Controversies in Clinical Trials

Controversies in Clinical Trials Christopher B Cooper, MD Professor of Medicine and Physiology David Geffen School of Medicine Medical Director, UCLA COPD Center

Methodological issues discussed Pitfalls of randomized clinical trials Limitations of meta-analysis Immortal time bias Intention to treat versus per protocol analysis Reporting relative risk versus risk difference Effect of treatment withdrawal

Levels of evidence Level I: Evidence obtained from at least one properly designed randomized controlled trial. Level II-1: Evidence obtained from well-designed controlled trials without randomization. Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group. Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence. Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. US Preventive Services Task Force

Are randomized controlled trials always necessary?

Are randomized controlled trials always necessary? Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomised controlled trials Gordon C S Smith, Jill P Pell BMJ 2003; 327: 459-461

Parachute study

Systematic review of parachute studies

Conclusion of systematic review of parachute studies

Parachute study

Effect of ICS on disease progression in COPD Relatively large studies >4 years duration

Meta-analysis of effect of inhaled corticosteroids on decline of FEV 1 Study Patients, N Vestbo et al 290 Weir et al 98 Pauwels et al 1277 Lung Health Study Research Group 1116 Renkema et al 39 Burge et al 751 Total 3571-5.0±3.2 (95% CI, -11.2-1.2) -300-200 -100 0 100 200 300 Difference Between Placebo and Treatment Groups in FEV 1 Decline (ml/y) Highland et al. Ann Intern Med. 2003;138:969-973.

Meta-analysis of relative risk of exacerbations with ICS in COPD Reference Vestbo et al, 1999 Bourbeau et al, 1998 Burge et al, 2000 Lung Health Study, 2000 Weir et al, 1999 Overall RR, 0.70 (95% CI, 0.58-0.84) Paggiaro et al, 1998 Overall 0 0.5 1.0 1.5 2.0 2.5 3.0 Relative Risk Alsaeedi et al. Am J Med 2002;113:59-65.

Reduction in exacerbations with ICS depends on COPD severity Increasing Efficacy of Inhaled Corticosteroids Log Relative Risk of Exacerbation 0.0-0.1-0.2-0.3-0.4-0.5-0.6-0.7-0.8 Weir Bourbeau Burge Van der Valk Paggiaro Vestbo 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 P=0.02 Sin et al. JAMA. 2003;290:2301-2312. FEV 1 (L)

Findings from observational studies Soriano, et al. Eur Respir J 2002; 20:819-825

COPD survival in patients receiving LABA/ICS versus SABA Soriano, et al. Eur Respir J 2002; 20:819-825

Concept of immortal time Suissa S. Eur Respir J 2004; 23: 391-395.

Crude and adjusted rate ratios for death Suissa S. Eur Respir J 2004; 23: 391-395.

Immortal time bias Subjects might have been unexposed before switching to the exposed group They must be alive to switch from the unexposed to the exposed group Valid unexposed person-time is not accounted for Artificially increases the death rate in the unexposed or reference group Results in a spurious appearance of effectiveness

Recent major clinical trials in COPD OPTIMAL INSPIRE TORCH 1 year 2 years 3 years T TS TSF T SF P S F SF Age (years) 68 68 68 65 64 65 65 65 65 Male (%) 54 57 58 84 81 76 76 75 75 Post bd FEV1 (L) 1.08 1.08 1.12 1.13 1.11 1.22 1.21 1.22 1.22 Post bd FEV1 (%) 42 41 42 39 39 44 44 44 44 Prior ICS (%) 77% 79% 73% 51% 48% 52% 45% 47% 47% E past 12 m (%) 100% 100% 100% 88% 85% * * * * SGRQ 51 48 49 49 49 49 50 49 49 Withdrawals (%) 47 43 26 42 35 44 37 38 34 E (/year) 1.61 1.75 1.37 1.32 1.28 1.13 0.97 0.93 0.85 Deaths (%) 2.6 4.1 4.1 6.0 3.0 15.2 13.5 16.0 12.6 Deaths/year (%) 2.6 4.1 4.1 3.0 1.5 5.1 4.5 5.3 4.2 Change SGRQ -4.5-6.3-8.6 0.4-1.7 2.0 1.0 0.0-1.0 *Average for each group was 1.0 exacerbations in the previous 12 months

Rates and crude rate ratios of death Suissa S. Eur Respir J 2004; 23: 391-395.

