`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`205029Orig1s000
`
`STATISTICAL REVIEW(S)
`
`
`
`
`
`
`
`

`

`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
`
`S T A T I S T I C A L R E V I E W A N D E V A L U A T I O N
`CLINICAL STUDIES
`
`NDA #:
`Drug Name:
`Indication(s):
`
`Applicant:
`Date(s):
`Review Priority:
`Biometrics Division:
`Statistical Reviewer:
`Concurring Reviewers:
`Medical Division:
`Clinical Team:
`Project Manager:
`
`205029
`Epinephrine Injection, USP 1:1000 (mg/mL)
`increasing systemic arterial blood pressure in acute hypotensive
`states associated with septic shock
`Belcher Pharmaceuticals, LLC
`11/30/2012
`Standard
`Division of Biometrics I
`Steve Bai, Ph.D.
`James Hung, Ph.D. Director DBI
`Division of Cardiovascular and Renal Products
`Gail Moreschi, MD
`Russell Fortney
`
`Reference ID: 3370368
`
`

`

`Table of Contents
`1 EXECUTIVE SUMMARY.................................................................................................... 4
`2
`INTRODUCTION.................................................................................................................. 4
`2.1 OVERVIEW.......................................................................................................................... 4
`2.2 STATISTICAL ISSUES AND FINDINGS ................................................................................... 5
`2.3 DATA SOURCES .................................................................................................................. 5
`3 STATISTICAL EVALUATION........................................................................................... 5
`3.1 EVALUATION OF EFFICACY................................................................................................. 5
`3.1.1
`Literature Search Strategy.......................................................................................... 5
`3.1.2 Clinical Efficacy Studies............................................................................................. 6
`3.1.2.1
`Patients with septic shock and no previous vasopressor treatment..................................................................... 6
`3.1.2.2
`Patients with septic shock and previous treatment with dopamine or dobutamine............................................. 8
`3.1.2.3
`Patients with septic shock and failed response to dopamine .............................................................................. 9
`3.1.2.4
`Patients with septic shock, right ventricular failure, and failed response to dopamine and dobutamine ............ 9
`3.1.2.5
`Patients with septic shock or other conditions treated with epinephrine ............................................................ 9
`3.2 REVIEWER’S CONCLUSION ................................................................................................. 9
`4 CONCLUSIONS AND RECOMMENDATIONS............................................................. 11
`
`Reference ID: 3370368
`
`2
`
`

`

`LIST OF TABLES
`
`Table 1 Tabular Summary of efficacy studies from published literature I ................................. 6
`Table 2 Effects of MAP on epinephrine and norepinephrine-dobutamine, Levy(1997)........... 10
`
`LIST OF FIGURES
`
`Figure 1
`Effects of treatment on mean blood atrial pressure .................................................... 7
`Effects of Epinephrine and Dopexamine-Norepinephrine on MAP........................... 8
`Figure 2
`Figure 3 Hemodynamic data during epinephrine infusions ...................................................... 8
`Figure 4
`Blood pressure of Epinephrine in Lipman (1991) ...................................................... 9
`Figure 5
`Blood pressure effects of Epinephrine in Levy (1997)............................................... 9
`Figure 6
`Comparisons between epinephrine and norepinephrine on MAP in Myburgh......... 11
`
`Reference ID: 3370368
`
`3
`
`

