Blood Products Advisory Committee August 3, 2011 Dorothy Scott, M.D.

1. Update: FDA/PPTA/HHS Workshop: Risk Mitigation Strategies to Address Procoagulant Activity in Immune Globulin Products Blood Products Advisory Committee August 3, 2011 Dorothy Scott, M.D.

2. Thrombotic Adverse Events (TAE) and Immune Globulin Products • First literature report in 1986* • Serious events - Myocardial infarction, stroke, deep venous thrombosis, pulmonary embolism, miscellaneous other large arterial and 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. Use of a Thrombin Generation Test to study TAE-associated products • 2010: Manufacturer reports thrombotic adverse events (TAEs) in two product lots • FDA and manufacturer’s investigations implicated Factor XIa as the most likely procoagulant contaminant • Thrombin generation test (TGT) with FXI-deficient plasma • FXIa chromogenic assay • As a result of TAE reports and testing that revealed an unexpected increase in FXIa, the firm voluntarily withdrew the product from the U.S. market *

4. September-May • FDA TGT and FXIa test protocols shared with manufacturers and regulatory authorities • Methods development • Product and intermediates testing • Investigation of test methods and product assessment by regulatory authorities, manufacturers and NIBSC • NIBSC begins TGT standards development in collaboration with regulatory authorities and manufacturers

5. Workshop Goals • Identify most likely cause(s) of thrombotic adverse events in IG product recipients • Identify promising test methods that can be validated, and that are likely to predict in vivo thrombogenic potential of IG products • Discuss risk-mitigation strategies • Provide information on techniques and standards development

6. Participants • FDA and International Regulatory Authorities (EMA, Germany, France, Australia, Israel, Spain, Canada, Japan) • Investigation and test development • PPTA and Manufacturers • Specific products and methods investigations • Academic Experts • NIBSC • Immune Deficiency Foundation

7. Session 1Pathogenesis, Epidemiology, Lab Investigations • Arterial and venous TAEs are a known risk of IG therapy • This now includes a SC as well as IV products • TAE rates in a U.S. medical claims database and by reporting rate in Europe varied by product • Procoagulant activity likely explains some, but not all TAEs • Other product and patient-related factors may affect risk of TAEs • Viscosity • Dose, rate of infusion • Cytokines and other cellular derived factors (inflammation) • Potentially platelet-activating substances

8. Session 1 • Host factors affect TAE risk (e.g. age >45y, prior TAE, hypercoagulable state, hypertension, hyperlipidemia, atherosclerosis, ?hemolysis, oral estrogens, immobility) • Risks are likely multiplicativerather than additive • Risk mitigations discussed: • Slow infusion without “escalation as tolerated” • Limited daily dose • Premedication with aspirin and heparin/enoxaparin in patients with higher risk • Assure adequate hydration • Viscosity testing • Monitoring coagulation • Doppler to assess venous clots in patients with venous risk factors

9. Conclusions - Session 1 • Laboratory investigation of products associated with higher TAE rates by three regulatory agencies and NIBSC showed increased clotting activity and increased FXIa in products associated with higher TAE rates (FDA, PEI, Afsaaps, NIBSC)

10. Conclusions – Session 1 • Association of FXIa with arterial and venous thrombosis is not fully understood, but is biologically plausible • Most but not all lots associated with thrombosis had increased FXIa • Both global and specific assays for IG procoagulant activity are informative about product safety • Global assays of procoagulant activity could add assurance that other procoagulant activities are not overlooked in assuring product safety • FXI activation and copurification with IG are an inherent risk of plasma fractionation suggesting the importance of monitoring FXIa removal in manufacturing

11. Conclusions – Session 1 • Collaborative studies are ongoing to determine the most informative and reproducible assays (TGA, NAPTT, FXIa, chromogenic protease, NATEM, ELISA) to measure procoagulant activity in IG products • There is a need for an International Reference Material or Standard for FXIa

12. Session 2Manufacturer and PPTA Presentations • Manufacturing conditions that may influence procoagulant copurification with IG: • Specific Fraction III precipitation parameters/matrix • Fraction II + III resuspension pH • Precipitation of Fraction II from I+II+III supernatant • Anion exchange • Filter aid – context of use can dictate outcomes • Fortuitous coagulant protein-inactivating steps (such as heat treatment) • Starting plasma – do recovered plasma from Whole Blood donors and Source plasma have different risks of procoagulant activity? * Generalizations should be avoided; each manufacturing scheme needs to be assessed in its entirety due to process-specific matrices and sequential effects of manufacturing steps

13. Session 2 • Challenges of procoagulant test validation • Absence of standards • For intermediates: complex matrix, presence of filter aid; ELISA tests for zymogens may be helpful • Assays shown to be appropriate for the test material may be justifiable for process validation • Combinations of tests may be useful for final product characterization • Increased product safety is predicated on understanding partitioning and activation of procoagulant activity

14. Conclusions – Session 2 • Discussions of test limit values for products – what data could be useful? • Baseline test results from products with low TAE rates • Validation of HealthCore database • Improve reporting of product brand and lot numbers for TAE reports • Procoagulant activity data from implicated lots • Many implicated lots have increased FXIa levels, but some do not – possible other causes, or chance • Data presented nevertheless suggests there are levels that are likely unsafe for certain patients

15. Session 3 Test methods and validation feasibility • Which global procoagulant activity test may be most useful for IG products? • Thrombin generation test (TGT) or NaPTT • NaPTT interference with antibodies; less sensitive under some circumstances • TGT may be more mechanistically relevant • Either test could be suitable in a specific context • Is a standard platform needed for TGT? • Standards are needed: Broad support for WHO initiative for FXIa standard and NIBSC development of TGT standards (normal plasma and pos. control IG) • Wessler test is the only current in vivo clotting test that is useful (in spite of some limitations)

16. Conclusions – Session 3 • General consensus that studies are needed to show that procoagulant activity is minimized by specific manufacturing processes; this requires testing of intermediates with assays “fit for purpose” • Difference of opinions on need for routine batch release testing • General consensus that better knowledge of patient case specifics, event rates and studies of implicated lots are needed

17. Improving Safety - 1 • Ongoing work with manufacturers to minimize thrombogenic activity in products • Laboratory investigation of implicated product lots by FDA and manufacturers • May reveal manufacturing conditions that contribute to higher-activity lots • May shed light on other causes of TAE’s • Provides additional data regarding procoagulant activity levels (relevant to establishing cutoff limits) • Standards development – collaborative studies • TGT standards, test methods (NIBSC) • FXIa standard possible

18. Improving Safety - 2 • Regulators and manufacturers– importance of demonstrating process capability to remove procoagulant activity • Future Considerations for U.S. products • Should routine final product testing be performed by manufacturers? • If so, • Which tests? • What circumstances? • How should limits be established that would enhance product safety?

19. Improving Safety – Considerations Physician and Patient Level • Systematic investigation of host risk factors is needed • Obtaining implicated lot numbers – frequently not reported on MedWatch forms • Identify lot-associated clusters • Retrieve samples for investigation • Consider labeling changes for at-risk patients • Dose, infusion rate minimization • Additional risk factors – add to standard label; comment on multiplicative nature of risk factors • Patient and physician organization informational outreach • Immune Deficiency Foundation/FDA collaborative efforts