1. “ Understanding Progression-free Survival” Thoughts around some clinical and methodological issues and possible regulatory consequences EFSPI, Basel, June 2010

2. Clinical issues Is delaying PFS per se of value? –Yes, tumour progression heralds symptomatic progression. Patients rarely die of non-progressing tumours. If you compare AB and A, is an event of progression on AB the same as an event on A? –Probably not, at least progression on AB signifies resistance to both A and B BJ, June 20102

3. Methodological Issues Independent review (IR) vs. Investigator’s assessment (IA) –Poor concordance –Investigator events are censored –Informative censoring –Time to event is prolonged based on IR data BJ, June 20103

4. Methodological Issues Patients withdrawn prior to event, if not followed off therapy until event –Irrespective of cause –In many cases informative censoring –Direction might be hard to understand Only “non-progressing” and tolerability problems Open label BJ, June 20104

5. Regulatory Considerations AB vs. B and the progressing tumour –Focused on introduction of maintenance therapy and compounds designed to delay premalignant disorder to progress to malignant disorders. –(At least) ORR on next-line therapy – How to compare? –If we could assess all patients enrolled, no problems –But a sub-set? (e.g. 40% in the exp. arm vs. 55% in the control) and if the ORR tend to be lower in the exp. arm? BJ, June 20105

6. Tumour Progression Angiogenesis inhibitors (AI)? –If the PFS benefit is e.g. 3 months, survival benefit tends to be similar –Does this hold true for AI? –Non-clinical data indicate that tumour characteristics may change towards a more “metastatic behaviour” –PFS is a composite –At least to look into proportion of events new lesions, increased size of existing lesions, deaths BJ, June 20106

7. PFS as an informative composite Targeted drugs and “new toxicities” –Hard to differentiate deaths due to cancer and complications related to therapy. –Events of death in the PFS composite BJ, June 20107

8. Primary analyses? IR vs. IA IR mainly to confirm absence of bias. IA as primary analysis. –Should we recommend a confirmatory round of imaging after investigator assessed progression? BJ, June 20108

9. ”ITT” Main concern, informative censoring. Follow patients until PFS event on or off study therapy or next line therapy. Primary or secondary/sensitivity analysis? – To me no major issue BJ, June 20109

10. Summary ”PFS” has served us reasonably well But –The definition of ”progression” is rather arbitrary (WHO, RECIST) –The meaning of ”progression” is likely to differ between treatment arms –It is a composite where the components are rarely analysed and discussed –The otherwise standard ITT approach has been ”forgotten” – We have accepted a method leading to informative censoring as ”gold standard” BJ, June 201010

11. Back-up topics Interim analyses –NfG – to be done only when data are ”mature” Treatment effect might differ btweeen those with good and bad prognosis. ”Mature” when there is a ”sufficient” number of events after the median Has never been challenged from a statistical perspective Still we see this in many ScA procedures BJ, June 201011

12. Back-up topics When OS and when PFS? –NfG – OS when the expected OS after progression is short and no known active next-line therapies –Haematological Appendix – focuses on B/R in the planning – if major difference in toxicity is expected favouring the control – OS – Class of compounds of importance??? BJ, June 201012

13. Revision of the NfG foreseen Concept paper Official comment on CP to EMA Personal comments on this presentation/topics discussed today and on the current NfG and appendices may be directly sent to me Bertil.Jonsson@mpa.se BJ, June 201013