Bios 6648: Design & conduct of clinical research

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1 Bios 6648: Design & conduct of clinical research Section 3 - Essential principle Lecture schedule Nov 11: Special topics and designs 5.1 Design and analysis of crossover studies 5.2 Design and evaluation of factorial studies * Project presentations (part 1, con t) Nov 18: Essential principles of trial conduct 3.2 Randomization, stratification, and blocking 3.3 Study quality control * Project presentations (part 2) Dec 2: Documenting the study 4. Trial protocol and statistical analysis plan * Project presentations (part 2, con t) Dec 9: Summary and final presentations Dec 16: Final exam Bios pg 1

2 3.2 Treatment allocation (randomization) 3.3 Study quality control Bios pg 2

3 Example: ROCKET-AF This trial illustrates the importance of good blinding, randomization, and good trial conduct. Design: Key references: * Design: ROCKET-AF exec steering committee: Am Heart J 2010;159: e1. * Results: Patel, et.al. (2011) N Engl J Med 2011;365: * Perspective: Fleming and Emerson (Oct 2011) N Engl J Med 365;17: Patients with non-valvular atrial fibrillation. Double-blind comparison of 20mg rivaroxaban versus dose-adjusted warfarin. Objective: evaluate non-inferiority of rivaroxaban (NI margin: HR = 1.46) Primary result: Per-protocol analysis: HR = 0.79; 95% CI: 0.66 to 0.96 Intent-to-treat analysis: HR = % CI: 0.74 to 1.03 Bios pg 3

4 Example: ROCKET-AF Blinding: Adjusted-dose warfarin (target international normalized ratio [INR], 2.0 to 3.0). Rivaroxaban plus warfarin placebo Dose-adjustment: * Encrypted INR values sent to independent study monitor, who provided either real INR values (for patients in the warfarin group in order to adjust the dose) or sham values (for patients in the rivaroxaban group receiving placebo warfarin) during the course of the trial. Randomization Central 24-hour, computerized, automated voice-response system. [Often called IVARS".] Bios pg 4

5 Example: ROCKET-AF Perspective: major points from FDA advisory committee. Results (highlights): * 95% confidence interval excluded prespecified noninferiority margin. * Risk of major bleeding events was somewhat higher with rivaroxaban. Important strengths * Double-blinding * Ruled out prespecified NI margin. Issues affecting interpretation * 5% discontinue follow-up due to withdrawal of consent". * Warfarin: INR in therapeutic range (2 to 3) only 55% of time; in other trials this was 62-73% of time. * Shorter time in therapeutic range seems to have more events. * Per-randomization is important: - Events may have been missed in per-protocol analysis - Per-randomization analysis had important differences (HR=0.88, upper CI limit = 1.03). * Increase in death rates after discontinuation of randomized treatment. Bios pg 5

6 Example: ROCKET-AF Discussion: So what s all the fuss about?! What are some potential effects of inadequate blinding/masking? Bios pg 6

7 Consider the scientific objective Research process: Inferential Question: µ A = µ B Underlying Population: µ A : Hypothetical mean, treatment A µ B : Hypothetical mean, treatment B Statistics: X A Treatment A Sample Treatment B X B We want inference about what would happen to a population if standard care used either treatment A or treatment B. Standard care is the treatment plus: Ancillary care of side effects Monitoring progress/symptoms Diagnostic procedures for secondary effects Rescue and follow-up care Blinding avoids(?) bias due to extraneous perception of treatment effects. Bios pg 7

8 Consider the scientific objective ICH guidelines ( part E9 Statistical Principles The most important design techniques for avoiding bias in clinical trials are blinding and randomisation, and these should be normal features of most controlled clinical trials intended to be included in a marketing application." Similar criteria are required in the CONSORT guidelines. Bios pg 8

9 (ICH and CONSORT) (c) Need for and types of masking: Blinded allocation Blinded treatment Blinded outcome assessment/adjudication Single-blind vs double-blind vs triple-blind studies Bios pg 9

