Why Software as a Medical Device (SaMD) is Prioritized in the EU MDR - Celegence

Introduction to Clinical Reports: What Are They, When/Where Are They Used, and Why?

The current European medical device regulatory framework set its precedence in the early 1990s when the rules relating to the safety and performance of medical devices were first harmonized in the European Union (EU). These guidelines were summarized in the European Commission’s Directive 93/42/EEC and later amended by Directive 2007/47/EC. The European Union – Medical Device Regulations (EU MDR) have promoted a more uniformed approach towards conformity assessment procedures of the directives within the EU.

What Is Clinical Evaluation?

Clinical evidence is collected throughout the life cycle of a medical device and is an ongoing process. It is first performed during the development of a medical device to identify data that needs to be generated for market access and is updated regularly thereafter per regulations. Continued clinical evaluation is necessary as it ensures the safety and performance of the device throughout the lifetime that the medical device is on the market through comprehensive data review. Clinical evaluation is a methodologically sound ongoing procedure to collect, appraise, and analyze clinical data pertaining to a medical device. Its core objective is to analyze whether there is sufficient clinical evidence to confirm compliance with relevant general safety and performance requirements (GSPRs) when using the device according to the manufacturer’s instructions for use. CERs are not a new requirement, however, under the EU MDR, the acceptability of content has changed – highlighting key requirements on transparency and traceability with an increased level of scrutiny over clinical evidence and levels of examination.

Specific requirements of the evaluation include appropriateness to the intended purpose of the device, benefits and risks pertaining to their nature, probability, extent, duration, and frequency. Key issues for a successful clinical evaluation methodology include the proper determination of the benefit/risk profile in the intended target groups and medical indications, and the demonstration of acceptability of that profile based on current knowledge/the state of the art in the respective medical field. This process is the device manufacturer’s responsibility, and the clinical evaluation plan and report form the documentation presenting the technical and clinical evidence summary of the device.

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When is a Clinical Evaluation Undertaken?

Clinical evaluation is conducted throughout the life cycle of a medical device as an ongoing process. To gain market access, it is first performed during the development of a medical device for an initial CE mark and then updated regularly as per mandated standards.

When a clinical evaluation is undertaken for the development a new medical device – premarket research and development processes guide the evaluation process. Manufacturers conduct gap searches to identify any gaps in the current data, determine if equivalence is to be claimed, and to define the requirements for demonstrating safety and performance of the device. Therefore, as the initial clinical evaluation identifies the questions to be answered by a clinical investigation, the clinical evaluation process should generally commence in advance of any clinical investigation.

Whereas, when a clinical evaluation is undertaken for an initial CE mark and subsequent placement of the device on the market, the purpose is to identify aspects that need to be addressed systematically during post-market surveillance (PMS), e.g., estimating the requirement of a post market clinical follow-up (PMCF) study. These aspects include an estimation of the residual risks and uncertainties, or any unanswered questions (such as rare complications, uncertainties regarding long-term performance, safety under wide-spread use). Additionally, the evaluation process aims at documenting sufficient clinical evidence to demonstrate conformity with the GSPRs covering clinical performance and clinical safety.

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How is Clinical Evaluation Performed?

The clinical evaluation is based on a comprehensive analysis of available pre-and post-market clinical data relevant to the intended purpose of the device in scope.

There are 4 stages in performing a clinical evaluation, described below in detail:

Stage 0: Defining the scope and planning the clinical evaluation.
Stage 1: Identifying pertinent data.
Stage 2: Appraisal of data sets for scientific validity, weightage, and relevance.
Stage 3: Analyze the data, whereby conclusions are reached about:

  • compliance with GSPRs on performance and safety, and the benefit/risk profile of the device.
  • the contents of information material supplied by the manufacturer.
  • residual risks and uncertainties required to be addressed during PMS.

Stage 4: Finalize the clinical evaluation report.

