6/23/2010. Publicly Funded Clinical Trials in the Era of Comparative Effectiveness Research. Goals of Therapeutic Clinical Trials

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1 Publicly Funded Clinical Trials in the Era of Comparative Effectiveness Research Richard L. Schilsky, M.D. Professor and Chief Section of Hematology-Oncology University of Chicago Deputy Director, Comprehensive Cancer Center Goals of Therapeutic Clinical Trials Commercial Sponsor Public Sponsor Goals of Therapeutic Clinical Trials Commercial Sponsor Public Sponsor Drug Registration Optimize Treatment 1

2 Goals of Therapeutic Clinical Trials Commercial Sponsor Public Sponsor Drug Registration Optimize Treatment Label Extension Label Extension Goals of Therapeutic Clinical Trials Commercial Sponsor Public Sponsor Drug Registration Optimize Treatment Label Extension Label Extension Expand Market Share Create New Knowledge Goals of Therapeutic Clinical Trials Commercial Sponsor Public Sponsor Drug Registration Optimize Treatment Label Extension Label Extension Expand Market Share Create New Knowledge Create Shareholder Value Improve Public Health 2

3 Why Publicly Funded Trials are Important Compare the effectiveness of various treatment options Combine/compare drugs developed by different sponsors Develop therapies for rare diseases Address optimal dosing Test multi-modality therapies such as radiation therapy in combination with drugs Why Publicly Funded Trials are Important Identify patient and tumor subsets most likely to benefit from interventions Study screening and prevention strategies Focus on survivorship and quality of life Publish negative results Assess cost and costeffectiveness Provide gold standard databases for registry studies Comparing Efficacy 3

4 SWOG Comparison of Lymphoma Treatments Fisher R et al. N Engl J Med 1993;328: ECOG Comparison of 4 Chemotherapy Regimens for NSCLC Schiller J et al. N Engl J Med 2002;346:92-98 Compare Treatments from Different Sponsors 4

5 CALGB/SWOG R A N D O M I Z E FOLFOX 6 or FOLFIRI * *M.D. Choice Bevacizu mab Cetuxima b Bevacizu mab + Cetuxima b CALGB/SWOG Roche R A N D O M I Z E FOLFOX 6 or FOLFIRI * *M.D. Choice BMS Bevacizu mab + Cetuxima b CALGB A randomized phase 3 trial of weekly paclitaxel compared to weekly nanoparticle albumin bound (nab)-paclitaxel or ixabepilone combined with bevacizumab as first or second-line therapy for locally recurrent or metastatic breast cancer R a n d o m i z e Paclitaxel d 1,8,15 q 28d + Bev nab-paclitaxel d 1,8,15 q 28d + Bev Re-stage q 3 cycles until PD Ixabepilone d 1,8,15 q 28d +Bev Pre- Rx D1 C2 D1 C3 D1 Q 3C P D CTC samplin g 5

6 CALGB A randomized phase 3 trial of weekly paclitaxel compared to weekly nanoparticle albumin bound (nab)-paclitaxel or ixabepilone combined with bevacizumab as first or second-line therapy for locally recurrent or metastatic breast cancer R a n d o m i z e Generic Abraxis Re-stage q 3 cycles until PD Bristol Myers Squibb Pre- Rx D1 C2 D1 C3 D1 Q 3C P D CTC samplin g ECOG 2805 ASSURE Trial R A N D O M I Z E Sunitinib Sorafenib Placebo Primary endpoint, DFS patients/ 842 events required for HR 0.80 of either treatment compared to placebo (4.9 to 6.5 y) ECOG 2805 ASSURE Trial Renal Cell Carcinoma post- nephrectom y Stratify by risk group, histology, PS, type of surgery Renal Cell Carcinoma post- nephrectom y Stratify by risk group, histology, PS, type of surgery R A N D O M I Z E Pfizer Bayer Placebo Primary endpoint, DFS patients/ 842 events required for HR 0.80 of either treatment compared to placebo (4.9 to 6.5 y) 6

7 Rare Disease Treatments 5-Azacitidine in MDS Silverman, L. R. et al. J Clin Oncol; 20: Copyright American Society of Clinical Oncology Optimize Dosing 7

