2023-07-14-世界卫生组织-WHO_BS_2023.2454_WHO_4th_International_Standards_for_TSH_human,_pituitary_33页_909kb

Summary of the 4th WHO International Standard for Thyroid-Stimulating Hormone (TSH), Human, Pituitary

Core Content

This document outlines the evaluation of a candidate replacement for the 3rd WHO International Standard for Thyroid-Stimulating Hormone (TSH), human, pituitary, coded 81/615. The study was conducted by the Expert Committee on Biological Standardization (ECBS) in collaboration with the UK Medicines and Healthcare Products Regulatory Agency (MHRA) National Institute for Biological Standards & Control (NIBSC) and the International Federation of Clinical Chemistry & Laboratory Medicine (IFCC) Committee for Standardisation of Thyroid Function Tests (C-STFT). The goal was to assess the suitability of the candidate preparation for use as the 4th WHO International Standard (IS) for TSH immunoassays.

Main Objectives

The primary objectives of the study were:

• To demonstrate the suitability of the candidate IS, 81/615, for calibration of TSH immunoassays.
• To value-assign the TSH content of the candidate IS relative to the current IS, 81/565.
• To assess the commutability of the candidate and current IS with patient serum samples.
• To predict the long-term stability of the candidate IS through an accelerated thermal degradation (ATD) study.

Key Findings

Value Assignment

• The candidate IS, 81/615, was evaluated using 15 different immunoassay methods.
• The geometric mean TSH content was estimated at 11.7 mIU per ampoule.
• The results are consistent with previous studies, which had estimated the content at 11.5 mIU/ampoule and 11.3 mIU/L.
• The inter-lab geometric coefficient of variation (GCV) was 4.5%, indicating acceptable consistency across laboratories.

Commutability Assessment

• Both the candidate IS, 81/615, and the current IS, 81/565, were found to be non-commutable with patient samples in the majority of immunoassays.
• Bias values for estimates relative to the standards varied significantly, ranging from 78.4% to 124.4%, indicating poor commutability.
• Some laboratories showed consistent bias close to 100%, suggesting good commutability in those specific immunoassays.
• A significant slope in bias values was observed in certain laboratories, indicating variable commutability across TSH concentration ranges.
• The IFCC C-STFT panel was used to mitigate the non-commutability issue, leading to improved harmonisation of TSH measurements.

Stability Prediction

• An ATD study was conducted on 30 ampoules of the candidate IS, stored at elevated temperatures (+4°C, +20°C, +37°C, and +45°C) for 2.6 years.
• The results, combined with historical data, suggest that the candidate IS, 81/615, will have good long-term stability when stored at -20°C.

Participants

• 17 laboratories from 8 countries participated in the study.
• Each laboratory used their chosen immunoassay method for analysis.
• Two laboratories (Lab G and P) were excluded due to outlying results, likely due to issues with the ampoule integrity or measurement anomalies.

Materials and Methods

• Candidate IS, 81/615: Prepared from the same pituitary extract batch used for the 3rd IS, 81/565, and has the same formulation.
• Current IS, 81/565: Used as a reference for value assignment.
• IFCC C-STFT Panel: A set of approximately 100 human serum samples used for commutability assessment.
• Methods: All participants performed a single immunoassay with serial dilutions at six specified concentrations.
• Statistical Analysis: Parallel-line analysis with log transformation of assay response was used to estimate relative potency. The correlation coefficient (r) exceeded 0.99 and the 90% confidence interval for the slope ratio was within 0.90–1.11 for valid assays.

Conclusion

• The candidate IS, 81/615, has been shown to be suitable as a replacement for the 3rd WHO IS, 81/565.
• It is proposed that the candidate preparation be established as the 4th WHO International Standard for TSH, with an assigned content of 11.7 mIU per ampoule.
• The continued use of the IFCC C-STFT panel is recommended to ensure harmonisation of TSH measurements across different immunoassays, due to the non-commutability of the WHO standards.