Combination Products: EU MDR and FDA Requirements Compared

Introduction

Combination products are the one category in which a manufacturer has to satisfy two regulatory cultures at once, and the United States and the European Union have drawn opposite conclusions about how that should work. FDA keeps the product whole: one legal definition, one lead centre, one application, and both sets of manufacturing rules running in the same plant. The EU has no such category. It sends the entire product down either the medical device track or the medicinal product track, and then borrows a slice of the other regime to cover the part that does not belong there.

The consequence is practical, not academic. The same drug-eluting stent is a class III device with a medicines authority consultation in Europe and a PMA with a drug consult in the US. The same prefilled pen is a medicinal product that needs a notified body opinion in Europe and an NDA that carries design controls in the US. A team that has already built EU MDR technical documentation and a GSPR checklist against Annex I has done part of the work for both jurisdictions, and none of the work that is specific to the combination.

This guide covers how each system defines and assigns these products, the device-led route under Rule 14, the medicine-led route under Article 117, FDA premarket review, 21 CFR Part 4 as amended by the QMSR, design controls and human factors, post-market reporting, the two EU reforms now in the legislative procedure, and the six gaps that stall files.

Table of Contents

• Combination products exist in US law and not in EU law
• The four types in 21 CFR 3.2(e)
• The EU vocabulary: integral, co-packaged, referenced
• One question decides the pathway: which action is principal
• Primary mode of action in the United States
• Principal and ancillary action in the European Union
• A device with an ancillary medicinal substance takes the heaviest route in the MDR
• What Rule 14 and Annex IX Section 5.2 add
• Substance-based devices are a separate problem
• Devices that only administer a medicine stay ordinary devices
• Article 117 turned every prefilled syringe into a device file
• FDA reviews combination products as one product under one lead centre
• 21 CFR Part 4 lets combination products run on one quality system
• Design controls and human factors apply to the combination, not to its parts
• Drug delivery performance is a design output
• Use-related risk is where approvals are lost
• After approval the reporting duties stack up; they do not merge
• Two EU reforms are about to redraw the lines
• The six gaps that stall combination product files
• Frequently asked questions
• Conclusions

Combination products exist in US law and not in EU law

The term is American. It comes from section 503(g) of the Federal Food, Drug, and Cosmetic Act, it is defined in 21 CFR 3.2(e), and since the Medical Device User Fee and Modernization Act of 2002 it has had its own office inside FDA, the Office of Combination Products. Neither Regulation (EU) 2017/745 nor Directive 2001/83/EC uses the term. The European Medicines Agency speaks of drug-device combinations, MDCG 2022-5 rev.1 speaks of medical device and medicinal product combinations, and the legal text itself only describes situations in Articles 1(8) and 1(9) of the MDR. Anyone who carries the US vocabulary into an EU file will sooner or later claim a status that does not exist.

The four types in 21 CFR 3.2(e)

A combination product is a product made of two or more different types of regulated article: drug and device, biological product and device, drug and biological product, or all three. Each of them is a constituent part. The regulation lists four configurations. A single-entity product, under 3.2(e)(1), has its constituent parts physically, chemically or otherwise combined and produced as one item: a drug-eluting stent, a prefilled syringe, a transdermal system. A co-packaged product, under 3.2(e)(2), places separate products in one package or unit: a vial with a syringe and a transfer device. A cross-labelled product, under 3.2(e)(3), is packaged separately but is intended, according to its labelling, for use only with an approved and individually specified other product, where both are needed to achieve the intended effect and the labelling of the approved product would have to change. Paragraph 3.2(e)(4) applies the same logic to two investigational products.

What falls outside matters as much. Two drugs in one tablet are not a combination product, because both parts are the same type of article. An empty general-purpose syringe is a device. A drug labelled for use with any infusion pump of a general class is a drug, because no individually specified device is named. The phrase “individually specified” in 3.2(e)(3) does most of the limiting work, and it is the phrase sponsors most often read past.

The EU vocabulary: integral, co-packaged, referenced

EU law reaches the same products through four situations. The first subparagraph of Article 1(8) MDR covers a device that incorporates, as an integral part, a substance which used separately would be a medicinal product and whose action is ancillary to that of the device: the product is a device. The second subparagraph covers the reverse case, where the action of the substance is principal: the product is a medicinal product under Directive 2001/83/EC or Regulation (EC) No 726/2004. Article 1(9) deals with devices intended to administer a medicinal product. They are devices, unless device and medicine are placed on the market as a single integral product intended exclusively for use in that combination and not reusable, in which case the whole is a medicinal product. In both medicine-led cases the relevant general safety and performance requirements of Annex I MDR still apply to the device part.

