Update Rapid HIV Test Approval Requirements and Standards BPAC September 15, 2000 Kimber Poffenberger, Ph.D.

Rapid HIV Tests u The extended standards and revised requirements described today apply exclusively to rapid HIV tests intended for diagnosis. DO NOT apply to tests for blood screening.

Summary from June 15 BPAC u Discussion of public health needs u Manufacturers, CDC, and WRAIR presented performance data for some rapid tests. u FDA actions to facilitate approval of rapid HIV tests u Committee concurred with revised standards for rapid tests.

Sensitivity Standard, June 15 u 100% sensitivity on the FDA HIV-1 Panel (11 out of 11) u The lower bound for the 95% confidence interval must be at least 98% for all confirmed positive serum or plasma samples from: –positive individuals (n=1000), plus –positives from high-risk population study (n=500 individuals of unknown serostatus)

Specificity Standard, June 15 u The lower bound for the 95% confidence interval must be at least 98% for serum or plasma samples from individuals in low risk populations (n = 6,000)

Extending the Rapid HIV Test Standards u The 98% (LB of 95% CI) minimum acceptable performance standard for sensitivity and specificity is being extended to all sample types (i.e., venipuncture whole blood, fingerstick whole blood, oral fluid, as well as for serum and plasma).

Revising the Rapid HIV Test Trial Requirements u Requirements (historically based on blood screening intended uses) are being revised to reflect the distinctly different intended uses for the rapid tests. That is, a test that will primarily be used on fresh specimens, in populations with unknown HIV prevalence.

Revised HIV-1 Sensitivity Study Requirements u Previous –1,000 known positive samples (repository and/or fresh) »at least 200 AIDS u Revised –manufacturers may propose trial size of sufficient power –minimum of 500 fresh* samples of each specimen type »AIDS samples are not required, »recent seroconverters are desirable –*FDA strongly recommends 1,000 samples

HIV-1 Prospective Study (High Risk) Requirement u Previous –at least 500 fresh samples in sites of intended use in an HIV-1 endemic area u Revised –no change to trial requirements –negatives and confirmed positive samples from this trial contribute to determination of sensitivity and specificity

Revised HIV-1 Specificity Requirements u Previous –6,000 samples in a low risk population u Revised –manufacturers may propose trial size of sufficient power –minimum of 500* fresh samples from a low risk population for each specimen type –minimum of 500* fresh samples from a high risk population for each specimen type –*FDA strongly recommends 1,000 each

Revised Sensitivity and Specificity Studies u Manufacturer may choose study size, but: –absolute minimum of 500 fresh samples for each study –risk that study will not meet 98% standard is increased for smaller sample sizes (e.g., 500) (FDA recommends 1000) –if study fails, a second trial or an increased sample size with p-value correction would be necessary (Need statistically sound protocol before starting trial)

Other Revisions u Adding group O antigen to test is not required u Claim for HIV-2 is optional u Test performance with stored samples (if tested) will be listed separately in the labeling. Study should include a minimum of 500 samples.

Pre-Clinical HIV-1 Sensitivity Requirements u No change; manufacturer encouraged to use fresh specimens where feasible: 200 worldwide high risk (HIV-1 subtype) >10 seroconversion panels >10 HIV-1 dilution series 1-3 Low titer panels >10 group O samples

Pre-Clinical Specificity Requirements u No change; manufacturer encouraged to use fresh samples where feasible: > 200 samples from individuals with medical conditions (e.g., HCV, HBV) > 100 samples with interfering substances (e.g., abnormal bilirubin levels)

Sensitivity Requirements for HIV-2 (no change) u > 200 confirmed positive samples (repository and/or fresh) u > 500 freshly obtained, prospectively collected samples from a high risk population in an HIV-2 endemic area u > 10 Dilutional Series

For Approval of Rapid HIV Tests u Standards apply to all rapid tests. u Revised trial requirements apply to all manufacturers that have not completed their studies. u Manufacturers with completed studies that meet previous trial requirements may be labeled differently.

FDA Contacts u FDA has contacted all rapid test manufacturers with whom we have previously discussed clinical trial plans u Manufacturers/sponsors with questions or concerns should contact FDA to request a teleconference or meeting. u Division of Blood Applications (DBA) at