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Biostatistics in Cancer Clinical Trials
Dr. Bhaswat S. Chakraborty
VP, R&D, Cadila Pharmaceuticals Ltd.
Presented at the “Recent Trends in Bio-Medical Biostatistics”,
Gujarat University, Ahmedabad on 24.02.2007
Contents Research and Regulations of Cancer Trials Pivotal Cancer Trials (Phase III)
Efficacy end points Merits and demerits
Optimum Study Designs Superiority Non-Inferiority and other designs
Sample Size Considerations Scientific questions Basics of sample size calculation
Statistical Plan for a Cancer RCT Statistical Analysis of Cancer Data Tumor Data Analysis – an Example Conclusion
From Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.
Worldwide Cancer Statistics (All Types)
From Parkin, D. M. et al. CA Cancer J Clin 2005;55:74-108.
Population Based Cancer Registries in India
(PBCR)(PBCR)
Cancer Research Today Research is conducted mainly on
New Drugs New Combinations Radiotherapy Surgery
In the West, research is usually done by large co-operative groups, in addition to those mentioned for India
In India Large Pharmaceuticals Co-operative Groups, e.g., ICON (Indian Co-operative Oncology Network)
Regional Cancer Centres & Govt. sponsored studies Academia
What does FDA Look for?
FDA approves a drug application based on Substantial evidence of efficacy & safety from
“adequate and well-controlled investigations” A valid comparison to a control Quantitative assessment of the drug’s effect
(21 CFR 314.126.)
The design of cancer trials intended to support drug approval is very important
Study Design: Approaches Randomised Controlled Trials (RCT) most preferred
approach Demonstrating superiority of the new therapy
Other approaches Single arm studies (e.g., Phase II)
e.g., when many complete responses were observed or when toxicity was minimal or modest
Equivalence Trials No Treatment or Placebo Control Studies Isolating Drug Effect in Combinations Studies for Radio- and Chemotherapy Protectants
Randomized Clinical Trials Gold standard in Phase III
Single centre CT Primary and secondary indications Safety profile in patients Pharmacological / toxicological characteristics
Multi-centre CT Confirmation of the above Effect size Site, care and demographic differences Epidemiological determination Complexity Far superior to meta-analyzed determination of effect
Non-Inferiority Trials
New drug not less effective by a predefined amount, the noninferiority (NI) margin
NI margin cannot be larger than the effect of the control drug in the new study
If the new drug is inferior by more than the NI margin, it would have no effect at all
NI margin is some fraction of (e.g., 50 percent) of the control drug effect
Placebo Control Equality Trials No anticancer drug treatment in the control arm is
unethical Sometimes acceptable
E.g., in early stage cancer when standard practice is to give no treatment
Add-on design (also for adjuvants) all patients receive standard treatment plus either no
additional treatment or the experimental drug
Placebos preferred to no-treatment controls because they permit blinding
Unless very low toxicity, blinding may not be feasible because of a relatively high rate of recognizable toxicities
Drug or Therapy Combinations Use the add-on design
Standard + Placebo Standard + Drug X
Effects seen in early phases of development Establish the contribution of a drug to a standard
regimen Particularly if the combination is more effective
than any of the individual components
What to Measure? Time to event end points
Survival Disease free survival Progress (of disease) free survival
Objective response rates Complete Partial Stable disease Progressive disease
Symptom end points Palliation QoL
Cancer Trials – End Points
Endpoint Evidence Assessment Some Advantages Some Disadvantages
Survival Clinical benefit RCT needed Blinding not essential
Direct measure of benefit Easily measured Precisely measured
Requires larger and longer studies Potentially affected by crossover therapy Does not capture symptom benefit Includes noncancer deaths
Disease-Free Survival (DFS)
Surrogate for accelerated approval or regular approval*
RCT needed Blinding preferred
Considered to be clinical benefit by some Needs fewer patients and shorter studies than survival
Not a validated survival surrogate in most settings Subject to assessment bias Various definitions exist
Cancer Trials – End PointsEndpoint Evidence Assessment Some Advantages Some Disadvantages
Objective Response Rate (ORR)
Surrogate for accelerated approval or regular approval*
Single-arm or randomized studies can be used Blinding preferred in comparative studies
Can be assessed in single-arm studies
Not a direct measure of benefit Usually reflects drug activity in a minority of patients Data are moderately complex compared to survival
Complete Response (CR)
Surrogate for accelerated approval or regular approval*
Single-arm or randomized studies can be used Blinding preferred in comparative studies
Durable CRs represent obvious benefit in some settings (see text) Can be assessed in single-arm studies
Few drugs produce high rates of CR Data are moderately complex compared to survival
0
Design Concepts
Dif
fere
nce
in C
linic
al E
ffic
acy
(Є)
= Meaningful Difference
Non-Inferiority
Equivalence
