Introduction to Bayesian Adaptive Methods

Introduc)on
to Bayesian
Adap)ve Methods
Lecture notes modied from Dr.
Melanie Quintana, Fall, 2013
Common Trial: How do I get to work?

Start a new job and need to gure out the
fastest way to get to work
Could take the highway
Could take the back roads
How do you decide which way to go?

How do you decide how to decide?

Put 30 envelopes in your car where each has one
of 3 routes wriPen on the inside. Randomly select
an envelope each morning and drive that route.
Record drive )me and at the end of the 30 days
choose the route with the quickest average drive
)me.
Drive one route on the rst day. Make note of
how long it took you. Drive a dierent route the
next day. If it took you longer than the rst route
you switch back to driving the rst route the next
day

Adap)ve aspects of fastest route trial?
Adap)ve Randomiza)on
If one route took too long once you tried it you would
be less likely to try it again.
Arm Dropping
If a route took WAY too long then you may want to
drop it all together from your op)ons and never take it
again
Early Stopping
How long un)l you had enough data to convince you
of the fastest route?
Example: RESPECT Trial

Inves)gate whether the closure of pa)ent foramen
ovale (PFO) using the Amplatzer PFO Occluder is
superior to medical therapy in preven)ng stroke
Randomized 1:1 to closure and medical therapy groups
Original Design:
Report primary results once 25 events (strokes) had been
observed
If 19 or more of these strokes were in the medical therapy
group declare success!
Es)mated 80% power to show a reduc)on in risk with
closure of approximately 75%


An)cipated Regret
Imagine that we run the trial and it is a near miss
What reasons can you see that would have made
it unsuccessful?

Data at )me of primary analysis
980 pa)ents enrolled in the study across 69 sites
499 in the device group
481 in the control group
851 (86.8%) remained in ac)ve follow-up

dropout rate was 9.2% in the closure group
17.2% in the medical therapy group
In the inten)on-to-treat cohort, there were 9 events

in the device group and 16 events in the control
group.
Inves)gators were not able to claim success
1.00
0.85
0.90
Control Group
(n=16)
HR, 0.49 (95% CI, 0.201.08)

Post. Prob. HR < 1 = 96%
0.80
Eventfree Probability
0.95
Device Group
(n=9)
4
Years to Event

What went wrong?
Dieren)al drop out: Many of the pa)ents in the
medical therapy group dropped out of the study
or went to the closure group
Does not appear to be a closure benet within the
rst year
Biological reasoning behind this: takes )me for the hole
to close

What could we have done dierently?
Allow the data to tell us when to stop

Posterior probability that closure was superior to
medical therapy (HR <1) at )me of primary
analysis was 0.96.

Would you have chosen to stop the trial?

What are Adap)ve Designs?

Adap)ve Design
A design that changes depending on observed
values in the trial
Prospec)ve Adap)ve Design

A design that has pre-specied dynamic aspects
that are determined by the accruing informa)on
Every )me I say Adap)ve Design I mean

Prospec)vely Adap)ve Design
What are Adap)ve Trials?

Trials in which key design parameters change
during trial execu)on based upon a priori
predened rules and accumula)ng data from the
trial to achieve goals of validity, scien)c
eciency, and safety
Planned: All possible adapta)ons dened a priori
Well-dened: Criteria for adap)ng clearly explained
Key parameters: Not minor inclusion or exclusion
criteria, rou)ne amendments, etc.
Validity: Reliable sta)s)cal inference
What are Adap)ve Trials?

Trials that change based on prospec3ve rules & the accruing
informa3on
Adap)ve sample sizes based on predic)ve probabili)es
Stop early for success
Terminate early for fu)lity
Adap)ve randomiza)on
For sta)s)cal eciency

For improved pa)ent treatment
Drop/Re-enter arms or dose groups
Adapt to responding sub-popula)ons

Adap)ve borrowing of informa)on
Seamless Phase 2/3 Designs

Drug already approved in Japan but not in the US.

It seems ecacious there, but the popula)on here might
be dierent.
For the sake of pa)ents we start randomizing 3:1 so most
pa)ents get something we think is eec)ve.

