Many thanks to all of you who provided their feedback to Part 1 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, please find below the respective text form the TOPRA articles (italic) and my interpretation / suggestion:

The applicant for NB opinion. Article 117 is clear in that it requires the marketing authorisation applicant to provide an NB opinion. However, it is not clear whether the Notified Body opinion should be assigned to the would-be marketing authorisation holder; or could be assigned to a different party. For an NB to form an opinion, certain data and documentation will need to be submitted by an “applicant”, and that the applicant is assumed to be either:
• A device technology developer
A medicinal product developer, or
• A third-party acting on behalf of the above.
It is recommended that all the above should be possible, however confirmation of this would be beneficial alongside any specific associated requirements.

I agree that all of the above listed possible applicants should be able to obtain an opinion but the competent authorities really need to clarify what is acceptable to them. However, as long as there is a clear link between the device intended to be used and the device covered by the opinion, it should be fine.
Important from an overall perspective (= article 117) is that all relevant GSPRs are covered in the technical documentation submitted by the applicant. In many cases we see in practice, the technical documentation is partly owned by the technology developer (e.g. as part of a device platform which covers the more technical aspects of the documentation) and the medicinal product developer which covers the aspects related to the medicinal product (e.g. possible hazards, drug-device interaction, user population and labeling). While a platform may fulfill all technical requirements perfectly it may fail with regard to compatibility with the medicinal product or human factors issues (i.e. the design of the device doesn’t suit the specific needs of the patient population, e.g. for people suffering from rheumatoid arthritis, visual impairment, or pediatrics).
Relevant GSPRs where information from the marketing authorization applicant is key are (not exhaustive):
• GSPR 5: Eliminating or reducing risks related to use error
• GSPR 10.3: Compatibility with medicinal products concerned ( stability, extractables, leachables)
• GSPR 22: Products intended for use by lay persons (usability / human factors); if applicable
• GSPR 23: Label and instructions for use

Summary: it is very important that the opinion provided by the NB covers ALL applicable GSPRs of the final product; otherwise the opinion is incomplete from a medicinal competent authority perspective.

Submissible documentation package for an NB opinion. For pharmaceutical companies familiar only with handling medicinal products and not CE-medical devices, the technical documentation concept presented in the Summary Technical Documentation (STED) format is completely new. Those who have dealt with medicinal product devices are most likely to be familiar with compiling device-related topics into the Regional Module (3.2.R.) of a marketing authorisation dossier. Guidance is needed around how an applicant may leverage the existing eCTD structure to submit an NB opinion.

The format of a technical documentation submitted to a NB is neither defined in article 117 nor other parts of the MDR. The MDR only states it must be presented in a clear, organized, readily searchable and unambiguous manner (see Annex II of the MDR).
Of course the content of the technical documentation depends on the complexity of the device in question. However, neither module 3.2R nor 3.2P of the (pre-defined) eCTD structure provide an adequate level of detail which is helpful for an applicant to establish a technical documentation and required by a Notified Body to provide an opinion regarding meeting the GSPR. While some information may be part of both the marketing authorization dossier and the submission to the NB, the overall content and level of detail may in fact be significantly different. For certain devices, e.g. pre-filled syringes, 3.2R already covers a lot of what is required but imagine a more complex patch-injector containing electronics and software? This wide range of products is one of the reasons why the medical device industry struggles since many years to define a structure similar to the eCTD.
Also a technical documentation in the STED format may not be sufficient because it is mainly based on summary documents. With regard to assessments of technical documentations for CE marking, the NB often requires more detailed documents than just the summary documents (e.g. risk analyses, calculations, software design, details regarding design verification, process validation and design validation) and this will likely also happen with combination products. Again, it very much depends on the risk posed to the user and the design of the product.
An alternative format may be the structure provided in Annex II and III of the MDR or (significantly more detailed) IMDRF/RPS WG/N9 FINAL:2018: Non-In Vitro Diagnostic Device Market Authorization Table of Contents (nIVD MA ToC) (27 March 2018; Whatever format an applicant may use, it is important that it provides objective evidence that all applicable GSPRs are met.

Documentation to be issued by an NB. An NB forming a positive opinion on this kind of product would presumably not issue any of the existing certificates associated with CE-marking. It is proposed that any document issued to convey an NB opinion should not carry the CE-mark and should be clearly different from any of the above.
Some NBs have indicated that their preferred approach to providing an opinion would be a report issued to the applicant, concluding their opinion, and elaborating their assessment/ analysis. This report can also be used to convey the detail on to a CA (see also NB and medicine CA communication, below).
The content of such a report may be very “technology-dependent” but should follow some form of consistent template to ensure key areas are always examined. A standardised format could mimic the CMC module of a marketing authorisation dossier, to support ease of medicines CA review. An alternative could be the IMDRF-RPS structure.
It is proposed that a standard template with fixed headings as utilised for example in EU marketing authorisation application (MAA) assessment reports, could increase the efficiency of review by facilitating location of key information.

I completely agree with the authors that a standard template with fixed headings should be developed to be used to document the opinion of the NB. The NBs view on this will probably be that it should be the same or at least a very similar format compared to the one they use to document their assessment of the technical documentation of a product to be CE marked with the only difference that no EC certificate is issued following that. Some NBs hand those reports out to their clients and in the case of an opinion according to article 117 it should be mandatory. If we compare e.g. the assessment of a (to be CE marked) pen-injector with replaceable cartridge and a (not to be CE marked) autoinjector containing a pre-filled syringe, it also makes sense that the assessment follows the same principles because both need to fulfill the applicable GSPRs regardless of their regulatory pathway. Currently, many NBs have a template that follows the respective NBOG document (Guidance on Design-Dossier Examination and Report Content; Such a structure (aligned with the MDR of course) may be helpful to have a standardized way of assessing the technical documentation and documenting the opinion as required by article 117. I also suggest it is used for all type of products, regardless of complexity. The difference between simple and complex devices should be in the depth of the assessment.

More to follow in Part 3… 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