Clinical interpretation and validity of trials: when do they become practice changing

Transcription

1 Clinical interpretation and validity of trials: when do they become practice changing Alberto Sobrero Oncologia Medica 1 Ospedale Policlinico San Martino Genova Italy

2 Clinical trials: the 5 phases and their actors The clinical investigators and the statisticians Design Conduct Analysis Reporting Interpretation The patients and an army of people

3 INTERPRETATION SO WHAT?

4 Clinical interpretation of new data Are these data true? Are they relevant? Are they practice-changing?

5 Clinical interpretation of new data 1.Are these data true? Internal validity methodology Identification primary aim Endpoint Statistical plan Randomization procedures ITT analysis Internal consistency results External consistency results Biological and clinical plausibility logic

6 Clinical interpretation of new data: known problems with FIRE III FIRE III 1. Are these data true? Internal validity X Internal consistency X External consistency Plausibility 2. Are they relevant? Size of the delta benefit External validity/generalizability Degree of innovation 3. Are they practice-changing? True and relevant enough feasible affordable

7 Clinical interpretation of new data 1. Are these data true? Internal validity Internal consistency External consistency Biological and clinical plausibility 2. Are they relevant? Size of the delta benefit External validity/generalizability Degree of innovation 3. Are they practice-changing?

8 2. How relevant? Size of benefit 1. Which endpoints? OS PFS RFS RR QOL 2. How were these expressed? Median, HR, % at. 3. Under which condition? 4. Which toxicity? 5. How much inconvenience? 6. Overall magnitude of benefit

9 The hierarchy of endpoints of treatment in advanced cancer Cure OS RFS (CR) QOL Sx palliation PFS PR SD

10 The four ways to assess OS benefit OS BENEFIT HR and gain in MST Absolute and proportional gain in long term OS (2 3 years) Small benefit for many Large benefit for few Sobrero et al Clin Ca Res 2015

11 The four ways to assess OS benefit OS BENEFIT HR and gain in MST Absolute and proportional gain in long term OS (2 3 years) Small benefit for many Large benefit for few Hard to understand Hard to communicate to pts Highly desirable, easily communicated, but rarely available Sobrero et al Clin Ca Res 2015

12 2. How relevant? Size of benefit 1. Which endpoints? OS PFS RFS RR QOL 2. How were these expressed? Median, HR, % at. 3. Under which condition? 4. Which toxicity? 5. How much inconvenience? 6. Overall magnitude of benefit

13 2. How relevant : How generalizable? EXTERNAL VALIDITY Pt characteristics Comparator arm Therapeutic regimen Compliance

14 Clinical interpretation of new data: known problems with FIRE III and CALGB FIRE III CALGB 1. Are these data true? Internal validity X Internal consistency X External consistency Plausibility 2. Are they relevant? Size of the delta benefit External validity/generalizability X Degree of innovation 3. Are they practice-changing? True and relevant enough feasible affordable

15 Clinical interpretation of new data 1. Are these data true? Internal validity Internal consistency External consistency Biological and clinical plausibility 2. Are they relevant? Size of the delta benefit External validity/generalizability Degree of innovation 3. Are they practice-changing? True and relevant enough feasible affordable

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17 Prospective Pooled Analysis of Six Phase III Trials Investigating Duration of Adjuvant Oxaliplatin-based therapy (3 vs. 6 months) for Patients with Stage III Colon Cancer: The IDEA (International Duration Evaluation of Adjuvant Chemotherapy) Collaboration Qian Shi, Alberto F. Sobrero, Anthony F. Shields, Takayuki Yoshino, James Paul, Julien Taieb, Ioannis Souglakos, Rachel Kerr, Roberto Labianca, Jeffrey A. Meyerhardt, Franck Bonnetain, Toshiaki Watanabe, Ioannis Boukovinas, Lindsay A. Renfro, Axel Grothey, Donna Niedzwiecki, Valter Torri, Thierry Andre, Daniel J. Sargent, Timothy Iveson

18 Primary Efficacy Analysis Duration 3 Months 6 Months Percent Without Event Years from Randomization Presented by: Qian Shi, PhD on behalf of IDEA collaborators

19 IDEA: ADVERSE EVENTS 3 vs 6 NEURO 2 to 6 times lower DIARRHEA 20% to 30% lower! MUCOSITIS 2 times lower H+F SYN 2 to 3 times lower

20 The hard road to data interpretation: IDEA ASCO, june 1, 2017 : risk based JAPAN, july 10, 2017: regimen based ESMO, sept 7, 2017: pt based!!!!!

21 From clinical evidence to daily practice Clinical trials General principles Personalized decisions

22 From clinical evidence to daily practice Clinical trials General principles Guidelines Personalized decisions

23 From clinical evidence to daily practice Clinical trials and guidelines practice most efficacious deltas, p values best.

24 From clinical evidence to daily practice Clinical trials and guidelines practice most efficacious deltas, p values best.

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