Statistical Reviewer: Jiang Hu

STN: 125329/112

Application Type BLA

STN 125329/112

CBER Received Date September 29, 2014

PDUFA Goal Date July 30, 2015

Division / Office OBRR/DH

Committee Chair
Clinical Reviewer(s) Daniela Vanco, M.D.

Project Manager Edward Thompson

Priority Review No

Reviewer Name(s) Jiang Hu, Ph.D.

Review Completion Date /

Stamped Date
Supervisory Concurrence Renée C. Rees, Ph.D. Team Leader, Therapeutics
Evaluation Branch, (HFM-219)
Boguang Zhen, Ph.D., Branch Chief, Therapeutics
Evaluation Branch, (HFM-219)

Applicant Bio Products Laboratory

Established Name Immune Globulin Intravenous [Human], 5% Liquid

(Proposed) Trade Name Gammaplex

Pharmacologic Class
Formulation(s), including
Adjuvants, etc
Dosage Form(s) and Liquid solution containing 5%IgG (50 mg/mL)

Route(s) of Administration
Dosing Regimen 300-800 mg/kg every 3-4 weeks

Indication(s) and Intended This supplement seeks to extend Gammaplex’s

indication in treating Primary Immunodeficiency
Population(s) Disease from adult patients to pediatric patients (>2
to 16 years of age).

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Table of Contents

Glossary .............................................................................................................................. 3

1. Executive Summary ........................................................................................................ 4

2. Clinical and Regulatory Background .............................................................................. 4

2.1 Disease or Health-Related Condition Studied ............................................................................... 4
2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s) for the
Proposed Indication ....................................................................................................................... 4
2.4 Previous Human Experience with the Product (Including Foreign Experience) ....................... 5
2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the Submission .......... 5
3. Submission Quality and Good Clinical Practices ........................................................... 5
3.1 Submission Quality and Completeness .......................................................................................... 5
5. Sources of Clinical Data and Other Information Considered in the Review .................. 5
5.1 Review Strategy ............................................................................................................................... 5
5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review................................... 6
5.3 Table of Studies/Clinical Trials ...................................................................................................... 6
6. Discussion of Individual Studies/Clinical Trials ............................................................ 6
6.1.2 Design Overview ..................................................................................................................... 6
6.1.3 Population ............................................................................................................................... 7
6.1.4 Study Treatments or Agents Mandated by the Protocol .......................................................... 9
6.1.6 Sites and Centers ..................................................................................................................... 9
6.1.7 Surveillance/Monitoring.......................................................................................................... 9
6.1.8 Endpoints and Criteria for Study Success ............................................................................... 9
6.1.9 Statistical Considerations & Statistical Analysis Plan ...........................................................10
6.1.10 Study Population and Disposition ........................................................................................11
6.1.11 Efficacy Analyses .................................................................................................................13
6.1.12 Safety Analyses ....................................................................................................................17
10. Conclusions ................................................................................................................. 18
10.1 Statistical Issues and Collective Evidence ..................................................................................18
10.2 Conclusions and Recommendations............................................................................................18

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GLOSSARY
AE(s) Adverse event(s)
AESI Adverse Events of Special Interest
ALT Alanine aminotransferase
AR Adverse Reaction
AST Aspartate aminotransferase
BLA Biologics License Application
BUN Blood urea nitrogen
CI Confidence interval
CL Confidence limit
CVID Common variable immunodeficiency
HCG Human chorionic gonadotrophin
IgA Immunoglobulin A
IgG Immunoglobulin G
IGIV Intravenous immunoglobulin
ISG Immune serum globulin
ITP Idiopathic Thrombocytopenic Purpura
IP Investigated product
IV Intravenously
ITT Intent-to-treat
LDH Lactate dehydrogenase
MHRA Medicines and Healthcare products Regulatory Agency
PAS Prior Approval Supplement
PID Primary immunodeficiency disease
PIP Pediatric Investigational Plan
PK Pharmacokinetics
PLV Product License Variation
PMR Postmarketing Requirements
SABI Serious, Acute, Bacterial Infections
SAE Serious Adverse Event
sBLA Supplementary Biologics License Application
SCIG Subcutaneous immunoglobulin
SD Standard deviation
ULN Upper limit of normal

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1. Executive Summary
This submission is an efficacy Prior Approval Supplement (PAS) to fulfill a deferred
pediatric requirement for Gammaplex (BLA 125329, approved on September 19, 2009).
The objective of this BLA supplement is to extend the age range of patients suitable for
Gammaplex to include the pediatric population.

