Early

Stopping of Clinical Trials

Early Stopping of Clinical Trials

Up un5l now, we have only discussed analysis of data at one point in 5me-a>er
trial ends.
Ethical and prac5cal considera5ons warrant periodic monitoring of data during
course of study.
The trial is some5mes stopped early (early termina5on) for reasons including:

Serious toxicity or adverse events

Established benet
Fu5lity-or no trend of interest
Design or logis5cal issues too serious to x.

The possibility of stopping early gives rise to sta5s5cal issues in the design and
analysis, which are generally referred to as group sequen+al methods.

Early Stopping of Clinical Trials

Clinicial trials are monitored by an independent Data Safety and Monitoring

Board (DSMB)

DSMB responsible for safety and well being of pa5ents in trial.

Inves5gators have too much invested scien5cally, emo5onally, and nancially to

be the best suited for deciding when/if a trial should stop.

DSMB usually comprised of someone with exper5se in each of:

Clinical area related to trial
Laboratory
Epidemiology
Biosta5s5cs
Data Management
Ethics.

It is expected that there is no conict of interest and that discussions of DSMB are
conden5al.

Early Stopping of Clinical Trials

DSMB responsibili+es:
Protocol review-make sure blueprint (plan) for trial makes sense.

Early stage review-make sure no iden5able issues administra5vely regarding conduct of
study
Recruitment/entry criteria
Baseline comparisons
Design assump5ons and modica5ons
entry criteria
Treatment dose
Sample size adjustments
Frequency of measurements
Measurement quality

Interim reviews-make sure no evidence of problem or iden5ca5on of benet making it
unethical to con5nue.
Study progress
Data quality
Safety
Ecacy and benet

Manuscript review-accurate repor5ng and dissemina5on of results.

Early Stopping of Clinical Trials

Deciding whether a trial should be stopped early depends on if dierence during

interim analysis is suciently large or small warran5ng early termina5on.

Group-sequen+al methods are rules for stopping a study early based on

treatment dierences that are observed during interim analyses.
Data is monitored sequen5ally at a nite number of 5mes (xed and
predetermined).

We are going to focus on sta5s5cal issues in the design and analysis of trials using
group sequen5al methods.

The approaches used are referred to as informa+on-based design and monitoring

of clinical trials.

Early Stopping of Clinical Trials

The typical scenario where these methods can be applied is as follows:

Data in a study are collected over calendar 5me, and can be from new entering
pa5ents or new data from exis5ng pa5ents at dierent 5me points.

Want to address a research ques5on..ie..want to see if one treatment (new) is
beWer than the other (old).

Conduct interim analysis to assess whether there is sucient strong evidence to
warrant early termina5on of the study

At each monitoring 5me, a test sta5s5c is computed and compared to a stopping
boundary. This is a pre-specied value computed for each interim analysis to be
conducted.

The stopping boundaries are chosen to preserve certain opera5ng characteris5cs
that are desired; i.e. level and power

Early Stopping of Clinical Trials

The methods we will discuss are general enough to include problems where

t-tests are used to compare the mean of con5nuous random variables between
treatments

propor5on tests for dichotomous response variables

log-rank test for censored survival data

tests based on likelihood methods for either discrete or con5nuous random
variables; i.e. Score test, Likelihood ra5o test, Wald test using maximum likelihood
es5mators

Early Stopping of Clinical Trials

Assume test sta5s5c generated from some distribu5on where denotes the
primary parameter of interest (treatment eect).

We are interested in tes5ng (we will discuss two-sided but can be modied):

vs.

At each interim analysis 5me t, our decision making will be based on the test
sta5s5c:

where the numerator is an es5mator for and the denominator is the es5mated
standard error of the numerator. This will use all data up to 5me t.

Early Stopping of Clinical Trials

Early Stopping of Clinical Trials

Example 2 (+me to event)

Suppose we assume PH model and want to test the null hypothesis of no treatment
dierence.

At 5me t, we compute the test sta5sic:

where, for a PH model, is the maximum par5al likelihood es5mator .

Note:
The material on the use and the proper5es of the maximum par5al likelihood es5mator
are taught in the classes on Survival Analysis. However the logrank test computed
using all the data up to 5me t is equivalent asympto5cally to the test based on T(t).

Early Stopping of Clinical Trials

Actually for any parametric model where we es5mate, , we can nd the MLE and
its standard error and conduct tes5ng using:

Where the es5mated standard error is the square-root of the inverse of the
observed informa5on matrix using data up to 5me t.

