What is the Clinical Investigation Report for medical devices, and how to prepare it to comply with the European regulation? Continue reading to learn more.

Following the end of a clinical investigation and irrespective of its outcome, the Regulation (EU) 2017/745 (MDR) and the International Organization for Standardization (ISO) 14155:2020, the Sponsor shall prepare a Clinical Investigation Report (CIR) or sometimes also called the Clinical Study Report for medical devices.

The CIR is a document that provides a comprehensive description and evaluation of the conduct and results of a clinical investigation. The Clinical Investigation Report should be signed by the investigator and shall contain a critical evaluation of all the data collected during the clinical investigation, including any negative findings.

Icing on the Clinical Investigation: The Clinical Investigation Report according (2023/C 163/06)

According to the MDR, the CIR shall be accompanied by a summary presented in terms that are easily understandable to the intended user.

According to Section 7, Chapter III of Annex XV of the MDR, the summary of the CIR should at least cover the title, purpose of the investigation, description of the investigation, investigational design and methods used, the results of the investigation and conclusion of the investigation. Moreover, the completion date of the investigation, and details of early termination, temporary halts, or suspensions of investigations, should also be included.

Considering until recently this was the main requirement for the development of the Clinical Investigation Report, lack of consistency among the summaries presented by different sponsors and, frequently, missing information were common. To address this issue, on May 8th 2023, the European Commission has made available a Commission Guidance (2023/C 163/06) that provides clear instructions and guidance on the content and structure of the clinical investigation report summary, aimed at promoting harmonization, ensuring completeness, and improving the quality of clinical data provided by manufacturers.

Shedding light on the summary of the CIR: Commission Guidance (2023/C 163/06)

The European Commission recently released the “COMMISSION GUIDANCE on the content and structure of the summary of the clinical investigation report (2023/C 163/06)”, which aims to ensure that the summary of the clinical investigation report presents information about the design, conduct, analysis, and results of the clinical investigation in terms and format that are easily understandable to the intended user of the medical device.

The main points outlined in the Commission Guidance are:

• The guidance is in accordance with Article 77(6) of Regulation (EU) 2017/745, which specifies the requirements of the clinical investigation report.
• The summary must be concise, avoid copying text from the full report, and be free of promotional content. It should consider the health literacy and numeracy of the intended user(s) of the device.
• The summary should include the following sections:
• Cover page with basic information about the clinical investigation, including date of summary, title of clinical investigation, entities sponsoring and funding the study, the single identification number, and the CIP number.
• Title of the clinical investigation and summary information, including brief and full study titles, start and end date of the clinical investigation, location and reason for temporary halt or early termination, if relevant.
• Purpose of the clinical investigation, including brief rationale for the clinical investigation, current standard of care and other possible interventions.
• Description of the investigation device, clinical investigation, and methods used, including eligibility criteria, comparators (if any), procedures to use the device, study design description and justification, objectives and endpoints, sample size, randomization and blinding, follow up duration, concomitant treatments, statistical analysis methods, and substantial modifications of the CIP.
• Results of the investigation, including participant flow, baseline demographic and clinical characteristics, outcome of the intervention, safety outcomes (adverse events, adverse device effects and device deficiencies), and deviations to CIP.
• Conclusion of the clinical investigation, including description and discuss of results related to assessment of benefits vs risks, added value of the clinical investigation to the current scientific knowledge, limitations, and potential for future studies.

Clarifications provided by the Commission Guidance (2023/C 163/06)

The Commission Guidance also explains that, prior to the full functioning of EUDAMED, the single identification number is the Clinical Investigation Identification (CIV-ID) number provided by the authorizing Competent Authority. Once EUDAMED is functional, the single identification number should be included.

The Commission Guidance provides orientation on the reasons for temporary halt or early termination expected. These may include positive active findings, positive control findings, safety findings, futility, slow recruitment, or external evidence, among others.

To ensure a clear summary is presented, the Commission Guidance explicitly indicates not to include any results, analysis, conclusions, or discussion points in the description of the investigation device, clinical investigation, and methods used section.

Regarding the description of the investigational device, the Commission Guidance indicates the version/variant and intended purpose including the different components required for the medical intervention(s) involving the device under investigation should be detailed.