`

`1 EXECUTIVE SUMMARY
`Belcher did not conduct any clinical studies to assess the potential benefit of Epinephrine
`Injection USP, 1:1000 (1 mg/mL) in the aspects of the artial blood pressure. In stead, Belcher
`relied on the established safety on the listed drug Twinject and the published literature. The
`clinical studies identified from the published literature seem to suggest that Epinephrine may
`have an effect to increase the arterial blood pressure, measured by MAP, in patients with septic
`shock. Although a large body of published literature is available, these studies do not rise to the
`level to be able to provide evidence for concluding the effectiveness of Epinephrine in increasing
`systemic arterial blood pressure in acute hypotensive states associated with septic shock.
`
`2 INTRODUCTION
`
`2.1 Overview
`
`Belcher submitted this 505(b) (2) application for Epinephrine Injection USP, 1:1000 (1mg/mL).
`The proposed indication is for use in increasing systemic arterial blood pressure in acute
`hypotensive states associated with septic shock. This submission relies on published literature to
`support the efficacy of Epinephrine. Belcher is relying on safety information from Twinject
`(NDA 20800). Twinject is an approved Epinephrine (0.3 mg/mL) product for use in the
`emergency treatment of severe allergic reactions (Type I).
`
`No clinical studies of Belcher’s Epinephrine Injection USP, 1:1000 (1 mg/mL) have been
`conducted. The Agency agreed that a literature-only NDA submission was acceptable on an End
`of Phase I meeting held on 25 July, 2012. The published literature was searched for clinical
`studies of epinephrine used in the treatment of shock. A search of PubMed, using the terms
`epinephrine (adrenaline), hypotension, infusion, shock, sepsis, septic shock, human, patients,
`study, and/or clinical trial was performed. Searching all fields for “(septic shock)”, “(blood
`pressure)”, “infusion”, “hypotension”, and “(epinephrine or adrenaline)” led to 33 results. From
`these studies, articles relevant to epinephrine’s use in hemodynamic support were reviewed, and
`14 key articles (emphasizing randomized, controlled studies comparing intravenous epinephrine
`to alternative treatments) were selected to be summarized.
`
`The Septic Shock (SS) in adults refers to a state of acute circulatory failure characterized by
`persistent arterial hypotension unexplained by other causes. Septic shock is a severe form of
`sepsis with arterial hypotension despite adequate body fluid resuscitation (replacement).
`Furthermore, the sepsis is the clinical syndrome defined by the presence of both infection and a
`systemic inflammatory response (SIRS), and more specifically, SIRS in response to infection.
`The Septic shock accounts for about 9% of admissions to intensive care units, and its short-term
`mortality ranges between 40% and 60%.
`
`Vasopressor is an intriguing hormone in that it has little vasoconstrictor effect in
`hemodynamically normal subjects, but is an important pressor in states where arterial pressure is
`threatened. It has been used in prevention and management of vasodilatory shock, as an
`alternative of catecholamine pressors. Intravenous Epinephrine has been used as a vasopressor
`
`4
`
`Reference ID: 3370368
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`

`for over 50 years in treating hypotension associated with septic shock, as epinephrine
`significantly improves systemic arterial blood pressure. Intravenous infusions of epinephrine are
`well-defined both in published clinical studies and the algorithms of numerous medical
`organizations around the world, and are consistently recommended for the management of
`hemodynamic support.
`
`2.2
`
`Statistical Issues and Findings
`
`The clinical efficacy data in this NDA come from published literatures. These studies were
`published and studied between the years of 1991 and 2007 within various countries. Therefore
`the data inherit biases such as publication bias, time lag bias, multiple publication bias, citation
`bias, language bias and outcome reporting bias.
`
`In the clinical studies identified to support efficacy, none of them meets the standards of
`“adequate and well controlled study” for conducting a confirmatory trial. Statistical issues are
`found in all the studies, such as the endpoint of interest, MAP, was never defined in any studies,
`some studies did not have pre-defined primary endpoint, multiple endpoints yet without
`multiplicity adjustment, selectively reporting study result, and etc.
`
`Therefore, the evidence for concluding the efficacy of Epinephrine in increasing systemic arterial
`blood pressure in acute hypotensive states associated with septic shock does not appear to be
`solid, because of the potential biases from published literature and the unresolved issues that
`hinder proper interpretation of the results of the studies. In this reviewer’s opinion, the results
`from the identified studies and analyses are only exploratory.
`
`2.3 Data Sources
`
`There are no SAS datasets in this submission. The literature references and sponsor’s summaries
`are stored in the directory of \\cdsesub1\EVSPROD\NDA205029 of the Center’s electronic
`document room.
`
`3 STATISTICAL EVALUATION
`
`3.1 Evaluation of Efficacy
`
`3.1.1 Literature Search Strategy
`
`Currently, there are several unapproved and at least 39 approved drug formulations containing
`epinephrine currently marketed. Epinephrine injection is available in 1 mg/mL, (1:1000), 0.1
`mg/mL (1:10,000), and 0.5 mg/mL (1:2,000) solutions. However, there is no FDA-approved
`intravenous epinephrine product for providing hemodynamic stabilization in septic shock
`patients. The only FDA-approved epinephrine products are intramuscular/ subcutaneous products
`(0.3 mg/delivery) for treating anaphylactic shock.
`
`5
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`Reference ID: 3370368
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`

