Prospective clinical investigations are the gold standard for generating clinical evidence under EU MDR 2017/745. This guide covers everything device manufacturers need to design, submit, and run a compliant prospective investigation — from protocol development and ISO 14155:2020 requirements to ethics submissions and EUDAMED registration.
Under EU MDR 2017/745 Article 62, all clinical investigations of medical devices conducted in the EU must comply with ISO 14155:2020 — the international Good Clinical Practice (GCP) standard for medical device investigations. This is not optional. It applies to pre-market pivotal studies and post-market clinical investigations (PMCI) equally. Unlike pharmaceutical GCP (ICH E6), ISO 14155:2020 was written specifically for the medical device context and reflects the unique challenges of device trials: operator-dependent outcomes, learning curves, device iterations, and the absence of placebo equivalents in many indications.
The Clinical Investigation Plan (CIP) is the foundational document governing the investigation. ISO 14155:2020 specifies mandatory content including the scientific rationale, objectives, primary and secondary endpoints, study design, subject population, inclusion/exclusion criteria, statistical analysis plan, and risk management measures. The CIP must be approved by the ethics committee and, where required, the national competent authority before any subject is enrolled.
Every prospective clinical investigation under EU MDR requires ethics committee approval before enrolment begins. In France, this means submission to the CPP (Comité de Protection des Personnes). In Germany, the Landesärztekammer. In the UK (post-Brexit), the HRA and MHRA. For multi-country investigations, each participating Member State requires separate ethics approval — though the CIP can be identical across countries. Timelines typically range from 45 to 90 days per country.
Informed consent under ISO 14155:2020 must be prospective (before any study procedure), voluntary, and documented with date, time, and version of the consent form. For multi-country investigations, the consent form must be translated and back-translated for each language. Re-consent is required when protocol amendments materially affect subject risk. The consent process — not just the form — must be documented in the clinical site's investigator file.
ISO 14155:2020 requires a risk-based monitoring strategy with documented on-site monitoring visits, source data verification (SDV), and protocol deviation management. The Clinical Research Associate (CRA) must verify that data in the eCRF matches source documents, that the site is following the approved CIP, and that adverse events are being captured and reported correctly. Monitoring visit reports must be filed in the TMF within a defined timeframe.
The investigational device must be registered in EUDAMED with a valid UDI-DI before the clinical investigation can be registered. Economic operator registration must also be complete. For devices not yet CE-marked, a specific investigational device UDI format applies.
Submit the clinical investigation application via EUDAMED, including: CIP summary, device information, investigator details, Member State list, and ethics committee approval status. The application generates a Single Identification Number (SIN) used across all regulatory submissions.
For investigations covered by EU MDR Article 62 (interventional, with higher risk), notification to the national competent authority (ANSM in France, BfArM in Germany, MHRA in the UK) is required. The EUDAMED SIN is referenced in all national submissions. Member States have 30 days to raise objections.
Ethics committee approval must be confirmed in EUDAMED before enrolment commences. For multi-country investigations, each Member State's ethics approval is recorded separately. The EUDAMED record is updated as approvals are received country by country.
Once the investigation is active, Serious Adverse Device Effects (SADEs) must be reported in EUDAMED within defined timelines. Annual progress reports and the Clinical Study Report (CSR) at completion are also submitted via EUDAMED. The record remains publicly visible on the EUDAMED portal.
Different prospective study designs serve different regulatory purposes and are appropriate for different device classes, indications, and evidence gaps. Choosing the right design at protocol development — not after data collection has started — is the single most important decision in a clinical investigation program.
Gold standard design where subjects are randomly assigned to the investigational device or a control group. Provides the strongest evidence of device efficacy and safety through rigorous comparison. Required by Notified Bodies for Class III devices where meaningful comparators exist.
Class III preferredAll subjects receive the investigational device — no control group. Appropriate for novel devices where a meaningful comparator is impractical or for rare conditions with small patient populations. Performance goals derived from literature or registry data replace the control arm.
Novel devices · Rare conditionsSmall prospective study (typically 10 to 30 subjects) to assess preliminary device safety and performance before a pivotal investigation. Used to refine protocol design, endpoint selection, and sample size assumptions. Often the first regulated clinical investigation for an early-stage device.
First-in-human · Protocol refinementSubjects assigned to the device or control through non-random methods (e.g., historical controls, concurrent comparison at different sites). Used when randomisation is not feasible. Requires more stringent bias management and often a larger sample size than an RCT.
When randomisation is not feasiblePassive observation of device use in routine clinical practice. No protocol-driven intervention beyond data collection. Used for PMCF investigations where interventional design is not warranted. Must still comply with ISO 14155:2020 and require ethics committee approval.
PMCF investigations · Real-world useSystematic prospective data collection from multiple sites using a centralised registry. Enables long-term monitoring, large patient numbers, and real-world evidence generation. Particularly valuable for Class IIb/III implants where 5 to 10-year follow-up is required under EU MDR.
NJR · EPRD · Swespine · Long-term PMCFThe CIP is the single most scrutinised document in a clinical investigation. Notified Bodies assess protocol quality before approving the resulting clinical evidence. These eight principles, derived from ISO 14155:2020 and current Notified Body expectations, are the foundation of every investigation Eclevar designs.
Define specific, measurable primary and secondary objectives before investigation starts. Objectives must address the regulatory question — not just scientific curiosity.
Inclusion/exclusion criteria must be specific enough to ensure a homogeneous population while remaining representative of the intended real-world device users.
Primary endpoint must be directly measurable, clinically relevant, and achievable within the study timeline. Surrogate endpoints require justification of clinical validity.
Sample size must be calculated with appropriate statistical power (typically 80% or 90%) and a pre-specified effect size. Assumptions must be documented and justified by literature or pilot data.
