Precision medicine in clinical research has changed how trials are conducted and created opportunities for matching interventions with patients with specific genetic mutations. New trial designs are replacing standard Phase I, II, and III protocols, allowing for accelerated drug evaluation and molecular-based individualized treatment. Overall, clinical trials have shifted from tumor type-centered to gene-directed and histology-agnostic trials, with adaptive designs and personalized treatment strategies tailored to individual biomarker profiles.
In oncology, discovering biomarkers and genetic mutations potentially predictive of treatment benefits has motivated a move toward precision medicine. Novel study designs which have become more prominent include biomarker-guided trials such as basket, umbrella, or platform trials (collectively known as Master Protocols). These novel study designs enable efficient clinical evaluation of multiple therapies in various histologically and biologically defined cancers. These complex trials require extensive planning and attention to many factors, including statistical design, monitoring, and analysis of sub-studies. In turn, trial teams require expertise in biology, clinical oncology, bioinformatics, and statistics.
Master Protocols Defined
In March 2022, the FDA provided a guidance document on Master Protocols. According to the FDA, “master protocols use a single infrastructure, trial design, and protocol to simultaneously evaluate multiple drugs and/or disease population in multiple substudies, allowing for efficient and accelerated drug development.” Due to the complexity of these trials, researchers must design and conduct them well to ensure patient safety and generate data that complies with regulatory standards for demonstrating the safety and effectiveness of the intervention. Master protocols types include
- single investigational drug or investigational drug combination across multiple cancer populations
- investigational drugs or investigational drug combinations in single cancer type
- master protocol designs which incorporate design features common to both basket and umbrella trials and may evaluate investigational drugs and/or drug combination regimens across multiple tumor types
Source: U.S. FDA
Master Protocol in Practice
The Lung Cancer Master Protocol (Lung-MAP) is a completed biomarker-driven master protocol for advanced lung squamous cell carcinoma (LUSC), which began in 2014. The Lung-MAP study was the first biomarker-driven master protocol launched by the U.S. National Cancer Institute (NCI). The trial demonstrated that biomarker-driven master protocols are feasible for aggressive disease and that the infrastructure of a biomarker-driven master protocol is an efficient approach for targeted therapies in rare populations.
Master Protocol: Potential Benefits
Flexibility and efficiency. The FDA highlights the potential advantages of using a master protocol, including flexibility and efficiency in drug development. In addition, a master protocol provides an opportunity to incorporate efficient approaches, such as centralized data capture systems. A recent review described other potential benefits of the master protocol framework, including not requiring individual protocols for each sub-study and increased operational efficiency as the same infrastructure is used across sub-studies. It also allows information sharing across sub-studies through innovative statistical methods. Additionally, master protocol trials enable recruitment from a broader population than traditional trials, and each participant has a greater probability of being on an experimental arm.
Cost and Time. An economic evaluation of the cost and time required for platform trials vs. conventional trials concluded that the former could improve efficiencies in terms of cost and effort. The authors compared three scenarios:
- Scenario 1: a single platform trial.
- Scenario 2 (conventional trials): a multigroup followed by five 2-group trials.
- Scenario 3 (conventional trials): a series of ten 2-group trials.
Platform trials (Scenario 1) have higher setup time and cost requirements. However, the cumulative setup costs of multiple conventional trials in Scenarios 2 and 3 demonstrated an increase of 216.7% and 391.1%, respectively, compared to Scenario 1. Compared to the platform trial, the median increase in total cost for Scenario 2 and 3 was 17.4% and 57.5%, respectively. Lastly, the median increase in cumulative trial duration was 171.1% for Scenario 2 and 311.9% for Scenario 3 compared to Scenario 1.
The benefits of increased efficiencies brought about by master protocol design in oncology have created interest in its application in non-oncology research.
Pediatric Drug Development. The authors of a recent article on the role of master protocols in pediatric drug development describe the usefulness of a single infrastructure and how two competing companies can work together to design and execute the platform. To address the challenge of conducting clinical trials in small pediatric populations, Janssen and Lilly have collaborated on a cross-company pediatric platform trial in pediatric Crohn’s disease.
Novel Therapeutic Oncology Devices. In answer to the challenges faced by clinical testing of radiation oncology devices, the authors of a recent review propose using master protocols to optimize regulatory, financial, administrative, quality assurance, and statistical efficiency.
Looking Ahead for Protocol Design
Prior to the FDA 2022 guidance, there was an inconsistency in definitions for master protocol trials. Due to this and the complexity of such trials, there were challenges in protocol design and execution with potential implications for patient safety and data generation in compliance with regulatory standards. The master protocol framework requires new statistical designs and consideration for operational challenges. In response, contract research organizations (CROs) like Vial can work with sponsors to improve operational efficiency through genetics-driven and adaptive design. Click here to learn more about the Vial Oncology CRO.