This document discusses the challenges of obtaining approval for generic inhaled drug products in Europe. It provides examples of several inhaled generics that have received approval and the types of data submitted, including: 1) Rolenium, a salmeterol/fluticasone combination, which received approval after submitting pharmacokinetic and pharmacodynamic data but no in vitro bioequivalence data. 2) A fluticasone propionate MDI from Cipla that was approved with two pharmacokinetic studies but no in vitro data. 3) Airflusal, a salmeterol/fluticasone combination DPI that was approved with normalized pharmacokinetic data but no demonstration of

1. Lessons
learnt:
The
reality
of
Inhala2on
Gx
Filings
©
Copyright
Aedestra
2015
Philippe
Rogueda
30
March
2015
Aedestra
Ltd
1

2. Disclaimer
The
informa9on
contained
in
this
presenta9on
is
privileged.
This
presenta9on
contains
the
personal
opinions
and
thoughts
of
the
presenter
and
may
not
be
assumed
to
represent
the
opinion
of
Aedestra
Ltd
nor
of
any
employer
or
company
or
learned
society
with
whom
the
presenter
might
be
or
might
have
been
associated.
Aedestra
Ltd
makes
no
representa9ons
to
the
accuracy
of
the
informa9on
contained
therein.
Aedestra
Ltd
declines
any
responsibility
on
the
use
of
the
informa9on
contained
in
these
slides.
Aedestra
Ltd
does
not
recommend
any
course
of
ac9ons
resul9ng
directly
or
indirectly
from
the
informa9on
presented
in
these
slides.
©
Copyright
Aedestra
2015
2

3. European
aspira2ons
©
Copyright
Aedestra
2015
3
In
vitro
BE
PK
BE
PD
BE
The
orderly
stepwise
approach
of
the
European
Union

4. European
“perpetuum
mobile”
©
Copyright
Aedestra
2015
4
In
vitro
BE
The
PK
study
merry
go
round
PD
BE
PK
BE
X

5. Some
famous
UK
Gx
products
©
Copyright
Aedestra
2015
5
u Salbutamol:
3
pMDI
6
DPI
u Beclomethasone:
2
pMDI
4
DPI
u Most
of
these
products
were
not
filed
as
generics,
but
as
brands.
That
in
itself
is
quite
revealing
of
the
difficul9es
in
crea9ng
generics
in
the
inhala9on
space.
u Only
one
product
seems
to
have
been
filed
on
in
vitro
data
in
Europe
…
More
about
this
a
moment
u Formoterol:
1
pMDI
4
DPI
u Budesonide:
7
DPI

6. ©
Copyright
Aedestra
2015
Salmeson
-­‐
Rolenium
-­‐
Elpen
Flu9casone
pMDI
-­‐
Cipla
Airflusal
-­‐
Forspiro
-­‐
Sandoz
DuoResp
-­‐
Spiromax
-­‐
Teva
Formoterol
DPI
-­‐
ELC
1
2
6
5
3
4

7. ©
Copyright
Aedestra
2015
7
1.
Rolenium:
the
challenger
Branded
Gx
–
2
blisters
–
250/50
and
500/50
strengths.
Filed
in
Greece
18
June
2009.
First
EU
DCP
approval
30
Nov
2011
RMS
Sweden.
No
in
vitro
BE.
PK
BE.
PD
data.

8. ©
Copyright
Aedestra
2015
8
Commercial
claims
–
ACI
data
Flu9casone
FPF:
Rolenium
16±6%
Sere9de
Diskus
23±13%
ERS
2013
Abstract
#
4967
Pub
#
P714
Elpen
commercial
lit.

