Many thanks to all of you who provided their feedback to Part 1 and 2 of this series of articles – highly appreciated and overall a lot of great information for all stakeholders!

In May and June 2018, TOPRA ( published two highly interesting articles written by Mark Chipperfield and Tim Chesworth that list a number of concerns and open questions that require clarification. As in part 1 and 2, please find below the respective text form the TOPRA articles (italic) and my interpretation / suggestion:

Review of the product as a system. In an integrated product format, the constituents have their “own” attributes, plus have attributes that influence, interact and in some cases interfere; with the other constituents. Combination products are typically multi-constituent and should be thought of as a ‘system’.
A system may comprise a drug formulation housed in primary packaging materials, integrated within a medicinal product device, and presented alongside supportive information and materials within secondary packaging. (In some cases, additional CE-medical devices or accessories to devices may be included; however, these are out of scope of this discussion.)
The medicine CA retains overall responsibility for approval of the product. With the medicinal product device assigned to an NB for the forming of an opinion, the review of areas of drug-to-device-to-packaging interaction should be clarified.
It is thus important that any review of the medicinal product by whichever party (medicines CA or NB) considers not just the risk, function and performance of any constituent, but also the interaction with the other constituents. The degree of influence, interaction and/or interference between constituents could be either overlooked; or become a duplicative review area. In addition, as more complex delivery systems emerge, medicines CAs, NBs and industry are trying to move forward without the benefit of suitable precedents.
Clarification and clear guidance are required on how areas of drug-to-device-to-packaging interaction will be reviewed. It is important that CAs, NBs and industry work together to agree a mutually acceptable set of approaches.

Interfaces to other constituent parts (regardless of whether these are the drug product, CE marked medical devices, accessories or functional packaging) are covered in the GSPR and should therefore be part of the Notified Body opinion:
• GSPR 10.3: Compatibility with medicinal products concerned ( stability, extractables, leachables)
• GSPR 14.1: Compatibility with other devices or equipment
• GSPR 14.5: Interoperability and compatibility
While I don’t see so much a risk that an important aspect is overlooked, there is a risk regarding possible duplicative review with regard to GSPR 10.3. This should indeed be clarified.

Applicability of normative standards and compendial monograph tests. This is a specific topic discussion related to the review of the product as a system, as discussed above. Normative and harmonised standards are very often used for CE-medical devices as a mechanism to demonstrate conformity to Essential (Safety and Performance) Requirements, being upheld as state of the art.
Medicinal product developers typically use compendial monograph (pharmacopeia) tests to demonstrate certain attributes. Some such tests extend to functionality of container closures and delivery systems.
It is proposed that any party reviewing the medicinal product device would need to be specifically and particularly familiar with the applicable, overlapping or even contradicting sets of test frameworks that could be applied to such a product.
It is recommended that any review of medicinal product device technical data and documentation considers all the relevant testing frameworks that may apply.
It is also recommended that guidance encourages the necessary clarification of the intended use, purpose, and basis for design inputs, to be shared with the NB prior to the opinion assessment.

Annex I of the MDR (and this is comparable to the requirements of Annex I of the MDD) requires a device to be safe and effective taking into account the generally acknowledged state of the art. The concept of harmonized standards is neat because meeting a harmonized standard provides presumption of conformity with the relevant GSPR(s) because it’s considered state of the art. However, standards are not laws and therefore a firm may choose to provide evidence in a different manner but then the burden of demonstrating that the alternative method is “as good as” from a safety and performance perspective is with the applicant.
Regarding monographs: similar to the MDD, also the MDR recognizes the monographs of the European Pharmacopoeia. This is defined in Article 8 (2): “References in this Regulation to harmonised standards shall also include the monographs of the European Pharmacopoeia adopted in accordance with the Convention on the Elaboration of a European Pharmacopoeia, in particular on surgical sutures and on interaction between medicinal products and materials used in devices containing such medicinal products, provided that references to those monographs have been published in the Official Journal of the European Union.
In the context of Article 117 it is also fair to say that for several devices, no device-specific harmonized standards exist. However, there are other relevant ISO standards that are considered state of the art (e.g. ISO 11608 series concerning needle-based injection systems).
In case of overlapping or contradicting sets of test frameworks, the burden is on the applicant to establish a documented rationale for why he considers his framework “state of the art” and meets the requirements regarding safety and performance. Given the wide variety of possible products and technological advancement it may be difficult to establish clear guidance.

