Les 11 choses à savoir pour préparer son entrée sur le marché européen (article en anglais)

1.      EMA and FDA do not have the same requirements when evaluating a registration file. Anticipate the design of your phase 2 and 3 clinical trials to account of these differences.

2.      Every European country has a specific healthcare system, with variations of reimbursement procedures and requirements (timing, dossier, price). Reimbursement decisions will be made by a combination of regional and national committees: national has precedence in some countries like France but regions can be the main decision-makers in other countries like Germany or Italy, despite using guidelines issued by national committees.

3.      Medical practices are rather homogeneous across Europe. There is generally a European Expert Society for each therapeutic area, gathering members of national societies. Therefore, practitioners usually follow the same guidelines, published by these European Expert Societies.

4.      There are numerous patient advocacy groups and associations, organized at the regional, national, and pan-national level. In some disease areas, such as AIDS, these groups can be quite influential. This is true both in the US and the EU, and it is normal for groups focused on the same areas to exist on both continents.

5.      The registration procedure (CE mark) for medical devices and diagnostics is more simple and straightforward than in the US, but reimbursement is country-dependent and may be quite slow (up to several years). However, regulations are changing, and the registration process will become more demanding for Class 2b and 3 devices. Read more here.

6.      For diagnostics, there is no such thing in Europe as the LDT status allowing quick commercialization on a limited scope through CLIA labs.

7.      Depending on disease areas, your commercial model will be different across countries. You will generally have to be more payor-centered in Northern Europe and more physician-centered in Southern Europe, with several countries such as Germany standing in-between.

8.      All European payors will demand comparative trial data with the standard of care. This will have tremendous implications on your trial design and must be anticipated.

9.      HEOR studies may be quite useful in some countries but not relevant in others due to different funding processes and stakeholders, or different evaluation methodologies at national level. For example, France’s HAS does not fully recognize QUALYs as a valid outcome measure.

10.   Private health insurance companies have little influence over the reimbursement process of most drugs and devices. They usually follow the decisions of the National Healthcare System.

11.   For most drugs, a certain launch sequence has to be followed in order to maximize reimbursement prices. You must start with countries with fast processes and high historical prices, and end with low-price and/or slow countries such as Italy, Spain or Eastern European countries.

Le futur de l’IVD en Europe: les changements qui vont redistribuer les cartes (article en anglais)

With the new European in vitro Diagnosis Device Regulation (IVDR), published in May 2017 [1], but fully in place in 2022, the rules will change for IVD players in Europe. American companies will feel more at home due to the system becoming aligned with that in the US, in addition to having the possibility to replicate processes used in their operations. Although European firms not accustomed to the US market will be starting from scratch, US companies will need new protocols to ensure efficient operations in Europe in order to develop a competitive advantage, and may benefit from specific European support, particularly to go through the reimbursement process.

The current European directives are more manufacturer-friendly than the US regulation

In the current “In Vitro Diagnostic Medical Devices Directive” (IVDD). There are four list-based categories. In the EU, manufacturers have to follow the EC’s IVDD and will have to comply with the IVDR by 2022. The current requirements address the design, production, labelling, and instructions for use. Depending on the technical specificities and indication, an IVD belongs to one of the four categories specified in the classification (General, Self-test, List B, and List A). [2]

With the current IVDD, 80% of the IVDs are self-declared. Even though there are four categories, with the current IVDD 80% of the IVDs belong to the Class I category, and so, do not need a Notified Body, making it simpler and cheaper to go through the EU regulatory pathway. [3]

The US was the only country, until now, to take patient safety into consideration, and is the most regulated one for IVDs

FDA classification is divided into three categories based on risk. It is the risk and the level of control necessary to provide reasonable assurance of the safety and effectiveness of the device that will determine its category, unlike the aforementioned list based approach of the IVDD. Depending on its risk, the device belongs to one of the three (and not four as in the EU) following categories:

In addition to classification, the FDA enforces the Clinical Laboratory Improvement Amendments (CLIA). A categorization based on the technical competence required by the user is made by the FDA (scoring of 1, 2, or 3). For example, a test that is cleared by the FDA for home use would receive a CLIA-waiver (score 1) because it requires minimum competence from the user. Whereas the Centers for Medicare & Medicaid Services (CMS) enforces the CLIA in the locations where the tests are performed, which means it controls the laboratories. [3] [4].

The IVDR brings about a convergence of the US and EU classification of IVDs, which are now both risk-based approaches

The new regulation is risk-based as the FDA, and Notified Bodies will have more products to control and power than ever before. Now, there are four categories from low to high risk (A, B, C, and D). Class D refers to IVDs dealing with high public health and high personal risk, and degressively, class A being low personal and low public health risk, and therefore the only category to be self-declared. As a result of these changes, Notified Bodies will have to assess more products than before: 80% of IVDs’ manufacturers will need them. Other new measures include clinical performance studies, the Unique Device Identification (UDI) and post-market safety surveillance. [5] [6]

An opportunity for US companies to expand into Europe

This new regulation will give a competitive advantage to companies used to the US market. It will lead to the implementation of new manufacturing processes and post-market surveillance systems in addition to an increase in legal costs (Notified Bodies’ related fees) and so on. The level of time and investment needed in designing, implementing, and managing these new processes will force companies to build more robust business cases. But for companies already competing in the US market, the internal regulatory resources, the quality assurance measures, and the clinical evidence they adopt for the FDA will be useful in their applications for CE marking. Therefore, they will not feel the impact of the changes in the same way EU companies do, thus the cards will be extensively redistributed amongst the competitors on the European market.