We incorporate borrowing from the Japanese trial to
eec)vely increase the control popula)on. But if the
control group here has a dierent rate than in Japan,
maybe we borrow less and even change the randomiza)on
probability here back to 2:1 or even 1:1.
Typical Prospec)ve Adap)ve Design

Begin Data Collection with Initial
Allocation and Sampling Rules
Analyze
Available Data
Continue Data
Collection
Revise Allocation
and Sampling Rules
per Adaptive Algorithm
Stopping
Rule Met?
Stop Trial or
Begin Next
Phase in
Seamless
Design
Adap)ve Advantages
Companies save resources and successful
drugs/devices get to market faster
Stop a trial early if it is most likely fu)le and move
on to the next promising drug/device
Stop a trial early for success
More pa)ents get treated with the bePer

drug /device during the trial
Would you rather be the last pa)ent enrolled in a
clinical trial or the rst person treated aper its
results are published?
Adap)ve Design Tools
Using Bayesian tools to help us design the trial?

Posterior Probability
Probability that the drug is eec)ve given the data you have seen so far
Probability that the dose is the maximum eec)ve dose given the data
you have seen so far
Can use these to allocate pa)ents and to declare success
Predic/ve Probability
Probability trial will be successful aper outstanding data you have not yet
observed
Can help us determine the likelihood that a trial will be successful before
it even starts
Example will our Phase 3 trial be successful given our Phase 2 data??
Help us decide if we want to stop the currently enrolling trial due to
fu)lity
Clinical Trial Simula/ons
Simula)ons of scenarios of how the trial could go
Help us test our design

What is Bayesian?
X ~ N ( ,1
Frequen/st
is an unknown
constant
If the true mean,
, were 0, how
likely is
2?
0.1
0.2
0.3
0.4
0.0
Pr ( X | = 0 )
What is Bayesian?

X ~ N ( ,1
Bayesian
is a random
variable!
What is the
distribu)on of
aper observing
X?
Pr ( | X )
What is Bayesian?
do we get there?
How
2
From X
~ N

,1
to Pr
(
| X
) ?
Bayes Theorem (the theorem of Inverse
Probability) is the crank that gets from
Pr(A|B) to Pr(B|A)
Pr ( A | B ) Pr ( B )
Pr ( B | A ) =
Pr ( A | B ) Pr ( B ) + Pr ( A | BC ) Pr ( BC )
What is Bayesian?
Beliefs + Data = Posterior Probability
Prior

Prior Probability
Pr ( A | B ) Pr ( B )
Pr ( B | A ) =
Likelihood (data)
Simple Bayes Example
Coin, Pr(HEADS) =
= 0.25 or =0.75, equally likely.
DATA: Flip coin twice, both heads.
???
Simple Bayes Example

Pr ( A | B ) Pr ( B )
Pr ( B | A ) =
Pr ( p = 0.75 | DATA )
Pr ( DATA | p = 0.75 ) Pr ( p = 0.75 )

=
Pr ( DATA | p = 0.75 ) Pr ( p = 0.75 ) + Pr ( DATA | p = 0.25 ) Pr ( p = 0.25
2
0.75 ) ( 0.5 )
(
=
( 0.75 )2 ( 0.5 ) + ( 0.25 )2 ( 0.5 )
= 0.90
Bayes Rule More Generally

( | X ) =
L ( X | ) ( )
L ( X | ) ( ) d
For our simple example =

Dont really just have two op)ons
= 0.25 or =0.75
= any con)nuous value from 0 to 1
Bayes Rule More Generally
0.4
0.4
0 1 2 3 4
0.8
0.0
0.4
0.8
After SSF
After SSFS
After SSFSF
0.8
Density
Density
0.4
0.0
0.4
0 1 2 3 4
Pi
0 1 2 3 4
Pi
0.8
0.0
0.4
0.8
Pi
After SSFSFS
After SSFSFSS
After SSFSFSSSFSSSSSSFS
0.4
Pi
0.8
Density
0.0
0.4
Pi
0.8
0 1 2 3 4
Pi
0 1 2 3 4
Pi
Density
0.0
Density
0.0
Pi
0 1 2 3 4
0.0
After SS
0 1 2 3 4
0.8
0 1 2 3 4
Density
0.0
Density
After S
Density
0 1 2 3 4
Density
Prior Beta(1,1)
0.0
0.4
Pi
0.8
Interac)ve Drug Development