9. ©
Copyright
Aedestra
2015
9
Advanced
Drug
Delivery
Reviews
75(2014)
18–31
Flow
dependence
of
Flu2casone
FPF

10. ©
Copyright
Aedestra
2015
10
R.
Price
DDL
2013
PK
study,
2
way
crossover,
single
dose
500/50

11. ©
Copyright
Aedestra
2015
11
Rolenium
Approval
History
u 18
June
2009:
Greece
–
What
data
was
presented?
u 4
May
2011:
DCP,
RMS
Sweden,
CMS
Bulg.
Est.
Lat.
Lith.
Lux.
Rom.
Slv.
-­‐No
In
Vitro
BE
-­‐PK
efficacy
500/50,
with
charcoal,
60
Healthy
subj.,
extrapolated
to
250/50.
-­‐No
PK
safety,
in
vitro
bioavailability
knowledge
sufficient.
-­‐2
informa9ve
PD
studies
(500/50
&
250/50),
FEV1,
n=28
u 30
Nov
2011:
DCP,
RMS
Sweden,
CMS
Cze.
Ge.
Hu.
Icl.
It.
Pol.
Slk.
-­‐Same
as
4
May
2011
u 13
March
2013:
DCP,
RMS
Sweden,
CMS
Fl.
Fr.
No.
Pol.
DCP,
RMS
Sweden,
CMS
Au.
Bel.
Dk.
Ir.
Nl.
-­‐2011
+
PK
safety
250/50,
without
charcoal,
Asthma
pa9ents
2
PK,
2
PD
studies
acknowledged
Not
approved
in:
France,
UK,
Spain

12. ©
Copyright
Aedestra
2015
12
2.
Flu2casone
pMDi:
luck
incarnate?
u Flu9casone
pMDI
CIPLA
agains
Flixo9de
Evohaler.
u 2
strengths
approved
11
June
2013,
RMS
Sweden,
CMS
Ge,
Sp.
u 2nd
approval:
25
Sept
14,
RMS
Sweden,
CMS
Fl,
Ge,
Hu,
It,
No,
Sp
u No
in
vitro
BE,
2
PK
studies
acknowledged.
u PK
studies
WO
charcoal:
-­‐32
subjects
-­‐28
subjects
with
spacer
How
many
studies
were
necessary
to
fine
tune
this
formula2on?

13. ©
Copyright
Aedestra
2015
13
3.
Airflusal:
normalised
data
u Flu9casone
+
Salmeterol
DPI
u 2
Strengths
approved
500/50
&
250/50
u No
in
vitro
match
u 3
PK
(W/Wo
Charcoal),
2
PD
(one
PIF)
u PD
studies
(n=555)
and
PIF
study
(n=60)
u Major
point
of
applica9on:
FPD
of
Flu9casone
was
normalised
to
yield
an
IVIV
correla9on
with
Cmax,
and
achieve
Cmax
BE

14. ©
Copyright
Aedestra
2015
14
AUC0-­‐tpg*h/ml
Cmax
pg/ml
Test
328.57
±
109.00
297.50
±
111.29
Reference
282.11
±
90.83
265.69
±
84.21
Normalised
Ra9o
(90%CI)
1.1592
(1.1243-­‐1.1952)
1.1041
(1.0574-­‐1.1528)
Natural
Ra9o
1.1647
1.1197
AUC0-­‐tpg*h/ml
Cmax
pg/ml
Test
1083.11
±
311.76
148.03
±
45.16
Reference
1166.84
±
260.88
176.53
±
49.99
Normalised
Ra9o(90%CI)
0.9129
(0.8791-­‐0.9479)
0.8340
(0.8022-­‐0.8671)
Natural
Ra9o
0.9282
0.8386
u Flu9casone,
PK,
2
x
50/500,
n=59.
u Salmeterol,
PK,
2
x
50/500,
n=59.

15. ©
Copyright
Aedestra
2015
15
4.
DuoResp:
11
clinical
studies
2
strengths,
11
clinical
studies,
628
volunteers,
77
children,
20
years
in
the
making

16. ©
Copyright
Aedestra
2015
16
Centralised
procedure:
seal
of
quality?
u Dossier
received
29
Jan
2013,
posi9ve
opinion
20
Feb
2014
u 3
strengths
submired,
2
approved:
160/4.5
&
320/9
u Asthma
and
COPD
u Children
and
adolescent
excluded
u 8
scien9fic
mee9ngs:
24
Sept,
6
Nov,
8
Dec
2009;
9
April,
22
April,
18
Nov
2010;
22
Sept
2011;
16
Feb
2012
u No
in-­‐vitro
BE
u 9
PK
studies
submired
(3
strengths)
and
2
PD
(one
safety
study
in
children)

