1. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 1 FDA perspective on “Where are we? Where can we go?” 12 th Annual FDA & the Changing Paradigm for Blood Regulation 16 January 2009 -- Las Vegas, NV Gilliam B. Conley Director, Division of Inspections & Surveillance FDA, Center for Biologics Evaluation & Research Office of Compliance & Biologics Quality

2. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 2 Introduction We will discuss l FDA inspection data l Fatalities reported to FDA l Biological Product Deviation Reports l Where (can) should we go?

3. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 3 FY-2008 Inspections Conducted Blood Bank – Level 1679 Blood Bank – Level 2316 Blood Bank – Total:~ 1,000 Source Plasma – Level 189 Source Plasma – Level 260 Source Plasma – Pre-license/Pre-approval19 Source Plasma – Total:165 note: totals may not match because some inspections are for products in multiple categories

4. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 4 Top 10 Biologics Observations FY-2008 (Oct. ’07 through Sept. ’08)

5. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 5 Top 10 Blood & Blood Component Observations FY-2008 (Oct. ’07 through Sept. ’08) Cite IDCount21 CFR…Text #176116606.100(b) Written standard operating procedures including all steps to be followed in the [collection] [processing] [compatibility testing] [storage] [distribution] of blood and blood components for [homologous transfusion] [autologous transfusion] [further manufacturing purposes] are not always [maintained] [followed] [maintained on the premises]. Specifically, *** #29831606.100(c) Failure to [perform a thorough investigation] [make a record of the conclusions and follow-up] of [an unexplained discrepancy] [a failure of a lot or unit to meet any of its specifications]. Specifically,*** #3922529606.171 Failure to submit a biological product deviation report [within 45 days from the date you acquired information suggesting that a reportable event occurred]. Specifically, ***

6. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 6 Top 10 Blood & Blood Component Observations FY-2008 (Oct. ’07 through Sept. ’08) - continued Cite IDCount21 CFR…Text (abbreviated) #43126606.20(b)Personnel…to assure competent performance of their assigned functions, and to ensure that the final product has the safety, purity, potency, identity and effectiveness it purports or is represented to possess. #5442523606.60(a)Equipment…to assure that it performs in the manner for which it was designed. #616019606.160(a)(1)Records…so as to provide a complete history of work performed.

7. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 7 Top 10 Blood & Blood Component Observations FY-2008 (Oct. ’07 through Sept. ’08) - continued Cite IDCount21 CFR…Text (abbreviated) #715417606.160(a)(1)Records concurrently maintained with the performance of each significant step… #86716606.65(e)Use supplies and reagents in a manner consistent with instructions provided by the manufacturer #915515606.160(b)Failure to maintain…records #1015910606.160(a)(1)Records…

8. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 8 Inspection Classification – FY-2008 Blood BanksSource Plasma NAI743107 VAI24350 OAI131 Note: These numbers represent a snapshot in time from our inspections database. Because of the further routine review following an investigator’s initial recommendation for an OAI inspection decision, the year-end actual numbers are fewer than the 14 reported here.

9. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 9 Regulatory Actions – FY-2008 l Warning Letters > 1 – Source Plasma > 3 – transfusion services or blood centers l Adverse Determination Letters > 1 – issued under consent decree covered multiple facility inspections Find on the web: WL - http://www.fda.gov/foi/warning.htm ADL - http://www.fda.gov/ora/frequent/default.htm

10. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 10 Adverse Reactions Regulatory Requirements, Guidance, Reports Requirement 21 CFR 606.170(a) Requires Records & Investigation Requirement 21 CFR 606.170(b) Requires reporting to FDA “a complication … confirmed to be fatal … as soon as possible” Requirement 21 CFR 640.73 – re: Source Plasma Requires reporting “a fatal reaction which, in any way, may be associated with plasmapheresis…” Guidance http://www.fda.gov/cber/gdlns/bldfatal.htm Sept., 2003 Final Guidance Reports & FDA contacts http://www.fda.gov/cber/transfusion.htm 2nd annual report was posted in mid-Nov.

11. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 11 Transfusion-related fatalities ComplicationFY ’05FY ’06FY’ 07Total TRALI 29353498 (55%) HTR (non-ABO) 169227 (15%) Microbial Infection 87621 (12%) TACO 18514 (8%) HTR (ABO) 63312 (7%) Anaphylaxis 012 3 (2%) Other 200 2 (1%) Totals:626352177

12. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 12 Reports of TRALI by implicated Blood Product

13. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 13 Hemolytic Transfusion Rx.

14. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 14 Microbial Infection by Implicated Organism OrganismFY ’05FY ’06FY ’07Total Babesia microti0235 (24%) Staphylococcus aureus3014 (19%) Escherichia coli0303 (14%) Serratia marcescens2002 (10%) Staphylococcus lugdunensis1001 (05%) Staphylococcus epidermidis1001 (05%) Eubacterium limosum1001 (05%) Morganella morganii0101 (05%) Yersinia enterocolitica0101 (05%) Streptococcus dysgalactiae0011 (05%) Klebsiella oxytoca0011 (05%) Total:87621

15. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 15 Biological Product Deviation Reports Regulatory Requirements, Guidance, Reports Requirement 21 CFR 600.14 § 606.171 Report any event … may affect safety, purity, or potency of distributed product Guidance http://www.fda.gov/cber/gdlns/devbld.htm Oct., 2006 – Final Guidance Reports & FDA contacts http://www.fda.gov/cber/biodev/reports.htm 5 years of annual reports are available

16. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 16 BPDR for Blood & Blood Components Manufacturing SystemFY-2003FY-2004FY-2005FY-2006FY-2007 Donor Suitability32,45328,95229,14829,06732,280 Post Donation Info30,33126,85427,45227,42730,033 Donor Screening2,0302,0071,6281,5482,027 Donor Deferral92916892220 QC & Distribution2,7063,7403,9344,1344,555 Labeling2,4292,4152,4052,1992,309 Laboratory Testing1,1261,1229811,0131,163 Routine Testing1,0371,0279129451,103 Viral Testing8995696660 Collection1,133851972718704 Component Preparation371368407401419 Miscellaneous2883825256581,400 Total:40,50637,83038,37238,18842,830

17. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 17 Biological Product Deviation Reporting

18. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 18 Blood Establishments

19. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 19 Blood Establishments

20. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 20 Blood Establishments

21. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 21 Plasma Establishments

22. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 22 Plasma Establishments

23. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 23 Plasma Establishments

24. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 24 Donors who subsequently test positive for viral marker FY-’05FY-’06FY-’07 Lookback; Subsequent unit confirmed pos (MI-02) – total: 4956081,367 HIV (MI-02-02)9299210 HBV (MI-02-03)5090344 HCV (MI-02-04)333372708 From FY-2007 annual BPDR summary report l Blood Safety Team (BST) reviewed rising numbers of reports l BST requested additional information from several manufacturers l Rise appears to be the result of > Altered reporting patterns after the October, 2006 final Guidance published Biological Product Deviation Reporting for Blood and Plasma Establishments > Rising numbers of collections – especially in Source Plasma centers l BST will continue to monitor these seroconversion rates

25. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 25 Where (can) should we go? l We will continue to gather information l We will continue to report information (web based information, public presentations, …) l We are interested in learning: > How do you use FDA’s posted data? Analyze with own data? Institute quality change? > Which FDA-posted data is most useful? > What are your success stories? Please find a way to share with others

26. 12 th Annual FDA & the Changing Paradigm for Blood Regulation – 01/16/2009 – Las Vegas, NV – Gilliam B. Conley 26 Questions Please join in the Q & A session at the conclusion of this morning’s session.