FDA Final Guidance 8th August 202415 Dec 2024 13:58
Dosages selected for administration in a clinical trial(s) should be adequately supported by data
appropriate to the stage of development. Relevant nonclinical6 and clinical data (such as PK, PD,
safety, tolerability, dosage convenience, and activity), as well as the dose- and exposure-response
relationships should be evaluated to select a dosage(s) for clinical trial(s). An approach where a
dosage is chosen for a trial without adequate justification or consideration of all relevant data
may not be acceptable, because FDA may determine that patients are exposed to unreasonable
and significant risk, or there is insufficient information to determine risk, or the design of the
trial is deficient to meet its stated objectives and may place a protocol on clinical hold.
We support the principles of the “3Rs,” to reduce, refine, and replace animal use in testing when feasible. We
encourage sponsors to consult with us if it they wish to use a non-animal testing method they believe is suitable,
adequate, and feasible. We will consider if such an alternative method could be assessed for equivalency to an
animal test method.
FDA recognizes that the best approach to determining the optimized dosage(s) for a specific drug
development program depends upon a variety of factors including but not limited to the drug
class, proposed indicated patient population, and prior knowledge about the drug that is pertinent
to dosing. Sponsors are therefore strongly encouraged to discuss their plans for dosage
optimization with FDA during formal meetings, including early in clinical development.
8,9 The
briefing document should include a brief summary of available relevant data used to select the
proposed dosage(s); the oncology dosing tool kit is an available resource to summarize the
relevant data10. Sponsors may also consider the Model-Informed Drug Development (MIDD)
paired meeting program,11 if appropriate.
FDA recommends the following regarding collection of relevant data and trial design to identify
optimized dosages:
A. Clinical Pharmacokinetics, Pharmacodynamics, and Pharmacogenomics
• A PK sampling and analysis plan should be included in each protocol.
— The PK sampling and analysis plan for dose-finding trials should be sufficient to
adequately characterize the PK (e.g., linearity, absorption, distribution,
elimination) following the first dose and at steady-state (or after administration of
multiple or repeated doses if steady-state will not be reached) for each dosage
evaluated in the trial.
— The PK sampling and analysis plan for all clinical trials should be sufficient to
support population PK12 and dose- and exposure-response13 analyses for safety,
activity, and efficacy.
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