The Commission Guidance highlights that a clear definition of the primary and secondary objectives, the hypothesis tested, and the primary and secondary endpoints is crucial for ensuring a good understanding of the clinical investigation.

The Commission Guidance recommends including a table describing any substantial modifications to the CIP, where the relevant versions of the CIP, dates of these modifications, and confirmation of approval of these modifications from an ethics committee should be clearly indicated.

Moreover, the Commission Guidance provides a participant flowchart, and encourages manufacturers to use the provided flowchart or a similar one. It should be considered the flowchart is for randomized two arm studies, and therefore,  it should be adapted to the corresponding study design.

When presenting results, the Commission Guidance recommends the use of absolute numbers instead of percentages directly (e.g., 10/20, not 50%). The type of analysis conducted should be clearly identified: intention-to-treat or per protocol. The adverse events, adverse device effects and device deficiencies should be presented in a listed table in order of most to least frequent, including absolute numbers (X out of YX subjects), percentage (X% of subjects) and whether the events were expected or unexpected. Moreover, only aggregated information related to these events/effects should be presented. If any, the number of subjects withdrawn and reasons, as well as list of subject deaths, should be also included.

In line with the increasing presence of the risk-based approach in regulatory documents, the Commission Guidance indicates that the conclusions of the clinical investigation should be related with a benefit-risk assessment of the intervention in light of the investigation, as well as with a benefit-risk assessment of the investigational medical device in the context of current evidence.

With this new Commission Guidance, entities involved in medical device clinical investigations are expected to improve the quality and consistency of summaries of Clinical Investigation Reports, ultimately enhancing transparency and promoting informed decision-making.

Relationship between Commission Guidance (2023/C 163/06) and other regulatory documents

In the recently released guidance on the summary of clinical investigation reports, there are notable connections to the MDR and ISO 14155:2020. Understanding these relationships can provide better context and improve compliance with both the regulations and the standards.

Commission Guidance and Regulation (EU) 2017/745 (MDR)

The guidance is developed in accordance with Article 77(6) of MDR, which outlines the requirements of the CIR. The MDR aims to ensure a high level of safety and health protection for patients and users while supporting the innovation and competitiveness of the medical device industry.

The key aspects related to MDR found in the Commission Guidance (2023/C 163/06) are:

• The sponsor of a clinical investigation must submit a study report and summary within one year of the end of the clinical investigation or within three months of the early termination.
• The minimum requirements of the clinical investigation report are outlined in Section 7, Chapter III of Annex XV of the MDR.
• The report and summary shall be submitted to Member States through the electronic system referred to in Article 73 of the MDR and become publicly accessible.

Commission Guidance and ISO 14155:2020

The ISO 14155:2020 standard provides guidance on the requirements for clinical investigations of medical devices involving human subjects. It aims to ensure that clinical investigations are designed, conducted, recorded, and reported ethically and scientifically.

The key aspects related to ISO 14155:2020 found in the Commission Guidance (2023/C 163/06) are:

• The guidance integrates and adapts elements from ISO 14155:2020, particularly in the sections on participant flow, baseline demographic and clinical characteristics, outcome of the intervention, safety outcomes, and limitations.
• The guidance also refers to ISO 14155:2020 Annex D.7, focused on the presentation of the results in the CIR, and to Annex D.8, addressing the discussion and overall conclusions of the CIR, for further information on those sections of the summary.

Commission Guidance and other MDCG Guidance Documents

MDCG 2021-6 Regulation (EU) 2017/745 – Questions & Answers regarding clinical investigation

The MDCG 2021-6 is Questions & Answers document intended for sponsors of clinical investigations of medical devices conducted within the scope of the Regulation (EU) 2017/745 (MDR).

The Commission Guidance refers to the MDCG 2021-6 to provide more clarity on definitions of the start and end date of the clinical investigations, as well as on substantial modification to the CIP. 

MDCG 2020-10/1 Rev 1 Safety reporting in clinical investigations of medical devices under the Regulation (EU) 2017/745

The MDCG 2020-10/1 Rev1 is focused on proving guidance on safety reporting in clinical investigations of medical devices according to the requirements of the MDR. This document defines Serious Adverse Event (SAE) reporting modalities (in the absence of Eudamed) and includes a summary tabulation reporting format.

