What is the Impact of Article 117 on the Pharma Industry?

Currently, such products with device components marketed in the EU are required to conform with Essential Requirements of the Medical Device Directive 93/42/EC., as described in Annex I of the Directive, and information on how the device component meets the Essential Requirements is typically provided in the Marketing Authorization Applications (MAA) for the medicinal product. The Medical Device Regulation’s Annex I is a substantial revision of the Essential Requirements, now called General Safety and Performance Requirements (GSPR) which requires a major increase in information to be provided for medical devices and as such the device constituent of an integral drug-device combination.

Article 117 of the Medical Device Regulation amends the Medicinal Product Directive (MPD) to say that the Marketing Authorization Applications for an integral drug/ device combination must now include either a CE certificate for the medical device or evidence of review by a Notified Body (NB), consisting of a Notified Body Opinion (NBo) on the conformity of the device component against Annex I of the Medical Device Regulation.

CE marking is available for medical devices that could meet the definition of a medical device separately from use with the drug. The manufacturer of the medical device obtains CE marking using the Notified Body conformity assessment process applicable to the device type. The CE Certificate is to be submitted in the Marketing Authorization Applications. This requirement remains unchanged with the implementation of the Medical Device Regulation itself.

Where the device component does not have (or is not eligible for) a CE mark, the manufacturer must seek the Notified Body’s opinion on the conformity of the device. NBs require technical documentation providing scientific data to support product claims and evidence that the device component meets relevant requirements of the GSPR. Documentation expectations are outlined in Annex II, Section 4 of the Medical Device Regulation. The Notified Body then issues an opinion report, describing how the device component does (or does not) conform with the requirements. Note that the Notified Body does not “approve” the device. The report goes into the Marketing Authorization Applications and the Competent Authority determines, based on the Notified Body opinion, whether the device is acceptable for use with the drug.

According to an EMA Q&A document on Implementation of the Medical Devices Regulations (EU) 2017/745 issued in June 2019, the Article 117 requirements are not being applied retrospectively to on-market products. Manufacturers do not have to submit Notified Body Opinion reports for products with a current Marketing Authorization Applications. The Medical Device Regulation requirement comes into play when a significant device change is to be implemented that could impact safety or performance - at this point Article 117 then applies. All new Marketing Authorization Applications with products containing a device component, submitted after May 26, 2021, need a CE mark or Notified Body Opinion.

What Are the Roadblocks?

Limited Notified Body capacity

There are many drug/biologic companies with full pipelines and few designated bodies (all Notified Bodys had to reapply) to review new devices. The first Notified Body Opinion was issued early this year, and demand is likely to increase which is also competing against Notified Body resources as the deadline approaches for medical devices to be compliant against the Medical Device Regulation. BioPharma companies with a portfolio that does not include medical devices sold in the EU may not have a standing relationship with a Notified Body and find application queues are long.

Unfamiliar Process

Each Notified Body is a separate organization with an independent process and variation in staff support for this new type of review. There is uncertainty with the level of detail needed and how to submit information. Unlike the MAA, Technical Files are not in eCTD format, and each Notified Body has to design and implement their own interface for handling submissions. Team Notified Body, the European Association of Medical Devices-Notified Bodies, issued a Position paper on Documentation Requirements for Drug Device Combination Products recommending documentation structure which hopefully most NBs will adopt. Each submission will be a learning experience for all involved.

Critical Path

Unless there is prior agreement with the Committee for Medicinal Products for Human Use (CHMP), the device CE certification or Notified Body Opinion must be included in the MAA, meaning that device development work has to be complete earlier in the overall product development process. The CE mark or Notified Body Opinion is anticipated to take 2-6 months. Since device decisions are often made late in the drug development cycle, Article 117 requirements put additional pressure on an already accelerated timeline.

Conclusion

BioPharm manufacturers must work closely with their regulatory and device engineering groups to consider timing and budget changes introduced by this legislation. Although aimed at medical device manufacturers, the impact of brief Article 117 will have a substantial effect on our industry.