Drug-device and device-drug combination products
A combination product joins a medicinal substance and a device, in one product or in one use. How it is classified decides which framework governs each half, which body assesses which part, how many applications there are, what evidence and medicinal-substance content the device half of the file needs, and which reporting system an event belongs to.
Size of the category
Drugs, devices, diagnostics and digital products may now not merely coexist but be combined, intertwined and interdependent. By one 2025 account, 20% of approved medicinal products are combination products comprising both a medicine and a medical device, and one in five healthcare products under development is a combination product.
Forms of combination product
Definitions of a combination product differ by region, but one can generally be defined as two or more regulated products, such as transdermal patches for drug delivery, inhalers including corticosteroid inhalers, prefilled syringes, prefilled injection pens and drug-eluting stents. The FDA defines drug-device combination products as therapeutic and diagnostic products that combine drugs, devices and/or biological products.
A drug and a device can be physically or chemically combined, co-packaged, or cross-labelled, each referring to the other. The United States defines and categorises combination products formally in 21 CFR Part 3.2(e) as physically or chemically combined, co-packaged together, or cross-labelled to create a new intended use. One pharmaceutical company's products include each of these forms. Among them, a software-and-hardware add-on that goes onto an inhaler, communicates with an app that sends reminders and tracks medication use, and passes data to a portal the healthcare professional can read is a medical device in its own right. The company's largest group is single-integral: a prefilled syringe, a prefilled injector or a prefilled inhaler, in which the drug is preloaded in the device. A capsule inhaler in development is co-packaged: the dry powder has to be kept dry, so it comes as capsules in a separate container in the same pack, and the patient loads them before use. A cardiac drug in development is cross-labelled: it will not be co-packaged with a device, and will state only that it needs another device, a heart catheter, to deliver it.
In 2019 the line between drugs and devices was blurring as biology and technology merged. The European Medicines Agency, which traditionally dealt only with medicinal products, had recently released a draft guideline on quality requirements for drug-device combinations, and where the term combination products brought to mind prefilled syringes and antihistamine pens, the trend was towards more complex combinations and delivery systems. One is a digital pill, marketed as Abilify MyCite: a tablet of the antipsychotic aripiprazole with an embedded ingestible sensor whose chip, once in the stomach, sends a signal to a wearable sensor or dermal patch that is recorded in an app, so that adherence to treatment can be monitored; the FDA approved it in 2018. Others in 2019 were an ingestible self-orienting millimetre-scale applicator, then in testing, whose needle is made of insulin and delivers it into the peritoneal wall when swallowed, and drug-releasing textiles under development with potential uses from wound care to glucose monitoring. Writers need to step out of their comfort zone to deal with the new terminology such products may bring from engineering, informatics and materials science.
Primary mode of action
Which regulatory pathway applies turns on whether the device or the medicinal substance has the primary mode of action. In a device-led combination the device does the work and the drug is ancillary: a drug-eluting stent mechanically opens the vessel, and the drug is there to help prevent restenosis. In a drug-led combination the medicinal substance does the work, so an inhaler for chronic obstructive pulmonary disease filled with nothing but air would probably be useless. There are also borderline products whose primary mode of action is not easy to classify, and the classification is usually decided before a medical writer is involved.
Regulation in the United States
As of 2023, no harmonised regulatory framework existed globally for combination products, medical devices and digital health technologies. In the United States a combination product follows a single regulatory pathway, whose requirements are set by its primary mode of action, the product's most important therapeutic action. As of 2023, the formal definition and categorisation in US regulations streamline premarket submissions and post-market activities. The primary mode of action decides which FDA centre reviews the whole submission. A drug-led product, such as a single-integral medicinal product with a co-packed needle, is a drug submission to the Center for Drug Evaluation and Research, with the device information in Module 3 of the eCTD, while a device-led one includes the drug information in the pre-market notification or application to the Center for Devices and Radiological Health. The Office of Combination Products assigns the lead review division on the basis of the primary mode of action, and a request for designation is available where that is unclear. In one device writer's view, the US market is conceptually similar to the European one. The relevant parts of 21 CFR apply, clinical data in humans are usually needed, and a combination product usually may not go through a 510(k) and needs pre-market approval instead, the most extensive US route to market. A drug master file is also needed, usually bought from the pharmaceutical company supplying the drug and referenced by its number.
