Cancer immunotherapy alternative dosing regimens: New FDA draft guidance

Regulatory NewsRegulatory News | 25 August 2021 |  By 

New draft guidance for developers of cancer immunotherapies will help them support alternative dosing regimens with pharmacokinetic-based criteria.
The newly available draft guidance from the US Food and Drug Administration (FDA), wrote the agency in the draft, can be used when sponsors “seek approval of alternative intravenous (IV) dosing regimens that are different from those tested in clinical efficacy and safety trials.”
Programmed cell death receptor-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) blocking antibodies have become a mainstay of oncology treatment. Since the first approvals of Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab) for melanoma in 2014, the number of cancer immunotherapies has grown, as have indications; between the two drug classes, the number of indications for these antibodies now nears two dozen.
However, the potential for infusion reactions and the burden and infection risk of hospital- or infusion center-based administration of the IV agents can make alternate dosing intervals an appealing option for patients and clinicians. Stretching dosing out from a 3-week to a 6-week interval can reduce the therapeutic burden on all parties. Alternate dosing regimens may also switch from body weight-adjusted dosing to flat dosing.
The new draft guidance points to an approach grounded in population pharmacokinetic (pop-PK) modeling to support alternative dosing regimens for an already-approved PD-1 or PD-L1 blocking antibody.
The population used for the modeling should include “all indicated patient populations,” and a wide range of dosing regimens should be included. A validated, fit-for-purpose pop-PK model should be employed; a draft guidance is available as part of FDA’s model-informed drug development suite of resources. (RELATED: FDA revises 1999 draft guidance on population pharmacokinetics, Regulatory Focus 11 July 2019)
Sponsors should make sure that a pop-PK-based application for an alternative dosing regimen uses the regimen used to show efficacy in clinical trials as the reference dosing regimen.
In terms of PK, the average area under the curve and the trough serum concentration should not drop more than 20% lower compared to the reference regimen. The average steady state maximum serum concentration should not exceed the reference regimen’s; an exception to this should be backed with evidence that the new regimen would have an acceptable safety profile.
Early interaction is encouraged for sponsors planning to use the pop-PK strategy to support submission of an alternative dosing regimen, taking advantage of the model-informed drug development paired meeting pilot program if needed.
The draft guidance outlines information that should be included in a meeting package, including relevant background information, a summary of exposure-response relationships for both safety and efficacy, a strategy and plan for simulation, and specific questions related to the proposed strategy.
Finally, the draft guidance lists documents that should be included in submissions requesting approval for alternative dosing regimens. In addition to a summary document, sponsors should submit a pop-PK report that includes up-to-date information on model validation and performance; a PK study report, “if applicable; a simulation report detailing the strategy and including a “direct comparison of PK profiles and parameters from 117 alternative and reference dosing regimens;” and other supporting documents.
FDA is seeking comment on the draft guidance within 60 days.


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