BPAC Meeting Summary – 11/30/17-12/01/17

The 116th meeting of the Blood Products Advisory Committee (the Committee) to the Food and Drug Administration (FDA) was convened in Silver Spring, Md., on Nov. 30-Dec. 1, 2017. On Nov. 30 the committee met in open session to discuss bacterial risk control strategies for blood collection establishments and transfusion. In the afternoon, the committee was seated as a device classification panel to discuss the appropriate classification of human leukocyte antigen (HLA), human platelet antigen (HPA) and human neutrophil antigen (HNA) devices.

On December 1, the committee again met in open session to discuss strategies to reduce the risk of Transfusion-Transmitted Zika virus (ZIKV). In the afternoon, an informational session on the Transfusion Transmissible Infections Monitoring System (TTIMS) was presented to the Committee. To close the day, the Committee heard an update of the April 6, 2017 public workshop on emerging tick-borne diseases and blood safety.

Day 1 Nov. 30, 2017 In Open Session

Topic I - Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion

Background

Bacterial contamination of platelets continues to be a public health concern despite current interventions. Extension of dating (duration of storage beyond 5 days) of otherwise suitable platelets depends on control of bacterial contamination. Under current regulations, platelets are tested at least one time for bacterial contamination, or treated with a device approved to reduce pathogens. In most cases, “primary testing” (bacterial culture) is performed prior to release of platelets by the collection establishment. However, FDA has considered whether to require additional “secondary testing” (bacterial culture or rapid detection assay) by the transfusion service at later times of storage. FDA currently permits extension of dating based on secondary testing with a rapid assay labeled as a “safety measure.”

The Committee was asked to consider whether specific strategies of later and larger volume sampling of platelets for culture (relative to current practices) can provide adequate assurance of bacterial safety of 5-day and 7-day stored platelets in the absence of secondary testing. The Committee was also asked whether secondary testing by culture on day 4 of storage is sufficient to assure bacterial safety of platelets stored for 7 days without further testing more proximate to the time of issuance. FDA sought advice from the Committee regarding whether the available scientific data support the adoption of certain newer strategies to a) control the risk of bacterial contamination in 5-day platelets; and b) to extend platelet dating beyond 5 days and up to 7 days.

The session began with an update on FDA’s current considerations given by Salim Haddad, MD, Office of Blood Research and Review (OBRR). Dr. Haddad described the background of platelet storage and control of bacterial risk, including FDA policy initiatives, current U.S. practices and proposed considerations to further reduce the risk of bacterial contamination.

Jennifer Scharpf, MPH, Associate Director for Policy and Communication, OBRR/FDA then presented a summary of comments submitted to the public docket in response to the March 2016 draft Guidance.

Ralph Vassallo, MD, Chief Medical & Scientific Officer, Blood Systems Inc. (BSI), described BSI’s experience in a presentation entitled “Platelet Bacterial Contamination Risk Mitigation-Another Successful Approach.” Key topics included BSI’s algorithm, surveillance study results, and strategies to enhance safety and availability.

Carl McDonald, PhD, MSc, BSc of the National Health Service Blood and Transplant, United Kingdom, gave an overview of his 2017 TRANSFUSION article describing the feasibility of implementing large-volume cultures of final platelet units in both aerobic and anaerobic bottles without adversely affecting platelet availability.

Stephen Field, MBChB, MA, MMed, FCPath (SA) of the Irish Blood Transfusion Service, outlined their 5-day and 7-day expiration strategy. The 7-day expiration involves a two-test strategy with the second bacterial test occurring on day 4.