Regulation in the European Union
Europe gives the category no pathway of its own: a combination is regulated as a device or as a medicinal product according to its principal intended action. As of 2019 that yielded two main routes, medicinal products with a device component and devices incorporating an ancillary medicinal product. Either way the product has to comply with the device regulation or the in vitro diagnostic regulation, which adds new requirements, including a notified body, for products that previously would have followed mainly the pharmaceutical route, and raises the regulatory burden for both medicinal products and devices. The device regulation states that combination products are regulated either under it or under Directive 2001/83/EC, and that the two acts should ensure appropriate interaction through consultation during the premarket assessment and exchange of information in vigilance. Developing a combination product may require following both frameworks, which should be settled case by case. As of 2023 the EU formally recognised neither the term nor the US categories. A product combining a drug with a device is referred to as a drug–device combination and involves more than one authority, so the marketing authorisation application needs device information and a notified body opinion or declaration of conformity for the device part. Coordinating that is compounded by development timelines of, for example, 10 to 15 years for the drug against 2 to 5 for the device, and by the different clinical evidence each component needs.
For a device-led combination the European medical device regulation applies, while the medicinal substance has to satisfy Annex I of the pharmaceutical legislation, and for a drug-led combination the reverse holds. A medical device does not achieve its principal action by pharmacological or comparable means, and for combinations the regulation adds that the medicinal substance's action must be ancillary rather than primary. In one device writer's account, the ancillary substance must also genuinely have an action rather than being present for marketing purposes: this was less clearly defined in the past, and now the action has to be shown.
As of 2025, the most important regulation for a device-led combination is the medical device regulation, Regulation (EU) 2017/745, which covers definitions, classification, clinical investigation, clinical evaluation and the content of the technical documentation. Its 2023 amendment only extends timelines, and Annex I of the pharmaceutical directive applies to the medicinal substance. That writer finds the European Medicines Agency's documents not essential but helpful to read, because they show how a notified body connects with the agency over the medicinal part, whom to contact about a classification question, and that pre-submission meetings should be held. Local regulations also apply, but are usually more or less the same as the European ones. Guidance on borderline products carries examples, decision trees and whom to consult when a classification is unclear.
The device and in vitro diagnostic regulations changed the European legal structure for devices, giving the European Medicines Agency and national competent authorities new responsibilities in assessing certain categories of devices used in combination with medicines. Under the device regulation the agency provides consultation on certain medical devices and drug-device combinations, and an opinion on borderline products. The agency's practical guidance on implementing the device and in vitro diagnostic regulations for combinations is a questions-and-answers document for applicants, marketing authorisation holders and notified bodies. Its May 2024 revision rests on the experience gained since the regulations applied and on actual cases, and covers integral combinations such as pre-filled syringes and their lifecycle management, medicines co-packaged with a device and how they are labelled, the consultation procedure for devices with an ancillary medicinal substance, and the consultation procedure for companion diagnostics.
Devices incorporating a medicine and medicines delivered by a device
The devices that may interact with medicines run from devices that are not combinations to true combinations. At one end sit in vitro diagnostics, from a glucose monitor that shows how a drug is performing to a companion diagnostic that shows how a drug is performing or when one is needed. Next come standard devices used with a medicine without being combined with it, such as imaging equipment used with a contrast agent: the two have very separate regulatory pathways, but in looking at the device it matters how it is used with the medicine. Then come devices intended to administer a medicine, such as a syringe pump, where the questions are which medicines it will be used with, how they vary in volume and viscosity, and whether the device has been validated across that range. Past those come the true combinations, which one notified body specialist calls device-drug and drug-device combinations. A medicinal product goes through the medicines competent authorities or the European Medicines Agency for its marketing authorisation, and a device goes through a notified body for a certificate that allows a CE mark; the combination products are where things get greyer.
