What are Randomized Control Trials

randomized control trials

Randomized control trials(RCT) as described by John M.Last as

“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 therapeutic procedure, maneuver or intervention”

Design Of Randomized Trial

Why Randomized Controlled Trials?

Gold Standard of study design. Avoids selection bias. Improves comparability of intervention and control arm populations( e.g can match or block units of randomization). Fulfills assumptions underlying tests for statistical inference.

Makes group comparable –

  1. Controls for co-founding(known and unknown)
  2. Prevents Selection Bias

What do “Controlled” trials imply?

“Controlled” implies predefined –

  • Eligibility Criteria
  • Specified hypotheses
  • Primary and Secondary endpoints(e.g behavioral change, HIV incidence) to address hypotheses.
  • Methods for enrollment and follow up.
  • Rigorous Monitoring.
  • Analysis Plans and stopping rules.

Population hierarchy for intervention study

Why do RCTs?

Observational and quasi-experimental designs are subject to potential bias cofounding due to – self-selection (lack of comparability), Observer bias and Secular trends(e.g before and after study). The RCT provides the “gold standard” for proof of concept.

Are the results of RCT valid?

RCTs can provide conflicting results. RCT design, execution or analyses can be flawed. Intervention vs control comparisons are internally valid, but restrictions on participant eligibility can reduce external validity. (e.g specific age or sex groups omitted).

Types of Trials

Individually Randomized Trials:

  • Eligible individuals are randomized(conventional medical RCTs and many behavioral RCTs)
  • Self-selection of persons volunteering for enrollment.

Cluster-Randomized Trials:

  • Clusters(e.g communities, hospitals or other aggregates of people) are randomized, and all consenting persons enrolled.
  • Less individual-level self-selection.

randomized control trials

Limitation of Cluster-Randomized Trials

Cluster randomization more vulnerable to lack of comparability between study arms than individual randomization(fewer units of randomization, more correlated characteristics within members of clusters). Cluster randomized trials increase sample size requirements and are less efficient than individually randomized trials due to intra-cluster correlation.

When is it unethical to randomize?

  • Known effective treatment – Cannot use a placebo. Needs to provide a higher standard of care. For Example- Trials to prevent mother-to-child HIV transmission.
  • Personal Choice – Cannot randomize very different interventions. For Example – Trials of different types of contraceptives(pill or IUD) are ethically questionable because women have the right to select the method of their choice. It is ethically possible for them to choose between certain methods (pill A or pill B).
  • Risk of new treatment likely to exceed the risks of existing treatments.

mesurement

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Control Groups

Controls may receive no treatment (e.g placebo) if there is no standard of care. If there is an established standard of care it would be unethical to withhold this from controls, so standard of care becomes the reference control.

Eligibility and Enrollment for RCT

Eligibility is predefined to:

  • Ensure that participants meet the criteria for the intervention (e.g., have a specific disease for a therapeutic trial, are free of disease for a preventive trial, etc.)
  • Usually, eligibility is also defined by age, gender, race, state of health (absence of contraindications, etc.)
  • The narrower the eligibility criteria, the less generalize will be the results.
  • Participants must consent to screen for eligibility.

Enrollment occurs after:

  • Eligibility is established.
  • Consent is provided after the explanation of
    • All study procedures.
    • Risk and benefits.
    • Measures to reduce risk.
    • Voluntary participation (i.e., can refuse in part or in whole, or withdraw at any time).
    • Compensation for injury.
    • Compensation for time and effort (e.g., money/gifts).

Analyses

  • Intent to treat
    • Analyze all persons randomized, even if some do not receive the intervention or drop out before completion of treatment.
    • Least biased and most conservative.
  • As treated (“per protocol”)
    • Analyze only those who actually complete the treatment.
    • Potentially biased by selection of the most compliant and often lowest risk population.

Statistical methods

  • Outcomes at fixed points in time
    • The proportion with the outcome at each follow-up.
    • Logistic or log-binomial regression
      • Odds ratio (OR) or prevalence rate ratio (PRR) intervention/control
  • Events in-person time
    • Rate of outcomes per 100 person-years
      • Poisson regression, incidence rate ratio (IRR) intervention/control
  • Time to event
    • Time from enrollment until outcome
    • Cox proportional hazard regression, hazards ratio(HR)
    • Kaplan-Meier survival analyses, log-rank test

 

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