Efficacy Endpoints in Oncology

Geneva Branch
EFFICACY ENDPOINTS IN ONCOLOGY
IS01
Bruxelles 13-16/10/2013
Angelo Tinazzi
Cytel Inc., Wilmington Del. USA
Succursale de Meyrin Geneva Switzerland
angelo.tinazzi@cytel.com
Cytel Inc. - Confidential 2
Efficacy Endpoints in Oncology

Disclaimer Geneva Branch
The information contained in this

presentation is based on personal
Introduction
Overall Survival
research of the author and does not Surrogate Endpoints
necessarily represent Cytel Inc.. Regulatory Req.
Data Management
Analysis
Conclusions

Introduction Geneva Branch
Introduction
Overall Survival
Oncology Endpoints in Drug Development Surrogate Endpoints
Early Phase Regulatory Req.
Safety and Evidence of Drug Activity Data Management
Identification of possible indications Analysis
Conclusions
Late Phase
Seeks for Clinical Benefit

Introduction Geneva Branch
Introduction
Overall Survival
Key Requirements for Drugs Approval Surrogate Endpoints
Demonstration of efficacy with acceptable safety in Regulatory Req.
adeguate and well-controlled studies Data Management
Benefits/Risks asssessment
Analysis
Conclusions
Longer Life
Better Life (Quality)
Safety
Cost
Clinical Trials Enpoints for the Approval of Cancer Drugs and Biologics
Guidance for Industry, FDA, May 2007

Overall Survival (OS) Geneva Branch
Introduction
Overall Survival
The Gold standard for demonstrating clinical benefit
Surrogate Endpoints
Definition Time from randomization until death Regulatory Req.
from any cause Data Management
Pros Measure of direct benefit Analysis
Easy to measure (Unbiased) Conclusions
Cons It may require large population and follow-up

It includes deaths unrelated to cancer
It may be affected by crossover or subsequent
therapies
Censor Last date subjects was seen alive

Surrogate Endpoints Geneva Branch
Introduction
Overall Survival
History of (FDA) Drugs Approval Surrogate Endpoints
70: Objective (tumor) Response Rate (ORR) Regulatory Req.
Data Management
80: More evidence of clinical benefit: Analysis
Conclusions
Survival, QoL, Physical functioning, Tumor-
related symptoms
90: use of Surrogate endpoints predicting
clinical benefits
1992: FDA adopted accelerated drug approval
J. McCain, "The Ongoing Evolution of Endpoints in Oncology," 2010.


Introduction
A surrogate endpoint is an alternative endpoint that if validated
Overall Survival
allows inference on the effect of an intervention on a true
Surrogate Endpoints
endpoint often requiring a shorten observaion period
Regulatory Req.
Surrogate efficacy endpoints in oncology aim to replace OS, Data Management
the endpoint to predict Analysis
Conclusions
Endpoints used for

basis of oncology drug
approvals
(FDA 19902002)
Primary endpoints in randomized controlled

trials of treatments for advanced breast
cancer 2000-2007)

Introduction
The concept of Tumor Response and Progression in Solid Tumors Overall Survival
Standard set of Criteria (RECIST) Surrogate Endpoints
Identification and Classification of Tumor Lesions Regulatory Req.
Measurable (Target) vs Non Measurable (Non-Target) Data Management
Periodicity (e.g. CT-Scan every 6 or 8 weeks) Analysis
Response evaluated vs Baseline (baseline assessment prior Conclusions
to study entry)
A 30% decrease in the sum of all lesions measurement (mm)
Progression evaluated vs Nadir (best response prior to current
assessment)
A 20% increase in the sum of all lesions measurements (mm)
An increase / prgression of any non-target lesion or new lesion identified
after study entry determines also the progression

Introduction
Standard set of Criteria (RECIST) Surrogate Endpoints
Identification and Classification of Tumor Lesions Regulatory Req.
Measurable (Target) vs Non Measurable (Non-Target) Data Management
Periodicity (e.g. CT-Scan every 6 or 8 weeks) Analysis
Response evaluated vs Baseline (baseline assessment prior Conclusions
to study entry)
A 30% decrease in the sum of all lesions measurement (mm)
Progression evaluated vs Nadir (best response prior to current
assessment)
A 20% increase in the sum of all lesions measurements (mm)
An increase / prgression of any non-target lesion or new lesion identified
after study entry determines also the progression