Early Stopping of Clinical Trials

We use the distribu5on under the null as the basis for determining boundary values
b(tj ) to use in our group sequen5al test monitoring at 5mes j=1,..K.

Group sequen+al test procedure:

Determine the total number of interim analysis K.
Determine boundary values b(tj) for j = 1, 2, ...,K.
Reject H0: = 0 at the rst 5me tj when |T(tj)| b(tj), if we consider two-sided test.

Ques+ons:
How do we determine the boundary values b(tj ) and how do we control the overall
type I error probability ?

Rejec5ng the null hypothesis corresponds to the event:

Similarly failing to reject the null corresponds to the event:

So how big should the treatment dierences be during interim analysis before we
reject? This determines boundary values.

What are the consequences aec5ng power and sample size ?

Early Stopping of Clinical Trials

We know that if we naively reject H0 at the rst monitoring 5me the test sta5s5c
(absolute value) exceeds 1.96, then type I error is inated. Ie..

The table below reects the actual type I error if b(tj ) = 1.96 is used:

Early Stopping of Clinical Trials

Our rst objec5ve is to derive group-sequen5al tests (i.e. choice of boundaries

b(t1), . . . , b(tK)) that have the desired prespecied type I error of . This means:

P[reject H0 | H0 ]= or equivalently : P[fail to reject H0 | H0 ]=1-

The strategy goes like:

Stop and reject H0 at the rst interim analyisis if

Stop and reject H0 at the second interim analysis if

Stop and reject H0 at the last interim analysis if

Otherwise fail to reject H0

Early Stopping of Clinical Trials

Thus we have represented the sample space into mutually exclusive rejec5on
regions, and a region of acceptance (failed to reject at any 5me). In order for
tes5ng strategy to have level , boundary values must sa5sfy:

Thus we need to know the joint distribu5on of T(t1), T(tK ), a mul5variate

sta5s5c, in order to compute the necessary probabili5es to ensure an level test
as well as to compute power.

A major result which allows use of general methodology for monitoring clinical
trials is:

Any ecient based test or es+mator for , properly normalized, when
computed sequen+ally over +me, has, asympto+cally, a normal independent
increments process whose distribu+on depends only on the parameter and the
sta+s+cal informa+on. Scharfstein, Tsia5s and Robins (1997). JASA. 1342-1350.

Early Stopping of Clinical Trials

Test sta5s5cs are constructed so that when =* ,

and we can approximate the sta5s5cal informa5on I(t, * ) by

Dene :
When
Thus we have normalized by mul5plying the test sta5s5c by the square root of the
informa5on. This normalized sta5s5c, computed sequen5ally over 5me will have
normal independent increments structure described in the presented result.

Thus: is asympto5cally normal with mean vector

and covariance matrix where

Early Stopping of ClinicalTrials

The sta5s5c W(tj) has mean and variance propor5onal to the sta5s5cal
informa5on at 5me tj

The increments are independent. Thus:

has the same distribu5on as a par5al sum of independent normally distributed

random variables.

Thus for j < :

cov{W(tj),W(t)} = cov[W(tj), {W(t) W(tj)} +W(tj)]

= cov[W(tj), {W(t) W(tj)}] + cov{W(tj),W(tj)}

= 0 + var{W(tj)}
= I(tj ,).

Early Stopping of Clinical Trials

Since ,

we have that is also mul5variate normal with:

and covariance matrix where:


and for j < :

Early Stopping of Clinical Trials

What this means is that the covariance of T(tj) and T(t) is the square root of the
rela5ve informa5on at 5mes j and .

Under H0 : =0, the sequen5ally computed test sta5s5c {T(t1), . . . , T(tK)} is a

mul5variate normal mean zero vector with covariance (and correla5on since all
variances equal to 1) matrix given by:

So the joint distribu5on of this test sta5s5c is completely determined by the

rela5ve propor5on of informa5on at each of the monitoring 5mes.

We will use this to evaluate probabili5es at each monitoring 5me to nd

appropriate corresponding boundary values necessary to achieve a desired type I
error of .

Early Stopping of Clinical Trials

Consider the special case where we have equal increment of informa5on:

Note: for trials where outcome, or response, is observed instantaneously, the

informa5on is propor5onal to sample size under study. Thus equal increments
would mean calcula5ng test sta5s5c each 5me an equal number of pa5ents enter
study. For 5me to event outcomes, informa5on is directly propor5onal to number
of events this would correspond to calcula5ng test sta5s5c when equal numbers
of event is observed.