The EMA Guideline on quality documentation for medicinal products when used with a medical device, in effect since 1 January 2022, supplies the working vocabulary for the medicine-led side. A combination is integral when it meets the conditions just described, co-packaged when a CE-marked device is supplied in the same pack as the medicine, and referenced when the product information names a specific device that the user obtains separately.

“Single-entity” is a US description of how a product is physically made. “Integral” is an EU legal status reserved for combinations regulated as medicines. A drug-eluting stent is single-entity in Washington and is not an integral drug-device combination in Amsterdam. Treating the two words as synonyms is how a device manufacturer ends up asking a notified body for an Article 117 opinion it does not need.

One question decides the pathway: which action is principal

Both systems resolve the drug-or-device question with the same scientific test and very different procedures. The test asks which constituent delivers the therapeutic effect the product is sold for. Everything else, the application type, the reviewing body, the fee, the quality regime in Europe, follows from that single answer, which is why it has to be settled on evidence of mechanism before the design is frozen and not argued from the business case afterwards.

Primary mode of action in the United States

Under 21 CFR 3.2(m), the primary mode of action is the single mode of action that provides the most important therapeutic action of the combination product, meaning the one expected to make the greatest contribution to its overall intended therapeutic effects. A stent holds a vessel open, and the drug reduces restenosis: device. A prefilled syringe delivers a monoclonal antibody: biological product. Where the primary mode of action cannot be determined with reasonable certainty, 21 CFR 3.4(b) applies a two-step algorithm. FDA first assigns the product to the centre that regulates other combination products presenting similar questions of safety and effectiveness for the product as a whole. If no such products exist, it goes to the centre with the most expertise in the most significant safety and effectiveness questions.

The 21st Century Cures Act of 2016 tightened this in the sponsor’s favour. FDA may not conclude that the primary mode of action is that of a drug or biological product solely because the product has a chemical action within or on the body, and a sponsor who disagrees with an assignment can demand the substantive scientific rationale. The decision in Genus Medical Technologies v. FDA, handed down by the D.C. Circuit in April 2021, pushed in the same direction: a product that meets the statutory device definition cannot be regulated as a drug at the agency’s discretion. One practical result was that ophthalmic drugs packaged with eye cups, droppers and other dispensers are now regulated as drug-led combination products. That put Part 4 on the agenda of ophthalmic manufacturers who had never applied a device regulation, although FDA has so far held back from enforcing the device quality requirements for the lower-risk dispensers.

The formal instrument is the Request for Designation under 21 CFR 3.7. It is limited to 15 pages, FDA must answer within 60 days of filing, and if it does not, the sponsor’s own recommendation becomes the designation. Under 21 CFR 3.9(b) the designation can be changed only with the sponsor’s written consent, or without it to protect the public health or for other compelling reasons. The Pre-RFD is the informal, non-binding version, and it is the right first step whenever the mechanism is genuinely contestable.

Principal and ancillary action in the European Union

The EU test sits in the definition of a medical device in Article 2(1) MDR: a device does not achieve its principal intended action by pharmacological, immunological or metabolic means, although it may be assisted in its function by such means. MDCG 2022-5 rev.1, endorsed in October 2024, defines the three terms and gives worked examples. The Court of Justice added an important gloss in Case C-308/11, Chemische Fabrik Kreussler: a pharmacological action does not require an interaction between the substance and a cellular constituent of the user’s own body. An interaction with any cellular constituent present in the body, bacteria included, is enough. Many antimicrobial coatings fail the device test on that ground alone.

The procedure is where the systems part ways. There is no European equivalent of the Request for Designation. The manufacturer takes a position, the notified body or the medicines authority may reject it, national competent authorities coordinate through the borderline group, and under Article 4 MDR the Commission can settle the status of a product by implementing act at the request of a Member State. In cases of doubt, where a product could fall under both regimes, Article 2(2) of Directive 2001/83/EC gives precedence to the medicinal product rules. The December 2025 proposal to amend the MDR would codify the coordination procedure and allow a manufacturer to ask an expert panel directly for an opinion on regulatory status, which would be the first route in EU device law that a company can trigger itself.

A device with an ancillary medicinal substance takes the heaviest route in the MDR

When the substance is ancillary, the product stays a device and the manufacturer stays in the MDR. That sounds like the easy outcome. It is the most demanding conformity assessment the Regulation contains, because it adds a second regulator to a class III file.

