In this article, we will delve into the intricacies of developing a robust Clinical Evaluation Plan using expert regulatory terminology, equipping you with the knowledge to navigate this essential aspect of your MedTech product development.

As the medical device industry evolves and regulatory requirements become more stringent, the need for a well-defined Clinical Evaluation Plan (CEP) has become paramount.

The CEP plays a crucial role in assessing the safety and performance of medical devices, ensuring their compliance with Annex XIV of the Regulation (EU) MDR 2017/745 (MDR), MDCG 2020-6, and MEDDEV 2.7.1. Rev.4.

In this article, we will delve into the intricacies of developing a robust Clinical Evaluation Plan using expert regulatory terminology, equipping you with the knowledge to navigate this essential aspect of your MedTech product development.

1. Clinical evaluation of your medical device

The clinical evaluation of a medical device must be thorough and objective. Manufacturers should consider both favourable and unfavourable clinical data when developing the Clinical Evaluation Plan.

The depth and extent of the clinical evaluation must remain proportionate to the device. This includes its nature, risk class, intended purpose, manufacturer claims, and associated risks.

Manufacturers may base a clinical evaluation on clinical data from an equivalent device when they can demonstrate equivalence. The demonstration of equivalence must cover technical, biological, and clinical characteristics. Notified Bodies strongly recommend claiming equivalence against only one equivalent device.

Under MDR Article 61(1) and Annex XIV, manufacturers must plan, conduct, and document the clinical evaluation. The planning phase must be documented in a Clinical Evaluation Plan. The outcomes of the evaluation and the supporting clinical evidence must then be documented in a Clinical Evaluation Report.

2. What is a Clinical Evaluation Plan?

A Clinical Evaluation Plan (CEP) is a documented strategy that defines a systematic and planned approach to assess the safety and performance of a medical device throughout its lifecycle.

This clinical evaluation plan template provides the framework for collecting, appraising, and analyzing clinical data. Its purpose is to demonstrate conformity with the General Safety and Performance Requirements (GSPRs) set out in Annex I of the MDR.

3. Navigating Annex XIV of MDR 2017/745: Key Requirements

According to Part A, Section 1 of Annex XIV of the MDR, the manufacturer must establish and regularly update the Clinical Evaluation Plan. This ensures that the clinical evaluation remains planned, continuously performed, and properly documented.

Annex XIV defines the minimum requirements that every Clinical Evaluation Plan must address.

Minimum Requirements of a Clinical Evaluation Plan

The CEP must include:

• A clinical development plan outlining the progression from exploratory investigations to confirmatory clinical investigations and PMCF activities, including milestones and acceptance criteria.
• Identification of GSPRs that require support from relevant clinical data.
• Specification of the intended purpose of the device.
• Clear definition of target groups, including indications and contraindications.
• Description of intended clinical benefits with defined clinical outcome parameters.
• Methods for evaluating qualitative and quantitative aspects of clinical safety, including residual risks and side effects.
• Parameters used to assess the acceptability of the benefit-risk ratio based on the current State of the Art.
• An explanation of how benefit-risk issues related to specific components, such as medicinal substances or animal or human tissues, are addressed.

3.1. Clinical Data from Systematic Scientific Literature Reviews

Manufacturers should conduct a systematic scientific literature review to identify relevant clinical data for the device and its intended purpose.

The review should also identify gaps in the available clinical evidence. This supports a complete and transparent understanding of the existing data landscape.

Using structured methodologies such as PRISMA and PICO is recommended, as these approaches improve the systematic nature and reproducibility of the literature search.

3.2. Clinical Data from Clinical Investigations

Manufacturers should design and conduct clinical investigations in line with the Clinical Development Plan.

These investigations should generate new or additional clinical data when existing evidence does not sufficiently demonstrate safety and performance. The generated data should directly support the objectives of the Clinical Evaluation Plan.

3.3. Clinical Data Appraisal and Suitability

Manufacturers must appraise all relevant clinical data to determine their suitability for demonstrating device safety and performance.

