Challenges in the development of affordable orally … in the development of affordable orally...
Transcript of Challenges in the development of affordable orally … in the development of affordable orally...
Challenges in the development of affordable orally inhaled products IPAC-RS/UF Orlando Inhalation Conference March 18, 2014
The information and views set out in this presentation are those of the presenter and do not necessarily reflect the official opinion of Cipla Ltd
Juliet Rebello
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Overview
• Drivers and Barriers to developing affordable OIPs • Challenges in choosing a Reference drug • Study conduct challenges
• Key regulatory challenges •Summary
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Drivers and Barriers to developing affordable OIPs
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Asthma Prevalence Versus Cost of Care in Developed and Emerging Markets
North America $ 18.2 bn*
EU $ 9.0 bn*
Rest of the world = $ 3.6 bn *
Source: GINA guidelines 2013 IMS Worldview
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*asthma & COPD inhaled drugs
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3 million deaths every year 65% of all global COPD deaths occur in India and China
Territories are sized in proportion to the absolute number of people who died from chronic obstructive pulmonary disease in one year.
China
India
United States
Indonesia
Brazil
Russian (Fed)
Japan
Nigeria
Germany Turkey
Ethiopia Congo (DR)
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1000
2000
3000
4000
5000
6000
0 100 200 300 400 500 600 700 800 900 1,000 1,100 1,200
cum
ula
tive p
opula
tion (
mill
ions)
proportion killed by cause in 2002 (per million persons 2002)
The Changing Spectrum of COPD
4: Source: International Classification of Diseases-10 codes: J40-J44,
Country Avg number of Cigarettes smoked per capita
Russia 2786
Japan 1841
China 1711
Turkey 1399
US 1028
Brazil 504
Source: World Lung Foundation, American Cancer Society
COPD estimated deaths in 2002
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Drivers And Barriers for the development of affordable inhalation products Dr
ivers
• Government and Payer demands • Rising healthcare costs • Increasing prevalence of respiratory disease in developed and emerging markets • Demand for cost effective OIPs • Greater availability of OIP BE Guidances
Barri
ers
• Freedom to operate • Balance of development costs and profitability • Unharmonized and changing regulatory requirements • Requirements for evaluation in children/adolescents • Complex delivery devices • Commercialization
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Challenges in Choosing a Reference Product
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Choosing a reference listed drug (RLD) for global development
• Regulatory authorities often require studies to be conducted with their national RLDs and may even require that the studies be conducted at certified centres in their respective countries • Reference product can suddenly be withdrawn from the market • Selection of a “representative” reference batch can be a major problem especially when limited RLD batches are available in the market • Batch to batch variation is observed for the same RLD by country/within a market
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RLD differences within a market/across markets
Source: Cipla, Data on file 2013
Not within 15%
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3mo 6mo 6mo 3mo 8 mo 8 mo 7 mo 9 mo 10 mo 17 mo 12mo 12mo 12mo 5mo 5 mo 8 mo
mo = months from date of manufacture ; FPM = Fine particle mass
Study Conduct Challenges
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Study Conduct Challenges
•Phase I centers with respiratory expertise
•Complex, skill-based analytical methods and testing. • Country restrictions in the inclusion of vulnerable populations (e.g., children, adolescents, women of child bearing potential). • RLD blinding • Estimating sample size/designing dose response studies when limited data is available
• Assuring proper device training
| Newman et al Eur J Resp Dis Suppl 1982: 63 (suppl 119): 57- 65.
Lung deposition changes with Inspiratory flow rate
Inhalation rate SLOW (30 L min-1) FAST (60 L min-1)
FEV1 55% predicted
% L
ung
Dep
ositi
on
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Inhaler Technique : Critical Errors %
mak
ing
at le
ast o
ne c
ritic
al e
rror
Melani et al Respir Med 2011, 105: 930-938
• Risk of critical error increased (p<0.001) with age, lower schooling, lack of instruction provided for the inhaler • Critical errors associated with (p<0.001) ↑ hospitalisation risk, emergency room visits, oral corticosteroid, poor disease control
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N=1664
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Challenges in conducting paediatric PK BE studies
• EMA generally requires in vivo studies in children. • PK studies in children are prohibited in many countries for ethical reasons • PK profiling has to be truncated due to blood loss limitations • Centers with the required expertise are limited. • Prohibitive sample size requirements due to
• Training limitations • Need to evaluate asthma patients • Variability associated with tidal versus deep breathing through a spacer.
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EMA OIP guidelines – A standard for most markets?
EMA – OIP guidelines
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In vitro
PK
Clinical
Required
Required
Is it required?
Key Regulatory Challenges
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Demonstrating equivalence for Stages with Low Mcg Quantities May not be Possible
AAPS PharmSciTech 2007; 8 (4) Article 110 (http://www.aapspharmscitech.org).
Low amount of drug
deposition
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Figure 1: Mass collected on each component of an Andersen 8-stage cascade impactor .