Example
Suppose in Phase II, with 20 pa)ents on Dose
2, we saw 6 successes and 14 failures
Assume a prior distribu)on for Pr(Response)
(p) of beta(1,1)
What is the posterior distribu)on of p?
What is the posterior probability p>.20
95 % probability that the response rate is
between ___ and ___?
Data|p ~ Bin(6,20)
p ~ Beta(1,1)
p|Data ~ ?
!
Beta(a,b) =
!
(a + b) (a1)
x
(1 x)(b1)
(a)(b)
(a) = (a 1)!
pr(p|Data) pr(Data|p)pr(p)
20 6
14
p
(1
p)
6
Beta(7,15)
20! 6
14
!
p (1 p)
6!14!
(21)
p(71)(1 p)(151)
(7)(15)
3
0
Density
2
1
0
Density
Posterior Distribution
p|data~Beta(7,15)
Prior Distribution
p~Beta(1,1)
0.0
0.2
0.4
0.6
p
0.8
1.0
0.0
0.2
0.4
0.6
p
0.8
1.0
4
Posterior Prob. Response Rate > .20
2
1
0
Density
Pr(p>.20|6S and 14F) = 0.89
0.0
0.2
1.0
p
2
1
0
Density
Posterior 95% CI
0.0
0.15
0.52
p
1.0

Example
With 20 pa)ents on Dose 2 we saw 6
successes and 14 failures
Assume a prior distribu)on for Pr(Response)
(p) of beta(1,1)
What is the posterior distribu)on of p?
What is the predic)ve probability of success in
300 pa)ent Phase 3 given this data?
Predic)ve Probability
If we have 74 or more successes out of 300 we
will win Phase 3 (alpha = .025)

How likely is it that we will see 74 or more
successes given data we have seen so far?
What is the the distribu)on of future data
given data we have seen so far?
Predic)ve Probability
Pr(x | data) = pr(x | p) pr( p | data) dp
Beta-Binomial Dist
300 x
(22)
300x
151
71
=
p (1 p )
p (1 p ) dp
( 7 ) (15)
x
Simulate a (p | data) from beta(7,15)
Simulate an (x | p) from bin(300,p)
Distribu)on of xs is beta-binomial the predic)ve
distribu)on
Can count the propor)on of these xs that are
greater than or equal to 74 to get the predic)ve
probability of success in Phase 3

Condi)onal Probability vs. Predic)ve

Probability
Predictive Distribution
p~Beta(7,15)
0.05
0.05
Binomial Distribution
p=6/20
0.04
0.03
0.02
Density
0.03
0.75
0.00
0.01
0.02
0.01
0.00
Density
0.04
0.98
50
100
150
200
250
Number Successes Phase III
300
50
100
150
200
250
300
Beta-binomial has much more variability we are

much less condent that we will be successful in
phase 3 than if we would have just assumed the
response rate was 6/20 (= 0.3) and found the
condi)onal power in phase 3 given this response
rate!
What does the predic)ve probability look like if we
recruit an addi)onal 20 and we see we see 12/40 at
our next interim analysis?

Probability
p~Beta(13,29)
0.05
0.05
p=12/40
0.04
0.03
0.02
Density
0.03
0.80
0.00
0.01
0.02
0.01
0.00
Density
0.04
0.98
50
100
150
200
250
300
50
100
150
200
250
300

Same condi)onal power (since we are
condi)oning on same value of p=0.3) but
predica)ve power changes even though the
es)mate of the response rate does not change!
Predic)ve power takes into considera)on how
much data we have seen and how certain we are
of the response rate.

Probability
p~Beta(31,101)
0.05
0.05
p=30/100
0.04
0.03
0.02
Density
0.03
0.87
0.00
0.01
0.02
0.01
0.00
Density
0.04
0.98
50
100
150
200
250
300
50
100
150
200
250
300
Bayesian Advantages to Trial Design

Provide Intui)ve Inference
Posterior probability of treatment eect

Posterior probability that the es)mate of the treatment eect is
in some interval
What most people think their frequen)st condence intervals and
p-values are telling them
Provide predic)ve probabili)es of success before and during

trials
Take into account uncertainty of the treatment eect
Change based on how much data we have seen
Synthesis of Evidence

Mul)ple sources of informa)on can be combined (previous trials)

Expert opinion can play a role in inference
Trial Simula)on
For complex adap)ve designs you can not
calculate opera)ng characteris)cs
analy)cally (Type I Error and Power)
(integra)on can not be done in closed form)

Simula)on the only way to do this


An example in drug development considering molecule
with unknown eect to assess in a dose nding Phase
2 trial.
3 doses of the molecule
The goal of the trial will be to determine if the

molecule should be developed in Phase 3, and if so
which dose should be developed.
The company will have resources for a 300 pa)ent Phase 3

trial
Your goal is to design their Phase 2 trial in stages,

adap)ng the number of pa)ents assigned to each dose
aper each stage.