The medical device regulation sets out the European split in Article 1(8), for devices that incorporate a medicine, and Article 1(9), for devices intended to administer one. A device incorporating a medicine is a single integral device in which the medicinal substance has an ancillary action and the device the primary one, as in a drug-eluting stent, a device that happens to contain a drug rather than a device for delivering one. These fall under Rule 14, which sends them down the device conformity assessment route with one addition: as part of that assessment the notified body asks a European medicines competent authority for a scientific opinion on the medicinal part, assessed by analogy to the medicinal product directives for quality, safety, non-clinical work and clinical efficacy. A positive opinion lets the notified body complete the assessment and award the certificate. Such a product is sometimes informally called a device-drug combination, abbreviated DDC like the integral kind, and is not to be confused with the integral combinations under Article 117.
In a Rule 14 product the device has the main effect and the medicinal substance a supportive one. Pacing leads carrying electrical impulses from a pacemaker may contain dexamethasone as an anti-inflammatory, so that implanting the lead does not provoke an inflammatory reaction that gets in the way of the signal. A drug-eluting stent holds the artery open while the drug prevents restenosis. Bone cement physically joins bone and may carry an antibiotic against deep-seated infection. A condom is a physical barrier that may carry a spermicide as an additional one. A silver dressing covers the wound and provides a healing environment while the silver, a medicine in that context, is there to prevent infection, particularly within the dressing. Media used in in vitro fertilisation often contain antibiotics, against infection, and human serum albumin, to support the gametes and embryos. All of these get a device conformity assessment and a CE mark, and all of them need a medicines consultation, whose report on the medicinal aspects is combined with the notified body's report on the device. The IVF media are a special case: human serum albumin is derived from blood, so their consultation goes to the European Medicines Agency rather than to a national competent authority. Rule 21 covers devices containing substances, such as a paraffin dressing, which need to comply with Directive 2001/83/EC.
Article 1(9) is put into effect through Article 117 of the device regulation, which amends the medicinal product directive. The product, such as a prefilled syringe or an inhaler, is a medicinal product and goes through the medicinal conformity route, but the relevant general safety and performance requirements from Annex I of the device regulation also apply, as justified by the device's intended purpose, and the manufacturer needs an opinion from a notified body on the device constituent to file with the marketing authorisation application. From 26 May 2021 such a product has needed either CE marking on the device component or a notified body opinion included in the marketing authorisation application. Article 117 requires that application to include a declaration of conformity or relevant certificate issued by a notified body. The qualifying tests are that the device is single integral, not reusable, and intended exclusively for use in that combination. An inhaler may be multi-dose and a prefilled syringe single-dose, but once the inhaler is finished the whole product is discarded, and although many inhalers share a shape, each one carrying a different drug is a separate medicinal product. The notified body opinion is not required for class I non-sterile and non-measuring devices. Integral means that manufacturing and design run together throughout, not that the two parts are integrated later: a prefilled syringe cannot work without its drug, nor the drug without the syringe.
Two dry powder inhalers delivering the same drug can go down different pathways. In the first the drug is preloaded, so the device is single integral, exclusively for use and not reusable, and the whole product is a medicinal product under Article 117. In the second the user loads capsules, so it is not single integral, and whether it is exclusively for use and not reusable is arguable: the manufacturer may say it is only marketed that way, while a different capsule could theoretically be loaded and the inhaler reused. There the capsules are a medicinal product and the inhaler is a medical device needing its own conformity assessment.
Where a standalone CE-marked device is used with a drug, an arrangement FDA vocabulary calls cross-labelled, the device needs a CE mark and goes through the whole conformity assessment. New under the device regulation are the relevant general safety and performance requirements in Annex I, and the results of assessing them go to the notified body for its opinion or into the device conformity assessment as usual.
