Regulatory Q&As – Clinical Evidence & Investigations

Clinical evaluation is a mandatory process for all medical devices under the EU Medical Device Regulation (MDR) 2017/745 (Article 61 and Annex XIV) and is a continuous process throughout the device lifecycle.

For in vitro diagnostic devices, the equivalent process is the performance evaluation required under the EU In Vitro Diagnostic Regulation (IVDR) 2017/746 (Articles 56–58 and Annex XIII), including the preparation of a Performance Evaluation Plan (PEP) and Performance Evaluation Report (PER) to document data collection, analysis, and conclusions.

Key elements of the clinical evaluation include:

1. Clinical Evaluation Plan (CEP) / Performance Evaluation Plan (PEP)

• Define objectives, scope, applicable GSPRs and strategy for assessing clinical data.
• Include rationale for the chosen patient population, endpoints and study design, especially for rare conditions.
• For IVDs, the PEP should describe the scientific validity, analytical performance, and clinical performance studies to be conducted.

1. Identification of Relevant Clinical Data

• Clinical investigations of the device concerned (MDR) or performance studies (IVDR).
• Scientific literature and published studies.
• Clinical/performance data with equivalent devices, where equivalence can be scientifically demonstrated.
• Real-world evidence sources, such as patient registries or post-market data.

1. Appraisal and Analysis of Data

• Critically evaluate the quality, relevance, and scientific validity of the collected clinical evidence or performance evidence.
• For orphan devices, a proportionate approach may be justified, taking into account the limited size and heterogeneity of the patient population, provided that safety and performance can still be adequately demonstrated.

1. Gap Analysis and Additional Data Generation

• Perform a gap analysis to identify limitations in the available clinical evidence.
• Plan additional data generation, which may include clinical investigations, registry-based studies, or post-market clinical follow-up (PMCF) activities for MDR or performance follow-up (PMPF) for IVDR.

1. Clinical Evaluation Report (CER) / Performance Evaluation Report (PER)

• Document the methodology, analysis, and conclusions of the clinical evaluation (CER) or performance evaluation (PER).
• The report must demonstrate compliance with the general safety and performance requirements (GSPRs) or IVDR requirements, include the benefit-risk assessment, and describe planned PMCF or PMPF activities.

1. Continuous Updates

• The clinical evaluation must be continuously updated throughout the device lifecycle, incorporating new clinical evidence, PMCF results, or post-market performance results, registry data, and post-market experience.

The MDR and IVDR do not establish specific regulatory requirements for orphan devices. However, as recognised in MDCG 2024-10, clinical or performance evidence generation may follow a proportionate approach reflecting the challenges associated with small patient populations.

More information:

Regulation (EU) 2017/745 on Medical Devices (MDR) – Article 61 and Annex XIV

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR) – Articles 56–58 and Annex XIII

For orphan medical devices, additional considerations apply due to small patient populations, limited clinical experience and challenges in generating large clinical datasets.

According to MDCG 2024-10, particular considerations apply to the clinical evaluation of orphan medical devices:

• Proportionality. Clinical evidence requirements may be adapted to small and heterogeneous patient populations.
• Use of real-world evidence and registries. Strongly encouraged to complement limited clinical trial data.
• Equivalence assessment. When using data from similar devices, manufacturers must carefully justify technical, biological, and clinical equivalence, taking into account differences in patient populations.
• PMCF/PMPF planning. Robust post-market clinical follow-up activities, including registries or follow-up studies, are essential to confirm safety and performance after market access.

More information:

MDCG 2024-10

Regulation (EU) 2017/745 on Medical Devices (MDR) – Article 61 and Annex XIV

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR) – Articles 56–58 and Annex XIII

MDCG 2024-10 is the primary guidance on clinical evaluation, subpopulation justification, and proportionality.

MDCG 2024‑10 provides detailed recommendations on:

• Clinical evidence generation, especially for rare conditions or small patient populations;
• Proportionality, tailoring data requirements to device and patient characteristics;
• Documentation and reporting, for submissions to notified bodies or expert panels.

This guidance helps manufacturers and developers prepare robust clinical evaluation and regulatory documentation for orphan medical devices across all risk classes.

More information:

MDCG 2024-10

Generating extensive clinical evidence for orphan medical devices and in vitro diagnostic (IVD) devices may be challenging due to small patient populations, heterogeneous disease conditions, and limited clinical experience.

Under the EU Medical Device Regulation (MDR) 2017/745 and In Vitro Diagnostic Regulation (IVDR) 2017/746, manufacturers must demonstrate that the device meets the General Safety and Performance Requirements (GSPRs),  in accordance with the dispositions of the Articles 61-62 (MDR) or Articles 56–58 (IVDR) and Annexs XIV (MDR) or XIII (IVDR).  The clinical or performance evaluation shall systematically provide the evidence of the safety, performance, and clinical benefit of the device, ensuring it achieves its intended purpose.  However, MDCG 2024-10 recognises that a proportionate approach to clinical or performance evidence generation may be appropriate for orphan devices.