This submission includes the final report of a phase 4, multicenter, open-label study
(GMX04) to evaluate the efficacy and safety of Gammaplex in primary
immunodeficiency diseases (PID) in pediatric patients between 2 and 16 years of age.

This study enrolled 25 pediatric subjects. The primary efficacy endpoint is Serious, Acute,
Bacterial Infection (SABI) rate. With a 0.085 infection rate per subject year, the one-sided
99% upper confidence limit was 0.358 per subject year, which is less than FDA’s efficacy
threshold value of 1. For the safety endpoint of the proportion of infusions associated with
one or more Adverse Events (AEs) that begin during the infusion or within 72 hours after
completion of the infusion, the upper one-sided 95% confidence limit for the proportion of
infusions with at least one temporally associated AE (regardless of relationship) was
30.4%, less than the pre-specified criterion of 40%. The statistical report supports the
indication of Gammaplex in pediatric patients with PID in both efficacy and safety.

Comparison of data from this pediatric study with those from the previous study of
mostly adult subjects (GMX01) identified no clinically significant differences in the
efficacy, safety and tolerability of Gammaplex between adults and children. There is no
statistical issue in the submission.

2. Clinical and Regulatory Background

2.1 Disease or Health-Related Condition Studied

Primary immunodeficiency diseases are a heterogeneous group of disorders that involve
an intrinsic defect in tissues, cells and/or proteins of the immune system that result in
immune deficiency. Many of these disorders are characterized by
hypogammaglobulinaemia and/or defective antibody production and, as a consequence,
increased susceptibility to infection.

2.2 Currently Available, Pharmacologically Unrelated Treatment(s)/Intervention(s)

for the Proposed Indication
Replacement therapy with immunoglobulin G (IgG), purified from pools of plasma from
multiple donors, has been used since the early 1950s. The initial products were
administered intramuscularly but were of limited efficacy because of the relatively small
quantities that could be administered by that route. Intravenous (IV) immunoglobulin
(IGIV) became available in the US in the 1980s and, along with subcutaneous
immunoglobulin (SCIG) therapy, has since become the current treatment of choice for
patients with PID whose humoral immunity is impaired.

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2.4 Previous Human Experience with the Product (Including Foreign Experience)
Gammaplex® (immune globulin intravenous [human] 5% liquid) is a highly purified
unmodified human IgG product intended for IV administration. Gammaplex is
manufactured by Bio Products Laboratory Ltd. (BPL) (London, UK) using plasma from
healthy US donors. It was licensed by the FDA on September 17, 2009 for use in PID in
adults. Gammaplex is now licensed in the UK (approved on March 15, 2012), Israel
(February 13, 2011), Brazil (July 16, 2012), and Lebanon (Feb 15, 2014).

2.5 Summary of Pre- and Post-submission Regulatory Activity Related to the

Submission
The original BLA submission for Gammaplex was approved by FDA with a deferred
pediatric study requirement as a post-marketing requirement (PMR) for ages ≥2 to 16
years; a pediatric study requirement for ages 0 to <2 years was waived. A deferral
extension for the PMR was granted by the FDA on September 25, 2013 (125329/66) to
extend the final report submissions to December 2014.

A supplemental biologics license application (sBLA) to extend the clinical use of

Gammaplex to include chronic autoimmune (idiopathic) thrombocytopenic purpura (ITP)
was approved for adults by the FDA on March 08, 2013 (125329/55). The pediatric
requirement was exempt for the ITP indication because the biological product for ITP
indication has an orphan drug designation. During the licensure for the product in ITP, the
US Prescribing Information was changed to exclude children with PID in 2013.

The GMX04 study included in this BLA supplement is a phase 4 study in a pediatric
population with PID conducted under IND 12569. This study was first presented to FDA
as a phase 3 study in 2011, but the applicant was informed that GMX04 should be
defined as a phase 4 study. BPL’s rationale for conducting study GMX04 is to extend the
age range for the Gammaplex license to include pediatric patients for the PID indication.

3. SUBMISSION QUALITY AND GOOD CLINICAL PRACTICES

3.1 Submission Quality and Completeness

This submission was adequately organized for conducting a complete statistical review
without unreasonable difficulty.

5. SOURCES OF CLINICAL DATA AND OTHER INFORMATION CONSIDERED IN

THE REVIEW

5.1 Review Strategy

This review memo focuses on both efficacy analyses and safety analyses of the pediatric
study GMX04. GMX01 was the pivotal study for the adult PID indication and GMX02 for
the ITP indication.

