QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Unresolved procedural, regulatory and statistical issues

QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD

Unresolved procedural, regulatory and statistical issues in assessing human QT prolongation and performing the

‘thorough QT study’

Borje Darpo MD PhD, FESC

Associate Professor in CardiologyPharmaceutical Consultant

[email protected]


Objective of presentation

To outline some areas within clinical QT assessment, which I believe need more studies and publicly shared data to allow

for definitive recommendations

‘More than one road lead to Rome –

until someone builds a motorway’Hieronymus ‘Filibuster’ Hippocampus A.D. -07


Some unresolved issues – not necessarily the most important ones

Thorough QT study1. Baseline assessment2. Heart rate correction algorithm for drugs without

or with a small inherent effect on the heart rate3. The role of the positive control4. Which effect of the positive control establishes

assay sensitivity?5. How should emerging new techniques be

validated?


1. Baseline in the TQT study

Background: Adjustment for baseline measurements is important for

reducing the influence of inter-subject differences and general, as well as study-specific, diurnal effects such as those due to food

Currently ‘recommended’ (code for ‘recently requested by the FDA’s IRT’):

Cross-over studies:Predose baseline immediately before dosing on treatment day in each period

Parallel studies:One full, ‘time-matched’ baseline on the day before dosing in each treatment group


Baseline in parallel TQT studies

1. Pre-dose baseline:Immediately before dosing on Day 1 in each Tx group.

2. Time-matched baseline (‘recommended’):Recorded at same time-points on Day -1 as after dosing on Day 1.

3. Time-averaged: Recorded as above, but baseline derived from average of Day -1 values



Study # subjectsplacebo/moxi

PositiveControl

Collection days

ECGsReplicates; time points

(hours)1 25/24 Blinded moxi 400 mg qd

for 5 days,-1 and 5 1x; 0, 0.5, 1, 2, 3,

4, 5, 6, 7, 8, 10, 12, 14, 24

2 46/44 Open label moxi 400 mg, single dose

-1 and 1 3x; 0, 1, 1.5, 2, 3, 4, 6, 8, 12, 24

3 47/48 Blinded moxi 400 mg for 6 days

-1 and 6 3x; 0, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 14, 24

4 35/35 Open label moxi 400 mg for 7 days

-1 and 7 3x; 0, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 16, 23

In manuscript Darpo, Ferber, Sarapa


Baseline adjusted, placebo corrected QTcF after 400 mg moxifloxacin for 7 days

SD varied between 11 and 13 across baselines and Tx


Baseline assessment in parallel TQT studies

Ratio between SD’s predose or averaged / time-matched

Median SD values ranged from 8 to 17 across studies and Tx

Conclusion: Variability consistently lower with averaged baseline compared to time-matched or predose



Conclusions:• ‘Averaged’ baseline reduced total variability more than time-

matched, thus allowing for more efficient study designs

• If the subject-specific part of circadian variability was substantial, time-matched BL would have significantly reduced the total variability

• Our data suggest that the subject-specific circadian variability was relatively small and ‘averaging’ therefore resulted in an over-all lower variability


2. Heart rate correction algorithm for drugs without an effect on the heart rate

• Full time-matched baseline is often advocated in cross-over studies to allow for individual heart rate correction (QTcI)

often also recommended for drugs without effect on the heart rate• ECGs are often recorded after 10-20 minutes of supine rest

which generates relatively narrow heart rates recorded at rest

This approach generates QTcI values, • which rarely are different from QTcF for drugs without or with a small

effect on the heart rate, but certainly requires more ECGs and 1 additional study day/Tx period

• for which the utility for drugs with an effect on the heart rate can be questioned (or at least warrants further studies).

