In the field of In Vitro Diagnostics (IVD), product registration is not only an essential procedure for market access, but also a vital guarantee for product safety, effectiveness and compliance with clinical requirements. Characterized by unique clinical attributes, IVD products do not come into direct contact with the human body yet play indispensable roles in disease diagnosis, treatment monitoring and prognosis evaluation, and their accuracy and reliability directly affect patients’ clinical diagnosis and treatment decisions.
Currently, the review philosophy adopted by CMDE under NMPA for IVD products has shifted from conventional compliance verification to full-lifecycle risk management. Enterprises preparing IVD registration applications can hardly pass increasingly stringent reviews if they only satisfy superficial requirements including qualified performance data and complete document formatting. Only by establishing an integrated evidence chain covering analytical performance verification, clinical performance confirmation and quality management system can applicants meet the rigorous review standards set by regulatory assessors.
Full name of IVD is In Vitro Diagnostic, referring to in vitro diagnostic products (or in vitro diagnostic reagents). It covers reagents, instruments and systems that test human specimens such as blood, urine and tissues in vitro for disease diagnosis and health status assessment.
IVD products have diversified intended application scenarios with varying high, medium and low risk levels. Therefore, the core difficulty of IVD registration lies in accurate definition of product attributes at project initiation. The definition result directly determines subsequent classification administration, registration route and resource input; inaccurate definition may lead to massive rework or even registration failure.
From reviewers' perspective, intended use wording is the first reviewed content. Many manufacturers overstate intended use to expand market coverage with vague descriptions such as "for auxiliary diagnosis of various diseases", without specifying concrete clinical scenarios and target populations. Such ambiguous statements mislead subsequent verification planning.
Project teams shall finalize detailed intended use, detection principle and target users of IVD products in early phase. Random revision of above core information during development is prohibited, since relevant changes may alter product classification and registration route fundamentally and trigger full project restart.
Classification of IVD products defines the stringency of registration requirements. Classification shall not be judged empirically; teams must thoroughly study Classification Rules for In Vitro Diagnostic Reagents and relevant regulatory documents, and apply to NMPA for official classification definition when necessary. Wrong classification identified in late-stage development requires full reconstruction of verification system and results in severe waste of time and resources.
In line with current regulatory trends, review focus for IVD products has shifted from mere compliance of analytical performance indicators to systematic full-lifecycle risk assessment.
Reviewers prioritize stable and reliable performance under real clinical conditions rather than favorable test results obtained under ideal laboratory settings.
Sample representativeness: Many registration submissions adopt only healthy specimens or samples from a single source without adequate assessment across diverse populations (varying age, gender, disease status) and interfering substances (hemolysis, lipemia, icterus). Manufacturers shall provide verification data covering diversified real-world clinical specimen scenarios as required by regulators.
Relevance of performance indicators: Precision and accuracy data alone cannot substantiate clinical value. Regulators focus on the correlation between performance parameters and clinical decision-making, such as whether LoD (Limit of Detection) can identify the minimum clinically significant concentration and whether precision satisfies routine clinical monitoring demands. Only tests supporting clinical decisions deliver practical product value.
Clinical performance verification constitutes the core of IVD registration and remains a frequent trigger for supplementary data requests.
Importance of reference standard: Multiple manufacturers empirically select commercially available products with comparable performance as comparative methods while ignoring golden standards or clinical diagnostic criteria. Full justification for comparative methodology is mandatory during review, and sufficient scientific evidence shall be supplied if non-gold-standard methods are adopted.
Sample size and statistical methodology: Unsubstantiated sample size calculation and inappropriate statistical approaches are prevalent deficiencies. Reviewers require complete, well-documented sample size calculation derived from clinical requirements and statistical theories, alongside analytical methods tailored to product characteristics.
Modern regulatory reviews adopt a risk-based philosophy requiring manufacturers to establish robust risk management systems at early development stages.
Comprehensive risk identification: Risk scope covers technical risks (cross-reactivity, interfering substances), user-associated risks (operational complexity, result interpretation difficulty) and supply chain risks (stability of critical raw materials).
Traceable risk mitigation: A full closed-loop workflow shall be built covering risk identification, control measure formulation and effectiveness verification. Each identified risk shall be matched with corresponding control actions and supporting validation data for clear and efficient review assessment.
Complete quality management documents alone fail to satisfy current regulatory requirements; reviewers now attach greater importance to the practical implementation effectiveness of manufacturers' quality management systems.
