1. SJS Dundonald RoadThe Story of MTA021 The Story of MT/A02 Stephen Senn

2. SJS Dundonald RoadThe Story of MTA022 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 Road3

4. The Story of MTA024 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 company’s point of view to start all over again. Hence an equivalence route was sought.

5. SJS Dundonald RoadThe Story of MTA025 Bioequivalence of two bronchodilators given by inhalation Bronchodilators are inhaled hence classical bioequivalence impossible. A pharmacodynamic solution is necessary. Standard bronchodilator doses are very often on flat part of dose-response curve. Hence what is really required is a parallel dose assay.

6. SJS Dundonald RoadThe Story of MTA026 Problems Three doses of test and reference were required. Placebo should also be included. Patients could not be treated more than 5 times. Very high precision was required. This made a parallel group trial unattractive.

7. SJS Dundonald RoadThe Story of MTA027 The Pre-specified Analysis Pre-specified to target log-AUC forced expiratory volume in one second (FEV 1 ) over 12 hours Model to fit patient & period effects and log- baseline FEV 1 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

8. SJS Dundonald RoadThe Story of MTA028 Solution Incomplete blocks design in seven treatments (three doses test, three doses reference and placebo) and five periods. This required twenty-one sequences in order to balance treatments. Sequences to be replicated 6 times = 126 patients. Trial run in over a dozen centres.

9. SJS Dundonald RoadThe Story of MTA029 A Fraction of an Incomplete Blocks Design

10. SJS Dundonald RoadThe Story of MTA0210 It is impossible to balance the design in seven sequences because although every treatment can appear equally often in every period and over the design as a whole, pairs of treatments do not appear equally often within patients. There are (7x6)/2 = 21 possible treatment pairs. Every patient permits (5x4)/2 = 10 possible pairwise comparisons. Hence if 7 patients are used there are 70 possible within-patient comparisons. But 21 does not divide into 70. In fact some 7 pair-wise comparisons appear 4 times and 14 comparisons 3 times in the 7 sequences above. However if 21 sequences are used the design can be balanced.

11. SJS Dundonald RoadThe Story of MTA0211 Some People Involved Denise Till – project statistician for formoterol Francesco Patalano – medical advisor Stephen Senn – group leader IBA ex project statistician Jürgen Lillienthal head of Datamap, the CRO analysing the trial

12. SJS Dundonald RoadThe Story of MTA0212

13. SJS Dundonald RoadThe Story of MTA0213

14. The Story of MTA0214 Fixed Effects Analysis * run a fixed effects analysis of the data; Title2 'Fixed patient effects'; proc glm data=incomp; class TREAT PERIOD PATIENT; model AUC=PATIENT BASE PERIOD TREAT; estimate "MTA6" TREAT 0 0 0 0 0 1 -1 ; estimate "MTA12" TREAT 0 0 0 1 0 0 -1 ; estimate "MTA24" TREAT 0 0 0 0 1 0 -1 ; estimate "ISF6" TREAT 0 0 1 0 0 0 -1 ; estimate "ISF12" TREAT 1 0 0 0 0 0 -1 ; estimate "ISF24" TREAT 0 1 0 0 0 0 -1 ; estimate "treatment" TREAT 1 1 1 1 1 1 -6 / divisor=6; estimate "formulation" TREAT -1 -1 -1 1 1 1 0/ divisor=3; estimate "dose" TREAT 0 1 -1 0 1 -1 0/divisor=2; estimate "parallelism" TREAT 0 1 -1 0 -1 1 0; estimate "curvature" TREAT -2 1 1 -2 1 1 0; estimate "opposing curvature" TREAT -2 1 1 2 -1 -1 0; run;