There is yet no general agreement on how to study the QTc effect with drugs with an inherent effect on the

heart rate, through e.g. autonomic alteration


3. Why are we using a positive control?

According to ICH E14:“The confidence in the ability of the study to detect QT/QTcprolongation can be greatly enhanced by the use of a concurrentpositive control group to establish assay sensitivity“

“…, the positive control (whether pharmacological or non-pharmacological) should be well-characterized and consistentlyproduce an effect corresponding to the largest change in theQT/QTc interval that is currently viewed as clinically not importantto detect (a mean change of around 5 ms or less)”


Establishing assay sensitivity

• Uncontroversial in X-over studies with short duration in which + control can be included as separate Tx period

• Challenging in studies with long duration of Tx or long wash-out (e.g. dose escalation, drug accumulation)

• Recently the IRT has requested running the positive control in separate Tx group in parallel TQT studies

– which means that 67% of subjects are exposed to either placebo or one dose of moxifloxacin


IRT request for parallel-group studies

Subjects1 - 40

Baseline Day 21Drug

Subjects41 - 80

Baseline Day 21Placebo

Subjects81 - 120

Baseline Day 21Separate + control

Day of primaryassessment

67%


Question: Does the gain with separate + control Tx-group justify the added cost and complexity of the study?

Could an alternative approach be acceptable?All Tx periods are extended by 1 day and a single-dose of + control/placebo is added on this day

Issue: Baseline adjustment and placebo-correction will be within group for + control effect but not for drug effect


Parallel-group studies

Subjects1 - 40

Baseline Day 21Drug

Subjects41 - 80

Baseline Day 21Placebo/+ control

Day of primaryassessment

X

Means 33% less subjects


4. How does the + control establish assay sensitivity?

Moxifloxacin 400 mg SD

Hour 1

Hour 2

Hour 3

Hour 4

Hour 8

Hour 12

Mean ms

10.7 13.3 11.2 12.3 8.9 5.9

95% CI, ms

8.7; 12.8

10.8; 15.9

8.3; 14.0

9.6; 15.0

5.7; 12.1

2.6; 9.3

1. FDA IRT: The effect should be comparable to other similar studies using

moxifloxacin and an effect > 5 ms should be demonstrated (lower CI > 5 ms).2. Health Canada: The peak effect of the + control should be ‘around 5 ms’

and the lower bound of the CI above 0 ms 3. Others 1: There is no difference between a peak effect and an effect at other

time-points. An statistically significant effect ‘around’ 5 ms at any time point is therefore sufficient

4. Others 2: The precision of the effect should allow detection as small as 5 ms, i.e. the width of the CI should be < + 5 ms.


Study Drug-free

N Auto Manual/CA Difference

1 1846 374 + 25.7 394 + 25.5 -20 + 10.6

2 531 380 + 26.9 399 + 28.9 -19 + 9.1

3 2610 404 + 32.3 391 + 28.2 13 + 16.2

4 2803 391+ 26.9 377 + 27.1 14 + 11.4

5 1408 401 + 28.6 389 + 28.6 12 + 13.6

5. How to validate emerging techniques?

Different methods generate different absolute values

Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo


5. How to validate emerging techniques?Apply to data set from more than one TQT study and compare the standard output (time-matched, BL adjusted, placebo-corrected QTcF) with accepted method

Result:Good agreement(can be quantitativelydefined)

Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo


Another example….

0 2 4 6 8 10 12 140

5

10

15

20

25Difference from Placebo in QTcF: Study 5

Time Post Dose (hours)

QT

cF D

iffe

ren

ce (

ms)

Method 1

Method 2

Cross-over, 4 days of moxifloxacin 400 mg qd

Not so good agreement




Recommendations• Validate new measurement methods

(techniques) on data set from TQT studies– Ideally, same dataset(s) for all….

• Look at data several ways, e.g.– Absolute values in drug-free condition

– Time-matched QTcF

– Bland Altman plots (slope, LoA)

– Proportion of categorical outliers

• Create quantitative standards for output

How to validate new techniques?


Conclusions• Many of these topics can be studied, thereby allowing

unbiased recommendations;• The generation of a publicly accessible database

comprised of several moxifloxacin / placebo datasets from TQT studies will greatly facilitate this research;

• Much of this research is ‘precompetitiv’ research – all findings rapidly become public and will not provide anyone individual player competitive edge;

• Sponsors with experience from many TQT studies can obviously also contribute individually and are encouraged to publish their results.


THANK YOU

Borje Darpo MD PhDAssociate Professor of Cardiology

Pharmaceutical Consultant

[email protected]

Documents

QT and arrhythmia issues in drug development. DIA Washington DC, April 2008 Borje Darpo MD PhD Unresolved procedural, regulatory and statistical issues