A combined ATMP is an advanced therapy medicinal product that contains one or more medical devices as an integral part. The medical device component can, for example, serve as the matrix into which cells are incorporated, or permanently connect a delivery device to the medicinal product. The classification therefore links pharmaceutical law with the requirements of medical device law.
Legal Product Definition
Article 2 of Regulation (EC) No 1394/2007 describes a combined ATMP as an ATMP that contains a medical device or an active implantable medical device as an integral part. Its cells or tissues must either be viable or expected to exert the primary action on the human body. It is this combination of ATMP and an inseparable product component that distinguishes the combined ATMP from a mere co-administration of two products.
The medical device part must meet the relevant essential safety and performance requirements. For the integrated product component, not only its technical function but also its compatibility with the biological component must be described. The EMA explicitly states that some ATMPs may contain one or more medical devices as an integral part.
Assessment at the Interface
The centralized authorization assesses the combined product as an advanced therapy medicinal product. However, the results of the conformity assessment of the medical device component are taken into account during the scientific evaluation. The requirements for the medical device do not disappear simply because it becomes part of a medicinal product.
Developers must therefore align the content of the technical documentation and the medicinal product dossier. Information on material, sterility, biocompatibility, performance, and interactions can be significant for both assessment streams. For example, a matrix with cells is not merely packaging if it co-determines the application and effect of the product.
Distinction from Medical Device and ATMP
An independent medical device remains a medical device if it is not an integral part of an ATMP. Conversely, not every ATMP with accessories automatically becomes a combined ATMP. The decisive factor is the fixed, inseparable connection of the product component with the ATMP and its function in the final product.
The entry ‘medical device’ deals with the independent legal category; ‘eu-mdr-2017-745’ concerns the EU legal framework for medical devices. The combined ATMP represents the special interface: the marketing authorization for medicinal products applies to the overall product, while the relevant medical device requirements must additionally be demonstrated for the embedded product component.
The interface question begins already during product development and not just at the time of authorization. It must be determined what function the medical device component fulfills in the final product, whether it is in contact with cells, tissues, or another ATMP component, and whether the connection can be separated before application. For clinical trials, this can influence what training is required and which product-related incidents are recorded. If different components are delivered separately and only combined at the site, the study plan must demonstrate how they form the defined final product. A designation as a “combination” in common parlance does not replace this legal review.
The question of the integral component is also relevant for changes. If a material, coating, or connected application element is exchanged, this cannot be treated as a technical detail change without review. It must be assessed whether this affects the properties of the overall product, human application, or previously collected non-clinical data. The regulatory argumentation must describe not only the individual component but also the interaction between the medicinal product part and the medical device.
Relevance for clinical trials
Studies with combined ATMPs require a precise description of what is actually delivered and applied to the clinical trial site. Changes in materials, application systems, or adjustments to a cell carrier matrix can affect quality and clinical application. Training materials must therefore address the handling of the product, the traceability of the medicinal product component, and technical specifications for the integrated component together.
Full-service CROs like Mediconomics support the alignment of the study plan, Investigator’s Brochure, and eCRF with the specific characteristics of the combined product. They organize regulatory affairs contributions to the dossier structure, coordinate sites regarding application and documentation, and monitor whether product identification, implantation or administration, and technical incidents are comprehensibly recorded.
Frequently Asked Questions (FAQ)
Can a syringe constitute a combined ATMP?
Not every delivery device makes an ATMP a combined ATMP. The decisive factor is whether a medical device is present as an integral part of the final product and whether the legal criteria are met.
Does medical device assessment remain relevant for centralized authorization?
Yes. The applicable requirements for the medical device component must be met; the relevant assessment results are included in the medicinal product evaluation.
Why is cell viability legally significant?
For living cells or tissues, their action in the body can be decisive for the definition of the combined ATMP. The regulation also mentions cases where they are expected to exert the primary action.
Regulatory References
- Regulation (EC) No 1394/2007 on advanced therapy medicinal products – defines the combined ATMP and its product components.
- Regulation (EU) 2017/745 on medical devices – contains the framework for the medical device component.
- EMA Advanced therapy medicinal products: Overview – explains combined ATMPs as ATMPs with integral medical devices.