Transcript 8 Trial Monitoring and Independent Data Monitoring Committee

Interim Analysis of Clinical Trial
Liying XU
CCTER, CUHK
Clinical Trial Protocol
• Data safety and monitoring
• Safety Analysis
• Monitoring of the trial
Data and Safety Monitoring Committee
 External Advisory Committee

Data and Safety Monitoring
Committee (DSMC)
• independent with the investigators, participants or
sponsors.
• Including experts: clinicians, epidemiologist, and biostatisticians (and lay representatives).
• To review accumulating data related to treatment
effects, adverse events and trial performance.
• To protect the integrity of the clinical trial from
adverse impact resulting from access to trial
information with pre-defined SOPs.
• DSMC is a separate entity from an IRB or IEC.
The Evaluation of Subcutaneous Proleukin(interleukin-2)
in a Randomized International Trial (ESPRIT)
• Patients with HIV
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diseases,CD4>=300cells/mm3
Primary objective: to determine whether the
addition of IL-2 to combination antiretroviral
therapy improves morbidity and mortality
Sample size:4000
Follow-up: 5 years
27 sites and 23 countries
Statistical considerations
• Time to event methods including stratified
proportional hazard models, log-rank
tests, and Kaplan-Meier cumulative event
curves will use used to summarize the
major outcomes of HIV-disease
progression including death and survival.
• These analysis will be stratified by centre.
Data monitoring
• The independent DSMC will meet twice
each year to review interim analyses.
• O’Brien-Fleming boundaries and the
Lan-DeMets spending function will be
used as monitoring guidelines for for
the primary endpoint comparisons.
Other reason for early termination
• The DSMB will also consider results from
other studies and recommend early
termination or modification of ESPRIT
only when there is clear and substantial
evidence of benefit or harm.
Other reason for early termination
• The EC or DSMB may consider early
termination of trial for reasons of poor
accrual, less than anticipated CD4 cell
count differences between treatment
groups, or excessive loss to follow-up.
Data monitoring?
• Asking the same question several times,
with the only difference being the amount
of data available to answer it.
The Prehospital Treatment of Status
Epilepticus (PHTSE) study:
• 1) to determine whether administration of
bezodiazepines by paramedics is an
effective and safe means of treating
status epilepticus in the prehospital
setting and whether this therapy
influences longer-term patient outcome
• 2) to determine whether lorazepam is
superior to diazepam for the treatment of
status
Safety analysis
• Interim safety analysis are performed
after the enrollment of 25, 50,100 and 150
unique subjects.
Interim analysis
• Detect:
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early dramatic benefits
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potential harmful effects.
• Done by independent person.
• Statistic technique(s) is not the sole basis
for the decision to stop or continue the
trial.
Rational for interim analysis
• Ethical
• Scientific
• Economic
Decision making process
• Statistical results of interim analysis.
• The merits of the treatment.
• The availability and usefulness of alternative
treatments.
• The seriousness of the conditions being
treated.
• The acceptability of the treatment to patients,
• Other findings
Decision to extend a trial
• To maintain the power
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To increase the sample size.
To extend the length of follow-up.
Frequency of interim analysis
• Long term clinical trials, 4 to 6 month intervals.
• The time lag between entry and response
evaluation.
• Special meeting for unexpected toxicity of one
intervention.
• Rate of patients accrual.
• 10%, 25% 75% and 100% of the primary
outcomes have been observed.
Examples
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One full interim analysis will be undertaken
when half the participants have followed for 3
years
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Three planned analysis when the subjects
are 18 months, 3 years and 5 years of age
Statistical stopping rules
• A simple rule to ensure that the overall
probability of type I error is controlled.
• In one anticipates no more than 10 interim
analyses and there is one main response
variable, one can adopt P<0.01 as the
criterion for stopping the trial, since the
overall type I error will not exceed 0.05.
Group sequential methods
(Pocock 1977)
• What is the maximum number of interim
analyses (or groups)?
• How many patients should be evaluated
between successive analysis, i.e. what
should be the size of each group?
Risk of false positive
• If one carries out 10 interim analyses the
chance of at least one analysis showing a
treatment difference significant at the 5%
level increases to 0.19 even if the
treatments are truly equally effective.
Repeated significance tests on accumulating data
No. of repeated tests at the 5% level
Overall significant level
1
2
3
4
5
10
20
50
100
1000
0.05
0.08
0.11
0.13
0.14
0.19
0.25
0.32
0.37
0.53
1.0
For two treatments, a normal response
with known variance and equally spaced
analyses
Though broadly similar results
for other type of data
Nominal significance levels
• A more stringent nominal significant
level for each repeated test, to keep
overall significant level at some
reasonable value, 0.05 or 0.01.
Nominal significance level required for repeated two-sided
significance testing with overall significance level (0.01 or 0.05)
and various N
N (Max. tests)
 = 0.05
 = 0.01
2
3
4
5
10
15
20
0.029
0.022
0.028
0.016
0.0106
0.0086
0.0075
0.0056
0.0041
0.0033
0.0028
0.0018
0.0015
0.0013
Fig. 1
Three group sequential stopping boundaries for the standard normal
statistic (Zi) for up to five sequential groups with two sided
significance level of 0.05
Table 1. Nominal P values for overall type I error of (=0.05)
k
Pocock
O’Brien—Fleming
1
2
0.0294
0.0294
0.0051
0.0415
1
2
3
0.0221
0.0221
0.0221
0.001
0.0151
0.0471
1
2
3
4
0.0182
0.0182
0.0182
0.0182
0.001
0.0039
0.0184
0.0412
1
2
3
4
5
0.0158
0.0158
0.0158
0.0158
0.0158
0.001
0.0013
0.0085
0.0228
0.0417
Group sequential tests boundaries
(see Fig.1)
• Pocock (1977)
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Divides equally the overall significance levels
• Peto (1976)
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Interim tests are run with a very low level of
significance (0.001), which has little impact on the level
of significance of the final test.