Despite the Commission Guidance does not explicitly reference MDCG 2020-10/1 Rev1, the review of this MDCG to complete the safety outcomes in the summary of the CIR is strongly recommended.

In conclusion, the new guidance on the summary of clinical investigation reports is closely aligned with both MDR and ISO 14155:2020. By following the Commission Guidance, entities involved in medical device clinical investigations can ensure compliance with the relevant regulations and standards, ultimately contributing to patient safety and the advancement of the medical device industry.

Relevance of the Commission Guidance: Its Impact on Manufacturers and Clinical Investigations

The Commission Guidance on the content of on the content and structure of the summary of the clinical investigation report (2023/C 163/06) is relevant for several reasons:

• Provides Clarity: The Commission Guidance provides clarity on the content and structure of the summary of the clinical investigation report, helping manufacturers to prepare high-quality summaries of clinical investigation reports that fulfill MDR 2017/745 and ISO 14155:2020 expectations.
• Promotes Harmonization: The Commission Guidance promotes a harmonized approach to the content and structure of the clinical investigation report summary, reducing the inconsistencies and confusion among manufacturers, and ensuring a consistent interpretation and implementation of the regulatory requirements.
• Improves Efficiency: The Commission Guidance provides clear instructions on how to structure and present the summary of the clinical investigation report, making it easier for sponsors to prepare, and for regulatory authorities to review and assess the data, improving the efficiency of the regulatory process.
• Enhances Patient Safety: The Commission Guidance emphasizes the importance of providing complete and accurate information in the summary of the CIR, promoting patient safety by ensuring that the medical devices on the market have been rigorously tested and evaluated.

Overall, this Commission Guidance document will help to ensure that medical devices on the market are safe and perform as intended by the manufacturer, improving patient outcomes, and enhancing public health.

How can MDx CRO help with a Clinical Investigation Report and its summary?

MDx CRO is a regulatory consulting firm that specializes in helping medical device & IVD manufacturers comply with regulatory requirements in their clinical investigations and clinical performance studies. We offer a range of services to help manufacturers prepare for the new MDR/ IVDR requirements for clinical investigations, from the study design and submission of the clinical regulatory package to Ethics Committees and Regulatory Authorities, to monitorization of the clinical study and preparation of the clinical investigation report and summary.

The EU Medical Device Regulation has introduced significant changes to the requirements for clinical evaluation reports of medical devices. This article will provide a comprehensive guide on incorporating the most relevant guidance from MDCG 2020-6, MDCG 2020-5, MDCG 2020-13, MEDDEV 2.7.1 rev4, and EU MDR Annex XIV into your EU MDR Clinical Evaluation Report (CER). By adhering to these guidelines, manufacturers can ensure their CER is compliant with regulatory requirements and demonstrates the safety and performance of their medical device.

1. Complying with MDR Annex XIV: MDR Clinical Evaluation Report Requirements

Annex XIV of the EU MDR outlines the requirements for the clinical evaluation of medical devices. The key points to consider when incorporating these requirements into your clinical evaluation process include:

Clinical evaluation plan (CEP)

Manufacturers must develop a clinical evaluation plan (CEP) that outlines the objectives, methodology, data sources, and criteria for appraisal. The CEP should be a living document that is regularly updated throughout the device lifecycle.

Safety and performance demonstrations

Manufacturers must demonstrate the safety and performance of their medical devices through clinical evaluation, which should be based on clinical data that is methodologically sound, relevant, and sufficient.

Risk-benefit analysis

The clinical evaluation reports should include a thorough risk-benefit analysis that considers the device’s intended use, performance, and safety. This analysis should weigh the device’s potential benefits against its possible risks.

Data sources and appraisal for the MDR Clinical Evaluation Report

Clinical data should be obtained from various sources, such as literature, clinical investigations, and post-market surveillance. The data should be appraised for quality, relevance, and strength to ensure it is adequate

2. Adhering to MEDDEV 2.7.1 rev4 Guidelines for CERs

The MEDDEV 2.7.1 rev4 is a guidance document titled “Clinical Evaluation: A Guide for Manufacturers and Notified Bodies.” It aims to help manufacturers and notified bodies understand and comply with the requirements for clinical evaluation under the EU Medical Device Directive (MDD) and Active Implantable Medical Devices Directive (AIMDD). Although this guidance is not specifically tailored for the new EU MDR, it is still relevant and useful for manufacturers working to comply with the MDR.

