EBM: Randomized Controlled Trials Gil C. Grimes, MD 10 August 2006

Objectives Familiar with benefits of RCT Familiar with methods of randomization Describe importance of concealment of allocation Describe methods of blinding Understand CONSORT flow of patients Understand Jadad score Familiar with limitations of RCT

History of RCT First RCT occurred in 1944 Streptomycin for treatment of TB Limited amounts available Question asked “what is the effectiveness of streptomycin in acute bilateral pulmonary tuberculosis compared to conventional therapy?” 1

History of RCT Demonstrated improved outcomes NNT to prevent one death 5 –14 of 52 in Control –4 of 55 in Experimental Why do this? What is the Benefit?

History of RCT Archie Cochrane was a POW in WWII Served as medical officer for 20,000 over 4 years Cholera, Typhoid, Diphtheria, malnutrition raged Despite lack of ‘modern medicine’ 4 POW died, none due to disease Concluded that modern medicine may not be all that great 2

Benefits of RCT 4 Name some benefits of RCT design Reduces over-estimate of benefit Tests efficacy of intervention Demonstrates real effect Reduces or eliminates chance Allows natural course of disease to be expressed Decreases Bias

Methods of Randomization 3 Randomization- the assignment of a patient to a group independent and without constraint Requires random allocation sequence

Generating Sequence Odd even approach using random numbers Multiple groups based on two digit random number –1-25; 26 to 50; 51-75; Using either method at any point the numbers in each group may differ considerably

Block Randomization Maintains closer sample size per group –Example abba, abab, baab, baba, aabb, bbaa Block size is multiple of arms in study Can randomize based on subgroup based on blocks –Those with DM, CAD, COPD, Obesity, age etc Block randomization assures that each subgroup remains balanced

Concealment 4 Knowing what will happen changes everything Prevents foreknowledge of assignment Blinds people enrolling patients Concealment allows true randomization Methods –Numbered sealed opaque envelopes –Call in central randomization Removes the lure of finding out

Why Conceal Failure to conceal allocation may lead to a significant overestimation of effect One review demonstrated an average 41 % increase in treatment effect 5 Preserves the intent of randomization

Blinding is like an Ogre 6 It has Layers Who can you blind? –Patients –Treatment teams –Assessors –Data analysis teams –Writing teams

Why blind….. Human behavior is influenced by what we know or believe 6 Why would you blind patients? –If measurements are subjective Those on placebo feel let down Those on treatment feel great –Less important if end points objective Death needs no blinding

Why blind…… Treatment teams? –May influence decision to withdraw –Minimize bias in treatment outside of study protocol Assessors? –Corrupt results –Bias interpretation of outcome measured –Color the results –Grade up or down based on preconceived value of therapy

Blinding others Data analysis –Statistics pure –No hedges –Minimize gray area Writers –True discussion of outcomes –Minimizes editorials in paper

Examples Placebo therapy –Pills look smell and taste alike –Use of active control ACE vs ARB CCB vs Beta blocker HCTZ vs the field –Double Dummy Two pills one active one placebo Patients take both and do not know which is which

Examples Blind Assessments –Photographed lesions –Assessors do not know when the photos are taken –Grade each independently

CONSORT Statement 8 Describes the Ideal RCT Several Journals now ‘Require’ CONSORT format If followed provides sufficient info to determine validity

CONSORT Table 1

CONSORT Table 2

CONSORT Flow

Scoring RCT Jadad score is a method of scoring quality of RCT Has been validated prospectively Can serve as personal method of rating trials

Jadad Score

Limitations Real Life Multiple Problems Artificial patient populations Some things cannot be randomized Toxin exposure Trauma Malnutrition Environment

Questions? Referances 1.1 Maynard A, Chalmers I (eds). Non-random reflections on health services research. London, BMJ Publishing Group page Cochrane AL, Blythe M. One man’s medicine: an autobiography of Professor Archie Cochrane. London, British Medical Journal Memoir Club, Altman, D. G. and J. M. Bland (1999). "Statistics notes: How to randomise." BMJ 319(7211): Altman, D. G. and J. M. Bland (1999). "Statistics notes: Treatment allocation in controlled trials: why randomise?" BMJ 318(7192): Schulz KF, Chalmers I, Hayes RJ, Altman DG. (1995) Empirical evidence of bias: dimensions of methodological quality associated with estimates of effects in controlled trials. JAMA 273: Day, S.J. and Altman, D.G. (2000) Blinding in clinical trials and other studies BMJ 321: Begg C, Cho M, Eastwood S, Horton R, Moher D, Olkin I, et al.(1996) Improving the quality of reporting of randomized controlled trials: the CONSORT statement. JAMA 276: Jadad, A.R. Randomized Controlled Trials A User’s Guide, BMJ Publishing Groups 1998