NMPA published the Registration Technical Review General Guideline for Performance Evaluation of the Reagents Used for Tumor Related Genetic Mutation Test (high-throughput sequencing) on December 5th, 2019.
Please see the summary below:
The guideline is applicable for both new registration applications and modifications of related matters focusing on the detection of genetic mutations of clinical significance in somatic cell.
Areas exclude whole-exome testing, tumor whole genome sequencing, de novo sequencing, free DNA testing, direct RNA sequencing, pathogenic microorganism/metagenomics sequencing, pre-implantation testing, risk evaluation/prediction for certain diseases, direct-to-consumer sequencing, and healthy population screening.
The application materials for evaluation are divided into four categories which include overview, research materials for reagents and data, research materials related to the production process and reaction system, materials for analytical performance evaluation.
The overview should cover the intended use, product description, biosafety description, the summary and evaluation of studies, as well as the listing information of similar products available in the market etc.
The performance indicators and corresponding requirements should be determined in advance. If any test fails to meet the pre-defined standards, analysis and revalidation should be performed. The pre-defined parameters may be modified if necessary. All the research plan, study process, research data and the principle for each study should be kept in records.
The SOP document for the whole testing process should be provided and steps involved (sample collection/processing process, library construction, sequencing, data analysis, results report etc.) should be described.
This part of the guideline is mainly about the quality control and requirements on the reagents used for sample collection/processing, the reagents (dNTPs, enzymes, primers, linker etc.) involved for library construction and sequencing, bioinformatics analysis, database, and reference standards.
The reference standards are of significant importance to ensure the consistency of product performance as well as the traceability of test results. The detailed requirements for the positive/negative reference standards, positive/negative quality control materials, precision reference, and no template control are described in detail. The applicants need to validate the information (the source of internal positive/negative reference, the DNA sequence) and provide the corresponding materials for
registration.
NGS is a complex system which includes many individual steps. For each step, the applicant should set up the performance indicators and standards correspondingly. Every single step should be optimized separately, so that the best operating conditions can be determined. The data collected during the optimization process should be provided.
Analytical performance evaluation is adopted to determine whether the selection of raw material, the set value of parameters involved in the production process and reaction system are appropriate. This part of guideline is divided into two parts: the quality control requirements during the NGS testing process and the major performance indicators.
The quality control requirements for the whole NGS testing process including sample preparation, library preparation, sequencing and base reading, bioinformatics analysis, software study, the storage, transport and share of NGS data and application of public/internal database were all described in detail. All the key factors, such as instrument, software, consumables, reagents should be indicated clearly. The study plan and standards should be made, the data related to the development process should be kept in records. The limitation of testing key factors, such as coverage ratio, base quality in each step involved in the testing process should be documented. Moreover, possible situations which may affect the or limit the testing performance should be indicated in the product instruction and/or product label.
Analytical performance evaluation is to evaluate if the performance can meet the pre-defined standards and the requirements of the product’s intended use through pre-defined performance evaluation methods. The requirements for sample set up, evaluation standards for testing accuracy, limit of detection, limit of blank, analytical specificity, and precision, studies for discriminating somatic and germline mutations, and supplementary studies on bioinformatics analysis are described in detail.
After the launching of the product, through post market clinical data collection and analysis, or genes (can be clearly used for companion diagnostics) indicated in the drug IFU, applicant can apply for the modification of clinical application through collection of post market clinical efficacy data, as long as the original reaction system and testing methods etc. are not changed, which is promising to CDx manufactures.
Source from: “Summary of NMPA Tumor Mutation Reagents Guideline”China Med Device, LLC , 5 February 2020, https://chinameddevice.com/coronavirus-antigen-antibody-reagent/.
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