interimanalysis14nov (20024)

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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 bio-statisticians (and lay representatives).

� To review accumulating data related to treatment

effects, adverse events and trial performance.

� To protect the integrity of the clinical trial fromadverse 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

diseases,CD4>=300cells/mm3

� Primary objective: to determine whether theaddition 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 eventcurves 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 ESPRITonly 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 cellcount 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 treatingstatus epilepticus in the prehospitalsetting and whether this therapyinfluences longer-term patient outcome

� 2) to determine whether lorazepam issuperior 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:

early dramatic benefits

potential harmful effects.

� Done by independent person.

� Statistic technique(s) is not the sole basisfor 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 beingtreated.

� The acceptability of the treatment to patients,

� Other findings



Decision to extend a trial

� To maintain the power

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 responseevaluation.

� Special meeting for unexpected toxicity of oneintervention.

� Rate of patients accrual .

� 10%, 25% 75% and 100% of the primaryoutcomes have been observed.



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 thecriterion 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% levelO

verall 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

0.531.0

For two treatments, a normal response

with known variance and equally spaced

analyses

Though broadly similar results

for other type of data



Nominal significance level required for repeated two-sided

significance testing with overall significance level (0.01 or 0.05)

and various N

N (Max. tests) E = 0.05 E = 0.01

2

3

4

5

1015

20

0.029

0.022

0.028

0.016

0.01060.0086

0.0075

0.0056

0.0041

0.0033

0.0028

0.00180.0015

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 (E=0.05)

k Pocock O¶Brien²Fleming

1

2

1

23

1

2

3

4

1

2

3

4

5

0.0294

0.0294

0.0221

0.02210.0221

0.0182

0.0182

0.0182

0.0182

0.0158

0.0158

0.0158

0.0158

0.0158

0.0051

0.0415

0.001

0.01510.0471

0.001

0.0039

0.0184

0.0412

0.001

0.0013

0.0085

0.0228

0.0417



Group sequential tests boundaries

(see Fig.1)

� Pocock (1977)

Divides equally the overall significance levels

� Peto (1976)

Interim tests are run with a v ery low lev el of

significance (0.001), which has little impact on the level

of significance of the final test.

� O¶Brien and Fleming (1979)

It is a int ermed i at e 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

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

CP CVP X2

(withoutcontinuity

correction )

Analysis 1

Analysis 2 Analysis 3

Analysis 4

Analysis 5

3/14

11/2718/40

18/54

23/67

5/11

13/2417/36

24/48

31/59

1.63

0.920.04

3.25

4.15

0.05<P<0.1

0.016<P<0.05



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 f iv e interim

analysis.



� It is sensible to consider just t wo 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 ov erall power there

is a reasonable chance of being able to stop

halfway though.

How many interim analysis



Alpha-spending functions (Lan and DeMets)

Flexible group sequential procedures (1983)

� The limitation of group sequential methods.

To specified the number K of planned interimanalyses in advance.

The requirement for equal numbers of either

participants or events between each analysis.

The exact ti me of the interim analysis is specified.



Calendar time and information fraction

� At any particular calendar time t in thestudy, a certain fraction t* of the total

information is observed such as:

expectednumber totalThe

pointat thatrandomizedts participanThe/ ! N n

expectednumber totalthe

studies)survivalin(observedeventsof number the/ ! Dd



� For regression slops: the information fraction

is more generally defined in terms of the ratio

of the inverse of the variance of the teststatistic at the particular interim analysis and

the final analysis.

� The alpha spending function E(t*), determines

how the pre-specified E is allocated at each

interim analysis as a function of the

information fraction.

Calendar time and 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-specifiedE

level.



A Example of group sequential methods

in the Beta-Blocker Heart Attack Trial

� Specifications of the group sequential boundary:

The O¶ Brien-Fleming group sequential procedure.

Seven meetings scheduled to review interim data.

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.



� From the second analysis on, the conventional significant value of 1.96 was exceeded.

q

� the trial was continued.q

� at the six meeting, the O¶Brien-Flemingboundary was crossed

q� a decision was made to terminate the trial

� Crossing the O·Brien-Fleming boundary was only one

of the factors in this decision!

Interim log rank tests in the

Beta-Blocker Heart Attack Trial



Figure 2 Cumulative mortality curves comparing propranolol and

placebo in the Beta-Blocker Heart Attack Trial.



What should be in a interim report� 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

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 ClinicalTrials

� CYTEL Software Corporation� E-mail:[email protected]

interimanalysis14nov (20024)

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