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Clinical investigations (Annex XV)

Regulatory basis

MDR Art. 62–82 and Annex XV. Clinical investigations — structured studies in human subjects — are the gold standard for clinical evidence. They are mandatory for certain device classes and may be required when existing evidence is insufficient.

Disclaimer

This site provides general information only and does not constitute legal or regulatory advice. Clinical investigation conduct is strictly regulated and requires ethics committee approval and NCA authorisation. Always consult the official regulation text and specialist regulatory and clinical advice.

What is a clinical investigation?​

A clinical investigation is any systematic investigation in one or more human subjects, undertaken to assess the safety or performance of a device. Under MDR, clinical investigations include:

  • Pre-market investigations: conducted before CE marking to generate evidence for the initial conformity assessment
  • PMCF investigations: conducted post-market to fulfil PMCF obligations
  • Investigational device studies: studies using unapproved (investigational) devices

When is a clinical investigation required?​

Clinical investigations are mandatory under MDR Art. 61(4) for:

  • Implantable Class III devices, unless the device is a modification of an already-marketed device where existing data is sufficient
  • Class III devices in general, unless adequate equivalence data exists from the same manufacturer's marketed device

Clinical investigations are strongly expected when:

  • No genuine equivalent device exists
  • The device uses novel technology with limited literature
  • Residual uncertainties from the clinical evaluation cannot be addressed by PMCF alone
  • A notified body or expert panel concludes that the clinical evidence is insufficient

Regulatory framework — key requirements​

Ethics committee approval​

Clinical investigations must be approved by an ethics committee in each participating member state before commencement. Ethics committee requirements and processes vary by country.

NCA authorisation​

Before starting a clinical investigation in an EU member state, the manufacturer must obtain authorisation from the relevant National Competent Authority (Art. 62(4)). The NCA must be notified and given time to review; for most investigations, there is a 30-day review window (45 days for certain complex devices).

Some member states have a formal authorisation process; others proceed unless they object within the review window.

Registration in EUDAMED​

All clinical investigations must be registered in EUDAMED before commencement. This provides transparency and enables NCA oversight across member states.

Subjects must provide written informed consent before participation, following Good Clinical Practice (GCP) principles aligned with EN ISO 14155:2020.

Annex XV — clinical investigation requirements​

Annex XV Part A sets out the general requirements for clinical investigations:

  • The investigation must follow the Clinical Investigation Plan (CIP)
  • A clinical investigation report must be prepared
  • Serious adverse device events must be reported to NCAs immediately
  • Sponsor responsibilities (which may be the manufacturer or a third party) are defined

Clinical Investigation Plan (CIP)​

The CIP is the master document governing the investigation. Required content includes:

  • Objectives and hypotheses
  • Design (RCT, single-arm, observational) and rationale
  • Subject population — inclusion/exclusion criteria
  • Investigational and comparator device descriptions
  • Primary and secondary endpoints
  • Sample size justification (statistical power)
  • Adverse event definitions and monitoring
  • Stopping rules
  • Statistical analysis plan

Clinical investigation report​

After completion, a full clinical investigation report must be prepared documenting:

  • Conduct of the investigation vs. CIP
  • Subject demographics and baseline characteristics
  • Results for all endpoints
  • Adverse events and device deficiencies
  • Discussion and conclusions

Investigational device logistics​

Devices used in a clinical investigation are investigational devices — they are not placed on the market. The manufacturer must:

  • Mark investigational devices clearly ("for clinical investigation use only")
  • Maintain records of all investigational devices
  • Ensure the devices meet the requirements of Annex XV §2 (safety requirements for investigational devices)

Expedited investigation pathways​

Compassionate use investigations (Art. 62(4)(f))​

For devices intended for seriously ill or life-threatening conditions with no adequate alternative, member states may allow expedited NCA review and ethics committee approval.

First-in-human and pivotal investigations​

For novel, Class III, first-in-human technologies, early engagement with the relevant NCA and ethics committee is strongly advisable. Some NCAs offer pre-submission scientific advice meetings.

PMCF investigations​

Post-market clinical investigations conducted as part of PMCF are also regulated under MDR Annex XV but with a lighter-touch framework:

  • Registration in EUDAMED required
  • CIP and investigation report required
  • Ethics committee approval required
  • NCA notification (not necessarily authorisation) typically required

PMCF investigations are commonly used to:

  • Generate real-world evidence for devices initially CE marked on limited data
  • Address specific clinical questions identified in the post-market phase
  • Demonstrate long-term safety of implantable devices

Official references​

ReferenceDescription
MDR Art. 62–82Clinical investigation requirements
MDR Annex XVClinical investigation — detailed requirements
MDR Art. 61(4)When clinical investigations are required
EN ISO 14155:2020GCP for medical device clinical investigations
MDCG 2021-8Clinical investigation application guidance
MDCG 2020-10/2Serious adverse event reporting in clinical investigations