• O’Brien and Fleming (1979)
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It is a intermediate between the previous two methods,
have slightly increase in the significance level on each
following test.
Pocock’s method
• A trial in non-Hodgkins lymphoma compared two
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drug combinations CP (cytoxan-prednisone) and
CVP (cytoxan-vincristine-prednisone)
Outcome measure: tumor shrinkage.
Patient accrual lasted over two years
120-130 patients were entered.
Five interim analysis were planned: one after
about every 25 patients were entered.
Interim analyses for a trial in
non-Hodgkins lymphoma
Response Rate
Analysis 1
Analysis 2
Analysis 3
Analysis 4
Analysis 5
CP
CVP
3/14
11/27
18/40
18/54
23/67
5/11
13/24
17/36
24/48
31/59
X2 (without
continuity
correction )
1.63
0.92
0.04
3.25
0.05<P<0.1
4.15
0.016<P<0.05
Conclusion
• The superiority of CVP is interesting but
inconclusive.
• However, further data on response
duration and survival eventually clarified
that CVP did appear to be a better
therapy.
How many interim analysis
• The theoretical results indicate that there
is little statistical advantage in having a
large number of repeated significant tests.
As a general rule, it would seem sensible
to plan on a maximum of five interim
analysis.
How many interim analysis
• It is sensible to consider just two analyses for the
trial currently undertaken without interim analysis.
One half way through and the other at the end.
There can still be a major reduction in the number
of patients exposed to an inferior treatment since
for such a trial with sufficient overall power there
is a reasonable chance of being able to stop
halfway though.
Alpha-spending functions (Lan and DeMets)
Flexible group sequential procedures (1983)
• The limitation of group sequential methods.
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To specified the number K of planned interim
analyses in advance.
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The requirement for equal numbers of either
participants or events between each analysis.
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The exact time of the interim analysis is specified.
Alpha-spending function
• To allow investigators to determine how they want
to “spend” the type-I error or alpha during the
course of the trial.
• The alpha spending function guarantees that at
the end of the trial, the overall type I error will be
the pre-specified value of .
• This approach is a generalization of the previous
group sequential methods so that Pocock and
O’brien Fleming monitoring procedures become
special cases.
Calendar time and information fraction
• At any particular calendar time t in the
study, a certain fraction t* of the total
information is observed such as:
T heparticipants randomizedat thatpoint
n/ N 
T he totalnumber expected
thenumber of eventsobserved( in survivalstudies)
d/D
the totalnumber expected
Calendar time and information fraction
• For regression slops: the information fraction
is more generally defined in terms of the ratio
of the inverse of the variance of the test
statistic at the particular interim analysis and
the final analysis.
• The alpha spending function (t*), determines
how the pre-specified  is allocated at each
interim analysis as a function of the
information fraction.
Advantages
• Neither the number nor the time of the interim
analyses need to be specified in advance.
• Once the spending function is selected, the
information fractions t*1, t*2…. Determine the
critical or boundary values exactly.
• The frequency of the interim analyses can be
changed during the trial and still preserve the
pre-specified  level.
A Example of group sequential methods
in the Beta-Blocker Heart Attack Trial
• Specifications of the group sequential boundary:
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The O’ Brien-Fleming group sequential procedure.
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Seven meetings scheduled to review interim data.
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The trial was designed for a two-sided 5%
significant level.
Fig.1
Six interim log rank statistics plotted for the time of data monitoring
committee meeting with a two –sided O’Brien-Fleming significance
level boundary in the Beta-Blocker Heart Attack Trial. Dashed line
represents Z=1.96.
Interim log rank tests in the
Beta-Blocker Heart Attack Trial
• From the second analysis on, the conventional
significant value of 1.96 was exceeded.
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• the trial was continued.
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at the six meeting, the O’Brien-Fleming
boundary was crossed
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a decision was made to terminate the trial
• Crossing the O’Brien-Fleming boundary was only one
of the factors in this decision!
Figure 2 Cumulative mortality curves comparing propranolol and
placebo in the Beta-Blocker Heart Attack Trial.
What should be in a interim report
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Patients recruitment progress
Data quality
Baseline characteristics
Patients compliance
Primary and secondary outcomes
Adverse events
Other safety measures
Who should have access to the report?
• DSMB members only
• Confidential!!
Practical Issues of Interim Results
• Consequences
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Continuation
Termination
Modification
Unblinding of the code (unmasking)
Modification of Patient Information Sheet
Notification of ethics committees (and /or FDA,
Human Rights Committee)
Re-estimating sample size
Timing and extent of unblinding of interim results
A software: EaSt 2000
• Interactive Software and Consulting
Services for the Design and Interim
Monitoring of Group-Sequential Clinical
Trials
• CYTEL Software Corporation
• E-mail:[email protected]
A book
• Group Sequential Methods with
Applications to Clinical Trials
By Christopher Jennison and Bruce W.
Turnbull. 2000
 CHAPMAN & HALL/CRC
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