8 GOG 172: IP vs IV Cisplatin plus Paclitaxel in Advanced Ovarian Cancer Armstrong D et al. N Engl J Med 2006;354:34-43 CALGB 9741: Comparing Density and Sequence Copyright American Society of Clinical Oncology Citron, M. L. et al. J Clin Oncol; 21: CALGB 9741: Disease-Free S By Density Proportio on Disease-Free Years From Study Entry 2 wksn= 988 Events= 270 Median= Chi-square= NA wksn= 984 Events= 328 Median= p-value= NA

9 CALGB 9741: Overall Survi By Density Propo ortion Surviving Years From Study Entry 2 wksn= 988 Events= 220 Median= Chi-square= NA 3 wksn= 984 Events= 266 Median= p-value= NA Combine Treatment Modalities Intergroup Gastric Adjuvant Trial Macdonald J et al. N Engl J Med 2001;345:

10 RTOG 9111 Larynx Preservation Forastiere A et al. N Engl J Med 2003;349: Identify Patient Subsets Adjuvant Paclitaxel for Breast Cancer Henderson, I. C. et al. J Clin Oncol. 2003;21:

11 Copyright restrictions may apply. 6/23/2010 Who Benefits from Adjuvant Paclitaxel? Adjuvant paclitaxel primarily benefits women with ER negative and/or Her2 positive breast cancer Hayes D et al. N Engl J Med 2007;357: Study Prevention Strategies STAR Trial Breast Cancer Cumulative Incidence of Invasive and Noninvasive Breast Cancer Invasive Cancer Non Invasive Cancer Vogel, V. G. et al. JAMA 2006;295:

12 Copyright restrictions may apply. Copyright restrictions may apply. Copyright restrictions may apply. 6/23/2010 STAR Trial Adverse Events Cumulative Incidence of Invasive Uterine Cancer and Thromboembolic Events Uterine Cancer Thromboemb olism Vogel, V. G. et al. JAMA 2006;295: STAR Trial Breast Cancer Cumulative Incidence of Invasive and Noninvasive Breast Cancer 2010 Update: Tamoxifen superior to raloxifene in reducing risk of invasive breast cancer, RR 1.24, p=0.01 Invasive Cancer Non Invasive Cancer Vogel, V. G. et al. JAMA 2006;295: STAR Trial Adverse Events Cumulative Incidence of Invasive Uterine Cancer and Thromboembolic Events 2010 Update: Tamoxifen increases risk of invasive uterine cancer (RR 0.55, p=0.003) 003) and of thrombotic events (RR 0.75, p=.007) Uterine Cancer Thromboemb olism Vogel, V. G. et al. JAMA 2006;295:

13 Publish Negative Results CALGB 9082 High Dose Chemotherapy for High Risk Breast Cancer Peters, W. P. et al. J Clin Oncol; 23: Copyright American Society of Clinical Oncology CALGB 9082 Outcomes Peters, W. P. et al. J Clin Oncol; 23: Copyright American Society of Clinical Oncology 13

14 Assess Cost Effectiveness BR.21: Erlotinib vs. Placebo in Advanced NSCLC-Overall 100 Survival HR=0.70 ( ) Stratified log rank p< centage Perc 20 0 Erlotinib Placebo Time (months) At risk Erlotinib Placebo Shepherd F, 00 et al. N Engl J Med 2005 BR.21 Cost Effectiveness Median overall survival benefit: 2 months Incremental cost effectiveness ratio: $94,638/year of life saved ICER for EGFR amplified subset: $33,353 ICER for Never-smoker subset: $39,487 Bradbury, et. al. JNCI 102:1-9,

15 Economic Evaluation: Implications of K-ras Determination HR =.77 HR =.55 All Patients: CEA ratio: $199,742 / LYG CUA ratio: $299,613 / QALY K-ras Wild-type Patients: CEA ratio: $120,061 / LYG CUA ratio: $186,761 / QALY Mittmann, JNCI 2009 Provide Gold Standard Databases Practical Problem Most people who are diagnosed with cancer are elderly Most people who are on clinical trials of anti-cancer therapy are not elderly The risks and benefits of anti-cancer therapies in the elderly is uncertain 15

16 CALGB-Medicare Data (N=175) Unique ID# CALGB DATA Drug DFS CTC Toxicities MEDICARE DATA Part A MEDPAR file Part B NCH file OUTPT file DFS According to Data Source Days Since Enrollment CALGB CMS Advantages of Groups Access to large, diverse (unique) patient populations Research resources: administrative and data management centers; specimen e repositories; es; reference laboratories; image archives Quality assurance procedures in place Staff and investigator training and mentoring Study results definitive 16

of complex data sets difficult Competing

17 Disadvantages of Groups Cumbersome bureaucracy with review at many levels Years to launch and complete may limit relevance Results may not be reproducible in real world patients Uniform tissue handling and acquisition of complex data sets difficult Competing priorities with industry Time to Activation of Cooperative Group Phase III Trials ( ) Review/Revision of Phase III Protocols ( ) 17

