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
2 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Disc Disclaimer laimer Geneva Branch The information contained in this presentation is based on personal research Introduction of the author. The author may or may not Overall Survival be experts in the field. Surrogate Endpoints Regulatory Req. Data Management Cytel Inc. does not guarantee for the Analysis correctness of the displayed information. Conclusions
3 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Intr Introduction oduction Geneva Branch Introduction Oncology Endpoints in Drug Development Overall Survival Surrogate Endpoints § Early Phase Regulatory Req. § Safety and Evidence of Drug Activity Data Management § Identification of possible indications Analysis § Late Phase Conclusions § Seek for Clinical Benefit
4 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Intr Introduction oduction Geneva Branch Introduction Key Requirements for Drugs Approval Overall Survival 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
5 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Ov Over erall Sur all Survival (OS) vival (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
6 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te 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 demonstration of clinical benefit: Analysis Survival, QoL, Physical functioning, Tumor- Conclusions 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.
7 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction A surrogate endpoint is an alternative endpoint that if validated Overall Survival allows conclusions to be made about the effect of an intervention Surrogate Endpoints on a true endpoint often requiring a shorten observaion period Regulatory Req. § Surrogate ‘efficacy’ endpoints in oncology aim to replace OS, the Data Management endpoint to ‘predict’ Analysis Conclusions Endpoints used for basis of oncology drug approvals (FDA 1990–2002) Primary endpoints in randomized controlled trials of treatments for advanced breast cancer 2000-2007)
8 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction The concept of Tumor Response and Progression in Solid Tumors Overall Survival § Change in Tumor Mass Surrogate Endpoints § Shrinkage (Response) Regulatory Req. § Growth (Progression) Data Management § Instrumental Evaluation / Radiological Evaluation (e.g. CT-Scan) Analysis § Periodic and Regular Assessments Conclusions Source: Gonçalves et al. BMC Cancer 2008 8:169 doi:10.1186/1471-2407-8-169
9 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch 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 (assessment prior to study Conclusions 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
10 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction The concept of Tumor Response and Progression in Solid Tumors Overall Survival § 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. ¡
11 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction The concept of Tumor Response and Progression in Solid Tumors Overall Survival 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 Analysis (Response Target Lesions) SD PR PR PD NT1 NA Stable Stable Stable Stable Conclusions New Lesion NA No No No No PR SD SD PD PR PR PD EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247
12 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction The concept of Progression and Response Overall Survival Surrogate Endpoints Decrease with PD Regulatory Req. respect to baseline... Data Management Analysis PR … but also increase Conclusions with respect to prior reduction showing PR the «re-growth» of the cancer and therefore the failure of the treatment SD
13 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction The concept of Progression and Response Overall Survival data respT; set SOLD; Surrogate Endpoints by USUBJID VISITNUM; retain NADIR BASE; PD 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’; else if abs(PCTBASE)>30 then NTRESP=‘PR’; PR else SOLDMM ne . Then NTRESP=‘SD’; else NTRESP=‘NE’; output; Timepoint SOL BA PCTB NA PCTN NTRE NADIR=min(NADIR,SOLDMM); SD DMM SE ASE DIR ADIR SPT run; 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
14 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch The concept of Progression and Response in non Solid Tumors Introduction Overall Survival (e.g. Acute Multiple Lymphoma) Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions atlasgeneticsoncology.org
15 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Sur Surroga ogate Endpoints te Endpoints Geneva Branch Introduction Time to Tumor Progression (TTP) Overall Survival Surrogate Endpoints Definition Time from randomization until radiolagical tumor progression Regulatory Req. Data Management Pros • Requires smaller sample size Analysis • Not affected by crossover or subsequent therapies Conclusions • 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
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