This appraisal should consider data quality, reliability, and relevance. It should also follow the hierarchy of clinical evidence described in Appendix III of MDCG 2020-6 when assessing conformity with MDR GSPRs.

3.4. Clinical Data Analysis and Conclusions

Manufacturers must analyze all relevant clinical data, including literature data, existing clinical studies, and newly generated clinical investigation data.

The analysis should support clear conclusions on safety, clinical performance, and clinical benefits. This process includes data interpretation, statistical analysis, and benefit-risk assessment. The outcome must support robust, evidence-based conclusions within the Clinical Evaluation Plan.

4. Navigating MDCG 2020-6: Key Considerations for Your Clinical Evaluation Plan

The MDCG 2020-6 guidance, “Regulation (EU) 2017/745: Clinical evidence needed for medical devices previously CE marked under Directives 93/42/EEC or 90/385/EEC”, provides detailed direction on how to perform a clinical evaluation under the MDR. It supports both manufacturers and Notified Bodies in assessing clinical evidence for legacy medical devices.

This guidance is particularly relevant when preparing a clinical evaluation plan template that complies with MDR requirements.

4.1. Clinical Evaluation Plan Documentation Requirements

MDCG 2020-6 confirms that manufacturers must document a Clinical Evaluation Plan in accordance with MDR Annex XIV. The guidance also provides practical recommendations to support compliance with Annex XIV, Section 1(a).

A compliant Clinical Evaluation Plan should include:

• Identification of the applicable General Safety and Performance Requirements (GSPRs).
• A clear definition of the intended purpose, target patient groups, indications, and contraindications.
• A detailed description of the intended clinical benefits, supported by defined clinical outcome parameters.
• Specification of qualitative and quantitative aspects of clinical safety and clinical performance.

4.2. Sources of Clinical Data

According to MDCG 2020-6, the Clinical Evaluation Plan must clearly identify all relevant sources of clinical data. These sources may include pre-market, post-market, and newly generated clinical data.

Pre-market clinical data may consist of:

• Clinical investigation reports for the device under evaluation.
• Clinical investigations or studies published in scientific literature for equivalent devices.
• Peer-reviewed literature reporting other clinical experience with the device or an equivalent device.
• Additional pre-market data, such as case reports related to device use.

Post-market clinical data may include:

• Post-Market Surveillance (PMS) clinical data.
• Complaint handling and vigilance reports.
• Post-Market Clinical Follow-up (PMCF) studies and investigations.
• Independent clinical studies, device registries, and relevant literature data.

Newly generated clinical data should also be included when available and justified.

The Clinical Evaluation Plan must also describe the system used to appraise and analyze all clinical data sources.

4.3. Minimum Content of a Clinical Evaluation Plan for Legacy Devices

Appendix II of MDCG 2020-6 defines the minimum content required for a Clinical Evaluation Plan for legacy devices. This minimum content includes:

• Identification of GSPRs that require support from clinical data.
• Specification of the intended purpose of the device.
• Clear definition of target groups, including indications and contraindications.
• Description of intended clinical benefits with defined clinical outcome parameters.
• A strategy to identify, analyze, and assess alternative treatment options.
• Methods for evaluating qualitative and quantitative aspects of clinical safety, including residual risks and side effects.
• Defined parameters to assess the acceptability of the benefit-risk ratio based on the current State of the Art.
• An explanation of how benefit-risk issues related to specific components, such as medicinal substances or animal or human tissues, are addressed.
• A strategy and methodology to identify, analyze, and appraise all relevant clinical data under the MDR definition of clinical data.
• Evidence supporting equivalence when clinical data from an equivalent device is used.
• A justification of the required level of clinical evidence based on device characteristics and intended purpose.
• A strategy for the systematic collection, analysis, and assessment of post-market surveillance data to demonstrate continued safety and performance of legacy devices.

4.4. Hierarchy of Clinical Evidence Under MDCG 2020-6

Appendix III of MDCG 2020-6 introduces a hierarchy of clinical evidence to support conformity with MDR GSPRs. This hierarchy ranks different types of clinical data from strongest to weakest.

