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Regulatory Focus – NCI official raises concerns about FDA’s cancer drug dose optimization guidance

Regulatory Focus – NCI official raises concerns about FDA’s cancer drug dose optimization guidance

The head of the National Cancer Institute’s (NCI) investigational drug research branch said that recent draft guidance from the US Food and Administration (FDA) on finding the optimal dosage for cancer drugs could slow drug development. On the other hand, several stakeholders praised the guidance while asking for additional details such as how to factor in dosing for multi-drug treatments.

Earlier this year FDA published a draft guidance to help sponsors identify the optimal dosage for cancer drugs earlier in clinical development. The agency recommended a new approach for selecting such dosages for modern, targeted oncology drugs. (RELATED: FDA details approach for finding optimal dosages for new cancer drugsRegulatory Focus 17 January 2023)

FDA said that dose-finding trials for cytotoxic chemotherapy drugs have historically been designed to determine the maximum tolerated dose (MTD), the approach may not be suitable for modern oncology drugs such as kinase inhibitors and monoclonal antibodies. Instead, the agency proposes a number of recommendations in the draft guidance to help sponsors determine proper drug dosage sooner for such drugs.

Jeffrey Moscow, chief of the NCI’s Investigational Drug Branch center under the National Institutes of Health (NIH), wrote to the agency expressing his concern that the guidance could lead to more burdensome clinical development and raises ethical concerns.

“We have concerns with the guidance that requires studies of oncologic investigational agents to enroll additional patients on multiple dose levels to assess activity (for the purpose of dose optimization) before the clinical effectiveness of the therapy has been established, and before the tolerability of therapy has been determined to be unacceptable,” he wrote in comments to the guidance docket, which closed on 20 March.

Moscow noted that most phase 1 studies don’t lead to marketable drugs that show benefits for patients. He said that subjecting a substantial number of additional patients to dose optimization studies where the drug may be ineffective or non-viable may mean exposing a larger number of patients to unnecessary toxicity.

“Most investigational drugs that are developed into marketable agents are tolerable at the dose used in phase 3 studies,” Moscow added. “Only a minority of drugs are dosed too high. The FDA guidance focuses on a small minority of approved oncologic agents.”

Moscow also argued that FDA’s proposed guidance does not contain clear criteria for defining tolerability and adds that if the agency plans to use it as a primary endpoint it needs to be defined as rigorously as efficacy. The NCI chief also said it is “pure conjecture” for most drugs when trying to determine a suitable level of target engagement based on an arbitrary point in time when trying to understand effective dosage.

Moscow said that NCI agrees with the principle behind trying to determine dose optimization but said it should only be considered in phase 2 clinical trials and after there is clear evidence of the drug’s efficacy and tolerability.

“Our concern is that the proposed implementation of the FDA’s guidance will significantly slow oncology drug development and will substantially increase the cost of oncology drug development; runs counter to FDA initiates to streamline clinical trials by requiring additional correlative studies on additional patient cohorts; will require dose finding patient cohorts for drugs and drug combinations that will ultimately prove to lack significant clinical activity; and will require patients to enroll in cohorts without statistically defined scientific goals,” he said. “Furthermore, in the context of precision oncology, where drug development is focusing on progressively smaller subpopulations, the proposed approach is unlikely to be sustainable.”

In contrast to Moscow, the Friends of Cancer Research (Friends), a cancer research advocacy group, said it mostly agrees with FDA’s guidance. The group noted that the guidance considers concerns raised during multi-stakeholder meetings it organized that dose-finding oncology trials to identify MTDs may not be sufficient.

“With the advent of precision medicines designed to interact with specific oncologic pathways, the MTD may not only be unachievable but lower doses may achieve similar efficacy as higher doses while also having better tolerability,” said the group. “Several recent Oncologic Drugs Advisory Committee (ODAC) meetings have highlighted the importance of sufficiently characterizing and justifying the dosage in advance of the registrational study. FDA may issue post-marketing requirements (PMRs) to evaluate additional dosages, but these studies can be lengthy and challenging to conduct once a product is on the market.”

Friends noted that while FDA said that dose-finding trials do not necessarily need to be powered, the group wants more clarity in the guidance about statistical power and methods for evaluating the data collected to justify the optimal dosage. It also said that having lessons learned from drugs in the same class and suggestions for how to incorporate patient reported outcomes (PRO) in early trial designs may be useful.

The cancer research advocacy group also said the guidance should also address instances where it would be acceptable for patients participating in dosage optimization studies to cross over to an alternate dosage study.

“Additionally, the FDA should discuss the acceptability of combining data from patients receiving different dosages when dose-finding studies occur early enough in development to support other regulatory discussions, such as qualifying for breakthrough therapy designation,” Friends said.

The group also asked for more detail on how FDA plans to evaluate and interpret data justifying the dosage for the registrational trial, how the agency plans to incorporate dosage trials for expedited pathways, and about opportunities for sponsors to talk with the agency early and often.

Several drug developers, including Amgen, wrote in support of FDA’s draft guidance. The California-based biotech company offered some recommendations to include in the final guidance.

Amgen asked FDA to make it clear that dose optimization and dose finding should be data-driven and there are multiple ways to achieve that. While it appreciates the agency’s approach in determining dosing for single-agent monotherapies, it has asked regulators to take a case-by-case approach when looking at dose optimization determinations based on a combination of drug studies.

“We believe the guidance should also address how to optimize dosage for oncology products in development that have minimal activity as a monotherapy or are expected to provide the optimum results when used in combination, and thus are developed for use in combination with other oncology therapies,” said Amgen. “We believe a case-by-case approach is needed for optimizing dosage in these scenarios as well.”

Finally, the company asked FDA to include details in the final guidance on how to approach efficacy assessments, and which types of efficacy markers could be considered reasonable to measure.