Precision medicine is reshaping how we view and treat disease. However, with that promise comes complexity: new therapies are increasingly targeted, diseases are redefined by molecular profiles, and patient populations are more fragmented than ever. Traditional clinical trial designs often can’t keep up. Accordingly, master protocols have emerged as an innovative solution that is built for the precision era.
Master protocols are adaptive, efficient frameworks that allow researchers to test multiple therapies or hypotheses within a single overarching trial. These designs break away from the one-drug, one-disease model. They have gained traction in areas like oncology and rare diseases, where matching targeted therapies to small patient cohorts is key.
Master protocols reduce redundancy, speed up timelines, enhance efficacy and efficiency, and reduce unnecessary burden on patients by limiting their exposure to interventions they are not suitable for. In this blog, we cover the three main master protocol designs: basket trials, umbrella trials, and platform trials.
Basket trials: One intervention, many diseases
Basket trials group patients with different diseases who share a common molecular alteration, allowing researchers to test a single therapeutic intervention across various conditions. This design has been widely used in oncology, where mutations in the same oncogene may be present across various types of cancers.
For instance, the MyPathway trials featured multiple “baskets” to evaluate the efficacy of pertuzumab and trastuzumab in patients with solid tumors with amplification, overexpression, or mutation in HER2. The trial's primary endpoint was objective response rate (ORR), with survival and safety outcomes as secondary endpoints. By grouping patients based on shared genetic alterations rather than disease, basket trials create a more efficient route for testing targeted treatments. This is especially useful when the alteration of interest is rare in any one condition.
The biotech company Alltrna is extending the utility of the basket trial approach beyond oncology. Alltrna is developing therapeutic tRNA molecules designed to target stop codon disease by restoring protein production. For the next phase of drug development, the company is using basket trials to evaluate the safety and efficacy of a single tRNA molecule across hundreds of diseases that share the same underlying mutation which creates a premature stop codon. Instead of designing separate drugs and trials for each condition, this innovative disease- and protein-agnostic strategy could dramatically reduce time and cost, while accelerating access to treatment for patients.
Umbrella trials: One disease, many precise interventions
Umbrella trials, by contrast, enroll patients with the same disease and stratify them into subgroups based on specific molecular or genetic markers. Each subgroup receives a treatment tailored to its unique biomarker profile. This approach enables a comparative evaluation of several targeted therapies within one disease area.
Lung cancer was previously approached as a single disease in clinical trials. In precision medicine trials for lung cancer, patients are instead stratified by subtypes such as adenocarcinoma and small cell lung cancer, and receive targeted therapies based on specific mutations that often involve EGFR and ALK. This biomarker-supported approach and evaluation of various interventions in one trial improves efficacy and accelerates drug development.
Platform trials - One disease, infinite adaptability
Platform trials represent the most flexible of the three designs. They incorporate multiple therapies and arms within a single, ongoing framework, allowing for seamless adaptation based on interim data. As data is collected, treatment arms may be dropped due to lack of efficacy or safety concerns, while new interventions can be introduced.
A notable example is the STAMPEDE trial, which began in 2005 to evaluate novel treatment strategies for men with high-risk, locally advanced or metastatic prostate cancer. As a multi-arm, multi-stage platform trial, STAMPEDE allows for the continual assessment of new therapies added to standard androgen deprivation therapy. More than 10,000 patients have been enrolled across several research arms, with ineffective treatments removed based on interim failure-free survival analyses.
This impactful trial demonstrates how a flexible and responsive platform design, built around a consistent standard-of-care control group, can rapidly generate conclusions about the efficacy of new treatments within a large patient population. This level of efficiency and adaptability would be difficult to achieve using traditional trial models.
Paving the way for scalable precision medicine
The growing adoption of these trial designs reflects a broader trend toward more efficient, personalized, and data-responsive research. A 2019 review found that the number of basket, umbrella, and platform trials had increased nearly threefold in just five years. As modern treatments become more complex, master protocols are increasingly seen as a key tool for enabling more efficient and widespread adoption of precision medicine in clinical trials.
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