Every procedure, visit schedule, and assessment must be standardised across all participating sites. Operator training and qualification criteria must be defined in the CIP.
Statistical Analysis Plan (SAP) must be finalised and approved before database lock. Analysis populations, methods, and interpretation criteria pre-specified to prevent post-hoc bias.
SADE reporting timelines, stopping rules, Data Safety Monitoring Board (DSMB) charter, and adverse event coding conventions must be defined in the CIP before enrolment.
EDC platform must be validated (IQ, OQ, PQ) with a 21 CFR Part 11-compliant audit trail. DMP and DVP must be approved before any eCRF configuration begins.
Timelines vary significantly by device class, investigation type, number of countries, and indication. The following represents a typical multi-country prospective investigation for a Class IIb device managed by Eclevar MedTech. Class III pivotal programs typically add 6 to 12 months to the pre-study and enrolment phases.
CIP development and internal review. Ethics committee submissions (CPP/national bodies per country). EUDAMED registration. Investigator selection, site feasibility assessments, contract negotiations, and budget agreements. MILO Health EDC configuration and validation. CRA training and site initiation preparation.
Site Initiation Visits (SIV) completed before first subject enrolled per site. Progressive site activation as ethics and competent authority approvals are received country by country. Subject screening, informed consent, and device implantation/application. Real-time data entry into MILO Health EDC with automated query management.
Subject follow-up visits according to CIP visit schedule. CRA monitoring visits with source data verification. Protocol deviation management and SADE reporting. Annual EUDAMED progress reports. Duration depends on study design — 12 months is typical for many Class IIb devices; 10 years for Class III AIMDs.
Final data cleaning and query resolution. Database lock with multi-party sign-off (sponsor, data manager, biostatistician). Statistical analysis per pre-specified SAP. CDISC CDASH/SDTM export from MILO Health for regulatory submission datasets.
Clinical Study Report (CSR) preparation per ISO 14155:2020 requirements. EUDAMED CSR registration. Integration of investigation findings into the CER and PMCF Report. Technical file submission to Notified Body with updated clinical evidence package.
Understanding the distinction between pre-market and post-market clinical investigations is essential for planning your regulatory pathway and evidence strategy.
| Criterion | Pre-Market Clinical Investigation | Post-Market Clinical Investigation (PMCI) |
|---|---|---|
| Purpose | Generate clinical evidence for conformity assessment and CE marking. Address safety and performance questions before the device is placed on the market. | Address residual data gaps identified in the CER after CE marking. Confirm long-term safety and performance in real-world use conditions. |
| Regulatory basis | EU MDR Article 62 — specific pre-market investigation requirements and notification procedures. | EU MDR Annex XIV Part B — PMCF requirements. PMCI is one type of PMCF activity. |
| EUDAMED registration | Mandatory before first subject enrolment. Generates a Single Identification Number (SIN). | Required. PMCI registered in EUDAMED as part of the PMCF programme documentation. |
| Competent authority notification | Required for interventional investigations. 30-day review period per Member State. Authority may object or require modifications. | Notification requirements depend on investigation type and Member State. Less prescriptive than pre-market pathway. |
| Device CE status | Device is not CE-marked. Investigational device label required. Subject to specific import and distribution restrictions. | Device is CE-marked and placed on the market. Investigation uses commercially available device within its intended purpose. |
| ISO 14155:2020 | Full compliance required. All elements of the standard apply. | Full compliance required. Same GCP standards apply regardless of market status of the device. |
| Typical duration | 12 to 36 months for most Class IIb/III investigations. Feasibility studies: 3 to 6 months. | Variable. PMCI for PMCF may run 1 to 5+ years depending on device class and unresolved evidence gaps. |
| Eclevar service | Pre-market clinical investigation services | PMCF and post-market clinical investigation services |
A prospective clinical investigation under EU MDR 2017/745 is a systematic study designed to collect clinical data on a medical device in human subjects, following a pre-specified protocol governed by ISO 14155:2020. All prospective clinical investigations require ethics committee approval. Pre-market investigations additionally require EUDAMED registration and, in most cases, notification to the national competent authority before enrolment.
Yes. Under EU MDR 2017/745 Article 62, all clinical investigations of medical devices conducted in the EU must comply with ISO 14155:2020 — the Good Clinical Practice standard for medical device investigations. This applies to both pre-market pivotal studies and post-market clinical investigations (PMCI). Non-compliance is a critical finding at Notified Body inspections and may invalidate the clinical evidence generated.
EUDAMED (European Database on Medical Devices) is the EU-wide database for medical device information. For clinical investigations under EU MDR, manufacturers must register the investigation in EUDAMED before the first subject is enrolled. Registration requires device UDI-DI, investigator details, protocol summary, and ethics committee approval confirmation. The EUDAMED record remains publicly accessible and is updated throughout the investigation lifecycle — including progress reports and the Clinical Study Report at completion.
A pre-market clinical investigation (covered by EU MDR Article 62) is conducted before CE marking to generate the clinical evidence required for conformity assessment. A post-market clinical investigation (PMCI) is conducted after CE marking as part of the PMCF programme, to address residual data gaps identified in the CER. Both must comply with ISO 14155:2020, but pre-market investigations require more extensive regulatory submissions and are subject to competent authority review before commencement. See our PMCF guide for post-market investigation details.
Pages that link to this guide and receive links here — strengthening the EU MDR clinical investigation cluster.
Eclevar MedTech's clinical operations team manages pre-market and post-market clinical investigations across France, Germany, UK, Italy, Spain, and beyond — with in-house CRAs, ISO 14155:2020 expertise, and MILO Health EDC for full inspection readiness from Day 1.
