Clinical Overview

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BLES, BLES Biochemicals Inc.

2.5: Clinical Overview Page 1
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2.5 Clinical Overview
TABLE OF CONTENTS
2.5 Clinical Overview ...................................................................................................................... 1

2.5.1 Product Development Rationale ................................................................................... 2
2.5.2 Overview of Biopharmaceutics (Not applicable).......................................................... 3
2.5.3 Overview of Clinical Pharmacology............................................................................. 3
2.5.3.1 Pharmacokinetics (Not applicable) .................................................................. 3
2.5.3.2 Pharmacodynamics .......................................................................................... 4
2.5.4 Overview of Efficacy .................................................................................................... 6
2.5.4.1 Study Populations ............................................................................................ 6
2.5.4.2 Duration of Treatment and Follow-Up ............................................................ 7
2.5.4.3 Study Design .................................................................................................... 7
2.5.4.4 Relationship between Efficacy and Dose ...................................................... 13
2.5.4.5 Clinical Relevance of Efficacy Results.......................................................... 14
2.5.4.6 Applicability of Data to Other Regions ......................................................... 14
2.5.5 Overview of Safety ..................................................................................................... 15
2.5.5.1 Suitability of Safety Outcomes ...................................................................... 15
2.5.5.2 Common Adverse Events .............................................................................. 16
2.5.5.3 Serious Adverse Events and Deaths .............................................................. 19
2.5.5.3.1 Serious Adverse Events ............................................................... 19
2.5.5.3.2 Deaths .......................................................................................... 20
2.5.5.4 Interpretation of Safety Data among Studies or Subgroups........................... 21
2.5.5.5 Long-Term Safety .......................................................................................... 23
2.5.5.6 Management of Adverse Events .................................................................... 23
2.5.5.7 Overdose and Dependence Issues .................................................................. 24
2.5.5.8 Post-market Experience ................................................................................. 24
2.5.5.9 Applicability of Data to Other Regions ......................................................... 26
2.5.6 Benefits and Risks Conclusions .................................................................................. 26
2.5.7 Literature References .................................................................................................. 30
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2.5.1 Product Development Rationale

Pharmalogical Classification: Lung Surfactant (Bovine)
ATC Code: R07AA02: Lung surfactant, natural phospholipids
Indication: Rescue treatment of neonatal respiratory distress syndrome.
Scientific Support for Investigations
The lung produces endogenous surfactant that reduces the surface tension in the alveoli, thus
preventing their collapse (Jobe, 1987:1256; Section 4.3; Ishisaka, 1996:389, Section 5.4.15,
and Walther, 1991:10; Section 5.4.26). The human fetus starts to produce surfactant at 22 to
23 weeks gestation. Antenatal steroids given to mothers in premature labour can accelerate
lung development and hence surfactant production, but cannot prevent all RDS. By 32 to 33
weeks, most human infants have sufficient endogenous surfactant. However, premature
infants are at risk of surfactant deficiency, which impacts on lung compliance and produces
the condition of respiratory distress syndrome. It is estimated that respiratory distress
syndrome affects about 1% of all newborn human infants.
BLES is a natural surfactant with the hydrophilic proteins have been removed, as these may
be allergenic. This leaves the phospholipids in their original ratios, along with surfactant-
associated hydrophobic proteins SP-B and SP-C, which facilitate dispersion of the lipids into
a monolayer.
Two preclinical pharmacodynamic studies in rabbits with rabbit lung surfactant and one study
in sheep with the original formulation of BLES, 25 mg phospholipid/mL, demonstrated the
efficacy of exogenous surfactant in surfactant-deficient animal models. The sheep study
supported administration by intratracheal instillation over aerosolized administration. (See
Section 4.3: References, Metcalfe, 1982a, Metcalfe, 1982b and Lewis 1996.)
One repeat-dose toxicity study was conducted with the current 27 mg phospholipid/mL
formulation of BLES administered intratracheally to newborn lambs (Study 452C-801-930-
94, Section 4.2.3.2.1). The lambs were given a 270 mg/kg dose of BLES, which is two times
the intended human dose of 135 mg/kg. There were no signs of toxicity other than apnoea
from too high a volume. This was remedied by giving subsequent doses in aliquots.
The preclinical studies supported a dose of 100 to 135 mg phospholipid/kg in human infants.
This dose was established empirically in the published literature, from estimations of the
alveolar surfactant pool size of the premature neonate.
Clinical Development Programme
Preclinical pharmacology studies and the Phase I, II and III clinical trials were conducted
with the original formulation, 25 mg phospholipid/mL, administered at a dose of 100 mg/kg.
The formulation was adjusted to the current 27 mg phospholipid/mL for the Phase III
comparison trial with Exosurf Neonatal.
Phase I and II studies compared the safety and efficacy of BLES against placebo. However,
by the time that the Phase III studies were being conducted, other exogenous surfactants had
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been in clinical use and accepted as standard treatment. Thus, it was considered unethical to
have a placebo arm by that time.
Some Phase II studies treated infants at risk of RDS prior to their first breath (prophylactic
treatment), and others after the infants were diagnosed with RDS (rescue treatment). Phase II
Study No. 4 found no advantage for prophylactic over rescue treatment. The disadvantage for
prophylactic treatment was in treating an infant unnecessarily, which would subject the infant
to some risk. The increased use of antenatal steroids during this period also reduced the
incidences of RDS in premature infants. Thus, further studies used BLES for rescue
treatment of infants already confirmed to have RDS.
All studies were conducted in Canada. There are no plans to conduct any further nonclinical
or clinical trials. The ethnicity of the infant is not expected to influence the safety or efficacy
of BLES, as surfactant acts locally within the lung in a physical manner, as would
endogenous surfactant. Exogenous surfactant is metabolized by the same pathways as
endogenous surfactant and does not interfere with the production of endogenous surfactant.
(Hallman, 1994:221; Section 5.4.10 and Morton, 1989:56; Section 5.4.18)
Concordance with Current Standard Research Approaches
Investigator INDs were filed with Health Canada, independent of the sponsor of this
application. All studies were conducted according to Good Clinical Practices.
2.5.2 Overview of Biopharmaceutics (Not applicable)

As discussed under Pharmacokinetics, Section 2.5.3.1, below, it is not applicable to measure
blood levels of exogenous surfactant, as it is applied directly to the target organ and acts
locally in a mechanical fashion. Exogenous surfactant is recycled within the lung tissue and
metabolized by the same pathways as endogenous surfactant (Hallman, 1994:221; Section
5.4.10).
2.5.3 Overview of Clinical Pharmacology
2.5.3.1 Pharmacokinetics (Not applicable)

No pharmacokinetic studies have been conducted with BLES.
Hallman states that surfactants are applied directly to the airways and do not diffuse readily
into the blood stream; thus, blood concentrations of exogenous surfactant components have
little practical importance (Hallman, 1994:221; Section 5.4.10). Even in neonates with lung
oedema and lung tissue of high permeability, surfactant complexes are largely catabolized
within pulmonary compartments. Only small quantities of intact surfactant components are
cleared into the blood.
Hallman describes the bioavailability of surfactant administered through the endotracheal

tube (Hallman, 1994:222). When 1 to 2 large boluses, each containing 1.5 to 3 mL/kg, or 4
smaller boluses, each containing 1 to 1.5 mL/kg, are introduced, 70% to 95% of natural
surfactant reaches the distal airways and alveoli. Only small proportions of the dose are
retained in the central airways or regurgitated. During administration, positioning the patient
on their right and left side allows gravity to assist in the distribution of surfactant. This
decreases the chances of gross distribution inequalities.
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Administration of the surfactant in a relatively high volume, saline-containing aqueous