Inferiority
Superiority
-
+
Non-Superiority
Equality
Phase III Cancer Trials
0
10
20
30
40
50
60
70
80
90
Survival DFS QoL
New
Standard
New Drug (or Regimen) is Compared with a Standard
Superiority Trials
Phase III Cancer Trials
0
5
10
15
20
25
30
35
40
Survival DFS QoL
New
Standard
Non-Inferiority or Equivalence Trials
Understanding Basics μ0 and μA
Means under Null & Alternate Hypotheses σ0
2 and σA2
Variances under Null & Alternate Hypotheses (may be the same) N0
and NA Sample Sizes in two groups (may be the same)
H0: Null Hypothesis μ0 – μA = 0
HA: Alternate Hypothesis μ0 – μA = δ
Type I Error (α): False +ve Probability of rejecting a true H0
Type II Error (β): False –ve Probability of rejecting a true HA
Power (1-β): True +ve Probability of accepting a true HA
Basics of Sample Size Calculation
Answer the scientific questions for the Trial size
Understand the distribution and variability of the data
Construct correct Null and Alternate hypotheses
From the hypotheses derive formula for sample size
Also make sure that this size trial has adequate power to establish a true alternate
Five Key Questions1. What is the main purpose of the trial?2. What is the principal measure of patient outcome?3. How will the data be analysed to detect a treatment
difference?4. What type of results does one anticipate with standard
treatment?5. How small a treatment difference is it important to detect
and with what degree of certainty?
Answers to all of the five questions above enable us to calculate the sample size and analyze the data with most appropriate test of hypothesis.
Pocock SJ: Clinical Trials: A Practical Approach Chichester: Wiley; 1983
Reliable or historical data available? No
Yes Use conventional methods for analysis
Start Planning
Normally distributed continuous data? Summary
measure: mean & mean difference
Yes
Use parametric methods of analysis, two sample ‘t’ or
ANOVA
Use non-parametric methods of analysis, Mann-Whitney U or Proportional Odds Model
Use bootstrap simulation for sample size
μT – μC
σ∆normal =
Effect Size
Nnormal =2 [Z1-α/2 + Z1-β/2]2
∆2normal
Sample Size
No
α/2
Understanding Sample Size DeterminationH0: μ0 – μA = 0 HA: μ0 – μA = δ
α/2
Power = 1-β
β
S.Error =σ(√2/N) S.Error =σ(√2/N)
0+Z1-α/2σ√(2/N)
0
δ–Z1-βσ√(2/N)
δX0–XA
Critical Value
From the Previous Graph, We have
0+Z1-α/2σ√(2/N) = δ–Z1-βσ√(2/N)
Upon simplification,
Nnormal =2 [Z1-α/2 + Z1-β/2]2
∆2normal
Sample Size: 2-Sample, Parallel Superiority/Non-Inferiority Trial
(z+ zβ)2 (p1 (1– p1) + p2(1 – p2))
(Є – )2
N in each arm =
Power: 2-Sample, Parallel Superiority/Non-Inferiority Trial
Sample and Power for Simulated Tumor Data
0
0.2
0.4
0.6
0.8
1
0.3 0.4 0.5 0.6 0.7 0.8
Relative risk
86
64
50
110
n
Expected Relative Risk
Statistical Plan Primary outcome considerations Study Design Sample size calculation Randomization Statistical consideration in Inclusion/Exclusion criteria
(Homogeneity within centre and strata) Accrual of patients Cleaning of data Interim Analysis
Go/No go criteria α Considerations
Final analysis Final conclusions
Accrual of Patients
Study of the statistical trends in accrual patterns Seasonal Planned approaches Reasons for drop outs and loss to follow up Motivational factors
Monitoring of recruitment progress and strategies Frequency Parameters Duration
Understanding natural history and non-cancer, non-intervention deaths
Changes in accrual after Interim Analysis
Randomisation
Generation of randomisation scheme according to Centre Block Strata
Patient Investigational Product to be given Measures of ensuring non-bias
Allocations What should go on the labels
Primary, secondary, tertiary packaging
Blinding
Often difficult in oncology trials Test and control are of different characteristics
Different routes of administration Different schedules
New low toxicity oral treatments are relatively easy to blind
In other cases the end-point evaluating investigator must be different from the one administering the drugs
Data Capture Manual or Electronic CRF is the main source of raw data capture Data must be quality assured
Integrity, accountability, traceability Data must be validated All production and/or quality system software, purchased or
developed in-house Should document
Intended use, and information against which testing results and other evidence can be compared
To show that the software is validated for its intended use
Data Cleaning & Locking
Data are cleaned based on a good plan for interim or final analysis E.g.,
Hundred percent data are made quality checked and assured Eligibility criteria for data selection Correction and editing Double data entry or other methods of data integrity
Data will be locked after cleaning the data and resolving all the queries SOP for data locking No change after locking
Only locked data are used as input into data analysis program
Interim Analysis of Data
0
0.005
0.01
0.015
0.02
0.025
0.03
0.035
0.04
0.045
0.05
1 2 3 4
Nominal p
Looks
Interim Analysis of Data
Look
No
min
al P
valu
e
0.0
0.0
10
.03
0.0
5
1 2
2 Looks
o pococko ob+fleo fle+har+ob
Look
No
min
al P
valu
e
0.0
0.0
10
.03
0.0
5
1 2 3
3 Looks
Look
No
min
al P
valu
e
0.0
0.0
10
.03
0.0
5
1 2 3 4
4 Looks
Look
No
min
al P
valu
e
0.0
0.0
10
.03
0.0
51 2 3 4 5
5 Looks
How many times can you look into the data?
