A medicinal substance as an integral part of a device exists when a medical device contains, as an integral part, a substance which, if used separately, would be considered a medicinal product, but whose action is ancillary to the principal intended action of the device. For such products, the consultation procedure involves the competent medicinal product authority or the EMA in the conformity assessment. Consequently, the Notified Body must not assess the pharmacological component solely from the perspective of medical device law.
Determining the Presence of a Medicinal Substance
The decisive factor is the principal intended action of the overall product as defined by the manufacturer. If a stent achieves its primary therapeutic function by keeping a vessel open and additionally releases an active substance, it remains a medical device with an ancillary medicinal substance. A heparin-coated central venous catheter is another example, as the coating complements the function of the catheter.
The substance must be an integral part of the device and have an action ancillary to that of the device. Classification requires a scientific evaluation of the substance, its release, its contact surfaces, and its contribution to the benefit-risk profile. Coatings or excipients can influence the release characteristics and thus the clinical performance.
Consultation within the Conformity Assessment
The Notified Body first verifies whether the substance is useful in relation to the intended purpose of the device. It then seeks a scientific opinion from a medicinal product authority designated by a Member State or from the EMA regarding the quality, safety, and benefit-risk ratio of the incorporation. For medicinal products derived from human blood or plasma, the EMA must be consulted.
Changes to the medicinal component or its manufacturing process may also trigger a renewed professional assessment. For documentation purposes, this means the technical documentation must not only name the substance but also transparently integrate its quality, safety data, method of incorporation, and the potential impact of changes. An unfavorable opinion limits the certification decision of the Notified Body.
The scientific opinion does not replace the overall assessment of the medical device; rather, it complements it at the interface with medicinal product law. The manufacturer must structure the documentation so that the authority can review the composition, specification, and toxicological aspects of the substance, while the Notified Body assesses the requirements for the overall product. In cases of systemic absorption, the evaluation of metabolism, excretion, and potential adverse reactions carries particular weight.
A similar basic design is insufficient for an equivalence comparison if the substance, excipient, or coating differs. Specifically, interaction with tissue and body fluids can preclude the claimed comparability. The procedure thus ensures transparency by treating the medicinal sub-component as a distinct line of evidence within the clinical evaluation.
Distinction from Medicinal Products
A device with an ancillary medicinal substance is not, by that fact alone, a medicinal product. Its principal action continues to be determined by its intended purpose under medical device law; the substance merely complements this action. Nevertheless, the relevant requirements of Annex I to Directive 2001/83/EC must be applied for the assessment of the component.
This is distinct from products whose principal action is achieved pharmacologically, immunologically, or metabolically. In those cases, the focus is not on the ancillary role of a substance integrated into a device, but on medicinal product law. This technical boundary-setting prevents the regulatory pathway from being chosen solely based on the dosage form.
The Inverse Case: Notified Body Opinion under Article 117 MDR
The inverse case concerns medicinal products that contain a fixed medical device part as a “single integral product.” If this part lacks its own EU declaration of conformity or a certificate from a Notified Body, Article 117 MDR, in conjunction with Annex I point 12.2 of Directive 2001/83/EC, has required a Notified Body Opinion since May 26, 2021. An MDR-notified body assesses exclusively the conformity of the medical device part with the general safety and performance requirements according to Annex I MDR, based on test reports, risk management reports, and clinical and biological evaluations. The pharmaceutical applicant or marketing authorization holder is responsible for the application, not the medical device manufacturer.
Thus, the two consultation pathways differ in their direction of focus: the consultation procedure under Annex I point 12.2 MDR assesses the medicinal substance from a medical device perspective, whereas the Notified Body Opinion under Article 117 MDR assesses the medical device part from a medicinal product perspective.
Relevance for clinical trials
In a clinical investigation of a coated or drug-eluting product, the clinical investigation plan, Investigator’s Brochure, and risk analysis must describe the contribution of the component separately from the mechanical or technical action of the device. Clinical endpoints, laboratory values, and follow-up must be selected to identify risks related to release, local compatibility, and interactions. Furthermore, changes to the coating or manufacturing process may affect the comparability of the investigational products used during the study.
Full-service CROs like Mediconomics support the compilation of clinical and non-clinical evidence for the medicinal component, the alignment of the clinical investigation plan with the risk analysis, and medical writing for the technical documentation. They also coordinate data flows between Regulatory Affairs, trial sites, and safety assessment when the clinical investigation provides additional information on the quality or compatibility of the integrated substance.
Frequently Asked Questions (FAQ)
Is a drug-eluting stent automatically a medicinal product?
No. If its principal action is achieved through the stent function and the active substance supports this function, it is assessed as a medical device with an ancillary medicinal substance.
Who obtains the scientific opinion on the medicinal substance?
The Notified Body conducts the consultation with a medicinal product authority of a Member State or the EMA after verifying the usefulness of the substance as part of the device.
Does equivalence to a predecessor product replace the consultation?
No. The MDCG guidance clarifies that consultation remains necessary for the device under assessment, even if equivalence has been demonstrated.
Regulatory References
- Regulation (EU) 2017/745, Article 52(9) – governs the consultation for integrally contained ancillary substances.
- Regulation (EU) 2017/745, Annex IX Section 5.2 – describes the assessment of the quality, safety, and benefit of the component.
- Directive 2001/83/EC, Annex I – provides the requirements to be applied for the substance assessment.
- MDCG 2020-12 – explains consultations during the transition from the Directives to the MDR.