Companion Diagnostic Studies Under IVDR: Regulatory Requirements, Study Design, and Clinical Evidence Generation

Clinical Performance Studies Building IVDR-Compliant Evidence for Companion Diagnostics

08 Jul, 2026

Regulatory Requirements, Study Design, and Clinical Evidence Generation Under Regulation (EU) 2017/746 (IVDR)

Introduction

Companion diagnostics (CDx) are in vitro diagnostic devices that provide information essential for the safe and effective use of a specific therapeutic product. As defined under Regulation (EU) 2017/746 (IVDR), these devices identify patients most likely to benefit from a treatment, exclude those at risk of adverse reactions, monitor therapeutic response, or support dose selection and treatment decisions.

Under IVDR, manufacturers of companion diagnostics classified as Class C devices are required to generate clinical evidence in accordance with Annex XIII. Where a Clinical Performance Study (CPS) is necessary, Annex XIV and Article 58 establish the applicable procedural requirements, including the need for a Performance Study Authorisation (PSA) or Performance Study Notification (PSN) prior to study initiation.

Regulatory Framework

IVDR Performance Evaluation Requirements (Annex XIII)

Annex XIII of IVDR requires manufacturers to establish clinical evidence through a performance evaluation covering three interdependent domains:

Scientific validity: demonstrating the association between the biomarker and the targeted clinical condition or therapeutic response.

Analytical performance: establishing that the device accurately and reliably measures the analyte of interest.

Clinical performance: confirming that the diagnostic result accurately predicts clinically meaningful outcomes in the intended patient population.

Figure 1: Three Pillars of CDx Clinical Evidence under IVDR Annex XIII

IVDR Annex XIII – Performance Evaluation Framework Regulation (EU) 2017/746
▼
Scientific Validity	Analytical Performance	Clinical Performance
Biomarker–disease association Biological rationale	Accuracy \| Precision Sensitivity \| Specificity LOD \| Cut-off	CPS under Annex XIV Patient outcome prediction
▼
Conformity Assessment & CE Marking

Table 1: Key IVDR Provisions Governing Companion Diagnostic Studies

IVDR Reference	Subject	Requirement
Annex XIII	Performance Evaluation	Establishes requirements for scientific validity, analytical performance, and clinical performance.
Annex XIV	Performance Studies	Defines requirements for generating clinical evidence through Performance Studies.
Article 58	PSA / PSN	Sets out authorisation and notification requirements for Performance Studies.
Article 10	Obligations of Manufacturers	Manufacturers must establish, implement, and maintain a quality management system.
Article 66	Good Study Practice	Performance studies must be conducted in accordance with applicable Good Study Practice.

Performance Study Classification: PSA and PSN (Article 58)

Article 58 of IVDR distinguishes between two procedural pathways for Performance Studies based on the nature of the study and the risk introduced to participants:

Table 2: Performance Study Authorisation (PSA) vs Performance Study Notification (PSN)

Criterion	PSA	PSN
Applicable Study Type	Interventional; studies influencing patient management or introducing additional risk.	Non-interventional studies meeting specific IVDR criteria.
Regulatory Approval	Competent authority approval required before study initiation.	Notification to competent authority; prior approval not required.
Ethics Review	Required	Required
Risk Basis	Higher – additional procedures or risk introduced.	Lower – no additional burden or risk to participants.
Key IVDR Reference	Article 58(1)	Article 58(2)

Figure 2: PSA vs PSN Decision Pathway (IVDR Article 58)

CDx Clinical Performance Study Planner

▼

Is the study interventional?
Does it influence patient management or involve additional procedures/risks?

▼

YES → Performance Study Authorisation (PSA) Required

PSA

Competent authority approval required before initiation.

NO → Evaluate for Performance Study Notification (PSN)

PSN

Notification to competent authority; non-interventional criteria apply.

Designing a Companion Diagnostic Clinical Performance Study

Intended Purpose and Endpoint Alignment

IVDR Annex XIV requires that a Performance Study be designed to confirm that the device meets the performance claimed in the intended purpose. The intended purpose must specify the target population, intended clinical setting, sample type, intended users, and the clinical decision the device supports. Every study endpoint should directly substantiate the intended clinical claim stated in the device labelling.

Analytical Cut-Off Validation

For companion diagnostics, the analytical cut-off determines patient classification and subsequent treatment decisions. IVDR Annex XIII requires that cut-off justification be documented as part of the performance evaluation, addressing the clinical rationale, the sensitivity and specificity trade-offs, and the impact on patient outcomes. Regulators assess whether inappropriate thresholds could expose patients to ineffective therapies or unnecessary adverse reactions.

Statistical Planning

ISO 20916:2024, referenced under IVDR Article 66, requires that Performance Studies be conducted under Good Study Practice principles. Statistical planning must include power calculations, disease prevalence estimates, expected effect sizes, and pre-defined acceptance criteria aligned with the device’s performance claims. A Statistical Analysis Plan should be established prior to data collection.

