Designing clinical trials for rare diseases can prove challenging with limited resources and high operation costs. But three nontraditional trial designs—platform trials, basket trials, and umbrella trials—could revolutionise the space. In this series, Clinical Trials Arena will explore each design and its potential to shape the future of rare disease research.

Basket and umbrella trial designs could open new doors in therapeutic rare disease research, but they remain largely underutilised outside of cancer. Even though basket trials have gained some momentum in rare diseases, umbrella trial use remain relatively stagnant.

Growth in use of basket and umbrella trials has primarily been in oncology, according to GlobalData’s clinical trials database, which collates publicly available protocols of therapeutic trial designs. An analysis of all therapeutic clinical trials with “basket” or “umbrella” in their trial title or description, sorted by initiation year over the past six years, shows that these designs have remained underused in indications outside of cancer. A slight uptick of these nontraditional trials in infectious disease treatments over the past two years is likely a consequence of Covid-19 investigations.

Pharmaceutical companies are leading the recent surge in basket and umbrella trials for rare diseases, according to the GlobalData database. In 2016, companies began an estimated ten such trials while institutions started to run around six. Fast forward to 2021, companies initiated an estimated 40 basket or umbrella trials while institutions started approximately eight studies.

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Umbrella trials lag behind basket approach

Basket trials can investigate multiple rare diseases simultaneously with a single treatment intervention. Meanwhile, umbrella trials can look at multiple treatments for one disease, saving on recruitment and protocol design costs.

But thus far, there have been far fewer clinical studies for rare disease treatments described as “umbrella” than as “basket” trials. Nevertheless, both nontraditional designs still make up only a very small fraction of the total number of rare disease investigations. In 2021, there were an estimated 42 basket trials and seven umbrella trials initiated, but more than 5,000 rare disease trials started in the same year.

Because umbrella trials require multiple treatments for one disease, they often require various companies and institutions to provide therapies. This requires more risk and complicated collaboration, which could include different stakeholders that normally don’t work together, explains NIH Director of Rare Disease Research Anne Pariser. As a result, it would likely take multiple umbrella trials in rare diseases before significant efficiencies appear, she notes.

Like platform trials, umbrella trials would work well for gene therapies in rare diseases areas such as neuromuscular junction disorders, Pariser says. A single capsid could be used as a delivery mechanism for multiple genes targeting a single disease, streamlining the normally extensive safety testing, manufacturing, and designing protocols that comes with running a single trial, she adds.

Basket trials target shared mutations

Rare diseases with shared underlying genetic mutations could benefit from basket trials, including when these clusters of diseases have different clinical manifestations, Pariser explains. Rare demyelinating diseases, which often have similar underlying causes, would also make sense for this design, notes a former FDA official who now works in regulatory consulting. Examples of rare demyelinating diseases include acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorders, as well as multiple sclerosis and its rarer variants.

Rare metabolic disorders often have causes within the same pathway, making them strong candidates for a basket trial design, Pariser says. Rare metabolic disorders include Fabry disease, Crigler Najjar syndrome, and Gaucher disease. The purpose of the basket designation is to save on administrative costs, such as avoiding the need to rerecruit clinical sites, a biostatistician adds.

For a nontraditional trial design to lead to an approval, the individual components of the basket trial would need conventional trial designs, the biostatistician adds. As in the case with platform trials, drug companies should propose basket or umbrella trial designs to the FDA with extensive animal studies, natural history data, and examples of previous, similarly structured trials, the former FDA official notes. There is always room for the FDA to be flexible, but due diligence in compiling non-clinical supporting research is essential, she says.