New requirements of the European regulations: demonstration of clinical evidence

To improve the health and safety of patients and users, Regulation (EU) 2017/746 relating to in vitro diagnostic medical devices (IVDs) considerably reinforces certain essential aspects of the current regulatory approach, especially in regards to the risk-based classification of these devices, compliance assessment procedures, performance evaluation, vigilance and post-market surveillance. New requirements have been set in this regulation, such as the need to validate, on the basis of clinical evidence, the intended use of the device, as claimed by the manufacturer. This demonstration of the validation will represent an essential part of the technical dossier for CE marking of all IVDs and will be assessed by a notified body for the majority of devices. It is therefore crucial for IVD manufacturers to clarify the procedures for demonstrating clinical evidence, particularly in the specific case of « companion diagnostics(1) ».

Demonstration of clinical evidence

Clinical evidence should scientifically demonstrate that the expected clinical benefit(s) and safety will be achieved in compliance with current best medical practices when used for its intended purpose. Demonstrating clinical evidence is therefore based on data related to scientific validity as well as on analytical and clinical performances of the device. The Regulation provides with precise definitions of these terms, « clinical evidence(2)», «clinical benefit(3)» and « scientific validity(4)» of an «analyte(5) », which were not included in the text of Directive 98/79/EC on IVDs.

Clinical evidence will be documented in a consolidated assessment report. This document will be comprised of a report on scientific validity, a report on analytical performance and on clinical performance, as well as an evaluation of these reports to support the clinical evidence. The data and conclusions drawn from the evaluation of these elements will thus constitute the clinical evidence for the device.

The clinical evidence must be demonstrated by performance studies of the device that will be carried out under the sponsor's responsibility (i.e. manufacturer or other person or legal entity that will be accountable for these studies). To obtain reliable and robust data, these performance studies must be based on a performance assessment plan that will be methodologically defined in the technical dossier. This performance assessment plan will specify the characteristics and performance(s) of the device, as well as the processes and criteria applied to obtain the required clinical evidence.

Depending on how innovative the device is, the clinical evidence may be supported totally or partially on data collected from other devices deemed equivalent. In this case, the alleged equivalence as well as the relevance and validity of the data will be evaluated to demonstrate conformity fo the device. When appropriate, relevant and valid literature data may also be used to discuss the clinical evidence of a device. 

It is important to highlight that assessing the performance of a device is a continuous process and clinical evidence must therefore be updated throughout the device life cycle. To do so, the manufacturer will plan to monitor scientific progress and advances in medical practices (i.e. scientific and medical surveillance), and collect all new relevant information leading to re-evaluating the clinical evidence for the device to ensure its safety and performance.

It should also be mentioned that the concept of clinical benefits for IVDS is fundamentally different from what is applicable to drugs or therapeutic medical devices. Clinical benefits of IVDs can actually be obtained using patient medical information often collected through various diagnostic technologies; final clinical outcome for the patient will then depend on these potential multiple diagnostic and/or therapeutic available solutions.

Role of the notified body

While examining a technical dossier for CE marking, the notified body will evaluate clinical evidence presented by the manufacturer in the performance assessment report. This evaluation will be performed by an internal reviewer from the notified body having relevant clinical expertise and by external clinical experts with direct recent experience related to clinical use of the device involved.

The notified body will verify the validity of clinical evidence and performance assessment, evaluate the manufacturer's conclusions in regards to the device compliance with the general regulatory requirements applicable to safety and performance. This verification will include the relevance of the risk/benefit ratio determination, risk management plan, instructions for use (IFUs), user training plan and post-market monitoring plan.

Based on this evaluation, the notified body will decide on the need to set specific deadlines in the post-market phase, in order to examine updates to the clinical evidence based on data from post-market surveillance and performance monitoring.

Special case of companion diagnostics

The definition of a companion diagnostic is precisely stated in the Regulation. This device category is classified high risk (Class C) and a notified body will therefore be involved in the process of CE marking of these diagnostic tests.

On the basis of the draft summary of safety and performance characteristics produced by the manufacturer(6) and the draft instruction leaflet, the notified body will request the opinion of one of the competent authorities designated by the Member States under Directive 2001/83/EC or from the EMA(7) (called the « Consulted Drugs Authority ») on the suitability of the device for the medicinal product of interest and will duly consider the opinion issued by the Consulted Drugs Authority.

In this special case of companion diagnostics co-developed with a drug, the level of analytical and clinical validation required for the use of these diagnostic tests will be correlated to the clinical study protocols during the different development phases of the drug. In all cases, the clinical evidence for these companion diagnostics will also be demonstrated by the results of clinical studies conducted with the associated drug, showing that this device is essential for safe and effective use of the medicinal product. Robust scientific data will be needed for this demonstration and the requirements associated with this clinical evidence will depend on the tests and technologies used. The level of these requirements for companion diagnostics remains to be defined by the regulatory authorities involved. Noteworthy, the EMA has recently published a «Concept paper»(8) on this subject (Concept paper on predictive biomarker-based assay development in the context of drug development and life cycle).


The IVD manufacturers will have to take into account the new Regulation 2017/746 requirements during the development of their new devices, especially in regards to demonstrating of the clinical evidence required to validate these devices. It is important to note that the technical dossiers for devices already CE marked under the IVD Directive 98/79/EC will also have to be updated during the 5 year transition period, during which the two sets of regulations are applicable, so that these dossiers comply with the new Regulation. To do so, manufacturers will have to contact a notified body, which will issue a CE compliance certificate for the majority of IVDs (i.e. Classes B, C and D). Relevant and valid literature data will also support this demonstration of clinical evidence and may be used and described in CE technical dossiers.

  1. Companion diagnostic» : any device essential for safe and effective use of a given drug, aiming to: a) identify, before and/or during treatment, the patients most likely to benefit from the drug in question; or b) identify, before and/or during treatment, the patients likely to present an increased risk of serious adverse effects in response to treatment using the drug in question;
  2. Clinical evidence» : clinical data and results of the performance assessment relating to a device, the volume and quality of which are adequate to assess, with full knowledge of the facts, if the device is safe and offers the expected clinical benefit(s) when it is used for the purpose intended by the manufacturer;
  3. Clinical benefit» : the positive effect of a device due to its function, such as screening, surveillance, diagnosis or aid for diagnosing patients, or a positive effect on the treatment of patients or in terms of public health;
  4. Scientific validity of an analyte» : the association of an analyte to a clinical condition or a physiological state;
  5. Analyte »: substance or chemical product constituting the centre of interest of a chemical or toxicological analysis procedure;
  6. The content of the summary of safety and performance characteristics is described in article 29 of Regulation (EU) 2017/746 relating to IVD-MDs
  7. Depending on the regulatory route chosen to obtain Marketing Authorisation for the drug
  8. Concept paper

Published 16th July, 2018

Sylvie Le Glédic, Ph.D. Director, Medical Devices & IVD

Sylvie Le Gledic, Director Medical Devices & IVD

Sylvie Le Glédic is in charge of the design and implementation of global regulatory strategies for the development and registration of in vitro diagnostics medical devices (IVDs). Sylvie helps IVD manufacturers in the creation of CE mark technical files and US regulatory dossiers for FDA approval, advising on the required Quality Management System. She assists pharmaceutical companies developing Companion Diagnostics (CDx) in the drug/CDx co-development and facilitates liaison between both pharmaceutical and diagnostic developers. She is actively involved in the evolution of the EU IVD regulation, and closely follows the new rules for regulatory approval of CDx both in EU and US. Sylvie is based in Voisin Consulting Life Sciences’ (VCLS) Paris office.

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