17. ©
Copyright
Aedestra
2015
17
In
vitro
data
–
Middle
strength
DUORESP
SYMBICORT
T/R
L/min
40
60
90
40
60
90
40
60
90
%
LC
BUDESONIDE
TD
94.78
97.08
99.94
70.73
85.52
93.94
1.34
1.14
1.06
IP+PS
59.25
53.81
50.02
37.16
35.47
37.73
1.59
1.52
1.33
FPD
31.07
38.39
44.21
29.19
45.23
51.47
1.06
0.85
0.86
MMAD
2.41
2.2
2.09
2.58
2.25
2.01
0.93
0.98
1.04
GSD
1.86
1.94
1.98
1.78
1.83
1.95
1.04
1.06
1.02
FORMOTEROL
TD
88.04
91.15
96.76
69.9
84.53
93.86
1.26
1.08
1.03
IP+PS
57.27
51.85
49.29
37.43
35.38
38.61
1.53
1.47
1.28
FPD
27.54
35.51
42.44
27.93
43.95
50.19
0.99
0.81
0.85
MMAD
2.39
2.18
2.11
2.63
2.3
2.08
0.91
0.95
1.01
GSD
1.86
1.9
2.01
1.78
1.84
1.94
1.04
1.03
1.04

18. ©
Copyright
Aedestra
2015
18
Spiromax
PIF
studies

19. ©
Copyright
Aedestra
2015
19
5.
Formoterol
DPI:
a
rare
case
of
in
vitro
filing
u RMS
Sweden,
CMS
France
u Authorisa9on
granted:
12
Dec.
2014

20. ©
Copyright
Aedestra
2015
20
Formoterol
DPI:
a
rare
case
of
in
vitro
filing
u Ref:
Foradil,
Aerolizer
u In
vitro
BE
only
Same
device
design
Same
cri9cal
dimension
Same
handling
Same
device
resistance
u Special
request:
PIF
and
FIVC
study
on
20
subjects
REF
&
TEST
REF
TEST
FIVC
(L)
2.2
2.1
PIF
(L/min)
101.23
102.65
u Let’s
study
its
in
vitro
performance!

21. Lessons
learnt
©
Copyright
Aedestra
2015
21
Products
In
Vitro
BE
PK/PD
studies
PIF
studies
Rolenium
✗
4
✓
Seroflo
pMDI
✗
2
!!
✓
Airflusal
✗
5
✓
DuoResp
✗
11
✓
Formoterol
DPI
✓
✗
✓
When
mul9ple
strengths
are
available,
the
lower
strength
seems
impossible
to
match
and
file.

22. Lessons
learnt
©
Copyright
Aedestra
2015
u In
vitro
filing
is
possible
in
the
EU.
It
is
the
excep9on
rather
than
the
norm.
u In
vitro
filing
requires
same
device,
formula9on,
API,
groupings.
Further
requirements:
PIF
study,
Handling
studies,
knowledge
of
bioavailability
of
API/
Formula9on.
A
stage
by
stage
match
is
difficult,
groupings
will
be
accepted
when
jus9fied.
u Some
countries
are
more
recep9ve
to
in
vitro
filing
than
others.
u Most
products
will
be
approved
aver
PK
studies.
Study
the
reference
product
in
depth.
How
many
PK
studies
will
you
conduct?
u Do
not
assume
a
linear
development:
in
vitro
followed
by
PK.
This
is
a
very
naïve
approach.
u The
variety
of
PK
studies
presented
and
their
jus9fica9ons
show
the
complexity
of
the
inhala9on
field,
and
the
recep9veness
of
regulatory
authori9es.
22

23. The
most
likely
filing
scenario
©
Copyright
Aedestra
2015
23
In
vitro
BE
PK
BE
+
Aim
to
achieve
PK
In
Vitro
BE
is
nigh
impossible

24. ©
Copyright
Aedestra
2015
www.inhalationasia.org
Follow
us
on
24

25. With
compliments
AEDESTRA
Ltd
©
Copyright
Aedestra
2015
25