The design and development of IVD products shall comply with the Requirements of Appendix for In Vitro Diagnostic Reagents to the Good Manufacturing Practice for Medical Devices. Key review focuses include:
Adequacy of design input: whether regulatory requirements, user needs and risk management outputs are fully covered.
Traceability of design transfer: whether the conversion from design output to production specifications is complete and accurate.
Distinction between design verification and design validation: these two concepts are frequently confused by manufacturers. Verification confirms compliance with design input specifications, while validation proves conformance to user needs and intended use; both items are indispensable.
Raw material management: strict control shall be imposed on supplier administration, quality specifications and test protocols for critical raw materials such as antibodies and enzymes. A common non-compliance observed during review is over-reliance on suppliers' COA (Certificate of Analysis) without in-house verification data. Applicants shall implement full-process strict control over raw materials with sufficient supporting evidence to guarantee consistent quality.
Adequacy of process validation: sufficient process validation data demonstrating batch-to-batch consistency is mandatory especially for products susceptible to inter-batch variation. Stable and consistent product quality is a core assessment criterion for reviewers.
The following deficiencies frequently occur during IVD registration review and shall be addressed by manufacturers at early project stage:
| Common Risk Items Prone to Supplementary Document Requests |
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Verification is merely performed under ideal laboratory conditions without consideration of complicated real clinical scenarios. Insufficient assessment is conducted regarding test interference from lipemic, hemolytic, icteric, hyperbilirubinemic and high-viscosity specimens, as well as common therapeutic drugs, anticoagulants including EDTA, heparin and sodium citrate, preservatives and specimen collection containers.Only stability data of finished products are submitted while specimen stability validation after collection, centrifugation, storage and transportation is omitted.Clinical evaluation specimens fail to achieve adequate representativeness, lacking diversified target populations of varying disease stages, age groups and ethnicities as well as interfering and borderline samples, which makes it impossible to verify product robustness around cutoff values.Statements specified on instructions and labels are inconsistent with validation data, e.g. claimed rapid detection duration or high sensitivity cannot be verified via analytical performance tests.Inadequate risk warnings are provided on labels and IFU with insufficient alerts and countermeasures for potential false-positive or false-negative results.Undefined screening criteria and quality control specifications for critical raw materials such as antigens, antibodies, primers and probes plus nonstandard change control bring risks of remarkable performance discrepancy across production batches. |
To ensure efficient technical review approval of IVD projects, enterprises are recommended to complete the following key preparations at the early project stage:
Regulation Priority: Before project initiation, assemble a professional team with regulatory specialists to comprehensively sort out applicable regulations, guiding principles and industry standards. Special attention shall be paid to the latest updates of review requirements, including the revised contents of the Guideline for Clinical Trials of In Vitro Diagnostic Reagents.
Evidence Chain Oriented Thinking: Take the establishment of a complete evidence chain as the core objective from the initial product development stage. The outputs of each development phase shall serve as the inputs of the subsequent phase, ultimately forming a systematic evidence system covering design and development, verification and validation, and clinical evaluation.
Professional Resource Integration: For complex products such as companion diagnostics and NGS detection reagents, introduce a multidisciplinary expert team including clinical experts, statisticians and regulatory experts at an early stage. Meanwhile, establish cooperation with professional CRO institutions to fully leverage their professional experience and resource networks.
Communication Mechanism: Build a regular communication mechanism with regulatory review authorities. For innovative products or technical issues with uncertain regulatory attribution, proactively apply for official communication and guidance to detour potential development deviations and avoid ineffective work.
From the perspective of review experts, a successful registration project is supported by a professional team that is well-versed in regulatory requirements, equipped with scientific thinking and rigorous in detail control. Enterprises shall involve professional registration teams in the early project stage and integrate regulatory compliance requirements into the whole process of product design and development. Cooperation with premium CRO institutions not only provides professional technical support, but also helps enterprises avoid common regulatory pitfalls and optimize application strategies based on rich review experience.
With in-depth industry insights and extensive practical experience in IVD reagent registration, Deda Medical delivers full-process professional services covering product classification determination, research protocol design, verification test implementation and registration dossier compilation. We are committed to helping enterprises build scientific and rigorous evidence systems to cope with stringent technical reviews, and ultimately provide safe and effective diagnostic solutions for clinical practice.
Against the backdrop of increasingly stringent supervision in the IVD industry, only scientific methodology, professional teams and systematic planning can support steady and long-term progress in registration and application. Partnering with professional institutions enables enterprises to transform document piling into standardized evidence construction. This not only guarantees registration success, but also constitutes an essential core competitiveness for enterprises.
