The Future of Clinical Trial Design in Oncology

Abstract

Clinical trials represent a fulcrum for oncology drug discovery and development to bring safe and effective medicines to patients in a timely manner. Clinical trials have shifted from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to become adaptively designed and biomarker-driven evaluations of molecularly targeted agents and immune therapies in selected patient subsets. This review will discuss the scientific, methodological, practical, and patient-focused considerations to transform clinical trials. A call to action is proposed to establish the framework for next-generation clinical trials that strikes an optimal balance of operational efficiency, scientific impact, and value to patients. SIGNIFICANCE: The future of cancer clinical trials requires a framework that can efficiently transform scientific discoveries to clinical utility through applications of innovative technologies and dynamic design methodologies. Next-generation clinical trials will offer individualized strategies which ultimately contribute to globalized knowledge and collective learning, through the joint efforts of all key stakeholders including investigators and patients.

Figure 1:. Key Considerations and Clinical Trials Framework from Drug Discovery, to Clinical Trials, to Post Market Surveillance.

The current drug development pathway, including the number of compounds entering clinical testing, number of study participants in phase I, II, and III trials, and the timeline from preclinical testing to market approval is provided. Advances in trial design, conduct and analysis (summarized in white boxes) may lead to more focused trials involving fewer participants with an accelerated timeline for clinical development.

Figure 2:. The Journey of a Clinical Trial Participant in the Next Decade

As cancer clinical trials continue to evolve over the next decade to transform patient care, a forward looking vision into the journey of a cancer clinical trial participant in 2030 helps to set an inspirational goal (top pathway in red): A patient undergoes curative surgery in a local hospital with tumor specimen and germline blood immediate processing in a centralized laboratory for multi-omic molecular evaluation, digital spatial profiling and immunophenotyping. In addition to engrafting the tumor in patient-derived models, blood and other body fluid samples and conventional radiological imaging are collected pre- and post-surgery for ctDNA and radiomic analyses. All deidentified clinical, molecular and radiological data are entered into an international database with an integrated computational model for AI-based prediction of relapse risk. These results are deliberated via a virtual tumor board with clinical input from the local treating physician teams to recommend the best course of action. Persisting ctDNA as quantified by a tumor-informed, ultrasensitive assay suggests the evidence of molecular residual disease (MRD). The patient is recruited to an interception clinical trial with an anticancer drug combination based on analysis from the multidimensional characterization of resected tumor, as well as from functional drug sensitivity testing of the patient-derived models. There are frequent dynamic assessments of ctDNA to determine if there is molecular response or clearance. Any increase in ctDNA and changes in radiomic profile, upon repeat confirmation, signify molecular progression. Clinical samples at molecular progression and patient-derived models that have been treated with the same drugs are interrogated to suggest treatments that can be used to pre-empt acquired clinical resistance. In this clinical trial, the patient alternates between virtual visits and in person visits, based on risks and occurrences of any treatment emergent adverse events. Throughout the duration of the clinical trial, the patient provides regular update through an ePRO app on a smart phone and wears a device that collects vital signs, cardiac rhythm, and blood glucose on a continuous basis. These data and all clinical information collected in the patient’s EMR are electronically compiled into summary statistics that can be generated into reports for specified time intervals. If any of the ePRO entries or physical measures reach a reportable threshold, an electronic alert is sent to the patient as well as treating physician. Upon publication of the clinical trial results, individual level data collected are deposited into an international database with open and controlled access to enable sharing with the public, as well as researchers and investigators respectively. In addition, the data are entered into a rapid learning system to understand how this case compares to other similar cases that have been collected on clinical trials as well as from RWE.