Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials

1. Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials Benny Zee Centre for Clinical Trials The Chinese University of Hong Kong

3. Centre for Epidemiology and Biostatistics Centre for Clinical Trials Cochrane Centre International Cooperative Group Studies Academic Research Industry Studies Medical Research Support in CUHK Medical Research Support Committee (MRSC)

5. Missions Statement for the Centre for Clinical Trials (CCT) • Missions include: • Provide methodological advice in clinical trials • Regulatory submission assistance and contract negotiation with industry • Study and data management support • Act as a contract research organization (CRO) in the management of clinical trials • Academic single-institution trials • Multicentre cooperative group trials • Industry trials

6. Any differences between a CRO and CCT? Commercial Benefits Medicine & Therapeutics Obs & Gyn Other CRO’s Comm & Family Med Pediatrics Chem Path, ACP Microbiology Centre for Clinical Trials Surgery Benefit Community Clinical Research Multicentre Trials Diagnostic Radiology …others Clinical Oncology Big Pharma & Biotech Companies, NCI US, etc.

7. Services of CCT • Support Faculty with sound design methodology and analysis of clinical trials • Provide infrastructure for conducting clinical trials • Provide Good Clinical Practice (GCP) training for personnel from pharmaceutical and biotechnology companies, hospitals and clinical trials centers in Asia • Promote clinical trials methodology through research in biostatistics methodology, data management, bioinformatics, etc.

8. Lunch Time Seminar Series • Surrogate Outcomes and Handling Multiple Endpoints in Clinical Trials • Repeated Measures in Randomized Controlled Trials (Oct 15) • Other suggestions of Topics, Speakers, Joint Events, etc? • Please contact me, Shirley Xu or Jennifer Mao

9. Introduction to Surrogate Endpoint • Why do we use surrogate endpoint? • Can be measured earlier • Convenient or less invasive • Can be measured more frequently • Can accelerate the approval process • Advantages: • May reduce the size of clinical trials • May shorten the duration of clinical trials • May reduce the cost of clinical trials

10. Endpoints inappropriately characterized as surrogates • Quality of life • It is an outcome measure (not a surrogate endpoint) • Morbidity scale • It is a clinical benefit endpoint (not a surrogate endpoint)

11. Endpoints For Clinical Trials • A surrogate endpoint does not directly measure any clinical benefit to patient, it only predicts the outcome • A mixed surrogate/clinical benefit endpoint directly measures significant benefit to patient and predicts an additional, more substantial benefit to patient • A clinical outcome directly measures substantial clinical benefit to patient

12. When is the use of surrogate endpoints justified? • Screening • For promising new therapies • Evaluation of biological activity in phase I/II trials • Caution in using surrogate endpoints: • Using biological markers as a surrogate endpoint, one may obtain misleading false positive or false negative conclusion when assessing treatment effects of longer term clinical outcome • Requirements: • Before a surrogate endpoint can replace a primary endpoint, it must be formally validated

13. Surrogate Marker S Clinical Outcome T Treatment Z Relationships between treatment, surrogate and clinical outcome

14. Surrogate Marker S + + Clinical Outcome T Treatment Z o Other Biological Processes Ideal treatment, surrogate and clinical outcome relationships • + positive effect • negative effect • o no effect

15. 2. Surrogate marker may be strongly predictive of the clinical outcome 1. Treatments are chosen based on their anticipated effect on CD4 count CD4 Lymphocyte Count AIDS Event or Death AZT vs control 3. Treatments may also affect other biological processes 4. Clinical outcome may be affected by other biological processes Other Biological Processes Affecting Prognosis Problems in Surrogate Endpoint: Example in HIV

16. + + Treatment Effect Cancelled - + Example in HIVFalse Positive Case 2. Surrogate marker may be strongly predictive of the clinical outcome 1. Treatments are chosen based on their anticipated effect on CD4 count CD4 Lymphocyte Count AIDS Event or Death AZT vs control 3. Treatments may also affect other biological processes 4. Clinical outcome may be affected by other biological processes Other Biological Processes Affecting Prognosis