carrier, at a dose of 4 to 6 mL/kg, promotes distribution of the surfactant throughout the
respiratory tree (Hallman, 1994:223). The recommended dose of BLES is 5 mL/kg.
BLES has an advantage over Survanta in having a viscosity one-eighth that of Survanta
(Lewis, 1996:1162; Section 4.3.9). Lewis, et al., found that animals given Survanta had
slower peripheral distribution and increased airway obstruction compared to those receiving
BLES. BLES may have a similar advantage over Curosurf, as the concentration of
phospholipids in Curosurf is three times that of BLES.
2.5.3.2 Pharmacodynamics
Phase I Studies
Two Phase I studies were conducted, one in neonates with severe hyaline membrane disease
(now named respiratory distress syndrome), and the other in infants with early chronic lung
disease. Infants were treated with the original formulation of BLES, 25 mg
phospholipids/mL, with infants in the first study receiving about 200 mg/kg and infants in the
second study receiving 100 mg/kg. In both studies, lung compliance was improved and there
were no safety issues. Both these studies were summarized from published articles, and the
raw data is not available to the sponsor. See Tabular Summaries 2.6.7.2 and 2.6.7.3, Smyth,
1983 and Pandit, 1995b, respectively. as well as the articles in Sections 5.3.4.2.1 and
5.3.4.2.2.
Bridging Study for the Change in Formulation and Dose
Phase II studies used the original 25 mg/mL formulation and the 100 mg/kg dose. In order to
blind the treatments in the comparative Phase III trial, BLES was reformulated to contain 27
mg phospholipids/mL and the dose changed to 135 mg/kg to match more closely the volume
and phospholipid content of Exosurf Neonatal. As a result, a Phase I bridging study was
conducted in seven neonates with NRDS in order to look for any notable differences in safety
or effectiveness of the new formulation. The investigator based his observations on his prior
extensive experience with the original formulation and dosage, and found there to be no
obvious difference between the two regimens. The new formulation and dosage continued to
effect rapid lung compliance with few safety issues. See Tabular Summary 2.6.7.4, Study
HPB-PID-6420, as well as the report in Section 5.3.4.2.3.
Timing and Number of Multiple Doses
The timing of subsequent doses in the proposed labelling is based on a persistent decline in
ventilation parameters, as followed in most of the clinical studies:
• a positive response to the first dose of surfactant, demonstrated by a decrease in FiO2
by at least 0.1 and/or down to 0.21; and
• a respiratory deterioration signalled by a gradual increase in FiO2 by 0.1 (10%).
The exception was the last of the Phase II studies, Study No. 5, where the standard
retreatment strategy described above and a more liberal one were compared. The liberal
retreatment strategy required an increase in FiO2 by 0.01 (1%). The result was a more
sustained improvement in lung function, but no differences in outcome. Thus, the subsequent
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Phase III studies continued to use the standard retreatment strategy. Exogenous surfactant
ceases to be required once the infant is producing its own surfactant, normally within one or
two days of birth, and the average number of doses required in the two large Phase III studies
was 1.7 doses. A more liberal retreatment may result in more doses being given to a patient
population with a self-limiting condition. Each dose is not without consequences, and the
fewer doses given, the better. Thus, the proposed labelling recommends the standard
retreatment strategy.
In the Phase III Open Study 90-001, up to four additional doses were recommended within
the first five days of life. In the Phase III Comparison Study 92-001, up to three additional
doses were allowed. The proposed labelling will recommend up to three additional doses in
the first five days of life.
Effect of BLES in Related Diagnoses
BLES may be useful to infants with other pulmonary disorders that have similar symptoms as
NRDS. Small premature neonates with mature surfactant do not generally experience RDS;
however, they may develop respiratory failure clinically indistinguishable from RDS as a
result of lung oedema, delayed clearance of pulmonary fluid and the presence of surfactant
inhibitors in the epithelial lining fluid (Hallman, 1994:217; Section 5.4.10). Hallman found
that administration of exogenous surfactant in such infants reduced the severity of respiratory
failure and increased the saturated phosphatidylcholine concentration in the epithelial lining
fluid. This also demonstrates that surfactant therapy is not detrimental in infants that are not
surfactant deficient.
In the Phase III Open Study 90-001 with BLES, an efficacy analysis was conducted on the
2312 infants enrolled in the first five years of the trial. Ten percent of the infants were not
diagnosed with NRDS, but instead had pneumonia, meconium aspiration, transient tachpnea
of the newborn (wet lung) or pulmonary hypoplasia. Infants with TTN/wet lung showed the
strongest response to treatment, but there was at least a partial response in many of the other
infants without NRDS. (See the Summary of Clinical Efficacy, Section 2.7.3.2.7 and the
efficacy report in Section 5.3.5.2.1.) The open trial continued for another 4.5 years, but the
efficacy was not analyzed for the latter part of the trial. Instead, the efficacy was established
with the two comparison trials with Exosurf and Survanta.
Thus, BLES may still be helpful to infants with neonatal pulmonary disorders who are
incorreclty diagnosed with RDS.
Surfactant Inhibition
Surfactant inhibitors decrease surface activity. Many of them are plasma proteins that leak
into the alveolar space as a result of lung oedema or haemorrhage. The following compounds
decrease surface activity in vitro: fibrin, fibrinogen, fibrin monomer, meconium, transferrin
saturated with iron, albumin, 110 kDa surfactant inhibitor, haemoglobin, lactocyclceramide,
bilirubin and cationic amino acids (Hallman, 1994:228; Section 5.4.10). Hallman reported
that surfactant proteins improve the resistance of surfactant against inhibitors, and that
surface activity is restored when the supply of surfactant is increased.
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BLES is prepared from bovine lung lavage which is purified to remove the hydrophilic
proteins which may be immunogenic. The resulting product does retain the hydrophobic
surfactant-associated proteins SP-B and SP-C. Schürch, et al., described SP-B and SP-C as
substantially increasing the surface activity of surfactants. SP-C is important for rapid
adsorption, whereas SP-B promotes both adsorption and the removal of phosphatidylglycerol
from the monolayer. (Schürch, 1992:L210; Section 5.4.22)
Cummings (1992) and Pandit (1995a) pointed out that natural surfactant extracts such as
BLES seem to be more resistant to inhibition by plasma proteins than Survanta, which is
obtained from minced lung tissue, while both BLES and Survanta are more effective than
synthetic Exosurf (Cummings, 1992:1003 and Pandit, 1995a:35; Sections 5.4.2and 5.4 19,
respectively). Thus, BLES has a pharmacodynamic advantage over Survanta and Exosurf
due to its higher concentration of surfactant-associated proteins.
2.5.4 Overview of Efficacy
2.5.4.1 Study Populations

BLES is indicated for and was administered in clinical trials to newborn infants with
respiratory distress syndrome. The initial Phase II studies included infants that were given
BLES as soon as possible after birth, in anticipation that the infants might develop RDS due
to their prematurity. Prophylactic treatment has since fallen out of favour due to the now
common use of prenatal steroids in mothers in premature labour, the steroids helping to
mature the infant’s lungs prior to birth. Prophylactic treatment would subject many more
infants to unnecessary treatment. Rescue treatment is now the more common use for
exogenous surfactants, and is the subject of the remaining clinical trials with BLES. The
exception is the Phase III Open Study 90-001, where about 10% of infants treated did not
have a primary diagnosis of RDS, but had related conditions that received varying degrees of
benefit from treatment with BLES.
Phase II Study No. 5 found that liberal retreatment produced a more sustained improvement
in lung function than the standard treatment; however, there were no differences in long-term
outcome. The strategy for liberal retreatment was to retreat when the FiO2 had increased by
only 1% instead of 10%. However, the later Phase III studies used the standard retreatment
strategy, as a limited number of doses are required before the infant produces its own
surfactant. The average number of doses required with standard retreatment in the two large
Phase III studies was 1.7 doses. Switching to a more liberal retreatment strategy would have
increased the number of doses given and not improved the overall outcome. Each dose is not
without risk, and the recommendation of Study No. 5 for more liberal retreatment was not
implemented.
A total of 3531 infants were treated with the original formulation of BLES and 2549 received
the current formulation.
The primary demographic characteristics that might affect the outcomes of the studies are the
birth weight and gestational ages, which reflect the lung maturity and surfactant sufficiency
of the infants. Sex ratios and Apgar scores also were compared. In all studies except Phase
II Study No. 1, treatment groups were well matched for these demographic characteristics.
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Study No. 1 showed a bias to female infants in the treatment group compared to the placebo
group, and the protocol was repeated as Study No. 2. In all other Phase II and III studies, the
ratio of males to females was roughly 60% to 40%, which follows the theory that male
neonates are more prone to respiratory stress.
The mean birth weights, and the corresponding gestational ages and Apgar scores, varied
across the studies. These were lower in Study No. 1, which was a prophylactic study that
anticipated RDS due to the infants’ prematurity. Rescue treatment studies tended to include
larger infants who also developed RDS.
The weight ranges used in the Phase II and III studies represent the intended treatment
population. For analysis of efficacy, Phase III Comparison Study 92-001 was designed to
have three birth weight arms. Each successive birth weight range would be expected to
represent a different level of lung maturity and surfactant sufficiency. As this was a
comparative trial, a closer match of lung maturity allowed a more precise comparison of the
efficacy of BLES versus that of Exosurf.
2.5.4.2 Duration of Treatment and Follow-Up

BLES is not indicated for use after the first five days of life.
Infants enrolled in five Phase II Studies were treated within the first five days of life, and
were followed until discharge from Level III care, for the purpose of recording efficacy and
safety parameters. Infants in the first four studies were then followed for up to two years to
look for long-term effects, in particular allergenic manifestations and neurodevelopment
handicap.
Infants in the three Phase III Studies were followed until discharge from Level III care.
2.5.4.3 Study Design

Table 2.5.4.3 summarizes the design of individual studies.
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Table 2.5.4.3: Study Design

