EUDAMED (electronic system referred to in Article 73 of the MDR) was deemed to be functionally in June 2022, instead of 26 May 2021, but this is still delayed. Per MDR 2017/745, Sponsors of clinical investigations are required to submit an application/notification to participating Member State(s) via EUDAMED.
The MDCG created guidance MDCG 2021-8 to support Sponsors and Competent Authorities in the submission processes for clinical investigation application/notification in the absence of the European EUDAMED system.
Understanding MDCG 2021-8 Guidance
MDCG 2021-8 provides comprehensive guidance on the documentation and forms required for clinical investigation applications and notifications under the EU Medical Device Regulation (MDR 2017/745). This guidance is essential for sponsors planning to conduct clinical investigations in the European Union.
The main part of this guidance document are the six Annexes included in and downloadable on the last page of this document. These forms and templates provided by the MDCG may be helpful for the Competent Authorities and sponsors, though it is always requested to check with the relevant NCA if they require their own official application forms to be used.
Six Key Annexes of MDCG 2021-8
MDCG 2021-8 provides six annexes that form the foundation of clinical investigation applications and notifications:
Annex 1: Application/Notification Form
The primary clinical investigation application/notification form incorporating all required data fields based on the EUDAMED system under development.
Annex 2: Additional Investigational Device(s)
Duplicate of Section 3 for studies using more than one investigational device, ensuring comprehensive device documentation.
Annex 3: Additional Comparator Device(s)
Duplicate of Section 4 for studies with multiple comparators (therapy, placebo, no treatment, or medical device).
Annex 4: Additional Investigation Site(s)
Duplicate of Section 5 for additional national sites, completed for each participating country.
Annex 5: Supporting Documents Checklist
Comprehensive checklist of mandatory and conditional documents required to support clinical investigation submissions.
Annex 6: GSPR & Standards Checklist
Updated checklist of General Safety and Performance Requirements (GSPR), standards, and scientific advice requirements.
Annex 1: Clinical Investigation Application/Notification Form
The application/notification form is the cornerstone of any clinical investigation submission. It incorporates fields based on the EUDAMED system under development, providing a first overview of what the EUDAMED module for clinical investigations will include.
Section 1: Clinical Investigation Identification
- Sponsor identification and contact information
- Legal representative identification (if applicable)
- Clinical investigation type (pilot, pivotal, post-market)
- Submission type (initial, substantial modification, withdrawal)
- Participating countries within EU/EEA/UK (Northern Ireland), Turkey, and Switzerland
- Participating countries outside EU/EEA/UK
- Clinical investigation plan (CIP) attachment
- Clinical investigation title
Section 2: Clinical Investigation Description
Key Information Required
This section captures the scientific and methodological foundation of the clinical investigation, including design, objectives, population characteristics, and duration.
- Scientific opinion and rationale
- Design of the clinical investigation
- Design methodology (randomized, blinded, controlled, etc.)
- Development stage (pilot, pivotal, or post-market)
- Objectives and endpoints (primary and secondary)
- Synopsis of the clinical investigation
- Planned number of subjects (by geographic region: Europe, Asia, Africa, North America, South America, Oceania)
- Duration of clinical investigation
Section 2.9: Population Characteristics
Detailed specification of the target population is critical for regulatory approval and ethical review:
Medical Condition & Therapeutic Area
Clearly define the medical condition to be studied and specify the therapeutic area (e.g., orthopedics, wound care, cardiovascular, etc.).
Gender & Inclusion/Exclusion Criteria
Specify gender distribution and provide comprehensive inclusion and exclusion criteria that define eligible subjects.
Special Populations
Indicate if the study includes vulnerable populations, incapacitated subjects, minors, pregnant women, breastfeeding women, or patients in emergency situations.
Age Range Categories
Select applicable age categories: in utero, newborns (0-27 days), infants/toddlers (28 days-23 months), children (2-5 years), adolescents (12-17 years), adults (18-84 years), or elderly (85+ years).
Section 3: Investigational Device(s)
Comprehensive documentation of the investigational device is essential for regulatory assessment and safety monitoring:
- Device purposes and intended use
- Device type and classification
- Invasiveness level (non-invasive, minimally invasive, invasive)
- Device identifiers (UDI, model numbers, versions)
- Information on previous clinical investigations
- Scientific opinion or view on device safety and performance
- Manufacturer identification and contact information
- Authorized representative details (if applicable)
Sections 4 & 5: Comparator & National Information
Section 4: Comparator Information
If the study includes a comparator, specify the type (therapy, placebo, no treatment, or medical device). If multiple comparators are used, complete Annex 3 for each additional comparator.
Section 5: National Information
For each participating country, provide study site information, ethics committee details, expected number of subjects to be recruited, and current status of the clinical investigation.
Annex 5: Clinical Investigation Supporting Documents
A comprehensive checklist of supporting documents is essential for a complete submission. The use of this checklist is recommended for traceability, though it is not mandatory.
Important: Always check with the relevant National Competent Authority (NCA) regarding expectations, as there might be additional required documents specific to a single Member State.
