1. Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER

2. Overview 3 hydroxyethyl starch (HES) solutions — Hespan, Hextend, and Voluven — are licensed for treatment of hypovolemia HES solutions are associated with 3 toxicities of concern: –Pruritus –Bleeding –Acute Kidney Injury

3. FDA-Licensed HES Solutions Hespan (B. Braun) Hextend (Biotime) Voluven (Fresenius Kabi)

4. Licensed HES Solutions Hespan, Hextend, Voluven Derived from maize starch (amylopectin) Vehicles –Hespan: normal saline –Hextend: lactated electrolyte solution –Voluven: normal saline Different chemical structure –Molecular weight (MW) –C 2 /C 6 ratio (number of hydroxyethyl (CH 2 CH 2 OH) groups at C 2 vs. C 6 of glucose subunits) –Molar substitution (MS) (percent of glucose subunits carrying hydroxyethyl groups)

5. Nomenclature Classification of HES depends on molar substitution –Hetastarch (0.7), e.g., Hespan, Hextend –Pentastarch (0.5), e.g., Pentaspan (not US licensed for hypovolemia) –Tetrastarch (0.4), e.g., Voluven

6. Nomenclature 6% HES 130/0.4 Molecular weight (kD)Molar substitution (percent of hydroxyethyl groups per glucose subunit) 6% HES 130/0.4/9:1 C2/C6 Ratio (ratio of hydroxyethyl groups at C2 vs. C6) Glucose

7. HES are Hydrolyzed by Plasma α-Amylase α-Amylase Glucose

8. Higher Molar Substitution Values Slow Hydrolysis ProductMW (kD) C 2 /C 6 Ratio (Ratio of CH 2 CH 2 OH groups at C 2 vs. C 6 ) Molar Substitution (Number of CH 2 CH 2 OH groups per glucose subunit) Half-Life (hours) Hespan/ Hextend 6705:10.746.3 Voluven1309:10.412.1

9. Summary Basis for Approval Hespan, Hextend, Voluven

10. Hespan (licensed 1972) US clinical studies –Study design 8 RCTs in different clinical settings (N=352): surgical, trauma, septic shock, burns, pump prime in open heart surgery –Treatment regimen Hespan vs. 5% human serum albumin (control) at a rate of 20 mL/kg/h –Outcomes Total dose: no difference reported in safety and efficacy from control with a range of 250 up to 2000 mL (specific numbers unavailable)

11. Hextend (licensed 1999) US clinical study –Study design Double-blind, 2-center, non-inferiority RCT in subjects undergoing elective non-cardiac surgery in patients with expected blood loss (EBL) > 500 mL –Treatment regimen Hextend vs. Hespan (control; albumin prohibited intraoperatively) according to prespecified hemodynamic triggers (SBP + HR + U/O) Both arms received LR bolus (7 mL/kg) + infusion (5 mL/kg/h) for duration of anesthesia –Sample size 60 subjects/arm = 80% power to detect a 30% difference Primary endpoint –Total volume of Hextend or Hespan administered by end of surgery Anesth Analg 1999;88:992-8

12. Hextend: Results Hextend (N=59) Hespan (N=58) Received > 20 mL/kg (number (%) of subjects) Total dose administered (mL) 25 (42) 1596±923 21 (36) 1428±1094 Achieved prespecified hemodynamic targets (number (%) of subjects) 39 (66)38 (66) Received allogeneic transfusion (post hoc) Number (%) of subjects Volume of pRBCs (mL) EBL (mL) Number of subjects requiring Ca ++ 35 (59) 642±1174 1560 1 34 (59) 538±694 2516 6

13. Voluven (licensed 2007) Non-U.S. clinical studies (Europe) –Study design 12 double-blind RCTs in subjects undergoing noncardiac elective surgery expected to require volume replacement –Treatment regimen Voluven vs. 6% HES 200/0.5 (not US licensed) –Aggregate sample size N=705 (N=355 vs. 350) –Primary endpoint Total volume of synthetic starch solution administered in the perioperative period

14. Voluven (cont’d) –Results Total dose administered: no difference (1613 – 2913 mL vs. 1584-2884 mL) –> 40 mL/kg in 27% of subjects –10-40 mL/kg in remaining 73% Severe bleeding: no difference Acute Kidney Injury (elevated SCr or RRT): no difference

15. Voluven (cont’d) U.S. clinical study –Design Double-blind RCT in subjects (N=100) undergoing major elective orthopedic surgery –Treatment regimen Voluven vs. Hespan (no other colloids allowed intraoperatively) –Primary efficacy endpoint Total volume required for intraoperative volume replacement (hemodynamic triggers prespecified) –Primary safety endpoints Estimated blood loss over 48 h, nadir VIII activity, nadir vWF concentration within 2 h after surgery, use of FFP Anesthesiology 2007;106:1120-7

