Regulatory Focus - Friends of Cancer Research urges early dose-finding studies to reduce treatment toxicity
Friends of Cancer Research is calling on all stakeholders in the cancer community to move away from the idea of “more is better” in drug dosing and begin to incorporate dose-finding studies into the cancer trial process.
Dose optimization is the focus of a new white paper that the group released at its 25th annual meeting. The paper offers recommendations for performing adequate dose optimization studies in oncology, with a focus on the pre-market setting. “These studies will improve care in oncology by decreasing toxicities while maintaining efficacy and ultimately allow more patients to benefit from treatments for a longer period of time,” according to the white paper.
During the meeting, Mirat Shah, MD, of the US Food and Drug Administration’s (FDA’s) Office of Oncologic Diseases and a member of the working group that developed the white paper, said that FDA is working on dose optimization guidance for oncology drugs that will provide general advice and recommendations, which would be broadly applicable across development programs. The forthcoming guidance is part of a new FDA effort known as Project Optimus.
“Within that overall framework, we are very interested in working with stakeholders and makers of individual drugs to figure out ways to apply those general recommendations to their specific development program,” she said. “This is coming.”
The concept of dose optimization is commonplace in other drug development areas, with most drug being evaluated in randomized dose-ranging trials to gain understanding of how different drug doses impact efficacy and toxicity. However, in oncology, dose-finding studies have been limited mainly to Phase 1 trials that seek to identify the maximum tolerated dose (MTD). Friends of Cancer Research has been raising the issue of dose optimization since 2013, but while there have been several workshops and publications on the topic, there has been limited progress.
One of the major hurdles to performing dose-finding studies in oncology is the perception that these studies will be too time-consuming and slow the approval of life-saving drugs. But the white paper counters this idea, saying that dose-finding studies are critical to understanding the therapeutic window of a drug and its full benefits for patients.
“Moving ahead with an ill-optimized dose for the registrational trial can negatively impact the ability to document the true benefit of the drug,” according to the white paper. “Identifying a dose with improved tolerability will lead to more patients missing fewer treatments due to toxicities while enabling them to remain on a working treatment for longer. In addition to individuals staying on treatment longer, a more appropriate dose may also provide an opportunity for additional patients with poor performance status to gain access.”
Spending time on dose-finding doesn’t need to slow the development process, Shah said. She encouraged drug sponsors to plan for dose optimization early in the process and begin to view it “as a key component of establishing that a drug is safe and effective.” FDA is “very open” to providing feedback on dose optimization plans early in development, including during the pre-Investigational New Drug (IND) meeting and again as data from the development program becomes available.
Another barrier to dose optimization is the idea, often shared by physicians and patients, that lower doses are not as effective in cancer treatment. In the white paper, Friends of Cancer Research calls for provider and patient education about the value of a lower dose. They also encourage sponsors to consider including an interim assessment into trials and allow for intra-patient dose escalation to address the potential for underdosing.
The white paper also suggests that sponsors use pre-clinical data to narrow the range of doses for clinical evaluation. A pre-registrational dose-finding study should ideally be randomized, compare at least two doses, and confirm the dose selected for the registrational trial. The selected dose should maximize benefit-risk by measuring efficacy in a “sizable number of patients,” according to the white paper.
Friends of Cancer Research white paper on dose optimization