ADA APS talk 4 APS 4 April 15

Lessons learnt: The reality of Inhala2on Gx Filings

© Copyright Aedestra 2015

Philippe Rogueda 30 March 2015

Aedestra Ltd

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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

European aspira2ons


In vitro BE

PK BE

PD BE

The orderly stepwise approach of the European Union

European “perpetuum mobile”


In vitro BE

The PK study merry go round

PD BE PK BE X

Some famous UK Gx products


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


Salmeson -‐ Rolenium -‐ Elpen

Flu9casone pMDI -‐ Cipla

Airflusal -‐ Forspiro -‐ Sandoz

DuoResp -‐ Spiromax -‐ Teva

Formoterol DPI -‐ ELC

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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.


Commercial claims – ACI data

Flu9casone FPF: Rolenium 16±6% Sere9de Diskus 23±13% ERS 2013 Abstract # 4967 Pub # P714

Elpen commercial lit.


Advanced Drug Delivery Reviews 75(2014) 18–31

Flow dependence of Flu2casone FPF


R. Price DDL 2013

PK study, 2 way crossover, single dose 500/50


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


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?


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


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.


4. DuoResp: 11 clinical studies

2 strengths, 11 clinical studies, 628 volunteers, 77 children, 20 years in the making


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)


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


Spiromax PIF studies


5. Formoterol DPI: a rare case of in vitro filing

u RMS Sweden, CMS France

u Authorisa9on granted: 12 Dec. 2014


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!

Lessons learnt


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.

Lessons learnt


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.

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The most likely filing scenario


In vitro BE

PK BE

+ Aim to achieve PK In Vitro BE is nigh impossible


www.inhalationasia.org

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With compliments

AEDESTRA Ltd


ADA APS talk 4 APS 4 April 15

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