The European Commission advocates that the new Medical Devices Regulation (EU) 2017/745 (MDR) and the In Vitro Diagnostic Medical Devices Regulation (EU) 2017/746 (IVDR) bring EU legislation into line with technical advances, changes in medical science and progress in law-making. The new regulations create a robust, transparent, and sustainable regulatory framework – recognised internationally – which improves clinical safety and creates fair market access for manufacturers and healthcare professionals. Unlike directives, regulations do not need to be transposed into national law. The MDR and the IVDR, therefore, limit discrepancies in interpretation across the EU market. Recent developments, such as the effect of the Covid-19 pandemic, led to the date of application for the MDR being postponed from the original date of 26 May 2020 to 26 May 2021. Despite the change, the provisions made under EU MDR Article 120.3 state that devices covered by valid AIMDD/MDD certificates may continue to be placed on the market or put into service until 26 May 2024, as long as they continue to meet the requirements of that legislation and there are no significant changes in their design or intended purpose.
Preparing for IVDR
With the IVDR conferring stricter safety standards, European regulators have orchestrated a paradigm shift in the world of in vitro diagnostics (IVDs). The date of application is on 26th May 2022, supposedly giving an ample transition period. But manufacturers and other industry stakeholders don’t believe this is long enough given the significant changes. The stricter rules are designed to enhance safety and efficacy, and are especially tough for advanced molecular diagnostics and lab-on-chip assays used in the clinic to help identify a patient’s pathology. Further considerations for scrutiny for the first time are point-of-care products, such as self-administered pregnancy kits or at-home nutrigenetic tests. This change extends the concept of in vitro diagnostic devices to include tests of ‘indirect medical purpose’ and ‘prediction’ that are not covered by the current IVD Directive 98/79/EC (IVDD).
The first of the fundamental changes is that IVDs will no longer be subject to the list-based system currently in the IVDD. Instead, they’ll be governed by the risk classes developed by the International Medical Device Regulators Forum (IMDRF), formerly known as the Global Harmonisation Task Force (GHTF). This approach uses a risk-based classification system, dividing the IVDs into risk classes from A (low risk) to D (high public and high patient risk), with seven classification rules.
The rule-based system is devised to allow manufacturers themselves to identify the applicable risk class and to help determine the appropriate conformity assessment route available to achieve a CE mark. With the IVDR, the notified bodies are to perform conformity assessments on all but class A devices. This is a huge task, and has transformed the IVD regulatory landscape in terms of files to be reviewed and audits to be performed pre and post-market. The increased volume of work for the notified bodies stems from the widened scope of the IVD definition and the conformity assessment routes that are amended to fit the new classification logic. IVDs that do not fit any of the other classification rules fall into class B and have to be certified by a notified body. This is a major change compared with the IVDD, which allows such IVDs to be self-certified. As a consequence, 80% of all IVDs are to be certified by a notified body under the IVDR, compared with 20% currently certified under IVDD.
In terms of technical documentation, evidence of clinical performance studies is required to support the CE mark under the IVDR and, as a result, IVD manufacturers will need to produce significantly more clinical evidence. The IVDR contains rules for interventional clinical performance studies and other clinical performance studies that largely overlap with the clinical studies regime in the MDR, bringing it in line with other global regulatory requirements. In preparation for compliance with IVDR, it is crucial for manufacturers of IVDs currently on the market and those entering the marketplace under the IVDR to plan the generation of additional clinical evidence well, and assess timely what’s required, how long it will take to generate it, and plan ahead for notified body slots for conformity assessment as part of the CE-marking process. The clinical performance evaluation includes not only the classic laboratory bench tests to support the clinical and analytical performance, but also scientific validity and, where applicable, using the appropriate statistical approach to substantiate claims.
At the present time, only a handful of the European Notified Bodies are designated to undertake IVD conformity assessment and, therefore, careful planning is important to avoid a bottle-neck situation closer to the IVDR date of application.
In the present Covid-19 pandemic era, the IVD sector has seen increased activities for the production and regulation of CE-marked test kits under the IVDD. This has had a knock-on effect on the preparation for the IVDR.
Classification
Article 47 requires all IVDs to be classified into one of four classes. The classification determines the conformity assessment route for the device. While classification is primarily the concern of the manufacturer, Article 47 confirms that if a manufacturer and notified body cannot agree on the classification, the competent authority of the manufacturer is the body that makes the final determination. Before attempting to classify any device, it is recommended that manufacturers prepare statements according to a set of conditions required for the technical documentation, which can be found in Annex II, 1.1 of the IVDR 2017/746 document.
Annex VIII contains the rules to be followed to determine the classification of the device, and is intended to be read and applied in sequence with Annex II. Therefore, referring as necessary to the documents (a), (c) and (d) listed on page 15, manufacturers must start by reviewing the implementing rules in chapter one. For example, is the device intended to be used in combination with another device? This is a particularly relevant question for software. After this, manufacturers must read through the seven classification rules in chapter two and work through them step by step in order to arrive at a classification that best describes the device under consideration. It is important to document the decision on the classification and the supporting justification, as this is another required item in Annex II, 1.1, listed as follows: (e) the risk class of the device and the justification for the classification rule(s) applied in accordance with Annex VIII.