Study /
Follow-Up
Report Phase Design Groups Endpoints Statistical Methods
Term
Location
Smyth, 1983 1 Open, single dose, 18 mo Rescue treatment of infants • Respiratory status over first 24 hr. None.
Sec. 5.3.4.2.1 single centre. with NRDS. • Ongoing ventilatory requirements.
• Incidence of PIE, pneumothorax and
BPD
• Other complications.
• Neurological development at 18 mo.
Pandit, 1995b 1 Open, single dose, None Rescue treatment of early • Ventilatory parameters over 72 hr. None.
Sec. 5.3.4.2.2 multi-centre. chronic lung disease.
Bridging Study 1 Open, multiple None Rescue treatment for NRDS • Ventilatory parameters (pre and None.
HPB PID 6420 dose, single-centre, with the new formulation and post-dose FiO2.
Sec. 5.3.4.2.3 bridging study (new dose. Investigator compared • Complications.
formulation and results against his experience
dosage). with the original formulation.
Study No. 1 2 Randomized, 2 yr Prophylactic treatment with • Blood gas values over the first 72 X2 tests for incidence data;
Sec. 5.3.5.1.1 double-blind, BLES, original formulation. hours. one-tailed unpaired Student's t
and placebo controlled, Placebo group received sham • Respiratory adjustments necessary test for numerical data.
5.3.5.1.2 single-centre. air instillation. to maintain blood gases at normal
values. For 2-year follow-up, X2
Two-year, blinded • Complications of RDS. analysis or Fisher exact test
follow-up period. • Total time of neonatal care. for incidence data and
• Follow-up over two years assessed unpaired Student's t test for
development, hospitalizations and population characteristics.
infective, allergic and respiratory
problems.
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Study /
Follow-Up
Term
Location
Study No. 2 2 Randomized, 2 yr Prophylactic treatment with • Blood gas values over the first 72 X2 tests for incidence data;
Sec. 5.3.5.1.3 double-blind, BLES, original formulation. hours. one-tailed unpaired Student's t
to 5.3.5.1.5 placebo controlled, Placebo group received sham • Ventilation index and duration of test for numerical data.
single-centre, with air instillation. respiratory support.
two post- • Complications of RDS For 2-year follow up, unpaired
conceptional age Two age range arms • Total time of neonatal care. Student's t test for population
range arms. represented different lung • Follow-up over two years assessed characteristics and X2 analysis
maturity. neurodevelopmental handicap and or Fisher exact test for
Two-year, blinded allergic manifestations. incidence data.
follow-up period.
Study No. 3 2 Randomized, non- 2 yr Three groups: rescue • Oxygen and ventilatory X2 and Fisher's exact tests for
Sec. 5.3.5.1.6 masked, placebo treatment with single dose, requirements during first week of incidence data, and two-tailed
and 5.3.5.1.7 controlled, dose- multiple dose or control. life. Student’s t-test for numerical
ranging study. Placebo group received sham • Time in neonatal intensive care data. Omnibus multivariate
air instillation. Not blinded, • Complications. analysis of covariance was
Two-year, blinded as treatment groups • Follow-up over two years assessed applied to sequential
follow-up period. responded very rapidly to neurodevelopmental handicap and numerical data.
dosing and required rapid allergic manifestations.
adjustment of ventilation. For 2-year follow-up,
Student’s t-tests for population
characteristics and X2 analysis
or Fisher exact test for
incidence data.
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Study /
Follow-Up
Term
Location
Study No. 4 2 Randomized, non- 2 yr Three groups: prophylactic, • Oxygen and ventilatory X2 and Fisher’s exact tests for
Sec. 5.3.5.1.8 masked, placebo rescue and control. Placebo requirements during the first week incidence data. Two-tailed
and 5.3.5.1.9 controlled, group received sham air of life. Student's t test for numerical
comparative, instillation. Not blinded, as • Blood gas values at intervals up to data. ANOVA for repeated
multiple dose study. treatment groups responded 168 hr of age. measures for sequential
very rapidly to dosing and • Duration of intermittent positive numerical data (FiO2, a/A PO2,
Two-year, blinded required rapid adjustment of pressure ventilation, respiratory ventilation index) to detect
follow-up period. ventilation. Treated infants support, and total neonatal intensive overall group differences over
were re-dosed if required. care unit stay. time. A one-way ANOVA
• Complications of prematurity and was performed at each time
assisted ventilation. point to compare the three
• Follow-up over two years assessed groups.
neurodevelopmental handicap and
allergic manifestations. For 2-year follow-up, unpaired
Student’s t-test for population
characteristics and X2 analysis
or Fisher exact test for
incidence data.
Study No. 5 2 Randomized, non- None Both groups treated with • Oxygen and ventilatory Statistical methods are not
Sec. 5.3.5.1.10 masked, same initial rescue dose. requirements during the first 120 hr mentioned in the abbreviated
comparative, multi- Standard retreatment versus of life. report.
dose study. liberal retreatment to • Complications.
determine ideal time to
retreat.
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Study /
Follow-Up
Term
Location
Study 92-001 3 Randomized, None Exosurf was chosen as the • The primary endpoint was Superiority was anticipated for BLES
Sec. 5.3.5.1.11 controlled, double- comparator, as this was the the incidence of intact over Exosurf.
blinded, only surfactant on the market cardiopulmonary survival
For the primary endpoint of
comparative, in Canada at that time. BLES (survival to 36 weeks
cardiopulmonary survival and for
multicentre trial, was reformulated to the adjusted gestational age with
other lung disease outcomes including
with three birth current formulation and given no bronchopulmonary
mortality, adjusted odds ratios and
weight arms. at the current recommended dysplasia (BPD)).
95% confidence limits were calculated
dose, to match the • Secondary measures
by study centre and were based on the
phospholipid concentration included: incidence of early
Mantel-Haenszel inference for the
and dosage for Exosurf. and late mortality; incidence
common odds ratio. The p-value was
Infants were stratified by of BPD; respiratory
based on the test for homogeneity of
birth weight range, as that is parameters at 4 and 8 hr after
the odds ratios (Zelen) across the
an indicator of lung maturity. the first dose and at 72 h
centres. This Zelen p-value was the
after last dose; duration of
result of an exact test of the hypothesis
mechanical ventilation and
that the odds ratios are equal across
supplemental oxygen; length
the centres, with a non-significant p-
of hospital stay;
value (>0.05) indicating that the odds
requirements for steroid use;
ratios were more or less consistent
and the number of doses of
over the hospitals.
surfactant. Also compared
are the complications of No adjustment for multiplicity
prematurity. (primarily multiple outcomes) has
• Safety analysis was carried been invoked, and thus statistically
out on the intent-to-treat significant results for parameters other
population for identified and than the primary endpoints must be
spontaneously-reported post- interpreted cautiously.
dose complications.
• Analysis was performed on Group comparisons between the two
the timing and causes of parallel arms were effected using the
unpaired Student’s t-test for
death.
continuous data and by the X2 test for
categorical outcomes.
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Study /
Follow-Up
Term
Location
Lam, 2005 3 Randomized, non- None This was an independent, • The primary outcome was the clinical Fisher’s exact test and a X2
Sec. 5.3.5.1.12 blinded, active- published study comparing response as indicated by the oxygen test for independence, and
controlled trial. BLES and Survanta. The index.. the Mann-Whitney test for
study was not blinded due to • Secondary outcome parameters nonparametrics.
the different doses and included mortality before discharge,
slightly different duration of supplementary ventilation,
recommended administration occurrence of chronic lung disease
methods. (defined as oxygen dependency at a
corrected age of 36 weeks) and other
complications of prematurity.
Study 90-001 3 Open, multi-dose, None This was a 9.5-year open • The primary outcome was the effect No statistical analysis.
Sec. 5.3.5.2.1 multi-centre study, study to look for any of FiO2 requirement within 6 hours For efficacy analysis,
and 5.3.5.2.2 unexpected safety issues. In post-dose, for each type of primary separate results were
addition, infants with diagnosis and for all RDS or non-RDS presented for different
diagnoses other than NRDS diagnoses. Of note, efficacy was primary diagnoses.
were included to see if BLES analyzed only for the original For safety analysis, patients
would effective. formulation, with data from the first with RDS (90%) and other
After the 5-year efficacy five years. The efficacy of the current diagnoses (10%) were
analysis, the new formulation formulation was established elsewhere combined. Separate results
and dose were used. with two Phase III comparative trials. were presented for original
• Safety analysis included the incidence and current formulations.
of post-dose complications and
adverse events prior to discharge from
Level III care, as well as the average
number of doses required.
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The Phase I studies used BLES treatment only. Phase II studies used a sham air instillation
as a placebo control, except for Study No. 5, which compared two treatment strategies. Phase
III studies did not employ a placebo arm, as exogenous surfactant is now considered standard
treatment for NRDS and placebo use would be considered unethical.
The Phase III Open Study 90-001 used BLES treatment only. After the first five years, a
switch was made to using the current formulation and dose of BLES. An efficacy report is
provided for the first five years, during which time the original formulation and dose were
used. The safety report covered all nine and one half years of the study and compared the
safety outcomes for the two formulations. The efficacy of the current formulation used in the
latter part of the open trial was not assessed, as this has been established with the two Phase
III comparative trials against Exosurf and Survanta.
The Phase III Comparison Study 92-001 compared BLES with Exosurf Neonatal. Exosurf
was chosen as the active control as it was the only surfactant on the market in Canada at that
time. Based on preclinical experience with exogenous surfactants, it was expected that a
natural surfactant such as BLES would have a clinical advantage over synthetic Exosurf,
which did not contain the surfactant-associated proteins to improve the action of the
phospholipids.
Three birth weight arms were designated, as birth weight is related to post-conceptional age
and, hence, to the degree of lung maturity. Infants with different lung maturity and surfactant
deficiency are anticipated to react differently to exogenous surfactant treatment. In addition,
infants of very low birth weights have health concerns that impact on the measures of
mortality and morbidity in the study.
Exosurf, as the active control in Study 92-001, was effective in improving ventilatory
parameters, thus demonstrating that the protocol had assay sensitivity. The protocol was
designed to detect superiority of BLES over Exosurf treatment. A p-value of < 0.05 was
accepted as significant. Aspects of the trial that balanced the two active groups were:
• compliance with therapy, as infants were treated impartially by blinded staff, based on
their ventilatory requirements;
• diagnosis of the same disease, neonatal respiratory distress syndrome;
• reformulation of BLES to match the dose and volume recommended for Exosurf; and
• measurement of the same endpoints.
2.5.4.4 Relationship between Efficacy and Dose