An Open Public Hearing followed which included 11 speakers:

• Michael Jacobs, MD, PhD- Case Western
• Jessica Jacobson MD- AABB
• Peter Tomasulo, MD- bioMérieux
• Ana Rosatos- Terumo BCT
• Richard Benjamin MD, PhD, FRCPath- Cerus Corporation
• Arthur Bracey, MD- St Luke’s Health Center
• Sarah K. Harm MD- University of Vermont Medical Center
• Neil Krueger, PhD- Oxford Immunotec
• Louis Katz, MD- America’s Blood Centers
• Joe Sanders- Verax Biomedical
• Axel Stover, PhD- Fresenius Kabi USA

Questions for the Committee

1. Do the available data support 5-day storage of apheresis platelets without secondary testing if platelets are cultured no sooner than 24-36 hours post collection with a sample volume of at least 3.8% of the collection?*
        Vote: Yes=16, No=1, Abstentions=0


2. Do the available data support the following measures to extend dating to day 7?
   1. Culture of apheresis platelets sampled no sooner than 36-48 hours after collection using a test volume of at least 16mL per split without secondary testing.*
           Vote: Yes=17, No=0, Abstentions=0
   
   
   2. Repeat culture on Day 4 with a volume of 16 mL per component divided into an aerobic and anaerobic culture tube.*
           Vote: Yes=16, No=0, Abstentions=0 Note: one committee member had left the meeting
   
   
   
   
3. Should primary testing of platelets with large volumes include the use of both anaerobic and aerobic systems? **
        Vote: Yes=17, No=0, Abstentions=0

* question revised during the session at the request of BPAC and FDA
** question added at the request of BPAC and FDA

Topic II - Classification of Human Leukocyte Antigen, Human Platelet Antigen and Human Neutrophil Antigen Devices

Background

In the afternoon, the Committee was seated as a device classification panel. In open session, the panel discussed the appropriate device classification of human leukocyte antigen, human platelet antigen and human neutrophil antigen devices that are intended for introduction into interstate commerce in the United States and are used to aid donor and recipient matching in transfusion or transplantation, or to aid in disease diagnosis.

The first presenter was Jennifer Lathrop, PhD, Scientific Reviewer, OBRR/FDA, who gave an overview of the FDA system for classification of medical devices. She described how FDA looks at device classification based on the risk and availability of controls that are necessary to provide a reasonable assurance of safety and effectiveness, the goal being to place a device in the lowest-risk category possible that still provides a reasonable assurance of safety and effectiveness.

The next speakers were Jason Liu, MD, PhD, Division of Blood Components and Devices (DBCD), OBRR/FDA, and Sharmila Shrestha, MBA, MT(ASCP), DBCD, OBRR/FDA, who presented the FDA’s proposed classification of HLA, and HPA and HNA devices.

Questions for the Committee

1. Following the review of relevant literature, medical device reports and recalls related to HLA, HPA and HNA devices, FDA has identified the following risks to health when these devices are used for transfusion, transplantation or disease diagnosis:
   
   Patient injury or death due to:
   
   • Poor graft survival or function due to transplantation of incompatible hematopoietic cells, tissue or organ.
   • Graft rejection because of the transplantation of incompatible hematopoietic cells, tissue or organ.
   • Graft-versus-host disease because of the transplantation of incompatible immune system cells.
   • Incorrect or delayed diagnosis of medically related conditions or assessment of future risk of adverse outcomes because of incorrect HLA, HPA or HNA test results.
   • Transfusion reaction (e.g. Transfusion Associated Lung Injury, Post Transfusion Purpura) due to incorrect HLA, HPA or HNA test results.
   • Platelet refractoriness because of incorrect HLA or HPA typing or antibody detection results.
   
   
   1. Do you agree that this is a complete and accurate list of the risks to health presented by HLA, HPA and HNA devices?
           Vote: Yes=14, No=0, Abstentions=0
   
   
   2. If you disagree, please comment on what additional risks should be included or explain which, if any, of the risks listed are not part of the overall risk assessment of HLA, HPA and HNA devices. n/a
      


2. Section 513 of the Food, Drug, and Cosmetic Act (FD&C Act) states:
   
   A device should be Class III if:
   
   
   • Insufficient information exists to determine that general controls are sufficient to provide reasonable assurance of its safety and effectiveness or that application of special controls would provide such assurance,
   AND
   • The device is life-supporting or life sustaining, or for a use which is of substantial importance in preventing impairment of human health, or if the device presents a potential unreasonable risk of illness or injury.
   