When pre-market clinical or performance data are limited, manufacturers should provide a robust scientific justification, typically documented in the Clinical Evaluation Report (CER) or Performance Evaluation Report (PER), including:

• A clear explanation of the rarity of the condition and the size of the target population;
• A justification of the clinical development/performance evaluation strategy, including the feasibility of conducting large clinical investigations or performance studies;
• A benefit-risk assessment demonstrating that the expected clinical benefits outweigh the uncertainties;
• A well-defined Post-Market Clinical Follow-up (PMCF) or Post-Market Performance Follow-up (PMPF) plan to generate additional clinical evidence after market access;
• The use of complementary evidence sources, such as scientific literature, registry data, or clinical experience.

More information:

MDCG 2024-10

Regulation (EU) 2017/745 on Medical Devices (MDR) – Article 61-62; Annex I; Annex XIV

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR) – Articles 56–58; Annex I; Annex XIII

Post-market clinical follow-up (PMCF) plays a particularly important role for orphan medical devices because pre-market clinical evidence may be limited due to the small size of the target population and the practical challenges of conducting large clinical investigations.

Under the EU Medical Device Regulation (MDR) 2017/745, PMCF is a mandatory component of the post-market surveillance (PMS) system and is required to continuously confirm the safety and performance of a device throughout its lifecycle. PMCF requirements are set out in Article 83 and Annex XIV Part B MDR.

For in vitro diagnostic devices, a similar concept applies through Post-Market Performance Follow-up (PMPF) under the EU In Vitro Diagnostic Regulation (IVDR) 2017/746, particularly Articles 78–81 and Annex XIII.

For orphan medical devices, PMCF or PMPF activities are particularly important because they allow manufacturers to generate additional clinical or performance data after market access, helping to address uncertainties that may remain at the time of CE marking.

These activities help confirm the device’s safety, clinical performance, and benefit-risk profile over time and support continuous updates of the clinical evaluation or performance evaluation.

More information:

MDCG 2024-10

Regulation (EU) 2017/745 on Medical Devices (MDR) – Articles 83–86; Annex XIV Part B

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR) – Articles 78–81; Annex XIII

Orphan medical devices must comply with the general EU Medical Device Regulation (MDR 2017/745) or In Vitro Diagnostic Regulation (IVDR 2017/746). These regulations provide the legal framework for:

• Clinical evaluation/ performance evaluation (Annex XIV MDR /  Annex XIII IVDR);
• Clinical investigations / performance studies (Articles 62 MDR / Articles 57-77 IVDR);
• Post-market clinical follow-up (PMCF) and Post-Market Performance Follow-up (PMPF) (Annex XIV part B MDR/ Annex XIII part B IVDR);
• Equivalence assessment (Annex XIV MDR / Annex XIII IVDR, Section 3.2).

Several MDCG guidance documents support the interpretation and implementation of these requirements, and are applicable to orphan devices:

• MDCG 2024‑10 – Clinical evaluation of orphan medical devices: evidence generation, proportionality, documentation, and reporting.

• MDCG 2021‑6 – Q&A on clinical investigations under MDR.
• MDCG 2020‑5 – Guidance on clinical evaluation and equivalence
• MDCG 2020‑7 / 2020‑8 – PMCF planning and reporting templates.
• MDCG 2022‑10 – Clinical evidence requirements under IVDR.
• MDCG 2023‑16 – PMPF (Post-Market Performance Follow-up) and equivalence under IVDR

Even if some guidance is not orphan-specific, it can be applied with proportionality and adaptation to small patient populations.
Using these documents helps manufacturers justify evidence, plan PMCF, and document equivalence for regulatory submissions.

Manufacturers developing medical devices for rare diseases are encouraged to seek regulatory or scientific advice at an early stage of development, particularly when planning the clinical development strategy and clinical investigations.

The expert panels established in accordance with MDR Article 106 may be requested to provide advice on the orphan device status and the clinical data needed for the clinical evaluation.

The consultation of an expert panel in relation to an orphan device is optional/voluntary, however the early interaction can help clarify key aspects of the development pathway.

This is particularly relevant for orphan medical devices, where small patient populations and limited clinical data may justify a proportionate approach to pre-market clinical evidence, as recognised in MDCG 2024-10.

Under Article 61(2) of the EU Medical Device Regulation (MDR) 2017/745, manufacturers of certain high-risk devices, specifically Class III devices and Class IIb active devices intended to administer or remove a medicinal product, may consult an EU expert panel before conducting their clinical evaluation or clinical investigation.

