Clinical Evaluation and Investigation of Medical Devices under the new EU-Regulation

1. Clinical Evaluation

1.1. Introduction

Both in the old and new EU regulatory system for medical devices (MD), the manufacturer has to demonstrate safety and performance of MDs not only by technical and preclinical evaluation but also by clinical evaluation on the basis of sufficient and relevant clinical data.

One of the main challenges for clinical evaluators is to adequately reflect the complex character of the clinical evaluation, ranging from regulatory, organizational, technological to clinical aspects. Subsequently, the expectations on the documentation of the clinical evaluation are manifold and in large parts related to the perspective of evaluators serving manufacturers or third parties (National Competent Authorities, Notified Bodies, Public…). This complexity is additionally increased since MDR is explicitly placing clinical evaluation as an active systematic life cycle process under the manufacturer's mandatory QMS.

From a regulatory perspective: In order to assure that the expectations, claims and requirements concerning clinical safety and effectiveness are fulfilled in the intended target population(s) and indications, the manufacturer must generate, identify, appraise, analyse, evaluate, document and update sufficient and methodologically valid clinical data over the life-cycle of the MD (including PMCF1) and demonstrate this as the clinical evidence in conjunction with the clinical evaluation report (CER), following a proper process of clinical evaluation.

From an organizational perspective: The improvement of the clinical evaluation (CEV) of MDs has been one of the main target areas of the new medical device regulation (MDR). MDR is explicitly placing clinical evaluation as an active systematic life cycle process under the manufacturer's mandatory QMS. Clinical evaluation is now more closely integrated into the systemic context of the new regulation, especially with regard to its connections to QMS, PMS, risk management, manufacturer’s obligations (Art. 10), demonstration of conformity with the general requirements for safety and performance (Annex I), technical documentation (Annexes II and III), tasks and competencies of notified bodies (Annex VII) and to conformity assessment (Annexes IX-XI2).

This also implies that the interconnections to other processes have to be established and be continuously evaluated. This integration into the quality management system requires that the responsible persons involved are adequately qualified3 - a respective rationale also needs to be provided if (parts of) the process is outsourced. These aspects can be seen as the organizational framework for the activities related to the clinical evaluation.

From a technological perspective it is expected that the device description within the clinical evaluation report 4 correctly identifies the current configuration of the medical device, including (but not limited to) the name, model, sizes, variants, components of the device (including software, accessories or intended product combinations). Clinical evaluators have to critically rely on previous technical and preclinical evaluation, based on concise physical, chemical, technical specifications and mechanical and functional characteristics and a clear understanding of the mode of action. Further on, the technological and biological differences between predecessor devices and potential equivalent devices must be precisely described and further discussed from a clinical perspective.

From this clinical perspective it is additionally expected that the clinical data supports the initial and continuous evaluation of the acceptability of the clinical benefit-risk ratio with respect to the current state of the art in medicine, including applicable clinical standards and guidance documents, scientific information regarding the medical condition managed, its natural course and the medical alternatives to the target population 5. This requires – relating to the device, its technology and its clinical application - deep, usually scientifically based knowledge and critical expertise.

It cannot be emphasized enough, that – due to the necessity of different perspectives - the clinical evaluation process typically cannot be conducted by one single person and in isolation from other processes. An effective implementation of the clinical evaluation requires deep and fundamental changes within the organizational structure of medical device manufacturers and a close interaction with the life-cycle processes of the device.

For clinicians and related scientists, the new EU medical device system offers excellent opportunities, based on their professional know-how and on their knowledge of regulatory, normative and scientific principles and processes. This applies both if you want to cooperate with the stakeholders (above all manufacturers, notified bodies or competent authorities) and even more if you want to make your own involvement stand out in start-ups, spin-offs or other development projects or in counselling services.

The increased emphasis on clinical aspects in the MDR is also reflected in the creation of an improved clinical infrastructure of the EU regulatory system with (clinical) expert panels6 and the provisions for product group-specific clinical guidelines as ‘Device Specific Guidance’ (DSG7) or in the form of implementing acts of the COM as Common Specifications (CS8) for clinical investigations and/or clinical evaluation and/or PMCF of certain types or groups of (usually high-risk) MDs. The clinical aspects are now more clearly highlighted in the terminology (Art.2 of MDR).

Clinical Evaluation and its assessment are now clearly at the centre of the manufacturer’s and notified bodies obligations; Clinical Evaluation and its assessment has to be properly set up, documented and updated. Its results will be more transparent to the public9.

1.2. Clinical Evaluation - Definitions

The following terms play an important role in clinical evaluation in the MDR10. More definitions and detailed explanations will be provided at respective chapters within this document.