Novel clinical trial design and analytic methods to tackle challenges in therapeutic development in rare diseases

Abstract

While only a fraction of the worldwide population may have a particular rare disorder, millions of people worldwide are affected across the over 6,000 rare disorders and do not have a safe and effective approved therapy to help them live or manage complications from the disorder. Challenges to clinical development of new therapies in rare disorders include difficulty in powering and recruiting into a study in small and often heterogenous population, scarcity of natural history data informing critical design elements such as endpoint selection and study duration, and ethical and recruitment challenges in randomizing patients to a placebo arm. In this review, we describe some existing and novel strategies to tackle these challenges, by efficient utilization of available resources. We discuss the role of natural history studies and endpoint selection as they remain critical features that apply across designs and disorders. We also review some novel clinical trial designs including incorporating external control and/or longitudinal measures, master protocol designs, and adaptive designs. Additionally, we review some analytic strategies that are often associated with these designs, such as the use of causal inference methods, and Bayesian methods. We hope this review will raise awareness of these novel approaches and encourage their use in studies of rare diseases.

Single-arm clinical trials: design, ethics, principles

“…31 Owing to the scarcity of patients, conducting controlled trials and recruiting patients becomes exceptionally difficult. 32 In such cases, finding a sufficient number of patients and control participants tends to be time-consuming and costly. However, the single-arm trial design does not include a parallel control group and only involves treating patients, conducting follow-up and analysing the data.…”

“…However, the single-arm trial design does not include a parallel control group and only involves treating patients, conducting follow-up and analysing the data. 32 Thus, single-arm trials are more suitable for rare disease research because of their smaller sample Review size while aiding in understanding the pathogenesis, pathophysiological characteristics and treatment and prevention of rare diseases. For example, Wagner et al analysed the therapeutic efficacy of malignant perivascular epithelioid cell tumour through self-controlled single-arm trial.…”

Reading Between the Lines: Navigating Nuance in Medical Literature to Optimize Clinical Decision-Making and Health Care Outcomes

“…○ How might study discontinuations have influenced the results, and was enrollment sufficient for the results to be clinically and/or statistically meaningful? 54 , 56 , 60 …”

“… 54–56 Numerous ways to limit or reduce the risk of methodological bias in clinical trials have been proposed. 52–55 , 59 , 60 …”

“…58 ○ How might study discontinuations have influenced the results, and was enrollment sufficient for the results to be clinically and/or statistically meaningful? 54,56,60 Clinical trial registration in a publicly accessible register such as ClinicalTrials.gov has been shown to decrease the risk of bias, and HCPs can employ the Cochrane Risk of Bias (RoB2) assessment tool to assess the risk of bias in randomized controlled trials. [54][55][56] Numerous ways to limit or reduce the risk of methodological bias in clinical trials have been proposed.…”