predicate matrices. What they had not done was treat the growth factor as a medicinal substance with its own clinical evaluation burden. The Notified Body's first question was not about the matrix. It was: "Where is the clinical data supporting the dose, the release profile, and the safety of the ancillary substance in this specific use?" The answer was three months of unplanned work.

This is the trap. You pass the classification test, you accept Class III, you plan your CER for the device — and you forget that the substance is not a material specification. It is a medicinal product that has been incorporated into your device, and the CER has to prove the combination is safe and performs as intended.

For background on how combination products are defined, see combination products MDR drug-device biologic-device rules and MDR Rule 14 devices incorporating a medicinal substance. This post focuses on the clinical evaluation angle.

The MDR text — what the regulation actually says

Three provisions govern the clinical evaluation of drug-device combination products.

Article 1(8) — devices incorporating a medicinal substance with ancillary action:

"Any device which, when placed on the market or put into service, incorporates, as an integral part, a substance which, if used separately, would be considered to be a medicinal product... and that is liable to act upon the human body with action ancillary to that of the device, shall be assessed and authorised in accordance with this Regulation." — Regulation (EU) 2017/745, Article 1, paragraph 8.

Article 1(9) applies the same logic to devices incorporating, as an integral part, a substance derived from human blood or plasma that would be considered a medicinal product if used separately and has an action ancillary to the device. These are also under MDR, with a specific consultation route involving the EMA. (Regulation (EU) 2017/745, Article 1, paragraph 9.)

Annex I Section 12.1 requires that where a device incorporates such a substance, the quality, safety, and usefulness of the substance must be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC. (Regulation (EU) 2017/745, Annex I, Section 12.1.)

This is the hinge. "Usefulness" means clinical evidence. The substance needs clinical data appropriate to a medicinal product, evaluated in the context of the device's intended purpose.

Annex VIII Rule 14 classifies all such devices as Class III, including those incorporating substances derived from human blood or plasma. (Regulation (EU) 2017/745, Annex VIII, Rule 14.)

Article 61 and Annex XIV set the clinical evaluation requirements. For Class III devices, clinical evaluation is based on data from clinical investigations unless one of the narrow Article 61(4)-(6) exemptions applies. MDCG 2023-7 clarifies those exemptions. (Regulation (EU) 2017/745, Article 61 and Annex XIV; MDCG 2023-7, December 2023.)

The CER scope for a combination product

A CER for a drug-device or biologic-device product answers two questions at once: does the device perform and is it safe, and does the incorporated substance support the device's intended purpose with an acceptable benefit-risk profile?

The CER scope definition (Annex XIV Part A Section 1) must explicitly cover:

  • The device, its intended purpose, target population, and clinical claims.
  • The ancillary substance — identity, dose, route and kinetics of release, and the clinical benefit it contributes.
  • The interaction — does the device change how the substance behaves, and does the substance change how the device behaves over its service life?

You cannot treat the substance as a line in the material specification. The clinical evaluation plan must identify data relevant to the substance in the specific use case: same indication, same dose range, same route, same exposure duration. If that data is not in the literature, you generate it.

Equivalence is harder here. MDCG 2020-5 requires technical, biological, and clinical characteristics to match. For a combination product, "biological" includes substance identity and release behaviour, and "clinical" includes indication and dosing. A predicate wound matrix with a different growth factor, or the same growth factor at a different dose, is not equivalent. (MDCG 2020-5, April 2020.)

The Article 52(9) consultation route

Under Article 52(9), for devices falling under Article 1(8), the Notified Body shall request a scientific opinion on the quality, safety, and usefulness of the substance from a competent authority designated by a Member State for medicinal products, or from the EMA in specific cases — notably when the substance falls within the scope of the centralised procedure or when it is derived from human blood or plasma under Article 1(9). (Regulation (EU) 2017/745, Article 52, paragraph 9.)

What this means for the CER: part of your clinical evidence is not evaluated by the Notified Body at all. It is evaluated by a pharmaceutical authority using pharmaceutical standards. The NB incorporates that opinion into its conformity decision.

You need documentation that two different reviewers will read:

  • Notified Body clinical reviewers — expecting a CER per Annex XIV and MEDDEV 2.7/1 rev 4, assessing device clinical performance, clinical safety, benefit-risk, and PMCF plan.
  • Medicines authority reviewers — expecting a substance dossier structured like a pharmaceutical Module 4/5, assessing quality, non-clinical safety, and clinical safety/efficacy of the substance at the proposed dose and route.

The CER and the substance dossier must tell the same story. Contradictions — different dose assumptions, different exposure estimates, different indications — are the single most common reason these submissions bounce.

Worked example 1: pre-filled syringe with a medicinal product

A pre-filled syringe delivering a medicinal product sounds like a combination product, but under MDR it usually is not an Article 1(8) device. The syringe administers a medicinal product; the medicinal product has its own marketing authorization. The two are regulated in parallel — the device under MDR, the drug under Directive 2001/83/EC or Regulation (EC) No 726/2004.

Where the syringe is placed on the market together with the medicinal product as an integral product and cannot be reused, the primary framework is pharmaceutical, and the device part is assessed against the relevant GSPRs. The CER is not a standalone MDR CER — it is a device-constituent evaluation feeding into a pharmaceutical marketing authorization dossier.

The lesson: confirm the regulatory route before you scope a CER. A pre-filled syringe is almost never an Article 1(8) device. A drug-eluting stent almost always is.

Worked example 2: drug-eluting coronary stent

A drug-eluting coronary stent is the textbook Article 1(8) device. The stent mechanically keeps the artery open; a limus-family antiproliferative is released locally to reduce restenosis. Device is principal mode of action; drug is ancillary.

