BPAC Meeting Summary – 07/18/18

The 119th meeting of the Food and Drug Administration’s (FDA) Blood Products Advisory Committee (the Committee) was convened in Silver Spring, Md., on July 18-19, 2018. On Day 1, the Committee met in open session to discuss bacterial risk control strategies to enhance the safety and availability of platelets for transfusion. In preparation for discussion of all available strategies to control the risk of bacterial contamination in platelets, the Committee heard updated information on 5-day and 7-day platelet storage based on bacterial testing using both culture-based devices and rapid bacterial detection devices, and options for use of pathogen reduction technology.

Note: This summary focuses on Topic I, presented on Day 1. This summary does not include Topic II, Reclassification of HIV Point of Care and Laboratory-based serological and NAT diagnostic devices from Class III (PMA) to Class II 510(k), which is not approved for use in donor testing. Please visit the FDA 2018 Meeting Materials webpage for more information on Topic II.

Topic I - Strategies to Control the Risk of Bacterial Contamination in Platelets for Transfusion

Background

Transfusion-transmitted sepsis caused by bacterially contaminated platelets remains the most common infectious cause of recipient mortality reported to the FDA. Nineteen fatalities have been recognized and reported in the past decade. Current interventions interdict about 30-50% of bacterially-contaminated platelet units, but surveillance is passive, and the clinical burden is believed to be greater. A Committee meeting was held November 30, 2017 to discuss and consider whether specific strategies using delayed and larger volume sampling of platelets for culture could provide adequate assurance of bacterial safety of 5-day and 7-day stored platelets in the absence of secondary testing; and 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 supported the adoption of certain newer strategies to a) control the risk of bacterial contamination in 5-day platelets; and b) to extend platelet storage beyond 5 days and up to 7 days.

On July 18, 2018, the FDA specifically requested the Committee discuss the advantages and disadvantages of various strategies to control the risk of bacterial contaminated platelets, including scientific evidence and the operational considerations involved. On several occasions the Committee has advised FDA on strategies to reduce bacterial contamination in platelets but, as FDA noted, this meeting was the first opportunity for the Committee to comment on all available strategies in one session. The following strategies were discussed:

For 5-day platelets:

  • primary culture followed by secondary rapid testing within 24 hours prior to transfusion;
  • primary culture followed by secondary culture on Day 3;
  • minimal proportional sampling volume (MPSV);
  • pathogen reduction technology.

For 7-day platelets:

  • primary culture followed by secondary rapid testing within 24 hours prior to transfusion;
  • primary culture followed by secondary culture on Day 4;
  • large volume delayed sampling (LVDS) culture-based testing.

The session began with an overview given by Emily Storch, MD, Office of Blood Research and Review (OBRR). Dr Storch provided background information on conditions conducive to bacterial growth and current FDA regulations and current accepted strategies to reduce risk. Dr Storch also reviewed FDA’s early efforts to address the risk:

BPAC 2012

Additional measures needed for 5-day platelets

  • Advised secondary rapid testing on Day 4 or 5
December 2014

FDA published draft guidance

  • Recommendations included BPAC’s 2012 advice
March 2016

FDA revised the draft guidance to include:

  • Pathogen reduction (5-day platelets)
  • 7-day storage (retested with “safety measure” test)
May 2016

Donor eligibility rule became effective

  • 21 CFR 606.145: Control of bacterial contamination of platelets
BPAC 2017

Additional culture-based strategies presented based on comments to the 2016 draft guidance and newly available data:

  • Supported additional culture-based strategies

The presentation outlined the current United States (US) platelet dating of a maximum of 5-7 days, based on preparation method, storage container and bacterial testing:

  • Methods for 5-day storage included primary culture no earlier than 24 hours after collection and treatment with an FDA-approved pathogen reduction device within 24 hours of collection.
  • A 7-day storage date is available for platelets having undergone a primary culture and additional secondary testing using a test labeled as a “safety measure” when collected into an appropriately labeled container.
  • Limitations of primary culture practices were also described and included 1) a low number of bacteria early in shelf life; 2) lag time between inoculation and growth; and 3) clinical sensitivity of day 1 culture for contamination on days 5-7 is less than forty percent.

Dr Storch also provided a list of current “FDA Cleared and Approved Devices for Bacterial Contamination of Platelets”:

Bacterial Culture:

  • BacT/ALERT, bioMérieux
  • eBDS, Haemonetics

Rapid Testing:

  • Platelet PGD Test, Verax Biomedical
  • BacTx Rapid Test, Immunetics, Inc.

