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)

0

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

| 17 Cipla, Data on file 2013 17

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

7

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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