Following MEDDEV 2.7.1 rev 4, the stages for conducting a Clinical Evaluation Report (CER) can be summarized as follows:

Stage 0: Clinical Evaluation Plan

Before diving into the clinical evaluation process, you need to define the scope of the evaluation based on the device’s intended purpose.

Stage 1: Identification of Pertinent Data

• Device Specification and State of the Art: Define the device’s intended purpose and its essential requirements. Understand the current state of the art to determine the acceptability of the device’s risks and benefits.
• Identification of Data Sources: This involves systematic identification of databases and other sources to obtain relevant pre- and post-market data about the device and equivalent devices. Data can come from clinical investigations, literature, and other relevant sources.

Stage 2: Appraisal of Pertinent Data

• Qualitative Data Appraisal: Assess the scientific validity and relevance of the identified data. Evaluate the quality of the study design, methodologies, and overall reliability of the data sources.
• Quantitative Data Appraisal: Analyze the clinical data for factors like statistical significance, clinical significance, and relevance to the safety and performance of the device.

Stage 3: Analysis of the Clinical Data

• Data Analysis: Analyze the appraised data to determine if there’s enough evidence that the device meets its essential requirements, especially concerning safety and performance. Compare the device’s clinical outcomes with the current state of the art.
• Risk-Benefit Analysis: Balance the device’s potential clinical benefits against its potential clinical risks.
• Conclusions: Document the results of the clinical evaluation and indicate whether there’s enough evidence to support the device’s conformity with relevant general safety and performance requirements.

Stage 4: EU MDR Clinical Evaluation Report (CER) Production

• Report Compilation: Combine all the analyzed data, appraisal results, and conclusions into a comprehensive clinical evaluation report (CER).
• Regular Review and Update: Based on MEDDEV 2.7.1 rev 4, clinical evaluations are not a one-time task. They should be updated regularly, especially when new information about the device becomes available. The frequency and extent of updates depend on the nature of the device and the risks involved.

Throughout these stages, it is essential to remain unbiased, ensure a methodological approach, and adhere to the highest standards of scientific rigor. The entire process should be systematic, transparent, and reproducible to guarantee the reliability and validity of the CER.

3. Understanding the MDCG 2020-6 Guidance for MDR Clinical Evaluation Report

The MDCG 2020-6 titled “Guidance on sufficient clinical evidence for legacy devices under the MDR,” aims to help manufacturers of medical devices marketed prior to the implementation of the EU Medical Device Regulation (MDR) demonstrate sufficient clinical evidence to meet the new regulatory requirements. The guidance specifically addresses the clinical evaluation of legacy devices, which are devices that have been previously approved under the Medical Device Directive (MDD) or Active Implantable Medical Devices Directive (AIMDD).

Key aspects of the MDCG 2020-6 guidance include:

Demonstrating sufficient clinical evidence

Manufacturers must demonstrate sufficient clinical evidence to support the safety and performance of their legacy medical devices. This includes a thorough clinical evaluation, which involves a systematic and planned process of gathering, appraising, and analyzing clinical data to verify the safety and performance of a medical device.

The role of clinical investigations in your MDR Clinical Evaluation Report for medical devices

While clinical investigations may not always be necessary for legacy devices, they might be required in cases where:

• Existing clinical data is insufficient to support the device’s safety and performance claims.
• The device has undergone significant changes that could impact its safety or performance.
• The device belongs to a high-risk category, such as implantable or Class III devices.

Post-market clinical follow-up (PMCF)

PMCF is a continuous process that manufacturers must undertake to update the clinical evaluation. It involves proactively collecting and evaluating clinical data from the use of a device after it has been placed on the market to confirm its safety and performance throughout its expected lifetime. Manufacturers should establish a PMCF plan and incorporate it into their post-market surveillance system.

