The (frequently long, circuitous, and bumpy) trip from clinical problems to clinical trials

1. The (frequently long, circuitous, and bumpy) trip from clinical problems to clinical trials Bill Burman Denver Public Health

2. One view of clinical trials

3. Clinical trials: cautionary notes • Time for a Phase 3 trial – a decade (or more!) • Trial development – 1 to 5 years, trial conduct – 4 to 8 years, trial analysis – 1 to 2 years • Will the question be relevant in 10 years? • Cost of classic clinical trials (GCP, professional site monitoring): • $5-25,000 per patient/year • For a trial of 1000 patients, $5 million to $25 million per year of the trial • Opportunity cost • Limited funding for TB clinical trials – Is this a durable and critical question?

4. Another view of clinical trials…

5. When to start antiretroviral therapy (ART) – classic case for a randomized trial Important clinical and programmatic question Randomization possible at the level of the patient Challenges for “When to start” study Shifting equipoise Concerns about feasibility Problems of not doing clinical trials: When to start ART

6. Shifting recommendations for “When to start ART” – IAS USA panel

7. Shifting recommendations for “When to start ART” – IAS USA panel “It is questionable whether a randomized trial to study the issue of When to Start will ever be feasible.” 2002 guidelines

8. Shifting recommendations for “When to start ART” – IAS USA panel “It is questionable whether a randomized trial to study the issue of When to Start will ever be feasible.” 2002 guidelines

9. Prevent classic AIDS outcomes Prevent irreversible loss of immune function (clonal deletion) Prevent other serious events: cardiovascular, renal, and hepatic events other cancers neurocognitive dysfunction Prevent HIV transmission When to start ART: Potential of ART

10. Short-term side effects – diarrhea, rash, etc. Long-term metabolic effects Hyperlipidemia, bone loss Renal and hepatic toxicity Behavioral disinhibition – leading to increased risk of transmission Acquired drug resistance, transmitted resistance Cost of antiretroviral therapy – drugs, monitoring, increased clinical care When to start ART: Problems of ART

11. CD4 > 350 Randomized Immediate ART Deferred ART: start when CD4 < 250 ART: physician/patient choice 477 enrolled (of 5472 in overall trial) 249 ART-naïve 225 off ART for > 6 months Median follow-up – 18 months SMART study – ART-naïve or off ART for > 6 months

12. Outcomes of SMART sub-study of “When to Start” P = 0.002 P = 0.02 P = 0.01 SMART Study Group. J Infect Dis 2008; 197: 1133-44

13. > 15 years of controversy not resolved by many, increasingly large and increasingly sophisticated observational studies Clarity provided by two relatively small randomized clinical trials (combined n = 1293, with median follow-up for < 2 years) Recommendations for common, important clinical decisions should be based on randomized trials Lessons of the “When to start ART” controversy

14. Examples of the problems of not doing clinical trials: TB

15. Examples of the problems of not doing clinical trials: TB • Sub-optimal treatments • Dosing of 1st (and 2nd) line TB drug in children • MDR-TB regimens without clarity on critical questions (e.g., number of drugs, length of aminoglycoside use, selection of fluoroquinolone) • Uncertainty about managing toxicity • Drug-related liver injury • Dosing of PZA, use of PZA in higher-risk patients • Key details about 1st-line therapy • Optimal duration • Intermittency – when during treatment, degree

16. Getting started • Identify a compelling clinical problem – important in terms of diagnosis, treatment effectiveness, toxicity, prevention, population control • Find relevant observational studies • Current practices • Key outcomes: definitions, rates, associated factors, estimation of the effect size of an intervention • Consider doing research on what to do research on • Survey clinicians: key questions, areas of equipoise • Survey patients: outcomes of TB treatment that are important to patients • Formal decision analysis – cost-effectiveness modeling of various forms of treatment of latent TB

17. Getting started • Identify a compelling clinical problem – important in terms of diagnosis, treatment effectiveness, toxicity, prevention, population control • Find relevant observational studies • Current practices • Key outcomes: definitions, rates, associated factors, estimation of the effect size of an intervention • Consider doing research on what to do research on • Survey clinicians: key questions, areas of equipoise • Survey patients: outcomes of TB treatment that are important to patients • Formal decision analysis – cost-effectiveness modeling of various forms of treatment of latent TB

18. Getting started • Identify a compelling clinical problem – important in terms of diagnosis, treatment effectiveness, toxicity, prevention, population control • Find relevant observational studies • Current practices (sometimes substantially different from guidelines) • Key outcomes: definitions, rates, associated factors, estimation of the effect size of an intervention • Consider doing research on what to do research on • Survey clinicians: key questions, areas of equipoise • Survey patients: outcomes of TB treatment that are important to patients • Formal decision analysis – cost-effectiveness modeling of various forms of treatment of latent TB