The TORCH study Calverley PMA, et al. N Engl J Med 2007; 356: 775-789.

TORCH classification table Calverley PMA, et al. N Engl J Med 2007; 356: 775-789.

TORCH:all cause mortality } Combination v Placebo Risk difference 2.6% HR 0.825 (RRR 17.5%) 95% CI (0.681, 1.002) P=0.052 (log-rank test) NNT 40? Treatment Group Deaths Withdrawals Placebo 231 (15.2%) 673 (44.2%) Salmeterol 205 (13.5%) 561 (36.9%) Fluticasone 246 (16.0%) 587 (38.3%) Combination 140 (12.6%) 522 (33.7%) Towards a Revolution in COPD Health. Calverley, et al. N Engl J Med 2007;356:775-789.

TORCH analysis of main effects Vecchia CL, Fabbri LM. N Engl J Med 2007; 356: 2211-2212.

Factorial analysis of TORCH data Suissa S, et al. Eur Respir J 2008.

Suissa paper

Analysis of ICS withdrawal on entry into clinical trials TORCH Placebo Salm Flut Sal/Flut Total Total 1524 1521 1534 1533 6112 Prior ICS 338 273 306 292 1209 Prior ICS/LABA 449 413 414 435 1711 %ICS withdrawals 52% 45% 47% 47% 48% OPTIMAL Tio Tio/Sal SFC Total Total 156 148 145 449 Prior ICS 39 52 39 130 Prior ICS/LABA 81 65 66 212 %ICS withdrawals 77% 79% 73% 76% INSPIRE SFC Tio Total Total 658 665 1323 Prior ICS 319 340 659 %ICS withdrawals 48% 51% 50%

Influence of prior ICS on clinical trials Examines Withdrawal of ICS Examines Introduction of ICS Suissa S, et al. Eur Respir J 2008; 31: 927-933.

Kaplan-Meier plots of time to first exacerbation in OPTIMAL study Suissa S, et al. Eur Respir J 2008.

Effect of ICS versus bronchodilators on time to exacerbation Suissa S, et al. Eur Respir J 2008.

INSPIRE Seemungal, et al. COPD 2007.

INSPIRE - Study Design Run-in Prednisolone 30 mg daily + Salmeterol bid Double-blind treatment SFC 500/50µg bid Tiotropium 18 µg daily -2 0 32* 56 80 104 Weeks N=1,323 randomized patients (SFC: 658, TIO: 665) *Clinic Visits also at weeks 2 and 8 (FEV 1 measured, not SGRQ)

INSPIRE Wedzicha, et al. Am J Respir Crit Care Med 2007.

Disposition of subjects in INSPIRE Wedzicha, et al. Am J Respir Crit Care Med 2007.

Time to withdrawal in the SFC and TIO treated groups High dropout rate within first 8 weeks Withdrawal difference occurred early in the trial and then plateaued Could run-in period have influenced this pattern?

Time to death in INSPIRE study No death on SFC treatment from week 80-104 Mortality imbalance occurred early in the trial Only 21% of patients included in this analysis

Risk of exacerbation/hospitalization by tiotropium withdrawal Placebo Tiotropium Hazard Ratio (95%CI) p-value* N (%) N (%) (tiotropium/placebo) Exacerbations Discontinued 1187 (42.7) 1221 (39.9) 0.83 (0.77, 0.90) <0.001 Not discontinued 1294 (41.9) 1154 (35.7) 0.79 (0.73, 0.85) <0.001 Hospitalized Exacerbations Discontinued 315 (11.3) 320 (10.4) 0.85 (0.73, 1.00) 0.042 Not discontinued 255 ( 8.27) 215 ( 6.65) 0.79 (0.65, 0.94) 0.006

Effect of tiotropium withdrawal on time to first exacerbation Tiotropium Discontinued Tiotropium Not Discontinued Pooled analysis of 10 randomized controlled trials (including UPLIFT)