“Basket” clinical trials: an innovative methodology to accelerate the development of treatments for rare diseases
Given the diversity and rarity of rare diseases, so-called “basket” clinical trials offer an innovative methodological approach: evaluating the same treatment in patients with different conditions but sharing a common biological mechanism. Building on the work conducted within the DREAMS consortium, coordinated by Xavier Nissan (CECS / I-Stem), a systematic review of recent literature, co-authored by AFM-Téléthon, the Institute of Myology, I-Stem, and Genethon, published in the Orphanet Journal of Rare Diseases (Wael et al. 2025), provides an overview of these approaches and the barriers to their implementation, despite their potential to accelerate the development of innovative drugs for rare diseases.
The development of treatments for rare diseases remains a major challenge. It faces several obstacles, such as the small number of patients, the heterogeneity of the diseases, the wide geographic dispersion, and the lack of natural history data and standardized evaluation criteria.
In this context, “basket” clinical trials represent a promising alternative. They involve evaluating the same therapeutic solution in patients with different diseases but who share a common biological (pathophysiological) characteristic, such as a genetic or molecular abnormality (e.g., autophagy).
Untapped Potential for Rare Diseases
KHAZEN W et al. (2025) report that “basket” trials are primarily used in oncology (rare forms of cancer, 27 out of 36 studies) and still too rarely for rare diseases. The majority of these studies (81%) were Phase 1/2 clinical trials, demonstrating the exploratory and early-stage nature of these innovative designs in clinical development.
Furthermore, these studies were predominantly non-randomized and open-label. Traditional clinical trial methodologies are difficult to apply to (ultra-)rare diseases, particularly due to the small number of patients (often spread across different countries or even continents) and the often marked heterogeneity of the conditions.
Particularly significant methodological constraints
This limited use in rare diseases (excluding oncology) can be explained by several factors:
- the lack of validated biomarkers shared across different diseases,
- the difficulty in defining harmonized efficacy assessment criteria,
- the regulatory and methodological complexity of multi-disease protocols,
- constraints related to the small number of patients, spread across multiple countries,
- and the underutilization of innovative statistical methodologies (Bayesian , AI).
A strategic lever to accelerate therapeutic innovation
Despite the identified challenges, the authors highlight the strong potential of “basket” trials in the field of rare diseases. These approaches could enable better utilization of knowledge regarding common biological mechanisms, optimize patient enrollment in clinical trials, promote the repositioning of existing treatments, and strengthen collaborations between researchers, clinicians, regulatory authorities, and patient associations. More broadly, they are part of a research dynamic that is more collaborative, cross-disciplinary, and resolutely centered on patients’ real needs.
In summary, this review highlights both the opportunities and limitations of “basket” studies in rare diseases and proposes a roadmap to fully exploit their potential. It calls for a concerted effort by regulatory authorities, physicians, researchers, methodologists, and patient representatives to expand their use and maximize their impact across the spectrum of rare diseases.
