Clinical Evaluation and Performance Evaluation

In the design and development of medical devices under medical device regulations, different evaluation requirements apply depending on the classification and type of the medical device.

Clinical evaluation is required for general medical devices (non-IVD products), while performance evaluation is required for in vitro diagnostic medical devices (IVD products). These evaluation requirements apply not only during the product development stage but also for continuous verification of safety and performance in the post-market phase.

Basis for the Distinction

This distinction is based on the intended use of medical devices and their method of contact with patients.

Clinical Evaluation for General Medical Devices

General medical devices are used directly on patients; therefore, clinical evaluation is required to confirm their safety and effectiveness in actual clinical environments.

Clinical evaluation includes collecting clinical trial data, reviewing existing clinical literature, or conducting comparative evaluations with equivalent already-approved medical devices. When conducting comparative evaluation with equivalent devices, it is necessary to strictly satisfy the equivalence requirements (technical characteristics, biological characteristics, and clinical characteristics) defined by each regulatory authority. Additionally, clinical evaluation must be conducted continuously throughout the product lifecycle, and comprehensive evaluation including post-market clinical data is required.

Under the EU Medical Device Regulation (MDR), the requirements for demonstrating equivalence have become more stringent. According to MDCG 2020-5 guidance, when claiming equivalence, manufacturers must demonstrate that the device under evaluation and the equivalent device are the same or similar in all technical, biological, and clinical characteristics. Detailed documentation of design differences and their impact on clinical safety and performance is required, and comparative drawings and diagrams should be provided. The demonstration of equivalence requires not only similarity in specifications but also comprehensive evaluation including clinical data supporting safety and performance.

Furthermore, clinical investigations conducted in the EU must comply with the requirements of ISO 14155:2020 and its amendment EN ISO 14155:2020+A11:2024 (published March 2025), which harmonizes with MDR Annex XV. Recent guidance documents including MDCG 2024-3 (Guidance on content of the Clinical Investigation Plan) and MDCG 2024-5 (guidance on the Investigator’s Brochure) provide detailed requirements for clinical investigation planning and documentation. These guidance documents emphasize alignment with technical documentation and the overall clinical evaluation process, requiring integration of pre-market clinical investigations with post-market clinical follow-up (PMCF) and benefit-risk analysis throughout the device lifecycle.

Performance Evaluation for In Vitro Diagnostic Medical Devices

On the other hand, in vitro diagnostic medical devices (IVD products) analyze specimens collected from patients and are not used directly on patients; therefore, performance evaluation that assesses the analytical capability of the product is emphasized.

Under the In Vitro Diagnostic Regulation (IVDR), performance evaluation emphasizes three elements: scientific validity, analytical performance (accuracy, precision, limit of detection, etc.), and clinical performance (sensitivity, specificity, positive predictive value, negative predictive value, etc.). These evaluations comprehensively verify the characteristics and clinical significance of the target analyte.

According to IVDR Article 56 and Annex XIII Part A, performance evaluation is defined as a continuous process by which data are assessed and analyzed to demonstrate the scientific validity, analytical performance, and clinical performance of the device for its intended purpose. The performance evaluation must be thorough and objective, considering both favorable and unfavorable data, with depth and extent proportionate and appropriate to the device characteristics, including risks, risk class, performance, and intended purpose.

Scientific Validity refers to the association of an analyte with a clinical condition or physiological state. Manufacturers must justify the scientific basis for using specific analytes, markers, or targets through literature review, clinical performance studies, or proof-of-concept studies. This requires demonstrating that the analyte measured by the device has a valid relationship with the clinical condition being diagnosed or monitored.

Analytical Performance refers to the ability of the device to correctly detect or measure a particular analyte. Manufacturers must demonstrate analytical performance characteristics as specified in Section 9.1(a) of IVDR Annex I, including accuracy (trueness and precision), analytical sensitivity and specificity, measurement range, linearity, repeatability and reproducibility, detection and quantification limits, analytical specificity including interfering substances and cross-reactivity, measuring interval, and stability of reagents and specimen stability. For novel markers without certified reference materials or reference measurement procedures, alternative approaches such as comparison to well-documented methods or composite reference standards may be used if appropriately justified. The analytical performance must be documented in an Analytical Performance Report.

