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The Story of MT

SJS Dundonald Road. The Story of MTA02. 2. Background. Formoterol is a long-acting extremely potent beta-agonist used in the treatment of asthma. Originally patented by Yamanouchi, who, however only developed an oral form, it was licensed in the mid 1980s to CIBA-Geigy.At the time of my arrival at, C-G Basle in 1987 it had just been scheduled for international development in solution form delivered by metered-dose inhaler.In the course of the next few years various other formulations: suspensi29882

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The Story of MT

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    1. SJS Dundonald Road The Story of MTA02 1 The Story of MT/A02 Stephen Senn Lecture at Newton Institute, Design of Experiments Workshop 24 July 2008Lecture at Newton Institute, Design of Experiments Workshop 24 July 2008

    2. SJS Dundonald Road The Story of MTA02 2 Background Formoterol is a long-acting extremely potent beta-agonist used in the treatment of asthma. Originally patented by Yamanouchi, who, however only developed an oral form, it was licensed in the mid 1980s to CIBA-Geigy. At the time of my arrival at, C-G Basle in 1987 it had just been scheduled for international development in solution form delivered by metered-dose inhaler. In the course of the next few years various other formulations: suspension, single-dose dry-powder inhaler and multi-dose inhaler were developed. MTA/02 was a trial designed as part of a programme to show equivalence of a new multi-dose dry powder form (MT&A) to an existing single-dose form (ISF).

    3. SJS Dundonald Road 3

    4. SJS Dundonald Road The Story of MTA02 4 Context Many trials had been run with formoterol solution This formulation could, however, only be kept stable using a cold chain for delivery and was not widely marketed. The suspension formulation had been abandoned because creaming tendency made it too potent. The dry powder ISF formulation was a technical success but required priming anew every time it was used. A multi-dose formulation was desirable from the patient and marketing point of view. There was no desire from the companys point of view to start all over again. Hence an equivalence route was sought.

    5. SJS Dundonald Road The Story of MTA02 5

    6. SJS Dundonald Road The Story of MTA02 6

    7. SJS Dundonald Road The Story of MTA02 7 The Pre-specified Analysis Pre-specified to target log-AUC forced expiratory volume in one second (FEV1) over 12 hours Model to fit patient & period effects and log-baseline FEV1 in addition to treatment. All factors to be treated as fixed Main comparison to based on 12?g doses Limit of equivalence targeted at +/- 10% 95% confidence interval to be contained in limits of equivalence

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    11. SJS Dundonald Road The Story of MTA02 11 Some People Involved Denise Till project statistician for formoterol Francesco Patalano medical advisor Stephen Senn group leader IBA ex project statistician Jrgen Lillienthal head of Datamap, the CRO analysing the trial

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    13. SJS Dundonald Road The Story of MTA02 13

    14. The Story of MTA02 14 Fixed Effects Analysis

    15. SJS Dundonald Road The Story of MTA02 15 Fixed Effects Results

    16. SJS Dundonald Road The Story of MTA02 16

    17. SJS Dundonald Road The Story of MTA02 17 Random Effects Analysis

    18. SJS Dundonald Road The Story of MTA02 18 Random Effects Results

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    20. SJS Dundonald Road The Story of MTA02 20

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    22. SJS Dundonald Road The Story of MTA02 22 Safety Not main purpose of trial However might give some clues regarding potency Clues to cardiac effects can be gained by studying QTc Typical value 410 milliseconds Prolongation can be a concern K Typical value 4.3 (3.5 5) mmols/L Depression can be a concern

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    25. SJS Dundonald Road The Story of MTA02 25 Safety Conclusion Little evidence of dose-effect for QTc At least as regards average Evidence of effect on Potassium at highest doses Effect small However, it is interesting that the effect reflects dose delivered rather than potency Implications for therapeutic ratio

    26. SJS Dundonald Road The Story of MTA02 26 Denouement The formulation was abandoned Despite the initial criterion of equivalence being satisfied MTA Had the potency of ISF It was recognised that the original criterion was too lax The company (now Novartis) continues to market formoterol (Foradil) ISF and develop new formulations but since the drug is long off patent faces competition from Astra-Zeneca (Oxis) and generic manufacturers

    27. SJS Dundonald Road The Story of MTA02 27 What would I do differently? Look at equivalence in terms of dose-scale rather than response scale Fiellers theorem Plus or minus 20% traditional on dose scale but unatainable using FEV1 and bronchodilators Decision-analytic approach? Will the regulator agree? NO!

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