17. Treatment effect Not detected + + Example in HIVFalse Negative Case 2. Surrogate marker may be strongly predictive of the clinical outcome 1. Treatments are chosen based on their anticipated effect on CD4 count CD4 Lymphocyte Count AIDS Event or Death o AZT vs control 3. Treatments may also affect other biological processes 4. Clinical outcome may be affected by other biological processes Other Biological Processes Affecting Prognosis

18. Cardiac Arrhythmia Suppression Trial (CAST) • Patients with myocardial infarction • Ventricular arrhythmia is a risk factor for subsequent sudden death • Arrhythmia was considered a surrogate endpoint • Encainide and flecainide are known effective anti-arrhythmic drugs • Approved by FDA • Their effect on survival was not established • CAST randomized more than 2000 myocardial infarction patients to receive either anti-arrhythmic drug or placebo

19. Cardiac Arrhythmia Suppression Trial (CAST) • Results • Death rates of the study treatment arm nearly tripled that of the placebo arm • Conclusion • This study had shown that a false positive conclusion can be made with a surrogate endpoint • FDA prematurely released antiarrhythmic drugs for patients with myocardial infarction due to the use of surrogate endpoint

20. Chronic Granulomatous Disease (CGD) • Background • Childhood disease, disorders in immune system • Phagocytes ingest microorganism but fail to kill them • International CGD Cooperative Group • Randomized patients between interferon- and placebo in a double-blind fashion • Superoxide measurements and bacterial killing can be used as surrogate endpoints • After a lengthy debate, rate of infection was finally used as primary endpoint • Individual follow-up extended from 1-month to 1-year

21. Chronic Granulomatous Disease (CGD) • Results • Interferon- significantly reduced the rate of recurrent of serious infections at interim analysis using O’Brien-Fleming rule • FDA approved the use of Interferon- in CGD patients • There were no significant differences between treatment arms on surrogate biological markers, superoxide measurements and bacterial killing • Reliance on surrogate markers would have led to false negative conclusion

22. Prentice’s Definition • A “surrogate” endpoint for which a test of the null hypothesis of no relationship to the treatment groups is also a valid test of the corresponding null hypothesis based on the true endpoint • Let T and S be random variables denote true and surrogate endpoints respectively, Z be indicator variable for treatment, and f(.) denotes p.d.f. such that S must satisfy: f(S|Z) = f(S)  f(T|Z) = f(T)

23. Validation • Criteria for checking if a triplet (T,S,Z) fulfills the definition are: (1)f(S|Z)  f(S), Z is significant on S (2)f(T|Z)  f(T), Z is significant on T • However, this validation is impossible since one may fail to detect differences due to lack of power • Other sufficient conditions: (3) f(T|S)  f(T), S is informative about T (4) f(T|S,Z) f(T|S), S fully captures the effect of Z on T

24. Comments on Validation • The condition f(T|S,Z) = f(T|S) • requiring the surrogate endpoint S fully capture the effect of treatment on the true endpoint T • so restrictive that this condition rarely holds in clinical application • even in a rare setting that data on treatment Z allow us to view S as a valid surrogate for T, we cannot extrapolate this to a new treatment Z* • Auxiliary variable • S provides additional information if it strongly correlates with outcome T • It can be used to increase efficiency

25. Freedman’s Proportion Explained (PE) • The Prentice’s criteria (1)-(3) are provided by tests of significance of parameters , , and  Sj|Zj = S + Zj + Sj Tj|Zj = T + Zj + Tj Tj|Sj =  + Sj + j • PE = 1 – (S/) • where  is the estimate of the effect of Z on T • and S is the estimate of the effect of Z on T after adjustment for S Tj|Zj,Sj = T + SZj + ZSj + Tj

26. Surrogate Endpoints in HIV and AIDS Trials

27. HIV Infection & AIDS • Early stages HIV infection • Used progression of disease rather than survival as endpoint • A decline of CD4+ cells count to less than 0.5 x 109/L has been used as endpoint • Advanced disease • Mortality remained as primary endpoint • Biological markers • e.g. CD4+

28. How can we assess the validity of a potential surrogate marker for trials of AIDS treatment? • A strong biological rationale • The marker value at a given time is strongly predictive of ultimate survival • The effect of treatment on the surrogate endpoint will reliably predict the effect of treatment on survival