`Epinephrine for treatment of hypotension associated with septic shock has been assessed in over
`two dozen clinical studies published in the literature. The sponsor conducted a comprehensive
`literature search using PubMed and identified 14 key studies, which they believe can be used to
`demonstrate that epinephrine significantly improves systemic arterial blood pressure in
`hypotensive states associated with septic shock.
`
`3.1.2 Clinical Efficacy Studies
`
`The individual summaries of studies from the literature are divided by previous treatment and
`patient type. They are grouped by section as follows:
`I.
`Patients with septic shock and no previous vasopressor treatment: 6 studies
`II.
`Patients with septic shock and previous treatment with dopamine or dobutamine: 1 study
`III.
`Patients with septic shock and failed response to dopamine: 4 studies
`IV.
`Patients with septic shock, right ventricular failure, and failed response to dopamine and
`dobutamine : 1 study
`Patients with septic shock or other conditions treated with epinephrine: 2 studies.
`
`V.
`
`3.1.2.1 Patients with septic shock and no previous vasopressor treatment
`
`The sponsor had identified six studies, which recruited patients with septic shock and had no
`previous vasopressor treatment, see Table 1.
`
`Tabular Summary of efficacy studies from published literature I
`Objective
`Study Design
`
`Compare norepi+dobutamine to epi in SS
`
`Multicenter,
`DB, randomized,
`active-controlled
`clinical trial
`Randomized,
`open-label trial
`
`Randomized,
`parallel group
`study
`Prospective
`clinical study
`
`Prospective
`study
`
`Open-label Study
`
`Table 1
`Author,
`year
`Annane,
`2007
`
`Seguin,
`2006
`
`Seguin,
`2002
`
`Moran,
`1993
`
`Wilson,
`1992
`
`Mackenzie,
`1991
`
`Reference ID: 3370368
`
`Compare norepi+dopexamine to epi in SS to assess
`effects on gastric mucosal blood flow and on
`oxidative stress
`Compare norepi+dobutamine to epi in SS to assess
`effects on systemic and pulmonary hemodynamics,
`hepatic function, and blood gases.
`To characterize the acute actions and physiologic
`dose profile of epi, as a single inotrope, in adult
`patients
`with SS
`To evaluate the effects of epi on Hemodynamics and
`oxygen transport when used as a first line inotropic
`agent in SS
`To document the effects of epi on hemodynamics
`and oxygen transport in patients with SS persisting
`after fluid loading
`[Source: Sponsor’s Table 2.7.3.6.1 of Summary of Clinical Efficacy]
`
`Patient
`Population
`330 septic
`shock
`patients
`
`22 septic
`shock
`patients
`22 septic
`shock
`patients
`9 male and 9
`female adult
`septic shock
`patients
`15 adult
`septic shock
`patients
`13 adult
`septic shock
`patients
`
`6
`
`