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5.2 BLA/IND Documents That Serve as the Basis for the Statistical Review
The following documents of 125329/112 formed the basis of this review.
• 2.5 Clinical Overview
• 2.7.2 Summary of Clinical Pharmacology Studies
• 2.7.3 Summary of Clinical Efficacy
• 2.7.4 Summary of Clinical Safety
• 5.3.5.2 – Study-report GMX04
This reviewer also used the original BLA 125329/0 as a reference.

5.3 Table of Studies/Clinical Trials

Table 1 summarizes all clinical studies for this product.

Table 1: Listing of clinical studies for Gammaplex

Study name Study type Study status Number subjects Indication Main criteria for
treated inclusion
Single-arm,
Open-label, ≥16 years
GMX01 complete 50 PID
Multi-center,
Phase 3
Single-arm,
Open-label, ITP
GMX02 complete 35 ≥6 years
Multi-center
Phase 3
Single-arm,
Open-label, ≥2 years, <16
GMX04 complete 25 PID
Multi-center, years
Phase 4

6. DISCUSSION OF INDIVIDUAL STUDIES/CLINICAL TRIALS

6.1 Trial #1: GMX04

6.1.1 Objectives
The primary objective of GMX04 is to determine the efficacy of Gammaplex by
measuring the number of SABIs over a 12-month period in pediatric and adolescent
subjects.

Secondary objectives include 1) to assess the safety and tolerability of Gammaplex in

pediatric and adolescent subjects, and 2) to compare the efficacy and safety data from this
study with that collected from adults in the GMX01 study.

6.1.2 Design Overview

This was a phase 4, multicenter, open-label, non-randomized study of Gammaplex.
Subjects were to receive 13 to 17 infusions (i.e. 12 months of therapy on either a 21-day
or 28-day treatment schedule) of Gammaplex.

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The total planned duration of treatment for each subject was 12 months. The total
duration of a given subject’s participation in this study was up to 16 months, including
screening (up to 30 days before enrolment), a 12-month treatment period and a 3-month
follow-up period.

The design of this open-label study, including the primary objective, primary efficacy
variable and analysis of the primary efficacy variable, was in accordance with the FDA
Guidance Safety, Efficacy, and Pharmacokinetics Studies to Support Marketing of
Immune Globulin Intravenous (Human) as Replacement Therapy for Primary Humoral
Immunodeficiency, dated June 2008.

6.1.3 Population
In order to qualify for the study, each subject had to satisfy all the criteria listed below:
1. The subject was between the age of, or was equal to, 2 and 16 years of age, of
either sex, belonging to any ethnic group and above a minimum weight of 10 kg.
At least four of the subjects enrolled were to be between 2 to 5 years of age, at
least four were to be between 6 to 11 years of age and at least eight were to be
between 12 to 16 years of age.
2. The subject had a PID, which had as a significant component
hypogammaglobulinaemia and/or antibody deficiency (e.g. common variable
immunodeficiency [CVID], X-linked and autosomal forms of
agammaglobulinaemia, hyper-immunoglobulin M [IgM] syndrome, Wiskott-
Aldrich Syndrome). Isolated deficiency of a single IgG subclass, or of specific
antibodies without hypogammaglobulinaemia per se, did not qualify for inclusion.
3. The subject required the following before the first infusion of Gammaplex:
o Documented IGIV dose(s) and treatment intervals for the last two
consecutive routine IGIV treatments (one of which could be the screening
visit result). The previous doses also should have met the following
conditions before study entry:
• Had not changed by ± 50% of the mean dose for at least 3 months.
• Was between 300 and 800 mg/kg/infusion.
• Was given every 21-28 days, inclusive.
• Was a licensed or investigational product (IP) (phase 3 or 3b).
o Documented previous IgG trough levels for the last two consecutive
routine IGIV treatments:
• Maintained at least 300 mg/dL above baseline serum IgG levels
(defined as before initiation of any gamma globulin treatment for
that subject).
• Must have been ≥ 600 mg/dL.
4. If a subject was a female of child-bearing potential, she must have had a negative
result on a human chorionic gonadotrophin (HCG)-based pregnancy test.
5. If a subject was a female who was or became sexually active, she must have
practiced contraception by using a method of proven reliability for the duration of
the study.
6. The subject was willing to comply with all aspects of the protocol, including
blood sampling, for the duration of the study.

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7. The subject, if old enough (generally 6 to 16 years), had signed a Child Assent
Form and the subject’s parent or legal guardian had signed the Informed Consent
Form, both approved by the IEC/IRB.

