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

SJS Dundonald Road The Story of MTA02 1

The Story of MT/A02

Stephen Senn


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).


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


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.


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.


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.


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


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.


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


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.


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


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)


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


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;


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


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


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;


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


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


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.


-0.1 0.0 0.1 0.2

log-AUC FEV1

Formoterol

Formulation

Dose

ParallelismParallelism

Curvature

Opposing Curvature

Orthogonal Contrasts for Parallel Assay


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


MTA6 MTA12 MTA24 ISF6 ISF12 ISF24

Treatment

-10

-5

0

5

10

Val

ue a

t one

hou

r

Analysis of QTC Values


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


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


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


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!


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

Documents

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