Updating the clinical evaluation

Manufacturers are required to update their clinical evaluations regularly, based on the risk profile of the device, the amount and quality of available clinical data, and any new information regarding the device’s safety or performance. Updates should consider post-market surveillance data, including data from PMCF activities, and any relevant scientific literature.

MDR CER Requirements for legacy devices

Legacy devices must comply with the EU MDR, which entails a comprehensive re-evaluation of their clinical data. Manufacturers of legacy devices should:

• Assess whether the existing clinical evaluation complies with the requirements of the MDR and the updated state of the art.
• Identify any gaps in the clinical data and address them through additional clinical investigations or other appropriate measures.
• Update the clinical evaluation, considering new scientific literature, post-market surveillance data, and any changes to the device or its intended use.
• Prepare and maintain an up-to-date clinical evaluation report (CER) as part of their technical documentation.

In summary, the MDCG 2020-6 guidance provides a framework for manufacturers of legacy devices to demonstrate sufficient clinical evidence under the EU MDR. It emphasizes the importance of a thorough clinical evaluation, the potential need for clinical investigations, the role of PMCF, and the continuous updating of the clinical evaluation to ensure the ongoing safety and performance of medical devices.

4. Incorporating MDCG 2020-5 Guidance on EU MDR Clinical Evaluation Report Equivalence

The MDCG 2020-5 guidance, titled “Guidance on Clinical Evaluation (MDR) / Performance Evaluation (IVDR) of Medical Device Software,” provides direction for manufacturers to demonstrate the equivalence between their medical device and another device (the “equivalent device”) as part of the clinical evaluation process. Establishing equivalence can be essential for utilizing existing clinical data from the equivalent device to support the safety and performance claims of the device under evaluation.

Key aspects of the MDCG 2020-5 guidance include:

Defining equivalence

Equivalence is established when the device under evaluation and the equivalent device have the same intended purpose, similar technical and biological characteristics, and comparable clinical performance. Demonstrating equivalence allows manufacturers to use clinical data from the equivalent device in their clinical evaluation.

Criteria for demonstrating equivalence in MDR Clinical Evaluation Report

To demonstrate equivalence, manufacturers must provide evidence that the device under evaluation and the equivalent device share the following three characteristics:

• Technical characteristics: The devices should have similar specifications, design attributes, and principles of operation.
• Biological characteristics: The devices should interact with the human body in the same way, utilizing similar materials, manufacturing processes, and intended patient populations.
• Clinical characteristics: The devices should exhibit similar performance and clinical outcomes, taking into account the intended purpose, clinical conditions of use, and target patient population.

Technical, biological, and clinical characteristics

The guidance provides detailed information on the types of characteristics that should be considered when assessing equivalence, including:

• Technical: Design, materials, specifications, principles of operation, energy source, and critical performance requirements.
• Biological: Biocompatibility, tissue/device interaction, patient population, and the presence of medicinal, human tissue, or animal-origin components.
• Clinical: Intended purpose, medical indications, intended patient population, user profile, medical claims, and clinical performance.

EU MDR CER equivalence documentation requirements

Manufacturers must provide robust documentation to support their claims of equivalence. This includes a thorough comparison of the device under evaluation and the equivalent device, considering their technical, biological, and clinical characteristics. Manufacturers should also provide evidence that they have access to the data from the equivalent device, which may require agreements with the manufacturers of the equivalent device or other legitimate data access arrangements.

Assessing and mitigating risks

Manufacturers should consider the potential risks associated with claiming equivalence, such as differences in the device’s materials, manufacturing processes, or clinical performance. These risks should be identified, assessed, and mitigated as part of the clinical evaluation process.

In summary, the MDCG 2020-5 guidance provides a framework for demonstrating equivalence between medical devices as part of the clinical evaluation process under the EU MDR. By following this guidance, manufacturers can ensure they have a clear understanding of the criteria for establishing equivalence, the types of characteristics to consider, and the documentation requirements needed to support their claims. Additionally, manufacturers should be aware of the potential risks associated with claiming equivalence and address them accordingly to ensure the safety and performance of their medical device.

