The randomized, concurrent-controlled (placebo) blinded trial is generally considered the ideal standard for establishing effectiveness and providing treatment-related safety data – randomization in early stages of development is encouraged. For your design, you should consider stratifying randomization across disease stage/severity. This improves the internal validity of the trial, enhances statistical power, increases generalizability, optimizes subgroup analyses, and promotes ethical allocation of interventions. It is also an effective strategy for minimizing bias, ensuring balanced treatment groups, and generating more reliable and informative results in clinical trials.
In certain situations when conducting a randomized, controlled trial is not feasible (e.g., small target population for rare diseases, ethical considerations withholding potentially effective treatment), a single-arm trial using historical controls may be considered. This approach may involve an initial observation period. However, it is crucial to have a good understanding of the natural history of the disease. If the natural history is well-known and it is not possible to conduct a randomized, concurrent-controlled trial, an available therapy can be used as a comparison to evaluate the clinical performance of the intervention being studied. Established biomarkers can be used to help guide the dose and estimate efficacy.
With advances in technology and the use of real-world data, “digital twin” technology can be another approach to utilize in your trial design. This technology allows you to create a digital control group of your study participants and more patients will receive the treatment. This would be particularly useful for gene therapy trials, given the ethical considerations around withholding a potentially life-saving treatment.
Clinical trials need to get more personalized. Assuming that we’re talking about applications where handfuls of individuals — maybe 20, 30, 40 people — are available for a clinical trial, one has to start to really look on a very individualized basis. In a rapidly progressing rare disease, a trial can show a new treatment’s efficacy fairly quickly. With a gene therapy for Spinal Muscular Atrophy type 1, for example, you know within a year’s time if an intervention made a big difference.
– Peter Marks M.D., PhD. | former Director - Center for Biologics Evaluation and Research (CBER). [2]