Manufacturers should consider this hierarchy when defining the appraisal methodology in their clinical evaluation plan template. Applying the suggested hierarchy supports a robust and transparent assessment of clinical evidence and strengthens the overall Clinical Evaluation Plan.

5. Navigating MEDDEV 2.7.1. Rev.4: What To Consider?

MEDDEV 2.7.1. Rev.4 refers to the fourth revised version of the Medical Device Vigilance Guidance Document.

This document encourages the adoption of a standardized approach to clinical evaluation for medical devices that fall under the regulation of directives 90/385/EEC and 93/42/EEC.

MEDDEV 2.7.1 Rev.4 continues to be used even after the implementation of MDR since it offers additional interpretive guidance and practical recommendations that complement the MDR requirements.

Section 7 of MEDDEV 2.7/1 rev. 4 addresses the definition of scope of the clinical evaluation, which constitutes the Stage 0 of a clinical evaluation, and, according to MDR and MDCG 2020-6, states that the manufacturer should set up a Clinical Evaluation Plan for the device under evaluation. 

Recognizing the wide range of technologies employed in medical devices, along with their diverse histories and associated risks, is crucial.

Therefore, Section 7 of MEDDEV 2.7/1 rev. 4 also examines the different aspects to be considered for setting up a CEP depending on the stage in the lifecycle of the product and its regulatory status (i.e., before CE-marking, For CE-marked devices).

Moreover, Appendix A3 of MEDDEV 2.7/1 rev. 4 lists information that can be relevant for planning clinical evaluations. It is paramount that the manufacturer ensures that input for the Clinical Evaluation Plan shows alignment with the device’s “label, instructions for use, promotional or sales materials or statements” and with the device’s updated risk management documentation.

Must have considerations for your Clinical Evaluation Plan Template MDR-based

At MDx CRO, we recognize the significance of a well-structured Clinical Evaluation Plan (CEP) in ensuring the safety and performance of medical devices.

The design of a Clinical Evaluation Plan (CEP) template according to the Medical Device Regulation (MDR) 2017/745 should be tailored to the specific typology of the manufacturer’s device.

This customization is critical as every medical device has unique attributes, different indications for use, target populations, and risk profiles.

Therefore, the use of a generic template for all devices is not recommended. Although it might be tempting to use a “one-size-fits-all” approach for efficiency reasons, such practice could overlook the MDR’s specific requirements for each individual device, potentially leading to non-compliance with established safety and efficacy standards.

Additionally, lack of specificity could lead to erroneous or inappropriate conclusions in the clinical evaluation, jeopardizing the device’s approval for marketing. In summary, it is essential that each Clinical Evaluation Plan is designed and tailored specifically for the device being evaluated, in line with the guidelines of the MDR 2017/745.

Despite the unique considerations required for each device’s Clinical Evaluation Plan (CEP) under the MDR 2017/745, we understand the value of having a general framework to start from. Therefore, we will provide a template that serves as a starting point for the development of a Clinical Evaluation Plan.

This template will include essential elements required under the MDR 2017/745 such as:

• Plan rationale
• Device description
• Clinical background
• Identification of pertinent data sources
• Clinical evaluation method
• Plan for the appraisal of clinical data.

Remember, this is a guide to help initiate the process and not a final document. You will need to tailor the template to fit your specific device, its indications, target population, risk factors, and other device-specific attributes.

Our intention is to help streamline the process, providing structure while also emphasizing the importance of customization to meet the regulatory requirements.

Clinical Evaluation Plan Template Guidance

To streamline the development process and support compliance with regulatory requirements, this clinical evaluation plan template outlines the recommended structure and content of a Clinical Evaluation Plan (CEP). It helps manufacturers document clinical evidence in line with applicable regulations and guidance.

• SECTION 1. SUMMARY
• SECTION 2. REFERENCES
• SECTION 3. ACRONYMS AND DEFINITIONS
• SECTION 4. RESPONSIBILITIES
• SECTION 5. SCOPE OF THE CLINICAL PLAN AS PART OF THE CLINICAL EVALUATION

This section defines the scope of the Clinical Evaluation Plan within the overall clinical evaluation process. It addresses the applicable General Safety and Performance Requirements (GSPR). It also references previous clinical evaluations and the current CEP.