5. Including insights from the MDCG 2020-13 Clinical Evaluation Assessment Report Template

The MDCG 2020-13 document provides a template for the Clinical Evaluation Assessment (CEA) report, which is intended to guide notified bodies in their assessment of clinical evaluation reports conducted by medical device manufacturers under the EU Medical Device Regulation (MDR). The CEA report template is designed to ensure a consistent and harmonized approach when notified bodies review clinical evaluation documentation submitted by manufacturers.

Key aspects of the MDCG 2020-13 CEA report template include:

General information

The template begins with a section for general information about the device under evaluation, the manufacturer, the notified body, the assessment team, and the dates of the assessment.

Device Description and intended purpose

This section of the template requires a comprehensive description of the device, including its technical specifications, intended purpose, medical indications, contraindications, target patient population, and any relevant accessories or companion devices.

State of the art

In this section, the notified body should assess whether the manufacturer has provided an adequate description of the state of the art in the clinical evaluation report (CER). This includes a review of the relevant scientific literature, existing devices, and current clinical practices.

Essential requirements

The notified body should evaluate whether the manufacturer has demonstrated that the device meets the essential safety and performance requirements as specified in the EU MDR.

Clinical Evaluation Plan and methodology

This section involves the assessment of the manufacturer’s clinical evaluation plan (CEP) and the methodology used to collect, appraise, and analyze the clinical data. The notified body should determine whether the CEP is appropriate and whether the chosen methodology is scientifically sound and unbiased.

EU Clinical Evaluation Report data sources and appraisal

The notified body should assess the data sources used by the manufacturer in the clinical evaluation, including literature, clinical investigations, and post-market surveillance data. The notified body should also evaluate the manufacturer’s appraisal of the data, ensuring that it is of high quality, relevant, and adequate to support the device’s safety and performance claims.

Analysis of clinical data

In this section, the notified body should assess the manufacturer’s analysis of the clinical data, determining whether the conclusions drawn from the data are valid and supported by evidence. This includes evaluating the risk-benefit profile, clinical performance, and safety of the device.

Conformity assessment and Post-market Clinical Follow-up (PMCF)

The template requires the notified body to evaluate the manufacturer’s conformity assessment and PMCF activities. This includes determining whether the manufacturer has appropriately considered the need for additional clinical investigations or PMCF activities to support the ongoing safety and performance of the device.

Overall conclusion

In the final section, the notified body should provide an overall conclusion on the adequacy of the clinical evaluation, summarizing the main findings and any identified gaps or issues that need to be addressed.

In summary, the MDCG 2020-13 CEA report template is a valuable tool for notified bodies to ensure a consistent approach when assessing clinical evaluations conducted by manufacturers under the EU MDR. By using this template, notified bodies can systematically review and evaluate the different aspects of the clinical evaluation process, including the device description, state of the art, essential requirements, clinical evaluation plan and methodology, data sources and appraisal, analysis of clinical data, conformity assessment, and PMCF activities.

6. MDR Clinical Evaluation Report Regulatory Compliance

Incorporating the most relevant guidance from MDCG 2020-6, MDCG 2020-5, MDCG 2020-13, MEDDEV 2.7.1 rev4, and EU MDR Annex XIV into your MDR Clinical Evaluation Report is crucial for ensuring regulatory compliance and demonstrating the safety and performance of your medical device. By understanding and adhering to these guidances, manufacturers can confidently navigate the complex EU MDR landscape and bring safe, effective medical devices to market.

How can MDx help with your EU MDR Clinical Evaluation Report?

MDx CRO is a leading quality, regulatory and contract research consulting company dedicated to the medical device and diagnostic sectors.

MDx CRO, a top consulting company for the medical device and diagnostic sectors, offers expert support for navigating the complex MDR requirements.

Our MedTech team assists healthcare institutions and commercial enterprises in developing a compliance strategy, providing services such as:

• Regulatory strategy formulation, focusing on reducing compliance costs.
• EU MDR Clinical Evaluation Report Template customized for your particular medical device.
• Clinical Evaluation Plan template customized for your particular medical device.
• CER and CEP medical writing
• Systematic Literature Review
• Clinical Investigation approach evaluation.
• Medical writing for clinical performance processes.
• In-house technical documentation development for medical devices.
• GSPR checklist creation and completion.
• Support with notified body applications and competent authorities.