What Rule 14 and Annex IX Section 5.2 add

Rule 14 of Annex VIII places in class III every device incorporating, as an integral part, a substance which used separately can be considered a medicinal product, including one derived from human blood or plasma, and which has an action ancillary to that of the device. The class does not depend on the amount of substance, the duration of contact or the class the device would otherwise have had. A heparin-coated catheter and a steroid-eluting pacing lead land in the same class as the stent.

Article 52(9) then requires the consultation procedure of Section 5.2 of Annex IX, or Section 6 of Annex X where type examination is used. The notified body first verifies the usefulness of the substance as part of the device. It then seeks a scientific opinion on the quality and safety of the substance, including the benefit or risk of incorporating it into the device, from a national medicines authority or from EMA. EMA is mandatory where the substance is derived from human blood or plasma or falls within the mandatory scope of the centralised procedure. The authority has 210 days from receipt of all the necessary documentation, and the notified body may not issue the certificate if the opinion is unfavourable. Those 210 days sit on top of the notified body’s own review, and they start only when the dossier is complete.

The documentary burden follows from Annex I Section 12.1, which requires the quality, safety and usefulness of the substance to be verified by analogy with the methods specified in Annex I to Directive 2001/83/EC, and from Annex II Section 6.2(a), which requires the technical documentation to identify the source of the substance and contain the test data on its safety, quality and usefulness. In practice this is a pharmaceutical quality module written for a device file: specification of the active substance, manufacturing controls, stability on the device, release kinetics, and a non-clinical and clinical argument for the dose. The clinical evaluation under Article 61 has to demonstrate the benefit of the device with the substance, and the usefulness argument has to show what the substance adds over the device without it.

The consultation does not end at certification. Under Section 5.2(f), any change to the ancillary substance, in particular to its manufacturing process, must be notified to the notified body, which goes back to the authority that gave the original opinion. That authority has 60 days. A change of active substance supplier is therefore a regulatory event for a device manufacturer in a way that few device quality systems anticipate.

Substance-based devices are a separate problem

Devices composed of substances that are introduced into the body through an orifice or applied to the skin, and that are absorbed by or locally dispersed in the body, are not combinations at all. They contain no substance that would be a medicinal product on its own. They are classified under Rule 21, in class III where they or their metabolites are systemically absorbed to achieve the intended purpose, and Annex I Section 12.2 requires them to meet the relevant requirements of Annex I to Directive 2001/83/EC for absorption, distribution, metabolism, excretion, local tolerance, toxicity and interactions. For the systemically absorbed class III cases, Annex IX Section 5.4 nonetheless sends the notified body to a medicines authority for an opinion. The December 2025 proposal describes that consultation as not appropriate and would remove it. Until it does, the consultation applies.

Devices that only administer a medicine stay ordinary devices

A reusable pen injector, an infusion pump, a nebuliser or a spacer placed on the market separately from the medicine is a device under the first subparagraph of Article 1(9), classified by its own characteristics. Rule 12 places active devices intended to administer or remove medicinal products in class IIa, or IIb where the manner of administration is potentially hazardous. Rule 20 places invasive devices that administer medicines by inhalation in class IIa, or IIb where their mode of action has an essential impact on the efficacy and safety of the medicine or they treat life-threatening conditions. No medicines authority is consulted. One special procedure does apply: under Article 54, class IIb active devices intended to administer or remove a medicinal product are subject to the clinical evaluation consultation procedure with an expert panel, unless an exemption applies. The December 2025 proposal would confine that procedure to class III implantable devices.

Article 117 turned every prefilled syringe into a device file

Article 117 is one of the shortest articles in the Regulation and it changed the work of every pharmaceutical company that fills a syringe. It amends point 12 of Section 3.2 of Annex I to Directive 2001/83/EC. Where a medicinal product is governed by the second subparagraph of Article 1(8) or of Article 1(9) MDR, the marketing authorisation dossier must include, where available, the results of the assessment of conformity of the device part with the relevant general safety and performance requirements: the manufacturer’s EU declaration of conformity, or the certificate issued by a notified body that allows a CE mark to be affixed. Where the dossier contains neither, and the device used separately would require the involvement of a notified body, the authority must require an opinion on the conformity of the device part issued by a notified body designated for that type of device. The requirement has applied to marketing authorisation applications since 26 May 2021.