The size of each dose is based on the estimated amount of lipid required to form an active
layer of surfactant within the lung. Exogenous surfactants cannot be measured in the blood.
Thus, the relationship between efficacy and dose is established with clinical outcomes. The
proposed labelling states that neonates can receive up to 3 additional doses of BLES within
the first 5 days of life. The criteria for an additional dose are a positive response to the
previous dose, and an increase in respiratory support as signalled by a gradual increase in
FiO2. This increase must be at least 10% greater than the FiO2 required after the initial
response to the previous dose of BLES. This is supported by the results of Phase III Studies
90-001 and 92-001.
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Phase II Study No. 4 compared prophylactic to rescue treatment and found no significant
difference in outcomes. However, with current use of prenatal steroids to hasten the maturity
of the neonates’ lungs prior to birth, prophylactic treatment has fallen out of favour.
Phase II Study No. 3 compared single versus multiple doses given to infants diagnosed with
RDS. Compared with a placebo instillation of air, there was a significant improvement in
ventilation parameters by 10 minutes post-dose. Giving multiple doses maintained this
improved state. However, multiple doses did not diminish the time to extubation or
development of chronic lung disease compared to single doses. Nor did multiple doses make
a difference in the incidence of air leaks, IVH or PDA. The majority of infants were weaned
to room air rapidly after treatment with BLES, implying almost complete alveolar expansion.
However, retreatment sometimes is needed, perhaps due to inhibition of the surfactant due to
leakage of serum into the lung. Retreatment is successful in restoring ventilation parameters.
It appears that retreatment is required until endogenous surfactant production takes over.
The average number of doses of BLES required in the large Phase III trials was 1.7 doses.
By birth weight group in Study 92-001, smallest to largest infants, the average number of
doses were 1.97, 1.71 and 1.48 for infants treated with BLES. There was no significant
difference in number of doses of Exosurf required in the lowest birth weight infants; however
significantly more doses of Exosurf (p=0.0000) were required for the middle and upper birth
weight groups.
This product is intended for use in the neonatal period only. Thus, there are no concerns
regarding long-term use.
2.5.4.5 Clinical Relevance of Efficacy Results

The efficacy results were clinically relevant. The effects on mortality and morbidity, as well
as improved ventilation parameters and effect on concomitant complications are the same
clinical results expected with surfactant treatment. In addition, the same population intended
for the drug product was used in the clinical trials.
The Phase II studies clearly demonstrated the efficacy of treatment over placebo. In the
Phase III Comparison Study 92-001, there were some similarities between BLES and
Exosurf, such as no significant difference in cardiopulmonary survival. However, the study
did show advantages to BLES treatment in other results, such as a significantly faster
improvement in ventilation parameters.
2.5.4.6 Applicability of Data to Other Regions

Clinical trials for BLES were carried out in Canada, where it has been marketed since
February 2002. One published clinical trial included in this application was conducted in
Hong Kong (Lam, 2005). BLES has a similar safety and efficacy profile in both regions.
BLES acts locally within the lung, in a physical manner, and is metabolized by the same
pathways as endogenous surfactant. Pharmacokinetic measurements cannot be conducted, as
BLES is not detectable in the blood. BLES also has a wide therapeutic dose range, being safe
and effective at doses of 100 mg/kg or 135 mg/kg. These factors make ethnic differences less
likely.
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Intrinsic factors such as gender, race and genetic diseases are not likely to influence the
physical action of BLES.
There are no concerns regarding cultural habits, food, the environment, drug compliance or
culture, as BLES is intended for newborn infants in intensive care. Exogenous surfactant use
is well established globally, with the same medical practice, disease definition, diagnosis and
therapeutic approach as proposed for BLES. BLES has the same indication for treatment of
NRDS, and similar administration techniques as other surfactants, and the age range is
narrow.
The clinical endpoints and methodology used in the Phase II and III trials are similar to those
that were used for other marketed surfactants. BLES trials were GCP-compliant.
There are no ethnic concerns with other approved surfactants, as their labelling is similar
among surfactants and among regions. Thus, it is assumed that BLES will be as safe and
effective globally as it has been shown to be in Canada and China.
In conclusion, the sponsor feels that bridging studies for other regions are not required.
2.5.5 Overview of Safety
2.5.5.1 Suitability of Safety Outcomes

For the Phase III studies, known adverse effects of other surfactants were included in
checklists on the case report forms. These included endotracheal tube complications during
drug administration, as well as effects of assisted ventilation, such as air leaks. Also included
were related complications of prematurity that may be affected by ventilatory parameters,
such as patent ductus arteriosus, intraventricular haemorrhage, pulmonary haemorrhage and
retinopathy of prematurity. Opportunity also was provided for spontaneous recording of
other adverse events. The Phase III study reports analyzed all of the adverse events recorded.
The Phase II abbreviated reports included a limited set of the more important safety
outcomes.
The repeat dose toxicity study in newborn lambs (Section 4.2.3.2.1) showed no systemic
adverse reactions. There were two early drownings due to the large dose being administered,
twice the human dose. This was remedied in the study by switching to delivering the dose in
aliquots.
There are no aspects of product quality that have safety concerns, other than lack of efficacy.
If the phospholipids in BLES were to degrade, the lyso-forms would inhibit the surface-
tension-lowering activity of the surfactant, which would impact the efficacy of the product.
In the Phase III Open Study 90-001, BLES was to be administered up to five times within the
first five days of life, if required. In the Comparison Study 92-001, a maximum of four doses
was recommended within the first five days of life. The product labelling recommends up to
four doses within the first five days of life. Thus, the potential safety of the product in the
marketplace has been adequately investigated in the clinical trials.
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2.5.5.2 Common Adverse Events

Common adverse events are discussed in Section 2.7.4.2.1.1 and tabulated in Section 2.7.4.7:
Appendix, Table 2.7.4.7.1 (all adverse events) and Table 2.7.4.7.2 (adverse events in ≥ 1% of
patients). Common adverse events by body system are discussed in Section 2.7.4.2.1.5.
Many of the common adverse events are also serious adverse events in premature neonates.
Common, non-serious adverse events were:

• bradycardia;
• desaturation on dosing (termed “Investigations / Pulmonary function test decreased”
in the tables);
• electrolyte imbalance;
• endotracheal tube complications;
• hypotension;
• metabolic acidosis; and
• respiratory acidosis.
Common, serious adverse events and complications of prematurity were:

• intraventricular haemorrhage (IVH);
• necrotizing enterocolitis (NEC);
• patent ductus arteriosus (PDA);
• periventricular leukomalacia (PVL);
• pneumothorax;
• pulmonary haemorrhage;
• pulmonary interstitial emphysema (PIE);
• retinopathy of prematurity (ROP); and
• sepsis.
A subset of common adverse events that occurred within two hours of dosing were:
• bradycardia;
• desaturation on dosing;
• endotracheal tube complications;
• hypotension; and
• respiratory acidosis
Phase II, Placebo-Controlled Studies
There was a lower incidence of the following events in infants treated with BLES vs. placebo
(instilled air):
• PDA (BLES 43% vs. placebo 52%)
• IVH (BLES 27% vs. placebo 42%)
• pneumothorax (BLES 10% vs. 30%)
• PIE (BLES 5% vs. placebo 26%)
• ROP (BLES 2% vs. placebo 8%)
There was a similar incidence of severe IVH, 6% with either treatment or placebo. There was
a higher incidence of NEC with BLES treatment (BLES 5% vs. placebo 2%)
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Phase III Comparison Study of BLES vs. Exosurf
In Study No. 92-001, there were significantly fewer incidences of the following events in
infants treated with BLES vs. Exosurf:
• PIE (BLES 9% vs. Exosurf 17%, p < 0.0005)
• pneumothorax (BLES 8% vs. Exosurf 12%, p < 0.05)
There was no significant difference between treatments for incidences of:

• PDA (44% for both treatments)
• desaturation on dosing (BLES 39% vs. Exosurf 41%)
• IVH (29% for both treatments)
• ROP (BLES 19% vs. Exosurf 20%)
• bradycardia (BLES 13% vs. Exosurf 15%)
• severe IVH (BLES 12% vs. Exosurf 11%)
• pulmonary haemorrhage (BLES 8% vs. Exosurf 7%)
• PVL (BLES 8% vs. Exosurf 7%)
• NEC (BLES 6% vs. Exosurf 7%)
• endotracheal tube complications (6% for both treatments)
• hypotension (2% for both treatments)
• metabolic acidosis (BLES 1% vs. Exosurf < 1%)
• infection (BLES 1% vs. Exosurf < 1%)
There were significantly more incidences of the following events in infants treated with
BLES vs. Exosurf:
• sepsis (BLES 28% vs. Exosurf 23%, p < 0.05)
• respiratory acidosis (BLES 4% vs. Exosurf 2%, p < 0.05)
• pneumonia (BLES 1% vs. Exosurf < 1%, p < 0.05)
Phase III Comparison Study of BLES vs. Survanta
In the published article by Lam, et al., 2005, only selected adverse events or complications
are provided, and there was no significant difference between the treatments. The number of
patients enrolled was low compared to the larger trials, with 29 treated with BLES and 31
receiving Survanta.
There were fewer incidences of the following complications in infants receiving BLES:
• sepsis (BLES 45% vs. Survanta 48%)
• NEC (BLES 26% vs. Survanta 30%)
• pulmonary haemorrhage (BLES 10% vs. Survanta 19%)
• ROP (BLES 8% vs. Survanta 13%)
• severe IVH (BLES 4% vs. Survanta 10%)
• pneumothorax (BLES 3% vs. Survanta 10%)
There were more incidences of PDA with BLES (59%) vs. Survanta (58%)
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Phase III Open Study with BLES
Study 90-001 lasted 9.5 years, and used the original formulation and dose of BLES for the
first five years, then switched to the current formulation and dose for the last 4.5 years. The
differences in formulation and dose were minor and were not expected to produce a different
safety profile.
Differences between the safety outcomes for the two formulations and doses may reflect the
advances in medical care that occurred during the long study. These advances may have
resulted in a decrease in adverse events due to better prevention or management, or to an
increase in adverse events due to longer survival times in an infant population in fragile
health and susceptible to infection and other complications.
Differences in adverse events between the two large Phase III studies are discussed in Section
2.7.4.2.1.1, subsection 1.3, Table 1.3b. The table compares adverse events for the current
formulation only. Differences between the studies may be due to the different case report
forms with different checklists.
Some outcomes were higher with the change in formulation in the open trial. However, there
was a stronger correlation between the original formulation in the open trial and the current
formulation in the comparison trial. This would indicate that the differences were not caused
by a change in formulation, but were due to different reporting practices as sites were
enrolled in the open trial, or to unequal events, such as the high incidence of sepsis at one site
in the open trial, particularly toward the end of the study.
Adverse Events in the Proposed Labelling
The proposed labelling will quote the adverse events reported in ≥ 1% of patients in the
pivotal Phase III Comparison Study 92-001. Also quoted will be the adverse events that
occurred within two hours of dosing in ≥ 1% of patients. (See Section 2.7.4.2.1.1: Common
Adverse Events, subsection 1.2.) These will be expressed in the original COSTART terms
used in the study report, or in MedDRA terms, as required by the local regulatory authority.
Summary of Common Adverse Events
In the Phase II trials, there was a higher incidence of NEC with BLES (6/122, 5%) compared
with placebo (1/60, 2%); however, this was from one study and the difference was not
significant.
In the Phase III Study 92-001, comparing BLES with Exosurf, there were significantly more
incidences with BLES for respiratory acidosis (4% vs. 2%; p < 0.0005), sepsis (28% vs. 23%;
p < 0.05) and pneumonia (1% vs. < 1%; p < 0.05). Respiratory acidosis occurred primarily at
one site with both treatments and likely represents premature weaning from supplementary
oxygen. Sepsis occurred in significantly more infants only in the lowest birth weight arm,
which may reflect the increased survival times in that arm, providing more time for infection
to occur in a population more susceptible to infection than the larger infants. The incidence
of pneumonia, although significantly different between treatments, occurred in only 1% of
infants who received BLES. In addition, seven of the nine infants with pneumonia were from
the same study site, which may reflect an environmental cause.
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Particular adverse events associated with surfactant administration include bradycardia,

