Last November, the European Medicines Agency-sponsored a virtual multistakeholder meeting on drug-device products to address the many unanswered questions regarding an amendment to Directive 2001/83/EC. The meeting was moved from May 2020 to November due to COVID-19.
In May 2019, EMA issued a draft guideline covering drug-device combinations (DDCs) impacted by implementation of Medical Device Regulation Article 117 (1-2). Article 117 amends Directive 2001/83/EC concerning marketing authorizations for medical device–medicinal product combinations as defined in Articles 1(8) and 1(9) of the MDR. Implementation of the MDR was also delayed until 26 May 2021 due to COVID (3).
The half-day stakeholder webinar in November focused on two topics of high priority: The notified body opinion (NBOp) process and the lifecycle management approach. The two topics were discussed by a representative from industry, a regulatory agency, and a notified body. Each elaborated on their experiences with the process, which would become applicable 26 May 2021, giving attendees a view from their perspective. After the presentations, all agreed on a list of open points to be resolved, although differences of opinion remained.
The discussion of the NBOp, which must be submitted to health authorities with the application dossier, revealed several points that require further alignment. NBOps address the conformance of the device or device constituent to the General Safety & Performance Requirements (GSPRs) laid out in Annex I of the MDR. Although there was agreement that the information reviewed and covered in these opinions should not duplicate or overlap the additional information requested by the EMA and provided in the marketing authorization application (MAA), the details of potential overlap were not delineated or discussed.
The exact structure and content for NBOps also remains unclear. Ireland’s Health Products Regulatory Authority (HPRA) has received opinions ranging from 20 to 100+ pages. Only some of them included a high-level summary in the beginning, and many did not include a clear conclusion or recommendation. Notified bodies, which have historically had the sole responsibility of assessing devices (nonintegrated, CE-marked devices), are accustomed to providing detailed reports to the manufacturer regarding compliance, not just an opinion. This might explain the extensive content in some opinions.
While templates for the NBOp have been provided; as yet none appears to have been used consistently. The Medical Device Coordination Group (MDCG) provided a template for the preliminary assessment report in 2018 (4) and the EMA provided a template in their 2019 guideline. The European Association of Notified Bodies in the medical device sector (Team-NB) announced their intent to publish a template with their own suggestions. Why some notified bodies have not accepted or used the existing templates is unclear.
Questions Remain about the Opinion
The key question regarding the content of the NBOp is whether it should only provide the final opinion, that is, a clear “yes, they comply with the applicable GSPRs” or “no, they don’t comply with the applicable GSPRs.” If more is required, what should be included? Should there be additional details on areas of partial- or non-conformance, which would allow the EMA to determine whether the nonconformances are critical to approval, or must it be an essay detailing the assessment itself? It would be unfortunate if overly detailed reports led EMA to review issues that notified body experts have already reviewed and addressed. The notified body is responsible for providing an opinion to eliminate the need for competent authorities to review everything again—not less but also not more.
To facilitate review, an NBOp should contain a short summary page with a clear conclusion and discernible recommendation. If gaps in conformance exist, the NBOp should contain a recommendation to the competent authority on how to handle those gaps. At the workshop, HPRA representatives favored including a table at the beginning of the NBOp listing all GSPRs with a brief assessment and justification.
Another open point was the timing of the NBOp relative to the MAA submission. Because the process is still new and a shortage of notified body resources still exists, the notified body’s review may be incomplete, with necessary data outstanding, when the MAA is complete and ready to submit. For instance, the NBOp may be delayed because it requires data from ongoing stability studies or because documents from suppliers are not yet ready.
How notified bodies should respond in such situations is not clear. Should the notified body finalize the opinion and point out the missing data in its gap assessment, or wait to issue the opinion once all data are obtained? This will have a meaningful impact on the approval timeline. A partial opinion might be workable, if EMA would allow parallel review of the MAA and finalization of the NBOp.
This would require careful communication between the notified body and the EMA to avoid duplication of work. However, one speaker at the workshop indicated that partial reports would not be accepted, based on feedback they had received from competent authorities.
What Constitutes Substantial Change?
Lifecycle management was the second main topic discussed. The most significant issue raised in this discussion was how to clearly define a “substantial/significant change” that would require a new opinion and submission of a variation, and how to handle such changes.
Team-NB considers a substantial change one that is likely to have an impact on:
- safety or performance
- compliance with applicable GSPRs
- device-related claims and intended use.