Conduc5ng interim analysis with equal increments of informa5on gives us:

Thus under the null, the joint distribu5on of the test sta5s5c a>er equal
increments of informa5on is completely determined given K (number of interim
analyses intended.

Early Stopping of Clinical Trials

Thus for given boundary values, bj=b(tj ) we can itera5vely calculate

This is done with recursive numerical integra5on. Details are provided in Armitage,
McPherson and Rowe (JRSS-A, 1969).

Innite combina5ons of boundary values such that

We must assess sta5s5cal consequences of dierent combina5ons of boundary

values to help choose which to implement.

Early Stopping of Clinical Trials

Choosing boundaries

Wang and Tsia5s (Biometric, 1987) propose exible class of boudnaries:

where is a shape parameter characterized by a power func5on.

For any value , K, and we can numerically derive the the constant c necessary
to sa5sfy:

Under the null, the joint distribu5on of the test sta5s5cs is completely known if
the 5mes are chosen at equal increments of informa5on. The above integral of
joint probability is calculated for dierent C un5l we solve equa5on. This
equa5on is monotone in C, so a solu5on exists.

Early Stopping of Clinical Trials

Table of c for given values of K, ,

and .

Two special cases of the class of

boundaries have been extensively
used and discussed in literature.

Pocock boundaries:

OBrien-Fleming boundaries:

Early Stopping of Clinical Trials

Pocock boundaries:

if K=5, =0.05, then c(0.05, 5, 0.5)=2.41. Thus, we reject H0: =0 the rst 5me
when:

which is when the P-value 0.0158.

OBrien-Fleming boundaries:


If K=5 and =0.05, then c(0.05, 5, 0)=4.56 and then we determine boundaries by:

Early Stopping in Clinical Trials

Early Stopping in Clinical Trials

Power and Sample Size Considera+ons:

When we only have one 5me point of analysis:

Under a clinically important alterna5ve:

where denotes sta5s5cal informa5on and can be approximated by

For a two sided test of size to have power 1- , we must have:
or

Early Stopping in Clinical Trials

Since we need to collect enough data so that:

One strategy could be to monitor and do the analysis when the above
equality is sa5sed (5me tF ) and then:

Reject

Note: this is an informa5on-based approach which depends only on the accuracy of the
normal approxima5on of the test sta5s5c and how well its standard error is
approximated using the Fisher informa5on. Sample sizes of phase III trials are usually
sucient for this to work well.

In reality we usually cant tell inves5gators to wait to analyze data un5l std error of
es5mated treatment dierence is suciently small (informa5on large) without giving
them some idea how many resources they need (i.e. sample size, length of study,
Generally, during the design stage, we posit some guesses of the nuisance parameters
and then use these guesses to come up with some ini5al design.

Early Stopping in Clinical Trials

Early Stopping of Clinical Trials

For a group sequen5al trial with K looks (5me points of analysis), lets denote the
maximum informa5on (MI) at the nal analysis 5me as MI.

Power for the group sequen5al test is

where bj , j=1,2,.,K are determined by , K, and .

Need to determine the maximum informa5on (MI), which is like maximum sample
size, needed. Note:
If we have equal increments with interim analysis, we have:

Early Stopping of Clinical Trials

Let: Then the distribu5on of the mul5variate test sta5sic is

completely determined by and K.

Thus we can determine for a given , K and so that power is at desired level.

Denote this by Thus for desired power, we need:

or

Early Stopping of Clinical Trials

Ina+on Factor
A useful way to think about the maximum informa5on necessary to achieve pre-
specied power with a group sequen5al test is to relate this to informa5on necessary
to achieve pre-specied power with a xed sample design.

Earlier, we showed the informa5on necessary to detect a clinically meaningful

alterna5ve at one analysis 5me is:

The maximum informa5on necessary at the same level and power to detect the same
alterna5ve using a K-look group sequen5al test with shape parameter is

is the ina5on factor, or rela5ve increase in

informa5on
informa5on necessary for a group sequen5al test to have the same power as a
xed sample test.

Early Stopping on Clinical Trials

Early Stopping of Clinical Trials

Early Stopping of Clinical Trials

Early Stopping of Clinical Trials

Early Stopping of Clinical Trials

Early Stopping of Clinical Trials

Remarks:

Numerical search can be used to nd op+mal shape parameter under a specied

clinically important alterna+ve. (Wang and Tsia+s, 1987, Biometrics).