Clinical evaluations are an integral support for a medical device’s regulatory conformity and its technical file for CE marking. A medical device manufacturer uses the information in the clinical evaluation to prove that the medical device meets the applicable essential requirements. As a result, the clinical evaluation is often the largest and most complex portion of a medical device’s technical file, and it’s easy to go astray and not show that the device meets the requirements. Unfortunately, it’s usually a big setback for a manufacturer when this happens, as it may need to get more research or run more studies in order to show compliance.
A clinical evaluation is an “…assessment and analysis of clinical data pertaining to a medical device to verify the clinical safety and performance of the device when used as intended by the manufacturer.”1 A clinical evaluations isn’t the same as a clinical investigation, which is a study done in human patients with the device, but a clinical result may be an input to a clinical evaluation. Both clinical evaluations and investigations give the manufacturer clinical data. It is this clinical data that the manufacturer evaluates and analyses to show how their device conforms to the essential requirements of the medical devices directives. Devices of all classes require a clinical evaluation.
How do I make a Clinical Evaluation?
Getting it right is a perennial dilemma in planning clinical evaluations. Some of the questions that manufacturers must answer are which route it chose, why, and how it shows the device’s conformity to the essential requirements. If a manufacturer doesn’t sufficiently answer these questions, its notified body may ask questions of its own, or may request additional clinical data. The culminating document to the clinical evaluation is the clinical evaluation report, which aggregates and analyses all the clinical data the manufacturer collects during their clinical evaluation. This report should contain enough information to stand on its own, and should include points like the type and extend of the clinical data that has been reviewed, how the data demonstrates the performance and safety of the device, and the device’s intended use.2 To be able to write the clinical evaluation report, the manufacturer needs the outputs of its clinical evaluation.
The first step in creating a clinical evaluation is to determine its scope by looking at the essential requirements that apply to the medical device. Some points the manufacturer should look at are if there’s anything special about the device’s design or its indication, if data from equivalent devices can help support its data, and the types and sources of data to be used in the evaluation. The Medical Devices Directive helps in this last question by requiring that, unless duly justified, the manufacturer must perform a clinical investigation for all class III and implantable devices.3 Once the manufacturer has the questions they need to answer from the first point, it can use three routes to collect clinical data for its evaluation.
One of the routes for collecting clinical data is by a critical evaluation of the existing scientific and clinical literature about the device or its equivalent. In evaluating the literature, the manufacturer assesses the data according to its possible contribution and weighs it according to the safety and performance of the device.
A key part of performing a clinical evaluation through the literature route is for the manufacturer to create its protocol for searching the available clinical data and literature. According to MEDDEV 2.7.1 Rev. 3, this protocol should include:
• The data sources and why the manufacturer chose them;
• The extent of the searches;
• The criteria to select and use a piece of literature and a justification for their choice;
• Any strategies for addressing the potential for duplication of data across multiple publications.
Once collecting the literature, the manufacturer’s clinical evaluator evaluates the protocol itself, the literature search report, and the articles and references themselves.4 This clinical evaluation report is written by someone suitably qualified in the relevant field and knowledgeable in the state of the art, and should be a critical evaluation of the data as well.5
Another route for collecting clinical data is for the manufacturer to run a clinical investigation, harvesting clinical data from its own studies. These clinical investigations should be conducted and reported according to the requirements in EN ISO 14155 and any regulatory requirements applicable in the country where the study is being performed. In evaluating the clinical data from a study, the manufacturer specifically looks at proving the device’s conformity to the essential requirements, as well as the clinical safety and performance of the device.
In order to conduct the evaluation, the clinical evaluator needs:
• The manufacturer’s clinical evaluation plan, its amendments, and justifications;
• The Ethics Committee’s opinions and documentations for each amendment;
• The investigation site, patient information, and informed consent forms;
• Case report forms and audit reports
• If required, any regulatory authority approvals and correspondence, and
• The signed and dated final investigation report.