Subjects were excluded if any of the following exclusion criteria were met:
1. The subject had not been treated with IGIV (treatment-naïve subject).
2. The subject had a history of any severe anaphylactic reaction to blood or any
blood-derived product.
3. The subject was known to be intolerant to any component of Gammaplex, such
assorbitol (i.e. intolerance to fructose).
4. The subject had selective immunoglobulin A (IgA) deficiency, history of reaction
to products containing IgA or had a history of antibodies to IgA.
5. Subjects who had completed the study and subjects who had withdrawn could not
participate in the study for a second time.
6. The subject was currently receiving, or had received, any investigational agent,
other than an immune serum globulin (ISG) preparation, that was being evaluated
in a phase 3 or 3b study within the prior three months.
7. The subject had been exposed to blood or any blood product or derivative within
the last six months, other than a commercially available IGIV or other forms of
commercially available and licensed ISG. If an unlicensed ISG product that was
in phase 3 or 3b had been given, the subject could not be infused with
Gammaplex until 20 days after the last dose was given.
8. The subject was pregnant or nursing.
9. The subject, at Screening, had levels greater than 2.5 times the upper limit of
normal (ULN) as defined at the central laboratory of any of the following: alanine
aminotransferase (ALT), aspartate aminotransferase (AST) or lactate
dehydrogenase (LDH).
10. The subject had a severe renal impairment (defined as serum creatinine greater
than 2 times the ULN or blood urea nitrogen [BUN] greater than 2.5 times the
ULN for the range of the laboratory doing the analysis); the subject was on
dialysis; the subject had a history of acute renal failure.
11. The subject was known to abuse alcohol, opiates, psychotropic agents or other
chemicals or drugs, or had done so within the past 12 months.
12. The subject had a history of deep vein thrombosis or thrombotic complications of
IGIV therapy.
13. The subject suffered from any acute or chronic medical condition (e.g. renal
disease or predisposing conditions for renal disease, coronary artery disease or
protein-losing state) that, in the opinion of the investigator, may have interfered
with the conduct of the study.
14. The subject had an acquired medical condition, such as chronic or recurrent
neutropenia (absolute neutrophil count < 1 × 109/L) or AIDS known to cause
secondary immune deficiency or was post or recovering from haematopoietic
stem cell transplantation.
15. The subject was receiving the following medication: systemic long-term
corticosteroids (i.e. not intermittent or burst, daily, > 1 mg of prednisone
equivalent/kg/day).

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16. The subject was receiving immunosuppressive or immunomodulatory drugs.

17. The subject had non-controlled arterial hypertension.
18. The subject had anaemia (haemoglobin < 10 g/dL) at Screening.

6.1.4 Study Treatments or Agents Mandated by the Protocol

Gammaplex was administered by intravenous infusion at a dosage of 300-800 mg/kg per
infusion (at the same dose of IGIV that was previously used to establish steady state),
once every 21 or 28 days.

6.1.6 Sites and Centers

There were nine sites in this study, with seven in the US, one in Chile and one in Israel.

6.1.7 Surveillance/Monitoring
No data monitoring committee was planned for this study.

6.1.8 Endpoints and Criteria for Study Success

The primary endpoint was the number of SABI per subject per year. It was based on pre-
specified events (i.e. bacterial pneumonia, bacteraemia or sepsis, osteomyelitis/septic
arthritis, visceral abscess and bacterial meningitis) in accordance with definitions
provided in the FDA guidance regarding use of IGIV as replacement therapy for primary
humoral immunodeficiency. An estimate of the SABI rate for Gammaplex was calculated
by dividing the total number of SABI events by the total number of subject years. The
number of subject years was obtained by summing the total subject days and dividing by
365. The subject study duration (days) was calculated as (date of last visit) – (date of
first infusion) +1. The one-sided 99% upper confidence limit for the annual SABI rate must
be less than 1 to meet the efficacy recommendation in the FDA Guidance Safety, Efficacy,
and Pharmacokinetics Studies to Support Marketing of Immune Globulin Intravenous
(Human) as Replacement Therapy for Primary Humoral Immunodeficiency, dated June
2008.

