Annex XV — Clinical Investigations

Source: EU MDR 2017/745 Annex XV | OJ L 117, 5.5.2017

Chapter I — General Requirements

Scope of Application

Annex XV applies to clinical investigations conducted for the following purposes:

• To demonstrate conformity of devices with the requirements of this Regulation (Article 62).
• Situations where clinical investigations are exempted (Article 61(4)-(6)).
• Post-market clinical follow-up (PMCF) investigations (Annex XIV Part B).

Ethical Principles

Clinical investigations must comply with:

• The principles of the Declaration of Helsinki.
• ICH E6 GCP (Good Clinical Practice).
• EN ISO 14155 (Clinical investigation of medical devices for human subjects).

Chapter II — Application Documentation

Application Documentation Checklist

When submitting a clinical investigation application to a competent authority, it must include:

Document Category	Specific Content
Application Form	Applicant information, device information, specific details of the investigation
Clinical Investigation Plan (CIP)	See Chapter III
Investigator's Brochure (IB)	Device description, pre-clinical data, existing clinical data
Informed Consent Form	Form to be signed by the subject or their legally designated representative
Ethics Committee Opinion	Approval document from the ethics committee
Proof of Insurance	Insurance dealing with compensation for damage suffered by subjects
Manufacturer's Declaration	Statement that the device conforms to the GSPRs apart from the aspects covered by the clinical investigation
Technical Documentation Summary	Technical overview of the device design, manufacturing, and intended purpose
EUDAMED Registration	Registration information of the clinical investigation in EUDAMED

Application Review Process

Applicant submits → Competent Authority review (30 days) → Approval/Refusal/Request for supplementary info
                                    ↓
                        Ethics Committee parallel review
                                    ↓
                  Investigation may commence after dual approval

Note: According to Article 62(4), the competent authority must notify the applicant of its decision within 30 days of receiving a valid application. For investigations involving implantable devices or Class III devices, this review period can be extended by a further 15 days.

Chapter III — Clinical Investigation Plan (CIP)

Mandatory Contents of the CIP

1. General Information

• Title of the investigation, single identification number (CIV-ID).
• Applicant/Sponsor information.
• Investigation sites and principal investigators.

2. Objectives and Design of the Investigation

• Primary and secondary objectives.
• Study design (randomised controlled, single-arm, prospective, etc.).
• Primary and secondary endpoints.
• Statistical methods and sample size calculation.

3. Selection of Subjects

• Inclusion criteria.
• Exclusion criteria.
• Description of the target population.

4. Device Information

• Description of the device and its intended purpose.
• Instructions for installation, maintenance, and use.
• Details of the comparator device (if applicable).

5. Investigation Procedures

• Schedule of visits and timeline.
• Methods for recording data.
• Duration of subject follow-up.

6. Safety Monitoring

• Definition and grading of adverse events.
• Procedures for reporting serious adverse events.
• Establishment of a Data Safety Monitoring Board (DSMB) (if applicable).
• Criteria for suspension/premature termination of the investigation.

7. Statistical Analysis Plan

• Primary analysis methods.
• Handling of missing data.
• Interim analysis plan (if applicable).

8. Ethical Considerations

• Informed consent procedures.
• Protection of subject privacy and personal data.
• Measures to protect vulnerable populations.

See MDCG 2024-3: Guidance on Content of the Clinical Investigation Plan

Chapter IV — Protection of Subjects

Informed Consent Requirements

Informed consent must meet the following:

• Must be in writing, signed and dated by the subject or their legally designated representative.
• Must be obtained prior to the start of any investigation-specific procedures.
• The subject has the right to withdraw consent at any time without any resulting detriment.

The informed consent form must include:

1. The nature, objectives, benefits, implications, risks, and inconveniences of the clinical investigation.
2. The expected benefits and foreseeable risks.
3. The subject's rights (including the right to withdraw).
4. Safeguards regarding the confidentiality of their personal data.
5. Compensation procedures and insurance arrangements.
6. Contact details of the investigator.