Where the plan tells how the study is to be conducted, the report should be signed and dated by its author and reviewers to show that it is a true and accurate reflection of the conduct and results of the study. The report should include the identification of the medical device, the objectives of the clinical investigation, the investigation’s methodology, and the results and conclusion of the investigation.6
Using Literature and a Clinical Investigation
A third route combines the two previous routes. One way that this method would be used is if, while conducting a clinical evaluation based on the literature routes, the clinical evaluator or the manufacturer discovers that the existing literature isn’t completely reliable for showing the device’s conformity safety and performances. In this instance, the scope of each evaluation and investigation, combined, covers all the essential requirements for the device. Likewise, the scope for the individual evaluations and studies may be limited to the portion that is not otherwise covered by the other evaluation or study.
What are Notified Bodies looking for in the Clinical Evaluations?
Overall, notified bodies are looking to ensure that the clinical evaluation shows how the device conforms to the essential requirements. Depending on the class of the device, and so the conformity assessment that the manufacturer chooses, notified bodies will examine the clinical evaluation a little differently. For devices that undergo a design examination or type examination, the notified body assesses the clinical data and the conclusions that the manufacturer draws from the data. Specifically, the notified body determines if the manufacturer sufficiently:
• Described and verified the clinical characteristics and performances that it had intended;
• Performed its risk analysis and estimated the undesirable side effects; and
• Had sufficient evidence for and concluded that the risks were acceptable when weighed against the intended benefits.7
When the notified bodies review the clinical evaluation as part of the quality system related procedures, the notified body is not only looking at the manufacturer’s conclusion, but also the manufacturer’s procedures for the documented evaluation of the clinical data. The evaluation should cover the identification of the data, how the data is relevant, assurance that investigations were performed according to the regulations and clinical investigation plan, and that any undesirable side effects are identified and evaluated. Specifically when sampling, the notified body looks at:
• If the clinical data is relevant to the device or the procedure involved;
• If the correct criteria for a literature review has been applied; and
• If the correct criteria for a clinical investigation has been applied.8
How do the proposed Regulations change things?
In 2012, the EU Commission proposed sweeping changes to the current EU medical device regulatory scheme, including changes to the clinical evaluation requirements. One of the first differences is that there are many more definitions in the regulation proposals than there were in the directives. Specifically for clinical evaluations and investigations, terms like Clinical Data, Serious Adverse Event, and Clinical Evaluation, among others, are expressly defined. Another difference is that the proposed regulations are much more prescriptive than the directives, including many more requirements for clinical evaluations. Clinical evaluations are discussed in Chapter VI and Annex XIII of the EU Commission’s proposals. Part A of Annex XIII contains the requirements for clinical evaluations, including how a manufacturer will run a clinical evaluation, how it will show equivalence with other devices, and other requirements.
The responses to the EU Commission’s proposed regulations, the EU Parliament’s amendments, tack on further proposed requirements for manufacturers performing clinical evaluations. For example, Amendment 173 links the annual updating the summary of safety and clinical performance with the clinical evaluation report. Amendment 328 proposes that the clinical evaluation also take into account clinical data from independent scientific laboratories or institutions on the manufacturer’s devices. Finally, Amendment 330 proposes that clinical data collected through a post-marketing clinical follow-up be made accessible to health professionals. At this time, these amendments aren’t finalized and still have a long way to go through the legislative process, in particular with the Council’s works on the proposals.
The clinical evaluation is one of the most important parts of a medical device’s technical file because it gives clinical evidence to the medical device’s conformity to its applicable essential requirements. Effectively compiling, analyzing, and reporting on the device’s clinical data is key to showing that the device conforms for the initial and renewal regulatory certifications.
In June 2014, LNE/G-MED North America Inc. conducted a free informative session on The Clinical Evaluation – Demonstration of clinical safety and performance. Prepared by Anne Le Rouzo, Implant specialist, Lead Auditor and Sr. Technical Documentation Assessor for LNE/G-MED, You can find a recording of the webinar here.
1 MEDDEV 2.7.1 Rev. 3.
2 MEDDEV 2.7.1 Rev. 3.
3 93/42/EEC Annex X.1.1a.