1. Effective Presentation of Study Results How are RCTs presented in abstracts & publications? and Some things to consider in your own presentations NCIC CTG New Investigators Course October 2009 Christopher Booth MD FRCPC Queen’s University Cancer Research Institute The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

2. Outline: Part I How are RCTs presented in abstracts & publications? Evolution of endpoints and perception of benefit in oncology RCTs over time What results are clinically meaningful? RCTs closed early for benefit How are RCTs presented at conferences? The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

3. Outline: Part II Issues to consider when presenting your study results… Audience Preparation Key messages Fancy PowerPoint Summary The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

4. How are RCTs presented in abstracts & publications? Part I How are RCTs presented in abstracts & publications? The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

5. 1. How have endpoints and perception of benefit evolved in oncology RCTs?

6. Study Design Overview of all RCTs systemic therapy in breast, NSCLC, colorectal cancer 1975-2004 6 major journals: JCO, Cancer Treatment Reports, JNCI, NEJM, Lancet, JAMA Data abstraction using standardized forms and methodology The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

7. Temporal Trends 1975-841985-941995-2004P value (trend) Total RCTs47 (15%)107 (33%)167 (52%)<0.0001 Breast RCTs19 (40%)53 (50%)81 (49%)0.475 NSCLC RCTs23 (49%)29 (27%)39 (23%)0.002 CRC RCTs5 (11%)25 (23%)47 (28%)0.017 321 RCTS over three decades involving >170 000 patients The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

8. Study Participants 1975-841985-941995-04P (trend) International26%28%52%<0.0001 Co-op group28%56%43%0.661 Sample size100249446<0.0001 Accrual time30 mo41 mo33 mo0.93 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

9. Statistics 1975-841985-941995-04P (trend) 1º endpoint Time to event39%72%78%<0.0001 RR54%25%14%<0.0001 ITT analysis Any70%87%93%<0.0001 33% of RCTs in 1995-2004 did not clearly identify primary endpoint The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

10. Sponsorship 1975-841985-941995-04P (trend) Government60%62%31%<0.0001 Industry4%23%57%<0.0001 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

11. Effect Size and Conclusions 1975-19841985-19941995-2004 Median HR (95%CI)1.4 (1.0-2.3)1.2 (1.0-2.4)1.2 (1.1-1.3) P<0.05 for primary EP23%30%42% Strong endorsement31%39%49% 1. Effect size stable over time 2. Modern RCTs more likely to have p<0.05 3. Modern authors more likely to call their trial “positive” The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

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13. Key Findings 1.Increase in number and size of RCTs 2.More international trials, faster accrual 3.Shift in primary endpoint from RR to survival EPs 4.Major shift towards for-profit sponsorship 5.Effect size has remained stable over time 6.Authors of modern RCTs more likely to endorse experimental arm 7.For-profit sponsorship and p<0.05 are independently associated with strong endorsement of experimental arm The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

14. 2. Are these results clinically meaningful? Clinically Relevant Endpoints Patients define a useful therapy as one that… increases survivalOR improves QOL/reduces symptoms of cancer Reassuring shift from RR to survival endpoints Increasing use and recognition of PROs Gemcitabine Pancreas TAX 327 HRPC The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

15. Clinically Relevant Endpoints Current standards for analyzing QOL and symptom control need improvement 112 RCTs for advanced cancer 19% established a priori hypothesis 21% defined minimal differences in QOL scores that were clinically meaningful Increasing use of surrogate endpoints (DFS, PFS) Joly et al Ann Oncol 2007 Sargent et al JCO 2005 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

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17. Clinically Relevant Endpoints Clinical benefit (CB) in trials of pancreas cancer composite improvement in pain, weight, performance status CB now widely (mis)used to describe PR/CR/SD 71 trials in JCO since 1997 28% used patient-centered definition 72% referred to objective tumor measurements Burris et al JCO 1997 Ohorodnyk et al ASCO 2009 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

19. 3. RCTs Closed Early for Benefit Korn et al JCO 2009 Sargent JCO 2009 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

20. Korn et al JCO 2008 27 NCI co-operative group trials that were closed early for benefit Of the 18 trials with follow-up available, initial magnitudes of benefit were preserved in 17 (94%) trials “…the system is working” Dan Sargent JCO 2008 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

21. Booth, Meyer et al Under Review Literature search identified 62 RCTCEB –Primary endpoint not explicitly stated in 19% –ITT all randomized patients in only 66% Most trials open to accrual (45/62, 73%) at the time of closure. Formal IA performed in 56 (90%) trials –75% (42/56) planned and 79% (44/56) reported stopping rules. Trials on average accrued 73% of the planned sample size. Follow-up reports for 18 (29%) RCTCEB show that results and conclusions were maintained.

22. 4. How are RCTs presented at conferences? The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

23. Trial Reporting: NFAs 138 RCTs published 2000-2004 –197 corresponding abstracts 1990-2004 Results were stated or implied to be non-final analyses in 86 abstracts (44%) 124 abstracts (63%) discordant with article Conclusions substantively different in 17 (10%) The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology Meeting abstracts often include NFAs and are often discordant with mature publication

24. Bias in Oncology RCTs Publication Bias 510 RCTs presented at ASCO 1989-1998 26% were not published within 5 years 81% of trials with p 0.05 This should improve with mandatory trial registration Krzyzanowska JAMA 2003 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

25. Bias in Oncology RCTs Sponsorship Bias Multiple studies have demonstrated that RCTs sponsored by industry are more likely to be “positive” than non-industry trials Reasons are likely complex and multifactorial Djulbegovic Lancet 2000 Booth JCO 2008 Peppercorn Cancer 2007 The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

26. ACS 2008 Statistics

27. Part I: SUMMARY 1. Major changes in cancer treatment/research since 1970s Patient outcomes have improved RCT methodology and reporting are improving Trials are larger, complex, stronger correlative component What constitutes a “positive trial” has changed 2. It is critical to keep in patient-centered outcomes in focus at every step of the drug development pathway 3. Be critical in the way you interpret results of RCTs in published form and at conferences The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

28. Acknowledgements Drs. Ralph Meyer and Bill Mackillop NCIC Clinical Trials Group Queen’s University Cancer Research Institute Kingston, Ontario Drs. Ian Tannock and Monika Krzyzanowska Princess Margaret Hospital, Toronto, Ontario The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

29. Part II: Things to consider when presenting your own study results The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology

30. Topics for Discussion 1.Audience 2.Preparation and timing 3.Key messages 4.Fancy PowerPoint (?) 5.Summary 6.Time for discussion The Cancer Research Institute at Queen’s University Division of Cancer Care and Epidemiology