by Dr Liezl Schonken, Safety Physician at Panacea
Drug/device combination products are unique in that they combine a medical device and a medicinal product, either integrated into a single unit with a unified purpose, or co-packaged with each retaining its individual identity. Single integral combinations, such as pre-filled syringes, are designed to provide a specific therapeutic effect or deliver medication in a controlled manner. The integrated system aims to improve the effectiveness, convenience and precision of drug delivery while ensuring patient safety and compliance.
Within the European Union, the regulation of these combination products falls under either the Medicinal Product Directive (Directive 2001/83/EC) for medicinal products or the Medical Device Regulation (2017/745) for medical devices. While co-packaged combination products are regulated individually, the classification of integral combination products is governed by their primary mode of action. The regulatory framework for medical devices incorporating medicinal substances as an ‘integral part’ is described in the Medical Device Regulation (MDR).1 According to this, the combination product is regulated under the medicinal products framework where the action of the medicinal substance is principal. In this case, the relevant general safety and performance requirements of the MDR apply to the device part. Likewise, if the administration device is marketed as a single integral product intended exclusively for use in the given combination and is not reusable, the medicinal products framework will apply. On the other hand, where the action of the medicinal substance is ancillary, the product is regulated as a medical device and must be CE marked. In this instance, a scientific opinion must be provided from a medicines authority before a Notified Body can issue a certificate for the combined product.
For those drug/device combinations that fall under the scope of the MDR, device vigilance will apply. For integral combinations regulated as a medicinal product, the device vigilance requirements of the MDR are not applicable. Device vigilance is a crucial process of monitoring medical devices, including their design, production, and use, in order to identify and address any safety issues that may arise. This is an important aspect of ensuring the safety and efficacy of medical devices, and it is an area that has received increased attention in recent years due to a number of incidents involving faulty or dangerous medical devices. The new device regulations that came into force in 2021, now require a more proactive approach to post-market surveillance.
Post-market surveillance (PMS) for medical devices is the ongoing monitoring and evaluation of a medical device after it has been placed on the market. It is an essential aspect of device vigilance and helps to ensure that medical devices continue to meet their intended purpose and remain safe and effective over their entire lifecycle. The objective of PMS is to identify any issues or potential safety concerns as early as possible, and to take appropriate action to address them. PMS activities typically include collecting and analysing data on the use of the device, monitoring adverse events and complaints, and conducting studies to assess the device's performance and safety in real-world settings. The specific requirements for PMS depend on the regulatory requirements in the country or region where the device is marketed.
As part of the more proactive approach, new incident reporting requirements have been introduced. Mandatory reporting of serious incidents within 15 days, previously 30 days, and the reporting of non-serious incidents within one month are now essential. Furthermore, the need for submitting periodic safety update reports (PSURs) has been introduced. Similar to pharmacovigilance requirements, PSURs are periodic reports that provide an overview of the safety and performance of a medical device over time, based on data from a range of sources including clinical studies, complaints, and adverse event reports. Manufacturers of class IIa, class IIb and class III devices are expected to prepare a PSUR for each device summarising the results and conclusions of the analyses of post-market surveillance data. These reports are periodically reviewed by the Notified Body and the timeframes are subject to the classification of device. For higher class devices, the PSURs are required to be submitted annually. The Medical Device Coordination Group, composed of representatives of all Member States, has developed a guidance document which incorporates a PSUR template to assist manufacturers to implement the legal requirements laid down in the MDR.2
While clinical evidence is an essential element of the premarket assessment process, it is important to recognise that there may be uncertainties that should be addressed in the post-market phase using one or more studies as part of PMS. A post-market clinical follow-up (PMCF) study is carried out to answer specific questions relating to safety, clinical performance and/or effectiveness of a device when used in accordance with its labelling. PMCF is similar to the post-approval studies for pharmaceuticals. Post-market performance follow-up (PMPF) studies are conducted to evaluate the long-term safety and performance of a medical device. Overall, post-market surveillance is a critical component of device vigilance and helps to ensure that medical devices remain safe and effective from design to production for use in real-world settings.
Similarly to Eudravigilance, which primarily deals with the safety monitoring of pharmaceutical products, the MDR also introduced a central database of information on medical devices. The European Databank on Medical Devices, known as EUDAMED, is a system for reporting and analysing incidents and safety issues, and is designed to facilitate the exchange of information related to medical devices. The aim of EUDAMED is to enhance overall transparency through better access to information for the public and healthcare professionals. A fully functional version is expected in the second quarter of 2024.
Navigating the intricacies of drug/device combination regulations demand a keen understanding of the scope of both medical devices and medicinal products. As such an informed decision can be made as to whether pharmacovigilance or device vigilance will apply. For those combinations that fall under the MDR framework, significant changes to device vigilance have been introduced in the EU, with a focus on proactive surveillance and reporting, increased transparency, and better tracking and monitoring of medical devices. These changes are designed to enhance patient safety and ensure that medical devices meet the highest standards of quality and efficacy.
References: