regulatory overview of hydroxyethyl starch (hes) solutions september 6, 2012 laurence landow md...
TRANSCRIPT
![Page 1: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/1.jpg)
Regulatory Overview of Hydroxyethyl Starch
(HES) Solutions September 6, 2012
Laurence Landow MDMedical Officer, CBER
![Page 2: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/2.jpg)
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
![Page 3: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/3.jpg)
FDA-Licensed HES Solutions
Hespan (B. Braun)Hextend (Biotime)
Voluven (Fresenius Kabi)
![Page 4: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/4.jpg)
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) – C2/C6 ratio (number of hydroxyethyl (CH2CH2OH)
groups at C2 vs. C6 of glucose subunits)– Molar substitution (MS) (percent of glucose
subunits carrying hydroxyethyl groups)
![Page 5: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/5.jpg)
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
![Page 6: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/6.jpg)
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
![Page 7: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/7.jpg)
HES are Hydrolyzed by Plasma
α-Amylase
α-Amylase
Glucose
![Page 8: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/8.jpg)
Higher Molar Substitution Values Slow Hydrolysis
Product MW (kD)
C2/C6 Ratio (Ratio of CH2CH2OH groups at C2 vs. C6)
Molar Substitution
(Number of CH2CH2OH groups per glucose
subunit)
Half-Life
(hours)
Hespan/Hextend
670 5:1 0.7 46.3
Voluven 130 9:1 0.4 12.1
![Page 9: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/9.jpg)
Summary Basis for Approval
Hespan, Hextend, Voluven
![Page 10: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/10.jpg)
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)
![Page 11: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/11.jpg)
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
![Page 12: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/12.jpg)
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
15601
34 (59)538±694
25166
![Page 13: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/13.jpg)
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
![Page 14: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/14.jpg)
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
![Page 15: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/15.jpg)
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
![Page 16: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/16.jpg)
Voluven: Results Voluve
n(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±6.6 11.7± 9.9
FVIII activity <LLNEnd of surgery (number of subjects)
2h post surgery (number of subjects)5 0
13 7
Severe bleeding (number of subjects) 0 3
Elevated SCr (number of subjects) Peak SCr (mg/dL)
2 1.5, 3.3
1 2.7
RRT (number of subjects) 0 0
![Page 17: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/17.jpg)
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
![Page 18: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/18.jpg)
Labeling
Dosage & Administration SectionWarnings Section
![Page 19: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/19.jpg)
Dosage & Administration Section
(Highlights, Package Insert)
Hespan/Hextend
Recommended dose: 500-1000 mLUpper 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
![Page 20: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/20.jpg)
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
![Page 21: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/21.jpg)
Overall Safety Review
Adverse Reactions
![Page 22: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/22.jpg)
Adverse Reactions
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
![Page 23: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/23.jpg)
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
![Page 24: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/24.jpg)
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
![Page 25: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/25.jpg)
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
![Page 26: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/26.jpg)
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
![Page 27: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/27.jpg)
CRYSTMAS Study
• Results– Baseline clinical characteristics: no difference– Efficacy: no difference
Voluven
(N=100)
Normal Saline(N=96)
Volume (mL) required to achieve HDS
1379 1709
Time to achieve HDS (h) 11.8 14.3
![Page 28: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/28.jpg)
CRYSTMAS Study
Safety
Voluven
(N=100)
Normal Saline(N=96)
SARs (serious adverse reactions)
53 44
SARs leading to death 38 32
Doubling of SCr (number of subjects)
8 11
Required RRT Number of subjects
Duration of RRT (days)219.1
114.3
![Page 29: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/29.jpg)
RIFLE Classification of AKI
RIFLE class is determined based on the worst of either GRF or U/O criteria
![Page 30: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/30.jpg)
CRYSTMAS Study
Voluven(N=100)
NormalSaline(N=96)
Rifle Score (number of subjects)
None 77 73
Risk 13 11
Injury 4 5
Failure 5 7
Loss(>4 weeks) 1 0
ESKD (>3 months) 0 0
![Page 31: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/31.jpg)
CRYSTMAS Study
P=0.063 log rank test
Normal saline
VoluvenProportion of subjects without RRT
![Page 32: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/32.jpg)
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
![Page 33: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/33.jpg)
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)
![Page 34: Regulatory Overview of Hydroxyethyl Starch (HES) Solutions September 6, 2012 Laurence Landow MD Medical Officer, CBER](https://reader035.vdocuments.net/reader035/viewer/2022062515/56649c775503460f9492c5c0/html5/thumbnails/34.jpg)
Thank you for your attention