18 OEWG Target Timeline 300 days Timeline pauses if industry negotiations cause delay Feedback on major challenges in 5 days If registration trial, FDA review in 30 days Conc ept revie w Concept revision/ review cycles Protocol development Proto Protocol col revision/review revie cycles w Forms development Time 0 0 (days) Timeline excludes IRB, contracting, drug supply Protocol terminated if not activated in two years IOM Report on CER Comparative effectiveness research is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat and monitor a clinical condition or to improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers and policy makers to make informed decisions that will improve healthcare at both the individual and population levels." Characteristics of CER CER has the objective of directly informing a specific clinical decision from a patient perspective or a health policy decision from the population perspective. CER compares at least two alternative ate at e interventions, e to each with the potential to be "best practice". CER describes results at the population and subgroup levels. CER is conducted in settings that are similar to those in which the intervention will be used in practice. 18

Cooperative Groups and CER Specialists from all oncology modalities and scientific disciplines Studies broadly accessible to patients through national networks Investigator-initiated trials that

19 Cooperative Groups and CER Specialists from all oncology modalities and scientific disciplines Studies broadly accessible to patients through national networks Investigator-initiated trials that directly compare therapies Collect cancer outcomes and QoL data High quality biospecimens to identify/assess subsets CER Strategies Pragmatic clinical trials Prospective observational studies Prospective or retrospective registries Meta analyses Literature review Technology assessments Pragmatic Clinical Trials Brass, EP, Clin Pharm Ther 87:351,

20 The Case of Laparoscopic Colectomy COST Trial Recurrence The Clinical Outcomes of Surgical Therapy Study Group. N Engl J Med 2004;350: COST Trial Overall Survival The Clinical Outcomes of Surgical Therapy Study Group. N Engl J Med 2004;350:

J Clin Oncol; 25:3061-3068 2007 Copyright American Society of

21 CLASSIC Trial 3 Year Overall Survival Colon cancer Rectal cancer Jayne, D. G. et al. J Clin Oncol; 25: Copyright American Society of Clinical Oncology Laparoscopic Colectomy Can Work! Laparoscopic Colectomy Can Work! But Does It? 21

22 Copyright restrictions may apply. Copyright restrictions may apply. 6/23/2010 Dissemination of LapCol Survey of 1266 members of Royal College of Physicians and Surgeons of Canada 462 (67% of respondents) perform colorectal surgery; 54% perform laparoscopic colorectal surgery Uptake related to fewer years in practice, male sex, practice in Quebec, university hospital affiliation, MIS fellowship Barriers: lack of OR time and formal training Mooloo, et. al., Canadian J. Surg. 52:455, 2009 Outcomes for Laparoscopic-Assisted Colectomy Compared with Open Colectomy for Cancer Bilimoria, K. Y. et al. Arch Surg 2008;143: Survival Comparing Laparoscopicassisted Colectomy with Open Colectomy LAC Bilimoria, K. Y. et al. Arch Surg 2008;143:

Arch Surg 2008;143:832-840. Conclusion Laparoscopic colectomy can work Laparoscopic colectomy does work But not as well as it can!

23 Copyright restrictions may apply. 6/23/2010 Comparison of Laparoscopic-Assisted Colectomies in the NCDB Population and the COST Prospective Randomized Controlled Trial Bilimoria, K. Y. et al. Arch Surg 2008;143: Conclusion Laparoscopic colectomy can work Laparoscopic colectomy does work But not as well as it can! Publicly Funded Trials in the Era of Comparative Effectiveness Research Publicly funded clinical trials are essential to: - directly compare drug treatments; - develop combined modality treatments; - study chemoprevention and rare diseases; - identify patient subsets; - study cost and cost-effectiveness Cooperative groups are wellpositioned to conduct comparative effectiveness research 23

The Clinical Research E-News

ISSUE 18: September 9, 2009 New Activations: The Clinical Research E-News SWOG0518, Phase III Prospective Randomized Comparison of Depot Octreotide Plus Interferon Alpha Versus Depot Octreotide Plus Bevacizumab