Taking a chance: How likely am I to receive my preferred treatment in a clinical trial?

Abstract

Researchers should ideally conduct clinical trials under a presumption of clinical equipoise, but in fact trial patients will often prefer one or other of the treatments being compared. Receiving an unblinded preferred treatment may affect the study outcome, possibly beneficially, but receiving a non-preferred treatment may induce 'reluctant acquiescence', and poorer outcomes. Even in blinded trials, patients' primary motivation to enrol may be the chance of potentially receiving a desirable experimental treatment, which is otherwise unavailable. Study designs with a higher probability of receiving a preferred treatment (denoted as 'concordance') will be attractive to potential participants, and investigators, because they may improve recruitment and hence enhance study efficiency. Therefore, it is useful to consider the concordance rates associated with various study designs. We consider this question with a focus on comparing the standard, randomised, two-arm, parallel group design with the two-stage randomised patient preference design and Zelen designs; we also mention the fully randomised and partially randomised patient preference designs. For each of these designs, we evaluate the concordance rate as a function of the proportions randomised to the alternative treatments, the distribution of preferences over treatments, and (for the Zelen designs) the proportion of patients who consent to receive their assigned treatment. We also examine the equity of each design, which we define as the similarity between the concordance rates for participants with different treatment preferences. Finally, we contrast each of the alternative designs with the standard design in terms of gain in concordance and change in equity.

Keywords: Clinical trials; patient recruitment; randomisation; study design; treatment preference.

Figure 1.

Six randomised trial designs: (a) conventional parallel group design; (b) two-stage randomised design; (c) partially randomised design; (d) fully randomised design; (e) Zelen single consent design; (f) Zelen double consent design. *In designs (e) and (f) details of treatment may alternatively be concealed or revealed at stage of seeking consent.

Figure 2.

Probability of concordance versus θ (proportion randomised to the choice arm in a two-stage design), for varying ρ (proportion randomised to treatment A). Fixed parameters: α = 0.4 (proportion preferring treatment A); β = 0.15 (proportion preferring treatment B); γ = 0.45 (proportion undecided). θ = 0 corresponds to the standard design.

Figure 3.

Probability of concordance versus β (proportion preferring treatment B), for varying ρ (proportion randomised to treatment A) in a two-stage design. Fixed parameters: α = 0.3 (proportion preferring treatment A); θ = 1/2 (proportion randomised to the choice arm).

Figure 4.

Probability of concordance for individuals who prefer treatment A, versus θ (proportion randomised to the choice arm) for varying ρ (proportion randomised to treatment A) in a two-stage design. θ = 0 corresponds to the standard design.

Figure 5.

Change in equity versus θ (proportion randomised to the choice arm in a two-stage design) over varying ρ (proportion randomised to treatment A). θ = 0 corresponds to the standard design.

Figure 6.

Probability of concordance versus φ (proportion accepting randomisation) in Zelen single consent, treatment concealed (solid lines) and treatment revealed (dashed lines) designs, for varying θ (proportion randomised to consent arm). Fixed parameters: α = 0.4 (proportion preferring treatment A); β = 0.15 (proportion preferring treatment B); γ = 0.45 (proportion undecided). φ = 1 is equivalent to the standard design.

Figure 7.

Probability of concordance versus φ (proportion accepting randomisation) in Zelen double consent, treatment concealed (solid lines) and treatment revealed (dashed line) designs, for varying θ (proportion randomised to consent arm). Fixed parameters: α = 0.4 (proportion preferring treatment A); β = 0.15 (proportion preferring treatment B); γ = 0.45 (proportion undecided).

Figure 8.

Change in equity versus θ (proportion randomised to consent arm) over varying φ (proportion accepting randomisation) in Zelen single consent, treatment concealed (solid lines) and treatment revealed (dashed line) designs. Fixed parameter: ρ = 0.5 (probability randomised to treatment A in standard design).

Figure 9.

Change in equity versus θ (proportion randomised to consent arm) over varying φ (proportion accepting randomisation) in Zelen double consent, treatment concealed (solid lines) and treatment revealed (dashed line) designs. Fixed parameter: ρ = 0.5 (probability randomised to treatment A in standard design).