draft guidance: collection of platelets by automated methods comments to the docket and questions...
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Draft Guidance: Collection of Platelets by Automated Methods
Comments to the Docket and Questions for the Committee
Alan E. Williams, Ph.D.Director, Division of Blood ApplicationsOffice of Blood Research and Review
CBER, FDA
Blood Products Advisory Committee, March 9, 2006
Collection of Platelets by Automated Methods: Background
Draft guidance published 9/30/2005
Updates October 1988, “Revised Guideline for the Collection of Platelets, Pheresis”
Draft Guidance addresses:– Donor selection and management– Information Provided to the donor– Component Collection and Management– Process Validation– Quality Assurance and Monitoring– Processing and Testing– Labeling– Reporting Changes to an Approved Biologics License Application– Appendix (Scan Statistics )
Numerous Comments to the docket received October – December 2005
Collection of Platelets by Automated Methods: Background
Limited time to consider docket comments, however some important common threads have received rapid attention. Some current FDA considerations to be presented today
– Three issues for which we will present our current considerations are specific discussion and voting topics for the Committee
» Validation procedures for bacterial contamination
» Donation frequency
» Donor Deferral for Medications (Dr. Vostal)
– All comments are being considered carefully and there remain multiple issues still to be discussed within FDA
Summary of Key (Draft) Recommendations and Comments
Medical CoverageFDA Draft: “Physician present on the premises” - interpreted as a qualified physician able
to arrive on-site within 15 min.
Comments: Apheresis is a safe procedure. Not feasible for mobile apheresis collections /supply impact Staff CPR /Emergency “911” is the more appropriate action
Current thinking:Delete recommendation. License supplement and blood establishment SOP
to specify emergency response per 21 CFR 640.22 (c)
Summary of Key (Draft) Recommendations and Comments
Target yieldFDA Draft:
Device target yield setting @ 6.5 x 10e11 for doubles; 10 x 10e11 for triples
Comments:
Operational detail
Targets should be facility and device-specific
Current consideration:
Target the final transfusable component to be ≥ 3 x 10e11
Summary of Key (Draft) Recommendations and Comments
Process validation (Platelet yield, pH, residual WBC)FDA Draft: Recommends pH meter be used routinely for pH measurement 95% conformance @ 95% confidence parameters for validation of platelet yield, pH, residual WBC
Comments: Interpretation of binomialAppropriate validation strata Criteria of 95% conformance @ 95% confidence too strict; (90%/90% more realistic) given inherent
variation in platelet counting, pH measure
Current considerations: Under consideration (Recognize need to ensure compatibility with performance parameters for
cleared devices)
Summary of Key (Draft) Recommendations and Comments
Process validation (Bacterial contamination)FDA Draft:
Bacterial contamination testing with bacterial detection system cleared or approved by CBER for use with Platelets, Apheresis components (99% culture negative/99% CI) Can be accomplished by QC of 500 components with zero failures.)
FDA rationale:Mean contamination rate for apheresis platelets is 1/2000, but >> higher rates have been
observed and may be procedure-relatedBacterial contamination of platelets is the third leading cause of post-transfusion fatality
and the leading cause of PT infection-related fatality .Current industry standard for 100% QC of all platelet components does not specify use
of cleared culture procedures. (culture is in common use for Platelets Apheresis - but full extent unknown)
Culture using devices cleared for the purpose provides important early stage detection of improper procedures that may result in gross contamination of components.
Summary of Key (Draft) Recommendations and Comments
Process validation (Bacterial contamination)Comments:
Zero failures in 500 cultures is problematic in light of false-positive initial cultures
Most establishments do not have a laminar flow hood
Platelet sterility is not an FDA requirement
Industry standard requiring 100% QC for platelet components makes validation unnecessary (*)
Summary of Key (Draft) Recommendations and Comments
Process validation (Bacterial contamination)Current considerations:
Early rule-out of high level component contamination due to improper new procedures is important
False positive issue is moot, since validation refers to confirmed positive cultures (i.e. repeated culture from same container)
FDA recognizes that recommending validation based upon 0/500 may be unduly stringent since there is a 14% likelihood of finding one positive sample in a set of 500 when the true contamination rate is 1/3000
It may be more operationally feasible to allow at most, a single failure in 500 tests (99% conformance /95% CI)
Summary of Key (Draft) Recommendations and Comments
Process validation (Bacterial contamination)
Question for the Committee:
Do BPAC members agree that bacterial testing of 500 consecutive collections is appropriate for validation of the aseptic process?
