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

1
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

2
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

3
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

4
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

5
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

6
West Nile Virus and Blood Safety FDAs Actions
to Date

• Alert notices posted on FDAs 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

7
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

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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.

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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

10
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

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CBER/FDAs 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

12
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

13
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)

14
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

15
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

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Questions for the committee

• Q.1 Please comment on FDAs 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.