The section explains any deviations from the CEP and justifies them when needed. In addition, it covers the Instructions for Use (IFU), device labeling, and related risk management activities.

SECTION 6. DEVICE DESCRIPTION

This section provides a clear and structured description of the medical device. It includes the device name, classification, and a brief technical overview. It also lists device components, materials, sizes, and available models.

The manufacturer name, generic device group, and device lifecycle stage must be stated. The section also explains the intended purpose of the device and how it achieves that purpose.

In addition, it defines the clinical condition, target patient population, and target user group. Contraindications, warnings, cautions, precautions, and known undesirable effects are documented to support the clinical evaluation.

SECTION 7. CLINICAL BACKGROUND AND STATE OF THE ART

This section describes the clinical background relevant to the device. It identifies the sources used for the clinical evaluation, including applicable standards and guidance documents.

The State of the Art analysis outlines current medical knowledge. It includes benchmark devices and other available treatment options. This comparison supports the assessment of safety and performance.

SECTION 8. EVALUATION OF THE DEVICE

This section explains the type of clinical evaluation performed. It defines the safety and performance parameters assessed during the evaluation process.

When applicable, the section describes how device equivalence is demonstrated. It also identifies the sources of clinical data. These sources may include manufacturer-generated data, data from systematic literature reviews, and post-market surveillance or vigilance activities.

SECTION 9. ANALYSIS OF CLINICAL DATA

This section outlines the methods used to analyze clinical data. It evaluates safety in accordance with GSPR 1 to 8 and performance in line with GSPR 1.

The section also assesses the benefit-risk profile and the acceptability of undesirable side effects, as required by GSPR 8. Any additional clinical claims are reviewed and supported with appropriate evidence.

SECTION 10. CLINICAL DEVELOPMENT PLAN

SECTION 11. ADDITIONAL ITEMS FROM APPENDIX II OF MDCG 2020-6 (LEGACY DEVICE)

This section describes planned or ongoing pre-market and Post-Market Clinical Follow-up (PMCF) investigations, when applicable. It explains how these activities support the clinical evaluation over the device lifecycle.

SECTION 12. PMS AND PMCF PLANS
SECTION 13. FREQUENCY OF CLINICAL EVALUATION UPDATES
SECTION 14. DATES AND SIGNATURES
SECTION 15. ANNEXES

This clinical evaluation plan template provides a structured guide to the essential elements of a CEP. It supports consistent documentation of device description, clinical data requirements, benefit-risk analysis, and post-market clinical follow-up activities.

Why use this Clinical Evaluation Plan Template?

This clinical evaluation plan template provides a structured and practical framework for preparing a compliant CEP. It supports consistent documentation of device description, clinical data requirements, benefit-risk analysis, and post-market clinical follow-up activities. As a result, it helps manufacturers meet regulatory expectations and maintain clinical evidence throughout the device lifecycle.

If you need help preparing your clinical evaluation plan template or developing a compliant Clinical Evaluation Plan, contact us to discuss your project and regulatory needs.

Alberto Bardaji de Qixano

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.

Understanding how to complete a clinical investigation submission in Spain with the AEMPS is essential for manufacturers and sponsors working under the EU MDR. Although the MDR brought greater harmonization across Europe, Spain maintains several national provisions that every sponsor must follow. Below is a clear, SEO‑optimized overview to help you navigate the updated process introduced on January 30, 2023.

How Clinical Investigations Are Regulated in Spain

Clinical investigations in Spain are governed by long‑standing national laws:

• Royal Decree 1591/2009 on medical devices
• Royal Decree 1616/2009 on active implantable devices
• Circular Nº 07/2004, which sets out ethical and methodological requirements similar to those used for medicinal product studies

Together, these regulations define how to obtain administrative approval and what documents sponsors must provide.

