Draft Guidance: Re-examined Oncology Protocols Say Maximum Tolerated Dose is Not for Everyone
Oncology drug trials should consider a wide range of dosages and how they impact a wide variety of participants, rather than immediately titrating patients up to the maximum tolerated dose (MTD), the FDA said in a new draft guidance.
The draft re-examines traditional oncology protocols, which typically attempt to get as many participants as possible to the MTD to balance maximum efficacy with minimum adverse events.
But while that technique may have worked for cytotoxic chemotherapy medications with a steep dose-response curve, it’s not optimal for many new agents, many of which target very specific biomolecular mechanisms. Once these drugs interact with their intended pathways, pushing the dose higher and higher does not necessarily increase benefit — but it does frequently increase the incidence of adverse events (AEs), which can be enough to impact patient quality of life and impair adherence, the agency said.
According to the draft, before launching studies, sponsors need to have various dose strengths available. “Perceived difficulty in manufacturing multiple dose strengths is an insufficient rationale for not comparing multiple dosages in clinical trials,” the guidance said.
Dose-finding trials should also investigate a wide range of doses in as widely varied a population as possible. This should identify any patient characteristics that might significantly affect pharmacokinetics. If there aren’t enough patients, or a wide-enough variety of patients, sponsors can use simulated exposure metrics in these subpopulations.
In addition, adaptive trial designs can be employed to drive patients to one or more dosage arms as interim analyses provide safety and efficacy data. But each dosing arm needs to collect safety and tolerability data, as well as the percentage of dosage interruptions and discontinuations, and these findings should be compared across the arms.
Sponsors should also focus on low-grade AEs as well as more serious problems. Low-grade AEs, like mild-moderate diarrhea, “may still significantly affect a patient’s ability to remain on the drug for extended periods,” the agency says. Patient-reported outcomes are a key way to assess these impacts, and they should be part of every dose-finding study, the guidance says.
Furthermore, dose optimization should be undertaken as part of a drug’s developmental pathway, or in registration trials. Sponsors should “plan their developmental programs such that identification of the optimal dosage can occur prior to or concurrently with the establishment of the drug’s safety and effectiveness,” before submitting a marketing application. Drugs on expedited pathways won’t be exempt from this requirement, the document notes.
The FDA has asked for comments on the draft by March 19.
Read the draft guidance here: https://bit.ly/3XDVyZD.