`

`Summary and conclusions:
`
`(cid:120) Five of above six studies are small, open-label, or single armed trials. Annane (2007) was the
`only large randomized double blind clinical trial, which conducted in 330 adults to compare
`the efficacy and safety of norepinephrine plus dobutamine with those of epinephrine alone.
`The primary outcome was 28-day all-cause mortality. There are various secondary outcome
`endpoints and blood pressure measurements were taken from the patients. No type I error
`rate was controlled for the secondary endpoints. The primary finding of the study was that
`there was no significant difference between the two groups in mortality rates. Comparing
`epinephrine to norepinephrine plus dobutamine, there were 64 (40%) versus 58 (34%) deaths
`at day 28 (p = 0.31). Arterial hypotension is a main hemodynamic parameter of sepsis, so
`another finding of the study was on the blood pressure. The study claimed that the mean
`blood pressure increased to much the same extent in both groups after randomization, see
`Figure 1.
`
`Figure 1 Effects of treatment on mean blood atrial pressure
`
`[Source: Annane 2007]
`
`(cid:120) Seguin (2006) was an open-label, parallel-group, randomized study performed in a surgical
`intensive care unit among adults fulfilling usual criteria for septic shock. Systemic and
`pulmonary hemodynamics, GMBF (laser-Doppler) and malondialdehyde were assessed just
`before catecholamine infusion (T0), as soon as mean arterial pressure (MAP) reached 70 to
`80 mmHg (T1), and 2 hours (T2) and 6 hours (T3) after T1. There was no significant
`difference between groups for MAP at T0, T1, T2, and T3.
`
`7
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`Reference ID: 3370368
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`Figure 2 Effects of Epinephrine and Dopexamine-Norepinephrine on MAP
`
`[Source: Seguin 2006]
`
`Epinephrine and dopexamine-norepinephrine both increased MAP in a similar extent when
`compared to baseline. It also appeared that blood pressures had been stabilized after T1 in
`both groups, see Figure 2.
`
`(cid:120) Seguin (2002) was a parallel group study comparing epinephrine (N = 11) with the
`combination of dobutamine and norepinephrine (N = 11) on gastric perfusion in patients with
`septic shock. At baseline, MAP was 54 ± 8 mmHg in the epinephrine and 51 ± 8 mmHg in
`the dobutamine-norepinephrine group, and at time of evaluation, MAP was 78 ± 3 mmHg in
`the epinephrine and 77 ± 5 mmHg in the dobutamine-norepinephrine group. Note, Seguin
`(2002) never stated when the time of evaluation is.
`
`(cid:120) Moran (1993) was a prospective clinical study conducted to characterize the acute actions
`and physiologic dose profile of epinephrine as a single inotrope in 9 male and 9 female adult
`(cid:83)(cid:68)(cid:87)(cid:76)(cid:72)(cid:81)(cid:87)(cid:86) (cid:90)(cid:76)(cid:87)(cid:75) (cid:86)(cid:72)(cid:83)(cid:87)(cid:76)(cid:70) (cid:86)(cid:75)(cid:82)(cid:70)(cid:78)(cid:17) (cid:44)(cid:81) (cid:87)(cid:75)(cid:72) (cid:71)(cid:82)(cid:86)(cid:72) (cid:85)(cid:68)(cid:81)(cid:74)(cid:72) (cid:82)(cid:73) (cid:22) (cid:87)(cid:82) (cid:20)(cid:27) (cid:541)(cid:74)(cid:18)(cid:80)(cid:76)(cid:81)(cid:15) (cid:72)(cid:83)(cid:76)(cid:81)(cid:72)(cid:83)(cid:75)(cid:85)(cid:76)(cid:81)(cid:72) (cid:83)(cid:85)(cid:82)(cid:71)(cid:88)(cid:70)(cid:72)(cid:71) (cid:79)(cid:76)(cid:81)(cid:72)(cid:68)(cid:85)
`increases in MAP, see Figure 3.
`
`Figure 3 Hemodynamic data during epinephrine infusions
`
`[Source: Moran (1993)]
`
`3.1.2.2 Patients with septic shock and previous treatment with dopamine or dobutamine
`
`Lipman (1991) was an open-label, single-group study in 10 patients with 11 episodes of septic
`shock to assess the hemodynamic effects of epinephrine in septic shock. The study showed that
`epinephrine increased MAP from baseline, see Figure 4.
`
`8
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`Reference ID: 3370368
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`

