Feasibility of Synthetic Materials as Primary Standards

1. Feasibility of Synthetic Materials as Primary Standards John Saldanha Medical and Scientific Affairs, Roche Molecular Systems, Pleasanton, CA, USA SoGAT XVIII, FDA, NIH Campus, Bethesda, MD, USA 24-25 May, 2005

2. YES! BUT NOT YET

3. Biological vs Synthetic Standards ParameterBiologicalSynthetic Actual agent determined/quantitated by assays √ X Matrix similar to matrix of specimen √ X Contains all sequences recognised by probes in all different assays √ X Different assays yield similar results √ ? Long term stability √ √

4. Biological vs Synthetic Standards ParameterBiologicalSynthetic Homogenous material with little inherent variability X √ Well-characterised material X √ Abundant source material X √ Consistency between replacement lots X √ Ease of calibration of subsequent replacement standards X √

5. Historical Results for the First WHO HCV International Standard ndu/ml ge/ml 1st IS Study (1997) 5.01(25)5.82(8) WR Calibration (1999) 5.26(18)5.70(3) Genotypes Study (2000) 4.92(22)5.78(1) ndu : NAT detectable units from qualitative assays ge : Genome equivalents from qualitative assays

6. Major Concerns • Establishment of replacement International Standards • WHO collaborative study to establish standard includes all laboratories → bias, inconsistent quantitation • Stringent requirements by regulatory authorities regarding assay performance necessitates accurate calibration of replacement standard with regard to previous standards

7. Establishment of the Second WHO HCV International Standard, 96/798

8. Discussion Points • Commutability with previous IS essential to prevent ‘drift’ in IU • Variation in assay results ~ log10 0.5-0.6 • Limited study using proficient laboratories to establish replacement standards • Feasibility of using synthetic materials as calibrators • Establishment of SI standard which will include reference material, reference method and reference laboratory