desaturation on dosing, endotracheal tube complications, hypotension and respiratory
acidosis. These would be expected to occur with handling premature infants and
administering an intratracheal drug. Acidosis occurred at one site, likely due to premature
weaning from ventilatory support.
Many of the other common adverse events are also serious complications of prematurity.
Exogenous surfactants have been in use clinically since the mid-1980s, and their safety
profile is well established. The adverse events seen in the clinical trials with BLES have not
revealed any new common adverse events.
2.5.5.3 Serious Adverse Events and Deaths
2.5.5.3.1 Serious Adverse Events

The serious adverse events identified in the clinical trials are also common complications of
prematurity and also are discussed in the previous section on Common Adverse Events.
Serious adverse events that may be related to surfactant treatment, and their incidence in the
pivotal Phase III Comparison Study 92-001 are provided below:
In Study No. 92-001, there were significantly fewer incidences of the following serious
events in infants treated with BLES vs. Exosurf:
• PIE (BLES 9% vs. Exosurf 17%, p < 0.0005)
• pneumothorax (BLES 8% vs. Exosurf 12%, p < 0.05)
There was no significant difference between treatments for incidences of:

• PDA (44% for both treatments)
• IVH (29% for both treatments)
• ROP (BLES 19% vs. Exosurf 20%)
• severe IVH (BLES 12% vs. Exosurf 11%)
• pulmonary haemorrhage (BLES 8% vs. Exosurf 7%)
• PVL (BLES 8% vs. Exosurf 7%)
• NEC (BLES 6% vs. Exosurf 7%)
There were significantly more incidences of the following serious events in infants treated
with BLES vs. Exosurf:
• sepsis (BLES 28% vs. Exosurf 23%, p < 0.05)
• pneumonia (BLES 1% vs. Exosurf < 1%, p < 0.05)
Section 2.7.4.2.1.3 compares the incidence of serious adverse events for BLES across studies.
The incidences of serious adverse events were similar across the studies.
There was a higher incidence of NEC in BLES-treated infants compared to placebo (5% vs.
2%); however, this was not significant.
In the Phase III Comparison Study 92-001, there was a higher incidence of sepsis with BLES
vs. Exosurf (28% vs. 23%, respectively; p < 0.05). There was a higher incidence of
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pneumonia with BLES vs. Exosurf (1% vs. < 1%; p < 0.05). Sepsis occurred in significantly
more infants only in the lowest birth weight arm, which may reflect the increased survival
times in that arm, providing more time for infection to occur in a population more susceptible
to infection than the larger infants. The incidence of pneumonia, although significantly
different between treatments, occurred in only 1% of infants who received BLES. In
addition, seven of the nine infants with pneumonia were from the same study site, which may
reflect an environmental cause.
As discussed in section 2.7.4.2.1.1: Common Adverse Events, subsection 1.8.1: Common

Adverse Events with Other Surfactants, the incidence of adverse events from published
sources, including serious adverse events, were similar for BLES and other surfactants.
In conclusion, BLES had an improved safety profile for serious adverse events compared to
Exosurf in the comparison trial. When results for BLES were compared across studies and
with published information on other surfactants, BLES had a similar safety profile with
regard to serious adverse events and there were no new serious adverse events identified.
2.5.5.3.2 Deaths
Causes of death that may be related to surfactant treatment include pulmonary haemorrhage
or air leaks that occur shortly after administration. Narratives of related deaths are provided
in Section 2.7.4.7, Tables 2.7.4.7.5 to 2.7.4.7.7. A table for placebo treatment is not included,
as the placebo treatment was instillation of air, and subsequent deaths would be due to the
disease state and not to treatment. Phase I studies did not provide enough information to be
included in the tables. In general, patients were followed until discharge from Level III care.
The incidence of deaths related to treatment are summarized below:
Table 2.5.5.3.2: Incidence of Deaths Related to Treatment

Source BLES Exosurf Survanta
Phase II Studies 7/257 (2.72%) -- --
Study 92-001 6/568 (1.06%) 6/565 (1.06%) --
Study 90-001 67/5181 (1.29%) -- --
Lam, et al., 2005 0/29 (0%) -- 1/31 (3.23%)
TOTAL 80/6035 (1.33%) 6/565 (1.06%) 1/31 (3.23%)
The incidences of deaths related to treatment are similar, approximately 1% in the largest
trials.
In the two lower birth weight arms of Study No. 92-001, the BLES groups experienced
significantly fewer deaths before 7 days of age than did the Exosurf groups. In the 750-1250
g birth weight arm, there were significantly fewer deaths before discharge in the BLES group
compared with the Exosurf group. In the >1250 g birth weight arm, there was no significant
difference between treatment groups for incidence of death at these two time points.
The significant increase in mortality in infants weighing <1250 g who received Exosurf
reflects the increased incidence of total air leaks and fatal air leaks in these infants. In
addition, there was a significant increase in the incidence of fatal pulmonary haemorrhage
before 7 days in infant of <750 g who received Exosurf.
In conclusion, infants receiving BLES are at no greater risk from death due to treatment than
those who receive Exosurf or Survanta.
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2.5.5.4 Interpretation of Safety Data among Studies or Subgroups

The proposed labelling contains a listing of adverse events as they occurred in the Phase III
Comparison Study 92-001. The following table contains those events for which there were
5% higher incidences in the Phase III Open Study 90-001. The Phase II studies and the
published Phase III study with Survanta are not included in this discussion, as their numbers
were fewer. The table is followed by a discussion of each adverse event and support for
using the adverse event rates for Study 92-001 in the proposed labelling.
Table 2.5.5.4: Incidence of Adverse Events Occurring More Frequently by ≥5% in the Open
Study than in the Comparison Study, with the Current Formulation of BLES
Phase III, Double-Blind, Standard-
Phase III Open Study
Controlled Study
(Study No. 90-001)
MedDRA SOC / (Study 92-001)
MedDRA Preferred Term BLES Original BLES Current BLES Current
Exosurf
Formulation Formulation Formulation
n = 3229 n = 1952 n = 568 n = 565
Infection 25.70% 24.13% 0.70% 0.18%
Anaemia 3.50% 15.63% -- --
Acidosis 1.55% 5.84% 0.88% 0.18%
Electrolyte imbalance 2.29% 9.84% -- --
Pulmonary valve stenosis 1.73% 6.66% 0.18% 0.35%
Hypotension 3.38% 14.60% 1.76% 1.95%
Pneumonia 2.07% 6.61% 1.41% 0.18%
Pulmonary hypertension 6.35% 6.25% 0.35% 0.71%
Gastrointestinal reflux 1.49% 5.99% 0.18% 0.53%
Note: Shaded columns represent the current formulation.
Infection
Although the incidence of infection appears much higher in the open study than in the
comparison study, when the rates of infection and sepsis are added, there is little difference
between groups within a study or between the two studies. In addition, the total incidences of
the body sytem Infections and Infestations was similar for all groups in the two studies. Use
of the term “sepsis” in the labelling will adequately convey the rate of infection to be
expected.
Anaemia
Anaemia was not reported in 92-001, nor in any of the other studies except the open study. In
the open study, it was reported in 4% receiving the original formulation and in 16% receiving
the current formulation. Personal communication with one of the clinical monitors revealed
that some hospitals reported any loss of blood as anaemia, even spotting in the endotracheal
tube which could have been from the intubation procedure. The monitor felt that these
reports of anaemia were subjective and not confirmed by laboratory analysis, as blood
samples are avoided whenever possible in such small infants. As reports of anaemia were not
made in any of the other studies and were likely not confirmed analytically, anaemia will not
be added to the list of adverse events in the proposed labelling.
Acidosis and Electrolyte Imbalance

