1. Comparative Effectiveness Research : Rethinking Therapeutic Evaluation in Chronic Diseases Ph Ravaud

2. Therapeutic Evaluation of Chronic diseases Today : mainly RCts and Meta-Analysis (one drug ) Tomorrow -RCTs -Meta-analysis and Network Meta-analysis (all drugs for a specific disease) -Observational Data

3.  Too slow  Too expensive  Doesn’t answer many critical questions ( or doesn’t answer questions relevant for physicians ( Short term, inadequate comparator, side effects)  Otherwise its great ( RCTs are the best way to obtain groups of patients comparable for known and unknown prognostic factors )

4. Applicability or generalizability of trials Patients included are not representative of the patients treated in usual care (trial patients are younger and with less co-morbidities) Setting is not representative (centers are highly selected) Treatments are evaluated mainly according to the principle “one size fits all”

5. Critical Knowledge Gaps The paradox - 18,000 RCTs published each year - more than 350,000 RCTs available Despite that available evidence remains limited or of poor quality

6. Much of Care Today is Not Based on Scientific Evidence Robert Califf, IOM Meeting on Evidence-based Medicine, December 2007 Less than 20% of AHA/ACC heart disease management recommendations are based on a high level of evidence and over 40% are based on the lowest level of evidence AND proportion of recommendations with high evidence levels has not increased over time

7. From Meta-analysis to Network Meta-analysis One treatment All treatments available for a disease Thousands/y Less than 50/y

8. Network meta-analysis Intervention C Intervention A Intervention E Intervention F Intervention B Intervention D Combining direct and indirect evidence

9. Biologic Treatment in Rheumatoid Arthritis: Ongoing Trials -Only 5 head to Head trials - Ongoing Trials recruiting patients failing to respond to Methotrexate and with high disease activity

10. Cost of RCTs: an example 18,000 patients Total crf pages 1.8 millions Total crf variables 2.5 Billions Total number of queries 600,000 Cost 700 millions Euros Treatment effects decrease over time, number of patients required mecanically increase

11. Unrealistic to expect head-to-head RCTs addressing all 2-by-2 comparisons Number of competing interventions Number of pair-wise comparisons 4 6 5 10 6 15 7 21 8 28 9 36 10 45 11 55 12 66

12. It is an unrealistic expectation that we will have randomized trials for every intervention and its combinations in every patient subgroup ( for example if for a disease we have 20 different treatment options and 3 different subgroups of patients, we need theoritically at least 470 head to head trials !) We need Effectiveness evidence in a timely manner. Randomized trials take time to conduct Therefore, 85% of the CER evidence is from non- experimental data!* * Academy Health Report June 2009

13. Transparency of clinical trials Reporting guidelines Clinicaltrial.gov 2005 FDA amendment act 2007

14. Consort Extensions Too many extensions Too many reporting guidelines Editors do not really implement the guidelines Quality of reporting remains poor

15. Trial registration mandatory since 2005 ( International Committee of Medical Journal Editors) 15

16. 16 Impact of dissemination bias Separate meta-analyses of the FDA and journal data sets show that the increase in effect size ranged from 11 to 69% for individual drugs and was 32% overall Turner et al. NEJM 2008 16

17. Selective Dissemination Bias

18. FDA Amendment Act US Federal law enacted in 2007 mandates registration and results reporting for clinical trials of drugs, biological products and devices at clinicaltrial.gov Study sponsors or PI are requires to report summary results information within 1 year of completing data collection for teh prespecified primary outcome

21. 21 Levels of “Transparency” Zarin DA, Tse T.. Science. 2008 Mar 7;319(5868):1340-2. 21