Medicinal product expiry date, drug product stability and medicinal product device shelf-life. This is a further specific topic related to review of the product as a system, as discussed above. Exploring medicinal product stability in a container is well-established, proven through ICH-guided stability programmes, both real-time and under accelerated aging conditions. However, system thinking is key to develop an understanding of product function and performance through the life of a combination product.
It is currently unclear how the responsibility for review of such data will be split between a medicines CA and an NB – in a way that ensures appropriate rigour without duplication. Guidance is needed here both in terms of responsibility for review and in terms of the focus of any review performed.

This reminds me to discussions we always have with the US FDA regarding the same topic during scientific advice meetings. It’s my understanding that the Medicines Competent Authority will review the information regarding all aspects related to the drug product stability (i.e. container closure) and therefore also the expiry date. The Notified Body on the other hand needs to ensure that the device constituent part is safe and performs as intended during the entire labeled lifetime of the device which may, depending on the specific embodiment of the device part, result in a range of design verification tests.
However, I agree that guidance is required regarding the interaction of the drug constituent and the device constituent part, in particular with regard to GSPR 10.3: Compatibility with medicinal products concerned).

Clinical data. The topic of generation and review of clinical data for a medicinal product device is one that has the potential to confound. As the drug and device worlds collide, the concepts of clinically proving a constituent also collide. They are borne of a different evolution and so in the context of an integrated product, will require additional guidance in defining an appropriate way to manage clinical data generation and evaluation. In the experience of the authors, it is typically not required to execute specific clinical evaluation or clinical investigation of the medicinal product device if that same device has been incorporated into the medicinal product clinical trial. However, this is not clearly outlined in regulation or guidance text at this juncture. The MDR should not create additional clinical data burden on medicinal product developers.
Clarity is required regarding the responsibility distribution between the medicines CA and the NB in relation to clinical data.

While the MDD required clinical data as part of meeting Annex I (i.e. ER 6a), this requirement is not part of Annex I of the MDR (although article 61 (1) defines the following: “Confirmation of conformity with relevant general safety and performance requirements set out in Annex I under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk- ratio referred to in Sections 1 and 8 of Annex I, shall be based on clinical data providing sufficient clinical evidence, including where applicable relevant data as referred to in Annex III”).
While clinical data may still be required for the device as part of design validation (e.g. ISO 11608-5:2012, Section 4.1 (g) requires manufacturers to determine the injection depth for needle-based injection systems through clinical evaluation), to demonstrate that the device part meets the intended use, this data would typically derive from publicly available literature and/or the clinical investigation of the medicinal product. If the device in question was incorporated into the medicinal product clinical trial I fully agree that most probably no additional clinical data needs to be obtained.

Equivalence and representativeness. It is both desirable and expected that material submitted to pivotal clinical trials be representative of (or even equivalent to) the final intended commercial material. This is not always achievable and must be recognised when conducting any assessment of data.
Guidance is needed regarding the expectations for equivalence and representativeness of product for NB opinion. It is assumed such clarity should come from medicines CAs.

For medical devices, Annex XIV Part A (3) defines requirements for equivalence and basically consists of 3 elements (technical, biological and clinical). From a Notified Body perspective I assume these requirements will also apply to device constituent parts of combination products. In the absence of more specific guidance I suggest to list differences between the product submitted to pivotal clinical trials and the final commercial product and provide a justification why respective data is still considered to be applicable and was not invalidated by the changes made.

More to follow in Part 4… Keep your eyes open!

I strongly encourage other professionals involved in this field to provide their opinion and start a lively conversation on this platform – the whole industry can only benefit from this!

by Beat U. Steffen, Founder & CEO of confinis ag