Type 1 error at kth
test is NOT the same as the nominal p value for the kth test
Considerations for IA
Stopping rules for significant efficacy Stopping rules for futility Measures taken to minimize bias A procedure/method for preparation of data for analysis Data has to be centrally pooled, cleaned and locked Data analysis - blinded or unblinded? To whom the interim results will be submitted?
DSMB Expert Steering Group
What is the scope of recommendations from IA results? Safety? Efficacy? Both? Futility? Sample size readjustment
for borderline results?
Final Analysis and Conclusion Clinically meaningful margins must be well defined in Control trials
prospectively Superiority and non-inferiority margins must not be confused
Two or one-sidedness of α should also be prospectively defined Power must be adequate Variance must be analysed using the right model Strategy for dealing with multiple end points must be prespecified
Too many end points ot tests will increase the false positive (α) error Sometimes (e.g., in equality trials) statistically significant results may not
be medically significant
Data censoring or skewed data E.g., time to event data
Intent-to-Treat Principle
All randomized patients Exclusions on prespecified baseline criteria permissible
also known as Modified Intent-to-Treat Confusion regarding intent-to-treat population: define and agree
upon in advance based upon desired indication Advantages:
Comparison protected by randomization Guards against bias when dropping out is realted to outcome
Can be interpreted as comparison of two strategies Failure to take drug is informative Refects the way treatments will perform in population
Concerns: “Difference detecting ability”
Per Protocol Analyses
Focuses on the outcome data
Addresses what happens to patients who remain on
therapy
Typically excludes patients with missing or
problematic data
Statistical concerns: Selection bias
Bias difficult to assess
Intent to Treat & Per Protocol Analyses
Both types of analyses are important for approval
Results should be logically consistent
Design protocol and monitor trial to minimize
exclusions Substantial missing data and poor drug compliance
weaken trial’s ability to demonstrate efficacy
Missing Data
Protocol should specify preferred method for dealing with missing primary endpoint ITT
e.g., treat missing as failures e.g., assign outcome based on blinded case-by-case
review Per Protocol
e.g., exclusion of patients with missing endpoint
Data Safety and Monitoring Board (DSMB)
All trials may not need a DSMB
DSMB Membership Medical Oncologist, Biostatistician and Ethicist
Statistical expertise is a key constituent of a DSMB
Three Critical Issues Risk to participants
Practicality of periodic review of a trial
Scientific validity of the trial
Simulated Tumor Data: An Example
time death group futime number reduction in size0 0 1 0 1 11 0 1 1 1 34 0 1 4 2 17 0 1 7 1 1
10 0 1 10 5 16 1 1 10 4 1
14 0 1 14 1 118 0 1 18 1 15 1 1 18 1 3
12 1 1 18 1 123 0 1 23 3 310 1 1 23 1 33 1 1 23 1 13 1 1 23 3 17 1 1 24 2 33 1 1 25 1 1
26 0 1 26 1 21 1 1 26 8 12 1 1 26 1 4
25 1 1 28 1 229 0 1 29 1 429 0 1 29 1 229 0 1 29 4 128 1 1 30 1 62 1 1 30 1 53 1 1 30 2 1
12 1 1 31 1 332 0 1 32 1 234 0 1 34 2 136 0 1 36 2 129 1 1 36 3 137 0 1 37 1 29 1 1 40 4 1
16 1 1 40 5 141 0 1 41 1 23 1 1 43 1 16 1 1 43 2 63 1 1 44 2 19 1 1 45 1 1
18 1 1 48 1 149 0 1 49 1 335 1 1 51 3 117 1 1 53 1 73 1 1 53 3 1
59 0 1 59 1 12 1 1 61 3 25 1 1 64 1 32 1 1 64 2 3
Simulated Tumor Data: An Example
time death group futime number reduction in size1 0 2 1 1 3
210 0 2 210 1 10180 1 2 180 8 8180 0 2 180 1 610 0 2 10 1 113 0 2 13 1 1