Introduction
Standard set of Criteria (RECIST) - Cont Surrogate Endpoints
5 Overall Response Criteria Regulatory Req.
CR Complete Response Data Management

PR Partial Response Analysis
SD Stable Response
Conclusions
PD Progressive Disease
NE Not Evaluable
Best Overall Response as the best response (criteria) assessed since the
subject is on-study (on-treatment)
P Therasse et al, "New response evaluation criteria in solid tumors: Revised RECIST
guideline (version 1.1)," European Journal of Clinical Oncology, pp. 45: 228-247, 2009.
MB Mayakuntla, PM Nidamathy, "RECIST and programming challenges," in IASCT, 2012.
Ji Yu, P Slagle, "Objective tumor response and RECIST criteria in cancer clinical trials," in
MWSUG, 2011.

Introduction
Lesion Baseline Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 Surrogate Endpoints

T1 (mm) 10 10 5 7 10
Regulatory Req.
T2 (mm) 25 15 5 5 5
T3 (mm) 15 15 15 15 20 Data Management
(Sum of Lesion mm) 50 40 25 27 35
(Response Target Lesions) SD PR PR PD Analysis
NT1 NA Stable Stable Stable Stable Conclusions
New Lesion NA No No No No
SD PR
PR PR PD
EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 247


Introduction
The concept of Progression and Response Overall Survival
Surrogate Endpoints
Decrease with
PD respect to baseline... Regulatory Req.
Data Management
Analysis
PR but also increase
Conclusions
with respect to prior
reduction showing
PR the re-growth of
the tumor and
therefore the
SD possible failure of
the treatment

Introduction
The concept of Progression and Response Overall Survival
data respT;
set SOLD; Surrogate Endpoints
by USUBJID VISITNUM;
PD
retain NADIR BASE; Regulatory Req.
if first.USUBJID then do;
NADIR=.; Data Management
BASE=SOLDMM;
end; Analysis
PR
PCTBASE=((SOLDMM-BASE)/BASE)*100;
PCTNADIR=((SOLDMM-NADIR)/NADIR)*100; Conclusions
if SOLDMM=0 then NTRESP=CR;
else if PCTNADIR>20 then NTRESP=PD;
PR
else if abs(PCTBASE)>30 then NTRESP=PR;
else SOLDMM ne . Then NTRESP=SD;
else NTRESP=NE;
output;
NADIR=min(NADIR,SOLDMM); Timepoint SOL BA PCTB NA PCTN NTRE
SD
run; DMM SE ASE DIR ADIR SPT
Baseline 50
Timepoint 1 40 50 -20 50 -20 SD
Timepoint 2 25 50 -50 40 -37.5 PR
Timepoint 3 27 50 -46 25 8 PR
Timepoint 4 35 50 -30 25 40 PD

Introduction
Overall Survival
Time to Tumor Progression (TTP)
Surrogate Endpoints
Definition Time from randomization until radiolagical
Regulatory Req.
tumor progression
Data Management
Pros Requires smaller sample size
Analysis
Not affected by crossover or subsequent
Conclusions
therapies
Based on objective and quantitative assessment
Cons Measurement may be subject to bias
Requires frequent radiologic assessment (e.g.
every 6 weeks) and same or similar among
treatment arms
In some settings can be difficult to validate
Censor Last date radiological tumor assessment

Introduction
Progression Free Survival (PFS) Overall Survival
A variant of TTP where deaths are also counted as events Surrogate Endpoints
In some protocols Death as event can be limited if occurred Regulatory Req.
within xx weeks from last tumor assessment (e.g. 12 weeks) Data Management
Applicable to study with patients with advanced cancer Analysis
Disease Free Survival (DFS)

Conclusions
Same as PFS but it assumes patients are disease-free

at study entry
Applicable to study testing adjuvant therapies with
patients where the disease (cancer) was previously
surgically removed

