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## Interim Analysis in Clinical Trials: A Bayesian Approach in the Regulatory Setting

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Title: Interim Analysis in Clinical Trials: A Bayesian Approach in the Regulatory Setting

1

Interim Analysis in Clinical Trials A Bayesian
Approach in the Regulatory Setting
Telba Z. Irony, Ph.D. and Gene Pennello,
Ph.D. Division of Biostatistics Office of
Surveillance and Biometrics Center for Devices
No official support or endorsement by the Food
and Drug Administration of this presentation is
intended or should be inferred.
2
The Frequentist Approach to Interim Analyses
Trial 200 patients Several interim analyses
planned If statistical significance is found at
any of the looks, the trial stops and is
successful.
In order to obtain a significance level of 0.05,
the levels at each possible stopping point must
be smaller than 0.05. Of course, there is an
infinite number of possibilities of
distributing the level 0.05 among the possible
stopping points.
3
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4
Other Ways to Penalize Multiple Looks
• The alpha spending function is a version of
stopping boundary that is a continuous function
of the percentage of the study completed.
• There are lots of different boundaries,
techniques, and software (PEST, EAST) to
control type I error while performing interim
looks in a clinical trial.
• You could create (and publish) your own boundary

5
That approach violates the Likelihood Principle!
Two companies come with the same data on 200
patients Both obtain the same p-value at the end
(0.045)
• One looked once at the data during the trial with
the intention of stopping but didnt gt does not
reach significance (required p-value 0.041) gt
not successful!
• The competitor did not look gt reached
significance (required p-value 0.05) gt
successful!
• Moreover reaching significance or not depends on
whose boundary you choose gt you have to tell in
advance which one you want and cannot change your
mind!

6
Why do frequentist and Bayesian approaches
differ?
Frequentists inferences are based on p-values
probabilities are on the sample space
Estimation P(data parameter) Hypothesis
testing P(data H )
Bayesians inferences are based on posterior
distributions probabilities are on the parameter
space Estimation P( parameter data) Hypothesis
testing P( H data) Likelihood Principle
prevails
7
The Bayesian Approach to Interim Analyses
modifications of trials in midcourse. In fact,
the decision of continuing the study or not
should be based on potential costs and benefits
weighed by the current posterior distribution of
the unknowns.
8
Example 1 Curtailment of the trial via
predictive distribution
Clinical trial
p chance of patient success
Interim Look 190 successes out of 200 observed
patients
Remaining 80 patients. How many successes
among the next 80 patients? Could we stop the
trial and make a decision already?
Predictive Distribution P( future observation(s)
prior, data)
9
Make sure that the remaining patients are
exchangeable with the observed patients.
Predictive probability of success for the next 80
patients (based on the posterior distribution
for p)
10
2. Interim Analyses Multiple Looks
We collect data to learn about an endpoint
When we know enough we should stop the trial
• Stop when the credible interval is small enough
• Stop when there is reasonable assurance that the
hypothesis is true (or false) or the device is
safe and effective (or is not).

11
Example A totally Bayesian approach Planned
ahead gt no penalty for multiple looks!
New treatment
Interest q - rate of adverse effect -
endocarditis
Prior P(q) - hierarchical model - used old
results Interest Posterior P(q data) Want q
to be small. How small?
12
• If there is a good chance that q lt target gt
success.
• If there is a good chance that q gt target gt
failure.

Target q 0.1
Pre-defined criterion Look at every 100 patient
years. Stop and approve if P(q lt target data) gt
0.99. Stop and dont approve if P(q gt target
data) gt 0.80.
Minimum sample size 300 patient years
(hierarchical model) Maximum sample size 800
patient years ( practical reasons)
The company could in fact go on for ever (!!)
13
target data1) gt 99 stop and approve. If P(q gt
target data1) gt 80 stop and cut losses.
If neither of the above continue sampling.
14
Sample 100 patient years more (data2). If P(qlt
target data1 data2) gt 99 stop and approve. If
P(q gt target data1 data2) gt 80 stop and cut
losses.
If neither of the above continue sampling.
15
..... Sample 100 more (data i). If
P(qlttarget data1data2...data i)gt 99 stop and
approve. If P(qgttarget data1data2...data
i)gt80 stop and cut losses.
Approved!
16
Problems
• Frequentists believe one may sample to a foregone
conclusion
• one may stop as soon as one gets significance or
• by repeatedly testing it is possible to reject Ho
with probability as close to 1 as desired
(probabilities of hypothesis are usually
martigales - D. Berry, 1987). It takes an
infinite amount of time, though.
• Controlling the overall type I error is a
critical concern in monitoring clinical trials -
Regulators.
• Some Bayesians (perhaps inspired by OBrien and
Fleming) believe that one needs to be more
restrictive in early stages of the trial,
requiring higher posterior probabilities for
termination at the beginning.

17
More Problems
Normal distribution paradox (D. Rubin) Two
Companies Frequentist and Bayesian
Both Perform Interim Looks. Bayesian uses
non-informative prior and stops when P(Hodata)
gt95. Frequentist use a nominal significance
level of 5. In the Normal case with
non-informative prior, the posterior probability
is numerically equal to 1-(p-value). The
Frequentist pays a penalty for the looks and the
Bayesian doesnt. The Frequentist may be
unsuccessful and the Bayesian may be successful
with the same data!
18
A Regulatory Solution
To illustrate what would happen in terms of type
I and II errors in a Bayesian Trial, we request
simulations at the design stage.
If the rate were actually below the target, what
would happen? How often would would the trial
stop for futility? (type II error)
If the rate were actually above the target, what
would happen? How often would the device be
approved? (type I error)
Whenever the type I error rate is too high, we
modify the design!
19
Evaluating the experimental design Heart Valve
For each rate, simulated 1000 trials