USFDA Guidance: Assessing the Effects of Food on Drugs in INDs and NDAs – Clinical Pharmacology Considerations

Sharan Murugan
7 hours ago
4 min read

The U.S. Food and Drug Administration (FDA) has issued Revision 1 of its guidance titled "Assessing the Effects of Food on Drugs in INDs and NDAs — Clinical Pharmacology Considerations" (May 2026), prepared by the Office of Clinical Pharmacology within the Center for Drug Evaluation and Research (CDER). This revision supersedes part of the 2022 guidance on Food-Effect Bioavailability and Fed Bioequivalence Studies and consolidates current FDA thinking on when, why, and how food-effect (FE) studies should be designed, conducted, and reported for orally administered drug products.

Why Food-Effect Studies Matter

Food-drug interactions can significantly impact the safety and efficacy of orally administered drug products. The FDA highlights that co-administration with food may:

Increase systemic drug exposure, potentially raising the risk of adverse reactions
Decrease drug absorption, thereby reducing therapeutic efficacy
Alter variability in pharmacokinetic (PK) profiles, complicating dosing decisions

Because patient diets vary widely and strict dietary control in real-world settings is difficult, the FDA strongly encourages developing formulations that are unaffected by food. When this is not feasible, well-conducted FE studies are essential to guide safe and effective drug administration instructions and inform product labeling.

Scope of the Guidance

This guidance applies to sponsors submitting INDs, NDAs, and supplements to these applications. It covers immediate-release, modified-release, and fixed-combination drug products of new or previously approved drugs. For fed bioequivalence studies in Abbreviated New Drug Applications (ANDAs), refer to the separate draft guidance on Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA (August 2021).

Key Recommendations for FE Studies

Assess the effect of a high-fat meal on drug PK early in development to inform dosing and administration decisions throughout clinical development and product labeling. If a significant food interaction is seen, assess the effect with a lower-fat meal as well.
Conduct FE studies before pivotal safety and efficacy trials to enable rational food-related dosing decisions.
Conduct a definitive FE study using the final to-be-marketed formulation. Exceptions apply when the clinical trial formulation showed no significant food effect and the marketed formulation is not significantly different, or when a biowaiver is applicable.
When fasted dosing is necessary, determine a practical and realistic interval between drug administration and food that patients can follow in real-world conditions.

Study Design Considerations

Pilot Studies

Early pilot studies provide a preliminary assessment of the high-fat meal effect on systemic drug exposure. Sponsors should carefully select doses to account for potential food-related exposure increases and associated adverse events.

Definitive Studies

The recommended design is a randomized, balanced, single-dose, two-treatment (fed vs. fasted), two-period crossover, with a washout period of three to five elimination half-lives separating treatments. For drugs with half-lives exceeding 24 hours, a parallel group design may be more practical, with each treatment administered to separate subject groups of similar demographics.

Meal Types to Evaluate

Meal Type	Total Kcal	Fat (Kcal)	Fat (Grams)	% Calories from Fat
High-Fat	800–1000	500–600	55–65 g	>50%
Low-Fat	400–500	100–125	11–14 g	25%

A high-fat meal FE study is required for all new orally administered drug products under development. Low-fat meal studies are recommended when a high-fat meal cannot be tolerated by the indicated patient population or when the high-fat meal causes unacceptable PK changes.

Subject Selection

FE studies may be conducted in healthy adult subjects, or in the patient population when safety concerns preclude healthy subjects, or when differential food effects are expected due to the underlying disease. Both male and female subjects should be enrolled unless the indication is sex-specific. Subjects should have normal renal and hepatic function, and concomitant drugs that could confound results should be excluded.

FE Study Doses

The clinically recommended dose should be used in definitive FE studies. For drugs with linear PK marketed at multiple doses, use the highest clinically recommended dose. For drugs with nonlinear PK across the therapeutic range, conduct single-dose FE studies at both the high and low doses proposed in labeling.

Administration Conditions

Fasted: Overnight fast ≥10 hours; drug administered with 240 mL (8 fl oz) of water; no food for at least 4 hours post-dose.
Fed: Overnight fast ≥10 hours; test meal started 30 minutes before drug administration, completed within 30 minutes; drug administered with 240 mL water; no food for at least 4 hours post-dose.
Modified Fasted: When standard overnight fasting is not practical for real-world patient use, conduct FE studies with varied separation times between drug and food to generate data that supports pragmatic, patient-friendly labeling instructions.

Samples should be collected across at least three to five elimination half-lives, typically requiring 12 to 18 samples per subject per period to fully characterize the concentration-time profile.

Data Analysis and Labeling

Key PK parameters to derive and report for all FE studies include: AUC₀-INF, AUC₀-t, Cmax, Tmax, Tlag (where applicable), t½, Cl/F, and Vd/F. Both individual subject data and summary statistics (means, standard deviations, CVs, ranges) must be reported.

Statistical standard: Exposure parameters must be log-transformed before analysis. The 90% confidence interval for the fed/fasted geometric mean ratio must fall within 80–125% for AUC and Cmax to establish no food effect. If either parameter falls outside this range, the sponsor must provide an assessment of clinical significance based on known exposure-response relationships.

Labeling: The "Effect of Food" subheading should appear under the "Absorption" heading in the Pharmacokinetics subsection of the Clinical Pharmacology section. Specific food-related dosing instructions belong in the Dosage and Administration section, with a cross-reference to Clinical Pharmacology. Drugs unaffected by food should be labeled "take with or without food."