Both acidosis and electrolyte imbalance increased with reformulation in the open trial, from
2% to 6% for acidosis and from 2% to 10% for electrolyte balance. The levels for acidosis in
the comparison trial were less than 1% for either BLES or Exosurf, and there were no reports
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of electrolyte imbalance. The values for the original formulation in the open study are similar
to those for BLES or Exosurf in the comparison study. The majority of cases of metabolic
acidosis and electrolyte imbalance occurred at one site that also reported an increase in sepsis
at the same time. As the increased metabolic acidosis and electrolyte imbalance appear to
have been the result of sepsis, not surfactant treatment, they will be included in the proposed
labelling at the rate of their appearance in the comparison study, in less than 1% of infants
treated.
Pulmonary Valve Stenosis

The incidences of pulmonary valve stenosis, reported only in the open trial, were likely to
have been congenital conditions not related to surfactant treatment. Thus, this term will not
be added to the list of adverse events in the proposed labelling.
Hypotension
With reformulation in the open trial, there was an increase in sepsis, in pneumonia, in
hypotension with PDA and in hypotension with IVH. All of these factors may be responsible
for the rise in hypotension in the open study from 3% to 15%. This is in contrast to the 2%
rate for hypotension for both BLES and Exosurf in the comparison study. As there were no
differences between the trials for sepsis/infection, PDA or IVH, the increased hypotension
was not a direct result of surfactant treatment. As a result, the proposed labelling will
continue to refer to the results of Study 92-001 for hypotension.
Pneumonia
The rise in pneumonia rates from 2% to 6% with reformulation is not related to surfactant
treatment, as the 1% rate in the comparison study is close to that for the original formulation
in the open study. Thus, the rate of 1% for pneumonia for the comparison trial will be
reported in the proposed labelling.
Pulmonary hypertension
Pulmonary hypertension occurred in 6% of infants in the open trial, with either formulation,
and in <1% of infants in the comparison study 92-001, with either drug product. Persistent
pulmonary hypertension of the newborn is persistent fetal circulation due to prematurity, and
not increased by surfactant administration. Thus, the rates reported for the pivotal
comparison study 92-001 will be quoted in the proposed labelling.
Gastrointestinal reflux
While gastrointestinal reflux increased from 2% to 6% with reformulation in the open trial,
its rate in the comparison trial with the current formulation was < 1% with either drug
product. BLES acts locally, within the lung, and is not likely to affect the rate of
gastrointestinal reflux. Thus, the rate of < 1% reported in the comparison study will be
quoted in the proposed labelling.
Other Events Not Reported in Comparison Study 92-001

There were no adverse events unique to the Phase II studies or the published Phase III study
by Lam.
There were many unique adverse events reported in the Phase III Open Study 90-001. The
unique respiratory system events each occurred in less than 1% of patients and added up to
1% for the original formulation and 2% for the current formulation. Unique events for other
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body systems occurred in 1% to 2% of infants, and were either not related to surfactant
treatment or were synonyms for other events that were reported in the comparison study 92-
001.
In conclusion, the rates of adverse events for Study 92-001 are suitable for quoting in the
proposed labelling. In addition, there were no unique adverse events reported in the other
trials that need to be added to the proposed labelling.
2.5.5.5 Long-Term Safety

The manufacturing process removes the hydrophilic surfactant proteins SP-A and SP-D,
leaving the hydrophilic SP-B and SP-C. Thus, there was a concern that the remaining bovine
proteins might be allergenic. SP-B and SP-C assist in the spreading and macro-configuration
of the phospholipids in the lung. Whitsett, et al, assessed whether antibodies to SP-B or SP-
C could be detected in serum from infants treated with Survanta (Whitsett, 1991:505; Section
5.4.28). Treated infants received single or multiple doses of Survanta and control infants
received an instillation of air. Serum samples were collected at time of treatment and at 1
week, 4 weeks and 6 months after treatment. No antibody responses to bovine surfactant
proteins SP-B and SP-C were detected in the treated infants.
Four of the Phase II studies with BLES included a two-year follow-up period during which
patients were screened for neurodevelopmental handicaps and allergic manifestations. These
are discussed in Section 2.7.4.2.1.1 Common Adverse Events, subsection 1.7. There were no
significant differences in neurodevelopmental handicap between patients given BLES or
placebo (a sham air instillation). In Study No. 3, there appeared to be a significantly greater
incidence of patients with recurrent wheeze (p = 0.04). When these studies were combined,
there was no significant difference between BLES and placebo groups for incidences of
allergic manifestations. In conclusion, the Phase II follow-up studies demonstrated that there
are no long-term safety concerns with the use of BLES.
Public information on long-term studies with a similar bovine surfactant, Survanta found no
increase in allergic manifestations or neurodevelopmental handicap. This is discussed in
Section 2.7.4.2.1.1: Common Adverse Events, subsection 1.8.3.
2.5.5.6 Management of Adverse Events

Many of the adverse events are complications of prematurity that are dealt with according to
standard supportive care of premature infants. Specific advice appropriate for those infants
treated with BLES is outlined here.
Cyanosis and Reflux on Dosing

Infants whose ventilation becomes markedly impaired during or shortly after dosing may
have mucous plugging of the endotracheal tube, particularly if pulmonary secretions were
prominent prior to drug administration. Suctioning of all infants prior to dosing may lessen
the chance of mucous plugs obstructing the endotracheal tube. If endotracheal tube
obstruction from such plugs is suspected, and suctioning is unsuccessful in removing the
obstruction, the blocked endotracheal tube should be replaced immediately.
Hyperoxia and Pulmonary Air Leaks

Infants receiving BLES should be monitored for oxygenation with a transcutaneous oxygen
probe or oxygen saturation monitor as well as occasional blood gas measurements. In
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addition, carbon dioxide (CO2) levels should be monitored with transcutaneous CO2 probe
correlated with blood gas readings.
BLES can rapidly affect oxygenation and lung compliance. In some infants, hyperoxia may
occur within minutes of administration of BLES. If hyperoxia develops and oxygen
saturation is in excess of 95%, FiO2 should be reduced until saturation is 90 to 95% to
decrease the risk of retinopathy of prematurity. If the improvement in chest expansion seems
excessive, peak ventilator inspiratory pressures should be reduced immediately. Failure to
reduce inspiratory ventilatory pressures rapidly can result in lung overdistention and fatal
pulmonary air leaks.
Bradycardia and Decreased Oxygen Saturation During Dosing

If bradycardia and decreased oxygen saturation occur during dosing, the dosing procedure
should be stopped and appropriate measures to alleviate the condition initiated. After
stabilization, the dosing procedure can be resumed.
Respiratory Acidosis
Respiratory acidosis occurred with both surfactants primarily at one study centre in Study 92-
001. Monitor lung compliance and oxygenation, as ventilation requirements may change
rapidly after dosing.
Acidosis, Hypotension, Hypoglycemia and Hypothermia

Vigilant clinical attention should be given to all infants prior to, during and after
administration of BLES. Correction of acidosis, hypotension, hypoglycemia and
hypothermia is recommended prior to administration.
2.5.5.7 Overdose and Dependence Issues

Exogenous surfactants do not have a systemic effect or dependence issues. Morton (1989:56;
Section 5.4.18) confirms that exogenous surfactant does not interfere with the production of
endogenous surfactant.
The very large doses (two times a human dose) administered in the repeat toxicity study,
resulted in drowning, until the protocol was changed to divide the doses into aliquots. No
deleterious effects are anticipated with an overdose of BLES in a patient, as the dose is
administered as aliquots, with the respiratory technologist watching for each aliquot of
surfactant to disappear from the proximal end of the feeding tube. There is a resting period
before each aliquot, to allow the infant to recuperate from handling and re-establish
ventilation.
Through the Emergency Drug Release Programme, a newborn infant who was waiting for a
lung transplant was treated with 87 doses of BLES over approximately 59 days, with no
untoward effects from the extended use of BLES.
2.5.5.8 Post-market Experience

