Surrogate Endpoints

1. Surrogate Endpoints

2. The Surrogates Story 3 Drug Trials 2 FDA Policy Issues • 1. CAST Trial –Cardiac Arrhythmias • 2. Concorde – AZT for AIDS • 3. Erythropoietin for Dialysis Pts • 1. Accelerated Approval (AA) • 2. Patient-Reported Outcomes (PRO)

3. PVCs

7. Managing the “Wild Card” of Cardiovascular Disease- Sudden Cardiac Death • Up to half of the ½ million cardiovascular deaths are “sudden” deaths • Known risk factors for sudden death • Cardiac ischemia (esp recent) • Poor ejection fraction fraction • Ventricular arrhythmias

10. Rigorous testing of new anti-arrhythmics

11. Antiarrthymics in the late 80’s • Antiarrthymics for PVCs & V-Tach widely prescribed • Between ¼ - ½ million patients/yr were taking • “New” antiarrthymic drugs more effective in suppression arrthymias • Scientific EPS selection of best therapies • Encainide Flecainide Moricizine • Placebo controlled trials considered unethical • Even tho no trails showing reduction of arrhythmias led to reduction of sudden death

12. Cardiac Arrhythmia Suppression Trial CAST-ing doubt on the dominant pradigms

13. High Risk Patients Require Treatment • “Unethical” not to treat such high risk patients • Have to do something • How would you feel if one of these patients you “ignored” suffered sudden death • Plus legal ramifications

14. Cardiac Arrhythmia Suppression Trial CAST-ing doubt on the dominant pradigms

15. CAST trial 1987 • Randomized, Double-Blind, Placebo Control • 27 clinical centers, 4,400 patients • Open-label titration to select drug-responsive patients: • 1,727 randomized to Encainide, Flecainide or Moricizine • Trial is discontinued early • Encainide and Flecainide 1989 • Moricizine 1991 http://clinicaltrials.gov/ct/show/NCT00000526

16. CAST Results

17. Cardiac Arrhythmia Suppression Trial CAST-ing doubt on the dominant pradigms

18. Surrogate Endpoints • Change in a clinical variablenot experienced directly by the patient • Blood pressure • Serum cholesterol • Serum Glucose • PVC’s • Not itself a direct measure of clinical harm or benefit • Patient does not necessarily feel better or worse

19. Clinically Relevant Endpoints • Mortality or survival benefit • Clinically important change experienced directly by the patient • Reduced pain • Improved functional status • Improved quality of life • Directly measures clinical benefit or harm

20. Hierarchy of endpoints Level 1: True clinical-efficacy measure Level 2: Validated surrogate endpoint Level 3: Non-validated surrogate endpoints reasonably likely to predict clinical benefit Level 4: A correlate that measures biological activity but whose clinical relevance is not well established Fleming, T. Surrogate endpoints and FDA’s accelerated approval process: the challenges are greater than they seem. Health Affairs (2005) 24(1) 67-78

21. Why Use Surrogate Endpoints? • Reduction in sample size, duration of trial and cost • Easier to show benefits: weeks to mos vs. years • Assess benefits of drug where measurement of clinical outcomes would be unethical/invasive • Because death and other “harder” outcomes are uncommon or delayed well into future

22. Surrogate Reductio ad absurdum • Elevated WBC count – surrogate for severity of pneumonia • So, why not give cytotoxic agents to reduce the white count?!

23. Limitations of Surrogate Endpoints • Surrogates may not be valid predictors of actual clinical outcomes • Rests upon physiologic assumptions • Persuasiveness of biologic plausibility • May be statistically significant but not clinically significant • Provide only partial picture of totality of drug’s effect • Lend themselves to manipulation by PhARMA • Many turn out to be misleading “red herrings”

24. Reasons for failure of surrogate end points Surrogate is not involved in disease pathway Prostate Biopsy Finasteride Trials Disease has multiple pathways and intervention effects only one pathway mediated through surrogate Ventricular Arrythmias Encainide and Flecainide Trials Surrogate is not affected by/ insensitive to intervention’s effect CD4 levels HIV drugs Intervention has mechanisms of action independent of disease process Ventricular Arrythmias Encainide and Flecainide Trials Fleming, T. R. et. al. Ann Intern Med 1996;125:605-613