That produces three evidence routes. If the device part already exists as a CE-marked device, the declaration of conformity or certificate goes into the dossier. If it would be a class I device with no sterile, measuring or reusable surgical function, the applicant demonstrates conformity with the relevant requirements in the dossier itself. In every other case a notified body opinion, the NBOp, is needed. Since a syringe barrel supplied sterile already brings a notified body in, and needles, pens, autoinjectors and inhalers sit in class IIa or above, the third route is the normal one.

The NBOp is not a certificate, and the differences define the scope of work. The notified body reviews documentation against the requirements of Annex I that are relevant to the device part. It does not audit the quality system, it performs no surveillance, and no CE mark, Basic UDI-DI or EUDAMED registration results. The argument with the notified body is therefore almost entirely about which requirements are relevant and what evidence closes each one. Chemical, physical and biological properties, sterility and microbial contamination, construction and interaction with the environment, protection against mechanical risks and the requirements for devices used by lay persons are nearly always in scope. Labelling requirements largely are not, because the labelling of the product follows medicinal product law. A file that marks requirements as not applicable without a written justification for each one gets the same question back every time.

In the dossier, the opinion or certificate sits in Module 3.2.R, with the description, development and control of the device part in Module 3.2.P. The EMA guideline sets out what is expected there: the functional performance of the device with this specific medicine, dose accuracy across the shelf life, compatibility, and usability evidence where the intended users or the conditions of use have not been covered before. That last point limits how far a platform opinion can travel. An autoinjector supplier can hold an opinion on its platform, but viscosity, fill volume, injection time and user population belong to the medicine, and a notified body cannot conclude on the relevant requirements without them.

Article 117 is not retroactive, as the EMA questions and answers on the implementation of the MDR and IVDR confirm. Products authorised before 26 May 2021 are not required to obtain an opinion for the device part as authorised. A substantial change to the design or intended purpose of the device part, or the introduction of a new device, does trigger the requirement, through a variation; the EU variations classification now has a dedicated section, Q.IV, for device-related changes. Co-packaged and referenced devices are outside Article 117 altogether. They must be CE marked in their own right, and the dossier has to show that the device is compatible with the medicine and suitable for the intended use.

The notified body opinion has no legal clock. The 210 days of Annex IX Section 5.2 bind a medicines authority that is consulted on a device; nothing binds a notified body that is consulted on a medicine. An application planned around the assessment timetable of the medicines authority, with the opinion treated as an attachment, is planned around the wrong critical path.

FDA reviews combination products as one product under one lead centre

Once the primary mode of action is settled, the lead centre is settled, and the application type follows the centre. A device-led product goes to CDRH under a PMA, a De Novo request or a 510(k). A drug-led product goes to CDER under an NDA or an ANDA. A biological-led product goes to CBER or CDER under a BLA. Section 503(g) directs FDA to review a combination product under a single application whenever appropriate, and the final guidance Principles of Premarket Pathways for Combination Products of January 2022 sets out how each pathway accommodates the other constituent part. The non-lead centre takes part through an inter-centre consult. The sponsor never files with it and frequently never meets it, which is exactly why the device section of a drug application has to be complete on its face.

For device-led products the 510(k) route remains open, but only where a predicate with the same intended use exists and the drug constituent does not raise different questions of safety and effectiveness. Antibiotic bone cements are cleared that way. A novel drug on an established device will not be. Where a device-led application relies on an approved drug, the Cures Act added a requirement that device teams rarely expect: the applicant must make the same patent certifications and respect the same exclusivities as a section 505(b)(2) applicant. A PMA can be held up by a pharmaceutical patent.

For drug-led and biological-led products, the device constituent is documented inside the common technical document, typically in Modules 3.2.P.7 and 3.2.R. What the consulting CDRH reviewer expects to find there is the output of design controls: design inputs and outputs, verification against delivery performance requirements, validation including human factors, biocompatibility, and the risk analysis that links them. The design and development file required by ISO 13485 Clause 7.3 is the source for all of it. Sponsors who assemble the device section from supplier brochures discover at the first information request that they cannot answer questions about a design they do not control.

Generic combination products have their own test. In an ANDA, FDA compares the user interface of the proposed product with that of the reference listed drug through labelling comparison, comparative task analysis and physical comparison of the device. Differences classed as other than minor may require a comparative use human factors study. For an injectable generic, the device is routinely the element that decides whether the product can be substituted.