Clinical Performance, as defined in IVDR Article 2(41), refers to the ability of a device to yield results that are correlated with a particular clinical condition or a physiological or pathological process or state in accordance with the target population and intended user. Clinical performance must be demonstrated in relation to parameters described in Section 9.1(b) of IVDR Annex I unless omission can be justified as not applicable. This includes diagnostic sensitivity and specificity, positive predictive value and negative predictive value, likelihood ratios, and expected values in normal and affected populations. Clinical performance demonstration may be based on clinical performance studies, published scientific literature, or documented routine diagnostic practice experience. According to IVDR Article 56(4) and recent guidance MDCG 2022-2 and MDCG 2025-5, clinical performance studies should be performed unless there is due justification for relying on other sources of clinical performance data. The clinical performance must be documented in a Clinical Performance Report.

The performance evaluation process results in a Performance Evaluation Report (PER), which must include the Scientific Validity Report, Analytical Performance Report, Clinical Performance Report, and an assessment demonstrating the clinical evidence. This PER is a central component of the technical documentation and must be kept updated throughout the device lifecycle through implementation of the Post-Market Performance Follow-up (PMPF) plan in accordance with IVDR Annex XIII Part B and the post-market surveillance plan.

As of the May 26, 2025 deadline, all IVD manufacturers must have implemented an IVDR-compliant Quality Management System. For Class D legacy devices, the Performance Evaluation Report and Post-Market Surveillance Plan must have been submitted by this date. With the publication of Regulation (EU) 2024/1860 in July 2024, extended transition timelines are provided for certain device classes, but these extensions are subject to specific conditions including no significant design changes and continued compliance with safety requirements.

Recent guidance MDCG 2025-5 “Questions & Answers regarding performance studies of in vitro diagnostic medical devices” published in 2025 provides comprehensive clarification on performance studies under IVDR Articles 57 to 77. This guidance defines performance studies as studies undertaken to establish or confirm the analytical or clinical performance of an IVD device, distinguishing between analytical performance studies (focusing on the ability to detect or measure a particular analyte) and clinical performance studies (establishing or confirming the ability to yield clinically relevant results). The guidance includes a decision tree for determining the appropriate regulatory pathway for performance studies and clarifies when studies require application or notification to competent authorities. It emphasizes that performance studies must comply with General Safety and Performance Requirements (GSPR) and that real-world evidence is increasingly important for demonstrating clinical performance.

Regulatory Framework and Requirements

These evaluation requirements constitute an important part of the medical device design and development process, ensuring that the safety and effectiveness or performance of products is appropriately demonstrated before they are introduced to the market. Regulatory authorities review these evaluation data and use them as a basis for approval or certification decisions.

Additionally, the stringency of required evaluation varies by risk class, with higher-risk medical devices requiring more comprehensive and rigorous evaluation. For example, high-risk devices such as Japan’s Class III and IV, the United States’ Class III, and the EU’s Class IIb and III require submission of more extensive clinical data and detailed evaluation reports.

Regulatory authorities in each country and region—such as Japan’s Pharmaceuticals and Medical Devices Agency (PMDA), the United States Food and Drug Administration (FDA), and the European Union’s Notified Bodies—define these evaluation requirements based on their respective regulatory frameworks. While international harmonization efforts through the International Medical Device Regulators Forum (IMDRF) are gradually aligning regulations across countries, region-specific requirements still exist.

The IMDRF has published several key documents that support global harmonization of clinical evaluation approaches. The Essential Principles of Safety and Performance of Medical Devices (IMDRF/GRRP WG/N47 FINAL:2024, Edition 2, published April 2024) provides fundamental principles applicable to all medical devices and IVD medical devices, including requirements for clinical evaluation. For Software as a Medical Device (SaMD), the IMDRF guidance “Software as a Medical Device (SaMD): Clinical Evaluation” (IMDRF/SaMD WG/N41 FINAL:2017) establishes a three-pillar framework consisting of: (1) Valid Clinical Association, (2) Analytical/Technical Validation, and (3) Clinical Validation. This framework has been adopted by the FDA and other regulatory authorities and emphasizes that clinical validation is necessary for any SaMD, with the level of evaluation and importance of independent review commensurate with the risk posed by the device.

