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Geneva Branch EFFICACY ENDPOINTS IN ONCOLOGY – IS01 Bruxelles 13-16/10/2013 Angelo Tinazzi Cytel Inc., Wilmington Del. USA Succursale de Meyrin – Geneva – Switzerland [email protected] 2 Cytel Inc. - Confidential 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. Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Cytel Inc. does not guarantee for the correctness of the displayed information. Analysis Conclusions 3 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Introduction 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 Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 4 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Introduction 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 Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 5 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Overall Survival (OS) Geneva Branch Introduction The «Gold» standard for demonstrating clinical benefit Overall Survival Surrogate Endpoints Definition Pros Time from randomization until death from any cause • 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 Regulatory Req. Data Management Analysis Conclusions 6 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction History of (FDA) Drugs Approval § ‘70: Objective (tumor) Response Rate (ORR) § ‘80: More demonstration of clinical benefit: Survival, QoL, Physical functioning, Tumorrelated 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. Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 7 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints 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’ Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management 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 Surrogate Endpoints 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 Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 9 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints 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 Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 10 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction 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. Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 11 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch The concept of Tumor Response and Progression in Solid Tumors Lesion Baseline Timepoint 1 Timepoint 2 Timepoint 3 Timepoint 4 T1 (mm) T2 (mm) T3 (mm) (Sum of Lesion mm) (Response Target Lesions) NT1 New Lesion 10 25 15 50 7 5 15 27 PR Stable No 10 5 20 35 PD Stable No PR PD NA NA 10 15 15 40 SD Stable No SD 5 5 15 25 PR Stable No PR PR EUROPEAN JOURNAL OF CANCER 45 ( 2009 ) 228 –247 Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 12 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Introduction The concept of Progression and Response PD Geneva Branch Overall Survival Decrease with respect to baseline... Surrogate Endpoints Regulatory Req. Data Management PR PR SD …but also increase with respect to prior reduction showing the «re-growth» of the cancer and therefore the failure of the treatment Analysis Conclusions 13 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction The concept of Progression and Response data respT; set SOLD; by USUBJID VISITNUM; retain NADIR BASE; PD if first.USUBJID then do; NADIR=.; BASE=SOLDMM; end; PR 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’; PR else SOLDMM ne . Then NTRESP=‘SD’; else NTRESP=‘NE’; output; Timepoint SOL BA NADIR=min(NADIR,SOLDMM); DMM SE SD run; Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 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 14 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints The concept of Progression and Response in non Solid Tumors (e.g. Acute Multiple Lymphoma) Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions atlasgeneticsoncology.org 15 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Time to Tumor Progression (TTP) Definition Pros Overall Survival Time from randomization until radiolagical tumor progression Surrogate Endpoints • Requires smaller sample size • Not affected by crossover or subsequent therapies • Based on objective and quantitative assessment Data Management 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 Regulatory Req. Analysis Conclusions 16 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Progression Free Survival (PFS) § A variant of TTP where death are also counted as event § In some protocols Death as event can be limited if occurred within ‘xx’ weeks from last tumor assessment (e.g. 12 weeks) § Applicable to study with patients with advanced cancer Disease Free Survival (DFS) § 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 Time to Treatment Failure (TTF) § Time from randomization to discontinuation of treatment for any reason § TTF not reccomended as regulatory endpoint for approval; «a regulatory endpoint should clearly distinguish the efficacy of the drug from toxicity, patient or physichian withdrwal or patient intolerance» Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 17 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Objective Response Rate (ORR) Definition Proportion of patients with tumor size reduction of a predefined amount and for a minumim time period. FDA has defined ORR as the sum of Complete and Partial Responses Pros • Can be assessed in single-arm studies • 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 Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 18 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Efficacy Endpoint – Example 1 § Responder § Progressing Overall Survival Surrogate Endpoints Regulatory Req. Data Management RAN SD SD PR CR PD Death / Alive Analysis Conclusions ORR PFS TTP Response Duration OS 19 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Efficacy Endpoint – Example 2 § Non Responder § Non Progressed § Death Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis RAN SD SD SD Off TRT TTF TTP PFS OS Death Conclusions 20 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Sensitivity Analysis in Tumor Response based endpoint § Use of Per Protocol Population § Include clinical progressions § Different Censoring/Event Date Methods § Backdating event date when tumor assessment are not performed within the 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 Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 21 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Modified Response / PFS Criteria e.g. Prostate Cancer according PCWG2 criteria Where disease progression is defined as the presence of at least one of the following conditions: § Bone Lesions Progression § 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. Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 22 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Other endpoints: Time to symptom progression (TTSP) e.g. TTSP in Lung Cancer Trials as per the Lung Cancer Symptom Scale (LCSS) § Symptomatic progression defined as an increase (worsening) of the average symptomatic burden index (ASBI, i.e., the mean of the six major lung cancer 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.. Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 23 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Quality of Life § Only used in support of primary endpoints § Several ‘validated’ questionnaires available for different indications Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions http://groups.eortc.be/qol/eortc-modules 24 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Duration of Complete Response in Leukemia Considered established endpoint of clinical benefit in leukemia § Less infection § Less Bleeding § Less use of blood product support (e.g. transfusion) Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management 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 25 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Surrogate Endpoints Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 26 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Regulatory Requirements FDA Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics (2007) § General regulatory requirements for efficacy § Detailed description of endpoints and how they can be used in various clinical settings § Pros and Cons § 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 Geneva Branch Introduction Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 27 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Regulatory Requirements Geneva Branch Introduction EMA Guideline on the evaluation of anticancer medical products in man § Guidance on all stages of clinical drug development for the treatment of malignancies § The current version of the guidance cover also noncytotoxic compounds and additional indication for 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. Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 28 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Data Management Issues Geneva Branch Introduction § Tumor Response § Missing Assessments § Consistent Lesions Reporting § Type, Site § Assessment of method used § 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 Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 29 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Analysis Geneva Branch Introduction ORR Analysis with proportion and %CI Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 30 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Analysis Geneva Branch Introduction Survival Analysis § Unadjusted (Kaplan Meier & Log-Rank Test) § SAS Proc LIFETEST § Adjusted (Cox proportional hazards regression model) § SAS Proc PHREG § Selection of covariates to be used depends on the indication and treatment setting. E.g. type and/or response to prior therapy § Examples of other possible covariates Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 31 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Analysis Geneva Branch Introduction Survival Analysis Overall Survival Surrogate Endpoints Regulatory Req. Data Management Analysis Conclusions 32 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Analyisis Subgroup Analysis with Forest Plot Geneva Branch Introduction 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 33 Cytel Inc. - Confidential Efficacy Endpoints in Oncology 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 34 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Conclusions Geneva Branch Introduction § Despite its complexity, “stable” standards exist for efficacy evaluation § Use of efficacy indicators may be different from an indication to another § Managing, deriving and analyzing efficacy endpoints 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 Overall Survival Surrogate Endpoints Regulatory Req. Analysis Data Management Conclusions 35 Cytel Inc. - Confidential Efficacy Endpoints in Oncology Questions New Geneva offices – November 2012 Geneva Branch