Feedback follows the lead centre’s own meeting procedures, as described in the final guidance Requesting Food and Drug Administration Feedback on Combination Products of December 2020, with both centres attending where the questions require it. The statute also provides the Combination Product Agreement Meeting, in which FDA and the sponsor can reach an agreement on the standards and requirements for the product that then remains in effect. It is a tool for disputes that the ordinary meetings have failed to resolve. Clinical investigation runs under one investigational application, an IND or an IDE according to the lead centre, and not under both.

21 CFR Part 4 lets combination products run on one quality system

The starting rule in 21 CFR 4.3 is that nothing is lost by combining: a product that includes a drug constituent part is subject to Parts 210 and 211, one that includes a device constituent part is subject to Part 820, and biological products and human cell and tissue products add Parts 600 to 680 and Part 1271. Under 21 CFR 4.2, a device that is a constituent part of a combination product is a finished device. Section 4.4(a) then offers two ways to comply for single-entity and co-packaged products. A manufacturer may demonstrate compliance with every applicable regulation in full, or it may use the streamlined approach of Section 4.4(b), in which one regime is implemented completely and specified provisions of the other are added to it.

The streamlined approach is what almost everyone uses, and the QMSR rewrote half of it. Since 2 February 2026, Part 820 incorporates ISO 13485:2016 by reference, and Section 4.4(b)(1), the option for a site built on drug CGMP, lists clauses of the standard instead of sections of the old Quality System Regulation.

The right-hand column is longer than the one it replaced. The six called-out sections of the old regulation covered management responsibility, design controls, purchasing controls, corrective and preventive action, installation and servicing. The current text adds the general quality system requirements of Clause 4.1, the provision of resources in Clause 6.1, complaint handling under Clause 8.2.2 with the complaint record requirements of § 820.35(a), and the analysis of data under Clause 8.4. It also states in terms that risk management processes in product realisation must be documented and their records maintained. A drug manufacturer that mapped its system to the old six sections in 2013 and has not reopened the mapping is working from a list that no longer matches the regulation.

The opposite option, Section 4.4(b)(2), is for a site built on the QMSR. It adds eight provisions of Part 211: testing and approval or rejection of components, containers and closures in § 211.84, calculation of yield in § 211.103, tamper-evident packaging for over-the-counter products in § 211.132, expiration dating in § 211.137, testing and release for distribution in § 211.165, stability testing in § 211.166, special testing requirements in § 211.167 and reserve samples in § 211.170. Stability and reserve samples are the two that device manufacturers underestimate, because nothing in a device quality system prepares a site to hold retained samples of every lot or to run a stability programme that sets an expiry date.

Two further paragraphs decide where the streamlined system may operate. Under Section 4.4(c), while a constituent part is manufactured at a facility separate from the other constituent parts, that facility complies with the regulations for its own type of constituent part only. Under Section 4.4(d), the streamlined system may begin when two or more types of constituent part have arrived at the same facility. The syringe moulder follows Part 820. The site that fills and assembles follows Part 4. Section 4.4(e) adds that the regulations supplement each other and that, in a conflict, the regulation most specifically applicable to the constituent part in question prevails. Cross-labelled products are outside Section 4.4 entirely: each constituent part is manufactured under its own regulation.

Design controls deserve particular attention, because FDA applies them to the combination product as a whole and not to the device constituent in isolation. The design inputs include the properties of the drug. Purchasing controls reach the supplier of the device constituent, which means a pharmaceutical company buying an autoinjector platform needs supplier evaluation, a quality agreement and change notification of a kind its excipient suppliers were never asked for. In the EU none of this is imposed on a medicine-led product by device law. The quality regime follows the track: a Rule 14 device runs on an MDR quality management system audited by the notified body, while an integral medicine runs on EU GMP, and the manufacturer of its device part needs no ISO 13485 certificate as a matter of law, however often the notified body and the marketing authorisation holder ask for one.

Design controls and human factors apply to the combination, not to its parts

The technical failure common to both jurisdictions is a device developed as if it would be filled with water and a drug developed as if it would be given from a vial. Regulators assess the product the patient holds. Three bodies of evidence have to be built on the combination: delivery performance, use-related risk and the interaction between materials and formulation.

Drug delivery performance is a design output

FDA’s draft guidance on Essential Drug Delivery Outputs for Devices Intended to Deliver Drugs and Biological Products, issued in June 2024 and listed on the Office of Combination Products guidance agenda for 2026, gives the current framework. The sponsor identifies the design outputs that are essential to delivering the intended dose to the intended site, such as delivered volume, injection depth, injection time, actuation force or emitted dose, and verifies them not only on new units but after preconditioning that represents shipping, storage and use, and at the end of shelf life. The draft is not final, and reviewers already ask the questions it describes. The ISO 11608 series for needle-based injection systems, ISO 11040 for prefilled syringes and ISO 20072 for aerosol drug delivery devices supply the verification methods, and the EU file relies on the same standards under Annex I.

