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

YES! BUT NOT YET

Biological vs Synthetic Standards Parameter Biological Synthetic 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 √ √

Biological vs Synthetic Standards Parameter Biological Synthetic 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 √

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

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

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

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