For in vitro diagnostic devices, manufacturers may similarly seek advice on their Performance Evaluation Plan (PEP) and proposed performance studies under IVDR Articles 56–58.

In the context of orphan medical devices, such consultation may be particularly useful to:

• review and discuss the manufacturer’s intended clinical development strategy;
• assess the justification for the orphan device status;
• evaluate the proposed clinical investigation design;
• consider plans for post-market clinical follow-up (PMCF) where limitations in pre-market clinical evidence are expected.

As part of this procedure, the expert panel will first assess the manufacturer’s justification for the orphan device status and then review the proposed clinical development strategy. Manufacturers are required to give due consideration to the expert panel’s views and document this consideration in the clinical evaluation report.

Early scientific advice can therefore help ensure that the clinical development programme is aligned with regulatory expectations, potentially reducing uncertainties during conformity assessment and facilitating the pathway to CE marking.

More information:

MDCG 2024-10

Regulation (EU) 2017/745 on Medical Devices (MDR)

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR)

Before starting a clinical investigation for a medical device in the European Union, the sponsor must ensure compliance with the requirements of the EU Medical Device Regulation (MDR) 2017/745 or, for in vitro diagnostic devices, the EU In Vitro Diagnostic Regulation (IVDR) 2017/746.
These requirements apply equally to orphan medical devices, although the specific characteristics of rare diseases, such as small patient populations and limited clinical data, should be considered when planning the clinical development strategy, as highlighted in MDCG 2024-10.

The key steps from clinical investigation to CE marking typically include:

a. Define the device and its intended purpose

The sponsor or manufacturer must clearly define the intended medical purpose, target population, and mode of action of the device.
Based on this information, the device is classified according to Annex VIII MDR/IVDR (considering factors such as invasiveness, duration of use, and potential risk. The classification determines the regulatory requirements and the role of the notified body.

b. Establish a clinical or performance evaluation strategy

A development plan should describe how clinical evidence (MDR) or performance evidence (IVDR) will be generated to demonstrate safety and performance.
For orphan devices, the strategy may include smaller clinical investigations, registry data, or other evidence sources, justified through a proportional approach.

c. Conduct a clinical investigation

For medical devices without CE marking, the manufacturer must conduct a clinical investigation in accordance with Article 62 MDR and Annex XV MDR.
For IVDs, the sponsor must conduct performance studies according to the PEP and submit documentation in accordance with IVDR Articles 56–58 and Annex XIII.

Clinical investigations or performance studies must receive and may start only after:

• Ethics committee approval;
• Authorisation from the Competent Authority of the Member State where the study will be conducted.

d. Perform the clinical evaluation / performance evaluation

All available clinical evidence (clinical investigations, literature, registry data, or equivalent devices) must be analysed in a Clinical Evaluation Report (CER) or Performance Evaluation Report (PER). For orphan devices, proportionality may apply when generating and assessing clinical evidence.

e. Prepare the technical documentation

The manufacturer must compile technical documentation in accordance with Annex II and Annex III MDR (or IVDR), including:

• Device description and specifications;
• Information to be supplied by the manufacturer;
• Design and manufacturing information;
• General safety and performance requirements, including the list of applicable Standards and Common Specifications;
• Benefit-risk analysis and risk management documentation;
• Product verification and validation, including Clinical Evaluation Report (CER) or Performance Evaluation Report (PER);
• Post market surveillance documentation, including PMS and PMCF/PMPF plans

f. Conformity assessment with a Notified Body

The specific conformity assessment route depends on the device risk class and type (MDR Annexes IX–XI; IVDR Annexes IX–XI). Notified Body involvement is mandatory for higher-risk classes (Class IIa, IIb, III for MDR; Class B, C, D for IVDR). In these cases, the Notified Body reviews the technical documentation and the quality management system in accordance with Article 52 MDR and Articles 48–50 IVDR.

g. CE marking and market access

If the conformity assessment is successful, the manufacturer may:

• Issue the EU Declaration of Conformity (Article 19 MDR; IVDR Article 17);
• Affix the CE marking on the device (Article 20 MDR; IVDR Article 19);
• Register the device in EUDAMED.

h. Implement post-market surveillance and post-market clinical/performance follow-up

After CE marking, the manufacturer must implement post-market surveillance (PMS) and post-market clinical follow-up (PMCF) or post-market performance follow-up for IVDs to continuously confirm the safety and performance of the device throughout its lifecycle (Articles 83–86 MDR; Articles 78–80 IVDR).

More information:

MDCG 2024-10

Regulation (EU) 2017/745 on Medical Devices (MDR)

Regulation (EU) 2017/746 on In Vitro Diagnostic Medical Devices (IVDR)