1. FDA/PPTA Workshop: Risk Mitigation Strategies to Address Procoagulant Activity in Immune Globulin Products Dorothy Scott, M.D. Mikhail Ovanesov, Ph.D.

2. Thrombotic Adverse Events and Immune Globulin Products First literature report in 1986* Serious events - Myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism, miscellaneous other arterial and deep venous events Precautionary labeling recommended by FDA for IGIV products since October, 2003 ( http://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/u cm093491.htm) Causes uncertain, theories include –Coagulation factor contaminants –Hyperviscosity –Vasospasm –Platelet activation/aggregation * Woodruff et al, Lancet 2(8500): 217-18, 1986

3. FDA Retrospective Analysis for TE’s 1998-2005* ~30 TE/year or 18% of SAE’s reported to FDA –spontaneous reporting Arterial events (strokes, MI’s) more common than venous events (DVT’s, PE’s) Reported for all products in the 1998-2005 timeframe Associated with increasing age, increased weight, cardiac risk factors, DVT risk factors Timing relative to infusion: 44% of arterial events occurred during infusion; 82% within the first 24 hours * Gaines and Scott, unpublished

4. Infusion and patient characteristics in FDA historical series Infusion factors –Dose < 1 g/kg in 2/3 patients –Infusion rates (where recorded) – infusion rates nearly always within licensed range Patients typically have underlying risk – preexisting “lesion” or propensity

5. Historical Observations - Coagulation factor contaminants in IG products Bouma & Griffin (1977) J Biol Chem –Factor XI(a) and immunoglobulins co-purify through successive ion- exchange columns Alving et al (1980) J Lab Clin Med –IG procoagulant activity mediated by FXIa; other contaminants: prekallikrein activator (PKA) and kallikrein Wolberg et al (2000) Blood Coag Fibrinolysis –IGIV procoagulant activity mediated by FXI and FXIa No direct correlation between in vitro results and IGIV thrombotic AE’s was published Tests for FXI not characterized for IG products Other procoagulant contaminants not excluded

6. Use of a Thrombin Generation Test to study TE-associated product 2010: Manufacturer reports thrombotic adverse events (TE’s) associated with several product lots FDA testing indicated a possible root cause for TE’s: Factor XIa is the likely contaminant –Thrombin generation test (TGT) with FXI-deficient plasma –FXIa chromogenic assay –Manufacturer testing confirms FDA results As a result of TE’s and TGT-based testing, the firm voluntarily withdrew the product from the U.S. market (August/September 2010)

7. Ongoing Work Distribution of the CBER TGT protocol to all major IGIV manufacturers Screening of IG products for thrombogenic contaminants Collaboration with other regulatory agencies and industry –Test development –Product testing Development of thrombogenicity standards (with NIBSC, PEI, EMA)

8. FDA/PPTA Workshop Risk Mitigation Strategies to Address Procoagulant Activity In Immune Globulin Products Date: May 17-18, 2011 Location: Rockville, Maryland Registration: http://www.fda.gov/BiologicsBloodVaccines/ NewsEvents/WorkshopsMeetingsConfere nces/ucm247285.htmhttp://www.fda.gov/BiologicsBloodVaccines/ NewsEvents/WorkshopsMeetingsConfere nces/ucm247285.htm.

9. Workshop Goals To identify most likely cause(s) of thrombotic adverse events in IG recipients To identify promising test methods that can be validated, and that are likely to predict in vivo thrombogenic potential of IG products To discuss risk-mitigation manufacturing strategies

10. Workshop – Session I Pathogenesis and epidemiology of IG product- related thrombotic events –Pharmacovigilance data –Scientific background – pathogenesis of large vessel thrombotic events –Laboratory investigations of products associated with TE’s – regulatory agencies –Thrombogenicity of FXI in vivo Discussion –Most likely biochemical causes of TE’s IG product recipients (list in order) –What other causes should also be considered?

11. Workshop – Session II Partioning and activation of clotting factors in IG product manufacturing processes Preliminary product testing and methods development – manufacturer presentations Panel Discussion –Manufacturing processes and procoagulant activity –Challenges to validation –Investigations of new products –What practical information is needed to establish upper limits of test results (“cutoff” values)

12. Workshop Session III Tests for thrombotic potential of IG products: methods and validation feasibility –Perspective on global tests for coagulation factors –Thrombin generation tests - technical challenges, methods comparability, standards development –FXIa assays and application of FXIa tests to predict in vivo thrombogenicity –Animal models to predict thrombogenicity

13. Workshop Session III Discussion –What global tests may be most useful for IG products with respect to range of relevant procoagulant proteins detected, and validation potential? –What specific tests may be most feasible and useful to estimate thrombotic potential of IG products? –What reagents and methods development are needed for these tests? –What animal models are available to support relevance of tests? –What additional clinical information would be useful to support relevance of in vitro tests?

14. Outcomes Identification in order of likelihood - most likely biochemical causes of IG product-related TE’s Identification of tests likely to have predictive value and detailed methods discussions Improved understanding of how procoagulant factors can partition with IgG during purification Presentation of standards under development Progress towards product characterization