   

   A device should be Class II if:

   • General controls by themselves are insufficient to provide a reasonable assurance of safety and effectiveness,
   AND
   • There is sufficient information to establish special controls to provide such assurance.
   
   

   A device should be Class I if:

   • General controls are sufficient to provide reasonable assurance of the safety and effectiveness,
   OR
   • Insufficient information exists to determine that general controls are sufficient or special controls can be established to provide a reasonable assurance of safety and effectiveness, but the device type is not purported or represented to be for a use in supporting or sustaining human life or for a use which is of substantial importance in preventing impairment of human health and does not present a potential unreasonable risk of illness or injury.
     
     General controls may include:
     
     • Prohibition against adulterated or misbranded devices
     • Good Manufacturing Practices (GMPs)
     • Registration of manufacturing facilities
     • Listing of device types
     • Recordkeeping, etc.
   
   
   1. FDA believes that general controls alone are not sufficient to provide a reasonable assurance of safety and effectiveness for HLA, HPA and HNA devices.
   
   
   1. Do you agree with this assessment?
           Vote: Yes=14, No=0, Abstentions=0
   
   
   2. If not, please discuss how general controls alone are sufficient to provide a reasonable assurance of safety and effectiveness for HLA, HPA and HNA devices.
           n/a
   
   
   2. Under the FD&C Act, a device is potentially class III if it is “life-supporting or life-sustaining, or of substantial importance in preventing impairment of human health.” FDA believes that HLA, HPA and HNA devices are not life-supporting or life-sustaining.
   
   
   1. Do you agree with this assessment?
           Vote: Yes=13, No=1, Abstentions=0
   
   
   2. If not, please explain why HLA, HPA and HNA devices are life-supporting or life-sustaining.
   
   
   3. Under the FD&C Act, a device is potentially class III if it is “of substantial importance in preventing impairment of human health.” FDA believes that HLA, HPA and HNA devices are of substantial importance in preventing impairment of human health.
   
   
   1. Do you agree with this assessment?
           Vote: Yes=14, No=0, Abstentions=0
   
   
   2. If not, please explain why HLA, HPA and HNA devices are not of substantial importance in preventing impairment of human health.
           n/a
   
   
   4. Under the statute, a device is potentially class III if it presents a “potential unreasonable risk of illness or injury.” Considering the risks and benefits of these devices, FDA believes that HLA, HPA and HNA devices present a potential unreasonable risk of illness or injury. (Note that such a device may still be classified as class II if application of special controls would provide reasonable assurance of its safety and effectiveness.)
   
   
   1. Do you agree with this assessment?
           Vote: Yes=14, No=0, Abstentions=0
   
   
   2. If not, please explain why HLA, HPA and HNA devices are not for a use which presents a potential unreasonable risk of illness or injury.
           n/a
   
   
   5. FDA believes sufficient information exists to establish special controls for HLA, HPA and HNA devices. FDA is proposing the following as special controls that would provide reasonable assurance of safety and effectiveness:
   
   
   1. Premarket submissions must include detailed documentation of the following information:
      
      1. Device accuracy study using well-characterized samples representing as many targets as possible.
      2. Precision studies to evaluate possible sources of variation that may affect test results
      3. Comparison studies to evaluate the device’s performance compared to a predicate.
      4. Specific information that address or mitigate risks associated with false positive antibody reactivity e.g., reactivity with denatured/cryptic epitopes, if applicable.
      5. Description of how the assay cut-off was established and validated as well as supporting data.
      6. Documentation for device software, including, but not limited to, software requirement specifications, software design specification, e.g., algorithms, alarms and device limitations; hazard analysis, traceability matrix, verification and validation testing, unresolved anomalies, hardware and software specifications; electromagnetic compatibility and wireless testing.
      7. For multiplex assays in which large numbers of probes and/or primers are handled during manufacturing process, premarket submissions should provide the design specifications that are in place to prevent incorrect reactivity assignment.
      8. Description of a plan on how to ensure the performance characteristics of the device remain unchanged over time when new {HLA, HNA or HPA} alleles are identified, and/or reactivity assignments are changed from the assignments at the time the device was evaluated.
   2. The device labeling must include:
      
      1. A limitation statement that reads, “The results should not be used as the sole basis for making a clinical decision.”
      2. A warning that reads “The use of this device as a companion diagnostic, has not been established.”
         Not voted. For comment purposes only.
   