The clinical evaluation report summarizes and draws together the evaluation of all the relevant clinical data documented or referenced in other parts of the technical documentation constituting evidence for the conformity assessment.

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Defining the Scope of a CER

Prior to beginning the clinical evaluation, the manufacturer must define the scope of the device based on the clinical perspective, nature, and history of the device thereby setting up the basis for further steps, such as identification of pertinent data. Following this, the manufacturer should submit, as part of their documentation of the quality management system, a clinical evaluation plan for review by the Notified Body. The plan outlines the strategies and procedures used in the clinical evaluation of the device and presents potential key factors determining the safety and performance of the device. This includes the scientific rationale for the design and mechanism of action of the device, taking into account the SOTA.

Per MDR 2017/745 Annex XIV Part A, a thorough CEP shall include at the minimum:

  • an identification of the general safety and performance requirements that require support from relevant clinical data.
  • a specification of the intended purpose of the device.
  • a clear specification of the intended target groups with clear indications and contra-indications.
  • a detailed description of the intended clinical benefits to patients with relevant and specified clinical outcome parameters.
  • a specification of the methods to be used for the examination of qualitative and quantitative aspects of clinical safety with clear reference to the determination of the residual risks and side-effects.
  • an indicative list and specification of the parameters to be used to determine, based on the state of the art in medicine, the acceptability of the benefit-risk ratio for the various indications and for the intended purpose or purposes of the device.
  • an indication of how benefit-risk issues relating to specific components such as use of pharmaceutical, non- viable animal or human tissues, are to be addressed.
  • a clinical development plan indicating progression from exploratory investigations, such as first-in-man studies, feasibility and pilot studies, to confirmatory investigations, such as pivotal clinical investigations, and a PMCF as referred to in Part B of this Annex with an indication of milestones and a description of potential acceptance criteria.

Identifying Pertinent Data for a Clinical Evaluation Report

There are often three key sources of data that can be included for devices:

  1. Studies published in medical journals.
  2. Unpublished, internal data.
  3. Complaint/post-market surveillance data.

Identifying high-quality data resulting from a well-controlled clinical trial process contributes as a valuable source for demonstrating safety and performance of the device and are key factors in drafting a CER.

To identify such pertinent data, a well-defined, systematic, and transparent literature search must be created. Literature search databases for identifying data must be chosen. The most commonly searched databases include: PubMed, Embase, Cochrane, and Google Scholar. Each database has its respective strengths and weaknesses and should be used based on the type of the device. An inclusion/exclusion criterion should be set to generate relevant data sets, limit the scope of the report, and to keep it manageable.

Analyzing the CER Data

It is mandatory to analyze and present the study results in terms of their quality, safety, and performance. There are two ways in which data can be presented in a CER:

  1. Text-based summaries of individual studies – it allows for comprehensive discussion of all studies included. However, the disadvantage here is that drawing conclusions from presenting numerical endpoints is inherently difficult.
  2. Visual summaries of pooled data – its advantageous in presenting individual endpoints through graphs, figures, tables etc. However, this method may be susceptible to errors, and thus, a quality check or aid from a statistician is recommended.

Finalizing the CER

Once the data is collected, appraised, and analyzed, the results are contextualized in terms of the wider picture of the device. The final CER should address any risks identified from the internal and external data sets and concludes with the mitigations provided.

The conclusion of the CER should demonstrate that the performance and safety of the device as claimed have been established; and the risks associated with the use of the device are acceptable when weighed against the benefits to the patient. Thereby, the CER concludes that the clinical evidence demonstrates conformity with the relevant GSPRs.

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Clinical Evaluation Report (CER) Specialists

Celegence has a wealth of knowledge to help you navigate through the complex regulatory challenges brought forth by the EU MDR. From consultative services to end-to-end writing capabilities, our expert team can support you in all aspects of your Clinical Evaluation.

For more information about how we can help with CER writing, reach out to us at info@celegence.com, contact us online or read more about Celegence’s medical device services.