16. Voluven: Results Voluven (N=49) Hespan (N=51) Total dose in mL [mL/kg]1613 [21.6 ]1584 [25.5 ] Volume of allogeneic blood transfused (mL/kg) 8.4±6.611.7± 9.9 FVIII activity <LLN End of surgery (number of subjects) 2h post surgery (number of subjects) 5050 13 7 Severe bleeding (number of subjects) 03 Elevated SCr (number of subjects) Peak SCr (mg/dL) 2 1.5, 3.3 1 2.7 RRT (number of subjects) 00

17. Voluven (cont’d) Two postmarketing RCTs to further evaluate safety –Adult patients with severe sepsis (CRYSTMAS study: Crystalloids Morbidity Associated with severe Sepsis) –Pediatric patients undergoing open heart surgery in association with CPB

18. Labeling Dosage & Administration Section Warnings Section

19. Dosage & Administration Section (Highlights, Package Insert) Hespan/Hextend Recommended dose: 500-1000 mL Upper limit: 20 mL/kg/per day (~1500 mL/day for 70 kg patient Voluven Upper limit: 50 mL/kg/per day (~3500 mL for a 70 kg patients

20. Warnings Section (Highlights, Package Insert) Hespan Not recommended for use as a CPB pump prime while the patient is on CPB or in the immediate post-CPB period because of the risk of increasing coagulation abnormalities and bleeding in patients whose coagulation status is already impaired (2003) Hextend Increased bleeding has been associated in patients undergoing open heart surgery in association with CPB following use of 6% hetastarch in normal saline Voluven At high dosages dilutional effects may result in decreased levels of coagulation factors and other plasma proteins and a decrease in hematocrit

21. Overall Safety Review Adverse Reactions

22. 1.Bleeding –Etiology incompletely understood Decreased availability of fibrinogen binding sites on platelets due to adherence of HES Impaired fibrin polymerization (Acta Anaesth Scand 2010;54:1241-1247) Decreased levels of Factor VIII, vWF, and XIII (> hemodilution alone) –Bleeding reportedly greater with higher molar substitution values

23. Adverse Reactions (cont’d) 2.Pruritus – Attributed to long-term deposition in liver, skin, cutaneous nerves – Tissue uptake independent of MW and substitution (Clin Pharmacokinet 2012;51:225-236) – Rx: resistant to steroids, antihistamines, acetominophen and neuroleptic drugs

24. Adverse Reactions (cont’d) 3. Acute Kidney Injury –2001: first clinical report of elevated serum creatinine values with use of HES ( 6% HES 200/0.6 ) Schortgen et al. Effects of HES and gelatin on renal function in severe sepsis. Lancet 2001;157:911-916

25. Safety Information Received Since 2008 2008: VISEP study in ICU patients –10% HES 200/0.5 vs. modified LR –Halted prematurely (excess RRT in HES subjects) 2010: Cochrane review of HES effects on kidney function –No difference in risk except in septic shock patients where risk is increased with 10% HES 200/0.5 or 6% HES 200/0.6 Safety assessment of these studies confounded by use of HES formulations different from those approved in US

26. Safety Information Received Since 2008 2012: CRYSTMAS study in severe sepsis subjects comparing Voluven vs. normal saline (postmarketing study) Methods –Design: double-blind, multicenter, RCT –Treatment: Voluven (N=100) vs. normal saline (N=96) –Primary endpoint: volume of study drug required to achieve hemodynamic stabilization (HDS; criteria prespecified) over 4 days –Safety endpoint: acute kidney failure prespecified as doubling of serum creatinine or need for RRT over study period, i.e., Schortgen criteria

27. CRYSTMAS Study Results –Baseline clinical characteristics: no difference –Efficacy: no difference Voluven (N=100) Normal Saline (N=96) Volume (mL) required to achieve HDS13791709 Time to achieve HDS (h) 11.814.3

28. CRYSTMAS Study Safety Voluven (N=100) Normal Saline (N=96) SARs (serious adverse reactions)5344 SARs leading to death 3832 Doubling of SCr (number of subjects) 811 Required RRT Number of subjects Duration of RRT (days) 21 9.1 11 4.3

29. RIFLE Classification of AKI RIFLE class is determined based on the worst of either GRF or U/O criteria

30. CRYSTMAS Study Voluven (N=100) Normal Saline (N=96) Rifle Score (number of subjects) None7773 Risk1311 Injury45 Failure57 Loss(>4 weeks)10 ESKD (>3 months)00

31. CRYSTMAS Study P=0.063 log rank test Normal saline Voluven Proportion of subjects without RRT

32. Change in Voluven Package Insert May 2012 Section 14 (Clinical Studies) expanded to include a discussion of outcomes from CRYSTMAS trial Section 6 (Adverse Reactions) expanded to include increased frequency and duration of RRT in CRYSTMAS among Voluven patients

33. 2012: S6 and CHEST Trials RCTs comparing Voluven vs. crystalloid in severe sepsis subjects and powered for death or dialysis-dependence at 90 days –S6 Trial (N=798) –CHEST (N=6999)

34. Thank you for your attention