   
   6. Based on the information presented today, please discuss whether you believe that sufficient information exists to establish special controls that can provide a reasonable assurance of safety and effectiveness of HLA, HPA and HNA devices. If not, please explain why not.
           Vote: Yes=12, No=1, Abstentions=1
   
   
   7. Do you agree that the list in e. 1) is a sufficient and accurate list of the special controls needed to provide reasonable assurance of safety and effectiveness for HLA, HPA and HNA devices?*
           Vote: Yes=13, No=0, Abstentions=1
           * question revised during the session at the request of BPAC and FDA
      
      If you disagree, please comment on what additional special controls are needed or explain which, if any, of the proposed special controls are not needed.
           n/a
   
   
   8. Do you agree that the Agency’s proposed classification for HLA, HPA and HNA devices as Class II with special controls will provide reasonable assurance of safety and effectiveness?
           Yes=14, No=0, Abstentions=0
      
      If you disagree, please discuss why special controls are not adequate to assure safety and effectiveness of HLA, HPA and HNA devices.
           n/a

Meeting adjourned for the day at 5:58pm.

Day 2 Dec.1, 2017 In Open Session

Topic III: Strategies to Reduce the Risk of Transfusion-Transmitted Zika Virus

Background

The second day of the Committee meeting began with an overview, given by Anne Eder, MD, PhD, Associate Deputy Director for Medical Issues and Policy Development, OBRR/FDA, to update the committee on the current strategies to reduce the risk of zika virus (ZIKV) transmission by blood and blood components. The presentation included a U.S. Zika timeline beginning in December 2015, when the first case of local transmission was documented in Puerto Rico, through the February 2016 Guidance, to the August 2016 revised Guidance, which recommended that all donations collected in the U.S. and its territories be tested by investigational Individual Donor-Nucleic Acid Test (ID-NAT) or be pathogen reduced using an FDA-approved Pathogen Reduction Technology (PRT) device. The licensing of the first donation screening test on Oct. 5, 2017 was noted.

Speakers

Carolyn Gould, MD, MS, Medical Epidemiologist, Arboviral Diseases Branch, Division of Vector-Borne Diseases, Centers for Disease Control and Prevention (CDC) gave an update on the epidemiology of ZIKV. As of August 2017, local mosquito-borne transmission had been reported in 48 countries and territories in the Americas. The only countries that have not reported local transmission are Bermuda, Canada, Chile, and Uruguay. Easter Island, which is a territory of Chile, did have cases prior to 2015 but nothing on the Chile mainland. As of November 9, 45 of the 52 countries in the Americas continued to report ZIKV disease cases in 2017. In the U.S., there were 37 Presumed Viremic Donations (PVDs), reported to ArboNET in 2016, and 15 cases reported in 2017. Florida still had the most cases, compared to last year, followed by California. All 2017 cases were travel related. In summary, there were large outbreaks in the Americas which peaked in 2016, with substantially decreased activity in 2017. However, there are smaller outbreaks and continued transmission in some countries and in some focal areas of countries. Some that stand out are Peru, countries in Central America, and Cuba. There is an increased incidence in disease risk among U.S. travelers that has followed the epidemiology of the outbreaks in the Americas. And for the U.S. territories, the incidence has markedly decreased, but sporadic infections are still being reported.

