The Consequences of EU Regulation 536/2014

The way clinical trials are conducted in the European Union (EU) will undergo a major change when the portal for upload of the lay summaries required by Clinical Trials Regulation (Regulation (EU) No 536/2014) opens on 31 January 2022. The Regulation harmonises the assessment and supervision processes for clinical trials throughout the EU, via a Clinical Trials Information System (CTIS). CTIS will contain the centralised EU portal and database for clinical trials required by the Regulation. The European Medicines Agency (EMA) sets up and maintains CTIS, in collaboration with the Member States and the European Commission.

The goal of the Clinical Trials Regulation is to create an environment that is favourable to conducting clinical trials in the EU, with the highest standards of safety for participants and increased transparency of trial information. The Regulation will require:
• Consistent rules for conducting clinical trials throughout the EU,
• Information on the authorisation, conduct and results of each clinical trial carried out in the EU to be publicly available.
This will increase the efficiency of all trials in Europe with the greatest benefit for those conducted in multiple Member States. It aims to foster innovation and research, while helping avoid unnecessary duplication of clinical trials or repetition of unsuccessful trials.

With the opening of the portal for upload of Clinical Trial Lay Summaries, the requirement for Lay Summary production is about to become mandatory. Sponsors will be required to submit a summary of the clinical trial results to the publicly available European database 12 months after the end of the trial.

 

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.