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1
Question:

A double-blinded, randomized controlled trial is being conducted to assess whether a new chemotherapeutic agent can prolong survival in patients with stage III non–small cell lung cancer.  Recent research studies using a small group of subjects reported that the agent demonstrated the ability to reduce tumor burden.  Investigators conducting the current trial now plan to randomly assign a larger number of participants to receive either the experimental treatment or a control intervention and measure differences in survival between the 2 groups.  Which of the following characteristics should be present within the research trial to ensure adequate protection of participants' welfare?

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Explanation:

Ethical considerations for randomized controlled trials

Appropriateness
of RCT

  • Intervention arms are at equipoise (ie, intervention is not already known to be superior to control)

Appropriateness
of control

  • Control is equivalent to the accepted standard of care
  • Control does not pose unacceptable risks to participant

Appropriateness
of inactive placebo

  • Acceptable when effective standard of care is unclear or does not exist

    OR

  • When effective standard of care exists, but temporarily withholding such therapy would not harm the participant

Appropriateness
of stopping RCT

  • Trial stopped when interim data analysis shows clear, highly significant benefit or harm

RCT = randomized controlled trial.

Randomized controlled trials (RCTs) are regarded as the most statistically unbiased method for determining whether an intervention (eg, new chemotherapeutic agent) causes an outcome (eg, increased survival).  However, RCTs pose ethical risks because participants lack autonomy in choosing their treatment and are randomly allocated to an intervention that may, depending on the study's results, be found to be inferior (eg, control or experimental arm).

Randomization of participants within an RCT is ethically permissible only if there is general uncertainty (ie, clinical equipoise) regarding the effectiveness of the experimental compared to the control intervention.  Equipoise is necessary in study design to ensure that the trial does not knowingly randomize participants at the outset to a clearly inferior or superior arm (Choice C).  For this reason, RCTs typically test interventions that are hypothesized to have benefit based on lower-quality evidence (eg, small pilot study) but lack robust evidence or widespread scientific consensus for their effectiveness.  Determining effectiveness then represents the primary purpose of the RCT.

(Choice A)  For RCTs to maintain statistical integrity, disease severity and other participant characteristics must be similarly distributed between the control and experimental groups.  Preferential allocation of subjects to a specific group violates the goals of randomization and would compromise the results of the study.

(Choice B)  In general, control treatments should reflect current standards of care (eg, standard chemotherapy regimen for lung cancer).  An inactive placebo (or intervention known to be less effective) is appropriate only when no effective treatment exists or when temporarily withholding treatment would not result in significant harm to participants.  Given the rapidly progressive nature of stage III non–small cell lung cancer, it is inappropriate to choose a control intervention that is less effective than the current standard of care (such as a placebo).

Educational objective:
In a randomized controlled trial, randomization is ethically permissible only if there is uncertainty (equipoise) regarding the comparative effectiveness of the experimental and control interventions.  Typically, control interventions for treatable, progressive diseases should reflect usual standards of care and not be known to be inferior to the experimental intervention.