The next speaker, Tony Hardiman, Life Cycle Leader, Blood Screening, Roche Molecular Systems Inc., provided an update on ZIKV Nucleic Acid Testing in blood donors tested using the Roche platform. Mr. Hardiman began with data from Puerto Rico. Donations as of Oct. 7, 2017 in Puerto Rico show 111,808 donations screened with cobas® Zika, of which 356 were confirmed positive for ZIKV RNA. Zika reactive donations continued to be detected in Puerto Rico in 2017 at a reduced rate, with the last confirmed positive donation in late May 2017. 70.5% of confirmed ZIKV-positive donations were detected in simulated pools of 6. A majority of samples that were not detected in simulated pools had low viral concentrations. In the U.S., figures were provided which showed testing of 4.34 million donations; 29 confirmed ZIKV positive donations were removed from the blood supply. Of those 29 donations, 39% were detected by mini-pool testing. For the donors that were confirmed positive for ZIKV, 85.2% of these had recent travel to Zika active areas, and 13% were domestic travel. ZIKV reactive donations have continued in the U.S. through 2017 - nine year-to-date.

The final speaker was Jeffrey Linnen, PhD, Vice President, Product Development, Grifols Diagnostic Solutions Inc., who gave a presentation on the investigational Procleix ZIKV Assay. The data was generated from 12 US sites. A total of 1.6 million donations were screened including over 1.2 million individual donations and over 24,000 pools of 16 donations, which then represented almost 400,000 donations that were tested in pools. A result was considered unknown if not confirmed at index and the donor did not participate in follow-up. For the more than 24,000 pools tested, there were no true positives, no unknown results and no false positives. The overall specificity for pool testing was 100%.

For the 1.2 million individual donations tested, there were a total of 12 true positives, eleven unknowns and 17 false positives. The overall specificity for individual donations for the study was 99.999%. There were two confirmed positive donations that were considered window period, and were IgM negative at index but showed seroconversion in a follow-up donation.

A summary of on-going testing under an Investigational New Drug Application through Nov. 18, 2017 shows 9.2 million tested, 376 initially reactive, 25 confirmed positive or 1 out of 370 donations, 205 false positive and 146 unknown. This calculates to an estimated specificity for the on-going study of 99.998%. The last confirmed positive was in October 2017 from a donor who traveled to Mexico. The majority of confirmed positives had a history of travel to areas with local ZIKV transmission. Also presented was data showing viral persistence for up to 154 days by follow-up testing of RBC samples with a Research TMA assay.

An Open Public Hearing followed which included:

• Michael Busch MD, PhD, Blood Systems Research Institute discussed 1) durations of viral RNA in blood compartments & body fluids 2) dynamics of epidemic and proportion of PR population infected with ZIKV in 2016 3) infectivity by transfusion in animal models 4) safety impact of conversion from ID-NAT to Mini-Pool (MP)-NAT.
• Steve Kleinman MD, Senior Medical Advisor, AABB, presented a joint AABB, ABC and ARC statement describing the blood community’s experience with ZIKV testing and the blood organizations’ proposal for on-going NAT testing in the US using the comparable model of West Nile Virus (WNV), to perform MP-NAT in small pools with conversion to ID-NAT following reports of local vector-borne transmission.

Questions for the Committee (Note: Questions were voted out of order)

1. At this time, do the available scientific data on the course of the ZIKV epidemic justify the elimination of all blood safeguards for ZIKV pending another significant outbreak in the United States or its territories?
        Vote: Yes=0, No=10, Abstentions=0


2. Do the available scientific data on the course of the ZIKV epidemic identify a risk to the blood supply that justifies continuing universal ID-NAT?
        Vote: Yes=0, No=10, Abstentions=0


3. 
   
   1. Do the available scientific data on the risk of transfusion-transmitted ZIKV support the regional use of ID-NAT in at-risk states and territories combined with the use of MP-NAT in all other states?*
           Vote: Yes=3, No=8, Abstentions=0
   
   
   2. Do the available scientific data on the risk of transfusion-transmitted ZIKV support the use of MP-NAT in all states and territories with a trigger for ID-NAT to be defined?*
           Vote: Yes=9, No=1, Abstentions=1
   
   
   3. Do the available scientific data on the risk of transfusion-transmitted ZIKV support discontinuation of all testing in some states and territories?*
           Vote: Yes=5, No=4, Abstentions=2
   
   * question revised during the session at the request of BPAC and FDA
   


4. Please comment on the following criteria to switch from MP-NAT to ID-NAT within a defined geographic area or a state:
   
   • A defined number of presumptive viremic donors in a 7-day rolling period based on results of MP-NAT in a defined geographic collection area
   • A defined number of cases based on 1) presumptive viremic donors in a 7-day rolling period and 2) a defined threshold of symptomatic clinical cases reported by national surveillance in a defined geographic collection area.
     This vote was deferred.