10 What is it? Blinding (or masking) is when neither the the study subject (single blind) nor the study investigator (double-blind) have knowledge of the treatment being received or delivered. Concealed allocation is when the study investigator (personnel) do not know the allocation sequence. ICH guidelines (part E9): Blinding or masking is intended to limit the occurrence of conscious and unconscious bias in the conduct and interpretation of a clinical trial arising from the influence which the knowledge of treatment may have on the recruitment and allocation of subjects, their subsequent care, the attitudes of subjects to the treatments, the assessment of end-points, the handling of withdrawals, the exclusion of data from analysis, and so on. The essential aim is to prevent identification of the treatments until all such opportunities for bias have passed. Bios pg 10

11 ... but, does this matter? Anticipating that which cannot be anticipated... Noseworthy (1994).Neurology 1994;44: All patients examined and response judged by both a blinded and unblinded neurologist. Bios pg 11

12 ... but, does this matter? Anticipating that which cannot be anticipated: Wright, Am Heart J (1948) 36: Odd/even day allocation in a trial of anticoagulants in MI gave 589 patients in the active treatment arm and 442 patients in the control arm. * 57% (589/1031) assigned to active treatment (95% CI for assignment probability: 0.54 to 0.60). * Clearly biased allocation; cannot rule out differences between treatment groups. Bios pg 12

13 ... but, does this matter? Schulz, JAMA (1995) 273(5): * Meta-analysis of 250 trials from Cochrane pregnancy and childbirth database. * In trials with inadequate concealment of treatment allocation, odds ratios for treatment benefit were 41% larger (i.e., 41% better) than in trials with adequate concealment: Bios pg 13

14 ... but, does this matter? Anticipating that which cannot be anticipated: Schulz, JAMA (1995) 274(18)1456:1458. * Subversion of randomization (a natural inclination?) Bios pg 14

15 (ICH and CONSORT) International Conference on Harmonisation (ICH: Launched in 1990: a harmonization of requirements for pharmaceutical registration in US, Europe, and Japan. An excellent resource for current best practice. ICH Part E9Statistical Principles (section see quotes above). CONSORT guidelines An agreement between major journals on standards of evidence. * The Revised CONSORT Statement for Reporting Randomized Trials: Explanation and Elaboration. * Douglas G. Altman, DSc; Kenneth F. Schulz, PhD; David Moher, MSc; Matthias Egger, MD; Frank Davidoff, MD; Diana Elbourne, PhD; Peter C. Gotzsche, MD; and Thomas Lang, MA, for the CONSORT Group. * Ann Intern Med. 2001;134: * Bios pg 15

16 (c) Need for and types of masking Concealed allocation Blinded treatment Blinded outcome assessment * Particularly if blinded treatment is not possible. Single vs double vs triple-blind studies: * Single: blinded outcome assessment, but care is unblinded (PROBE design). * Double: blinded care and blinded outcome assessment. * Triple: blinded care, blinded assessment, and blinded analysis ( blind stupidity?"). Allocation concealment seeks to prevent selection bias, protects the assignment sequence before and until allocation, and can always be successfully implemented. In contrast, blinding seeks to prevent ascertainment bias, protects the sequence after allocation, and cannot always be implemented." (Schultz, JAMA; 1995; 274(18)1456:1458) Bios pg 16

17 Anticipating that which cannot be anticipated: Haphazard is not randomized (CCF) Randomization code must be secure (impossible to break), but the key must be protected (at all cost!). Some personal (bad) experiences: * Conflicting randomization lists. * Data subset with incorrect sorting. * Failure discovered mid-study (pill-count discrepancy). Complex systems may be more likely to fail? Bios pg 17

18 (difficult placebos) Miller FG: Sham Surgery: An Ethical Analysis Internal mammary artery ligation surgery for angina: * Ref: Beecher H.K. (1961) Surgery as placebo. JAMA 176: * Sham surgery without ligation * Lack of informed consent Transplantation of embryonic dopamine neurons for Parkinson s disease: * Ref: Freed CR (2001) N Engl J Med 2001;344: * Sham surgery involved drilling holes in skull but no sham injection * Procedures: surgery, anesthesia, anti-rejection drugs, antibiotics, PET scans. Arthroscopic surgery for knee osteoarthritis * Ref: Moseley BJ (2002) N Engl J Med 2002;347:81-8. * Sham surgery involved three 1cm incisions, anesthesia, pain drugs ROCKET-AF (sham INR values) Bios pg 18