Analysis of FDA Guidance, Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components; Guidance for Industry – July 2018

Overview

The Food and Drug Administration’s (FDA) issued a final guidance, Revised Recommendations for Reducing the Risk of Zika Virus Transmission by Blood and Blood Components, for immediate implementation. The guidance supersedes the August 2016 ZIKV guidance requiring universal individual donor nucleic acid testing (ID NAT) for Zika virus (ZIKV). FDA’s August 2016 decision to name ZIKV as a relevant transfusion-transmitted infection (RTTI), for which testing is required under 21 CFR 610.40(a)(3), has not changed.

The guidance provides FDA’s revised recommendations permitting compliance with 21 CFR 610.40(a)(3), stating that:

1. You must test all donations collected in the U.S. and its territories:
   • With a licensed NAT for ZIKV, using either minipool nucleic acid testing (MP NAT) or ID NAT for screening.
   • Follow recommendations for use of ID NAT when local ZIKV transmission is possible based on:
     1. detection or notification of a ZIKV-reactive donation in a defined geographic collection area, or
     2. notification by CDC, or other public health authority, of areas at increased risk for ZIKV transmission. This applies even if you have not yet detected a ZIKV-reactive donation.
   
   OR
2. As an alternative, you must collect and prepare blood components using pathogen reduction technology with an FDA-approved pathogen reduction device. Based on currently approvals for pathogen reduction technology, this option is limited to use with platelets and plasma.
   
   The revised recommendations do not apply to the collection of Source Plasma because “Source Plasma is used for further manufacture of plasma-derived products. Viral inactivation and removal methods that are currently used to clear viruses in the manufacturing process for plasma-derived products are sufficient to reduce the risk of the transmission of ZIKV.”

Highlights of the Background Section

The Background Section tracks the progression from early cases to events in 2017, providing a comprehensive review of:

1. ZIKV Epidemiology and Clinical Features
   
2. ZIKV Epidemiology Since the 2016 Outbreaks in the U.S.
3. ZIKV Transfusion Transmission
4. FDA Policies to Address ZIKV Transfusion Risk in 2016
5. Blood Products Advisory Committee on ZIKV Blood Donor Screening Alternatives
6. Experience with ZIKV ID NAT Blood Donation Screening in the U.S.

The Background Section also describes the basis for FDA’s decision to name ZIKV as a RTTI and provides key information from US Blood centers that “implemented ID NAT under IND in phases in 2016, using the investigational cobas Zika (Roche Molecular Systems, Inc.) or the investigational Procleix Zika Virus Assay (Grifols Diagnostic Solutions, Inc.).”

Highlights of the Discussion Section

FDA describes their “Risk Assessment of MP NAT Strategy for ZIKV” following the November 2017 BPAC meeting. FDA defined the criteria that would trigger the conversion from MP NAT to ID NAT necessary to “safeguard against the current and future risk of ZIKV transmission through blood transfusion.” FDA used a computational model to simulate a “future outbreak and mathematically determined the likelihood of detecting or missing ZIKV-reactive donations by MP NAT compared to ID NAT.” The computational model, using data from 2016 outbreak in Puerto Rico, showed this MP NAT strategy would “adequately and appropriately detect early infections in an outbreak, while reducing the burden of ID NAT testing.”

FDA considers the “Public Health ZIKV Surveillance and Other Considerations” to be significant to identifying the first case of ZIKV infection before it is detected by testing in an “asymptomatic blood donor in the community.” FDA refers to the CDC’s Blood and Tissue webpage when speaking of the importance of the collaborative efforts of blood establishments, CDC, and state or local health departments to use blood donation screening, public health surveillance and other epidemiologic information to identify increased risk of ZIKV transmission.

FDA’s Revised Recommendations

Predonation Screening
Under Section III.B., FDA explains that the Director of the Center for Biologics Evaluation and Research is again providing an alternative procedure under the regulations at 21 CFR 640.120(b). This makes it possible for FDA to allow blood establishments to collect blood or blood components without first assessing donors for specific risk factors for ZIKV, as would be required by 21 CFR 630.10. This means FDA is not issuing recommendations for predonation assessment for risks related to possible exposure through travel or sexual contact. This decision is based on the use of “sensitive testing strategies” and other factors.

Donor Deferral, Counseling and Further Testing
Under section IV.C.3., FDA sets donor deferral for a reactive ID NAT at 120 days from the date of the reactive test or from the date of resolution of ZIKV symptoms, whichever timeframe is longer. FDA requires that you notify the donor of their deferral and recommends that you counsel the deferred donor about the possible medical significance of the results.

In section IV.4.C., FDA states that the responsible physician should consider further testing to provide more information on the donor’s infection, and as part of the epidemiological investigation. They suggest that testing on the index donation using the same or different FDA-licensed ZIKV NAT screening assay, an investigational ZIKV NAT test, or serological tests for ZIKV antibodies, may be of value in donor counseling.

Conversion to ZIKV ID NAT, Return to MP NAT, and Product Management
AABB has developed 3 flowcharts to reflect our understanding of the recommendations provided in Section IV. These flowcharts map a path to assist you in reviewing the guidance as you update your policies and procedures.

Refer to Flowchart 1 - Conversion to ZIKV ID NAT for use with Section IV.B: Recommendations Regarding Switch between MP NAT and ID NAT when Threshold Conditions to Trigger are Present:
If you perform MP NAT for ZIKV, FDA recommends that you convert from MP NAT to ID NAT when certain threshold conditions are present in a defined geographic collection area. This flowchart shows the criteria to trigger and the next steps.

Refer to Flowchart 2 - Return to ZIKV MP NAT for use with Section IV B: Recommendations Regarding Switch between MP NAT and ID NAT when Threshold Conditions to Trigger or Detrigger are Present:
Once triggered, FDA recommends that you continue ID NAT until defined conditions are present to resume MP NAT (i.e., detrigger). This flowchart shows defined criteria to detrigger and the next steps.

Refer to Flowchart 3 - Product Management for use with Sections III and IV.
If you perform screening using MP NAT, you may release all units from a non-reactive minipool. Refer this flowchart for inventory management decisions.

Important information from footnote 5 reminds you that you must not distribute a pathogen-reduced platelet or plasma product collected from an individual who tests ID NAT reactive for ZIKV, unless an exception exists (21 CFR 610.40(h)).

Labeling of Whole Blood and Blood Components Intended for Transfusion
Section IV.D. reminds blood establishments that regulations at 21 CFR 606.122(h) require that the circular of information “include the names and results of all tests performed when necessary for safe and effective use.” Refer to the Circular of Information webpage for more information on the required language when testing for ZIKV using an FDA licensed test. The following language, developed by AABB’s Circular of Information Task Force and accepted by FDA, must be added to the Circular until it can be incorporated in a future version: “A licensed nucleic acid test (NAT) for Zika Virus RNA has been performed and found to be nonreactive.” This is not a new requirement.

Implementation
Section V. addresses the reporting requirements for implementing the recommendations in this guidance. If the guidance is implemented without modification and in its entirety, the date of implementation for this minor change would be reported by licensed blood establishments in the annual report under 21 CFR 601.12(d), noting the change in method or process.

If implementing a modified MP NAT screening strategy that differs from the guidance, licensed blood establishments must submit this major change in a Prior Approval Supplement (PAS) under 21 CFR 601.12(b). Refer to Section V. of the guidance for a list of information that should be included in your supplement.

If you have questions, please contact us at regulatory@abb.org.