Transcript Document

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 Cardiology
Pharmaceutical Consultant
[email protected]
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Some unresolved issues
– not necessarily the most important ones
Thorough QT study
1. Baseline assessment
2. Heart rate correction algorithm for drugs without
or with a small inherent effect on the heart rate
3. The role of the positive control
4. Which effect of the positive control establishes
assay sensitivity?
5. How should emerging new techniques be
validated?
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Baseline in parallel TQT studies
Study # subjects
placebo
/moxi
Positive
Control
Collection
days
ECGs
Replicates;
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Baseline adjusted, placebo corrected QTcF after
400 mg moxifloxacin for 7 days
SD varied between 11 and 13 across baselines and Tx
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Baseline in parallel TQT studies
Conclusions:
• ‘Averaged’ baseline reduced total variability more than timematched, 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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
3. Why are we using a positive control?
According to ICH E14:
“The confidence in the ability of the study to detect QT/QTc
prolongation can be greatly enhanced by the use of a concurrent
positive control group to establish assay sensitivity“
“…, the positive control (whether pharmacological or nonpharmacological) should be well-characterized and consistently
produce an effect corresponding to the largest change in the
QT/QTc interval that is currently viewed as clinically not important
to detect (a mean change of around 5 ms or less)”
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
IRT request for parallel-group studies
Subjects
1 - 40
Baseline
Drug
Day 21
Subjects
41 - 80
Baseline
Placebo
Day 21
Subjects
81 - 120
Baseline
67%
Separate + control
Day 21
Day of primary
assessment
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Parallel-group studies
Subjects
1 - 40
Baseline
Subjects
41 - 80
Baseline
Drug
Day 21
Placebo/+ control
Means 33% less subjects
Day 21
X
Day of primary
assessment
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
4. How does the + control establish assay
sensitivity?
Mean
ms
95%
CI, ms
1.
2.
3.
4.
Hour
1
10.7
Moxifloxacin 400 mg SD
Hour
Hour
Hour
2
3
4
13.3
11.2
12.3
Hour
8
8.9
Hour
12
5.9
8.7;
12.8
10.8;
15.9
5.7;
12.1
2.6;
9.3
8.3;
14.0
9.6;
15.0
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).
Health Canada: The peak effect of the + control should be ‘around 5 ms’ and
the lower bound of the CI above 0 ms
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
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.
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
5. How to validate emerging techniques?
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
Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo
Different methods generate different absolute values
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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 quantitatively
defined)
Submitted 2008. Fosser, Duczinski, Agin, Wicker, Darpo
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
Another example….
Difference from Placebo in QTcF: Study 5
25
Method 1
Method 2
Not so good
agreement
QTcF Difference (ms)
20
15
10
5
0
0
2
4
6
8
10
Time Post Dose (hours)
12
14
Cross-over, 4 days of moxifloxacin 400 mg qd
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
How to validate new techniques?
Recommendations
•
Validate new measurement methods
(techniques) on data set from TQT studies
–
•
Look at data several ways, e.g.
–
–
–
–
•
Ideally, same dataset(s) for all….
Absolute values in drug-free condition
Time-matched QTcF
Bland Altman plots (slope, LoA)
Proportion of categorical outliers
Create quantitative standards for output
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
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.
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD
THANK YOU
Borje Darpo MD PhD
Associate Professor of Cardiology
Pharmaceutical Consultant
[email protected]
QT and arrhythmia issues in drug development. DIA Washington DC, April 2008
Borje Darpo MD PhD