The CER must cover:

  • Stent performance — deliverability, radial force, fracture resistance, patency, restenosis rate, major adverse cardiac events.
  • Substance performance — local concentration over time, systemic exposure, dose-response for restenosis prevention, safety at local concentrations.
  • Combination effects — does the polymer matrix affect drug kinetics, does the drug affect endothelialisation, and what is the benefit-risk versus bare-metal and other drug-eluting stents?

Clinical investigation is almost always required. MDCG 2023-7 exemptions rarely apply because the drug, polymer, or delivery profile is usually different enough from predicates that MDCG 2020-5 equivalence cannot be fully demonstrated. The investigation must be designed under EN ISO 14155:2020+A11:2024 with endpoints that satisfy both the Notified Body's CER and the medicines authority's substance opinion.

Ship — the evidence stack playbook

Assemble the clinical evidence stack in this order:

  1. Lock the regulatory route first. Article 1(8) device, Article 1(9) blood/plasma device, or medicinal product with device constituent? Get a written opinion before design work starts. The wrong route wastes 12 months.
  2. Write the CER scope and the substance dossier Table of Contents together. They reference each other. Do not let them drift.
  3. Map the substance data gaps. For a well-established substance (gentamicin in bone cement), published literature may cover most of the usefulness case. For a novel substance or novel dose, plan original studies.
  4. Design the clinical investigation to serve both audiences. EN ISO 14155:2020+A11:2024 is mandatory. Endpoints must satisfy device performance and substance benefit-risk.
  5. Engage the medicines authority informally. National competent authorities accept scientific advice requests. Use one — it is cheap compared to a failed Article 52(9) consultation.
  6. Plan the PMCF around the combination. Post-market clinical follow-up must track long-term substance-related outcomes, not only device performance.
  7. Budget the consultation time. Article 52(9) opinions add months on top of NB review.

For the general mechanics, see the clinical evaluation process under MDR.

Reality Check — Where do you stand?

Answer honestly. If any answer is "no" or "not sure," you have work to do before the NB submission.

  1. Have you confirmed in writing whether your product is an Article 1(8) device, an Article 1(9) device, or a medicinal product with a device constituent?
  2. Does your CER scope explicitly cover both the device and the ancillary substance, including dose, release kinetics, and clinical benefit of the substance?
  3. Have you identified the clinical data supporting the substance's usefulness at the dose and route used in your device — and is it specific enough to survive MDCG 2020-5 equivalence scrutiny?
  4. Have you planned the clinical investigation to EN ISO 14155:2020+A11:2024 with endpoints that satisfy both the Notified Body and the medicines authority?
  5. Do you know which competent authority (or EMA) will be consulted under Article 52(9) for your specific substance?
  6. Is your PMCF plan designed to track long-term substance-related outcomes, not just device performance?
  7. Have you budgeted time and money for the Article 52(9) consultation as a distinct line item, separate from NB review?

If you answered "no" to three or more, the combination product pathway is still ahead of you — not behind you.

Frequently Asked Questions

Is the clinical evaluation for a drug-device combination product one CER or two documents? It is one CER under MDR, but it must cover both the device and the ancillary substance. The substance dossier prepared for the Article 52(9) consultation is a separate document that the Notified Body routes to a medicines authority, and the CER must be internally consistent with it.

Can I use equivalence to avoid a clinical investigation for a combination product? Rarely. MDCG 2020-5 requires equivalence across technical, biological, and clinical characteristics. For a combination product, "biological" and "clinical" include the substance's identity, dose, release kinetics, indication, and route. A predicate with a different substance, a different dose, or a different release profile is not equivalent.

Who evaluates the substance — the Notified Body or a medicines authority? Under Article 52(9), the Notified Body requests a scientific opinion on the quality, safety, and usefulness of the substance from a national competent authority for medicinal products or the EMA. The Notified Body incorporates that opinion into its overall conformity assessment of the device.

When does EMA review the substance instead of a national competent authority? The EMA is consulted when the substance would, if used separately, fall within the scope of the centralised authorisation procedure, or when the substance is derived from human blood or human plasma under Article 1(9). National competent authorities cover the other cases.

Does a pre-filled syringe count as an Article 1(8) combination product? Usually no. A pre-filled syringe administering a medicinal product is typically a device used with a medicinal product, not a device that incorporates the substance as an integral part. The device and the drug are regulated in parallel, with the integral product frequently assessed primarily under pharmaceutical legislation.

How long does the Article 52(9) consultation add to the timeline? Plan for several months on top of Notified Body review. Exact duration depends on the authority consulted, the novelty of the substance, and the quality of the dossier. It is rarely faster than the NB review itself.

Sources

  1. Regulation (EU) 2017/745 of the European Parliament and of the Council of 5 April 2017 on medical devices — Articles 1(8), 1(9), 52(9), 61; Annex I Section 12.1; Annex VIII Rule 14; Annex XIV. Consolidated text on EUR-Lex.
  2. MDCG 2020-5, Clinical Evaluation — Equivalence: A guide for manufacturers and notified bodies, April 2020.
  3. MDCG 2023-7, Guidance on exemptions from the requirement to perform clinical investigations pursuant to Article 61(4)-(6) MDR, December 2023.
  4. EN ISO 14155:2020 + A11:2024, Clinical investigation of medical devices for human subjects — Good clinical practice.
  5. Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use (referenced in MDR Annex I Section 12.1 for substance quality and safety methodology).

Part of the Clinical Evaluation & Investigations series. Authored by Felix Lenhard and Tibor Zechmeister. Zechmeister Strategic Solutions offers both-sides device and pharmaceutical regulatory support.