BLES has been marketed in Canada since February 2002 and internationally since February
2007. Post-market safety data is summarized in Section 2.7.4.6. Since the International Birth
Date, approximately 161,307 patients have been treated with BLES.
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There were no new adverse events reported post-license, and the overall incidence of adverse
events post BLES administration remain lows (<0.1%) compared to those recorded in the
clinical trial. There have been no regulatory actions related to safety.
There has been a recent increase in the reporting of pulmonary haemorrhage in literature
(discussed below). Pulmonary haemorrhage occurred in 8% of patients treated with BLES in
the Phase III pivotal trial and is a common adverse reaction occurring in 3% -5% of preterm
infants suffering from respiratory distress and who have been given surfactant 1. In 18 years
marketing experience, there have been 16 spontaneous reports of pulmonary haemorrhage, as
well as 38 reports obtained from the literature. This is an incidence of 0.03% of estimated
patients treated. The majority of all reported cases of pulmonary haemorrhage after BLES use
occurred internationally, specifically in India and Iran. These two countries are also the
largest export markets for BLES.
Another frequent post-market adverse event has been endotracheal tube blockage sometimes
with resulting desaturation. This is usually a limited condition until the product has
distributed into the lung. In some cases, the blockage does not clear even with additional air
pressure from the ventilator and the endotracheal tube is replaced. ETT complications
occurred in 6% of patients in both treatment groups in the Phase III pivotal comparative trial
and is a known adverse event for other pulmonary surfactants. Post-market, in 18 years there
have been 23 spontaneous reports of endotracheal obstruction, as well as 11 reports obtained
from literature. This is an incidence of 0.02% of estimated patients treated.
When the drug product was launched in India, there were three deaths due to improper
administration in India. The hospital had been used to administering another surfactant,
Survanta (beractant) in small aliquots due to its viscous nature. The infants developed
pulmonary haemorrhage, patent ductus arteriosus and severe intraventricular haemorrhage.
As BLES is less viscous and spreads more rapidly due to a higher level of surfactant-
associated proteins, it is thought that the small aliquots entered the lungs in a gravitational
manner and resulted in uneven lung compliance. Once this difference between the products
was pointed out to the Indian physicians, it was reported to us that the subsequent ~80 Indian
patients that were treated using the correct administration protocol experienced no untoward
effects.
There were 13 adverse reactions reported from the same hospital in Haiti, where BLES was
sent on a compassionate release basis. The reactions are not likely due to BLES and can be
attributed to inadequate equipment and lack of resources for care of premature infants at the
Haitian facility.
There were two published comparative studies conducted in Iran in which adverse reactions
attributed to BLES were identified. In the Macooie et al., 2018 study 2, 13 serious reactions
and 16 deaths in the BLES group were recorded, however the number of patients that
experienced the 13 listed complications is not identified and it is also unclear whether the
deaths were related to those complications or to surfactant use. A further 24 serious reactions
1
Aziz A and Ohlsson A. Surfactant for pulmonary haemorrhage in neonates. Cochrane Database of Syst Rev.
2012 Jul 11; (7).
2
Macooie AA, Fakour Z, Roanaghi P, et al. Comparative evaluation of the effects of BLES and Survanta on
treatment of respiratory distress syndrome in newborns. J Family Med Prim Care. 2018 Sep-Oct;7(5):1063-
1067.
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attributed to BLES were identified in the Kheradmand Sarokolai et al. 3 2018 study, in which
all adverse events were categorized as pulmonary haemorrhage, representing 20% of the total
number of patients in the BLES group (n=120). This is higher than the 8% incidence of
pulmonary haemorrhage seen in the pivotal clinical trial. There were also 8 deaths noted in
the BLES group, likely attributable to the cases of pulmonary haemorrhage. A similar
frequency of complications was also noted for the competitor product in each study
suggesting surfactant administration and post-dose monitoring may be an issue at the study
centres. Preliminary review of both papers determined that poor methodology was used in the
studies. The BLES product labelling provides appropriate instructions on the dosing and
administration procedure.
2.5.5.9 Applicability of Data to Other Regions

Intrinsic factors such as gender, race and genetic diseases are not likely to influence the safety
profile of BLES internationally.
There are no concerns regarding cultural habits, food, the environment, drug compliance or
culture, as BLES is intended for newborn infants in intensive care. Exogenous surfactant use
is well established globally, with the same medical practice, disease definition, diagnosis and
therapeutic approach as proposed for BLES. BLES has the same indication for treatment of
NRDS and the age range is narrow.
2.5.6 Benefits and Risks Conclusions

Pharmacology
BLES is an exogenous surfactant that acts locally within the surfactant-deficient lung of
infants diagnosed with neonatal respiratory distress syndrome. BLES does not have systemic
pharmacological activity. It is metabolized by the same pathways as endogenous surfactant
and does not interfere with production of endogenous surfactant. Until the infant produces its
own surfactant, BLES allows the lung tissue to expand and contract, thus enabling the
respiratory system to function.
Because BLES acts locally within the lung in a physical manner and because it is
recommended for use only in neonates under five days of age, there are no concerns
regarding drug-food interaction or cognitive impairment. BLES has no systemic effect and,
to the sponsor’s knowledge, there are no drug-drug interactions. BLES also is not toxic to
those who are handling the product.
Indications
BLES is indicated for treatment of neonates who are diagnosed with RDS (“rescue
treatment”). Initial Phase II studies treated infants at risk of RDS (“prophylactic treatment”);
however, it was demonstrated that there was no significant advantage to this practice. As the
use of prenatal steroids increased, prophylactic treatment fell from favour. Thus, Phase III
studies with BLES used rescue treatment only. The proposed labelling indication is for
rescue treatment.
3
Kheradmand Sarokolai Z, Ninafs P, Azizzadeh F, et al. BLES Versus Curosurf for Treatment of Respiratory
Distress in Preterm Neonates and Their Adverse Effects. Iran J Pediatr. 2018;28(4):e11734.
CONFIDENTIAL
BLES is indicated for treatment in neonates during the first five days of life, as such infants
are more likely to be surfactant deficient. RDS after that time is less likely to be due to true
surfactant deficiency.
Recommended Dosage
Dosages in early trials were based on the available theoretical data that 100 mg/kg will cover
the entire lung surface (Hennes, 1991:104, Section 5.4.11).
A dose-ranging study in rabbit pups found the threshold dose of bovine lung surfactant for
immediate improvement of ventilation to be 46 mg/kg, while a dose range of 58 to 150 mg/kg
produced a dose-dependent improvement in immediate and maximal ventilation (Disse, 1987,
Section 5.4.5). A dose of 250 mg/kg induced a submaximal effect, perhaps due to lipid
overload.
The Phase III studies demonstrated that BLES administered at a dose of 135 mg
phospholipids/kg, in single or multiple doses, was both safe and effective.
Retreatment
In the Phase III Comparison Study 92-001, infants were retreated up to three times within the
first five days of age. The Phase III Open Study 90-001 allowed retreatment up to four times
within the first 5 days. The proposed labelling will recommend up to three additional doses.
Infants qualify for retreatment if they have a positive response to the first dose and have a
significant deterioration in the respiratory status with an increased FiO2 requirement by at
least 0.10 (10%). Results of the Phase III studies showed BLES to be both safe and effective
when re-administered in this way.
Administration
In all studies, each aliquot was administered by bolus intratracheal instillation via a #5 French
feeding tube cut to the appropriate length so it reached the tip of the endotracheal tube.
In the Phase III Comparison Study No. 92-001, doses of BLES were divided into two aliquots
so that the dosage volume and administration techniques would match those recommended
for the comparator product, Exosurf, in order to blind the treatments.
In the Phase II rescue studies Nos. 3, 4 and 5, and in the Phase III Open Study No. 90-001,
each dose was divided into three aliquots. With each aliquot, the infant was positioned on the
left side, the right side and in the supine position, to ensure proper distribution to all
pulmonary lobes. As the use of three aliquots has become standard practice for the
administration of BLES, the proposed labelling will recommend that BLES be administered
in three aliquots.
In the proposed labelling, BLES is contraindicated in infants with active pulmonary

haemorrhage. An increased risk of pulmonary hemorrhage has been reported in the literature
following surfactant treatment for RDS, perhaps secondary to improved pulmonary
CONFIDENTIAL
compliance, leading to reduced pulmonary vascular resistance, and left-to-right shunting at

the ductus arteriosus (Pandit, 1995a:35, Section 5.4.19). Thus existing pulmonary
haemorrhage may be exacerbated by surfactant treatment.
Benefits and Risks
In clinical trials, BLES has shown the following benefits:

• Improves lung compliance rapidly, thus reducing stress on the infant.
• Ventilation parameters are improved for a sustained period of time (72 hours).
• An average of 1.7 doses of BLES are required to establish lung compliance until
sufficient endogenous surfactant is produced.
• Reduces morbidity associated with RDS, including a reduced risk of pulmonary air leaks.
• Reduces mortality associated with RDS.
• Enhances bronchopulmonary survival in infants with RDS.
• Reduces the length of stay in Level III care, which reduces the cost of care.
• Reduces the requirement for post-natal steroids and bronchial diuretics, thus reducing
both the cost of treatment and exposure to medications.
• Does not increase the risk of developing neurodevelopmental handicap or allergic
manifestations compared to placebo.
BLES has shown the following three risks associated with its administration:
Transient bradycardia and decreased oxygenation during the dosing procedure may be caused
by acute airway obstruction from the instillation of fluid, combined with vagal reflexes from
handling the infant’s head and neck.
There was an increased risk of post-treatment sepsis and pneumonia in the very low birth
weight infants treated with BLES compared to those who received Exosurf in Study 92-001.
This was believed to be due to the increased survival rate in BLES-treated infants in this birth
weight arm, providing a greater opportunity for infection in this susceptible population.
There may be an increased risk of respiratory acidosis if there is a too rapid weaning of the
ventilatory rates or a lowering of inspiratory pressures. In Study 92-001, respiratory acidosis
occurred for the most part at one study site.
Comparison with Other Surfactants
Exogenous surfactants are now the standard for treatment of NRDS. The Phase III
Comparison Study 92-001 with BLES and Exosurf confirmed that ventilation parameters
improved much more rapidly with BLES, and fewer doses were required. BLES-treated
infants had significantly fewer pulmonary air leaks.
BLES is a natural surfactant extracted from lung lavage, and contains the same phospholipids
in the same concentration as found in natural lung surfactant. These are accompanied by the
hydrophobic proteins SP-B and SP-C. Survanta is a modified bovine surfactant extracted
from minced lung. The presence of other phospholipids from the cellular components of the
lung and the added lipid components make this a modified surfactant with a lower
CONFIDENTIAL
concentration of the hydrophobic surfactant proteins. Lewis (1996:1162; Section 4.3.9)