Key Stakeholders in a Clinical Investigation Submission in Spain (AEMPS)

Three main stakeholders are involved in every submission:

1. AEMPS (Spanish Competent Authority)

Reviews and authorizes the clinical investigation submission in Spain.

2. CEIMs (Ethics Committees)

Issue a favorable or negative ethical opinion for studies involving human subjects.

3. Clinical Sites (“Centros de investigación”)

Conduct the Clinical Investigation Plan (CIP) according to MDR and ISO 14155.

Updated AEMPS Submission Process Under the EU MDR

Since May 26, 2021, the MDR imposed stricter rules for clinical investigations. These requirements are mainly defined in:

• Article 70 (submission obligations for experimental devices)
• Annex XV, Chapter II (application content and documentation)

Previously, Spain used Circular Nº 07/2004, including templates such as:

• Annex B – application form
• Annex 1 – manufacturer’s essential requirements declaration
• Annex 2 – sponsor’s declaration

As of January 30, 2023, the AEMPS updated all annexes to match MDR requirements.

New AEMPS Annexes for Clinical Investigation Submissions

Annex A – MDR Submission Requirements

This annex explains all documentation needed for an MDR‑compliant clinical investigation submission in Spain AEMPS.

Annex B – Substantial Modification Requirements

Covers modifications following MDCG 2021‑28.

Annex C – Updated Application Form

Aligned with Annex XV Chapter 2.1 and includes new fields such as:

• Clinical Evaluation Plan reference
• Details on medicinal substances, human/animal tissues
• Identification of the Notified Body (if applicable)
• Confirmation of AEMPS–CEIM communication
• Manufacturer’s declaration on GSPRs (excluding aspects under investigation)
• Use of the term “Supervisor” instead of “Monitor”

Annex D – Updated Manufacturer GSPR Declaration

Now aligned with Annex XV Chapter 4.1.

Important Requirements for AEMPS Clinical Investigation Submissions

The updated process highlights several national expectations:

Site Director Agreement Required

In addition to AEMPS approval and CEIM opinion, the site director must sign a contract authorizing the clinical investigation.

Accepted Languages

• English accepted: Investigator’s Brochure (IB) and Clinical Investigation Plan (CIP).
• Spanish required: CIP summary, Patient Information Sheet, Informed Consent, Instructions for Use, labeling, and all authorization request forms.

Safety Reporting

Must follow MDCG 2020‑10/2 Rev 1 safety reporting procedures.

Submission Pathways for Clinical Investigations in Spain

Spain offers different submission pathways depending on the study type:

1. Full AEMPS Submission

Required for:

• Premarket clinical investigations with non‑CE‑marked devices
• CE‑marked devices used outside their intended purpose (MDR Article 74.2)

2. Notification via NEOPS

Used for PMCF studies with CE‑marked devices used within intended purpose but deviating from standard practice.

3. No Authorization or Notification

For observational PMCF studies fully aligned with CE‑marked intended use.

4. Consultation With AEMPS

For studies under MDR Article 82 involving non‑CE‑marked or off‑label CE‑marked devices, but not intended to support CE marking.

How MDx Supports Your Clinical Investigation Submission in Spain (AEMPS)

MDx CRO provides end‑to‑end support for sponsors navigating the updated Spanish submission pathway. Our services include:

• Clinical & regulatory strategy
• Medical writing
• GSPR checklist creation
• Notified Body application support
• Design of IB and CIP aligned with MDR & ISO 14155
• Ethics Committee submissions
• AEMPS clinical investigation submissions
• Site qualification, activation, monitoring & management
• PMCF and Article 82 studies

Our experts guide you through every stage (from planning to submission to study execution) ensuring full compliance with MDR and Spanish national requirements.

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.

