Quantitative tumor marker testing reagents encompass a wide variety of products with numerous applications. The revised Guideline on Quantitative Tumor Marker Testing Reagents, released on January 3, 2024, serves as the primary technical reference for evaluating these products. This article elaborates on common areas of focus during technical evaluations, integrating the requirements from the guidelines with real-world examples from registration documentation.
Key Points in Registration Documents Format
The Announcement on Requirements for In Vitro Diagnostic Reagent Registration Documentation and Approval Certificate Format (No. 122) published in 2021 specifies requirements for signatures and notarization. It states:
- For domestic products, all registration documentation must bear the applicant’s official seal unless otherwise specified.
- For imported products, original documentation must be signed by the foreign applicant, and Chinese translations must be signed by the domestic agent. Any associated files, conformity declarations, instructions, and labels provided by foreign applicants must also include notarized documents issued by a notary organization in the applicant’s home country.
Compliance with these requirements is a critical point of attention during evaluations. Common issues include missing signatures on registration documentation or untranslated/notarized instructions and labels for imported products. Ensuring that documentation adheres to these formatting requirements is essential to avoid delays or rejections in the review process.
Focus Areas of Performance Research Data
- Accuracy
Accuracy, as described in the Guideline on Analytical Performance Evaluation of Quantitative In Vitro Diagnostic Reagents, refers to the degree of agreement between the average value from infinite repeated measurements and a reference value.
The revised tumor marker reagent guidelines (2023) outline three methods to evaluate accuracy:
- Using reference materials: This involves materials such as certified reference substances, recognized reference standards, or clinical samples calibrated using reference measurement procedures.
- Method comparison studies: These should include clinical samples covering the reagent’s measurement range and be compared against similar reagents or reference methods.
- Recovery experiments: These are suitable for reagents lacking reference materials, measurement procedures, or similar marketed reagents. However, this approach has significant limitations and is only applicable when pure substances matching the analyte are available.
A common pitfall is using calibration standards or non-standard materials for accuracy verification. Researchers must adopt suitable methods, adhering to established protocols, and submit complete supporting documentation to address any gaps.
- Analytical Specificity
Beyond routine requirements, analytical specificity must account for factors unique to the product. For example, reagents using biotin-streptavidin detection systems are vulnerable to interference from high biotin levels in blood samples, which may lead to inaccurate results. Developers must anticipate such risks during the design phase and implement measures to mitigate potential adverse effects.
- Reportable Range
The reportable range defines whether a reagent meets clinical requirements. For instance, alpha-fetoprotein (AFP) reagents intended for monitoring hepatocellular carcinoma treatment should encompass AFP levels observed in clinical samples, which can reach extremely high concentrations. Developers must ensure the reagent’s reportable range aligns with its intended use, covering critical medical decision levels and accurately detecting varying concentrations in clinical samples.
- Compatibility Across Instrument Models
When reagents are compatible with multiple instruments, registration documentation should reflect performance evaluations conducted on each device. While clinical evaluations may not always be necessary for all instruments, analytical performance must be rigorously assessed to ensure consistency across models, especially when differences in reaction systems could impact results.
Key Considerations for Clinical Evaluation Documentation
- Clinical Evaluation Approach
The primary consideration is selecting an appropriate evaluation method. For products listed in the Exemption Catalog for Clinical Trials of In Vitro Diagnostic Reagents, equivalence to cataloged products must be demonstrated to qualify for trial exemption. Otherwise, a full clinical trial is necessary. A common oversight involves neglecting to compare the intended use, as tumor marker reagents often have diverse applications, such as aiding diagnosis or monitoring treatment. Notably, current exemptions only cover reagents intended for treatment/efficacy monitoring.
- Comparator Selection
When selecting a comparator for clinical studies, it is advisable to use high-quality, locally approved products rather than inferior alternatives. Common errors include failing to use matched calibration and quality control materials for each reagent, employing incompatible instruments, or using expired samples. Avoiding such issues ensures accurate and reliable evaluation outcomes.
- Subject Enrollment and Sample Selection
Samples must correspond to the product’s intended population. For example, in evaluating total prostate-specific antigen (tPSA) reagents, including only benign prostate condition samples without malignant cases does not accurately reflect the intended use for monitoring malignant tumors. In such cases, additional malignant tumor samples must be included for re-evaluation.
For entirely novel products with no comparable market counterparts or exemptions, longitudinal clinical trials involving at least 100 subjects are required.
Other Considerations
Documentation must align with the findings of supporting studies and adhere to guidelines such as the Revised Principles for Writing Instructions for In Vitro Diagnostic Reagents. Quantitative test results should present precise numerical values reflecting actual accuracy levels without arbitrary modifications.
Conclusion
Quantitative tumor marker testing reagents are widely used in clinical settings, and ensuring their safety and efficacy remains a core focus of pre-market technical evaluations. This article highlights common concerns during registration and offers insights for industry professionals. If you have any questions on testing, clinical trials or regulatory submission, please email us at info@ChinaMedDevice.com.