Strategic Approach for Manufacturers

Medical device manufacturers must understand the applicable evaluation requirements from the early stages of design and development and systematically collect the necessary data. This includes proper implementation of design controls, development of clinical development plans, and establishment of evaluation criteria.

Furthermore, it is effective to utilize early consultations with regulatory authorities (such as PMDA’s pre-consultation services in Japan, FDA’s Pre-submission Meetings in the United States, and the Scientific Advice Procedure under EU MDR/IVDR) to verify the validity of the evaluation approach in advance. Such strategic approaches enable efficient development processes and smooth approval processes, making it possible to deliver innovative medical devices to patients more quickly.

For manufacturers planning clinical investigations or performance studies in the EU, it is important to understand the regulatory pathways outlined in the recent guidance documents. The MDCG 2024-3 guidance emphasizes that the Clinical Investigation Plan (CIP) must align with the device lifecycle and technical documentation, particularly the clinical evaluation process. Manufacturers should consider which General Safety and Performance Requirements (GSPRs) require clinical data support (at minimum GSPRs 1, 6, and 8) and ensure that device identification and intended purpose in the CIP align with future labeling. For IVD manufacturers, the MDCG 2025-5 guidance provides a comprehensive decision tree for determining whether performance studies require application, notification, or fall under other regulatory pathways, helping sponsors navigate the complex regulatory landscape.

The key to successful regulatory compliance is early and continuous engagement with the evaluation process, understanding that clinical evaluation and performance evaluation are not one-time activities but ongoing processes that must be maintained throughout the entire product lifecycle from pre-market development through post-market surveillance and continuous improvement.

Summary Table: Comparison of Clinical Evaluation and Performance Evaluation

Aspect	Clinical Evaluation (General Medical Devices)	Performance Evaluation (IVD Medical Devices)
Applicable Products	Non-IVD medical devices used directly on patients	In vitro diagnostic medical devices analyzing specimens
Primary Purpose	Demonstrate safety and effectiveness in clinical use	Demonstrate analytical and clinical performance of diagnostic capability
Key Components	Clinical trial data, literature review, equivalence demonstration	Scientific validity, analytical performance, clinical performance
Regulatory Basis (EU)	MDR (EU) 2017/745, Annex XIV, Article 61	IVDR (EU) 2017/746, Annex XIII, Article 56
Key Standards	ISO 14155:2020+A11:2024 (clinical investigations)	ISO 20916:2019 (clinical performance studies for IVDs)
Recent Guidance	MDCG 2024-3 (CIP), MDCG 2024-5 (Investigator’s Brochure), MDCG 2020-5 (Equivalence), MDCG 2020-13 (Clinical Evaluation Assessment)	MDCG 2022-2 (General principles of clinical evidence for IVDs), MDCG 2025-5 (Q&A on performance studies)
Evaluation Report	Clinical Evaluation Report (CER)	Performance Evaluation Report (PER) including Scientific Validity Report, Analytical Performance Report, Clinical Performance Report
Post-Market Activity	Post-Market Clinical Follow-up (PMCF) under Article 74 MDR	Post-Market Performance Follow-up (PMPF) under Annex XIII Part B IVDR
Equivalence Requirements	Strict demonstration required for technical, biological, and clinical characteristics per MDCG 2020-5	Similar requirements for demonstrating equivalence, if applicable
High-Risk Device Requirements	More extensive clinical data, may require Clinical Evaluation Consultation Procedure (CECP) per Article 54 MDR	More comprehensive performance evaluation data, Class D devices had May 26, 2025 submission deadline
Continuous Process	Yes, updated throughout device lifecycle	Yes, continuous process by which data are assessed and analyzed

This table provides a clear comparison of the key differences and similarities between clinical evaluation for general medical devices and performance evaluation for IVD medical devices under current EU regulations.