Randomized Controlled Trials - The Basics Dr. Sathish Kumar, MD,DCH Professor of Pediatrics CMC, Vellore Outline • Randomised controlled trials/Randomisation • Main strengths and weaknesses • Types of RCTS • Analysing their results • How to conduct them? • How to report RCT? Epidemiological study designs Lancet 2002; 359: 57–61 Hierarchy of Epidemiologic Study Design Randomly assigned 12 sailors to 6 different candidate treatments for scurvy First RCT in medicine • Sir A. Bradford Hill, an epidemiologist for England's Medical Research Council. • Trial, published in the British Medical Journal in 1948, tested whether streptomycin is effective in treating tuberculosis. What is a randomized controlled trial? ”An epidemiological experiment in which subjects in a population are randomly allocated into groups, usually called study and control groups to receive and not receive an experimental preventive or therapetuic procedure, maneuver, or intervention” - John M.Last Randomisation is the only unique feature of RCTs Randomised control clinical Trial Intervention Intervention Group Group Population of interest Sample population Control Control Group Group Randomisation Assessment (T0) Assessment (T1) Why Randomise? • Tends to produce comparable groups • To get evenly balanced - measured and unmeasured, known and unknown prognostic factors and other characteristics of the participants at the time of randomisation x What elements of a trial can be randomized? • Most common unit is individual patient • Sometimes groups are randomized=cluster randomization • Examples: families, schools, towns, hospitals, communities • Worry about contamination in cluster randomization • Special statistical techniques needed to cope with the loss of independence of the individual units Example of a cluster randomized trial How is randomization achieved? • Two steps involved: • Generation of allocation sequence • Implementation of allocation (concealment of allocation) • While both are important, there is evidence that concealment of allocation is more critical Generation of allocation sequence – Fixed Randomization procedures • Simple randomization • Analogous to a repeated fair coin tossing • Restricted randomization • Blocking • Done to ensure equal balance of arms throughout all portions of the study • Stratified randomization • Individuals are identified based on important covariates (sex, age, etc.) and then randomization occurs within the strata Simple randomisation Block randomization A block randomization method can be used to periodically enforce a balance in the number of patients assigned to each treatment. A block randomization can be implemented in three steps: Step 1: Choose the block size and the number of blocks needed to cover the number of patients in the study. Step 2: List all possible permutations of treatments in a block. Step 3: Generate a randomization code for the order in which to select each block. Example: Step 1: Given a sample size of 24 and using a block size of 4, we need six blocks. Step 2: There are six possible permutations that allow two As and two Bs in each box: AABB, ABAB, ABBA, BAAB, BABA and BBAA. Stratified randomisation Stratified randomization takes the balance correction suggested by blocking one step further Concealment of allocation • Preventing foreknowledge of the next allocations • if randomization is unconcealed-- they may systematically enroll sicker-- or less sick-- patients to either treatment or control groups. • Defeat the purpose of randomization and the study will yield a biased result • Don’t confuse with blinding of participants, personnel, etc Example: RCT of open vs laparoscopic appendectomy Advantages of RCT • Efficient for investigating causality because ‘cause’ precedes the ‘effect’ • Possible confounding factors balanced- both known and unknown • Randomisation facilitates simple statistical analysis • Practical way to minimise several sources of bias (notably, selection bias) Disadvantages of RCT • Subjects are often a highly selected group and volunteers may differ from population of interest (i.e., generalizability may suffer). • Not suitable for rare outcomes • Not suitable for outcomes requiring long or extensive follow-up • Adherence/withdrawal issues • Limitations of external validity • Complex, Expensive, time consuming, ethically questionable 3. Types of RCTs • Based on the type of interventions being evaluated • Based on how participants are exposed to interventions • Based on the number of participants • Based on whether goal is evaluation of superiority vs. equivalence • Based on whether investigators and/or participants know which intervention is being studied RCTs Classified According to the Different Aspects of Interventions Evaluated • Based on the outcome of interest • Efficacy vs effectiveness trials • Phase I, II, III, IV trials Efficacy vs. effectiveness trials • Efficacy—does the intervention work in the people who actually receive it? • These trials tend to be explanatory • confirm a physiological or clinical hypothesis • Effectiveness—how does the intervention work in those offered it • Tend to be pragmatic • inform a clinical or policy decision by providing evidence for adoption of the intervention into real-world clinical practice. ‘Explanatory’ and ‘Pragmatic’ questions Explanatory Pragmatic • Does it work in the real world • Can it work in an ideal …..? setting …..? • Effectiveness • Efficacy • Choice between alternative • Hypothesis testing approaches to health care • Placebo controlled • Standard care • Double blind • Open Efficacy Trial Pragmatic Trial Clinical Trial phases Safety & Efficacy Safety Safety & dosing RCT Classification Based on hypothesis Testing superiority, equivalence/noninferiority Δ: margin for equivalence/noninferiority. Example of equivalence trial Why do an equivalence trial? • Existing effective treatment • Placebo-controlled trial unethical • Life-threatening illness. • New treatment not substantially better than existing treatment. • May have fewer side effects, greater convenience, lower cost, higher quality of life, or provide an alternative or second line therapy. Example of Non-inferiority trials RCTs Classification • Based on how the participants are exposed to the intervention • Parallel trials • Crossover trials • Trials with factorial design Simple, two-arm (parallel) RCT Treatment Group/ Arm Control Group/ Arm Exp. Drug • Most common clinical design. • Complete randomized design in which each patient receives one and only one treatment in a randomized fashion. Simple, two-arm (parallel) RCT Cross over design... RANDOMIZATION Group A Group B Drug A Drug B WASH OUT PERIOD WASH OUT PERIOD Drug B Drug A Example: Crossover trial Factorial designs 2× 2 Factorial design + Drug A Drug B Drug A+B Neither Drug •Used when it is desired to study the influence of a number of factors on the treatments compared as well as their interaction with different treatments. Example: factorial design RCTs Classification • Based on the number of participants • N-of-1 trials to mega-trials • Fixed size • Sequential trials N-of-1 trial • Form of crossover trial • Each participant receives the experimental arm for a period of time and then the control/comparison arm during a different period of time • There can be many such periods of time in these studies • XCCCXXCCXX • The participant does not know which intervention is occurring during each period Eligible patient Drug Placebo Placebo Drug Drug Placebo Example: N-of-1 trial Mega-trials (“Large simple trials”) • These studies are meant to be HUGE but to collect only a limited amount of data (to make them affordable and practical) • Are usually multi-center • Can pick up small effects Example: Mega-trial Randomized Withdrawal Design Exp. Intervention WITHDRAWN FROM STUDY • Here, individuals who respond (+)ly to an experimental intervention are randomized to continue receiving that intervention or to receive a placebo. • Return of symptoms in placebo group causes withdrawal of subject from that group. Lancet. 2008 Mar 22;371(9617):998-100 Open Label Lead in phase N=56 Double Blind withdrawal Open Label extension Randomised, double-blind, placebo-controlled, withdrawal study Tocilizumab 8 mg/kg Tocilizumab (n=25) Ped ACR30 -98% every 2 weeks Ped ACR50 -94% Ped ACR 70 -90% Placebo (n=23) ACR 30 response Tocilizumab - 16/20 (80%) ACR 30 response Placebo - 4/23 (17%) CRP < 5 mg/L P= <0.0001 51/56 (98%) P=0.003 6 weeks 12 weeks 48 weeks RCTs Classification • Based on level of blinding • Open trials • Single blind trials • Double blind trials • Triple and quadruple-blind trials Blinding • Relevant groups who may/may not have knowledge of treatment assignments • Participants • Investigators/clinicians administering intervention • Investigators assessing outcomes • Data analyst(s) • Open trials • All participants and investigators know who is getting which intervention • E.g. medical vs. surgical treatments Single, double, triple, and beyond • Single-blind • The participants (usually) or the investigators assessing outcome (alternately) do not the assignments • Double-blind • Two groups do not know— usually it is the participants and the outcome assessors/investigators • Triple or quadruple blinding • Three or four of the relevant groups are not aware of the treatment assignment Allocation concealment Vs Blinding Randomisation Time Concealment of allocation Blinding Selection bias Performance bias Minimizing bias in RCT • Can occur at all phases: • Planning, selection of participants, administration of interventions,