Secondary efficacy endpoints include the following variables:

• Number and proportion of subjects from Week 15 onwards who maintain trough IgG
levels at least as high as the average of the two previous trough levels before the first
Gammaplex infusion
• Number of days of school missed because of infection per subject year
• Number and days of hospitalizations because of infection per subject year
• Number of visits to physicians for acute problems and/or number of visits to hospital
emergency rooms per subject year
• Other infections documented by fever or a positive result on a radiograph and/or
culture per subject year
• Number of infectious episodes per subject per year
• Number of days on therapeutic and prophylactic antibiotics

Safety endpoints include assessment of:

• Adverse Events (AEs)

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 The number and percent of infusions associated with one or more AEs that
begin during the infusion or within 72 hours after completion of the infusion
will be calculated.
 Nature, severity, and frequency of AEs (tolerability)
 Suspected unexpected serious adverse reactions (SUSARs), if any
• Vital signs
• Clinical laboratory tests and Direct Coombs’ Test
• Transmission of viruses
• Physical examination

An important safety endpoint of this study is the proportion of infusions with at least one
AE that occurred during the infusion or within 72 hours after completion of the infusion.
If the upper bound of the one-sided 95% confidence interval (CI) of this proportion is less
than 40%, the incidence of infusion-related AEs associated with Gammaplex is
considered acceptable.

6.1.9 Statistical Considerations & Statistical Analysis Plan

For the primary efficacy analysis, the SABI rate for Gammaplex and the upper bound of
its one-sided 99% CI were estimated using the exact method for a one-sample Poisson
rate.

Sensitivity analyses using Poisson regression and weighted Poisson regression were also
planned. In the Poisson regression model, the upper one-sided 99% confidence bound
was obtained by using the generalized linear model for Poisson regression with the log
link. In the weighted Poisson regression, the weights was added in the Poisson regression
model and defined as the length of study time of each subject, i.e., weight = min (1,
number of days on study/365). Both models were performed with (b) (4) in SAS.

Secondary efficacy variables were summarized descriptively.

For safety, the number and percent of infusions with at least one AE that occurred during
the infusion or within 72 hours after completion of the infusion were calculated, and a
one-sided 95% CI was derived. Other safety assessments were summarized descriptively
by treatment group.

All subjects who received at least one infusion of Gammaplex were included in the
intent-to-treat (ITT) population. The ITT population was used for both efficacy and
safety analyses.

Age (years) was calculated as (date-of informed consent - date of birth)/365.25, rounded
down to the nearest whole number. Three categories in age were defined: 2-5 years, 6-11
years, and 12-16 years.

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6.1.10 Study Population and Disposition

6.1.10.1 Populations Enrolled/Analyzed

A total of 25 subjects were enrolled in the study and treated with Gammaplex.

All of the 25 subjects were included in the ITT population.

The PK population included 23 subjects. One subject (Subject (b) (6) ) discontinued
early and a second subject (Subject (b) (6) ) had limited PK samples taken because of
school commitments; therefore, these two subjects were excluded from the PK analysis.

6.1.10.1.1 Demographics

Table 2 summarizes the demographic and baseline characteristics for the ITT population.

Table 2: Demographic and Baseline Characteristics (ITT)

21-Day Infusion 28-Day Infusion Total
Schedule Schedule (N=25)
(N=14) (N=11)
Age (years)
Mean (SD) 11.8 (3.47) 8.5 (3.64) 10.4 (3.84)
Median 12.5 7.0 11.0
Min, Max 4, 16 3, 16 3, 16

Age group, n (%)

2-5 years 1 (7.1) 2 (18.2) 3 (12.0)
6-11 years 5 (35.7) 7 (63.6) 12 (48.0)
12-16 years 8 (57.1) 2 (18.2) 10 (40.0)

Gender, n (%)
Male 9 (64.3) 10 (90.9) 19 (76.0)
Female 5 (35.7) 1 (9.1) 6 (24.0)

Race, n (%)
Caucasian 14 (100) 11 (100) 25 (100)

Diagnosis, n (%)
Common variable 13 (92.9) 9 (81.8) 22 (88.0)
immunodeficiency (CVID)
X-linked and autosomal 1 (7.1) 2(18.2) 3 (12.0)
forms of
agammaglobulinaemia
Hyper-IgM syndrome 0 0 0
Wiskott-Aldrich syndrome 0 0 0

Baseline chest X-ray, n (%)

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Normal 12 (85.7) 11 (100) 23 (92.0)

Abnormal 2 (14.3) 0 2 (8.0)
Any planned elective
procedures scheduled, n (%)
Yes 1 (7.1) 0 1 (4.0)
No 13 (92.9) 11 (100) 24 (96.0)
Source: Original sBLA 125329/112; study report gamx04.report, Table 11-1, p.60.