A writer contributing to the pre-market applications of products under Rule 14, Rule 21 or Article 117 has to document against both the device regulation and Directive 2001/83/EC, whose reviewers and requirements differ. That may be a challenge for a writer used to one sector, and also an opportunity to learn the regulatory language such submissions need.
The notified body opinion under Article 117
At one notified body, an Article 117 assessment is much the same as a device assessment except in two ways: the notified body does not look at the quality management system, and it does not need to look at clinical evidence. For a medicinal product the quality management system is most likely good manufacturing practice, which falls to the national competent authority or the agency rather than the notified body, whereas for a Rule 14 device the notified body examines both the technical dossier and the quality management system, the latter assuming ISO 13485 is followed. The output is not a certificate but an opinion, issued to the manufacturer to be filed with the marketing authorisation documentation. The process in between is to choose a notified body, take a quote, sign a contract, plan the review, hand over the technical documentation, be assessed and, where necessary, answer questions. At that notified body the question-and-response cycle can run to three rounds, and once the questions are closed a technical specialist recommends the product and an independent review follows.
Devices a pharmaceutical organisation does not recognise
One pharmaceutical company employs hundreds of regulatory staff, of whom about ten work on medical devices, in a traditional business of small molecules and biologics that had only started device work in the preceding few years. One of its regulatory affairs directors illustrates the challenges such a company faces with medical devices through a few cases.
In the first, a CE-marked system developed by a third party was bought for use in company-sponsored studies, and after a study had started the team discovered that the CE mark had expired. The team knew it needed a CE-marked device but did not know what an expired certificate meant, and in a company of some 94,300 people it could not tell what the person able to answer would look like. It found the device regulatory team by luck, because that team was promoting itself and running education on device regulation at the time, and the team found a way to keep using the device, which saved the study.
In the second, a team planning a phase 1 study in Europe and the US to inject an investigational medicinal product into the heart assumed that because its devices were FDA-approved and CE-marked it could simply use them. The assumption surfaced when a briefing document about the drug submitted to the FDA came back with many questions about the device, which the regulatory colleague reported as the agency asking about a device the team did not have. What the team was using to deliver the drug was needles and syringes, which it did not regard as devices at all. An assessment found them to be hypodermic products used mainly for subcutaneous insulin injection, so injecting into the heart was use outside their intended purpose and required further device development.
By 2025 the FDA's combination-product definition had been known for almost 16 years, while Europe had no such approach until the device regulation of 2017, which created a lot of trouble for everyone, in the device world as well, because the approach was unknown. In one practitioner's experience, where all this was new to a drug company, it was important to align on the language and its meaning and on the regulatory processes behind it, which are not dissimilar to what the drug world is used to.
Device development in a pharmaceutical organisation
What device development means was itself the next obstacle in the second case: a pharmaceutical organisation that understands pharmaceutical development pictured printing some plastic parts and sticking them together. In that case it required substantial collaboration with surgeons, to check whether they could use the needles and syringes, since the procedure involves navigating a needle through small chest incisions to the right place in the heart; human factors studies, a term the team did not know; and the device engineering team and the clinical development team, who had never met, working together for the first time. The company also had to contract with and pay the manufacturer that sold it the devices for information on what had already been done, so that it could work out what remained, such as drug-device compatibility and the additional safety risks of using those needles and syringes in that setting. The development the team had expected to be simple was going to take more than a year, and that estimate was optimistic.
The third case was a system the company assembled itself from bought components, some CE-marked and some not, intended only to check in early-phase studies whether the drug worked and never for commercialisation. For a phase 2 study in Canada, the team debated whether to ask a regulatory person at all, some arguing that it had been done before and this was only a phase 2 study, and when someone eventually asked, the answer was that, because the device was not approved, an investigational testing authorisation was required, the Canadian device counterpart of a clinical trial application. Nobody in the company knew how to make one: there was no process, no capability, and no resource or budget had ever been set aside for it.