5. Would selective IDNAT performed based on the donors’ responses to questions about 1) travel to ZIKV endemic or epidemic countries; 2) sexual contact with partners diagnosed with ZIKV; and/or 3) sexual contact with partners having travel risk for ZIKV provide an adequate and appropriate safeguard against transfusion transmission of ZIKV?
        Vote: Yes=0, No=11, Abstentions=0


6. Would the option to provide ID-NAT negative blood to selected patients based on clinical indications (e.g., pregnant women, intrauterine transfusions, neonates) and ZIKV-untested blood components for all other transfusion recipients provide an adequate and appropriate safeguard against transmission of ZIKV?
        Vote: Yes=2, No=9, Abstentions=0

Topic IV: Informational Session on the Transfusion of Transmissible Infections Monitoring System (TTIMS)-Informational

Introduction

Alan Williams, PhD, Associate Director for Regulatory Affairs, Office of Biostatistics and Epidemiology (OBE)/FDA, presented data representing the progress of the program over the last 2 years.

Speakers

Whitney Steele PhD, MPH, Scientific Affairs, American Red Cross, presented the objectives of the TTIMS Donation Database Coordinating Center (DDCC) which she defined as 1) collect and maintain high quality data and 2) analyze the data to provide reliable national estimates. More specifically, the DDCC monitors Hepatitis B Virus (HBV), Hepatitis C Virus (HCV), and Human Immunodeficiency Virus (HIV) in US blood donors by developing and maintaining a database that includes information on nearly 60% of the blood supply. Dr. Steele reported that TTIMS has established the capacity to monitor infection prevalence using data from the four blood systems, developed consensus positive definitions used across all four systems, established the processes needed for secure data transfer, quality control, and identification of positive units, developed analysis programs to generate routine quarterly and annual monitoring reports, as well as analyzed and reported on 14 million donations during the 24 months of tracking. Prevalence rates are still very low among donations from U.S. blood donors, ranging from 2.6 per 100,000 in HIV to 20 per 100,000 for HCV. They are highest in donations from first-time donors, which are 4 to 35 times higher than repeat donation rates, and higher in males than females. There are higher HCV and HIV positive donations from the Southeast and South-Central regions, HBV positive Asian donors, and HBV in the Southeast and Western regions, and in younger donors, especially for HIV and HBV. The only significant trend to date is the increase in HCV prevalence in donations collected in the Southeast, South Central U.S., particularly from first-time and male donors.

Next, Brian Custer, PhD, MPH, Director Epidemiology and Health Policy Science, Blood Systems Research Institute, gave a presentation entitled “Proportion of HIV Seropositive Donors with Recently-Acquired Infection in the US and Updates on Other LRCC Activities.”

Alan Williams, PhD, OBE/FDA summarized the presentation describing that there has been no significant change in blood donor HIV prevalence since the December 2015 HIV Guidance, nor has there been an observed impact on the overall pool size directly related to the policy change. There was, however, an elevated HCV prevalence value, a single point, observed among first-time male donors in the Southeast, South Central U.S. during the July-August time frame and it is under evaluation. Dr. Williams stated that CBER is committed to developing a process to assess carefully, produce and improve the predictive value of the donor eligibility screening process. FDA will not only consider emerging data from the TTIMS but, also, the comments received to the docket and any additional new scientific data as it continues to reevaluate and update blood donor deferral policies.

Committee Update

The meeting closed with a summary, given by David Leiby, PhD, Chief, Product Review Branch, Division of Emerging & Transfusion Transmitted Diseases, OBRR/FDA, of the Public Tick-Borne Diseases and Blood Safety public workshop which was held in April 2017.

The meeting concluded at 3:23pm.