Mandatory Documents
- Clinical Investigation Plan (CIP) with protocol and amendments
- Curriculum Vitae of the coordinating investigator
- Investigator's Brochure (IB) or equivalent device documentation
- Quality Overall Summary (QOS) or equivalent technical documentation
- Risk Management Report (RMR)
- Clinical Evaluation Report (CER) or Clinical Evaluation Plan (CEP)
- Insurance or indemnity information
- Ethics Committee approval or opinion
- Competent Authority approval (if required by national law)
- Informed Consent Form (ICF) and any translations
Conditional Documents (As Applicable)
Depending on the type and regulatory stage of the clinical investigation, the following documents may be required:
- Substantial modification documentation (for amendments)
- Previous clinical investigation reports or summaries
- Pharmacokinetic/pharmacodynamic data (if applicable)
- Biocompatibility assessment (for implantable devices)
- Sterilization validation (for sterile devices)
- Post-market surveillance data or real-world evidence
- Scientific advice from expert panels (if obtained)
- Combination device documentation (if applicable)
- Pediatric investigation plan (PIP) or justification for non-applicability
Annex 6: General Safety and Performance Requirements (GSPR) & Standards Checklist
This checklist is well known from the essential requirements checklist under MDD/AIMDD. With MDR 2017/745, it has been updated to reflect the General Safety and Performance Requirements (GSPR) as per Annex I, Chapters I, II, and III of the MDR.
What's New in MDR 2017/745
The first part of this checklist now includes information on standards, common specifications, and scientific advice obtained from expert panels according to Articles 9 and 106 MDR (Provision of scientific, technical and clinical opinions and advice).
GSPR Coverage Areas
Risk Management
Compliance with ISO 14971 and risk management principles throughout the device lifecycle.
Design & Development
Design controls, design verification, and design validation requirements.
Biocompatibility & Safety
Biocompatibility assessment, sterilization, and chemical safety requirements.
Performance & Labeling
Device performance claims, instructions for use, and labeling requirements.
Post-Market Surveillance
Post-market surveillance planning and adverse event reporting requirements.
Clinical Evaluation
Clinical evaluation requirements and evidence standards for safety and performance.
EUDAMED Alignment & Future Implementation
Insofar as possible, the clinical investigation application/notification form includes the same data fields as the EUDAMED system in development. This ensures consistency and will facilitate the transition when the EUDAMED module for clinical investigations becomes fully functional.
The forms and templates provided by MDCG 2021-8 will serve as the interim solution until EUDAMED is fully operational. Sponsors should prepare their submissions using these forms while monitoring updates from the European Commission regarding EUDAMED implementation.
Related MDCG Guidance & Resources
MDCG 2021-8 references and complements other important guidance documents:
MDCG 2021-1 Rev.1
Provides additional guidance on clinical investigation requirements and complements MDCG 2021-8 for comprehensive understanding of clinical investigation submission requirements.
Classification & Combination Products
- MDCG 2021-24: Guidance on classification of devices and combination products
- MDCG 2022-5: Additional guidance on medicinal product and medical device combinations
- Helsinki Procedure 2021: Procedure for parallel clinical trials with medicinal products
Actor Registration
Additional guidance is provided for "actors" registration under MDR, including sponsors, manufacturers, authorized representatives, and other stakeholders involved in clinical investigations.
Clinical Investigation Submission Best Practices
- Verify all required data fields in Annex 1 are completed accurately and comprehensively
- Ensure the Clinical Investigation Plan (CIP) is scientifically rigorous and complies with ICH-GCP guidelines
- Provide clear and detailed device descriptions with technical specifications and identifiers
- Include comprehensive risk management documentation demonstrating device safety
- Attach all mandatory supporting documents with proper formatting and organization
- Obtain ethics committee approval before submission to competent authorities
- Verify compliance with national requirements for each participating country
- Use digital signatures for form authentication (PDF signature capability)
- Maintain organized documentation for audit trail and traceability
- Prepare for potential requests for additional information or clarifications
Key Takeaways
- MDCG 2021-8 provides interim guidance for clinical investigation applications pending EUDAMED implementation
- The six annexes form the complete submission package: application form, additional devices, comparators, sites, supporting documents, and GSPR checklist
- Annex 1 captures all essential clinical investigation information aligned with future EUDAMED requirements
- Comprehensive population characterization is critical for regulatory approval and ethics review
- Supporting documents must be complete, organized, and tailored to each participating country's requirements
- GSPR compliance must be demonstrated across all aspects of device design, safety, and performance
- Always verify with the relevant National Competent Authority for country-specific requirements
- Digital form signing is supported, improving submission efficiency and traceability
- MDCG 2021-8 forms will facilitate transition to EUDAMED once fully operational
- Proper documentation and organization are essential for successful regulatory approval
Conclusion
MDCG 2021-8 provides essential guidance for sponsors planning clinical investigations under the EU Medical Device Regulation. The six annexes—application form, additional devices, comparators, sites, supporting documents, and GSPR checklist—create a comprehensive framework for submission to National Competent Authorities.
Understanding and properly implementing MDCG 2021-8 requirements is critical for regulatory success. From detailed population characterization to comprehensive supporting documentation, each element plays a vital role in demonstrating device safety and performance.
At Eclevar MedTech, we understand the complexities of clinical investigation submissions under MD