25. Effective antimicrobial treatment or Useless surrogate? • 4,000 surgical patients • Treated patients for nasal staph carriage • Treated pts 4.6% vs. 21.3% control (p<.001) • No difference in surgical infections: 2.3% in treated vs. 2.4% in controls Perl NEJM 2003

26. Zidovudine -- AZT • Thymidine Analogue • Synthesized 1964 • Drug in the public domain • 1984 scientists approach drug companies to expedite R&D • Got Burroughs Wellcome to patent (w/ difficulty) Mitsuya, H. et al., 3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy associated virus in vitro, Proc. Natl. Acad. Sci USA (82) 1985

27. Pathophysiology of HIV AZT http://research.bidmc.harvard.edu/vptutorials/HIV/home.htm

28. The Evidence it “Works” Total viable cells x 10 -5 HIV positive T cells HIV negative T cells AZT uM Mitsuya, H. et al., 3'-Azido-3'-deoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy associated virus in vitro, Proc. Natl. Acad. Sci USA (82) 1985

29. AZT surrogate endpoints: the context • No treatments for AIDS  desperation • Bribery to enter trials • Difficulties of obtaining accurate results • Drug smuggling rings • Cook County: 100’s of deaths per quarter • Regan administration largely ignores HIV

30. AZT- The Hopes • New public private partnership • Burroughs Wellcome submits AZT application in 3 stages over 7 months • Drug companies, scientists and regulatory agency working together for good of the public • Sets stage for accelerated approval of other drugs

31. AZT: The Doubts • The myth of public health altruism • Burroughs Wellcome charges $10,000/year • Largely assumes credit for innovation • Despite doing relatively little of R & D • Clinical trials on limited population • White, gay males • Difficult to adhere to regimen • Initially 6x/day • Controversies and questions about role of the drug

32. 1994 CONCORDE Study

34. Kaplan-Meier Plot for all causes of death

35. Kaplan-Meier Plot for time to AIDS or Death

36. Kaplan-Meier for time to ARC AIDS or death

37. Kaplan-Meier for time to reduction in CD4 count less than half of baseline, AIDS or death

38. CONCORDE Conclusions The small but highly significant and persistent difference in CD4 count between the groups was not translated into a significant clinical benefit. Thus, analyses of the time until certain concentrations of CD4 were reached revealed significantly shorter times in the Deferred AZT treatment group. Had such analyses been regarded as fundamental, the trial might have been stopped early with a false-positive result.

39. CONCORDEConclusions The small but highly significant and persistent difference in CD4 count between the groups was not translated into a significant clinical benefit. Thus, analyses of the time until certain concentrations of CD4 were reached revealed significantly shorter times in the Deferred AZT treatment group. Had such analyses been regarded as fundamental, the trial might have been stopped early with a false-positive result.

40. CONCORDE Conclusions II This discrepancy in the differences between Immediate and Deferred AZT treatment groups in terms of changes in CD4 count and of long-term clinical response casts doubt on the uncritical use of CD4 counts as "surrogate endpoints" in trials, although their value as a prognostic marker for disease progression in cohorts and trials is beyond dispute. The reason for this discrepancy is unclear.

41. Conclusions Continued This discrepancy in the differences between Immediate and Deferred AZT treatment groups in terms of changes in CD4 count and of long-term clinical response casts doubt on the uncritical use of CD4 counts as "surrogate endpoints" in trials, although their value as a prognostic marker for disease progression in cohorts and trials is beyond dispute. The reason for this discrepancy is unclear.

44. History of Erythropoietin • U of C scientist Eugene Goldwasser starts research on erythropoietin 1960s • Purified in 1970s

45. Erythropoietin and Biotech Revolution • Amgen works with Goldwasser to sequence and clone erythropoietin • 1985 Amgen files patent • Orphan Drug • 1989 approved for marketing • Decade later $5b in profits

46. Erythropoietin Blood’s Life-Blood

48. Policy Context: Not that simple • Natl Kidney Foundation guidelines • Progressively raised Hb level w/out clinical evidence of benefit • Strong conflicts of interest • 10/18 panel members w/significant financial interest • 57% of NKF funding from industry • Medicare reimbursements  source of profit for dialysis centers

49. CHOIR and CREATE Studies • Researchers in US and France simultaneously conduct erythropoietin studies w/ clinical endpoints • Funded by Amgen’s competitors • Roche Johnson & Johnson • To get their “me-too” drugs to market

50. CHOIR: Enrollment and Outcomes Singh A et al. N Engl J Med 2006;355:2085-2098