Finally, it is also important to determine if the product is considered as a companion diagnostic (CDx), which is a specific type of IVD. CDx was not defined under the IVDD. But the IVDR, as well as ISO 20916, close this gap by defining CDx and identifying requirements for clinical performance studies.
The EU IVDR defines a CDx as a device that is essential for the safe and effective use of a corresponding medicinal product to identify – before and/or during treatment – patients who are most likely to benefit from the corresponding medicinal product, or who are likely to be at increased risk of serious adverse reactions as a result of treatment with the corresponding medicinal product.
Responsible persons
As with MDR and IVDR, the regulations oblige European companies to have a regulatory expert – a person responsible for regulatory compliance (PRRC) – at their disposal, to ensure the company is meeting certain specific EU requirements. The role of the PRRC is to ensure the compliance of released devices, as well as the postmarket surveillance (PMS) and vigilance activities concerning those devices (MDR recital 34, IVDR recital 33). Moreover, where a manufacturer is located outside the EU and an authorised representative (AR) is required, a secondary control is expected to be conducted by the PRRC of the AR in order to verify regulatory compliance of the devices produced by those manufacturers.
Both the manufacturers and the AR are required by MDR/IVDR Article 15 to have within their organisation, or at their disposal, at least one PRRC who possesses the required expertise and qualifications in the field of medical devices or in vitro medical devices, as applicable, in the EU. The responsibilities, qualifications and professional experience of the PRRC are also set in the regulations and interpreted in the MDCG Guidance 2019-7.
As a manufacturer, operating a comprehensive quality management system (QMS) is not a new requirement in the regulations of medical devices. However, the IVDR specifies what the QMS must include and how the manufacturer must operate it. There are also new roles introduced, like the PPRC. Manufacturers must establish this new role, meeting requirements such as ensuring the chosen person has at least four years of expert knowledge in the field of IVD devices.
Maintain surveillance and vigilance
Maintaining a post-market surveillance (PMS) in alignment with the requirement of the vigilance system are integral parts of any IVDR-compliant QMS, and are key in establishing robust systems and long-term quality and regulatory success. These are important elements that revolve around maintaining quality, performance and safety throughout the product life cycle. As the IVDR replaces the IVDD in 2022, there are many significant changes that IVD manufacturers must consider from a risk management perspective, as well as those pertaining to PMS to meet compliance requirements. Article 10(8i) states that a PMS system must be created and implemented and Article 10(9) states that this system must be kept up-to-date in accordance with Article 78.
PMS programmes should actively and systematically gather information from a device in a way that allows for regular updates to technical documentation and competent authorities’ communication in the areas of vigilance and market surveillance. The date of application is fast approaching, and if manufacturers are not already in the process of preparing for the transition, the sooner they start, the better.
IVD statements
Prior to classification, an IVD should have statements prepared to address the following in Annex II, 1.1:
(a) Determination if the product is an IVD and fits into the definition as per the IVDR.
(b) A general description of the device, including its intended purpose and intended users.
(b) The intended purpose of the device, which may include information on:
i. what is to be detected and/or measured
ii. its function, such as screening, monitoring, diagnosis or aid to diagnosis, prognosis, prediction or use as a companion diagnostic
iii. the specific disorder, condition or risk factor of interest that it is intended to detect, define or differentiate
iv. whether it is automated or not
v. whether it is qualitative, semi-quantitative or quantitative
vi. the type of specimen(s) required
vii. where applicable, the testing population
viii. the intended user
ix. in addition, for companion diagnostics, the relevant target population and the associated medicinal product(s).
(d) the description of the principle of the assay method or the principles of operation of the instrument.
Gabriel Adusei, director, Triune Technologies (Consulting), founder of International Association of Consultants
Gabriel Adusei has over 30 years of experience in the medical technology industry, interspersed with academic studies, research and a professional career. Adusei is a renowned medtech professional who is acknowledged as a thought leader and influential expert, having worked on many high-profile projects in the industry. His numerous publications have influenced some of the quality and regulatory developments in the industry.
PRRC requirements
The requisite expertise shall be demonstrated by either of the following qualifications:
(a) A diploma, certificate or other evidence of formal qualification, awarded on completion of a university degree or of a course of study recognised as equivalent by the member state concerned, in law, medicine, pharmacy, engineering or another relevant scientific discipline, and at least one year of professional experience in regulatory affairs or in quality management systems relating to medical devices.
(b) Four years of professional experience in regulatory affairs or in quality management systems relating to medical devices. Without prejudice to national provisions regarding professional qualifications, manufacturers of custom-made devices may demonstrate the requisite expertise referred to in the first subparagraph by having at least two years of professional experience within a relevant field of manufacturing.
Source: MDR and IVDR