Contact us today for a consultation with our Clinical Evaluation experts.

Relevant information about clinical investigations in Spain

Since the implementation of the new EU MDR, there has been significant standardization in the processing of clinical investigation submissions throughout Europe. Each country, however, may have its own national provisions.
This article is intended for clinical research experts who need to undertake a clinical investigation submission in Spain for medical devices using the new update process (January 30, 2023). This article  offers a general overview of the process.

In Spain, the conduct of clinical investigations with medical devices has been governed by

• The Royal Decree on Medical Devices (Royal Decree 1591/2009) and
• The Royal Decree on active implantable medical devices (Royal Decree 1616/2009)
• and the Circular Nº 07/2004

outlining the ethical and methodological rules that need to be followed (these are similar to the rules for clinical research with medicinal products), the steps that need to be taken to get administrative approval, and the paperwork that the sponsors of this research need to provide.

In Spanish Clinical Investigations, there are three key stakeholders.

• The Spanish Competent Authority, AEMPS: reviews and approves the submission of clinical investigations in Spain.
• The Ethics Committees, CEIMs: issue a negative or favourable opinion on the clinical investigation in human subjects.
• The Clinical Site, “centros de investigación”: perform the Clinical Investigation Plan with human subjects.

How to submit a submission for approval of a clinical investigation to the AEMPS.

After May 26th, the EU MDR 207/745 establishes new requirements for the submission of clinical investigations. Those requirements are mainly specified in

• Article 70: defines that the sponsor must prepare and submit a request for experimental devices covered by Article 62.
• Annex XV, Chapter II

Officially, the submission process had required using Circular Nº 07/2004, that provided the additional local requirements and templates such as

• Annex B. Application form for authorization of clinical investigations with medical devices.
• Annex 1. Template for the manufacturer’s declaration of compliance with the essential requirements
• Annex 2. Template for the sponsor’s declaration for devices intended for clinical investigations.

In January 30th, the AEMPS has updated the process and the Annexes that need to be included under MDR requirements.

• Annex A is the Submission Requirements for Clinical Investigations following EU MDR Annex XV.
• Annex B is the Substantial Modification requirements for clinical investigations under Medical Device Regulation (no previous annex to be updated) according to MDCG 2021-28.
• Annex C is the Application Form (updating the prior Annex B). The application form has been updated according to the Annex XV chapter 2.1. with the following fields:
  • Details and/or reference to the investigational device clinical evaluation plan;
  • Information as to whether the device incorporates a medicinal substance, including a human blood or plasma derivative or whether it is manufactured utilising non-viable tissues or cells of human or animal origin, or their derivatives;
  • Using the term of “Supervisor”, that covers the full implementation of the GCPs in the clinical investigation, instead of “Monitor”.
  • Details to identify the notified body, if already involved at the stage of application for a clinical investigation;
  • Confirmation that the sponsor is aware that the competent authority may contact the ethics committee that is assessing or has assessed the application; and
  • The statement by the natural or legal person responsible for the manufacture of the investigational device that the device in question conforms to the general safety and performance requirements apart from the aspects covered by the clinical investigation and that, with regard to those aspects, every precaution has been taken to protect the health and safety of the subject.
• Annex D is the manufacturer’s declaration of compliance with the General Safety and Performance Requirements (update to the prior Annex 1).This Annex has been updated according to Annex XV chapter 4.1

In the updated submission process, it is highlighted that:

• In addition to the AEMPS authorization and the ethics committee’s favorable opinion, the site director’s consent is required, which is a contract between the sponsor and each site where the clinical investigation will take place.
• The Investigator’s Brochure and the Clinical Investigation Plan (the study protocol) may be accepted in English.
• The Clinical Investigation Plan summary, the Patient Information and Informed Consent form, the Request for Authorization or Notification of Authorization, as well as the Instructions for Use and Labeling of the Investigational Medical Device, must always be presented in Spanish.
• Safety notifications for investigational medical devices can be done with MDCG 2020-10/2 Rev 1 “Guidance Safety report Form”

Clinical Investigations in Spain: Other National Provisions

Depending on the type and purpose of the investigation, communication with the AEMPS varies:

• Full AEMPS Submission Process – Required for pre-market clinical investigations with non-CE-marked devices or devices assessed outside their intended purpose (MDR Article 74.2).
• Notification via NEOPS – Applicable to Post-Market Clinical Follow-Up (PMCF) studies involving CE-marked devices used within approved indications but deviating from standard clinical practice.
• No Authorization/Notification Required – For observational PMCF studies where devices are used strictly according to their CE-marked indications and standard clinical practice.
• Consultation with AEMPS – For clinical investigations under MDR Article 82, which are non-regulatory but involve non-CE-marked or off-label CE-marked devices.

