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Transcript of EFFICACY ENDPOINTS IN ONCOLOGY - Lex Jansen Surrogate Endpoints Introduction Overall Survival...

  • 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

  • Geneva Branch

    Cytel Inc. - Confidential 2

    Efficacy Endpoints in Oncology

    Disclaimer

    The information contained in this presentation is based on personal research of the author. The author may or may not

    be experts in the field.

    Cytel Inc. does not guarantee for the correctness of the displayed information.

    Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

  • Geneva Branch

    Cytel Inc. - Confidential 3

    Efficacy Endpoints in Oncology

    Introduction Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    Oncology Endpoints in Drug Development § Early Phase § Safety and Evidence of Drug Activity § Identification of possible indications

    § Late Phase § Seek for Clinical Benefit

  • Geneva Branch

    Cytel Inc. - Confidential 4

    Efficacy Endpoints in Oncology

    Introduction Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    Key Requirements for Drugs Approval § Demonstration of efficacy with acceptable safety in

    adeguate and well-controlled studies § Benefits/Risks asssessment § Longer Life § Better Life (Quality) § Safety § Cost

    “Clinical Trials Enpoints for the Approval of Cancer Drugs and Biologics” Guidance for Industry, FDA, May 2007

  • Geneva Branch

    Cytel Inc. - Confidential 5

    Efficacy Endpoints in Oncology

    Overall Survival (OS) Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    Definition Time from randomization until death from any cause

    Pros •  Measure of direct benefit •  Easy to measure (Unbiased)

    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

    The «Gold» standard for demonstrating clinical benefit

  • Geneva Branch

    Cytel Inc. - Confidential 6

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    History of (FDA) Drugs Approval § ‘70: Objective (tumor) Response Rate (ORR) § ‘80: More demonstration of clinical benefit: 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.

  • Geneva Branch

    Cytel Inc. - Confidential 7

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    A surrogate endpoint is an alternative endpoint that if validated allows conclusions to be made about the effect of an intervention on a true endpoint often requiring a shorten observaion period § Surrogate ‘efficacy’ endpoints in oncology aim to replace OS, the endpoint to ‘predict’

    Primary endpoints in randomized controlled trials of treatments for advanced breast cancer 2000-2007)

    Endpoints used for basis of oncology drug approvals (FDA 1990–2002)

  • Geneva Branch

    Cytel Inc. - Confidential 8

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Tumor Response and Progression in Solid Tumors § Change in Tumor Mass

    § Shrinkage (Response) § Growth (Progression)

    § Instrumental Evaluation / Radiological Evaluation (e.g. CT-Scan) § Periodic and Regular Assessments

    Source: Gonçalves et al. BMC Cancer 2008 8:169 doi:10.1186/1471-2407-8-169

  • Geneva Branch

    Cytel Inc. - Confidential 9

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Tumor Response and Progression in Solid Tumors

    § Standard set of Criteria (RECIST) § Identification and Classification of Tumor Lesions

    §  Measurable (Target) vs Non Measurable (Non-Target) § Periodicity (e.g. CT-Scan every 6 or 8 weeks) § Response evaluated vs Baseline (assessment prior 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 measurement (mm) §  An increase / prgression of any non-target lesion or new lesion identified

    after study entry determines also the progression

  • Geneva Branch

    Cytel Inc. - Confidential 10

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Tumor Response and Progression in Solid Tumors § Standard set of Criteria (RECIST) - Cont

    §  5 Overall Response Criteria §  CR – Complete Response §  PR – Partial Response §  SD – Stable Response §  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.  

  • Geneva Branch

    Cytel Inc. - Confidential 11

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Tumor Response and Progression in Solid Tumors

    EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247

    Lesion Baseline Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 T1 (mm) 10 10 5 7 10 T2 (mm) 25 15 5 5 5 T3 (mm) 15 15 15 15 20 (Sum of Lesion mm) 50 40 25 27 35 (Response Target Lesions) SD PR PR PD NT1 NA Stable Stable Stable Stable New Lesion NA No No No No

    PR SD PR PD PR SD PD

  • Geneva Branch

    Cytel Inc. - Confidential 12

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Progression and Response

    PD

    PR

    PR

    SD

    Decrease with respect to baseline...

    …but also increase with respect to prior reduction showing the «re-growth» of the cancer and therefore the failure of the treatment

  • Geneva Branch

    Cytel Inc. - Confidential 13

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall Survival

    Surrogate Endpoints

    Regulatory Req.

    Data Management

    Analysis

    Conclusions

    The concept of Progression and Response

    PD

    PR

    PR

    SD

    data respT; set SOLD; by USUBJID VISITNUM; retain NADIR BASE; if first.USUBJID then do; NADIR=.; BASE=SOLDMM; end; PCTBASE=((SOLDMM-BASE)/BASE)*100; PCTNADIR=((SOLDMM-NADIR)/NADIR)*100; if SOLDMM=0 then NTRESP=‘CR’; else if PCTNADIR>20 then NTRESP=‘PD’; else if abs(PCTBASE)>30 then NTRESP=‘PR’; else SOLDMM ne . Then NTRESP=‘SD’; else NTRESP=‘NE’; output; NADIR=min(NADIR,SOLDMM); run;

    Timepoint SOL DMM

    BA SE

    PCTB ASE

    NA DIR

    PCTN ADIR

    NTRE 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

  • Geneva Branch

    Cytel Inc. - Confidential 14

    Efficacy Endpoints in Oncology

    Surrogate Endpoints Introduction

    Overall