confirms that BLES contains significantly more SP-B than Survanta. Supplementation of
Survanta with SP-B reportedly improved its surfactant qualities, and improved its resistance
to inactivation by plasma proteins (Chen, 1995:959-60; Section 4.3.4).
BLES has a lower ratio of small surfactant aggregates to large surfactant aggregates than does
Survanta. Lower SA/LA ratio is associated with a superior physiological response (Hallman,
1994:219; Section 5.4.10).
Survanta is approximately eight times more viscous than BLES (Lewis, 1996:1162; Section
4.3.9). A more viscous material could lead to a slower peripheral distribution of surfactant
when instilled through the endotracheal tube, resulting in increases in PIP and PaCO2 values
due to airway obstruction. In the comparative preclinical study of BLES and Survanta by
Lewis et al., animals given instilled Survanta had an acute deterioration in ventilatory
parameters compared with those treated with instilled BLES.
BLES was compared with Survanta in the published Phase III study by Lam et al. The BLES
group had a significantly improved oxygenation index throughout the 12-hour period after
dosing compared to the Survanta group. There was no difference in secondary outcomes,
including mortality, ventilator days and occurrence of chronic lung disease. The authors
concluded that the infants with RDS responded favourably to both surfactants, but that BLES
achieved a significantly faster clinical response in terms of oxygenation index.
Curosurf is a surfactant purified from minced porcine lung, while Infasurf and Alveofact are
extracted from bovine lung lavage. No comparative studies have been carried out between
BLES and these products. In Section 2.7.4.2.1.1: Common Adverse Events, subsection 1.8.1,
a comparison was made between in-house studies with BLES and Exosurf and public
information on Survanta and Curosurf. Rates of adverse events were similar for all products.
As Infasurf and Alveofact are natural surfactant extracts with similar compositions, it is likely
that BLES has a similar efficacy and safety profile to these products.
BLES may have an advantage over Curosurf in that Curosurf is three times as viscous as
BLES, which may lead to slower perfusion through the lung; however, this has not been
tested. In addition, Curosurf, like Survanta, is manufactured from minced lung, which means
that the active phospholipids and proteins are diluted by the other phospholipids from the
tissue components.
Conclusion
Risks associated with the dosing procedure are usually transient. When BLES is
administered to neonates with RDS, the benefits of BLES greatly exceed the identified risks.
BLES presents a significant advantage over Exosurf and Survanta, by more rapidly
improving ventilatory parameters. BLES presents no new safety concerns to those already
established with other surfactants.
This dossier supports the use of BLES in the 27 mg phospholipids/mL formulation, for rescue
treatment of NRDS, when administered at a dose of 135 mg/kg for up to four doses.
CONFIDENTIAL
2.5.7 Literature References
Citation Tab
Chen CM, Ikegami M, Ueda T, Polk DH, Jobe AH. Exogenous surfactant 4.3.4 Chen, 1995
function in very preterm lambs with and without fetal corticosteroid
treatment. J Appl Physiol 1995;78:955-60.
Cummings JJ, Holm BA, Hudak ML, Hudak BB, Ferguson WH, Egan EA. 5.4.2 Cummings, 1992
A controlled clinical comparison of four different surfactant preparations
in surfactant-deficient pre-term lambs. Am Rev Respir Dis 1992;145:999-
1004.
Disse B, Weller E, Lützen L, Ziegler H, Eberhardt H. Comparison 5.4.5 Disse, 1987

between natural and artificial surfactant preparations in premature rabbit
fetuses. In: Lachmann B, ed. Surfactant Replacement Therapy in Neonatal
and Adult Respiratory Distress Syndrome. New York : Springer-Verlag,
1987:42-6.
Hallman M, Merritt TA, Bry K. The fate of exogenous surfactant in 5.4.10 Hallman, 1994
neonates with respiratory distress syndrome. Clin Pharmacokinet
1994;26:215-32.
Hennes, HM, Lee MB, Rimm AA, Shapiro DL. Surfactant replacement 5.4.11 Hennes, 1991
therapy in respiratory distress syndrome. Am J Dis Child 1991;145:102-4.
Ishisaka DY. Exogenous surfactant use in neonates. Ann Pharmacother 5.4.15 Ishisaka, 1996
1996;30:389-98.
Jobe A, Ikegami M. Surfactant for the treatment of respiratory distress 4.3.7 Jobe, 1987
syndrome. Am Rev Resp Dis 1987;136:1256-75.
Lewis JF, Goffin J, Yue P, McCaig LA, Bjarneson D, Veldhyuizen RAW. 4.3.9 Lewis, 1996
Evaluation of exogenous surfactant treatment strategies in an adult model
of acute lung injury. J Appl Physiol 1996;80:1156-64.
Metcalfe IL, Burgoyne R, Enhorning G. (1982a) Surfactant 4.3.10 Metcalfe, 1982a

supplementation in the preterm rabbit: effects of applied volume on
compliance and survival. Pediatr Res 1982;16:834-9.
Metcalfe IL, Pototschnik R, Burgoyne R, Enhorning G. (1982b) Lung 4.3.11 Metcalfe, 1982b
expansion and survival in rabbit neonates treated with surfactant extract. J
Appl Physiol 1982;53:838-43.
Morton NS. Pulmonary surfactant: physiology, pharmacology and clinical 5.4.18 Morton, 1989
uses. Br J Hosp Med 1989;42:52-8.
Pandit PB, Dunn MS, Colucci EA. (1995a) Surfactant therapy in neonates 5.4.19 Pandit, 1995a
with respiratory deterioration due to pulmonary hemorrhage. Pediatrics
1995;95:32-6.
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Citation Tab
Pandit PB, Dunn MS, Kelly EN, Perlman M. (1995b) Surfactant 5.4.20 Pandit, 1995b
replacement in neonates with early chronic lung disease. Pediatrics
1995;95:851-4.
Schürch S, Possmayer F, Cheng S, Cockshutt AM. Pulmonary SP-A 5.4.22 Schurch, 1992
enhances adsorption and appears to induce surface sorting of lipid extract
surfactant. Am J Physiol 1992;263(2 Pt 1):L210 8.
Smyth JA, Metcalfe IL, Duffty P, Possmayer F, Bryan MH, Enhorning G. 5.4.23 Smyth, 1983
Hyaline membrane disease treated with bovine surfactant. Pediatrics
1983;71:913-7.
Walther, FJ, Taeusch HW. New approaches to surfactant therapy. Neonat 5.4.26 Walther, 1991
Resp Dis 1991;1:1,3,4,9-11.
Whitsett JA, Hull WM, Luse S. Failure to detect surfactant protein- 5.4.28 Whitsett, 1991
specific antibodies in sera of premature infants treated with Survanta, a
modified bovine surfactant. Pediatrics 1991;87:505-10.
Nouraeyan N, Lambrinakos-Raymond A, Leone M, Sant’Anna G. 5.4.33 Nouraeyan, 2014

Surfactant administration in neonates: A review of delivery methods. Can
J Respir Ther. 2014;50(3): 91–95.
CONFIDENTIAL

Clinical Overview

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Clinical Overview

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2.5 Clinical Overview

2.5 Clinical Overview ...................................................................................................................... 1

2.5.1 Product Development Rationale

ATC Code: R07AA02: Lung surfactant, natural phospholipids

Indication: Rescue treatment of neonatal respiratory distress syndrome.

Scientific Support for Investigations

Clinical Development Programme

Concordance with Current Standard Research Approaches

2.5.2 Overview of Biopharmaceutics (Not applicable)

2.5.3 Overview of Clinical Pharmacology

2.5.3.1 Pharmacokinetics (Not applicable)

Hallman describes the bioavailability of surfactant administered through the endotracheal

Administration of the surfactant in a relatively high volume, saline-containing aqueous

Bridging Study for the Change in Formulation and Dose

Timing and Number of Multiple Doses

Effect of BLES in Related Diagnoses

2.5.4 Overview of Efficacy

2.5.4.1 Study Populations

2.5.4.2 Duration of Treatment and Follow-Up

2.5.4.3 Study Design

Table 2.5.4.3: Study Design

Table 2.5.4.3: Study Design

Table 2.5.4.3: Study Design

Table 2.5.4.3: Study Design

Table 2.5.4.3: Study Design

2.5.4.4 Relationship between Efficacy and Dose

2.5.4.5 Clinical Relevance of Efficacy Results

2.5.4.6 Applicability of Data to Other Regions

2.5.5 Overview of Safety

2.5.5.1 Suitability of Safety Outcomes

2.5.5.2 Common Adverse Events

Common, non-serious adverse events were:

Common, serious adverse events and complications of prematurity were:

Phase II, Placebo-Controlled Studies

Phase III Comparison Study of BLES vs. Exosurf

There was no significant difference between treatments for incidences of:

Phase III Comparison Study of BLES vs. Survanta

Phase III Open Study with BLES

Adverse Events in the Proposed Labelling

Summary of Common Adverse Events

Particular adverse events associated with surfactant administration include bradycardia,

2.5.5.3 Serious Adverse Events and Deaths

2.5.5.3.1 Serious Adverse Events

There was no significant difference between treatments for incidences of:

As discussed in section 2.7.4.2.1.1: Common Adverse Events, subsection 1.8.1: Common

Table 2.5.5.3.2: Incidence of Deaths Related to Treatment

2.5.5.4 Interpretation of Safety Data among Studies or Subgroups

Acidosis and Electrolyte Imbalance

Pulmonary Valve Stenosis

Other Events Not Reported in Comparison Study 92-001

2.5.5.5 Long-Term Safety

2.5.5.6 Management of Adverse Events

Cyanosis and Reflux on Dosing

Hyperoxia and Pulmonary Air Leaks

Bradycardia and Decreased Oxygen Saturation During Dosing

Acidosis, Hypotension, Hypoglycemia and Hypothermia

2.5.5.7 Overdose and Dependence Issues

2.5.5.8 Post-market Experience

2.5.5.9 Applicability of Data to Other Regions

2.5.6 Benefits and Risks Conclusions