FDA finalizes PK-based dosing guidance for PD-1/PD-L1 inhibitors

Regulatory NewsRegulatory News | 08 December 2022 |  By 

Keytruda is a PD-1 inhibitor made by Merck. (Source: Merck)

The US Food and Drug Administration (FDA) this week finalized guidance detailing how sponsors of programmed cell death receptor-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) drugs can support alternative dosing regimens for such drugs using pharmacokinetic (PK)-based modeling and simulation.
Notably, the population-PK-based approach detailed in the final guidance can be used to support new dosing regimens in the pre- and post-approval settings.

“Sponsors may seek approval of alternative intravenous (IV) dosing regimens that are different from those tested in the original clinical efficacy and safety trials that served as the basis of approval of the current dosing regimen, or in the pre-approval setting, dosing regimens that differ from those tested in earlier PK and efficacy studies conducted during development,” FDA explains.
“These alternative IV dosing regimens are typically designed to change doses and dosing intervals. Longer dosing intervals can minimize patient burden and reduce risks associated with more frequent administration (e.g., infusion reactions), as well as exposure to communicable diseases (e.g., SARS-CoV-2) associated with visits to hospitals or infusion centers.”
FDA further explains that the guidance applies to both PD-1 and PD-L1 monotherapies and combination regimens for which the dose or dose schedule of the PD-1/PD-L1 component is the only proposed change.
PD-1 and PD-L1 blocking antibodies have become a go-to treatment in multiple areas of oncology since FDA approved Merck’s Keytruda (pembrolizumab) and Bristol Myers Squibb’s Opdivo (nivolumab). Both drugs were first approved to treat melanoma but have since amassed dozens of indications. In the meantime, sponsors have been working to figure out how to effectively dose patients for specific cancers while reducing potential side effects.
As a result, FDA first published a draft guidance on the topic in August 2021 that focused on using population-PK (Pop-PK) modeling and simulations to support new dosing regimens. (RELATED: Cancer immunotherapy alternative dosing regimens: New FDA draft guidance, Regulatory Focus 25 August 2021)
“The Pop-PK model should be established with sufficient PK data from all indicated patient populations over a wide range of dosing regimens (i.e., different from the alternative dosing regimens),” FDA restates in the final guidance. “The model itself should be well validated and determined to be fit for the purpose.”
The agency says sponsors should refer to its Pop-PK guidance recommendations about the appropriate use of models. Regulators also add that sponsors can use simulations to derive the PK profiles and parameters following the alternative dosing regimens.
A key recommendation is that sponsors should consider talking to FDA early in their development process if they plan to use a PK-based criteria to support their alternative dosing regimen.
“The sponsor can seek regulatory input through regular IND meetings,” FDA said. “If a more detailed discussion on modeling and simulation strategies is necessary, the sponsor may request specific meetings through the model-informed drug development (MIDD) paired meeting program.”


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