Sponsor Responsibilities

Under IVDR Annex XIV and Article 58, the sponsor retains ultimate responsibility for the conduct and compliance of a Performance Study, even where activities are delegated to contract research organisations or clinical sites.

Table 3: Sponsor Responsibilities in CDx Clinical Performance Studies

Responsibility Area	Key Activities	Regulatory Basis
Study Governance	Appropriate study design, regulatory compliance, resource allocation, and quality oversight.	IVDR Annex XIV; Article 58
Regulatory Submissions	PSA/PSN applications, ethics submissions, competent authority interactions.	IVDR Article 58; Article 66
Safety Oversight	Adverse event collection, SAE reporting, device deficiency investigations.	IVDR Article 64; Article 65
Data Integrity	Data traceability, audit readiness, documentation control, QA systems.	IVDR Annex XIV; ISO 20916:2024
Specimen Management	Collection, transport, storage, chain of custody, testing procedures.	ISO 20916:2024

Safety Reporting Obligations

IVDR Articles 64 and 65 establish specific reporting obligations for Performance Studies. Sponsors must report serious adverse events and device deficiencies that could have led to serious adverse events to the relevant competent authority without undue delay. Investigator sites must be trained on adverse event classification, serious adverse event escalation, and device deficiency reporting procedures, as required under ISO 20916:2024.

Drug-Diagnostic Co-Development

When a companion diagnostic is developed alongside a therapeutic product, two separate regulatory frameworks may apply concurrently: the Clinical Trials Regulation (EU) No 536/2014 (CTR) for the therapeutic investigation, and IVDR for the diagnostic performance study. Development teams must align study timelines, biomarker strategies, clinical endpoints, and regulatory submissions to ensure that clinical evidence generated supports both diagnostic approval and the therapeutic product labelling, as required by both frameworks.

MDCG guidance on performance studies under IVDR further underlines the importance of coordinating the intended purpose of the diagnostic with the clinical claims made for the therapeutic, to avoid inconsistencies during conformity assessment review.

Good Study Practice: ISO 20916:2024

IVDR Article 66 requires that Performance Studies be conducted in accordance with Good Study Practice. ISO 20916:2024 (Clinical Performance Studies of In Vitro Diagnostic Medical Devices — Good Study Practice) provides the applicable standards covering:

Study planning and protocol development
Specimen collection, transport, storage, and chain of custody
Data management and traceability
Monitoring, auditing, and quality oversight
Adverse event and device deficiency reporting

Risk-based monitoring approaches are recognised under ISO 20916:2024 and allow sponsors to direct oversight resources toward critical study processes and higher-risk sites.

What Celegence Can Offer

Successfully planning and executing Companion Diagnostic (CDx) and IVD Clinical Performance Studies requires expertise in regulatory strategy, clinical evidence generation, performance evaluation, and study execution.

Our team of regulatory, clinical, and scientific experts can support your organization throughout the entire product lifecycle, from Performance Study Authorisation (PSA) submissions to clinical performance study management, IVDR compliance, and CE marking readiness.

Whether you need end-to-end project support or additional expertise to strengthen your internal teams, we can help navigate complex regulatory requirements, optimize clinical evidence strategies, and streamline interactions with ethics committees, competent authorities, and notified bodies.

Contact us to learn how we can support your Companion Diagnostic and IVD development programs and help accelerate regulatory success.

Email:
info@celegence.com

References

The following references are issued by regulatory authorities or international standards bodies:

Regulation (EU) 2017/746.
IVDR Article 58 – Additional requirements for certain performance studies.
IVDR Article 64 – Performance studies in emergency situations.
IVDR Article 65 – Damage compensation.
IVDR Article 66 – Application for performance studies.
IVDR Article 10 – General obligations of manufacturers.
MDCG Guidance – MDCG 2025-5, MDCG 2024-4, MDCG 2022-9.
ISO 20916:2024 – In vitro diagnostic medical devices: Clinical performance studies using specimens from human subjects — Good Study Practice.
Regulation (EU) No 536/2014 (Clinical Trials Regulation, CTR).

AUTHORED BY

Associate Manager/SME, Medical Device Services & IVD

Prasad Ravichandran

Prasad Ravichandran is an experienced regulatory affairs professional with expertise in medical and in-vitro diagnostic devices. An IRCA-certified lead auditor for ISO 13485:2016, he has over 10 years of experience in regulatory compliance, quality management, and clinical trial submissions. At Celegence, he leads regulatory compliance initiatives, ensuring EU MDR and IVDR adherence while managing technical documentation, risk assessments, and post-market surveillance. His strategic approach and in-depth regulatory knowledge support seamless compliance for medical device manufacturers.

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