applications (775). A key focus of the guidance was encouraging trial sponsors to conduct more randomized controlled trials instead of the commonly used “single-arm” trials that lack control arms. While single-arm trials have been useful for developing new classes of drugs for diseases that previously had no effective treatment options, the clinical landscape has evolved (see Figure 14, p. 73). It is now more appropriate to compare new drugs against the current standard of care to ensure that novel treatments provide greater benefits or lower toxicities than what is currently available. The guidance also recommended that trial sponsors either continue and expand the trial used for Accelerated Approval or start a second confirmatory trial before Accelerated Approval is granted. Currently, companies often start confirmatory trials after Accelerated Approval is granted, which leads to delays in granting traditional approval. Advances in cancer care that prolong the lives of millions of cancer survivors are a major underlying reason for the increasing reliance on Accelerated Approvals for cancer therapies. This is because it is taking more time to demonstrate improvements in overall survival as patients live longer. However, there is ongoing concern that early endpoints do not always correlate with overall survival (776). One potential driver of this discordance is the way in which doses of new drugs are selected. Traditionally, cancer drug doses have been determined by escalating the dose given to patients until it is no longer tolerable. This strategy is less useful for targeted therapies and immunotherapies because they may be most effective and result in less severe side effects at doses lower than the “Maximal Tolerated Dose.” To encourage selection of optimal doses of new drugs, FDA issued a draft guidance titled “Optimizing the Dosage of Human Prescription Drugs and Biological Products for the Treatment of Oncologic Diseases,” in January 2023 (777). Additionally, a workshop in July 2023 co-organized by FDA, AACR, and the American Statistical Association titled “Overall Survival in Oncology Clinical Trials” convened experts from across the cancer research community to discuss best practices to improve how clinical trials collect and assess endpoint data. Some key recommendations for trial sponsors discussed during the workshop included: having a prospective plan to collect and analyze overall survival in all clinical trials, even if it is not the primary endpoint; considering the disease and treatment setting to determine how long data should be collected, instead of a standardized 5-year follow-up; and prioritizing recruitment of patients positive for predictive Summary of Current Clinical Trial Practices and Recommended Changes DRUG DEVELOPMENT TOPIC CURRENT PRACTICES RECOMMENDED PRACTICES Trial Diversity • Demographic data are analyzed after trials are completed • Build long-term partnerships with patient and community organizations • Develop diversity strategies prospectively • Address barriers to participation • Support clinical research sites in historically underserved communities Decentralized Trials • Patients have frequent in-person visits to a large academic medical center • Increase use of telehealth visits • Enable remote consenting • Utilize local health clinics and imaging • Minimize unnecessary data collection Accelerated Approval • Relies on single-arm trials • Confirmatory trials are initiated following Accelerated Approval • Increase use of randomized trials • Either start confirmatory trial before submitting Accelerated Approval application, or continue existing trial Dose Optimization • Gradually increase dose until patients cannot tolerate the drug • Identify doses that elicit the intended biological effects • Further study more than one dose following a dose-finding trial Overall Survival Data • Many trials do not collect or plan to analyze overall survival data • Patients are followed for standardized time frames • Plan to collect and analyze overall survival data for every trial, even if it is exploratory • Justify length of follow-up based on data • For targeted therapies, prioritize recruitment of biomarker-positive patients TABLE 4 AACR Cancer Progress Report 2023 157 Advancing the Future of Cancer Research and Patient Care Through the Adoption of Evidence-Based Policies
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