Approval Criteria for Assays for Testing Blood Donors for

West Nile Virus

Robin Biswas, M.D.CBER, FDA

Blood Products Advisory Committee MeetingMarch 13, 2003

Regulatory Pathway for Assays Used to Test Donors for West Nile Virus (WNV)

Tests used in the manufacture of blood and blood components are reviewed as biologic products under the PHS Act

Investigational New Drug (IND) Application

Biological License Application (BLA)

Assays Used to Test Blood Donors:Things to Consider

• Clinical Sensitivity• Clinical Specificity• Analytical Sensitivity • Analytical Specificity• Chemistry, Manufacturing and Controls• Reproducibility, Proficiency• Stability• Instrument, Software

Clinical Sensitivity

Reactivity of assay in individuals with WNV infection:

- test samples from persons with clinical

WNV infection

- test samples in epidemic WNV regions(?)

Analytical Sensitivity

Reactivity of assay in samples containing analyte of interest, e.g., WNV RNA:

- test serial dilutions of samples with

WNV.

- test serial bleeds from individuals with

WNV: closely spread in time

Analytical Sensitivity, contd.

• Viral load in samples associated with transmission = ~ 3 to 5 x103 copies /mL.

Current thinking Sensitivity of NAT should be targeted at < 100

copies/mL in the individual donation, to ensure 100% detection of 1000 copies/mL in the individual donation.

As data is gathered and technology improves this target might change.

Clinical Specificity

Reactivity of assay in individuals without WNV infection:

- test healthy individuals, e.g., blood donors, in winter, in non-epidemic regions.

- test individuals with other diseases ( including, if possible, those with infections

caused by related viruses, e.g., St. Louis encephalitis, Japanese encephalitis, Murray Valley encephalitis, Dengue)

Clinical Specificity, contd.

• Assay should be tested in the end-user setting with a U.S. donor population.

• In geographically separated donor sites.

• At least 3 lots of the assay.

• Confirmatory/Additional Testing Issue

Analytical Specificity

• Reactivity of assay with samples not containing analyte of interest (overlaps with clinical specificity):

- test samples with potentially interfering substances, e.g., high levels bilirubin, hemoglobin (hemolysed samples), lipids, etc.

Chemistry, Manufacturing and Controls

• Manufacturing controls required to assure lot-to-lot consistency of assay reagents:– Standards with varying degrees of

reactivity. – Endpoint titration curves from testing of

the final product should have slopes and midpoints that fall within validated acceptable limits.

Assay stability

• Studies on at least 3 lots to demonstrate stability claims:

For what time period, under what conditions?

Reproducibility, Proficiency

• A panel of plasma/sera composed of positive, negative and weakly reactive sera should be tested in at least 3 sites with different operators with at least 3 lots of the assay.

• Each study site should demonstrate proficiency with this panel before screening donors.

Instrument, Software

• The instrument and software portion of the application should be included in the BLA.

• If approved/cleared for another use, submit

data demonstrating it meets the new intended use

• Refer to the CDRH Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices

Additional Guidance Documents

• Guidance for Industry In the Manufacture and Clinical Evaluation of In Vitro Tests to Detect Nucleic Acid Sequences of Human Immunodeficiency Viruses, Types 1 and 2, December 14, 1999.

Considerations in this document may be applicable to other gene based tests for transfusion transmitted viruses.

Additional Guidance Documents, contd.

• Draft Points to Consider in the Manufacture and Clinical Evaluation of In Vitro Tests to Detect Antibodies to the Human Immunodeficiency Virus Type 1, August 8, 1989.

General guide to QC procedures.

The Way Forward

• FDA will continue to work together with NIH and CDC, other components of DHHS, manufacturers and blood organizations to facilitate assay development

• If necessary FDA would allow widespread study of appropriate tests under IND

• Sponsors are asked to seek FDA’s guidance and to submit a pre-proposal before initiating studies to support an IND or BLA