Pathogen Reduction Technology:

  • INTERCEPT Blood System for Platelets, Cerus Corporation

Dr Storch presented a series of slides to capture the following strategies for discussion:


 MethodDescription
5-Day storagePrimary Culture + Secondary Culture on Day 3

Primary Culture:

  • Performed ≥24 hours after collection
  • 8 mL sampling volume
  • Aerobic medium

Secondary Culture:

  • Performed on Day 3 after collection
  • 5 mL sampling volume
  • Aerobic medium
Primary Culture + Secondary Rapid Testing on the Day of Transfusion

Primary Culture:

  • Performed ≥24 hours after collection
  • 8 mL sampling volume
  • Aerobic medium

Secondary Rapid Testing:

  • Performed within 24 hours of transfusion
  • 0.5 mL sampling volume
Minimal Proportional Sampling Volume (MPSV)
  • Single culture, no secondary testing
  • Sampling volume increase proportionally to collection volume.

MPVS Strategy:

Sampling volume:≥3.8% of collection
Culture Timing:24-36 hrs after collection
Culture media:Aerobic
3 of culture bottles:1-3
Storage:5 days
Pathogen Reduction Technology
  • One device currently approved by FDA
  • Based on Amotosalen/UVA technology
  • Intended use: To reduce the risk of transfusion-transmitted infection (TTI), including sepsis
  • Performed within 24 hours of collection
7-day storagePrimary Culture + Secondary Culture on Day 4

Primary culture:

  • Performed 12-24 hrs (aph) or 36-48 hrs (pools) after collection
  • 16 mL sampling volume of main collection
    • 8 mL aerobic, 8 mL anaerobic
  • No hold period after testing/loading of bottles
    • Units immediately released after sampling

Secondary culture:

  • Performed on Day 4
  • Products sampled:
    • Each apheresis unit
    • Each pooled platelet
  • 16 mL sampling volume:
    • 8 mL aerobic, 8 mL anaerobic
Primary Culture + Secondary Rapid Testing to Extend Beyond Day 5

Primary culture:

  • Performed ≥24 hours after collection
  • 8 mL sampling volume
  • Aerobic medium

Secondary Rapid Testing:

  • Performed within 24 hours of transfusion with a test labeled as a “safety measure”
  • 0.5 mL sampling volume
Large Volume Delayed Sampling (LVDS)
*Single culture to allow storage to 7 days

LVDS Strategy:

Time of sampling:36-48 hrs after collection
Sampling volume:16 mL, each component
Culture media:Aerobic & Anaerobic
Hold period:6 hours after sampling
Shelf life:7 days

Dr Storch noted the following Challenges in Strategy Comparison:

Studies on the strategies for discussion are not directly comparable because:

  • Many variables affect bacterial contamination and/or detection rates, e.g.:
    • Apheresis technology/device
    • Sample timing after collection
    • Sample volume
    • Aerobic/anaerobic culture
    • Skin prep/diversion
  • Changes in standards and practices over time
  • Definitions and reporting of Septic Transfusion Reactions (STRs) vary
  • Different outcomes evaluated
  • Different strategies have not been evaluated in parallel

Dr Storch introduced the “Question for the Committee” as:
Please comment on the advantages and disadvantages of each of the various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved:

Strategies for discussion to control the risks of bacterial contamination in platelet products
5-day storagePrimary culture + secondary culture (Day 3)
Primary culture + secondary rapid testing
Minimal Proportional Sampling Volume (MPSV)
Pathogen Reduction Technology
7-Day storagePrimary culture + secondary culture (Day 4)
Primary culture + secondary rapid testing
Large Volume Delayed Sampling (LVDS)

FDA invited the following speakers to update the Committee:

  • Mary Beth Anheuser, Regulatory Affairs Specialist with bioMérieux, Inc.

Topic: Bacterial Culture Testing Strategy
Presentation: “Use of the BACT/Alert® BPA and BPN Culture Bottles for Secondary Safety Measure Testing of Platelets”

  • Evan Bloch, M.B. Ch.B., Johns Hopkins University School of Medicine

Topic: Primary Culture, and Secondary Culture on Day 3 Testing Strategy, with Dating to Day 5
Presentation: “Bacterial Contamination of Platelet Products”

  • Stephen Field, M.B ChB., MA, MMed., FCPath (SA), Irish Blood Service

Topic: Primary Culture, and Secondary Culture on Day 4 Testing Strategy, with Dating to Day 7
Presentation: “Screening of Platelets for Bacterial Contamination the Experience of the Irish Blood Transfusion Service”

  • Ralph Vassallo, MD, Blood Systems, Inc.

