# Presentation: 644280

## Validation of Nucleic Acid and Serological Tests to Screen Blood and Plasma donors for Acute infection with West Nile virus

- <date/time>

**Validation of Nucleic Acid and Serological Tests to Screen Blood and Plasma donors for Acute infection with West Nile virus**

- Hira Nakhasi, Ph.D.
- Director, DETTD/OBRR
- CBER, FDA

## Issue

- <date/time>

**Issue**

**FDA seeks advice on:**
- The design of scientific studies needed to validate NAT and possibly IgM for WNV as blood donor screening tests
- Whether available data on clearance of viruses in the manufacture of plasma derivatives are sufficient basis to obviate screening of Source Plasma donations
- Whether Strategies to limit screening to particular locations and time are appropriate

## Background Information

- <date/time>

**Background Information**

- WNV is an enveloped single stranded RNA virus
- WNV is a mosquito-borne falvivirus
-  Primarily infects birds
- Occasionally infects humans and other animals
- About 80% of human infection is asymptomatic, and 20% develop mild febrile illness (flu-like illness)
- Approximately 1 in 150 infections results in meningitis or encephalitis
- Advanced age is by far the most significant risk factor for severe neurologic disease
- Viremic period can occur up to 2 weeks prior to symptoms and last up to a month from the initiation of the infection

## Background Information.......

- <date/time>

**Background Information.......**

- The 2002 US outbreak of WNV resulted in the identification of other modes of transmission including:
-  Blood transmission, Transplantation, Breast-feeding, Transplacental and Occupational by percutaneus injury
- The magnitude of the risk of WNV from transfusion is unknown.
- Virus titer in blood is low compared to other transmissible viruses (~1-5x103 copies/ml) and the viremia is transient.
- Viremia in encephalitis patients can be as high as 2.5x106 copies/ml
- Viremia resolves rapidly after seroconversion to IgM
- IgM can persist for a long time in some cases up to a year
- No chronic stage of WNV infection has been reported

## Current status of WNV pathogenicity and epidemiology in the US

- <date/time>

**Current status of WNV pathogenicity and epidemiology in the US**

- In year 2002 total number of WNV cases reported were 4008 out which 263 deaths and 2741 cases of WNME
- 39 states including DC is endemic for WNV
- Estimated risk of 1.8-2.7 infections per 10,000 donations nation wide but can be high in endemic regions (16/10,000 with a mean of 6-8/10,000)
- During Aug 28, 2002-Jan 3, 2003,  61 possible Transfusion-Transmitted cases reported
- 21 are confirmed from 14 blood donations
- 19 are not transfusion related,
-  21 are under investigation

## West Nile Virus and Blood Safety: FDA’s Actions to Date

- <date/time>

**Alert notices posted on FDA’s website: **
- _August 17, 2002_: Vigilance in excluding symptomatic donors urged prior to any actual report of transmission
- _October 3, 2002_: FDA states its interest in facilitating development of donor screening & supplemental tests
**Congressional hearings on September 10 & 24, and October 3, 2002**
**FDA issued a guidance on “ Current thinking on management of donors and products” **(www.fda.gov/cber/gdlns/wnvguid.htm), Oct. 2002
**Cooperation with CDC, State Public Health Departments, Blood Organizations and Health Resources and Services Administration (HRSA)**
- Epidemiological investigation of all possible cases of transfusion transmitted WNV
- Advice provided on deferral of donors and withdrawal of in-date products collected from suspect donors

## WNV workshop held in NOV ‘02

- <date/time>

**WNV workshop held in NOV ‘02**

- Following topics were discussed:
- Methodologies suitable for donor screening
- Proposed studies on prevalence in donors
- FDA and industry perspective on developing WNV assays
- Strategies aimed at inactivation of WNV in plasma derivatives
- Implementation issues
- Summarized at the December 2002, BPAC meeting

## Regulatory Pathways for Assay Development

- <date/time>

**Regulatory Pathways for Assay Development**

**Donor screening and supplemental tests will be reviewed as biologic products under the PHS Act**** **
- IND Applications are needed
- Biological License Applications for pre-market approval
**The instrument and software portion of the application requires a separate 510(k) submission.  (See: CDRH *****Guidance for the Content of Pre-market Submissions for Software Contained in Medical Devices*****.)**
- A licensed test used for screening blood donors has been determined to be a “major level of concern.”