`Figure 4
`
`Blood pressure of Epinephrine in Lipman (1991)
`
`[Source: Lipman (1991)]
`
`3.1.2.3 Patients with septic shock and failed response to dopamine
`
`In these patients, Levy (1997) showed that epinephrine increased MAP when compared to
`baseline to a similar extent as norepinephrine with or without dobutamine, see Figure 5. The
`study enrolled 30 septic shock patients. The measurements were repeated 1, 6, 12 and 24 hours
`post baseline.
`
`Figure 5
`
`Blood pressure effects of Epinephrine in Levy (1997)
`
`[Source: Levy (1997)]
`
`3.1.2.4 Patients with septic shock, right ventricular failure, and failed response to
`dopamine and dobutamine
`
`Le Tulzo (1997) was a descriptive study with 14 septic shock patients, which showed the MAP
`increased to 74 mmHg within 2 hours after Epinephrine was started. The baseline MAP was 58
`mmHg.
`
`3.1.2.5 Patients with septic shock or other conditions treated with epinephrine
`
`Myburgh (2008) compared MAP between epinephrine (N=76) and norepinephrine (N=82), and
`claimed that epinephrine increased MAP compared to baseline to a similar extent as
`norepinephrine.
`
`3.2 Reviewer’s Conclusion
`
`Belcher did not conduct any clinical studies for Epinephrine Injection USP, 1:1000 (1 mg/mL).
`This NDA is a literature-based submission, which presented the summaries of efficacy results
`and key design elements of published articles found during searches of the literature. The
`reviewer had examined and provided the snapshots of the 14 key reference studies in the
`
`9
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`Reference ID: 3370368
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`

`

`previous sections. The findings on potential benefit on MAP were based on it being post-hoc
`endpoint and post-hoc analysis in above studies. These were driven by post-hoc explorations.
`Thus, these studies are exploratory to generate some interesting hypotheses.
`
`The applicant attempted to argue that in studies including patients with septic shock that assessed
`MAP in comparison to pretreatment values, epinephrine was shown to have effects on MAP. The
`reviewer has the following observations based on 4 double-blinded, active controlled studies:
`
`(cid:120) Annane (2007) is the only large double-blinded, randomized active-controlled clinical trial.
`The study did not list MAP as one of the efficacy endpoints, Figure 1 showed blood pressure
`quickly increased just after 2 days of treatment in both treatment groups and appeared to
`maintain the blood pressure goal of 70 to 80 mmHg throughout the remainder of the trial.
`
`(cid:120) Seguin (2002) compared various systemic and pulmonary hemodynamic values between 11
`Epinephrine and 11 dobutamine-norepinephrine patients. As the review had stated in the
`Section 3.2.2.1, that both groups raised MAP effectively at the time of evaluation. There was
`no significant difference between groups regardless of the systemic and pulmonary
`hemodynamic or blood gas variable considered.
`
`(cid:120) Levy (1997) was a prospective, randomized clinical trial to compare the effects of
`norepinephrine and dobutamine (N = 15) to epinephrine (N = 15) on hemodynamics, lactate
`metabolism, and gastric tonometric variables. No statistical difference was found between
`epinephrine and norepinephrine-dobutamine for systemic hemodynamic measurements.
`These measurements were repeated after 1, 6, 12, and 24 hours. As we can see from Table 2,
`epinephrine increased MAP from the baseline in both treatment groups.
`
`Table 2
`
`Effects of MAP on epinephrine and norepinephrine-dobutamine, Levy(1997)
`
`[Source: Levy (1997)]
`
`(cid:120) Myburgh (2008) was another large multicenter, double-blind, randomized, controlled trial
`conducted to determine whether there was a difference between epinephrine (N = 139 [76
`had septic shock]) and norepinephrine (Levophed; N = 138 [82 had septic shock]) in
`achieving MAP goal in a heterogeneous population of ICU patients requiring vasopressors
`for any cause at randomization. Patients with septic shock (N = 158; septic patients who
`required study drug were considered to have septic shock) and acute circulatory failure (N =
`128) were analyzed separately. Primary outcome was achievement of MAP goal for more
`than 24 hours without vasopressors. Secondary outcomes were 28 and 90-day mortality.
`
`10
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`Reference ID: 3370368
`
`COPYRIGHT MATERIAL WITHHELD
`
`