On the other hand, EMA defines a substantial change as one that is confirmed to affect the performance and safety characteristics of the device.
Historically, changes to medicinal products have followed Variation Regulations EC 1234/2008 and 2010/C 17/01 and EU GMP Guidelines (5–7). ICH Quality Guideline Q12 (2020), which includes DDCs in its scope, is not yet completely reflected in the EU regulatory framework, though the European Commission announced their intention to include the major missing parts in future revisions (8). The MDCG Guidance 2020-3 on significant changes provides a good overview, examples, and flow charts with regards to changes to the devices, as does the 2020 position paper by the Team-NB (9–10). The goal should be to bring these two worlds together and find alignment on the process.
If a change has (or may have) an impact, as defined by the notified bodies, no process yet exists to describe a regular update of the NBOp. It is unclear what process notified bodies will use to review these changes, and what format the opinion will take. If a change will both affect the NBOp and be a variation, the EMA would like the updated NBOp to be included in the variation package submitted for review. EMA does not believe that it would be realistic to update the NBOp in parallel with its review of the variation. This will certainly affect the timing of the release of improved products. Resolving these questions will require continued dialogue among all involved parties.
Other Issues Discussed
While these two topics were discussed during the webinar, many more issues remain. The following partial list of potential issues concern all key players in the process:
- For DDCs that were treated like primary packaging before implementation of the MDR, such as prefilled syringes, why is a NBOp necessary at all? Why can these not be assessed by the EMA without a NBOp?
- How are platform approaches acknowledged in this process?
- To avoid duplication, what information already provided in the MAA need not be reviewed by the notified body (e.g., drug compatibility with the device)?
- Is a Clinical Evaluation Report required to comply with GSPR, or is clinical evaluation of the final DDC only reviewed by the competent authority?
- Will the announced harmonized standards be made available so industry can apply them?
To best serve patients, the EMA, notified bodies and industry must come together quickly to resolve these issues. Patients, who have no input into this process, stand to be adversely affected by continued confusion and disagreement that lead to delays in new and improved products reaching the market. As all parties work together to reach solutions, the EMA and notified bodies should exercise the flexibility necessary to ensure that patient care is not impacted.
[Editor's Note: This article was corrected on 21 Jun 2021 to fix the date of the multistakeholder meeting.]
- Regulation (EU) 2017/745 on Medical Devices, https://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32017R0745
- EMA/CHMP/QWP/BWP/259165/2019: Guideline on the quality requirements for drug-device combinations (draft), https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-quality-requirements-drug-device-combinations_en.pdf
- Multi-stakeholder webinar to support implementation of the Medical Devices Regulation on drug-device combinations, https://www.ema.europa.eu/en/events/multi-stakeholder-webinar-support-implementation-medical-devices-regulation-drug-device-combinations
- Preliminary assessment review template NBOG F 2017-5, https://ec.europa.eu/docsroom/documents/29367
- Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products, https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2008:334:0007:0024:en:PDF
- Guideline on the details of the various categories of variations to the terms of marketing authorizations for medicinal products for human use and veterinary medicinal products (2010/C 17/01), https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:C:2010:017:0001:0044:en:PDF
- Commission Directive 2003/94/EC laying down the principles and guidelines of good manufacturing practice in respect of medicinal products for human use and investigational medicinal products for human use; and supplementing parts and annexes, https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2003:262:0022:0026:en:PDF
- EMA/CHMP/ICH/78332/2020: Note on EU implementation of ICH Q12 (guideline on technical and regulatory considerations for pharmaceutical product lifecycle management), https://www.ema.europa.eu/en/documents/other/note-eu-implementation-ich-q12-guideline-technical-regulatory-considerations-pharmaceutical-product_en.pdf
- MDCG 2020-3: Guidance on significant changes regarding the transitional provision under Article 120 of the MDR with regard to devices covered by certificates according to MDD or AIMDD, March 2020, https://ec.europa.eu/health/sites/default/files/md_sector/docs/md_mdcg_guidance_significant_changes_annexes_en.pdf
- TEAM-NB. Position paper for the interpretation of the device related changes in relation to a Notified Body Opinion as required under Article 117 of Medical Device Regulation (EU)2017/745, December 2020, https://www.team-nb.org/wp-content/uploads/2020/12/Team-NBPosition-Paper-Art117SubChangeLifeCycleMngt-202012.pdf