The median age of subjects was 11.0 years and ranged from 3 to 16 years. Three subjects
were between the ages of 2 to 5 years, 12 subjects between the ages of 6 to 11 years and
10 subjects were between the ages of 12 to 16 years. Subjects were predominantly male
(19 subjects, 76.0%). All of the subjects were Caucasian. Twenty-two subjects (88.0%)
entered the study with a diagnosis of CVID, and the remaining 3 subjects had a diagnosis
of X-linked agammaglobulinaemia. The baseline chest X-ray was interpreted as normal
for 23 subjects (92.0%); one subject (Subject (b) (6) ) h ad a baseline chest X-ray
finding of mild blunting of the costophrenic angles, and one subject (Subject (b) (6) )
had a finding of slight scoliosis and dextroscoliosis. Only one subject had a planned
elective procedure.

6.1.10.1.2 Medical/Behavioral Characterization of the Enrolled Population

All 25 subjects had at least one pre-existing medical condition other than PID (Table 3).
The most common systems affected were ear, nose and throat disorders (22 subjects,
88.0%) and respiratory disorders (20 subjects, 80.0%).

Table 3: Medical conditions for ITT population

Medical condition Number of Percentage
subjects (N=25)
Ear, nose, and throat 22 88%
disorders
Respiratory disorders 20 80%
Immune/allergy history 16 64%
Chronic sinusitis 15 60%
Allergic rhinitis 11 44%
Gastrooesophageal reflux 10 40%
disease
Source: Adapted from sBLA 125329/112, study-report gmx04.pdf, Section 11.2.2, page 61.

All 25 subjects had prior IGIV therapy. Prior IGIV therapy included Gamunex (9
subjects, 36.0%), Gammagard (4 subjects, 16.0%), Flebogamma (7 subjects, 26.0%),
Gammaplex liquid 5% (3 subjects, 12.0%) and Carimune, Omrigam, Privigen and
Sandoglobulin (1 subject each, 4.0%). Two subjects (8.0%) received NewGam (Octagam
10%).

The mean baseline trough IgG (prior IGIV treatment) was 973.8 mg/dl (SD 160.82
mg/dl).

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6.1.10.1.3 Subject Disposition

A summary of subject disposition is reported in Table 4.

Table 4: Subject Disposition

21-Day Infusion 28-Day Infusion
Schedule Schedule Total
(N=14) (N=11) (N=25)
n (%) n (%) n (%)
Enrolled 14 (100) 11 (100) 25 (100)
ITT population 14 (100) 11 (100) 25 (100)
PK population 13 (92.9) 11 (100) 24 (96.0)
Completed treatment 13 (92.9) 11 (100) 24 (96.0)
Discontinued treatment 1 (7.1) 0 1 (4.0)
Subject withdrew consent 1 (7.1) 0 1 (4.0)
Source: Adapted from sBLA 125329/112, study-report gmx04.pdf, Section 10.1, Table10-1, page 58.

6.1.11 Efficacy Analyses

6.1.11.1 Analyses of Primary Endpoint(s)

The estimate of SABI rate was obtained by dividing the total number of SABI events by
the total number of subject years. The total number of subject years was 23.44 (8557
days). Table 5 lists the study duration for all 25 subjects.

Table5: Subject duration (days)

Subject Duration Subject Duration Subject Duration
(b) (6) 88
342 (b) (6) 345
356
(b) (6) 369
350
355 343 352
355 347 350
364 340 352
351 341 351
348 361 344
376 350
369 358

Two events of pneumonia in two subjects were reported as SABIs. One is subject (b) (6)
(b) (6) male, 7 years old) and the other is subject (b) (6) (male, 17 years old). No SABI
(
events of bacteraemia, sepsis, osteomyelitis/septic arthritis, visceral abscess or bacterial
meningitis occurred in any subject.

There were two additional events of pneumonia that were not classed as SABIs. Both
subject (b) (6) (male, 12 years old) and subject (b) (6) (male, 8 years old) were
diagnosed with mild pneumonia.

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The primary endpoint was calculated using the two SABIs in the 23.44 subject years.
This led to a mean SABI event rate per subject year of 0.085 and a one-sided 99% upper
confidence bound of 0.358, which meets the efficacy requirement.

The sponsor performed a worst-case estimate of four possible SABIs in 25 subjects in

this study, and also combined data from this study with data from the earlier study
GMX01. The mean SABI event rate for all four scenarios is reported in Table 6.