Primary Endpoint:
Dose ecacy (0 = no response, 1 = benecial
response)
An eec)ve dose is any dose that has

Pr(response) >= 20%
Note that in a 300 person trail, we win
the trial if we observe at least 74
responses.


Thus there are 300 pa)ents to allocate to the

dose arms of your choice.
The trial is divided into 5 groups of 60 pa)ents,
recruited sequen)ally
There are 4 interim analyses where you will get
ecacy data and will have to decide one of three
things:
Terminate the trial for fu)lity

Stop the trial for success, pick dose and advance to
Phase 3 tes)ng
Con)nue to collect data, alloca)ng the next 60 pa)ents.
Simula)on of Interac)ve Drug

Development
Example Prospec)ve Design:
Interim analysis every 60 pa)ents

Begin adap)ve alloca)on aper we see rst 60
pa)ents
Sample pa)ents based on probability that each dose is

best
best dose is dened as the dose that provides that
highest response rate
Propose to stop for fu)lity if predic)ve probability

of success in Phase III for max dose is < 0.10
Propose to stop for early success if predic)ve
probability of success in Phase III for max dose is >.
95

Development: N=60
Prob. Dose has Max Response
1.0
0.8
0.6
0.6
0.4
Probability
0.4
Probability
0.2
0.2
0.2
50
100
Number of Subjects
0.4
Pr(Response)
0.6
150
0.8
1.0
*Low probability
Dose 1 is max
*Start with 20
pa)ents on each
dose
0.8
PPS in Phase III

1.0
Subject Allocation
200
Pr(Response)
Dose
2
Dose
0.0
0.0
0.0
2
Dose
2
Dose

Development: N=120
0.8
0.6
Probability
0.6
100
Probability
0.4
0.4
0.4
Number of Subjects
Pr(Response)
0.6
150
0.8
1.0
1.0
*Do not allocate

many new
pa)ents to dose 1
0.8
PPS in Phase III

1.0
Subject Allocation
200
Pr(Response)
0.2
0.2
2
Dose
2
Dose
0.0
0.0
0.0
50
0.2
2
Dose
2
Dose

Development: N=180
1.0
*Stop for success

if PPS in Phase III
is >.95 for max
dose
0.8
1.0
0.6
0.4
Probability
0.6
Probability
100
0.4
Number of Subjects
0.4
Pr(Response)
0.6
150
0.8
PPS in Phase III

1.0
0.8
Subject Allocation
200
Pr(Response)
0.2
0.2
0.2
50
2
Dose
2
Dose
0.0
0.0
0.0
2
Dose
2
Dose

Development: N=240
1.0
PPS in Phase III

1.0
Subject Allocation
200
Pr(Response)
0.8
0.6
0.4
Probability
0.6
Probability
100
0.4
0.4
Number of Subjects
Pr(Response)
0.6
150
0.8
0.8
1.0
*Stop for success

and take dose 3 to
Phase III!
0.2
0.2
0.2
50
2
Dose
2
Dose
0.0
0.0
0.0
2
Dose
2
Dose

Development
What scenarios should we simulate under?


Development
What scenarios should we simulate under?

Pr(Response)
Dose 1
Dose 2
Dose 3
All Null
.2
.2
.2
All Good
Max
Max
Max
One Good
.2
.2
Max
Increase
.2
1/2Max + .1
Max
Max Response Rate?

.3,.4,.5

Development
What opera)ng characteris)cs should we
report?


Development
report?
Probability of stopping for success or for fu)lity
Early or Late?