» If not, what sample size and acceptance criterion does the Committee suggest?
Summary of Key (Draft) Recommendations and Comments
Quality Assurance Monitoring (General)FDA Draft: Daily component specification check
Residual WBC count < 5x10e6 on collection and per componentResidual WBC count on all components (non-automated leukoreduction) Actual platelet yieldHematocritBacterial testing per device manufacturer
Comments: “Many”
Current considerations:Residual WBC count on statistically-based sample of components with supplemental
label option for WBC-counted components <1x10e6 All comments under consideration
Summary of Key (Draft) Recommendations and Comments
Quality Assurance Monitoring (Statistical Framework)FDA Draft: QA monitoring should have a statistical framework0.05 alpha/ ≥ 80% powerDetection of > 5% non-conformance rate.Scan statistics offered as an FDA-acceptable option, not a recommendation
Comments: Scan statistics complex, unnecessary, no basis for “requiring”
Current thinking:See slide presentation “The Evolution of Statistical Process Control Applied to Blood product
manufacturing” at http://www.fda.gov/cber/summaries.htm
Scan statistics option offered as example only. Parameters of 0.05 alpha and 80% power to detect non-conformance are realistic and in common scientific use. There are several published statistical approaches to achieve this.
FDA will provide options in a user-friendly tableFDA acknowledges that supporting software and pilot data for scan not yet available
Summary of Key (Draft) Recommendations and Comments
Donation FrequencyFDA Draft:
…collect no more than 24 total Platelets, Pheresis components in a 12-month period.
..no more than 2 procedures in 7 day period
7 day interval between double Platelets, Pheresis
14 day interval between triple Platelets, Pheresis
Post-donation platelet count
Summary of Key (Draft) Recommendations and Comments
Donation FrequencyRationale for FDA draft recommendations
– 24 collections per year specified in 1988 guidance pre-dated double and triple collections
– Collections have since been maximized through use of automated devices One publication (Lazarus, et al; Transfusion 2001(41):756-761) demonstrated lowered platelet counts after repeated apheresis (< 7.5 donations)
– Very limited data were available regarding long term health impact of repeated maximized platelet apheresis.
– Cannot rule out adverse events as a reason for cessation of donation
Sustained decreases in platelet count associated with multiple, regular plateletpheresis donations Transfusion 2001(41):756-761
Four year retrospective study. 11,464 collections/939 donors
Assessed mean difference in platelet counts (first to last observation)
50,000 platelets/ul decrease from baseline among frequent donor subgroup (250k to 200k) compared to research WB donors.
9% deferral for low platelet count (which was generally reversible)
Conclusion : platelet counts decrease 10-20% over time in frequent platelet apheresis donors, but decrease is not clinically significant with proper monitoring and deferral policies.
Summary of Key (Draft) Recommendations and Comments
Donation FrequencyComments to Docket:
Controls provided by integration of pre-donation count and volume with donor height and weight provide adequate safety controls
Apheresis frequency is well-established in practice w/o adverse eventsPlatelet supply will suffer 12-50 % lossData submitted to docket supports stable (or increasing) platelet baseline
counts for long-term apheresis donors.(Data Summary to be presented by Dr. Katz)
Post-donation count may require repeat phlebotomy and is unlikely to be accurate.
Summary of Key (Draft) Recommendations and Comments
Donation FrequencyFDA Current considerations:Minimum pre-donation count 150,000 based on prior actual determination, post-donation
count or facility meanMinimum targeted platelet count 100,000 post - donation.Consider modifying or removing recommendation for 24 component/year donation limit
based upon review of submitted safety data Maximum double unit for new donors lacking pre-donation platelet count Seven day deferral for collections > single (recognize potential operational problem
regarding donor scheduling).Solicitation of additional safety data (e.g. plasma proteins)Elimination of recommendation for collection of a post-donation platelet count
Request for BPAC discussion and recommendations» Louis Katz MD (representing blood collection community) – Potential impacts on
availability of the draft plateletpheresis guidance on collection facilities
Summary of Key (Draft) Recommendations and Comments
Question for the Committee:
Do the BPAC members agree that the proposed recommendations on donation frequency, interval between donations, and number of components collected per year are appropriate to protect the safety of the donor pending the availability of additional safety data on larger volumes of collection?
If not, please comment on limits that would be more appropriate.
Summary of Key (Draft) Recommendations and Comments
Donor deferral for medications:
Presented by Jaro Vostal, MD, PhD
OBRR, Division of Hematology