Maurie Markman, MD
Asserting that the clinical trials process in oncology is in a state of disarray is only to declare the obvious. Fewer than 4% of patients with cancer in the United States participate in clinical trials, the elderly and individuals with clinically relevant comorbidities (the “real world” of oncology) are strikingly underrepresented in the research portfolio, and there is no comprehensive and rational clinical trials strategy to move the essential precision medicine paradigm forward. These distressing observations make clear that major reform at multiple levels is needed.
<.005” is reached so that investigators can declare that one approach is superior to another in a phase III randomized trial that is preferably double-blind and placebo-controlled.
In the realm of oncology, noninferiority trials offer another approach for examining the clinical utility of a novel product or combination regimen. In these studies, the fundamental goal is to improve a nonefficacy endpoint such as a reduction in treatment-related adverse effects or shorter duration of therapy while not negatively affecting the efficacy, such as overall survival (OS), that has been established for the current standard of care.
The authors do not cite specific examples of sample size requirements in oncology studies but they make their point with an example from the realm of arthritis management. A randomized noninferiority trial comparing celecoxib versus ibuprofen or naproxen required a population of more than 24,000 participants to satisfy the statistical and regulatory mandates. Although such a large population could never be contemplated in an oncology trial, the potential for substantially larger studies than currently employed to document noninferiority in cancer care strategies is a very realistic possibility.
Consider, for example, the impressive activity observed in trials of combination immunotherapy in numerous clinical settings. The clinically relevant toxicity observed in studies of these therapies is highly concerning. No longer is the discussion regarding toxicity focused on grade 4 neutropenia or anemia, which are generally quite controllable, but rather on complex, expensive, often very difficult-to-manage, and potentially fatal immunological adverse effects that may require emergency department visits and hospitalizations.2
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