FDA/PPTA Workshop: Risk Mitigation Strategies to Address Procoagulant Activity in Immune Globulin Products

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/ucm093491.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to infusion: 44% of arterial events occurred during infusion; 82% within the first 24 hours * Gaines and Scott, unpublished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/WorkshopsMeetingsConferences/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