221 1 2 365 2 71 1 2 17 5 3
18 0 2 18 5 1142 1 2 365 1 5
2 1 2 19 5 176 1 2 21 1 422 0 2 22 1 125 0 2 25 1 1025 0 2 25 1 525 0 2 25 1 1
6 1 2 26 1 16 1 2 27 1 62 1 2 29 2 62 1 2 36 8 8
38 0 2 38 1 122 1 2 39 1 11
4 1 2 39 6 524 1 2 40 3 141 0 2 41 3 241 0 2 41 1 1
1 1 2 43 1 144 0 2 44 1 1
2 1 2 44 6 145 0 2 45 1 2
2 1 2 46 1 446 0 2 46 1 449 0 2 49 3 350 0 2 50 1 187 1 2 100 4 654 0 2 54 3 438 1 2 54 2 159 0 2 59 1 3
Simulated Tumor Data: An ExampleControl Group
0
10
20
30
40
50
60
70
1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46
Patient No
Su
rviv
al T
ime
(Day
s)
Experimental Group
0
50
100
150
200
250
1 3 5 7 9 11 13 15 17 19 21 23 25 27 29 31 33 35 37
Patient No
Su
rviv
al T
ime
(day
s)
0
20
40
60
80
100
120
1 2
group
tim
e
± Standard deviation
Descriptive Statistics
Variable: timegrouped by: group
95%N Mean Conf. (±) Std.Error Std.Dev.
1 48 15.77083333 4.241619672 2.108375644 14.607254952 38 47.73684211 19.66266124 9.704135603 59.8203094
Entire sample 86 29.89534884 9.420677178 4.738064537 43.93900293
Kaplan Meier
0
0.2
0.4
0.6
0.8
1
1.2
0 50 100 150 200 250
time
Pro
bab
ility Censored
1
2
Log-rank Test (Cox-Mantel)
Events observed
Events expected
1 29 21.092563062 18 25.90743694
Chi-squareDegrees of Freedom P
6.369814034 1 0.011607777
at Mean
0
0.2
0.4
0.6
0.8
1
1.2
0 50 100 150 200 250
time
Pro
bab
ility
Cox Regression
Equation95% Hazard =
Coefficient Conf. (±) Std.Error P Exp(Coef.)
group -0.823394288 0.667410889 0.340517244 0.015603315 0.438939237
Conclusion of Tumor Data Kaplan Meier
Two survival patterns are different with a median of 12 and 70 days for the Control and Experimental Groups
Log-Rank Test The p-value of 0.0116 indicates significantly higher survival
experience of the experimental group Cox Regression
Hazard of death for the Experimental group is estimated to be about 44% that of the Control group
The log hazard coefficient is – 0.8234 (hence, e-0.8234=0.4389, which gives us the estimated unadjusted Experimental hazard ratio). It means that the expected log hazard for the Experimental group is .8234 lower than it is for the Control group
Difference in survival time in Experimental & Control groups is highly significant (p=0.0156)
Conclusions
Clinical testing of new Oncology products is very sophisticated and complex
A Statistician’s role in Cancer trials is invaluable
Statistical considerations must be thoroughly given attention and built in while planning the study design and calculating the sample size
Cancer clinical data is very complex (censored, skewed, often fraught with missing data point), therefore, proper hypothesization and statistical treatment of data are required
Prospective RCTs are usually the preferred approach for evaluation of new therapies
Conclusions Survival as primary end point is preferred by regulatory agencies Randomisation and blinding offer a robust way to remove bias in end-point
estimations Data must be accurately captured without any bias and analysed by prospectively
described methods Interim analysis should carefully plan ‘ spending’ function Final analysis should be done carefully, independently and meaningfully (medical
as well as scientific) Choose clinically relevant delta Design, conduct, and monitor trials to minimize missing data and poor compliance to
drug Analysis
Both intent-to-treat and per protocol analyses should be conducted Sensitivity analyses
There are many oustanding statistical issues in Cancer trials that need no be discussed and solved
Acknowledgements
Dr. Nikunj Patel Dr. Sumit Goyal Dr. Manish Harsh Dr. Nilesh Patel Ms. Darshini Shah
Thank You Very Much