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Describe the characteristics of randomized-controlled trials
Discuss validity issues associated with randomized-controlled trials
Describe common randomized-controlled designs (parallel, crossover, adaptive)
Briefly explain key analytical aspects of randomized-controlled trials
Discuss the strengths and weaknesses of randomized-controlled trials
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Absolute risk difference
Active control
Adaptive designs
Allocation concealment
Ascertainment bias
Attrition bias
Bias
Blinding
Block randomization
Carryover effect
Clinical research protocol
Cluster randomization design
Crossover design
Data and Safety Monitoring Board
Detection bias
Double-blind trial
Drug effectiveness
Drug efficacy
Effect size
Exclusion criteria
External validity
Factorial randomized trials
Hawthorne effect
Historical control
History bias
Inclusion criteria
Instrumentation bias
Intent-to-treat analysis
Interim analysis
Internal validity
Investigator bias
Maturation bias
Noninferiority trial
Number needed to harm
Number needed to treat
Open label
Parallel study design
Per-protocol analysis
Placebo
Power
Primary outcome
Randomization
Regression to the mean
Relative risk
Relative risk difference
Risk difference
Sample size
Selection bias
Simple randomization
Single blind trial
Stratified randomization
Study sample
Subgroup analysis
Surrogate endpoints
Target population
Testing
To the mean
Validity
Washout period
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Randomized-controlled trials (RCTs) are widely regarded as the strongest type of primary study design to support evidence-based medicine and practices related to the beneficial and detrimental effects of novel drug therapies.1–3 The goal of these trials is to measure a primary outcome in a highly selected group of individuals, or study participants, that are given an equal chance of being assigned to receive one or more clinical interventions. In medicine, interventions may include drug therapies, prevention strategies, or medical procedures, and may occur in a variety of settings in which healthcare is provided, including academic settings. Most RCTs are designed to determine the effect of a specific intervention on health-related outcomes, including disease prevention and progression.
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The RCT is the most common type of trial that is used to determine the efficacy of an experimental intervention compared to a standard therapy or placebo. A key requirement by the Food and Drug Administration (FDA) in the clinical drug development cycle is the RCT as part of a new drug application (NDA).4 They are often referred to as Phase III studies or “pivotal trials,” since they are used to establish the relative efficacy and safety of an investigational drug compared to a control group. Adherence to very strict selection criteria, proper trial design, and minimization of bias are all critically important to establish the relative efficacy and safety of a drug. This chapter will review the most common characteristics of RCTs, including common variations on study design, sampling strategies, biases, and errors. This chapter will also address different ways to analyze the study data, including intention to treat and subgroup analysis.
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MAXIMIZING VALIDITY AND MINIMIZING BIAS
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Few, if any, clinical studies, including RCTs, are designed perfectly, despite having a highly qualified and dedicated research team assigned ...