Active Control: In situations where the experimental therapy is to be an alternative to some existing standard of care, ethical or logistical constraints may dictate that the experimental therapy be tested against that “active” therapy that has previously shown evidence in an adequate and well-controlled clinical trial as an effective therapy. The ideal would be that patients would be randomized in a double blind fashion to either the experimental therapy or the active control, though the logistical difficulties of producing placebos for each treatment sometimes precludes a double blind study structure.

Contrasted with Placebo control: In situations where the experimental therapy is to be added to some existing standard of care, it is best to randomize subjects in a double-blind fashion to either the experimental therapy or a placebo control that is similar in appearance.

Common Analysis Estimands:

Per Protocol: In a per-protocol analysis, the analysis may be restricted to participants who had some minimum exposure to the study treatments, who met inclusion/exclusion criteria, and for whom there were no major protocol violations. The specific reasons for excluding randomized participants from a per-protocol analysis should be specified in advance of unblinding the data.

Intention to Treat: In an intention-to-treat analysis, all participants that satisfy the exclusion criteria are analyzed as belonging to the treatment arms to which they were randomized, regardless of whether they received or adhered to the allocated intervention for the full duration of the trial.

As Treated: In an as-treated analysis, the participants are grouped according to the treatment regimen that they received, which is not necessarily the treatment to which they were initially assigned.

Complier-Averaged Causal Effect (CACE): A parameter used to estimate the average effect of the treatment in the subpopulation of individuals that could remain on study or control treatments for the full length of the study.

Dropout: Treatment dropout is the result of a participant in a clinical trial discontinuing treatment; analysis dropout is the result of the failure to measure the outcome of interest for a trial participant.

Enrichment: Treatments are often only tolerated by or are only efficacious for a subset of the population. To avoid problems associated with treatment discontinuation, and to test a treatment on the subpopulation that can most benefit from it, it can be advantageous to determine whether a potential trial participant is a member of the subpopulation that can either tolerate or benefit from a treatment. This pretesting and selection of participants for trial participation prior to randomization into the treatment and control arms is called enrichment, and can include (1) selecting people with potentially responsive disease, (2) selecting people likely to have an event whose occurrence is the outcome of interest, (3) selecting people likely to adhere to the study protocol, and (4) selecting people who show an early response to the test drug.

Last Observation Carried Forward (LOCF): A single imputation technique that imputes the last measured outcome value for participants who either drop out of a clinical trial or for whom the final outcome measurement is missing. Baseline Observation Carried Forward (BOCF): A single imputation technique that imputes the baseline outcome value for participants who either drop out of a clinical trial or for whom the final outcome measurement is missing.

Noninferiority vs. Superiority Trials: A noninferiority clinical trial compares the experimental therapy to some active control with the aim of establishing that the experimental therapy is not unacceptably worse than an active control that showed evidence as an effective treatment in previously conducted adequate and well-controlled clinical trials. A noninferiority trial is often conducted in a setting in which (1) the experimental therapy, if approved, would be used in place of some existing treatment that was previously found to show evidence of effect, (2) it is not ethical or feasible to conduct a placebo controlled trial, (3) it would be clinically appropriate to approve a new treatment that is only approximately equivalent to a current standard therapy with respect to some primary clinical outcome, and (4) the new experimental therapy might have other advantages such as a better adverse event profile, ease of administration, etc. Rather than rejecting a null hypothesis of equality between the experimental therapy and control treatment, a noninferiority clinical trial is designed to reject a null hypothesis that the experimental therapy is some specified amount (“the noninferiority margin”) worse than the active control. Selection of the noninferiority margin must consider such issues as the magnitude of effect estimated for the active control in prior clinical trials, any bias that might be present in those previous trials relative to the effect of the active control in the population and setting used in the noninferiority trials, the proportion of effect that must be preserved for any approved treatment, etc. A Superiority clinical trial is one in which an experimental therapy would be approved only if that therapy showed statistically credible evidence of superiority over a clinically relevant control therapy in an adequate and well-controlled clinical trial. The superiority trial is designed to reject a null hypothesis of equality between the experimental and control therapies.

Randomized Withdrawal: A clinical trial design in which all participants are initially provided the study treatment. Then, participants that have a positive response to the study treatment are randomly selected either to remain on the study treatment or to be switched to a placebo. Positive indications are when those that continue on study treatment are observed to have better outcomes than those who are switched to the placebo.

Run-In Design: Similar to an enrichment design, a run-in design is a design incorporating an initial period in which a subset of the participants are selected given indications as to their likelihood of compliance or the magnitude of their placebo effect. The key difference between a run-in design and an enrichment design is that the active treatment is not used to identify the subset of participants for study.

Titration: In opposition to a fixed dose protocol, titration is the adjustment of dosage to increase the treatment benefit and tolerability for participants during the course of a clinical trial.

Washout: (Placebo) washout is a period of time without active treatment that is scheduled before the beginning of use of study treatment, often used to eliminate any residual effects that might remain after a previous period on active treatment.