The drug determines the design inputs. Viscosity and its change with temperature set the spring force and the needle gauge. Fill volume and tolerance set dose accuracy. Sensitivity to shear, silicone oil or tungsten residues constrains the materials of the container. Stability is tested on the drug in its final container and device, because functional performance at expiry is part of the specification. Where the clinical studies used one presentation and the product to be marketed uses another, a vial in the pivotal trial and an autoinjector at launch for example, the gap has to be closed by a bridging argument, which FDA’s December 2019 draft guidance on bridging treats as a structured exercise of identifying the differences and the information that can be leveraged across them.

Materials are assessed from both sides. The device side asks for biological evaluation in a risk management process under ISO 10993-1. The medicine side asks for extractables and leachables, because a substance that migrates into the formulation is an impurity in the drug product whatever its biocompatibility. One chemical characterisation programme can serve both when it is planned as one. Run as two, it produces two data sets that reviewers will compare.

Use-related risk is where approvals are lost

Risk management has to join two traditions. Device risk management under ISO 14971 analyses hazards, hazardous situations and harm for the device. Quality risk management under ICH Q9(R1) addresses the quality of the drug product. AAMI TIR105:2020 was written to connect them for combination products, and the regulation now forces the issue: the amended Section 4.4(b)(1) requires documented risk management processes in product realisation even at a site built on drug CGMP. A single risk management file in the structure of ISO 14971, with the drug-related hazards of underdose, overdose, wrong route and delayed therapy carried through it, is the workable answer.

Human factors is the part of that file FDA reads most closely. The final guidance Application of Human Factors Engineering Principles for Combination Products: Questions and Answers of September 2023 defines a critical task for a combination product as a user task which, if performed incorrectly or not performed at all, would or could cause harm to the patient or user, where harm includes compromised medical care. That is broader than the definition CDRH applies to devices alone, which speaks of serious harm. An incomplete injection that leaves the patient under-dosed may fall short of serious harm. It is compromised medical care, and the task that leads to it is critical. A delay that has no consequence for the patient is not. The July 2024 draft guidance on use-related risk analysis sets out the document that organises this: every task, the possible use errors, the potential harm, whether the task is critical, the risk control and the method used to evaluate it.

The human factors validation study is then run with representative users, on the final finished combination product, with the final labelling and instructions for use, under simulated conditions of actual use. Results obtained on a prototype or with draft instructions do not validate the product that will be marketed, and discovering that after the pivotal trial costs a year. In the EU the same evidence answers Annex I Sections 5 and 22 and is built to IEC 62366-1. The EMA guideline asks for usability evidence in the dossier where the device part has not been used before in the intended population or setting, and the notified body will have looked for it when forming its opinion.

After approval the reporting duties stack up; they do not merge

Subpart B of 21 CFR Part 4, in force since January 2017, distinguishes two kinds of applicant. A constituent part applicant holds the application for one constituent part of a product whose other part is marketed by someone else. It reports under the rules for its own application type and, under Section 4.103, must pass information on any death, serious injury or adverse experience to the other applicant within 5 calendar days of receiving it. A combination product applicant holds the application for the product as a whole. It reports under the rules of its application type and, under Section 4.102(c), also submits the specified reports that belong to the other constituent part.

For a prefilled pen approved under an NDA, this means the pharmacovigilance group now owns malfunction reports and five-day reports, and under Section 4.102(d) the periodic safety report must contain a summary and analysis of them. For a drug-eluting stent approved under a PMA, the device vigilance group owns field alert reports and fifteen-day reports, with 30 days instead of 15 for the latter. Records are kept for the longest period that any of the applicable regulations requires. The organisational consequence is one complaint intake that can recognise both a device malfunction and an adverse drug experience in the same telephone call.

The EU again assigns one regime per track. A Rule 14 device is under MDR vigilance: serious incidents reported under Article 87, an annually updated periodic safety update report under Article 86, a summary of safety and clinical performance under Article 32 and post-market surveillance under Articles 83 to 86. An integral medicine is under pharmacovigilance alone. A failure of its device part is handled by the marketing authorisation holder as a quality defect and, where a patient is affected, as an adverse reaction, and MDR vigilance does not apply because the device part was never placed on the market as a device. Co-packaged and referenced combinations are the hard case, with two legal manufacturers, two reporting systems and one event, and they need a written agreement that says who receives the complaint, who investigates the device and who reports to which authority.