## Regulatory Pathway for WNV Blood and Plasma Donor Testing

- <date/time>

**Regulatory Pathway for WNV Blood and Plasma Donor Testing**

- Approval Mechanism
- Clinical and analytical sensitivity, specificity
- CMC
- Reproducibility, Stability
- Instrumentation and software
- Clinical Study Design
- Validation of Clinical Sensitivity of NAT and IgM assays
- Validation of Clinical specificity of NAT and IgM assays
- Approaches for test validations in the absence of reference assays
- Reproducibility studies

## Regulatory Pathway for WNV Blood and Plasma Donor Testing...........

- <date/time>

**Regulatory Pathway for WNV Blood and Plasma Donor Testing...........**

- Unit and Donor Management
- Algorithms for identifying reactive samples
- Confirmation and follow up of reactive samples
- Guidance for donor deferral
-  Product quarantine
- Product retrieval

## CBER/FDA’s efforts towards the development of WNV screening tests

- <date/time>

**CBER/FDA’s efforts towards the development of WNV screening tests**

**Development of Reference Panels for lot release testing**
- Panels to be tested by several laboratories in a collaborative study
**Development of Qualification panel of well-characterized and pedigree specimens**
- Establish relative sensitivity of NAT and IgM assays
**Development of in-house TaqMan PCR and IgM test for WNV Using in-house primers **
- Distribution in the blood components
- Infectious dose
- Viral tropism

## Review of methodologies that are suitable for blood and Source Plasma  donor screening

- <date/time>

**Review of methodologies that are suitable for blood and Source Plasma  donor screening**

**Nucleic acid based tests (NAT):**
- Whole Blood
- Source Plasma
- Supplemental tests
**Serological (IgM assays):**
- Whole blood
- Source Plasma
- Supplemental tests

## Review of proposed studies on prevalence in donors

- <date/time>

**Review of proposed studies on prevalence in donors**

**Development of analytical sensitivity panels**
**Comparison of WNV RNA and IgM assays**
**Prevalence of viremia (viral load, IgM antibody, virus culture status) **
**Comparison of MP vs ID- NAT**
**Confirm donor viremia by IgM and RNA testing of donor follow up sample**
**Assess disease outcome in Viremic donations, routine “call back” information**
**Establish back ground community-acquired WNV exposure rates**
**WNV incidence and transfusion-transmission rates**
**Exposure rates in recipients by testing autologous donations for IgM reactivity**
**Status of proposed studies on prevalence in donors (presentation by CDC, REDS group and ARC)**

## Testing Source Plasma Donors and Clearance of WNV from Plasma-Derived products

- <date/time>

**Testing Source Plasma Donors and Clearance of WNV from Plasma-Derived products**

**Testing of Source Plasma donations**
- Identifying positive units
- Reduction of viral load in the manufacturing pool
**Inclusion of viral clearance (inactivation and /or removal) steps in the manufacturing processes**
- Product specific
- Process-specific
- Model viruses
- WNV specific

## Implementation of WNV donor test

- <date/time>

**Implementation of WNV donor test**

**Blood supply management and triggers for WNV testing in the event the test is not available at the time of epidemic**
**Other implementation issues for WNV testing:**
- Seasonal vs Year round
- Geographical vs National
- Need for testing related viruses
- ID NAT vs minipool NAT
- Past experiences from SLE epidemic

## Questions for the committee

- <date/time>

**Questions for the committee**

**Q.1 Please comment on  FDA’s proposed criteria for validation of WNV NAT and IgM assays for donor screening.**
**Q.2. Do the committee members agree that product and process-specific clearance of the WNV agent (as opposed only to marker viruses) should be demonstrated in order to adequately assure the safety of plasma derivatives?**
**Q.3. Do the committee members agree that screening of all plasma for fractionation for WNV would add a safety margin in the manufacture of plasma derivatives?**
**Please comment on the scientific validity of possible strategies to limit WNV screening to particular locations and times depending on epidemic surveillance information and test availability.**