Detailed Project Description

Randomized clinical trials (RCT) are traditionally conducted in the context of demonstrating the efficacy and safety of medical products. For many disease areas, placebo response can be high in clinical trials and affect the ability of detecting a treatment effect. On the other hand, due to the concern of lacking adequate patients for some rare diseases or pediatric patients, enrichment designs or innovative designs are thought of as being able to provide a way to address these issues. Randomized designs for crossover trials and N-of-1 trials are attractive options in rare disease settings. They utilize within-patient variability to assess the efficacy of a treatment, but are limited to chronic, stable conditions for which efficacy disappears quickly after the treatment is withdrawn, posing a constraint to the feasibility of these designs.

A special class of RCT designs is characterized by re-randomization. Some types of enrichment are sequential parallel designs (3), two way enriched designs (5) and sequential enriched designs (SED) (4). These designs not only address the issue of high placebo response but also increase trial efficiency.

In these designs, responses are measured at intermediate points in a patient’s treatment regimen; based on these responses, patients may be re-randomized to a second group of treatments. The purpose of the re-randomization is to provide a second comparison of the drug and placebo. Because of multiple points of randomization, these designs demonstrate higher efficiency than the traditional randomized parallel design. They also do not require the same assumptions about the conditions as required for the N-of-1 or crossover trials.

Sequential multiple assignment randomized trial (SMART) (1) design is another example of a trial design that re-randomizes at least some of the patients. SMARTs examine viable treatment strategies and typically do not incorporate placebo arms. However, this is an area that needs more exploration, i.e. the use of placebos in SMART designs. SMARTs are usually done with the purpose of finding optimal sequencing of treatments that are tailored to the individual over time. This usually requires large sample sizes, however small sample SMART designs have also been proposed to more efficiently estimate initial treatment effects (9). These designs offer another option for rare disease research where the drug versus placebo comparison is necessary.

Various adaptive designs proposed in the past decade (6), may also provide improved efficiency in rare disease clinical trial design. Neither SMART designs nor enrichment designs are adaptive designs because the design characteristics are not a function of the accruing data. There are several drugs that have been approved from adaptive trial designs in the recent 3 to 5 years. Adaptive designs should certainly be considered to speed up the rare disease drug development. It is also possible to incorporate the ideas of adaptations, such as sample size re-estimation or adding or dropping arms in the aforementioned enrichment or SMART designs. Furthermore, it is known that RCTs can effectively avoid confounding and are the gold standard, but trial designers and analysts are not always trained on how to plan and implement randomization properly when considering the adaptive or innovative designs requiring re-randomization. In light of the increasing popularity of adaptive and enrichment designs with multiple stages, where updating the randomization ratio or re-randomizing the same or new patients is possible, it is important to monitor its practice and impact on ongoing trials.

Since this topic of assessing the use of re-randomization in clinical trials is an important topic which can assist in speeding up the drug development, not only in common disease areas but also rare diseases or small sized trials, we would like to revive this working group to continue to perform more research on this topic and also disseminate our methods and results to the public.