Early-phase trials usually focus on safety objectives and may not require a control or comparator placebo arm. Measures of efficacy or improvement in quality of life (e.g., mobility), if any are to be made, are usually exploratory. Therefore, in early-phase trials, a concurrent control group and blinding are generally not as critical as for a confirmatory efficacy trial (Phase 3 trial). However, in early phases of clinical development, a control group can be useful to interpret safety data and provide a comparator for any assessments of activity or efficacy.
Given the small number of patients with rare diseases, some experts advocate reducing the number of people who receive non-therapeutic doses in clinical trials. According to Peter Marks, M.D., PhD., former Director - Center for Biologics Evaluation and Research (CBER) even in phase 1 studies, you want to make sure that the doses of any therapy are optimized as quickly as possible. Skipping the very low doses could add a bit more risk to a clinical trial, but such risk can be mitigated by detailed pre-clinical data from cell-based studies or animal models. [2]
If a new therapy is very promising, it might be unethical to have patients receive a placebo. You may also find yourself in a situation where patients do not want to enroll in the trial, because they fear ending up in the placebo arm. Consequently, some trials put all patient participants on the investigational treatment. Although this prevents comparisons with patients who do not get the treatment, efficacy could be determined in other ways, such as comparing a patient’s status during and after the trial to a baseline determined at the start of the trial, or using a synthetic control arm, wherein a placebo group is modeled based on previously collected real-world data. [2]
Pro tip:
An increasingly popular approach to aid enrollment of more patients with a rare disease in a trial is to conduct decentralized trials, in which patients participate at various sites scattered around the country, or even across the world. Virtual consultations and wearable technology, from a smartwatch or a designed-for-purpose device, could collect data on patients from their homes, reducing the need for in-person visits.