19. Getting started • Identify a compelling clinical problem – important in terms of diagnosis, treatment effectiveness, toxicity, prevention, population control • Find relevant observational studies • Current practices (sometimes substantially different from guidelines) • Key outcomes: definitions, rates, associated factors, estimation of the effect size of an intervention • Consider doing research on what to do research on • Survey clinicians: key questions, areas of equipoise • Survey patients: outcomes of TB treatment that are important to patients • Formal decision analysis – for example, cost-effectiveness modeling of various forms of treatment of latent TB

20. Trials of treatment-shortening with fluoroquinolones • Rationale • Mouse model studies – moxifloxacin allowed treatment shortening to 4 months, especially if substituted for INH • Improved treatment completion, leading to improved TB control • Fluoroquinolones are well-tolerated, known to be safe • Three Phase 3 trials undertaken

21. Activity of moxifloxacin in combination therapy in a mouse model of TB 2.5 logs Am J Respir Crit Care Med 2004; 164:421-6

22. Concerns about fluoroquinolones for treatment-shortening • Toxicity/tolerability • Uncertainty about safety in pregnancy, children, and the elderly • Concerns about possible cardiotoxicity from moxi • Selection for resistance in M. tuberculosis might limit 2nd-line regimen potency • Broad activity against common bacterial pathogens – selection for resistant strains, C. difficile • Lack of consistent activity in Phase 2 trials • Opportunity cost

23. Effect of moxifloxacin on 2-month sputum culture conversion EMB

24. Effect of moxifloxacin on 2-month sputum culture conversion N = 102 N = 150 N = 336 N = 443 EMB

25. Treatment-shortening using moxifloxacin for drug-susceptible active disease • Relapses • IRZE – 12 (2%) • IRZM – 46 (9%) • MRZE – 64 (12%) • 2-month conversion • IRZE – 83% • IRZM – 85% • MRZE – 87% Gillespie S, et al. N Engl J Med 2014; 371: 1677-87

26. TB clinical trials: drug-susceptible TB • Lessons from the past decade • Regimens for drug-susceptible disease must be applicable to women of child-bearing age and children • Don’t start Phase 3 trials of treatment-shortening without compelling results from Phase 2 • Is treatment-shortening to 4 months the most important question in treatment of drug-susceptible TB? • We are far to quick to conclude that a new regimen is “safe and well-tolerated”

27. Sudden death is common after a heart attack Ventricular ectopyis a risk factor for sudden death Drugs are available that markedly suppress ventricular ectopy In a pilot randomized trial, these drugs were well-tolerated Clinicians started to prescribe these drugs to suppress ventricular ectopy Suppression of ventricular ectopy after acute MI

28. Efficacy in suppressing ventricular ectopy Am J Cardiol1988;61:501-9

29. Tolerability in Phase 2 Am J Cardiol 1988;61:501-9

30. Effect of flecainide, encainide on mortality - data from Phase 3 (n = 1500) N Engl J Med 1989;321:406-12

31. Fixing a surrogate marker may not fix the disease and may even exacerbate it Other examples: post-menopausal hormone replacement therapy and CVD risk effect of antiretroviral therapy on CVD risk effect of EPO on anemia in ESRD Sample sizes in most clinical trials are inadequate to detect unusual but serious adverse effects Lessons of the CAST study

32. TB clinical trials: drug-susceptible TB • Lessons from the past decade • Regimens for drug-susceptible disease must be applicable to women of child-bearing age and children • Don’t start Phase 3 trials of treatment-shortening without compelling results from Phase 2 • We are far to quick to conclude that a new regimen is “safe and well-tolerated” • Is treatment-shortening to 4 months the most important question in treatment of drug-susceptible TB?

33. Prospective study of tolerability of treatment for pulmonary TB • Multicenter prospective study – 4 regions of China, sampling scheme to assure representative sample of patients with pulmonary TB • Baseline survey and labs • Treatment: IRZE for initial treatment, Strep added for re-treatment • Symptom diary during treatment • Repeat labs at 2 months • Adverse events and TB treatment outcomes evaluated using standardized criteria

34. Demographic and clinical characteristics of the cohort Lv Z, et al. PLoS One 2013

35. Adverse drug reactions • Frequency • 766 (17%) had an adverse reaction, 1.4% had a serious adverse reaction, 1% hospitalized • Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity • Effect on TB treatment regimen • 43% of those with adverse reaction had regimen changed, 5% stopped all TB treatment • Effect on TB treatment outcomes • 2.8% with adverse reaction had unsuccessful TB treatment (vs. 1% of those without an adverse reaction) • 19% of all unsuccessful outcomes attributed to adverse reactions

