Clinical Evaluation Reports: General Structure and What to Include
April 21, 2024
EU Parliament Votes “Yes” to Extend IVDR Transition Period & Gradual Rollout of EUDAMED
April 25, 2024The MDCG issued new guidance on the minimum contents expected in an Investigator’s Brochure. It is available: HERE
An editable Word version of MDCG 2024-5, Appendix A is available: HERE
Background
The Investigator’s Brochure (IB) is a required element of a clinical trial application.
The EU MDR’s requirements are outlined under Annex XV (‘Clinical Investigations’), Chapter II (‘Documentation regarding the application for clinical investigation’), Section 2 (‘Investigator’s Brochure’). Further, the preparer should also consider ISO 14155:2020, Clinical investigation of medical devices for human subjects – Good clinical practice.
MDCG 2024-5 provides more detail on the expected minimum contents, and overall structure for the IB. “Brochure” is a bit of a misnomer, as the IB and its attachments can be a fairly extensive document.
Please refer to the guidance document for complete details, including a glossary of abbreviations.
Content of the Investigator’s Brochure
Administrative Details
The first few pages should contain:
- Name of the device
- Document reference number with version and date
- Confidentiality statement
- Summary of revision history
- Table of contents
- Name and address of the sponsor of the clinical investigation
- Name and address of the manufacturer, if different from the sponsor
- Page number and total number of pages should be indicated on each page
Investigational Device Information
This section should include the below (as applicable):
- Identification of the device, including explanation if there are several names used for the device.
- Intended purpose with clearly identified indications, contra-indications, target patient group(s) and intended users; plus:
- Outline any differences between the intended purpose as defined in the study versus when the device will be placed on the market.
- If the device has already been CE Marked, if the intended purpose in the investigation is different than under the CE Marking; or, if the study is to further assess the device within the scope of its intended purpose.
- Clinical performance the device is intended to achieve, i.e., how does it achieve its intended purpose, thereby leading to a (meaningful and measurable) clinical benefit.
- Qualification and classification, i.e., rationale for why the product qualifies as a medical device and that device’s risk classification.
- Literature, previous research, and evaluation supporting the rationale for the design and intended use of the device.
- General description of the device, including:
- Description of the critical and fundamental design, including mode of action; it should be written assuming that not all readers are already experts in the field.
- Written description of key functional elements, supported by drawings, diagrams, animations, and/or videos; it should outline all parts/components, software, formulation, composition, etc.
- Overview of materials used, including details on any materials coming in contact with the human body.
- Technical specifications, such as features, performance attributes, variants/configurations, and accessories.
- Summary of manufacturing process and corresponding quality controls (verifications and validations and final testing).
- Reference to previous and similar generations of the device; can be a table showing each iteration of the device with version number, photograph/drawing, brief overview, and rationale of changes.
- Overview of equivalent or similar devices, focusing on the novelty of the current device when compared to the other(s).
Labels and Instructions for Use
Include the manufacturer’s instructions, information to be placed on the label (to the extent possible), implant card, if applicable, and information relating to any relevant training required, plus plans for training if applicable.
Sponsor should verify local language requirements for the labeling and instructions for use.
Pre-clinical Evaluation
Include a summary of pre-clinical testing, together with an evaluation of the results of such testing. The data should justify its use on/in human subjects.
As the investigational device must conform to the MDR’s Annex I General Safety and Performance Requirements (GSPRs), this may include technical and biological safety testing, pre-clinical evaluation, and provisions in the field of occupational safety and accident prevention. If any aspects of pre-clinical testing have not been completed prior to the clinical investigation application, it should be highlighted and justified.
See the MDCG guidance for how the summarized information could be provided. As well, further detail on minimum testing expectations, e.g., on performance, reliability, interoperability and compatibility, usability, mechanical, electrical safety and electromagnetic compatibility, biocompatibility and biological safety, software verification and validation, cybersecurity, etc.
Existing Clinical Data
Include existing data, such as:
- Relevant scientific literature
- Overview of ongoing or completed clinical investigations with the investigational device
- If applicable, summary of the latest Periodic Safety Update Report (PSUR) or Post Market Surveillance Report (PMSR)
Risk Management
Include a summary of the benefit-risk analysis and risk management, including known or foreseeable risks, undesirable side-effects, contraindications, and warnings. Further, an assessment of anticipated frequency of occurrence of serious adverse events and serious adverse device effects.
If the investigational device is already CE Marked and the investigation is outside of the CE Marking’s intended purpose, ensure that 1) any differences in use and new risks are appropriately addressed, and 2) are clearly described in the Instigator’s Brochure.
See the MDCG guidance for more detail on risk management expectations, including recommendations to refer to ISO 14971:2019, ISO/TC 24971:2020, and Annex H in ISO 14155:2020.
Devices Incorporating a Medicinal Substance or Manufactured Using Non-viable Tissues or Cells
Include detailed information on the medicinal substance or on the tissues, cells, or their derivatives. Readers are recommended to consult with the European Medicines Agency (EMA) guidance documents on Investigational Medicinal Product Dossiers.
Fulfilment of General Safety and Performance Requirements (GSPRs)
Include an overview of which GSPRs apply to the investigational device and a brief justification for any that are not applicable. Further, provide objective evidence on how compliance to each applicable GSPR was achieved. This can include any standards and common specifications applied.
If any GSPRs have not yet been met, but will be covered by the investigation, 1) clearly identify them and 2) indicate how every precaution has been taken to protect the health and safety of the subjects and other users.
This will ideally be presented in checklist format, such as the one provided in MDCG 2021-8. Note that MDCG 2021-8 also includes the MDR clinical investigation application/notification form and Appendix of supporting documents that should be attached (such as the Investigator’s Brochure).
Procedures
Include a detailed description of the clinical procedures and diagnostic tests used in the course of the clinical investigation. It should particularly highlight and address any deviations from normal clinical practice, and describe what would be considered normal clinical practice as a baseline.
Further, specify any other devices or medicinal products to be used in combination with the investigation device and provide their regulatory status.
Appendix A (Checklist)
This is a cross-reference against each requirement under MDR Annex XV, Chapter II ‘Documentation regarding the application for clinical investigation’. By using this checklist, the sponsor can better ensure they have addressed each section.
The MDCG guidance contains a PDF copy (pages 30-34). An editable Word version of Appendix A is also available: HERE
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