Development
report?
Early or Late?
Mean subjects used

On average how many pa)ents did we use


Development
report?
Early or Late?
Mean subjects used

Mean dura)on of trial

On average how many interims did it take us to
either stop for success or fu)lity


Development
report?
Early or Late?
Mean subjects used

Mean dura)on of trial

On average how many interims did it take us to
either stop for success or fu)lity
Probability each dose was chosen as the best


Development
Scenario
All Null
(.2-.2-.2)
All Good
(Max-Max-Max)
One Good
(.2-.2-Max)
Increase
(.2-.5Max+.1-Max)
Max
Prob. of Prob. of Mean
Mean
Response Success Fu/lity Subjects Dura/on
Prob. Dose is Best

Dose 1
Dose 2
Dose 3
.2
0.04
0.13
280.56
4.68
0.34
0.31
0.35
.3
0.82
0.00
162.12
2.70
0.37
0.32
0.31
.4
1.00
0.00
75.60
1.26
0.32
0.34
0.34
.5
1.00
0.00
61.08
1.02
0.34
0.33
0.33
.3
0.49
0.01
231.30
3.86
0.04
0.06
0.91
.4
0.99
0.00
112.86
1.88
0.01
0.00
0.98
.5
1.00
0.00
76.20
1.27
0.01
0.00
0.99
.3
0.52
0.02
223.44
3.72
0.04
0.00
0.96
.4
0.99
0.00
108.00
1.80
0.01
0.00
0.99
.5
1.00
0.00
76.80
1.28
0.00
0.00
1.00

Development
What are the moving parts that we may
want to ne tune?
PPS threshold for success:
Are we sending too many null trials to Phase 3?
Are we not sending enough successful trials?

Development
Scenario
All Null
(.2-.2-.2)
All Good
(Max-Max-Max)
One Good
(.2-.2-Max)
Increase
(.2-.5Max+.1-Max)
Max
Mean
Prob. Dose is Best

Dose 1
Dose 2
Dose 3
.2
0.04
0.13
280.56
4.68
0.34
0.31
0.35
.3
0.82
0.00
162.12
2.70
0.37
0.32
0.31
.4
1.00
0.00
75.60
1.26
0.32
0.34
0.34
.5
1.00
0.00
61.08
1.02
0.34
0.33
0.33
.3
0.49
0.01
231.30
3.86
0.04
0.06
0.91
.4
0.99
0.00
112.86
1.88
0.01
0.00
0.98
.5
1.00
0.00
76.20
1.27
0.01
0.00
0.99
.3
0.52
0.02
223.44
3.72
0.04
0.00
0.96
.4
0.99
0.00
108.00
1.80
0.01
0.00
0.99
.5
1.00
0.00
76.80
1.28
0.00
0.00
1.00

Development
What are the moving parts that we may
want to ne tune?
PPS threshold for success:
Are we sending too many null trials to Phase 3?
Are we not sending enough successful trials?
PPS threshold for fu)lity:

Are we stopping a trial that may go on to be
successful?
Are we not stopping enough null trials?

Development
Scenario
All Null
(.2-.2-.2)
All Good
(Max-Max-Max)
One Good
(.2-.2-Max)
Increase
(.2-.5Max+.1-Max)
Max
Mean
Prob. Dose is Best

Dose 1
Dose 2
Dose 3
.2
0.04
0.13
280.56
4.68
0.34
0.31
0.35
.3
0.82
0.00
162.12
2.70
0.37
0.32
0.31
.4
1.00
0.00
75.60
1.26
0.32
0.34
0.34
.5
1.00
0.00
61.08
1.02
0.34
0.33
0.33
.3
0.49
0.01
231.30
3.86
0.04
0.06
0.91
.4
0.99
0.00
112.86
1.88
0.01
0.00
0.98
.5
1.00
0.00
76.20
1.27
0.01
0.00
0.99
.3
0.52
0.02
223.44
3.72
0.04
0.00
0.96
.4
0.99
0.00
108.00
1.80
0.01
0.00
0.99
.5
1.00
0.00
76.80
1.28
0.00
0.00
1.00

Development
Example Change in Prospec)ve Design:
Interim analysis every 60 pa)ents
Begin adap)ve alloca)on aper we see rst 60
pa)ents
Sample pa)ents based on probability that each dose is
the max
Propose to stop for fu)lity if predic)ve probability

of success in Phase III for max dose is < 0.15
Propose to stop for success if predic)ve probability
of success in Phase III for max dose is >.90