Changes follow the same split. In the US, a change to the device constituent of an NDA product is a change to the application and is reported in the category that its potential effect on the product warrants, whatever the device supplier’s own change classification says. In the EU, a change to the device part of an integral medicine is a variation, with a new or updated notified body opinion where conformity with the relevant requirements is affected, and a change to the ancillary substance of a device goes back to the medicines authority for its 60-day opinion.

Two EU reforms are about to redraw the lines

The EU side of this comparison describes law that is being rewritten from both directions, and both texts were still in the legislative procedure at the start of October 2026.

The first is the reform of pharmaceutical legislation, a new directive and a new regulation that will repeal Directive 2001/83/EC and Regulation (EC) No 726/2004. Political agreement was reached in December 2025, the compromise texts were published in March 2026, and the Council adopted its first-reading position on 28 September 2026. Formal adoption by the Parliament and publication in the Official Journal are expected by the end of 2026, with application 24 months after entry into force. The new directive gives combinations of medicinal products and devices dedicated provisions for the first time. As described in the compromise text, the applicant for an integral combination must submit data establishing the safe and effective use of the combination as a whole, the competent authority assesses the benefit-risk balance of the entire product, conformity of the device part with the relevant requirements of the device regulations must be demonstrated, and the marketing authorisation holder carries overall responsibility for the whole product. Point 12 of Section 3.2 of Annex I, the vehicle of Article 117, goes when the Directive that contains it is repealed. The obligation it carries does not go with it.

The second is the targeted revision of the MDR and IVDR, proposal COM(2025) 1023 of 16 December 2025. Its relevance to this subject lies in four measures. The consultation of medicines authorities for devices incorporating a medicinal substance would be streamlined and shortened. The consultation for systemically absorbed substance-based devices would be removed. The clinical evaluation consultation procedure would no longer cover class IIb active devices that administer or remove medicinal products. And a sponsor running a combined study, a clinical trial of a medicine together with a clinical investigation of a device or a performance study of a diagnostic, could file a single application leading to a coordinated assessment under the Clinical Trials Regulation, instead of the parallel procedures that apply today. The proposal also removes the five-year maximum validity of certificates, Rule 14 certificates included.

Two neighbouring regimes are worth keeping in view because they use the same consultation model. Under the IVDR, a notified body assessing a companion diagnostic must consult a medicines authority on the suitability of the device in relation to the medicinal product concerned. Under Regulation (EC) No 1394/2007, a combined advanced therapy medicinal product incorporates a device as an integral part of a cell or tissue product, is authorised as a medicine, and has its device part assessed against the device requirements. The first is generally not a combination product in the US sense; the second would be a biological-device combination product assigned to CBER. Both fail in the same way when the device evidence is left to the end.

None of this justifies waiting. A proposal confers no rights, the timelines above are expectations, and a file built to the law in force will survive either reform with a change of citations. A file built to a draft will not survive the draft being amended.

The six gaps that stall combination product files

The deficiencies that delay these products are consistent across notified body opinions, FDA information requests and inspections. They are organisational before they are technical: each one appears where the responsibility of the device function ends and that of the pharmaceutical function begins.

The choice of track comes first because it cannot be repaired later. A product whose mode of action was asserted and not demonstrated will be reclassified by the first regulator who reads the mechanism section, and reclassification in Europe means a different law, a different authority and a different quality regime. The missing Article 117 evidence is the same failure in scheduling form: a notified body has to be contracted, it has to hold the right designation codes for the device type, and it works to no statutory deadline.

The three major gaps are all failures to treat the product as one thing. Design controls kept at the device supplier leave the applicant unable to show that drug properties were design inputs. A Part 4 mapping that stops at the list of clauses, without a purchasing file for the device constituent or a route from device complaints into corrective action, satisfies nobody who asks to see a record. A human factors validation performed before the instructions for use were final validates a product that was never marketed.

The last gap is rated minor only because it is the cheapest to close. Two complaint systems, one for the medicine and one for the device, guarantee that a malfunction report is filed late or not at all. One intake procedure with two reporting clocks closes it.

Frequently asked questions

What is a combination product under FDA regulations?