Topic: Minimal Proportional Sampling Volume Testing Strategy, with Dating to Day 5
Presentation: “Platelet Bacterial Contamination Risk Mitigation-Minimal Proportional Sampling Volume (MPSV): Another Successful Approach”

  • Carl McDonald, PhD, MSC, BSc, National Health Service Blood and Transplant, UK

Topic: Large Volume and Delayed Sampling Testing Strategy, with Dating to Day 7
Presentation: “NHSBT Bacterial Screening: Two Million and Counting”

  • Michael R. Jacobs, MD, PhD, FRCPath, D(ABMM), F(AMM), Case Western Reserve University, on behalf of Verax and Immunetics

Topic: Bacterial Rapid Testing Strategy
Presentation: “Prevention of Bacterial Contamination of Platelets: Rapid Testing of Day of Transfusion Compared to Culture Approaches”

  • Richard Benjamin, MD, PhD, Cerus Corporation

Topic: Pathogen Reduction Technology Strategy
Presentation: “INTERCEPT Blood System for Platelets”

These presentations were followed by an Open Public Hearing with the following speakers:

Edward Snyder MD - Yale, Professor of Laboratory Medicine, Yale New Haven Hospital
Susanne Marschner PhD - speaking for TerumoBCT
Nancy Dunbar MD - Dartmouth-Hitchcock Medical Center, speaking for Verax
Peyton Metzel PhD - retired, Baxter/Fenwal
Mark Brecher MD - Emeritus Professor, University of North Carolina
Louis Katz MD - presented Joint Statement from AABB, America’s Blood Centers (ABC) and American Red Cross (ARC)
Heather Pidcoke MD PhD - Cellphire, speaking on behalf of Col. Andre Cap
Steve Wagner PhD - speaking for the ARC
Laurence Corash MD - speaking for Cerus Corp.
Ralph Vassallo MD - speaking for Blood Systems
Carl McDonald PhD, MSC, BSc - speaking for National Health Service Blood and Transplant, UK

The Joint Statement from AABB, ABC and ARC presented by Dr Katz reiterated the three organizations’ support of strategies to enhance bacterial safety using measures beyond the current approach of initial bacterial culture at 24-hours post-collection. The groups “strongly endorse providing multiple options based on both demonstrable enhanced safety and operational considerations for collection facilities and hospitals across the US, dependent on their ability to implement one or more allowable interventions.” On the topic of Pathogen Inactivation (PI), the organizations urged the manufacturer and the FDA to collaborate aggressively in pursuit of expanding existing guard bands and providing data in support of treating triple collections. Finally, the Joint Statement requested FDA consider a regulatory process that will be more conducive to timely implementation of PI. The Joint Statement clearly expressed and implied no preference for a specific mitigation option over others, nor did it commit any blood collector or hospital to a specific approach or combination of interventions.

The Open Committee Discussion began with instructions to the Committee from Nicole Verdun, MD, Acting Director, OBRR: “Please comment on the advantages and disadvantages of each of the various strategies to control the risk of bacterial contamination in platelets, including the scientific evidence and the operational considerations involved.”

Some committee members discussed the need for uniform, robust reporting of STRs and showed support for the AABB reporting criteria. A desire for additional data was frequently noted but it was understood that, while not optimal, the existing data was sufficient to advise FDA to act while additional data is collected. Additional topics discussed included:

  • The preference for use of an active surveillance system for monitoring bacterial contamination rates, rather than the passive system currently in place, and support for a required reporting system.
  • The value of culturing outdated products to monitor the effectiveness of strategies.
  • The use of an anaerobic bottle (Center for Disease Control and Prevention supports considering this option).
  • The cost of zero tolerance for failures and its potential to limit access to lifesaving products.
  • The benefit of a seven-day storage to increase inventory and compensate for discard due to false positive rates.

Overview of Discussion for Each Strategy:

The Committee indicated support of all 7 strategies, and an understanding that the local challenges and operational considerations would be best addressed by the blood supplier and the transfusion service. The following general comments were provided:

5-Day Strategies:

  1. Primary culture + secondary culture (Day 3):
    • Operational concerns for some transfusion services to implement a secondary culture.
    • Relatively low cost and showed good results.
  2. Primary culture + secondary rapid testing:
    • Preferred use of an anaerobic culture bottle with this strategy.
    • The second-generation test, currently in validation, is expected to show improved detection for anaerobes such as clostridium.
  3. Minimal Proportional Sampling Volume (MPSV):
    • Adequate but potentially less promising strategy.
  4. Pathogen Reduction Technology:
    • Would provide maximum assurance for a safe product.
    • Concerns around cost, time, guard band considerations, no triples.
    • The Committee had no objection to implementing but noted limited approval for other applications.

7-Day Strategies:

  • Primary culture + secondary culture (Day 4): Discussed the survival of seven-day platelets. The value of 5-day platelets if 7-day storage is available. Again, operational concerns were noted.
  • Primary culture + secondary rapid testing: Minimal discussion of this currently approved strategy.
  • Large Volume Delayed Sampling (LVDS): Concerns regarding culture at the lag phase. The NSBT data strategy is more convincing.

The meeting concluded at 4:30pm.