Draft Guidance: Collection of Platelets by Automated Methods Comments to the Docket and Questions for the Committee

1. Draft Guidance: Collection of Platelets by Automated MethodsComments to the Docket and Questions for the Committee Alan E. Williams, Ph.D. Director, Division of Blood Applications Office of Blood Research and Review CBER, FDA Blood Products Advisory Committee, March 9, 2006

2. Collection of Platelets by Automated Methods: Background • Draft guidance published 9/30/2005 • Updates October 1988, “Revised Guideline for the Collection of Platelets, Pheresis” • Draft Guidance addresses: • Donor selection and management • Information Provided to the donor • Component Collection and Management • Process Validation • Quality Assurance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

3. 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

4. Summary of Key (Draft) Recommendations and Comments Medical Coverage FDA 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)

5. Summary of Key (Draft) Recommendations and Comments Target yield FDA 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

6. 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 binomial Appropriate 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)

7. 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-related Bacterial 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.

8. 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 (*)

9. 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)

10. 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?

11. 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 component Residual WBC count on all components (non-automated leukoreduction) Actual platelet yield Hematocrit Bacterial 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

12. Summary of Key (Draft) Recommendations and Comments Quality Assurance Monitoring (Statistical Framework) FDA Draft: QA monitoring should have a statistical framework 0.05 alpha/ ≥ 80% power Detection 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 table FDA acknowledges that supporting software and pilot data for scan not yet available

13. Summary of Key (Draft) Recommendations and Comments Donation Frequency FDA 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

14. Summary of Key (Draft) Recommendations and Comments Donation Frequency Rationale 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

15. 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.

16. Summary of Key (Draft) Recommendations and Comments Donation Frequency Comments 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 events Platelet supply will suffer 12-50 % loss Data 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.

17. Summary of Key (Draft) Recommendations and Comments Donation Frequency FDA Current considerations: Minimum pre-donation count 150,000 based on prior actual determination, post-donation count or facility mean Minimum 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

18. 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.

19. Summary of Key (Draft) Recommendations and Comments Donor deferral for medications: Presented by Jaro Vostal, MD, PhD OBRR, Division of Hematology