15. SJS Dundonald RoadThe Story of MTA0215 Fixed Effects Results Parameter Estimate Error t Value Pr > |t| MTA6 0.07388008 0.01078364 6.85 <.0001 MTA12 0.11282581 0.01087733 10.37 <.0001 MTA24 0.13880211 0.01083390 12.81 <.0001 ISF6 0.15519157 0.01074491 14.44 <.0001 ISF12 0.17168025 0.01073995 15.99 <.0001 ISF24 0.19824573 0.01083830 18.29 <.0001 treatment 0.14177093 0.00828795 17.11 <.0001 formulation -0.06653652 0.00619103 -10.75 <.0001 dose 0.05398809 0.00758902 7.11 <.0001 parallelism -0.02186787 0.01509515 -1.45 0.1480 curvature -0.00289264 0.02632001 -0.11 0.9125 opposing curvature 0.02304623 0.02645516 0.87 0.3840

16. SJS Dundonald RoadThe Story of MTA0216

17. SJS Dundonald RoadThe Story of MTA0217 Random Effects Analysis *run a random effects analysis of the data; Title2 'Random patient effects'; proc mixed data=incomp; class TREAT PERIOD PATIENT; model AUC=BASE PERIOD TREAT; random patient; estimate "MTA6" TREAT 0 0 0 0 0 1 -1 ; estimate "MTA12" TREAT 0 0 0 1 0 0 -1 ; estimate "MTA24" TREAT 0 0 0 0 1 0 -1 ; estimate "ISF6" TREAT 0 0 1 0 0 0 -1 ; estimate "ISF12" TREAT 1 0 0 0 0 0 -1 ; estimate "ISF24" TREAT 0 1 0 0 0 0 -1 ; estimate "treatment" TREAT 1 1 1 1 1 1 -6 / divisor=6; estimate "formulation" TREAT -1 -1 -1 1 1 1 0/ divisor=3; estimate "dose" TREAT 0 1 -1 0 1 -1 0/divisor=2; estimate "parallelism" TREAT 0 1 -1 0 -1 1 0; estimate "curvature" TREAT -2 1 1 -2 1 1 0; estimate "opposing curvature" TREAT -2 1 1 2 -1 -1 0; run;

18. SJS Dundonald RoadThe Story of MTA0218 Random Effects Results Estimates Standard Label Estimate Error DF t Value Pr > |t| MTA6 0.07414 0.01133 602 6.54 <.0001 MTA12 0.1145 0.01143 602 10.02 <.0001 MTA24 0.1455 0.01136 602 12.82 <.0001 ISF6 0.1581 0.01128 602 14.02 <.0001 ISF12 0.1712 0.01129 602 15.17 <.0001 ISF24 0.2070 0.01136 602 18.22 <.0001 treatment 0.1451 0.008701 602 16.68 <.0001 formulation -0.06741 0.006505 602 -10.36 <.0001 dose 0.06013 0.007949 602 7.56 <.0001 parallelism -0.02253 0.01586 602 -1.42 0.1560 curvature 0.01339 0.02763 602 0.48 0.6282 opposing curvature 0.03193 0.02777 602 1.15 0.2507

19. SJS Dundonald RoadThe Story of MTA0219 Placebo and the 3 doses of the new formulation

20. SJS Dundonald RoadThe Story of MTA0220 With the 3 doses of reference formulation added...any d.f.

21. SJS Dundonald RoadThe Story of MTA0221

22. SJS Dundonald RoadThe Story of MTA0222 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

23. SJS Dundonald RoadThe Story of MTA0223

24. SJS Dundonald RoadThe Story of MTA0224

25. SJS Dundonald RoadThe Story of MTA0225 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 RoadThe Story of MTA0226 Denouement The formulation was abandoned –Despite the initial criterion of equivalence being satisfied –MTA Had ¼ 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 RoadThe Story of MTA0227 What would I do differently? Look at equivalence in terms of dose-scale rather than response scale –Fieller’s theorem Plus or minus 20% traditional on dose scale but unatainable using FEV 1 and bronchodilators Decision-analytic approach? –Will the regulator agree? NO!

28. SJS Dundonald RoadThe Story of MTA0228 Relative potency Estimate 0.18 95% CI 0.08-0.29