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.