Development
Scenario
All Null
(.2-.2-.2)
All Good
(Max-Max-Max)
One Good
(.2-.2-Max)
Increase
(.2-.5Max+.1-Max
Max
Response Success Fu/lity Subjects
Prob. Dose is Best

Mean
Dura/on
Dose 1
Dose 2
Dose 3
.2
0.12
0.25
253.20
4.22
0.34
0.32
0.34
.3
0.93
0.00
116.46
1.94
0.33
0.33
0.35
.4
1.00
0.00
63.96
1.07
0.32
0.36
0.32
.5
1.00
0.00
60.12
1.00
0.35
0.31
0.34
.3
0.70
0.02
181.02
3.02
0.08
0.07
0.86
.4
1.00
0.00
93.72
1.56
0.02
0.02
0.96
.5
1.00
0.00
67.92
1.13
0.01
0.01
0.98
.3
0.69
0.03
183.18
3.05
0.09
0.00
0.91
.4
1.00
0.00
93.84
1.56
0.02
0.00
0.98
.5
1.00
0.00
67.56
1.13
0.01
0.00
0.99
Clinical Trial Simula)on

We simulate trials to see how our adap3ve design machine works
Scenarios
Stress test the machine under dierent assumed truths (drug doesnt
work, drug is really good, etc)
Sample Trials
Watch progress of a virtual trial. The real trial should not be the rst )me
your design is run
Dont want surprises during the trial
Great for debugging (even when you think its right)
Great way to illustrate the adap)ve process to collaborators,
management, IRBs, DMCs, investors, etc.
Opera)ng Characteris)cs
Aggregate results of many sample trials under many dierent scenarios

to get an overall picture of how the design will perform
Usually have to control Type I error rate by trial & error
Set cri)cal value, run 1,000 sims, check Type I error
Adjust to get Type I error in worst case scenario at 2.5% or 5%

Introduction to Bayesian Adaptive Methods

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Introduction to Bayesian Adaptive Methods

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Introduc)on

Common Trial: How do I get to work?

Common Trial: How do I get to work?

How do you decide which way to go?

Common Trial: How do I get to work?

Common Trial: How do I get to work?

Example: RESPECT Trial

Example: RESPECT Trial

Example: RESPECT Trial

851 (86.8%) remained in ac)ve follow-up

In the inten)on-to-treat cohort, there were 9 events

Example: RESPECT Trial

HR, 0.49 (95% CI, 0.201.08)

Example: RESPECT Trial

Example: RESPECT Trial

What are Adap)ve Designs?

Prospec)ve Adap)ve Design

Every )me I say Adap)ve Design I mean

What are Adap)ve Trials?

What are Adap)ve Trials?

For sta)s)cal eciency

Adapt to responding sub-popula)ons

Drug already approved in Japan but not in the US.

Typical Prospec)ve Adap)ve Design

More pa)ents get treated with the bePer

Adap)ve Design Tools

Using Bayesian tools to help us design the trial?

Simple Bayes Example

Simple Bayes Example

Pr ( DATA | p = 0.75 ) Pr ( p = 0.75 )

Bayes Rule More Generally

For our simple example =

Bayes Rule More Generally

Interac)ve Drug Development

Posterior Prob. Response Rate > .20

Pr(p>.20|6S and 14F) = 0.89

Interac)ve Drug Development

Condi)onal Probability vs. Predic)ve

Number Successes Phase III

Number Successes Phase III

Beta-binomial has much more variability we are

Condi)onal Probability vs. Predic)ve

Number Successes Phase III

Number Successes Phase III

Condi)onal Probability vs. Predic)ve

Number Successes Phase III

Number Successes Phase III

Bayesian Advantages to Trial Design

Posterior probability of treatment eect

Provide predic)ve probabili)es of success before and during

Mul)ple sources of informa)on can be combined (previous trials)

Interac)ve Drug Development

The goal of the trial will be to determine if the

The company will have resources for a 300 pa)ent Phase 3

Your goal is to design their Phase 2 trial in stages,

Interac)ve Drug Development

An eec)ve dose is any dose that has

Interac)ve Drug Development

Thus there are 300 pa)ents to allocate to the

Terminate the trial for fu)lity

Simula)on of Interac)ve Drug

Interim analysis every 60 pa)ents

Sample pa)ents based on probability that each dose is