How can MDx help?

With the introduction of the MDR, the requirements for clinical investigations have grown significantly. Whether you are a medical device manufacturer or bioengineering research centre, our team can assist you in developing a compliance strategy and will be with you every step of the way.

Our Clinical Research Services for Clinical Investigations for MDR CE Mark have been tailored for the needs of manufacturers and sponsors of medical devices and include:

• Clinical and Regulatory strategy
• Medical writing
• Creation and completion of GSPR checklists
• Support with notified body applications
• Design the Investigator Brochure and the Clinical Investigation Plan according to the MDR and ISO 14155:2020
• Ethics Committee Submission
• AEMPS Clinical Investigation Submissions
• Site Qualification and Activation
• Site Monitoring and Management
• Submission and implementation of Clinical Studies under article 82
• Submission and implementation of PMCF studies

Please reach out today for a consultation with our team of MDx experts.

In light of the forthcoming Medical Device Regulation (MDR) and the delay in the complete functionality of the electronic system referenced in Article 73 (EUDAMED), the MDCG 2020-10 Rev 1 provides essential guidance. With Eudamed not being ready on the MDR’s effective date, the guidelines under MDCG 2020-10 Rev 1 become instrumental in outlining the processes for safety reporting in clinical research.

Key Points from MDCG 2020-10 Rev 1:

• Safety Reporting Modalities: The document thoroughly describes the reporting modalities for Serious Adverse Events (SAEs) and offers a summary tabulation reporting format.
• Adherence to Regulations: It emphasizes that medical device safety reporting during clinical studies must be consistent with the guidelines in Article 80 of Regulation (EU) 2017/745, also known as the Medical Device Regulation (MDR).

For a clinical investigation involving medical technology, utilizing the electronic system as stipulated in MDR Article 73 means the sponsor must promptly share the following with every Member State involved:

• Any SAE that can be directly or potentially linked to the investigational device, comparator, or the procedure.
• Any device defect that could have escalated to a serious adverse event under different circumstances.
• Further details on any aforementioned event.

The timeframe set for reporting these adverse events varies based on the severity of the incident. While the clinical trial sponsor might initially provide an incomplete report, it’s crucial to follow up with a detailed one to maintain timely reporting.

The guidance not only covers the basic safety reporting protocols but also delves deeper into the post-market clinical follow-up (PMCF) investigations for CE-marked MedTech products. Here, the guidelines laid out in MDR Articles 87 to 90 play a pivotal role.

Safety Reporting in PMCF Clinical Investigations

It’s noteworthy that while the vigilance measures outlined in the aforementioned articles are applicable to PMCF clinical studies, the MDCG 2020-10 Revision 1 remains relevant. This is primarily because the reporting of significant adverse events linked to previous investigational devices should align with the reporting prerequisites mentioned in EU MDR 2017/745 Article 80.

The guidance document provides an essential roadmap for Safety reporting SOPs, Safety reporting plans, and Clinical Investigation plans. This is invaluable for MedTech Manufacturers, sponsors, and CROs involved in clinical research activities with medical devices.

FAQs about MDCG 2020-10 Rev 1

• What events need reporting? Report all SAEs and suspected unexpected serious adverse device effects (SUSADEs).
• What’s the reporting timeframe? Report SAEs within 15 days and SUSADEs within 7 days post the sponsor’s awareness.
• What should a safety report include? Details about the sponsor, investigator, device, event date, event description, outcome, and other pertinent data.

For more comprehensive insights on safety reporting for medical devices, delve into the MDCG 2020-10 Rev 1 guidance document.