In the review reports released in December 2025, eight out of ten pertained to IVD reagents, reflecting the continued advancement and regulatory scrutiny in fields such as immunology and molecular diagnostics. Ventana Medical Systems secured five product approvals, while Roche Diagnostics obtained three:
- Roche Diagnostics: Elecsys Total-Tau CST
- Roche Diagnostics: Elecsys β-Amyloid (1-42) CSF II
- Roche Diagnostics: Elecsys Phospho-Tau (181P) CSF
- Ventana Medical Systems: Anti-MLH1 (M1) Mouse Monoclonal Primary Antibody
- Ventana Medical Systems: Anti-MSH6 (SP93) Rabbit Monoclonal Primary Antibody
- Ventana Medical Systems: Anti-MSH2 (G219-1129) Mouse Monoclonal Primary Antibody
- Ventana Medical Systems: Anti-PMS2(A16-4) Mouse Monoclonal Primary Antibody
- Ventana Medical Systems: Anti-PMS2(A16-4) Mouse Monoclonal Primary Antibody
- Taizhou Dubomai: Disposable sterile urinary catheter
- Shengxiang Biotech: Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis Nucleic acid detection kit (fluorescent PCR method)
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Value of Review Reports
Published review reports like these offer valuable insights into the criteria and priorities of regulatory authorities during the evaluation process. For several years, we have monitored such reports and analyzed relevant ones to better understand regulatory expectations. This practice helps our clients align their development and submission strategies with NMPA requirements, thereby improving efficiency and likelihood of approval. As the NMPA continues to standardize and accelerate its review pathways—including priority and fast-track approvals—both domestic and international IVD manufacturers can benefit from leveraging specialized regulatory expertise and experience.
The NMPA’s review of IVD reagents follows a rigorous, structured framework emphasizing analytical robustness, clinical relevance, and patient safety. Non-clinical requirements focus on extensive performance characterization under varied conditions, while clinical requirements demand well-designed trials that validate the test’s accuracy and utility in the target population. For companion diagnostics, additional bridging or co-development studies linking the test to therapeutic outcomes are imperative.
Non-Clinical Considerations
1. Product Composition and Description
A clear and detailed description of the reagent’s components is fundamental. Each constituent—such as magnetic particles, antibodies, buffers, and preservatives—must be specified with concentrations, volumes, and functional roles. For example, Roche’s Phospho-Tau (181P) CSF kit meticulously lists the coated microparticles, biotinylated anti-pTau antibody, and ruthenium-labeled anti-Tau antibody, along with their respective buffers and preservatives. Similarly, Ventana’s antibody reagents define the antibody concentration, carrier protein, and preservative (e.g., ProClin 300). Any statement that components from different lots are not interchangeable must be clearly stated to prevent misuse.
2. Analytical Performance Evaluation
This is a core part of non-clinical validation and typically includes:
– Accuracy/Method Comparison: Studies comparing the new reagent with a predecessor or a validated reference method are required. Both Roche and Ventana conducted extensive method-comparison studies using over 100 samples, demonstrating high correlation (e.g., Pearson correlation of 0.999 for Roche, >98% overall agreement for Ventana).
– Precision: Repeatability, intermediate precision, and reproducibility must be assessed under defined conditions (within-run, between-day, between-lot, between-instrument, between-operator). Roche evaluated precision for the individual biomarker and the ratio (pTau/Abeta42). Ventana conducted comprehensive studies covering batch-to-batch, inter-instrument, inter-day, and inter-operator precision, with results showing near-perfect agreement (100% in many cases).
– Limit of Blank (LoB), Limit of Detection (LoD), and Limit of Quantification (LoQ): These are established following CLSI guidelines. Roche determined an LoB of 4 pg/mL, LoD of 8 pg/mL, and LoQ of 8 pg/mL. The LoQ is particularly important as it defines the lowest concentration measurable with acceptable precision (CV ≤20%).
– Analytical Specificity: Cross-reactivity and interference studies are mandatory. Roche tested structurally similar peptides (Tau(172-205) amid) and numerous endogenous substances (bilirubin, hemoglobin, lipids, etc.) and drugs (17 common and 15 special medications). Ventana verified specificity via Western blot and peptide inhibition assays. Interference from substances like biotin, rheumatoid factors, or high-dose biotin must be ruled out within claimed ranges.
– Hook Effect: The absence of a high-dose hook effect should be demonstrated up to a certain concentration (e.g., Roche showed no hook effect up to 300 pg/mL).
– Measuring Range: The linear range must be established and verified using serially diluted samples. Roche’s measuring range is 8–120 pg/mL.
3. Positive Cut-off Value (Threshold) Determination
For qualitative or semi-quantitative tests, the cut-off value must be clinically validated. Roche established its cut-off based on a bridging study comparing the pTau/Abeta42 ratio with amyloid PET results, using overseas data (277 samples) and verifying it in a Chinese population (60 samples). The final cut-offs were defined as 0.023 for pTau/Abeta42 and 0.28 for tTau/Abeta42.
Ventana’s cut-off for MMR protein expression (intact vs. deficient) was derived from drug clinical trial data, linking dMMR status to pembrolizumab response. The panel result is interpreted as dMMR if at least one of the four MMR proteins (MLH1, PMS2, MSH2, MSH6) shows loss of expression.