Table 6: Sensitivity analysis SABI Mean Event Rate and the CI

Mean Event Rate per year One-sided 99% Upper
Confidence Bound
Two SABIs in 25 subjects 0.085 0.358
(GMX04 only; primary analysis)
Four SABIs in 25 subjects 0.171 0.495
(GMX04 only)
Two SABIs in 75 subjects 0.03 0.12
(GMX01 and GMX04)
Four SABIs in 75 subjects 0.06 0.17
(GMX01 and GMX04)
Source: Adapted from sBLA 125329/112; study-report gamx04.pdf, p.68.

The applicant also performed sensitivity analyses using Poisson regression and weighted
Poisson regression (Table 7).

Table 7: Sensitivity Analysis of SABI Mean Event Rate and the CI

Mean Event Rate per year One-sided 99% Upper
Confidence Bound
All subjects
Poisson regression 0.09 0.44
Weighted Poisson regression 0.08 0.46
Subjects receiving all infusions and attending the first follow-up
Poisson regression 0.09 0.45
Exact method for one- 0.09 0.36
sample Poisson rate
Source: Adapted from sBLA 125329/112; study-report gamx04.pdf, p. 280.

Results of the sensitivity analyses demonstrate the robustness of the primary analysis to
changes in assumptions.

6.1.11.2 Analyses of Secondary Endpoints

Trough IgG levels
All trough IgG levels were maintained above 600 mg/dL from Week 15 onwards. While
a high proportion of subjects had trough levels below the mean of the pre-study values
(18 subjects, 72.0%), there is no evidence of a systematic decline in IgG values over time
during Gammaplex treatment. Trough levels of total IgG were summarized overall and

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by infusion schedule by the applicant (Section 14.5, Table 42.1 and Table 42.2 in study-
report gmx04.pdf).

Number of days of school missed because of infection

Sixteen subjects (64.0%) missed at least one day from school or nursery because of an
infection or other problem. The mean (SD) number of days off from school or nursery
was 4.2 (8.28) per subject per year, and the maximum number of days missed was 32. No
subjects in the 2 to 5 year age group had days off from school or nursery. Seven of the 12
subjects (58.3%) in the 6 to 11 year age group missed days from school or nursery; mean
(SD) days missed for this age group was 2.3 (3.22). In the 12 to 16 year age group, nine
of the 10 subjects (90.0%) missed days from school or nursery. The mean (SD) for this
age group was 7.8 (12.06) days missed.

Number of days of hospitalization because of infection

The majority of subjects (22 subjects, 88.0%) did not require hospitalization because of
an infection or a medical problem during the study. The overall mean (SD) number of
days of hospitalization was 0.3 (0.87) per subject per year.

Number of visits to physician/emergency room for acute problems

The majority of subjects (18 subjects, 72.0%) visited a physician or hospital emergency
room because of an infection or other medical problem. Eighteen subjects (72.0%) visited
a physician and eight subjects (32.0%) visited the emergency room. Overall, the mean
(SD) number of visits to a physician or hospital emergency room was 4.0 (4.67).

Other infections documented by fever, positive result on radiograph and/or culture or

clinical examination
Twenty-one subjects (84.0%) experienced at least one infection during the study. Overall
upper respiratory tract infections were reported by more subjects than any other infection
(Table 8).

Table 8: Number of subjects with infections by type of infection

Type of infection Subjects with Subjects with Total subjects
non-serious serious with infections
infections infections (N=25)
(N=25) (N=25) n (%)
Subjects with at least one 19 2 21 (84.0)
infection
Sinus infections 10 0 10 (40.0)
Overall upper respiratory 16 0 16 (64.)
tract infections
Lower respiratory tract 5 2 7 (28.0)
infections
Urinary tract infections 1 0 1 (4.0)
Gastrointestinal infections 4 0 4 (16.0)
Other infections 8 0 8 (32.0)
Source: Adapted from sBLA 125329/112; study-report gamx04.pdf, Table11-6, p.74.

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Number of infectious episodes per subject per year

Twenty-one subjects (84.0%) experienced at least one infection during the study (Table
9). The mean (SD) number of infections per subject per year was 3.20 (2.713).

Table 9: Number of infections episodes per subject per year

Number of infections Number of subjects (N=25)
Subjects with any infection during study, 21 (84.0)
n (%)
Number of infections per subject per year
Mean (SD) 3.20 (2.713)
Median 3.08
Minimum, Maximum 0, 10.4
Number of infections per subject per year,
n (%)
None 4 (16.0)
>0 to <3 7 (28.0)
3 to <5 9 (36.0)
5 to <10 4 (16.0)
≥10 1 (4.0)
Source: Adapted from sBLA 125329/112; study-report gamx04.pdf, Table 11-7p.75.

