Under the new regulation, manufacturers will need to provide more in-depth clinical data to support safety and performance claims in both the pre- and post-market settings. Ultimately, more scrutiny will be placed on manufacturers to proactively collect and evaluate clinical data throughout the product lifecycle.
The MDR defines a clinical evaluation as “a systematic and planned process to continuously generate, collect, analyze, and assess the clinical data pertaining to a device in order to verify the safety and performance, including clinical benefits, of the device when used as intended by the manufacturer.” Manufacturers should plan, conduct, and document a clinical evaluation in accordance with MDR (Article 61) and Annex XIV (Part A). Clinical evaluations must be thorough and consider both favorable and unfavorable data. The extent to which clinical data is collected should be in line with the nature, classification, intended purpose, and risk of the device, as well as the manufacturer’s safety and performance claims.
Clinical Evaluation Plan (CEP)
The new regulation emphasizes the importance of early planning when it comes to clinical evaluations. As such, manufacturers will need to develop a clinical evaluation plan prior to gathering data. The clinical evaluation plan should include:
- General safety and performance requirements that need clinical data support
- Intended purpose of the device, as well as the intended target groups with clear indications and contraindications
- Intended benefits to patients with relevant clinical outcome parameters
- Methods to examine clinical safety with reference to the determination of residual risks and side effects
- Parameters to determine benefit-risk ratio acceptability for the various indications and intended purposes of the device
- Process for addressing benefit-risk issues relating to the use of components such as non-viable human or animal tissues
- Clinical development plan indicating the progression from exploratory investigations (e.g., feasibility and pilot studies) to confirmatory investigations (e.g., post-market clinical follow-up) with an indication of milestones and potential acceptance criteria
Clinical Data Sources
Once a plan is established, manufacturers should identify all available clinical data that is relevant to the safety, performance, and intended purpose of the device. Sources of clinical data include:
- Clinical investigation(s) of the device in question
- Clinical investigations(s) or other studies reported in scientific literature of a similar
device for which equivalence can be demonstrated*
- Reports in published peer-reviewed scientific literature on other clinical experience of either the device in question or similar device for which equivalence can be demonstrated*
- Clinically relevant information coming from post-market surveillance, in particular the post-market clinical follow-up
*Note: Although published articles and scientific journals are considered relevant sources for clinical data under the new regulations, a comprehensive and reproducible literature search should be conducted. The MEDDEV 2.7/1 Rev. 4 guidance document provides a detailed protocol for performing a scientifically valid literature search that meets compliance4.
For legacy devices (i.e., devices previously certified under the Medical Device Directive (MDD) or Active Implantable Medical Device Directive (AIMDD))—post-market clinical data, along with the clinical data generated for the conformity assessment under MDD/ AIMDD, will serve as the basis of the clinical evaluation under the new MDR. In addition, manufacturers should perform a gap analysis with the general safety and performance requirements of the MDR to determine if additional or new data is necessary.
Clinical Evaluation Assessment Report (CEAR)5
The clinical evaluation assessment report must be a part of the manufacturer’s quality management process. It should also be aligned with and reflected in other aspects of the technical documentation, such as:
- Interface of the clinical evaluation with the risk management process and its appraisal and analysis of the pre-clinical and clinical evaluation and their relevance for the demonstration of conformity with the relevant requirements in Annex I.1
- Post-market surveillance including any corrective and preventive actions involving the device
- Post-market clinical follow-up plan, and where appropriate, the post-market clinical follow-up report
- Instructions for use, which provide adequate information on intended purpose, proper use, and warnings about risks to patients and healthcare practitioners
Clinical Investigations for Class IIb, Class III, and Implantable Devices
Clinical investigations carried out by the sponsor/manufacturer should serve as the key source of clinical data for Class III and implantable medical devices. All clinical investigations should follow the good clinical practices set forth in ISO 14155. These devices may be exempt from clinical investigation if:
- The design is based on a modification of a device that is already marketed by the manufacturer
- The modified device has been demonstrated by the manufacturer to be equivalent to the marketed device and has been endorsed by a notified body
- The clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device with the relevant safety and performance requirements
For all Class III devices and Class IIb devices (referenced in MDR Article 54), manufacturers may consult with an expert panel regarding its intended clinical development strategy prior to conducting a clinical evaluation and/or investigation.