The last and worst case was a device the company is developing to commercialise. A traditional prefilled inhaler is single-integral, regulated by most health authorities as a drug only, and needs only one application at each stage, a clinical trial application for investigation and a marketing authorisation application for marketing. The new product, in which the drug is not preloaded, is regulated as two products: the device must comply fully with the medical device regulation, most regions require an application separate from the marketing authorisation application, and in Europe a separate clinical investigation had to be run for the device. That meant combined studies, the company's first two clinical studies of a medical device and a drug together, with no process, resources or budget allocated, and a long, hard battle to get people even to realise what was needed.
The company had no idea how to become the legal manufacturer of a medical device: people did not know what legal manufacturer or CE mark meant, and the answer to being told the device needed a CE mark was to ask whether one could simply be printed. Getting people, especially senior management, to understand what developing and commercialising a standalone device involves took a great deal of work before any of the work itself began.
Clinical evidence for the device part
One of the questions a notified body is most commonly asked is whether a clinical evaluation report is needed, and in 2025 one notified body's general answer was no: the clinical efficacy of a drug-device combination rests on the medicine, which competent authorities review and the notified body does not. There are exceptions. Where a clinical claim rests on the device, such as a syringe causing less pain than a competitor's, the notified body wants the clinical evidence behind that claim. Where the device carries clinical safety risks of its own, as when the combination is implantable, the notified body requires clinical evaluation. But 99% of the time no clinical evaluation report is needed, and for a prefilled syringe or an inhaler the notified body does not need to see one.
Whether the device performs as intended, under the general safety and performance requirements, is typically evidenced by things such as human factors studies, which need not be written up as a clinical evaluation report. The notified body asks whether the device can perform as intended for the right patient population and the right user group, which need not be shown with clinical evidence although it can be supported by it. The efficacy of the medicine is not assessed there, only whether the device can deliver the dose it has been asked to deliver. Usability validation is an important part of the assessment, but state of the art is not assessed as it would be for a device. Whether a prefilled syringe is marketed with a plain needle or with a state-of-the-art safety device is the company's choice; the notified body asks whether the product delivers what it is intended to and can be used by patients safely and effectively.
An industry association's representative held in 2025 that any claim for a device component needs clinical evidence behind it, that usability data are often not enough for that, and that even where the document is not called a clinical evaluation report, the device component needs clinical data confirming its performance and safety.
One pharmaceutical sponsor came to the device's evidence with far more clinical data than a normal device company. In its commercial inhaler programme, the drug side runs several phase 2 studies, two phase 3 studies and perhaps five more for additional indications, so the company expects to run something like ten clinical investigations on a class IIa device. Clinical evidence is therefore no difficulty for it.
The endpoints of a study of a combination product's device component depend on the device. For a standalone device used with a drug, the performance study or clinical investigation endpoints should relate to performance and safety, such as dose accuracy and the adverse events expected from contact with the patient's skin or from implantation. For an integral combination the minimum is safety and the accuracy of the dose delivered. Usability is part of the picture but belongs to the validation done beforehand; user errors that can count as device deficiencies can also be considered in the endpoints, and those not known in advance can be considered later in the safety assessment. In the industry representative's view, the endpoints should always cover safety and performance, especially where a claim is made for the device component.
What a device-led file has to show
In one device writer's view, writing for medical devices is straightforward even with an ancillary drug, because what must be shown is that the device is safe, that it does what it is supposed to do, that the benefit outweighs the risk, and that it is at least as good as the state of the art. That holds for a standalone device and for a combination alike. A clinical investigation plan for a first-in-human study cannot prove these things, since proving them is why the study is done, but it should show all the reasonable evidence that they hold.
Medicinal-substance content of a device file
For a device-led combination the drug is usually bought from a pharmaceutical company, together with its drug master file. Annex I of the pharmaceutical directive lists everything that must be shown for the medicinal substance, but one device writer rarely works through it item by item, because what is usually submitted is the open part of the drug master file obtained from the supplier, and a later request for the closed part is submitted by that supplier. What that writer usually includes is a statement that an ancillary medicinal product is present, its name, its manufacturer or supplier, its composition and chemical description, the drug content, the pharmacokinetics, and, very importantly, the benefits and risks of incorporating that substance.
