Harvey's Garden

Clinical trials

4 min read

Core Concepts

  • Definition: An experimental study design where participants are randomly assigned to an experimental group (receives intervention) or a control group (receives placebo or standard of care).
  • “Gold Standard”: Considered the highest level of evidence for determining the efficacy and causality of a therapeutic or preventive intervention.
  • Objective: To minimize bias when testing the effectiveness and safety of a new intervention.

Key Features

  • Randomization:
    • Each participant has an equal chance of being assigned to any group.
    • Purpose: To minimize selection bias and control for confounding variables (both known and unknown) by distributing them evenly among the groups.
    • Allocation Concealment: The process of hiding the next allocated group from the person enrolling the participant, which prevents selection bias during recruitment.
  • Control Group:
    • The group that receives a placebo, no treatment, or the current standard of care.
    • Purpose: Provides a baseline to compare the effect of the new intervention against.
  • Blinding (Masking):
    • Concealing group allocation from individuals involved in the trial to prevent bias.
    • Single-blind: Only the participant is unaware of their assigned group.
    • Double-blind: Both the participant and the investigators/clinicians are unaware of the group assignments. This is the most common and preferred method.
    • Triple-blind: Participants, investigators, and data analysts are all unaware of group assignments.
    • Purpose: Reduces performance bias (systematic differences in care) and ascertainment/observer bias (distorted outcome assessment).

Trial Designs & Phases

  • Common Designs:
    • Parallel Group: Each group receives a different treatment simultaneously (most common design).
    • Crossover: Each participant receives both treatments in a sequence, separated by a “washout” period. Participants serve as their own controls.
    • Factorial: Tests two or more interventions simultaneously using various combinations.

Clinical trials

Mnemonic

Does the drug SWIM? ⁣
🏊 “Is it Safe?” Assesses safety, toxicity, pharmacokinetics, and pharmacodynamics⁣
🏊 “Does it Work?” Assesses treatment efficacy, optimal dosing, and adverse effects.⁣
🏊 “Is it as good or better?” Compares the new treatment to the current standard of care (any Improvement?).⁣
🏊 “Can it stay?” Detects rare or long-term adverse effects (eg, black box warnings). Can result in treatment being withdrawn from Market.⁣
⁣

  • Phase 0 trial
    • Purpose: Exploratory phase with no therapeutic or diagnostic intent, aimed at gaining insight into pharmacokinetics and pharmacodynamics.
    • Only < ​1% of the therapeutic dose is used.
    • Safety and toxicity are not assessed.
    • Study population: Small sample consisting of either healthy individuals or a population with a disease of interest (∼ 10–15).
    • Study design: Open-label.
  • Phase I trial
    • Purpose: Evaluation of pharmacodynamic and pharmacokinetic properties of the drug, safety, and toxicity.
    • Evaluation of the maximum tolerated dose.
    • Study population: Small number of healthy individuals or patients with a specific disease (∼ 15–30).
    • Study design: Open-label.
  • Phase II trial
    • Purpose: Evaluation of efficacy, optimal dose range, and side effects (especially common and short-term side effects).
    • Study population: Moderate number of patients with a specific disease (∼ 10–100).
    • Study design: Randomized, Controlled, Anonymized.
  • Phase III trial
    • Purpose: Final confirmation of safety and evaluation of efficacy against placebo or the current standard of care.
    • Study population: Randomized control trial with a large number of patients with a specific disease (∼ 100–1000).
    • Study design: Randomized Controlled Trial.
  • Phase IV trial
    • Purpose: Postmarketing surveillance, comparing real-life efficacy to that described in research studies. Safety studies following approval (especially evaluation of rare and long-term side effects).
    • Study population: Large number of patients with a specific disease after drug approval.
    • Study design: Open-label.

Analysis & Interpretation

  • Intention-to-Treat (ITT) Analysis:
    • All participants are analyzed in the groups to which they were originally randomized, regardless of whether they completed or adhered to the treatment protocol.
    • Benefit: Preserves the benefits of randomization and gives a more realistic measure of the treatment’s effectiveness in a real-world setting. Minimizes bias from attrition.
  • Per-Protocol Analysis:
    • Only includes participants who strictly adhered to the protocol.
    • Risk: Breaks randomization and is more susceptible to bias, but may provide a better measure of the treatment’s effect under ideal conditions.

Potential Biases & Limitations

  • Selection Bias: Systematic differences between groups at baseline. Minimized by randomization and allocation concealment.
  • Performance Bias: Systematic differences in the care provided to groups (apart from the intervention). Minimized by blinding.
  • Detection/Ascertainment Bias: Systematic differences in how outcomes are assessed. Minimized by blinding of outcome assessors.
  • Attrition Bias: Systematic differences in withdrawals or loss to follow-up between groups. Addressed by Intention-to-Treat analysis.
  • Limitations of RCTs:
    • Costly and time-consuming.
    • Ethical concerns (e.g., withholding treatment, lack of clinical equipoise).
    • Limited external validity (generalizability): Strict inclusion/exclusion criteria may result in a study population that is not representative of the general patient population.

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