Summary of Safety and Clinical Performance (SSCP)6
Under the MDR, manufacturers will need to draw up a summary of safety and clinical performance (SSCP) for implantable Class IIb devices and for Class III devices, other than custom-made or investigational devices. The SSCP shall be validated by a notified body and made available to the public via the European database for medical devices (EUDAMED).
The SSCP serves as an important source of information for intended users—both healthcare professionals and patients. It is intended to help fulfil the objectives of the MDR by enhancing transparency and providing adequate access to information about the safety and clinical performance of the device.
The MDR has more stringent requirements for claiming equivalence, especially for Class III and implantable medical devices. Devices with “sufficient clinical data” under the previous MDD/AIMDD regulations will most likely need additional clinical data under the new regulation.
If the clinical evaluation is based on clinical data from an already marketed device, manufacturers will need to demonstrate that they have access to sufficient levels of clinical data to claim equivalence. In addition, the equivalent device must share the same technical, biological, and clinical characteristics.
- Technical: Device has similar design, specifications, and properties, is used under similar conditions, uses similar deployment methods, has similar principles of operation and critical performance requirements
- Biological: The same device materials or substances are in contact with the same human tissues or body fluids for a similar duration
- Clinical: Device is used for the same clinical condition or purpose in a similar patient population and has the same kind of user
For Class III and implantable medical devices, manufacturers can claim equivalence to an already marketed device (from a different company), under the following conditions:
- Manufacturer has a contract in place with the other company to allow full access to technical and clinical documentation of the equivalent device on an ongoing basis
- The initial clinical evaluation of the equivalent device has been performed in compliance with MDR requirements
- The equivalent device is certified under the MDR
For non-implantable and non-Class III devices, manufacturers can claim equivalence to an already marketed device (from a different company) without establishing a contract; however, the manufacturer will need to demonstrate sufficient levels of access to clinical data.
Data Appraisal and Analysis
Once the clinical data has been collected, manufacturers should conduct a qualitative or quantitative appraisal to determine the methodological quality and scientific validity of each data set. This involves examining the methods used to collect the data and determining the extent to which factors such as bias, random error, and misinterpretation affect the performance or safety outcomes of the device. Other components of the appraisal include determining the relevance of the clinical data and weighting the contribution of each data set.
The analysis portion of the clinical evaluation involves assessing whether proof of the performance and safety of the device has been adequately established. Detailed requirements for performing the data appraisal and analysis are outlined in the MEDDEV 2.7/1 Rev. 4 guidance document4.
Clinical Evaluation Report (CER)
The results of the clinical evaluation must be documented in a clinical evaluation report and included with the technical documentation that is provided for the conformity assessment. Clinical evaluation reports should be updated once per year (at minimum) for high-risk devices (i.e., Class III and implantable devices). For lower-risk or well established devices, the clinical evaluation report should be updated every 2 to 5 years. The frequency of updates should be justified in the clinical evaluation plan.
Post-Market Clinical Follow-up (PMCF)
To confirm the safety and performance of a device throughout its lifecycle and ensure the continued acceptability of identified risks, manufacturers will need to conduct a post-market clinical follow-up (PMCF) under the new MDR requirements.
The PMCF should be conducted using a device that is already placed on the market and bears the CE Mark. It should also be conducted according to a formalized plan7, which specifies the methods for proactively collecting and evaluating clinical data.
The findings of the PMCF should be analyzed and documented in a PMCF evaluation report8 and included with the technical documentation.