Expert panels on medical devices and in vitro diagnostic devices (Expamed)

What this post covers
This article explains and contextualizes a Clinical Evaluation Consultation Procedure (CECP) opinion issued by the EU Expert Panels (Expamed) on October 2022. We’re not republishing the scientific opinion; instead, we summarize what the panel concluded, why CECP matters for Class III and other high-risk devices, and what practical actions manufacturers and notified bodies (NBs) should consider. Our case study is the publicly available CECP opinion concerning a Class III implant used for reinforcement of abdominal soft tissue in ventral and hiatal hernia repair. We highlight how panels judge the sufficiency of clinical evidence, how benefit–risk is weighed, and how PMCF commitments—including registry follow-up—are used to address residual uncertainty. For the official documents, see the Commission’s expert-panel portal, the master list of CECP opinions, and the PDF of the specific opinion discussed here. 

CECP in a nutshell

Under MDR Article 54 and Annex IX, Section 5.1, certain high-risk devices undergo an additional, independent check of the Clinical Evaluation Assessment Report (CEAR) performed by the NB. The expert panel issues a scientific opinion that the NB must consider—especially if the panel finds the level of clinical evidence insufficient or raises concerns about benefit–risk, alignment of evidence with intended purpose and indications, or adequacy of the post-market clinical follow-up (PMCF) plan. If the NB does not adopt the panel’s advice, Annex IX, 5.1(g) requires the NB to justify that decision in its conformity-assessment report. 

Scope of the October 2022 opinion

The consultation related to a fully resorbable mesh with a resorbable hydrogel coating, indicated for reinforcement of abdominal soft tissue in ventral and hiatal hernia repair, assessed within the competence area of General and plastic surgery and dentistry (BSI NB 2797; file CECP-2022-000227). These administrative and device-scope details are recorded in the published opinion and its Commission news entry. 

What the expert panel decided

The panel concurred with the NB on the appropriateness and sufficiency of the manufacturer’s clinical data and agreed with the NB’s benefit–risk assessment. The opinion notes publication of a new multicentre study adding 84 patients with 24-month follow-up to the dataset and reports no indication of higher recurrence or complication rates compared with established routine techniques. At the same time, the panel emphasized that sample sizes across trials and registries were relatively small and follow-up relatively short, supporting the need for longer-term data. 

PMCF expectations and real-world data

The PMCF Plan was considered acceptable. It calls for further clinical-data collection to identify long-term adverse effects, including those related to device–tissue interaction, and for tracking in two quality registries—HerniaMed and ACHQC—to expand the evidence base over the device’s expected lifetime. The panel’s stance illustrates how CECP leverages real-world registries to complement trials and literature when total exposure and follow-up duration are still maturing. 

What manufacturers should take from this

• Think “totality of evidence.” CECP panels look at the sum of literature, clinical investigations, registries, and the PMCF plan. Smaller cohorts and shorter follow-up aren’t automatic blockers if a credible plan exists to close gaps post-certification, but the plan must be specific about endpoints, timelines, and data sources. For reference, the Commission’s “List of opinions provided under the CECP” shows multiple cases in which panels flagged evidence sufficiency, intended-purpose alignment, or PMCF robustness. 
• Align intended purpose, indications, and SSCP. Panels will check whether the intended purpose/indications match the evidence presented and whether claims are mirrored in the SSCP and labeling. Divergences often lead to scope restrictions, targeted PMCF, or time-limited certificates. The Commission’s Expert Panels hub outlines the panels’ remit and how their opinions integrate into NB assessments.
• Prepare for “justify if you diverge.” If your NB does not fully adopt the panel’s advice, it must justify why in its report (Annex IX, 5.1(g)). Anticipate this by designing evidence and PMCF strategies that are straightforward to adopt—e.g., leveraging recognized registries and clearly defining success metrics and risk signals. 

Why this opinion matters beyond hernia repair

Although device-specific, the October 24, 2022 case neatly shows how CECP functions as a calibrated check on high-risk devices: validate benefit–risk for the intended purpose, acknowledge dataset limits, and enforce structured PMCF to address residual uncertainty. For sponsors approaching CECP, this is a model of how to present fit-for-purpose clinical evaluation, align claims with evidence, and build PMCF that uses registries and longer-term outcomes to demonstrate continued performance and safety.

See the official CECP opinion (PDF) and the Commission’s news entry for the canonical record.