Introduction
Time to Treatment Failure (TTF) Overall Survival
Time from randomization to discontinuation of Surrogate Endpoints
treatment for any reason Regulatory Req.
TTF not reccomended as regulatory endpoint for Data Management
approval; a regulatory endpoint should clearly Analysis
distinguish the efficacy of the drug from toxicity, Conclusions
patient or physichian withdrwal or patient intolerance


Introduction
Objective Response Rate (ORR) Overall Survival
Definition Proportion of patients with tumor size reduction Surrogate Endpoints

of a predefined amount and for a minumim time Regulatory Req.
period. FDA has defined ORR as the sum of Data Management
Complete and Partial Responses Analysis
Pros Can be assessed in single-arm studies Conclusions

Can be assessed earlier and in smaller studies
Effect attributable to drug, not natural history
Cons Not a direct measure of benefit
Only a subset of patients who benefit
Response Duration (DR)

Time from first assessment of CR or PR until date of
progression or last tumor assessment
Applicable only to patients with ORR

Introduction
Efficacy Endpoint Example 1 Overall Survival
Responder Surrogate Endpoints
Progressing Regulatory Req.
Data Management
Death / Analysis
RAN SD SD PR CR PD Alive
Conclusions
ORR
PFS TTP
Response Duration
OS

Introduction
Efficacy Endpoint Example 2 Overall Survival
Non Responder Surrogate Endpoints
Non Progressed Regulatory Req.
Death Data Management
Analysis
Conclusions
RAN SD SD SD Off TRT Death
TTF
TTP
PFS
OS

Introduction
Sensitivity Analysis in Tumor Response based endpoint Overall Survival
Use of Per Protocol Population Surrogate Endpoints
Include clinical progressions Regulatory Req.
Different Censoring/Event Date Methods

Data Management
Analysis
Backdating event date when tumor assessment is not performed within the
Conclusions
pre-defined interval
Censoring at the date of subsequent cancer therapy if occurred before
progression
Use of Independent Review of Tumor Endpoints
Can minimize bias in readiographic interpretation of the radiological
findings (investigator)
Often Primary endpoints in non-blinded studies

Introduction
Modified Response / PFS Criteria Overall Survival
e.g. Prostate Cancer according PCWG2 criteria Surrogate Endpoints
Regulatory Req.
Where disease progression is defined as the presence of at
Data Management
least one of the following conditions:
Bone Lesions Progression
Analysis
Conclusions
Soft-Tissue Lesions Progression (RECIST)
Presence of Skeletal Events
HI Scher, "End Points and Outcomes in Castration-Resistant Prostate Cancer: From Clinical
Trials to Clinical Practice," J Clin Oncol, 2011.

Introduction
Other endpoints: Time to symptom progression (TTSP) Overall Survival
e.g. TTSP in Lung Cancer Trials as per the Lung Cancer Surrogate Endpoints
Symptom Scale (LCSS) Regulatory Req.
Symptomatic progression defined as an increase Data Management
(worsening) of the average symptomatic burden index Analysis
(ASBI, i.e., the mean of the six major lung cancer Conclusions
specific symptom scores [fatigue, pain, dyspnoea,

cough, anorexia and hemoptysis])
The worsening is defined as an at least 10% increase
of the scale breadth (i.e., at least 10 mm increase on
the 100 mm scale) from the baseline score.
Hollen PJ, Gralla RJ, Kris MG, et al. Quality of life assessment in individuals
with lung cancer: Testing the lung cancer symptom scale (LCSS). Eur J Cancer.
1993;29A(1):51-8..

Introduction
Quality of Life Overall Survival
Only used in support of primary endpoints Surrogate Endpoints
Several validated questionnaires available for Regulatory Req.
different indications Data Management
Analysis
Conclusions
http://groups.eortc.be/qol/eortc-modules

Introduction
Duration of Complete Response in Leukemia
Overall Survival
Considered established endpoint of clinical benefit in leukemia
Surrogate Endpoints
Less infection Regulatory Req.
Less Bleeding Data Management
Less use of blood product support (e.g. transfusion) Analysis
Conclusions
D Cheson et al, "Revised Recommendations of the International Working Group for Diagnosis,
Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in
Acute Myeloid Leukemia," Journal of Clinical Oncology, pp. Vol 21, No 24: pp 4642-4649, 2003

Introduction
Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

Regulatory Requirements Geneva Branch
Introduction
FDA Clinical Trial Endpoints for the Approval of Cancer Overall Survival
Drugs and Biologics (2007) Surrogate Endpoints
General regulatory requirements for efficacy Regulatory Req.