4. Stability Studies
Real-time, in-use, and transport stability must be demonstrated under recommended storage conditions. Roche confirmed a 24-month shelf life at 2–8°C, along with onboard stability (28 days) and opened-vial stability (8 weeks). Ventana similarly established 24-month stability at 2–8°C for MSH6 and 12 months for PMS2, with onboard stability of 8 days. Sample stability (e.g., CSF or FFPE sections) also needs to be documented—CSF samples, for instance, are stable for 8 weeks at –15 to –25°C, 14 days at 2–8°C, and 5 days at 20–25°C.
5. Reaction Principle and Protocol Optimization
The detection principle (e.g., electrochemiluminescence immunoassay for Roche, immunohistochemistry for Ventana) should be clearly explained. Steps such as incubation times, temperatures, washing, and signal detection must be optimized and fixed. Ventana specifically warns against deviations from the recommended antigen retrieval and incubation conditions, as these may lead to erroneous results.
6. Quality Control (QC) Procedures
Detailed QC measures are required, including the use of internal controls (e.g., normal adjacent tissue for IHC), external control materials, and negative control reagents. Ventana emphasizes the use of a negative control antibody slide for assessing background staining. Roche describes the use of preciControl materials and advises that QC rules should ensure system bias within ±10%, intermediate precision CV ≤10%, and total error within ±26.5%.
Clinical Considerations
1. Intended Use and Indications
The intended use must be precisely defined, including the specific biomarker, sample type (CSF, FFPE tissue, etc.), target population, and clinical context. Roche’s kit is intended for detecting phospho-tau-181 in CSF from adults ≥50 years with cognitive impairment, to be used in combination with Aβ1–42 results for an amyloid PET–consistent ratio.
Ventana’s antibodies are for detecting MMR proteins in FFPE tumor tissues, as part of a panel to identify dMMR patients eligible for pembrolizumab therapy—a clear companion diagnostic claim.
2. Clinical Performance Validation
Clinical trials must demonstrate that the test performs reliably in the intended population. Roche conducted a multi-center trial in 13 Chinese hospitals involving 245 subjects, comparing the pTau/Abeta42 ratio against amyloid PET as a reference. Results showed 97.39% sensitivity and 86.92% specificity.
Ventana performed trials across 5 Chinese centers with 1618 solid tumor samples, comparing its IHC results with already-marketed comparator antibodies. The agreement for MSH6 was >98.8% positive percent agreement (PPA) and >99.6% negative percent agreement (NPA). For the full MMR panel, PPA and NPA exceeded 99.7%.
3. Companion Diagnostic Validation
For tests claiming to guide therapy, robust evidence linking the test result to treatment response is required. Ventana conducted bridge studies using samples from the pivotal pembrolizumab trials (KEYNOTE-158, KEYNOTE-164). The panel showed 72.2% PPA and 98.5% NPA compared to the clinical trial assay (CTA). More importantly, in patients identified as dMMR by the Ventana panel, the objective response rate (ORR) to pembrolizumab was 40.3%, consistent with the original trial outcomes. An additional prospective cohort in KEYNOTE-158 (China cohort) showed an ORR of 66.7% in dMMR patients, further supporting the clinical utility.
Risk-Benefit Assessment
The reviewer must conclude that the product’s benefits outweigh its risks. Both companies provided risk analyses, identifying potential hazards (e.g., incorrect results due to interference, mishandling, or deviation from protocol) and implementing mitigations such as clear instructions, QC requirements, and warnings in the labeling. The benefit—enabling accurate diagnosis or identification of therapy-eligible patients—is deemed to justify the residual risks when the product is used as intended.
- Labeling and Instructions for Use (IFU)
The IFU must comprehensively cover all critical information: intended use, principle, components, storage, specimen handling, step-by-step procedure, QC, interpretation criteria, limitations, and performance data. Both Roche and Ventana provide extensive details, including analytical sensitivity, specificity, precision, and clinical performance. Limitations are explicitly stated—for example, Roche’s test is an adjunctive tool and not standalone for AD diagnosis; Ventana’s antibody is approved only for use on specific BenchMark instruments with specified detection kits.
- Post-Market Surveillance
Manufacturers must have systems to collect post-market data and report serious incidents. This indicates that any serious event related to the device should be reported to the manufacturer and the competent authority in the user’s country.
Common Themes and Regulatory Emphasis
– Thorough Verification in Chinese Populations: Even if overseas data exist, local clinical validation in Chinese patients is essential (as seen in Roche’s cut-off verification and Ventana’s multi-center trials).
– Comprehensive Interference Testing: A wide panel of potentially interfering substances, including endogenous compounds and common medications, should be tested.
– Precision Across Pre-Analytical Variables: Factors like sample collection tubes (e.g., only polypropylene for CSF), fixation time (6–72 hours for FFPE), section thickness, and slide aging can affect results and must be controlled and validated.
– Clear Definition of “Positive” and “Negative”: The criteria for result interpretation must be unambiguous, especially for IHC where patterns like focal, dot-like, or speckled staining can occur. Ventana provides detailed guidance on how to score these patterns.
– Instrument-Specific Claims: Reagents are often approved for use only on specified instrument platforms (e.g., cobas e 411/e 601 for Roche, BenchMark ULTRA/ULTRA PLUS for Ventana). Using them on other systems requires additional validation.
– Stability Claims Supported by Real-Time Data: Shelf life is granted based on real-time stability studies under recommended storage conditions, not just accelerated testing.