Randomized controlled trials Clinical Research Center Samsung Medical Center

1. Randomized controlled trials Clinical Research Center Samsung Medical Center

2. Randomized controlled trials Eliseo Guallar, MD, DrPH eguallar@jhsph.edu Juhee Cho, MA, Ph.D. jcho@jhsph.edu Gee Young Suh, MD, Ph.D. gy.suh@samsung.com

3. Cohort Study: issues for concern • Confounding • Selection bias • Misclassification of exposure and outcome

4. Methods to control for confounding • In the design of the study • Randomization • Restriction • Matching • In the analysis • Standardization • Stratification • Multivariate models • Inverse probability weighting • Sensitivity analysis

5. Learning objectives • To review the key aspects of designing RCTs • To review the design methods used to protect against selection bias, information bias, and confounding used in RCTs • To understand the basic analytical methods to protect against selection bias in RCTs • To discuss ethical issues, reporting standards, conflicts of interests, and other issues related to the role of RCTs in clinical research

6. Friedman LM, Furberg CD, DeMets DL. Fundamentals of clinical trials. 3rd ed. New York, Springer-Verlag, 1998

7. Piantadosi S. Clinical trials. A methodological perspective. 2nd ed. New York, Wiley, 2005

8. http://www.fda.gov/

9. http://www.jameslindlibrary.org/

13. James Lind and Scurvy • Aboard Salibury, 1747 • Non-randomized • Parallel group • 6 groups (n=2) • Quart of cider a-day • 25 drops of elixir vitriol x 3/day • Two spoonfuls of vinegar x 3/day • Sea water, half a pint a day • Two oranges and lemon for 6 days • Bigness of nutmeg x 3/day

15. Medical Research Council. BMJ 1948;2:769-82

16. Clinical trial: Definition An experiment designed to assess relative efficacy of a test intervention in comparison to one or more alternative interventions, in comparable groups of human beings

17. What is randomization? • Participants are assigned to one of two or more interventions using an explicit method that assures the assignment will be random, or by chance • “Similar” to flipping a coin

18. Types of interventions in clinical trials • Pharmaceutical • Drug treatment, preventive treatment, natural or synthetic products • Device • Prosthesis, ICD, thermal balloon • Procedure • Surgery, laser, radiological intervention • Behavior change • Smoking cessation, dietary change, exercise • Other • Counseling, information provision

19. Choice of interventions in clinical trials • Intensity (dose), duration, and frequency of the intervention • Feasibility of blinding • Single intervention vs. combination of interventions • Compliance with intervention • Generalizability to clinical practice • Balance between efficacy and safety

20. Choice of outcome measures in clinical trials • Primary vs. secondary outcomes • Main endpoint – sample size • Clinical outcomes vs. surrogate markers • Clinical importance • Cost of measure • Length of follow-up • Number of patients • Single clinical outcomes vs. composite outcomes • Mortality as an outcome • Adverse events • Not powered to detect difference in side effects • Trails included in applications for drug approval

21. Single vs. multicenter trials • Single center • Participants recruited at one site • Single site usually also responsible for data collection, management, analysis • Multicenter • Participants recruited at >1 site • Usually has data coordinating center and other resource centers

22. N=1548, surgical ICU Van den BergheN Engl J Med 2001;345:1359

23. N=6104, 42 hospitals, both medical and surgical THE NICE-SUGAR Study Investigators N Engl J Med 2009;360:1283

24. Assess eligibility Randomize Test intervention Comparison Follow-up for outcomes Follow-up for outcomes Basic structure of parallel group randomized controlled trial

25. Selection of study participants (inclusion criteria) • Clear case definition • Balance • Number of cases eligible for the trial • Risk of outcome • Likelihood of benefit from intervention • Generalizability • Design adequate sample size • Consider stratification • Consider run-in period

26. Reasons for excluding participants from a trial • A study treatment may be harmful • High risk of adverse reaction to intervention • Unacceptable risk of assignment to placebo • Active treatment unlikely to be effective • At low risk of outcome • Type of disease unlikely to respond • Taking a treatment that interferes with intervention • Unlikely to adhere to intervention • Unlikely to complete follow-up • Practical problems with following protocol

28. The PROTECT Investigators N Engl J Med 2011;364:1305-14

29. The PROTECT Investigators N Engl J Med 2011;364:1305-14

30. INTEVENTION The PROTECT Investigators N Engl J Med 2011;364:1305-14

31. Outcome Measurement The PROTECT Investigators N Engl J Med 2011;364:1305-14

32. Clear Definition of Outcome The PROTECT Investigators N Engl J Med 2011;364:1305-14

33. Baseline measurements in randomized clinical trials • Descriptive characteristics of participants • Key risk factors for outcome or variables that define key subgroups • Baseline value of outcome variable • BE PARSIMONIOUS • Establish a bank of biological materials

34. The PROTECT Investigators N Engl J Med 2011;364:1305-14

35. The PROTECT Investigators N Engl J Med 2011;364:1305-14

36. Types of drug clinical trials: Phase I • First step in testing a new treatment in humans • Usually conducted in healthy volunteers • Closely monitored • Designed to determine: • Metabolic and pharmacologic effects in humans • Side effects with increasing doses • Pharmacokinetics, drug metabolism, and pharmacological effects

37. Suntharalingam G, et al. N Engl J Med 2006;355:1018-28

38. Types of drug clinical trials: Phase II • Early controlled clinical studies to obtain preliminary data on efficacy for a particular indication • Conducted in a relatively small number of patients • Well controlled, closely monitored • Designed to determine: • Preliminary data on efficacy • Short term data on side effects and risks

39. Types of drug clinical trials: Phase III • Performed after preliminary data on efficacy from phase II studies is obtained • Include several hundred to several thousand patients • Designed to determine: • Efficacy • Safety • Information for extrapolating results to the general population and for physician labeling

40. Types of drug clinical trials: Phase IV • Evaluate the long term safety and efficacy of a drug • Usually after licensure granted by the FDA for the indication under study • May address: • Different doses or schedules of administration • Other patient populations or other stages of the disease • Use of the drug over a longer period of time

41. Key methodological tools in RCTs • Randomization • Masking (blinding) • Intention to treat analysis

42. What is randomization? • Participants are assigned to one of two or more interventions using an explicit method that assures the assignment will be random, or by chance • “Similar” to flipping a coin

43. Treatment Group Treatment Group Treatment Group Randomization Control Group Control Group Control Group

44. Randomization • Protects against selection bias and confounding • Results in groups similar on known and unknown prognostic factors (on average) • Provides a basis for standard statistical analysis • Adds credibility to study findings

45. Grady D, et al. JAMA 2002;288:49-57

47. van Vollenhoven, et al. Lupus 1999;8:181-7

48. Historical vs. randomized controls Sacks H, et al. Am J Med 1982;72:233-40

49. How is randomization done? • Table of random numbers • Computer-generated list of treatment assignments • Other methods designed to be random are subject to bias (eg, birth date, medical record number, etc)