Detailed description of endpoints and how these can Data Management
be used in various clinical settings Analysis
Pros and Cons Conclusions
Protocol and SAP design requirements

Data Collection for Tumor Measurement
Issue to consider in PFS analysis
Progression and Censore Date
How to handle Missing Data
Lesions evaluation
Sensitivity Analysis
Clinical Trial Endpoints for the Approval of Non-Small Cell Lung Cancer Cancer Drugs and
++ Biologics, FDA, 2011
Cancer Drug Approval Endpoints

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/CancerDrugs/ucm094586.htm

Regulatory Requirements Geneva Branch
Introduction
EMA Guideline on the evaluation of anticancer medical Overall Survival
products in man Surrogate Endpoints
Guidance on all stages of clinical drug development for Regulatory Req.
the treatment of malignancies Data Management
The current version of the guidance cover also non- Analysis
cytotoxic compounds and additional indication for Conclusions
exploratory studies.
Completed by a set of specific appendices covering
methodologial aspects related
Methodological Consideration for using Progression Free Survival
(PFS) and Disease Free Survival (DFS) in confirmatory trials
Confirmatory Studies in Haematological Malignancies
Condition specific Guidance such as NSCLC, Prostate
The EMA is also planning to provide an additional
appendix for Quality of Life/Patient Reported Outcome.

Data Management Issues Geneva Branch
Introduction
Overall Survival
Tumor Response Surrogate Endpoints
Missing Assessments Regulatory Req.
Consistent Lesions Reporting Data Management
Type, Site Analysis
Assessment of method used Conclusions
Disappeared Tumor Lesions (0mm)

Consisteny between lesions details (sum of diamaters
for target lesions) and overall response
Independent Review Committee
Keep follow-up up-to-date
CDISC SDTM 3.1.3 Tumor Response Domains
Overcoming Difficulties in Implementing RECIST criteria, PhUSE 2013, G. Ruhnke
++
CDISC Journey on Solid Tumor Studies using RECIST 1.1., PhUSE 2013, K. Lee

Analysis Geneva Branch
Introduction
ORR Analysis with proportion and %CI Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

Introduction
Survival Analysis Overall Survival
Unadjusted (Kaplan Meier & Log-Rank Test) Surrogate Endpoints
SAS Proc LIFETEST Regulatory Req.
Adjusted (Cox proportional hazards regression model) Data Management
SAS Proc PHREG Analysis

Selection of covariates to be used depends on the indication and Conclusions
treatment setting. E.g. type and/or response to prior therapy
Examples of other possible covariates

Introduction
Survival Analysis Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions

Analyisis Geneva Branch
Introduction
Subgroup Analysis with Forest Plot Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
Bursac, Z, "Creating Forest Plots from Pre-computed Data using PROC SGPLOT and Graph Template Language,
In SAS Global Forum, 2010

Analyisis Geneva Branch
Introduction
Tumor Shrinkage with Waterfall Plot Overall Survival
Surrogate Endpoints
Regulatory Req.
Data Management
Analysis
Conclusions
NJ Pandya, "Waterfall Charts in Oncology Trials - Ride the Wave,"

In PharmaSUG, 2012

Conclusions Geneva Branch
Introduction
Despite its complexity, stable standards exist for Overall Survival
Surrogate Endpoints
efficacy evaluation Regulatory Req.
Use of efficacy indicators may be different from an Analysis
indication to another Data Management
Managing, deriving and analyzing efficacy endpoints Conclusions
in oncology requires a clear understanding of the

disease
The use of efficacy endpoints in drug approval may
change again with the idea of targetting the therapies
based on molecular profiling

Questions Geneva Branch
New Geneva offices November 2012

Efficacy Endpoints in Oncology

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Efficacy Endpoints in Oncology

Uploaded by

Copyright:

Available Formats

Geneva Branch