ADA APS talk 4 APS 4 April 15

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Transcript of 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.

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  • European aspira2ons

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    In vitro BE

    PK BE

    PD BE

    The orderly stepwise approach of the European Union

  • European perpetuum mobile

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    In vitro BE

    The PK study merry go round

    PD BE PK BE X

  • Some famous UK Gx products

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    uSalbutamol: 3 pMDI 6 DPI

    uBeclomethasone: 2 pMDI 4 DPI

    uMost 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.

    uOnly one product seems to have been filed on in vitro data in Europe More about this a moment

    uFormoterol: 1 pMDI 4 DPI

    uBudesonide: 7 DPI

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    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.

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    Commercial claims ACI data

    Flu9casone FPF: Rolenium 166% Sere9de Diskus 2313% ERS 2013 Abstract # 4967 Pub # P714

    Elpen commercial lit.

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    Advanced Drug Delivery Reviews 75(2014) 1831

    Flow dependence of Flu2casone FPF

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    R. Price DDL 2013

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

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    Rolenium Approval History u18 June 2009: Greece What data was presented?

    u4 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

    u30 Nov 2011: DCP, RMS Sweden, CMS Cze. Ge. Hu. Icl. It. Pol. Slk.

    -Same as 4 May 2011

    u13 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

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    2. Flu2casone pMDi: luck incarnate? uFlu9casone pMDI CIPLA agains Flixo9de Evohaler. u2 strengths approved 11 June 2013, RMS Sweden, CMS Ge, Sp.

    u2nd approval: 25 Sept 14, RMS Sweden, CMS Fl, Ge, Hu, It, No, Sp

    uNo in vitro BE, 2 PK studies acknowledged.

    uPK studies WO charcoal: -32 subjects -28 subjects with spacer

    How many studies were necessary to fine tune this formula2on?

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    3. Airflusal: normalised data

    uFlu9casone + Salmeterol DPI

    u2 Strengths approved 500/50 & 250/50

    uNo in vitro match

    u3 PK (W/Wo Charcoal), 2 PD (one PIF)

    uPD studies (n=555) and PIF study (n=60)

    uMajor point of applica9on: FPD of Flu9casone was normalised to yield an IVIV correla9on with Cmax, and achieve Cmax BE

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    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

    uFlu9casone, PK, 2 x 50/500, n=59.

    uSalmeterol, PK, 2 x 50/500, n=59.

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    4. DuoResp: 11 clinical studies

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

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    Centralised procedure: seal of quality?

    uDossier received 29 Jan 2013, posi9ve opinion 20 Feb 2014

    u3 strengths submired, 2 approved: 160/4.5 & 320/9

    uAsthma and COPD

    uChildren and adolescent excluded

    u8 scien9fic mee9ngs: 24 Sept, 6 Nov, 8 Dec 2009; 9 April, 22 April, 18 Nov 2010; 22 Sept 2011; 16 Feb 2012

    uNo in-vitro BE

    u9 PK studies submired (3 strengths) and 2 PD (one safety study in children)

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    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

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    Spiromax PIF studies

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

    uRMS Sweden, CMS France

    uAuthorisa9on granted: 12 Dec. 2014

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    Formoterol DPI: a rare case of in vitro filing

    uRef: Foradil, Aerolizer u In vitro BE only

    Same device design Same cri9cal dimension Same handling Same device resistance

    uSpecial 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

    uLets study its in vitro performance!

  • Lessons learnt

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    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

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    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.

    uSome countries are more recep9ve to in vitro filing than others.

    uMost products will be approved aver PK studies. Study the reference product in depth. How many PK studies will you conduct?

    uDo not assume a linear development: in vitro followed by PK. This is a very nave approach.

    uThe 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

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    In vitro BE

    PK BE

    + Aim to achieve PK In Vitro BE is nigh impossible

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  • With compliments

    AEDESTRA Ltd

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