The different reimbursement systems in Europe stay a challenge for US manufacturers, harmonization is coming

The new IVDR regulation will quicken reimbursement processes. Despite the CE marking process for IVD products being previously quick and rather straightforward, reimbursement was slow, complex, and highly country-dependant. The new IVDR regulation, however, requires much higher levels of clinical evidence. This is exactly what payers in Europe demand to grant reimbursement. It is therefore to be expected, paradoxically, that the new IVDR regulation will speed up reimbursement processes in most EU countries. [7]

1 – European Commission website – Regulatory framework – “The new Regulations on medical device” – 15 November 2017

2 – BSI: an In Vitro Diagnostics Notified Body – “A guide to the In Vitro Diagnostic Directive” – 2012

3 – European Observatory on Health Systems and Policies – “Ensuring innovation in diagnostics for bacterial infection” – 2015

4 – FDA website – Medical Device

5 – Lloyd’s Register LRQA – “In Vitro Diagnostic Device Regulation (IVDR)” – 2017

6 – BSI: an In Vitro Diagnostics Notified Body – “IVD Regulation What you need to know” – 5 may 2017

7 – CEPTON Strategies’ article – “European medical device reform: the changes to expect for class IIb and class III medical devices” 2017

Le réforme Européenne des dispositifs médicaux: ce qui change pour les classes IIb et III (article en anglais)

In April 2017, a new Medical Devices Regulation (MDR) was published in Europe. The goal was to harmonize conformity assessments and clinical evaluations of medical devices at a European level to insure better safety. From a manufacturer’s point of view, class IIb and class III medical devices will have to undergo special procedures to reach the market. This regulation particularly affects class IIb and III devices.

Since the 90s, three directives regulated medical devices and in vitro diagnostic (IVD) medical devices in Europe. As the directives were open to interpretation, each country could adapt the text, leading to variations in procedures according to each state for a product to obtain a CE mark and reach the market. The European PIP scandal [1] in 2010 triggered a will to improve control of medical devices and their supply with a standardized model closer to the US one. Medical devices and IVD medical devices will now have to comply with MDR and IVD Regulation (IVDR) that will respectively provide a review of a larger proportion of devices and a greater control of diagnostics. The final implementation of regulations will happen in three years for MDR and five years for IVDR. Class IIb and class III medical devices are especially affected by MDR.

The classification of medical devices evolves with MDR

Medical device designation will extend to accessories related to medical devices (such as products used for washing medical devices), implantable non-medical products that may affect the body, and software used for a medical purpose. A larger number of medical devices will be classified as high risk (class III) and will therefore require a more demanding clinical evaluation [2].

A UDI system similar to the United States system will be launched

Medical devices will have to be registered under a Unique Device Identifier (UDI) composed of a constant device identifier, referring to the manufacturer and type of device, and a production identifier, referring to the batch of production. With this system, Europe is getting closer to the United States, where UDI legislation was implemented in 2014. Distributors and importers will then have to update the pathway of products. The UDI database will enable you to trace all medical devices in Europe through each stage in the supply chain until its use. This database is complementary to Eudamed, the transparency database containing all clinical evaluations of medical devices. For patients receiving implantable devices, an implant card will also be provided to allow the patient to have information regarding his device.

Notified Bodies will be reinforced and harmonized for conformity assessment

In order to get a CE mark and be marketed in Europe, medical devices need a conformity assessment based on relevant clinical investigations. With the new MDR, low risk device (class I) conformity is still declared by the manufacturer himself. Class IIa and not implantable class IIb devices need a generic group assessment to get the approval, and implantable class IIb and class III medical devices require a device assessment. Assessment still involves a Notified Body: an entity that can be physically present in every country in Europe. With the reform, Notified Bodies become harmonized between EU countries and will be regularly checked by national authorities to ensure compliance with MDR.

Class IIb and class III medical devices will require further clinical investigation

To be approved in conformity assessments, implantable class IIb and class III devices need a clinical evaluation more demanding than other devices. Before starting the clinical investigation, manufacturers can consult an expert panel at a European level to plan their clinical strategy and know what clinical results will be expected of them to obtain CE marking as fast as possible. In some cases, when an equivalent product is already on the market, and if a contract for sharing technical documentation is signed with the manufacturer of the already marketed device, the manufacturer can avoid clinical investigation and use equivalence for obtaining their CE mark.

In the case of a class IIb or a class III medical device, a scrutiny procedure can be put in place.

When being clinically evaluated, the Notified Body is responsible for writing a clinical evaluation report. However, this report may go through an expert panel to ensure the right level of expertise is used to assess the validity of an innovative product. This scrutiny procedure can delay market entry by 60 days.

The new mandatory post-market surveillance will require a yearly update for class IIb and class III devices

In addition to pre-market clinical evaluation, manufacturers must provide a Post-Market Surveillance plan when applying for CE mark. This plan will result in a Post-Market Clinical Follow-up that will be transcribed in a periodic safety update report. This is one of the major changes to the MDR reform and class IIb and III devices must update this report yearly.

The reform is driving high-risk medical devices closer to reimbursement, a factor of major importance in Europe

Even if, with the previous directives, clinical evaluations were less demanding to get approval for the European market, clinical expectations were high for getting reimbursement in each European country. As reimbursement is a major issue for insuring sales in Europe, a common strategy was to launch the product and then get reimbursement with clinical trials in various countries. As clinical investigation will be needed at a European level with MDR, clinical trials will be assessed in coordination with all countries where it takes place, resulting in an easier and more standardized approach for obtaining reimbursement.

With this new regulation, Europe wants to insure better safety for patients, and the European medical device system will become more structured and easily understandable at both country and European level.

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1 – Journal of the Royal Society Medicine “The PIP scandal: an analysis of the process of quality control that failed to safeguard women from the health risks” – 2013

2 – Official Journal of the European Union « Regulations on medical devices » – April 2017