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SJS Dundonald Road The Story of MTA02 1
The Story of MT/A02
Stephen Senn
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).
SJS Dundonald Road The Story of MTA02 3
1980 1985 1990 1995 2000 2005
Year
0
20
40
60
80
Pub
licat
ions
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
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.
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.
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.
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 12g doses• Limit of equivalence targeted at +/- 10%• 95% confidence interval to be contained in limits
of equivalence
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.
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
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.
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
SJS Dundonald Road The Story of MTA02 12
Table 4 Summary of demographic and baseline data
Variable N (%) Mean Range
Age (years) 48 16 - 73Sex: male female
107(66) 54 (34)
Height (cm): male female
176 163
162 - 191144 - 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 - 63Reversibility 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)
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
Formoterolversus Placebo
1/6 1/6 1/6 1/6 1/6 1/6 -1
MT&A versusISF
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
ParallelismDevices
1 0 -1 -1 0 1 0
Curvature 1 -2 1 1 -2 1 0
OpposingCurvature
-1 2 -1 1 -2 1 0
SJS Dundonald Road 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;
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 <.0001MTA12 0.11282581 0.01087733 10.37 <.0001MTA24 0.13880211 0.01083390 12.81 <.0001ISF6 0.15519157 0.01074491 14.44 <.0001ISF12 0.17168025 0.01073995 15.99 <.0001ISF24 0.19824573 0.01083830 18.29 <.0001treatment 0.14177093 0.00828795 17.11 <.0001formulation -0.06653652 0.00619103 -10.75 <.0001dose 0.05398809 0.00758902 7.11 <.0001parallelism -0.02186787 0.01509515 -1.45 0.1480curvature -0.00289264 0.02632001 -0.11 0.9125opposing curvature 0.02304623 0.02645516 0.87 0.3840
SJS Dundonald Road The Story of MTA02 16
6.0
6.5
7.0
7.5
8.0
ISF12 ISF24 ISF6 MTA12MTA24 MTA6Placebo
treatment
AU
C F
EV
1
-0.4 -0.2 0.0 0.2
05
01
00
15
02
00
residual
fitted
resi
du
al
7.0 7.5 8.0
-0.4
-0.2
0.0
0.2
theoretical
em
pir
ica
l
-3 -2 -1 0 1 2 3
-0.4
-0.2
0.0
0.2
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;
SJS Dundonald Road The Story of MTA02 18
Random Effects Results
Estimates
StandardLabel Estimate Error DF t Value Pr > |t|MTA6 0.07414 0.01133 602 6.54 <.0001MTA12 0.1145 0.01143 602 10.02 <.0001MTA24 0.1455 0.01136 602 12.82 <.0001ISF6 0.1581 0.01128 602 14.02 <.0001ISF12 0.1712 0.01129 602 15.17 <.0001ISF24 0.2070 0.01136 602 18.22 <.0001treatment 0.1451 0.008701 602 16.68 <.0001formulation -0.06741 0.006505 602 -10.36 <.0001dose 0.06013 0.007949 602 7.56 <.0001parallelism -0.02253 0.01586 602 -1.42 0.1560curvature 0.01339 0.02763 602 0.48 0.6282opposing curvature 0.03193 0.02777 602 1.15 0.2507
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
SJS Dundonald Road The Story of MTA02 20
Treatment Placebo MT&A 6 MT&A 12 MT&A 24ISF 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.
SJS Dundonald Road The Story of MTA02 21
-0.1 0.0 0.1 0.2
log-AUC FEV1
Formoterol
Formulation
Dose
ParallelismParallelism
Curvature
Opposing Curvature
Orthogonal Contrasts for Parallel Assay
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
SJS Dundonald Road The Story of MTA02 23
MTA6 MTA12 MTA24 ISF6 ISF12 ISF24
Treatment
-10
-5
0
5
10
Val
ue a
t one
hou
r
Analysis of QTC Values
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
Val
ue a
t one
hou
r
Analysis of Potassium Values
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
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
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!
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