Protection of Vulnerable Populations

Minors:

• Informed consent from their legally designated representative must be obtained.
• The explicit wish of a minor who is capable of forming an opinion and assessing the information to refuse participation or to withdraw from the clinical investigation at any time must be respected.
• Assent from the minor must be obtained where possible.
• Permitted only if the investigation relates directly to a medical condition from which the minor suffers or is of such a nature that it can only be carried out on minors.

Incapacitated Subjects:

• Informed consent from their legally designated representative must be obtained.
• The subject should take part in the consent procedure as much as possible.
• Permitted only if the investigation relates directly to a medical condition from which the subject suffers.

Emergency Situations:

• Subjects can be included without prior informed consent under specific strict conditions.
• Informed consent to continue participation must be obtained as soon as possible.
• An emergency procedure approved by the ethics committee must be in place.

Chapter V — Conduct of the Investigation

Duties of the Investigator

• Conduct the investigation in accordance with the CIP.
• Record all adverse events.
• Report serious adverse events to the sponsor without delay (within 24 hours).
• Keep investigation records for a specified period (at least 15 years, or 10 years for implantables).

Duties of the Sponsor

• Ensure the investigation is conducted in accordance with the CIP.
• Monitor the conduct of the investigation.
• Report serious adverse events to the competent authorities (within strict timelines).
• Submit annual safety reports.

Timelines for Reporting Serious Adverse Events

Event Type	Reporting Timeline
Unanticipated serious adverse device effect (USADE) leading to a serious public health threat	Immediately, but not later than 2 days
Death or unanticipated serious adverse device effect (USADE)	Without delay, but not later than 7 days
Other reportable events (e.g., SAEs)	Without delay, but not later than 15 days
Annual safety report	Annually

Chapter VI — End of Investigation and Reporting

Notice of the End of the Investigation

The sponsor must notify the Member State in which the clinical investigation was being conducted of the end of the clinical investigation within 15 days of its completion. If the investigation is halted temporarily or terminated early, the notification must be made within 15 days, stating the reasons.

Clinical Investigation Report

A clinical investigation report must be submitted within one year of the end of the clinical investigation, containing:

• A summary of the investigation.
• Main and secondary results.
• Statistical analysis results.
• Summary of safety data.
• Conclusion.

The report, accompanied by a summary presented in terms that are easily understandable to the intended user, must be uploaded to EUDAMED (once fully functional).

See MDCG 2024-15: Guidance on Publication of the Clinical Investigation Report

Exemptions from Clinical Investigations (Article 61(4)-(6))

Clinical investigations may be exempted under the following circumstances:

• Article 61(4): The device is demonstrated to be equivalent to an already marketed device, and the technical documentation of the equivalent device is accessible.
• Article 61(5): The device has no medical purpose, or is only used for measurement, and there is no scientific justification for conducting a clinical investigation.
• Article 61(6): Implantable and Class III devices are generally required to undergo clinical investigations, except in cases where:
  • The device has been designed by modifying a device already marketed by the same manufacturer, and the modifications do not adversely affect the benefit-risk ratio.
  • The modified device is demonstrated to be equivalent to the marketed device.
  • The clinical evaluation of the marketed device is sufficient to demonstrate conformity of the modified device.

See MDCG 2023-7: Guidance on exemptions from the requirement to perform clinical investigations

Related Pages

• Annex XIV — Clinical Evaluation
• Annex I — GSPR
• Article 10 — General Obligations of Manufacturers
• Harmonised Standards — Clinical Evaluation and Investigation

Official Sources

• EUR-Lex: Full text of EU MDR 2017/745 (including Annex XV)
• MDCG 2024-3: Guidance on content of the Clinical Investigation Plan
• MDCG 2021-8: Clinical investigation application/notification documents
• MDCG 2023-7: Guidance on exemptions from clinical investigation requirements
• EN ISO 14155: Clinical investigation of medical devices for human subjects