Under 21 CFR 3.2(e), a combination product is made of two or more different types of regulated article: a drug and a device, a biological product and a device, a drug and a biological product, or all three. It can be a single entity, co-packaged, or two separately packaged products labelled for use only with each other. Each article is a constituent part, and the product is assigned to one lead centre according to its primary mode of action.

Does the EU MDR define combination products?

No. Neither the MDR nor Directive 2001/83/EC defines the term. Articles 1(8) and 1(9) of the MDR describe four situations instead. A device with an ancillary medicinal substance is a device. A product whose medicinal action is principal, or a single-use integral delivery system, is a medicinal product whose device part must meet the relevant requirements of Annex I. A device supplied separately to administer a medicine is a device.

When is a notified body opinion required under Article 117?

When a medicinal product forms an integral combination with a device part, the device part is not CE marked, and that device part would need a notified body if it were placed on the market separately. In practice this covers sterile, measuring and reusable surgical class I devices and everything in class IIa, IIb or III. The opinion addresses conformity with the relevant general safety and performance requirements and is included in Module 3.2.R of the dossier.

Is a prefilled syringe a medical device or a medicinal product?

In the EU, a single-use prefilled syringe is a medicinal product, because syringe and medicine form a single integral product intended exclusively for use in that combination and not reusable. The syringe must still meet the relevant requirements of Annex I to the MDR. In the US it is a single-entity combination product with a drug or biological primary mode of action, reviewed under an NDA or BLA. An empty syringe sold on its own is a device in both jurisdictions.

What is the primary mode of action of a combination product?

It is the single mode of action that provides the most important therapeutic action of the product, defined in 21 CFR 3.2(m) as the one expected to make the greatest contribution to the overall intended therapeutic effects. It determines which FDA centre leads the review. Where it cannot be determined with reasonable certainty, FDA applies the algorithm in 21 CFR 3.4(b), looking first at how similar products are regulated and then at which centre has the most relevant expertise.

Which cGMP requirements apply to combination products after the QMSR?

Both the drug CGMP regulations and the QMSR apply. Under 21 CFR 4.4(b), the manufacturer of a single-entity or co-packaged product can implement one regime in full and add specified provisions of the other. Since 2 February 2026 the provisions added to a drug CGMP system are clauses of ISO 13485: 4.1, 5, 6.1, 7.3, 7.4, 7.5.3, 7.5.4, 8.2.2, 8.4 and 8.5, together with sections 820.10, 820.35(a) and 820.35(b).

Does a drug-eluting stent need a medicines authority consultation in the EU?

Yes. It is a device incorporating an ancillary medicinal substance, class III under Rule 14, and Article 52(9) of the MDR requires the procedure in Annex IX Section 5.2. The notified body seeks a scientific opinion on the quality and safety of the substance from a national medicines authority or from EMA, which has 210 days from receipt of complete documentation. The certificate cannot be issued if the opinion is unfavourable.

How long does a Request for Designation take?

FDA must issue its designation letter within 60 days of the filing of a Request for Designation under 21 CFR 3.7. If it does not, the centre recommended by the sponsor becomes the designated lead centre. The request is limited to 15 pages. A Pre-RFD is the informal alternative: its feedback is not binding, and it is the better first step when the mode of action is open to argument.

Conclusions

The strategic decision for a combination is made once, and it is the decision on principal action. It should be written down with the evidence of mechanism behind it, tested against MDCG 2022-5 rev.1 and 21 CFR 3.2(m) at the same time, and taken to FDA through a Pre-RFD where the answer is honestly open. Companies that defer it are deciding it anyway, by default and usually in the more expensive direction.

After that, the work is the same work in both jurisdictions under different labels. A design and development file for the whole product, a single risk management file that carries the hazards of the dose as well as those of the device, human factors validation on the configuration that will be sold, and a quality system that reaches the supplier of the other constituent part: these answer the notified body opinion, the medicines authority consultation, the CDRH consult and the Part 4 inspection alike. What differs is where the evidence is filed and who reads it.

The EU will look different in 2028, and the direction is towards the US model: the combination assessed as a whole, with one party responsible for it. Building the file that way now is not a bet on the reform. It is what the current law already rewards.

If you are building the device side of a combination, the MDR Complete Bundle on MD Regulatory brings together the technical documentation, risk management and clinical documentation templates in one cross-referenced set, aligned with Annex I, Annex II and Annex XIV of the MDR and immediately deployable in an existing ISO 13485 quality management system.

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• Biocompatibility Testing for Medical Devices Under ISO 10993
• ISO 13485:2016 — The Complete Guide to Medical Device Quality Management