In accordance with the European directive for medical devices 93/42/EEC, ‘manufacturers must provide proof of and document the performance and safety of medical devices in a “clinical evaluation”’. With the breast implant scandal in mind, in order to (re-)establish confidence in regulatory processes, authorities are demanding greater patient protection. This has led to increased market hurdles for medical devices and subsequently more exacting standards for clinical evaluation.
Since 1 July 2016, the revision 4 of the MEDDEV 2.7.1 guideline for clinical evaluations has been in effect. While it offers more detailed guidance than the previous version, it also formulates stricter requirements with a narrower focus on Europe.
Stricter standards to demonstrate equivalence of comparable products
The MEDDEV 2.7.1 revision 4 demands that Equivalence must be explained much more comprehensively and in more detail than it was previously required. This poses a challenge as more comprehensive equivalence would be partly based on information that can hardly be obtained other than from the manufacturer of the competing product itself (eg comparative product drawings, details of manufacturing processes, etc.).
Literature review must consist of a mandatory search in European databases
Until date PubMed has often been chosen as the single source for the main literature search as the probability of finding top-ranking studies is the highest here. However, an important amendment was published in MEDDEV 2.7 1 rev 4 wherein a Europe-centric clinical literature search must be conducted which is not always made available in databases such as PubMed. European databases such as Embase have been recommended with the rationale that “Studies yielding negative results or user experience (…) may not qualify for publication in high impact medical journals. Journals available to European users and other sources may therefore need to be searched.”
More stringent requirements regarding qualification of authors (chapter 6.4)
The MEDDEV 2.7.1 revision 4 lays even more emphasis on the requirements for multi-disciplinary qualifications and knowledge of the author of a clinical evaluation, such that it is nearly impossible for a single person to meet them.
The authors must also make a declaration of interest in which they disclose possible financial or personal conflicts of interest in their relationship with the manufacturer. In order to meet the increased requirements, an individual author may be replaced by a team of consulting specialized experts.
Reference products shall bear the European CE mark.
Also another new requirement in this guidance is that all equivalent devices must be CE marked. (Appendix 1) While the degree of equivalence must be demonstrated with regards to clinical, technical and biological aspects, according to new MEDDEV 2.7.1 revision 4, only CE-labeled devices can be used to collect data on equivalent devices. In other words only devices that meet the European market’s fundamental requirements shall be used as reference devices.
Updates are required in line with the frequency & criteria defined
MEDDEV 2.7 1 Rev 4: Conducting a Clinical Evaluation
General principles of clinical evaluation
The objective of the clinical evaluation is to prove that the product is safe and effective based on a set of clinical data, i.e. “the safety and/or performance information that is generated from the clinical use of a device” (MDD 93/42 EWG, article 1.2.k).
Clinical data can be used from the device itself, and also from similar devices (state of the art) where equivalence with the device under evaluation must be demonstrated. In the event that the available data is not sufficient, additional clinical data must be generated, especially for new and high-risk products.
Report (Chapter 11)
According to the latest MEEDEV 2.7/1 revision 4, the clinical evaluation’s results shall be presented in a report (“clinical evaluation report”, CER) which must reflect a systematic sequence of stages as explained in the section below. The manufacturer must plan and carry out regular updates to the report, which must be included in the technical documentation.
An Overview of the Structure and Content in MEDDEV 2.7.1 Revision 4
The guidance document details the format for reporting clinical evaluations, with detailed explanations on how to plan and prepare such a report systematically.
With an iterative cycle consisting of 5 steps, the report should reflect the sequence followed as below:
Defining the scope and presenting the focus, context, objective and structure of the clinical evaluation
This could include for example a description of the product to be evaluated and its purpose, as well as the technical and medical background. Based on the focus of the clinical evaluation, a plan (“clinical evaluation plan”) is drafted which must meet the fundamental requirements of clinical evidence. Manufacturers should ideally conduct their own clinical literature review for the introductory part on the medical background and treatment alternatives.
Identifying and collecting relevant data from scientific literature, clinical experience, and if possible, from their own clinical trials. The aim is to identify published scientific papers (clinical studies, reviews, meta-analyses) that contain meaningful and relevant results on the performance and safety of the product. It is imperative that sufficient clinical data is collected or generated which provides information on the device’s safety and performance objectively and reliably. The literature search conducted must be thorough and like the subsequent selection process, must be documented comprehensible.
Evaluating individual data sets with the following criteria – quality, validity, and relevance of evidence.
Here Revision 4 creates an explicit distinction between “pivotal data” and “other data” such that “When evaluating the relevance of collected data it is important to consider whether the data are intended to directly demonstrate adequate clinical performance and clinical safety of the medical device (often referred to as pivotal data), or whether the data serves an indirect supportive role.”
Thus, clinical literature search must consist of two different search requests, namely
(1) Information on the state of the art, state of knowledge, and medical and technological background
(2) Studies that directly contribute to the medical device’s clinical performance and safety.
Conducting an overall assessment of available data with the following criteria – Significance of the clinical data, conclusions regarding performance and safety, benefit/risk ratio positive
Here the evaluation of side effects (Essential Requirement no. 6) must be conducted to ensure that the benefit-risk ratio is maintained against the intended performance.
Reporting on the conducted clinical evaluation. The report should be detailed and comprehensive in its documentation of the stringent argumentation and conclusions of the clinical evaluation. Here, the explicit recommendation to design the report based on consecutive work packages (“stages”) was added in MEDDEV 2.7.1 revision 4. A structural template for the report has been provided in Appendix 9.
Additionally, a checklist for the clinical evaluation’s release has been provided in Appendix 10 which can be used to systematically review both regulatory as well as substantive issues at the end of the Clinical Evaluation report.
While regulations should ensure that medical devices on the market are safe and effective, they should not delay and hinder market access unless absolutely necessary. Restrictive regulations could just as easily cause harm as very lenient laws, that allow unacceptably dangerous medical devices from being in use, by delaying life-saving products from entering the market and reaching patients who need them.