Number of days on therapeutic and prophylactic antibiotics

Twenty-one subjects (84.0%) took systemic antibiotic medications during the study.
Therapeutic systemic antibiotic medications were taken by the same number of subjects
(21 subjects, 84.0%), and prophylactic systemic antibiotic medications were taken by six
subjects (24.0%).

Comparison of secondary efficacy variables between GMX01 and GMX04 was provided
by the applicant. No significant differences were detected between these two studies.

6.1.11.3 Subpopulation Analyses

The primary analysis was repeated for the age categories and sex subgroups (Table 10).
All SABIs occurred in male subjects. One subject in the 6 to 11 year age group (Subject
(b) (6) ) experienced a SABI of lobar pneumonia, and one subject in the 12 to 16 year
age group (Subject (b) (6) ) also experienced a SABI of lobar pneumonia. No SABIs
occurred in the 2 to 5 year age group. With the exception of this age group (due to its
small size), the subgroup results are consistent with the primary efficacy result.

Table 10: Subgroup Analysis of SABI Mean Event Rate and the CI by age and sex
Number of Number of Mean event One-sided 99%
subjects SABIs rate per year upper confidence
bound
Age group
2-5 years 3 0 0 1.59

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6-11 years 12 1 0.09 0.57

12-16 years 10 1 0.11 0.74
Sex
Male 19 2 0.105 0.442
Female 6 0 0 0.768
Source: Adapted from sBLA 125329/112; study-report gamx04.pdf, Table 11-4, p.68.

6.1.11.4 Dropouts and/or Discontinuations

Data from subjects who withdrew were included, where possible, in all summaries and
analyses. All summaries and analyses were based on observed data. No imputation was
performed for missing data.

6.1.11.5 Exploratory and Post Hoc Analyses

N/A.

6.1.12 Safety Analyses

6.1.12.3 Deaths
No death occurred during this study.

6.1.12.4 Nonfatal Serious Adverse Events

Two subjects had a total of two SAEs onset between first infusion date and
30 days after the last infusion. Subject (b) (6) experienced an SAE of lobar pneumonia
(left lower lobe pneumonia) of moderate intensity. Subject (b) (6) experienced an SAE
of lobar pneumonia (left lower lobe pneumonia) of severe intensity. Neither of the SAEs
was considered related to study drug.

Subject (b) (6) experienced an SAE of gastroenteritis with onset and resolution before
the first infusion of study treatment, which is not included in the summary tables.

6.1.12.5 Adverse Events of Special Interest (AESI)

Among 368 infusions, there were 97 infusions associated with temporally associated AEs
within 72 hours after infusion (26.4%). The upper one-sided 95% confidence limit for the
proportion of infusions with at least one temporally associated AE (regardless of
relationship) was 30.4% as calculated by the applicant using SAS. This reviewer
calculated the upper one-sided 95% confidence limit as 30.1% with R. This result met the
pre-specified criterion. This safety endpoint was also tested in GMX01. The upper one-
sided 95% confidence limit was 22.1% by 48 hours after the infusion and 23.9% by 72
hours after the infusion in GMX01.

6.1.12.6 Clinical Test Results

The applicant submitted laboratory results for blood biochemistry, hematology,
urinalysis, direct Coombs and CRP analysis in the study report.

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6.1.12.7 Dropouts and/or Discontinuations

N/A

10. CONCLUSIONS

10.1 Statistical Issues and Collective Evidence

Study GMX04 was the first pediatric study of Gammaplex. There were 25 pediatric subjects
enrolled in this study, with 3 subjects aged 2 to 5 years, 12 subjects aged 6 to 11 years, and
12 subjects aged 12 to 16 years.

The study results show that Gammaplex meets FDA’s efficacy and safety guidelines. Two
SABI events occurred for 25 subjects during the study period. With a 0.085 mean infection
rate per subject year, the one-sided 99% upper confidence limit was 0.358 per subject year.
This one-sided 99% upper confidence limit is less than FDA’s efficacy threshold value of 1.
For safety, the upper one-sided 95% confidence limit of the proportion of infusions with at
least one associated AEs (regardless of relationship) was 30.4%, less than the pre-
specified criterion of 40%.

Secondary efficacy endpoints and other safety analyses were also reviewed in this memo.
No statistical issues were detected.

10.2 Conclusions and Recommendations

Both efficacy analyses and safety analyses in this supplemental biologics license application
were verified to support the claim for the use of Gammaplex in pediatric subjects with PID.
There were no statistical issues in this submission.

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