The level of detail a document gives about the device part depends on whether the device and the drug are already approved or new. An approved drug in an approved device still needs a new approval when the two are newly combined, because new technical issues may arise, such as the drug slipping off a drug-coated balloon. A new drug with a new device is the most complex case. The level of detail also depends on the document. Potentially public-facing documents, such as the clinical investigation plan, the clinical investigation report and the instructions for use, should carry succinct but complete information while guarding intellectual property. The investigator's brochure is more comprehensive, mostly in preclinical work, meaning in vitro and animal testing, and the clinical evaluation report and its associated documents are what is submitted for the CE mark. The more clinical data there are, the less emphasis the preclinical work needs, while in a clinical investigation plan for a first-in-human study the preclinical information carries more weight. Clinical data from similar products can be added, and that writer recommends the FDA's summaries of safety and effectiveness data as a source. What counts as well established is always debated, and well established usually means at least ten years of experience.
In that writer's view, device people meeting pharmaceutical requirements have an easier time than pharmaceutical companies meeting device ones. Device companies almost always buy the drug in, usually an already known one with small modifications, so the knowledge is brought in and the work comes down to following Annex I of the 2001 directive, and not even word by word, because there is usually a drug master file. The knowledge inside a smaller device company may not be large, but awareness would be better, because pharmaceutical regulation is, or has been, the stricter of the two, particularly before the medical device regulation. That writer knows of no device company buying in anything other than a finished formulation, and for one device she knows of that combines three drugs, the drug company is asked to do that work.
Drug risks in a device file
The risk section has two important considerations. First, the drug dose carried on a device is usually lower than a systemic dose, so the risk is lower; this is usually stated in a disclaimer, and one device writer prefers to report the risks of the device and of the drug separately. Second, that writer urges taking the drug's risks from reliable references: companies like to copy the instructions for use of a competitor product, and she almost always sees flaws in their risk sections. Arguing for more risks to be listed may be a hard battle to win inside a company, but the writer needs at least to alert the company that the competitor's risk section is not comprehensive enough.
The writer as a bridge between the two worlds
In 2019 rapid innovation, an evolving regulatory framework and expected industry growth made combination products an opportunity for writers who understand both the pharmaceutical and device worlds, with more regulation and guidance expected.
That regulatory affairs director sees two roles for medical writers here. The first is to bridge the knowledge gap by translating specific terms between the two vocabularies, such as the clinical study protocol against the clinical investigation plan, and the clinical evaluation plan against the clinical investigation plan, which that director is often asked to tell apart. Understanding both worlds, with their many differences and many similarities, lets a writer communicate with both and speak both languages.
The second is raising awareness across the organisation, which writers who work closely with clinical teams can help with, because many of the issues in that company's cases came from the clinical side.
One writer facing a clinical investigation report on the aripiprazole tablet with an embedded ingestible sensor would split the research in two: the pharmaceutical component, more familiar ground covering the science, development history and rationale for the investigation, and the technological component, whose language and concepts need more research. Applying transferable skills in research, synthesis and critical appraisal would then make the technology familiar more efficiently and show how the two components work together.
Safety reporting
A combination product has two safety-reporting systems behind it. A drug-dominant event goes into pharmacovigilance and a device-dominant one into post-market surveillance, and for a combination the manufacturer ends up working with both the notified body and a medicines agency such as the European Medicines Agency. Adverse event reporting for a combination has to cover drug delivery malfunctions as well, and where the device is claimed to contribute to the delivery or use of the drug, it plays the dominant role and the event goes down the device route.
Whom a manufacturer should talk to first when something happens with a combination device that needed no clinical evaluation report, the notified body, the medicines agency or someone else, is unclear in practice. In one technology consultant's view, that confusion comes from a lack of interaction between disciplines: in drug-device combinations, one person often knows only the drug part and another the device part, and they do not cross-pollinate.