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The story of MTA/02

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History of how and why a complex cross-over trial was designed to prove the equivalence of two formulations of a beta-agonist and what the eventual results were. Presented at the Newton Institute 28 July 2008. Warning: following the important paper by Kenward & Roger Biostatistics, 2010, I no longer think the random effects analysis is appropriate, although, in fact the results are pretty much the same as for the fixed effects analysis.

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The story of MTA/02

  1. 1. SJS Dundonald Road The Story of MTA02 1 The Story of MT/A02 Stephen Senn
  2. 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. 3. SJS Dundonald Road 3 1980 1985 1990 1995 2000 2005 Year 0 20 40 60 80 Publications Number of Formoterol Publications by Year of Publication First Yamanouchi publications CIBA-Geigy international task force formed Foradil solution marketed CH First Astra publications appear First ISF publication MTA/02 Senn, Lillienthal, Patalano & Till, 1997
  4. 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 company’s point of view to start all over again. Hence an equivalence route was sought.
  5. 5. SJS Dundonald Road The Story of MTA02 5 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. 6. SJS Dundonald Road The Story of MTA02 6 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. 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 12µg doses • Limit of equivalence targeted at +/- 10% • 95% confidence interval to be contained in limits of equivalence
  8. 8. SJS Dundonald Road The Story of MTA02 8 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. 9. SJS Dundonald Road The Story of MTA02 9 A Fraction of an Incomplete Blocks Design Periods Ghost periods 1 2 3 4 5 6 7 A B C D E f g G A B C D e f F G A B C d e E F G A B c d D E F G A b c C D E F G a b B C D E F g a
  10. 10. SJS Dundonald Road The Story of MTA02 10 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. 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 • Jürgen Lillienthal head of Datamap, the CRO analysing the trial
  12. 12. SJS Dundonald Road The Story of MTA02 12 Table 4 Summary of demographic and baseline data Variable N (%) Mean Range Age (years) 48 16 - 73 Sex: male female 107(66) 54 (34) Height (cm): male female 176 163 162 - 191 144 - 190 Weight(kg):male female 81 69 60 - 120 43 - 113 Smoking habit: current smoker Non/Ex smoker 27(17) 134(83) Duration of ROAD (years) 16.4 0.6 - 63 Reversibility test at examination 1 Predicted FEV1 Baseline FEV1 % of Predicted FEV1 after inhalation % above baseline 3.34 2.02 60.2 2.52 26.0 1.87 - 4.85 0.93 - 4.11 34.1 - 84.9 1.21 - 4.72 14.6 - 72.5 Vital signs at examination 2 systolic blood pressure(mm Hg) diastolic blood pressure(mmHg) pulse rate (bpm) 126 80 76 100-169 55-100 54-104 Patients with concomitant diseases 75(47)
  13. 13. SJS Dundonald Road The Story of MTA02 13 Table 3: A set of contrasts representing an orthogonal decomposition for MT/A02. Treatment Contrast MT&A6 MT&A12 MT&A24 ISF6 ISF12 ISF24 Placebo Formoterol versus Placebo 1/6 1/6 1/6 1/6 1/6 1/6 -1 MT&A versus ISF 1/3 1/3 1/3 -1/3 -1/3 -1/3 0 Slope -1/2 0 1/2 -1/2 0 1/2 0 Parallelism Devices 1 0 -1 -1 0 1 0 Curvature 1 -2 1 1 -2 1 0 Opposing Curvature -1 2 -1 1 -2 1 0
  14. 14. The Story of MTA02 14 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. 15. SJS Dundonald Road The Story of MTA02 15 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. 16. SJS Dundonald Road The Story of MTA02 16 6.06.57.07.58.0 ISF12 ISF24 ISF6 MTA12MTA24 MTA6Placebo treatment AUCFEV1 -0.4 -0.2 0.0 0.2 050100150200 residual fitted residual 7.0 7.5 8.0 -0.4-0.20.00.2 theoretical empirical -3 -2 -1 0 1 2 3 -0.4-0.20.00.2
  17. 17. SJS Dundonald Road The Story of MTA02 17 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. 18. SJS Dundonald Road The Story of MTA02 18 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. 19. SJS Dundonald Road The Story of MTA02 19 Treatment Placebo MT&A 6 MT&A 12 MT&A 24 FEV1 (L) 2.0 2.5 Minute 0 180 360 720 Placebo and the 3 doses of the new formulation
  20. 20. SJS Dundonald Road The Story of MTA02 20 Treatment Placebo MT&A 6 MT&A 12 MT&A 24 ISF 6 ISF 12 ISF 24 FEV1 (L) 2.0 2.5 Minute 0 180 360 540 720 With the 3 doses of reference formulation added ...any d.f.
  21. 21. SJS Dundonald Road The Story of MTA02 21 -0.1 0.0 0.1 0.2 log-AUC FEV1 Formoterol Formulation Dose Parallelism Curvature Opposing Curvature Orthogonal Contrasts for Parallel Assay
  22. 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
  23. 23. SJS Dundonald Road The Story of MTA02 23 MTA6 MTA12 MTA24 ISF6 ISF12 ISF24 Treatment -10 -5 0 5 10 Valueatonehour Analysis of QTC Values
  24. 24. SJS Dundonald Road The Story of MTA02 24 MTA6 MTA12 MTA24 ISF6 ISF12 ISF24 Treatment -0.21 -0.16 -0.11 -0.06 -0.01 0.04 Valueatonehour Analysis of Potassium Values
  25. 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. 26. SJS Dundonald Road The Story of MTA02 26 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. 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 – Fieller’s theorem • Plus or minus 20% traditional on dose scale but unatainable using FEV1 and bronchodilators • Decision-analytic approach? – Will the regulator agree? • NO!
  28. 28. SJS Dundonald Road The Story of MTA02 28 1 0 1 0.05 0.1 0.15 0.2 ISF MTA Dose Relative potency Estimate 0.18 95% CI 0.08-0.29

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