Each year, the Friends of Cancer Research (Friends) Annual Meeting addresses critical issues in oncology drug development and features experts proposing unique approaches to overcoming current challenges. On Day 2 of the Friends Annual Meeting 2021, panelists will focus on the pressing need for improved dose-finding studies in oncology drug development and discuss proposals to replace the routine dose finding studies as outlined in the soon to be released white paper. The white paper proposes concepts to facilitate a paradigm shift to apply long standing guidance on dosing studies to oncology clinical trials to improve patient outcomes.
Historically, dose-finding trials conducted before registrational clinical trials focused on identifying the Maximum Tolerated Dose, or MTD, to select a dose that provided the highest concentration of drug with “tolerable” side effects. The MTD was selected on the theory that higher doses lead to better efficacy. However, with the advent of newer, sometimes targeted therapies, many drugs are efficacious well below the MTD and precipitate fewer side effects. Despite this, the MTD is often used for registrational trials and ultimately FDA approval.
“Using too high of a dose can lead to a poor quality of life and sometimes precludes patients from taking the very treatment they need. Instead of always going forward with the MTD, there should be due diligence up front to identify a dose that’s better optimized. Performing studies in the pre-clinical setting addresses the root cause of the dosing problem in oncology and will go a long way in changing the paradigm and improving patients’ quality of life.”
– Anne Loeser, a patient advocate who co-founded the Patient Centered Dosing Initiative (PCDI)
In 2013, Friends hosted its annual meeting focused on suggestions for dose-finding trials to support more appropriate doses and published an issue brief entitled “Optimizing Dosing of Oncology Drugs.” Yet many studies continue to use the MTD despite these recommendations. As such, Friends recently convened a multi-stakeholder group to identify challenges to implementing these trials, propose solutions to overcome issues, and set expectations for dose-finding studies in the oncology pre-market setting in the future.
The challenges to changing dose-finding studies in oncology include 1) a misconception that these studies are too time consuming, preventing patients from quickly getting access to the drugs they need, and 2) an antiquated assumption that higher doses of drugs always lead to increased efficacy. Taking time to perform appropriate randomized dose-finding trials with at least two doses before the registration trial supports a better characterization of the drug that can lead to optimal treatment for patients with fewer side effects. During the presentation on November 10, panelists will discuss their findings for overcoming these challenges and propose key considerations for dose-finding trials.
“An oncology drug development paradigm that defaults to selection of the maximum tolerated dose has too often led to doses and schedules that are inadequately characterized before initiating registration trials. The correct dose and schedule are the foundation of future drug development. Not having the right dose is virtually building a development program on an unstable foundation and can have repercussions on the entire development program.”
– Marc Theoret, MD, Deputy Center Director of the Oncology Center of Excellence, FDA.