SAGE IVD recommended listing the parathyroid hormone (PTH) test category in EDL 4
• as a disease-specific IVD for use in clinical laboratories (EDL 4, Section II.b);
• using an immunoassay format;
• using plasma and serum as specimen types;
• to aid in the evaluation of the causes of calcium homeostasis disorders and monitor the effects of treatment. SAGE IVD also recommended adding a footnote to the test category stating that the test is approved for both the second-generation (intact) and third-generation (bioactive or bio-intact) forms of PTH.

SAGE IVD agreed that PTH is an important test that needs to be available. However, it is expensive (a single test may cost US$ 20 to US$ 25) and as such should only be included in reference laboratories for second-level evaluation of changes in calcium or phosphorus, including kidney failure. The group also noted that there are different generations of tests, but that the application did not provide a good sense for how to use the second- and third-generation tests. Members of the group noted that generation (active, bioactive and so forth) probably matters more for procurement decisions made at the country or laboratory manager level. One SAGE IVD member pointed out that earlier- generation diagnostics are generally offered to countries in low-income settings, and that clarifying the generational differences enables countries to make better decisions. After discussion, the experts agreed to add a footnote specifying that the test is approved for both the second-generation (intact) and third-generation (bioactive or bio-intact) forms of the assay. Literature cited in the discussion: Smit MA, van Kinschot CM, van der Linden J, van Noord C, Kos S. Clinical guidelines and PTH measurement: does assay generation matter: Endocrine Rev. 2019;40(6):1468–80 (https://academic.oup.com/edrv/article/40/6/1468/5487988, accessed 14 December 2022).

The role between PTH assays differs, and for that reason the needed accuracy and clinical impact will differ. Therefore, it is difficult to know which test is being appraised in the context of this application (second generation or third generation). Clinical guidelines agreed upon testing for PTH for several indications, so for that reason PTH assays will have a positive impact on health in LMICs. Systematic review of the role of PTH for several indications and the potential clinical impact are given. However, systematic reviews on the accuracy of PTH testing are not given for each of the indications. In general: • First-generation assays are no longer in clinical use because of issues with clinical sensitivity and specificity due to cross-reactivity with inactive PTH fragments. • Challenges in determining the diagnostic accuracy include: (i) the lack of a reference method, (ii) the lack of standardization of the assays, (iii) on some occasions the lack of consistent reference range and (iv) stability problems/large intra-individual variation. How accurately can we assess the levels of PTH (with second- or third-generation assays) and for which indication does it matter the most? • For classic primary hyperparathyroidism (PHPT), the type of PTH assay used will not affect diagnosis or management because the precise concentration of PTH is less relevant. • In CKD, the guideline recommends treating secondary hyperparathyroidism above a twofold to ninefold PTH increase, which will result in different clinical decisions depending on the assay used. • For patients after bariatric surgery, guidelines state absolute cutoff values for PTH, but the impact of different-generation assays is unknown because direct comparison of PTH assays has never been performed. • During parathyroid surgery, PTH measurements with a third- generation assay reflect treatment success more rapidly than second- generation assays. Increased awareness among clinicians regarding the complexity of PTH measurements is warranted because it can affect clinical decisions. Diagnostic accuracy measures: • Regarding the utility of PTH levels in predicting temporary post- thyroidectomy hypocalcaemia for an absolute PTH threshold, the median accuracy, sensitivity and specificity were 86%, 85% and 86%, respectively. For a percentage change over time, the median accuracy, sensitivity and specificity were 89%, 88% and 90%, respectively (QUADAS-2: moderate to high quality). However, there was considerable selection bias among the studies. The studies included diverse populations. • Pooled sensitivity and specificity of selective parathyroid venous sampling (sPVS) in PHPT patients was 0.74 (95% CI: 0.70–0.77) and 0.41 (95% CI: 0.33–0.48), respectively. Summary performance estimates of positive likelihood ratio for sPVS was 1.55 (95% CI: 1.33–1.82) and for negative likelihood ratio was 0.47 (95% CI: 0.39–0.58). The area under the receiver operating characteristic curve was 0.684, indicating an average discriminatory ability of sPVS (QUADAS-2: moderate to high quality). Sensitivity issues: • Assay less sensitive at lower concentrations. • Percutaneous blood sampling for parathyroid gland localization showed poor sensitivity.

World Health Organization. (‎2023)‎. The selection and use of essential in vitro diagnostics: report of the fourth meeting of the WHO Strategic Advisory Group of Experts on In Vitro Diagnostics, 2022 (‎including the fourth WHO model list of essential in vitro diagnostics)‎. World Health Organization. https://iris.who.int/handle/10665/373322