36. Adverse drug reactions • Frequency • 766 (17%) had an adverse reaction, 1.4% had a serious adverse reaction, 1% hospitalized • Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity • Effect on TB treatment regimen • 43% of those with adverse reaction had regimen changed, 5% stopped all TB treatment • Effect on TB treatment outcomes • 2.8% with adverse reaction had unsuccessful TB treatment (vs. 1% of those without an adverse reaction) • 19% of all unsuccessful outcomes attributed to adverse reactions

37. Adverse drug reactions • Frequency • 766 (17%) had an adverse reaction, 1.4% had a serious adverse reaction, 1% hospitalized • Liver dysfunction – 6.3%, 0.6% had serious hepatotoxicity • Effect on TB treatment regimen • 43% of those with adverse reaction had regimen changed, 5% stopped all TB treatment • Effect on TB treatment outcomes • 2.8% with adverse reaction had unsuccessful TB treatment (vs. 1% of those without an adverse reaction) • 19% of all unsuccessful outcomes attributed to adverse reactions

38. Comparison of hepatotoxicity risk among antimicrobial agents * Andrade R, Tulkens PM. J AntimicrobChemother 2011; 66: 141-6 In population-based studies, TB drugs are among the most common causes of serious drug-related hepatotoxicity (Aliment PharmacolTher 2010;31:1200, Gastroenterol 2008;135:1924)

39. Changes in age-distribution among cases of active TB (Hong Kong) As transmission decreases, active TB becomes increasingly a disease of the elderly Wu P, et al. PLoS One, 2010

40. Age-specific rates of active TB, by WHO region http://www.who.int/tb/publications/global_report/en/

41. Toxicity considerations in treatment of drug-susceptible disease • INH and PZA are much more hepatotoxic than antibiotics that have been removed from the market • The new norm of TB: • Elderly, increased prevalence of comorbid disease • Higher risk of adverse effects, including hepatitis and CVD • Encourage enrollment of elderly and “complicated patients” into TB clinical trials • Is it time for trials comparing interventions for toxicity avoidance?

42. Clinical endpoints (TB, relapse, death) Infrequent events in TB patients Postulated differences in clinical event rates (treatment effect size) may be small Infrequent events analyzed as dichotomous endpoints + small effect size = large sample sizes Surrogate markers (EBA, effect on transaminases, cholesterol, etc.) Continuous variables with large dynamic range = markedly smaller sample size Endpoints – How to define “better” (or “not inferior”)

43. Surrogate markers – quite reasonable for initial studies, to generate hypotheses Effects of interventions may be much more complex than their effect on one or more surrogate markers Surrogate markers should not be relied on as the basis for major clinical decisions/policies Endpoints – the lessons of CAST and SMART

44. Dealing with complex clinical situations • Heterogeneity of “MDR-TB” • Primary vs. acquired • Degree of resistance to 2nd-line drugs • Different definitions of “resistance” • Limitations posed by intolerance to 2nd-line drugs • Severity of pulmonary disease • Common conclusion – Impossible to do clinical trials for MDR-TB

45. Study population Prior therapy with NRTI, NNRTI, PI Virological failure of current therapy (VL > 5000) Randomization Optimized Background Regimen (OBR) chosen by enrolling clinician – could include other investigational drugs OBR + T-20 (enfuvirtide) Example of “optimized background regimen” design for MDR-HIV

46. T-20 trial: baseline characteristics Characteristic Previous ART > 5 PIs Lopinavr/R Tenofovir Viral load < 40,000 > 40,000 T-20 49% 39% 3% 20% 80% Control 39% 28% 0 20% 80% N Engl J Med 2003;348:2175-85

47. T-20 trial: baseline characteristics Characteristic Genotypic susc. Score 0 1-2 3-4 >5 Use of other investigational agents Lopinavir/R Tenofovir T-20 16% 52% 28% 4% 62% 8% Control 13% 56% 27% 2% 62% 7% N Engl J Med 2003;348:2175-85

48. T-20 trial – efficacy results N = 501 N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:

49. T-20 trial – efficacy results from paired trials N = 501 N Engl J Med 2003;348:2175-85, N Engl J Med 2003;358:

50. Clinical trials for complex problems • Don’t try to over-simplify life – manage complexity, don’t try to eliminate it • We under-estimate the power of randomization to deal with clinical heterogeneity