29. Example: Concorde Trial • Double-blind randomized trial for asymptomatic HIV-infected individuals: • Imm: immediate zidovudine (AZT) • Def: deferred AZT until AIDS-related complex • Targeted sample size = 2000 • Endpoints: • Progression, haemoglobin, total white cells, total and CD4+ lymphocytes, CD4 percentage, CD4/CD8 ratio, CD8 cells, CD8 percentage, CD3+ cells, neutrophils, monocytes, platelets, p24 antigen, 2 microglobulin and weight

30. Patient Characteristics

31. Reasons Stopped Treatment

32. Proportion of Total Time Spent on AZT

33. Adverse Events

34. Time to reduction of CD4 to < half of baseline or time to AIDS or death

35. Change in CD4 counts

36. Concorde Trial: Summary • Final Results on Primary Clinical Endpoint • No significant difference between arms with respect to time-to-progression and survival • More toxicity in the Immediate arm • Do not encourage early use of AZT in symptom-free HIV infected adults • Results on immunological markers • In favor of Immediate arm: • CD4 cells, CD4 percentage, CD4/CD8, CD3 percentage, platelets • It would have been a false positive conclusion if based on surrogate endpoint

37. Surrogate Endpoints in Cancer Trials

38. Advanced Colorectal Cancer Meta-analysis • A Meta-analysis of 3791 patients • First-line treatment with standard bolus intravenous fluoropyrimidines versus experimental treatment • 5FU+LV • 5FU+methotrexate • 5FU continuous infusion • Hepatic-arterial infusion of floxuridine • To evaluate the relationship between tumor response and survival

39. Advanced Colorectal Cancer Meta-analysis • Tumor response • CR: disappearance of all detectable tumor • PR: decrease of 50% or more in the tumor surface area without new lesion • SD: decrease of less than 50% or increase of less than 25% • PD: increase of more than 25% • Tumor surface area is calculated by sum of the products of the largest perpendicular diameters • Best overall response for each patient was used as surrogate endpoint

40. Response odds ratios for Experimental vs Bolus fluoropyrimidines N=# patients; O=observed # of response; E=expected # response; V=variance

41. Survival hazards ratios N=# patients; O=observed # of response; E=expected # response; V=variance

42. P=0.42

43. Survival hazards ratios by PS and Response

44. Treatment effect on survival vs. response

45. Summary • Increase response rate  increase survival? • The benefits of experimental treatment are more obvious in tumor response than survival • No survival benefit from treatment within any tumor response categories • The survival benefit in favor of experimental arm was due to higher tumor response rates • Treatment effect on survival associated with treatment effect on tumor response, but with a low coefficient of determination 0.38, i.e., only 38% variation was explained • Benefit in tumor response does not imply survival benefit

46. Final Remarks • FDA review of first-line therapy for advance colorectal cancer • Required evidence of survival advantage • Control arm using 5-FU & leucovorin (LV) has response rate of 15-20% • Experiences of two new agents reviewed by FDA • Regarding the use of surrogate endpoint

47. Irinotecan Example • Irinotecan vs best supportive care as second-line treatment • Induced partial responses in 10-15% of patients who had not responded to 5FU/LV • Demonstrated survival advantages as second-line therapy in an European trial • FDA approved for use as second-line after 5FU/LV

48. Irinotecan Example • USA and Europe done studies on first-line treatment • comparing Irinotecan/5FU/LV versus 5FU/LV • Both studies showed significant improvement in response rate (35% and 39% for irinotecan-containing regimen vs. 21% and 22% for control) • Modest but significant improvement in survival • Irinotecan/5FU/LV was approved by FDA in Apr 2000

49. Oxaliplatin Example • First-line therapy studied in Europe • Response rate (51% for oxaliplatin/5FU/LV vs 23% for 5FU/LV) • Did not show significant improvement in survival • Not approved by FDA • Is effective new drug being withheld unnecessarily since FDA exclusively relies on improvement in survival? • Survival may not be significant since patients may benefit from second-line treatment • Can response be used as surrogate endpoint?

50. Surrogate Endpoints in Practice • The surrogate must be in the causal pathway of the disease process • An intervention’s entire effect on the clinical outcome of interest should be fully captured by the surrogate • We need to assess more than a single study to decide on the adequacy of a surrogate