The Medical Devices Regulations (MDR) of 2017 increased the requirements for documentation of clinical data in support of License Applications

Prior to 1993, documentation of a medical device’s clinical safety and performance was given much less attention than the documentation of its manufacture and quality. Since June 1993 a series of regulatory efforts were made to improve the safety of medical devices.

MDD = Medical Devices Directive (93/42/EEC); MDR = Medical Devices Regulations (2017/745)

In April 2017, the MDR was released and made the clinical evaluation of medical devices statutory for access to the EU market for all classes of Medical Devices. Although new guidelines derived from the MDR are expected, including guidance on specific types of devices, the MEDDEV guidelines relating to the clinical evaluation have remained largely valid. The MDR strengthened the requirement for the clinical evaluation of medical devices, particularly the need for a thorough documentation of pre-clinical and clinical data relating to the safety and performance of the device. The amount of pre-clinical and clinical data required for documentation depends largely on the level of risk to health and safety associated with the use of the device. Several new document types have been introduced:

  • Clinical Evaluation Report (CER)
  • Clinical Development Plan (CDP)
  • Clinical Evaluation Plan (CEP)
  • Post-market Clinical Follow-up (PMSF) Plan
  • PMSF Report
  • Failure Modes and Effects Analysis (FMEA)
  • Clinical Investigation Plan
  • Clinical Investigation Report

Not all these are required for all devices but a CER is now mandatory for all medical device license applications in Europe. For the regulators (Notified Bodies), the CER is a key element in assessing the fitness of a medical device for clinical use.

Details on the requirements of the clinical evaluation of a medical device were first provided in the MDD but details on the content of the CER first appeared in the EU MEDDEV Guideline 2.7/1 rev 4 (2016). It documents the clinical evidence that supports a licensing application and, after approval, it is regularly updated to enable the device to remain on the market.

The CER describes the clinical evaluation of the medical device and, according to the MDR 2017, “… shall be thorough and objective, and take into account both favourable and unfavourable data. Its depth and extent shall be proportionate and appropriate to the nature, classification, intended purpose and risks of the device in question, as well as to the manufacturer’s claims in respect of the device.”

The CER is a stand-alone document and is submitted as an attachment to the Technical File. It contains:

  • an assessment of the evidence of the device’s safety risks and expected clinical performance, and, in the updates, additional clinical data on its safety and performance in the field, using evidence actively acquired by the manufacturer during the post-marketing clinical follow-up,
  • a regularly updated review of relevant published literature, and,
  • depending on the class and type of device, data from clinical investigations of the device.

The EU MEDDEV Guideline 2.7/1 rev 4 (2016) remains the currently accepted guidance on the processes of clinical evaluation of medical devices and includes guidance on the structure and content of the CER. It proposes a table of contents for the CER that is now widely accepted as the standard.

The Consequences of EU Regulation 536/2014

This new European Clinical Trial Regulation redefines and tightens the basic regulatory framework covering clinical trials performed anywhere within the European Union (EU). This requirement had originally been planned to take effect in 2018, but the creation of the database and upload portal was delayed, and so it is likely that it will not be implemented before 2020.

The aim of the new regulation is to create an environment favourable to conducting clinical trials within the EU, with the highest standards of safety for participants. It also establishes new rules of conduct for clinical trials, consistent throughout the EU and transforms the level of information publicly available for each clinical trial by requiring transparency on the authorisation, conduct, and results of the trial.

Specific provisions of the new regulation with significant impact on the clinical documentation obligations are as follows:

  • To increase transparency, clinical trial data may in future only be submitted in support of a clinical trial application if that clinical trial has been recorded in a publicly accessible and free of charge database which is a primary or partner registry of, or a data provider to, the international clinical trials registry platform of the World Health Organization (WHO ICTRP). Relevant data will be expected to be submitted via EMA’s European Portal to the European Database.
  • Sponsors will be required to submit a summary of the clinical trial results to the publicly available European Database, and to provide an accompanying summary that is understandable to a layperson. Delay is only permissible if it is not possible to submit the summary of the results within the defined timelines for scientific reasons, for example when the clinical trial is still ongoing in third countries, and data from that part of the trial are not available – making a statistical analysis not relevant. In this case, the sponsor must justify the delay in the trial protocol and specify when the results are going to be submitted.
  • The public will be able to access extensive details of all clinical trials, including the major characteristics of the trial, the start and end of recruitment, end date of the trial, and substantial modifications to the trial. These details will be made public as they occur, starting with the decision on the trial. A summary of results and lay summary will be published 12 months after the end of the trial. For trials included in a marketing authorisation application in the EU, clinical study reports will also be published 30 days after the procedure for granting the marketing authorisation has been completed or the application has been withdrawn.