Nat
ural
ord
er o
f co
mpo
nent
s
Ran
k or
der o
f co
mpo
nent
s fr
om
high
est t
o lo
wes
t - Test
- Reference
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50.6
9
4.55
2.37
2.76
8.35
12.0
4
5.81
0.69
0.29
2.23
30.1
4
51.4
6
4.58
2.20
2.32
7.04
9.86
4.97
0.65
0.36
2.22
25.7
5
44.9
6
3.41
1.88
2.22
8.07
10.5
0
4.74
0.63
0.46
2.12
27.0
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44.8
6
4.09
2.27
2.35
7.22
10.1
6
4.55
1.20
0.62
2.15
26.5
2
45.6
1
4.36
2.19
2.54
7.16
10.8
9
4.49
0.92
0.44
1.77
26.3
7
0
10
20
30
40
50
60
IP S0 S1 S2 S3 S4 S5 S6 S7 FIL FPM
mic
rogr
ams
Stagewise Distribution by Cascade Impactor for RLD
Reference Batch 1 (Country A)-Age of sample 3 MonthReference Batch 2 (Country A)-Age of sample 6 MonthReference Batch 3 (Country A)-Age of sample 6 MonthReference Batch 4 (Country A)-Age of sample 8 MonthReference Batch 5 (Country A)-Age of sample 8 Month
Within reference batches may not pass within 15% at stages with low deposition
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B
Con
stra
ined
lung tissue Initial lung deposition
lung tissue Absorption and mucocilliary clearance
time
GI tract GI
tract
Aerolized drug
Aerolized drug
lung tissue
A
Nor
mal
GI tract
lung tissue
time
GI tract
Healthy volunteers vs patients – the debate continues
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Figure 2: Lung retention, attained by scintigraphy of 99m Technetum-labelled BDP liposomes delivered via Aerotech II nebuliser to patients with asthma .
Figure 1: Fate of inhaled drug in normal (A) and constrained (B) lung.
S. Edsbacker et al. / Pulmonary Pharmacology & Therapeutics 21 (2008) 247–258
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The Big question?
Do in vitro and PK bioequivalence assure comparable safety & efficacy?
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PD
PK
Formoterol DPI
PK/PD relationship - LABA
PK studies are designed to assess a defined 20% difference b/w two products which is a very conservative margin to confirm equivalence
1 Burgess et al. Eur J Clin Pharmacol 1998: 54:141-147 ; 2Arzneimittelforshung 2010;60(2):81-86 20
1 N =20; baseline FEV1 = 73% predicted 2 N =24 ; heatlhy volunteers
Dose (mcg) 12 mcg 24 mcg 48 mcg 96 mcg Heart rate (beats/min) 1 69 (10) 71 (10) 72 (11) 77 (11)
Serum potassium (mmol/L) 1 3.6 (0.2) 3.5 (0.2) 3.5 (0.2) 3.2 (0.3)
FEV1 (L) 1 3.86 (0.63) 3.96 (0.65) 4.01 (0.72) 4.04 (0.70)
QTc (ms) 1 399.6 (25.1) 409.2 (20.7) 414.0 (24.8) 423.1 (24.3)
Blood glucose (mmol/L) 1 6.2 (1.0) 6.7 (1.3) 7.1 (1.1) 7.4 (0.9)
AUC0-t (pg.hr/ml) 2 95.39 170.48
Cmax (pg/ml) 2 21.39 42.99
| Ref: 1. Product Label 2. Kunka et al 2000;94;S10-S16 3. Grahnen et al. Eur J Clin Pharmacol 1997;52(4):261-
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Cmax (pg/ml) AUC infinity (pg.hr/ml)
FP 50 mcg (dose: 400 mcg) 118.7 693.1
FP 125 mcg (dose: 1000 mcg) 237.7 1547.1
FP 250 mcg (dose : 2000 mcg) 506.8 3365.4
PK/PD relationship – ICS
PK studies based on a conservative margin of 80-125% are adequate to assess the lung and systemic exposure between two inhaled formulations
Figure 1: % Change from baseline in FEV1 predicted
Figure 2: Mean plasma cortisol suppression for single doses of budesonide 800 µg and FP 250 µg, 500 µg, 1000 µg, and following the last of 7 doses of FP 1000 µg twice daily. *P < 0.001.
Table 1: Pharmacokinetic parameters (Geometric mean values) for fluticasone HFA pMDI
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AUC0-30min is a good predictor of lung deposition
Salmeterol (Test)*
200 mcg
Salmeterol (Reference) *
200 mcg
T/R ratio
*AUC0-30 (with charcoal) hr. pg/ml 223 199 1.12
*AUC0-30 (without charcoal) hr. pg/ml 222 215 1.03
Beclomethasone (17 BMP-Test)*
2000 mcg
Beclomethasone (17-BMP Reference)*
2000 mcg
T/R ratio
**AUC0-30 (with charcoal) hr. pg/ml 1190 1250 0.95
**AUC0-30 (without charcoal) hr. pg/ml 933 1026 0.91
Source: *ERS 2010; **Inhalation Asia 2013 22 *Geometric mean values
Pharmacokinetic evaluations comparing AUC0-30 min (and Cmax) are important in understanding bioequivalence of inhaled drugs, and these estimates can provide reliable estimates of lung deposition
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Summary
•Equivalence to be evaluated using the most sensitive methodology i.e PK studies
•Population most sensitive to detect differences to be considered
•Leveragability of data and BE programs across countries
Harmonization of BE guidances for OIP across countries (sharing best practices) and improve global availability and access to affordable OIPs
•Engage Industry-Regulators communication to build best practices
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Acknowledgements
•Dr. Paul Dorinsky and the Respiratory Clinical Team
•Mrs. Geena Malhotra and the R&D Team
•Dr. Purandare and the Regulatory Team
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Thank You
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