`

`Figure 6
`
`Comparisons between epinephrine and norepinephrine on MAP in Myburgh
`
`[Source: Myburgh (2008)]
`
`The sponsor attempted to use Figure 6 suggest that the epinephrine increased MAP compared
`to baseline to a similar extent as norepinephrine. However, there are two curves with
`opposite trend in the figure, solid and hollow bullets. The paper never explained which curve
`is MAP.
`
`The identified four active controlled studies seem to suggest that Epinephrine may have an effect
`on improving arterial blood pressure in patients with septic shock. However, these clinical
`efficacy data came from published literatures. These data potentially inherited number of biases
`such as publication bias, time lag bias, multiple publication bias, citation bias, and outcome
`reporting bias. Furthermore, none of them met the standards of “adequate and well controlled
`confirmatory trial.” None of them provided the endpoint of interest, MAP, as the efficacy
`endpoint and some studies have multiple endpoints yet without multiplicity adjustment. There is
`another common statistical issue with all the active controlled studies. These studies are all
`designed as superiority studies, but all of them attempted to show the equivalence between the
`treatment arms in the specified primary efficacy endpoint, respectively. Therefore, based on
`these statistical issues, these studies do not provide conclusive evidence for the effectiveness of
`Epinephrine in terms of raising blood pressure. However, they may provide some possible
`signals on these benefits.
`
`4 CONCLUSIONS AND RECOMMENDATIONS
`Belcher did not conduct any clinical studies to assess the potential benefit of Epinephrine
`Injection USP, 1:1000 (1 mg/mL) in the aspects of the artial blood pressure. In stead, Belcher
`relied on the established safety on the listed drug Twinject and the published literature. The
`clinical studies identified from the published literature seem to suggest that Epinephrine may
`have an effect to increase the arterial blood pressure, measured by MAP, in patients with septic
`shock. Although a large body of published literature is available, these studies do not rise to the
`level to be able to provide evidence for concluding the effectiveness of Epinephrine in increasing
`systemic arterial blood pressure in acute hypotensive states associated with septic shock.
`
`11
`
`Reference ID: 3370368
`
`COPYRIGHT MATERIAL WITHHELD
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`STEVE G BAI
`09/09/2013
`
`HSIEN MING J HUNG
`09/09/2013
`
`Reference ID: 3370368
`
`

`

`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`NDA Number: 205029
`Drug Name:
`
`
`Applicant: Belcher Pharmaceuticals, Stamp Date: 12/4/2012
`NDA/BLA Type: NDA literature
`based 505(b)(2)
`
`On initial overview of the NDA/BLA application for RTF:
`
`2
`
`3
`
`
`1
`
`Content Parameter
`Index is sufficient to locate necessary reports, tables, data,
`etc.
`ISS, ISE, and complete study reports are available
`(including original protocols, subsequent amendments, etc.)
`Safety and efficacy were investigated for gender, racial,
`and geriatric subgroups investigated (if applicable).
`4 Data sets in EDR are accessible and do they conform to
`applicable guidances (e.g., existence of define.pdf file for
`data sets).
`
`Yes No NA
`X
`
`Comments
`
`X
`
`X
`
`X
`
`IS THE STATISTICAL SECTION OF THE APPLICATION FILEABLE? __Yes______
`
`If the NDA/BLA is not fileable from the statistical perspective, state the reasons and provide
`comments to be sent to the Applicant.
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
`Content Parameter (possible review concerns for 74-
`day letter)
`Designs utilized are appropriate for the indications requested.
`Endpoints and methods of analysis are specified in the
`protocols/statistical analysis plans.
`Interim analyses (if present) were pre-specified in the protocol
`and appropriate adjustments in significance level made.
`DSMB meeting minutes and data are available.
`Appropriate references for novel statistical methodology (if
`present) are included.
`Safety data organized to permit analyses across clinical trials
`in the NDA/BLA.
`Investigation of effect of dropouts on statistical analyses as
`described by applicant appears adequate.
`
`Yes No
`
`NA Comment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`X
`X
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`X
`
`X
`
`X
`
`X
`
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`
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`
`
`
`
`
`
`File name: 5_Statistics Filing Checklist for a New NDA 205029
`Reference ID: 3248937
`
`(b) (4)
`
`

`

`STATISTICS FILING CHECKLIST FOR A NEW NDA/BLA
`
`Steve Bai
`Reviewing Statistician
`
`
`
`James Hung
`Supervisor/Team Leader
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1/23/2013
` Date
`
`1/23/2013
`Date
`
`
`
`File name: 5_Statistics Filing Checklist for a New NDA 205029
`Reference ID: 3248937
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`STEVE G BAI
`01/23/2013
`
`HSIEN MING J HUNG
`01/23/2013
`
`Reference ID: 3248937
`
`