Reference Product Active Pharmaceutical Ingredient 

What is covered in this guidance? 

A final guidance has been issued to provide recommendations to 

sponsors on the conduct of bioavailability (BA) studies for orally 

administered drug products and certain non-orally administered 

drug products in investigational new drugs (INDs), 

new drug applications (NDAs), and supplements. 

Bioavailability Studies Submitted in NDAs or INDs 

General Considerations Final Guidance 

www.fda.gov

Bioavailability Studies 

Submitted in NDAs or INDs 

— General Considerations 

Why is this guidance important? 

Determining the BA of formulations is 

critical during the life cycle of drug 

products and aids in the Agency’s 

evaluation of the safety and 

effectiveness of a drug. Drug product 

formulation, and route of 

administration may affect 

BA and impact the benefits 

and risks of a drug product. 

Test Product Active Pharmaceutical Ingredient 

Cmax B 

Cmax A Concentration 

Time 

AUC B 

Tmax A 

Tmax B 

AUC A 

Cmax = maximum plasma concentration 

Tmax = time to maximum observed plasma concentration 

AUC = area under the curve 

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about assessing the bioavailability studies submitted in NDAs or INDs, read the guidance: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioavailability-studies-submittedndas-or-inds-general-considerations
WHEN? 

BA should be assessed preapproval and for postapproval changes to drug products. During development, BA 

comparisons may be needed to compare early versus late clinical trial formulations, clinical trial versus 

to-be-marketed drug products, and different product strengths, or to support pharmacokinetic (PK) comparison 

for a 505(b)(2) submission. After approval, major changes in a drug product’s components, composition, 

manufacturing site, or method of manufacture may require a BA assessment to determine bioequivalence (BE). 

HOW? 

Sponsors can determine the BA for orally administered drug products by comparing a plasma exposure 

profile to that of a suitable reference product. Sponsors must use the most accurate, sensitive, and reproducible method available to demonstrate the BA of a drug product. 

WHAT? 

BA is defined as the rate and extent to which the active ingredient or active moiety is absorbed from a drug 

product and becomes available at the site of action. BA data provide an estimate of the fraction of the drug 

absorbed as well as information related to the pharmacokinetics of the drug. 

Sponsors should use a non-replicate, randomized, Sponsors should determine the BA of the test 

product under fasting conditions. Fed conditions 

can be used if tolerability issues or serious 

adverse events are anticipated or if the 

reference product is approved under fed 

conditions. Evaluation of the effect of 

food on the BA of the test product 

should be consistent with the 

expectations outlined in the Food 

Effect Guidance. 

Sponsors should measure the 

active ingredient or moiety (or 

active metabolites when 

appropriate). In general, sponsors 

should use clinically relevant systemic 

exposure measures to determine BA, 

such as area under the curve (AUC) 

and peak drug concentration (Cmax). 

A confidence interval approach is used for 

BA comparisons. 

single-dose, crossover design to study BA in healthy 

adult volunteers.* Replicate study designs can be 

considered for use with reference-scaled BA 

approaches for products with high 

intrasubject variability or narrow 

therapeutic index. For certain products 

or situations, multiple-dose 

evaluations may be appropriate. 

Under certain circumstances, 

sponsors can determine BA 

preapproval and postapproval using in 

vitro approaches (e.g., dissolution, 

drug-release testing). In addition, an in 

vitro-in vivo correlation (IVIVC) modeling 

approach can be used to evaluate 

formulations such as extended-release (ER) 

dosage forms. When PK comparison is not 

possible, pharmacodynamic (PD) comparison or 

comparative clinical studies can be performed. 

ASSESSING 

BIOAVAILABILITY 

STUDY 

DESIGN 

FASTING 

OR FED

 CONDITIONS 

OTHER BA 

 ASSESSMENT

 APPROACHES 

PK

 MEASUREMENT 

METHODOLOGY 

*Sponsors can conduct a pilot trial with a small number of subjects to assess PK variability, determine sample size, and inform sample collection 

timing before proceeding with a full-scale BA study. 

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about assessing the bioavailability studies submitted in NDAs or INDs, read the guidance: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioavailability-studies-submittedndas-or-inds-general-considerations

www.fda.gov
 

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Background About the Guidance 

This guidance finalizes the revised draft guidance published in February 2019 

titled “Bioavailability Studies Submitted in NDAs or INDs – General 

Considerations” that provided recommendations to sponsors planning to 

include BA information for drug products in INDs, NDAs, and NDA 

supplements. FDA considered comments received on the revised draft 

guidance and made technical and editorial changes to address these 

comments and improve clarity of the document when publishing the final 

guidance. The technical changes are listed in the Background section of the 

Notice of Availability published in the Federal Register. 

Guidance Recommendations Apply Throughout the Drug 

Development Timeline 

Determining the BA of formulations is important during evaluations, and clinical trial results. In the presence of 

the entire life cycle of drug products and aids in the FDA’s certain major changes in the components, composition, 

evaluation of the safety and e ̃ectiveness of a product in manufacturing site, or method of manufacture of a drug 

an IND, NDA, or NDA supplement. To determine the safety after its approval, the sponsor should demonstrate the in 

and e°cacy of a drug product for the proposed indication, vivo BE for the drug product after the change compared to 

the FDA uses the totality of information available in the the drug product before the change. 

submission, which includes BA data, exposure-response 

Clinical Development 

Basic 

Research 

Prototype Design 

or Discovery 

Preclinical FDA Filing 

Post Approval 

Development Approval 

Post Market/ 

Studies 

Phase 1 Phase 2 Phase 3 

Click here to Listen Click here to read Transcript 

Guidance Recap Podcast – Hear Highlights Straight From FDA Staff 

Speaker: Dakshina Chilukuri, Ph.D., clinical pharmacology reviewer in the Center 

for Drug Evaluation and Research's Office of Clinical Pharmacology

Guidance Snapshots are a communication tool and are not a substitute for the guidance document. 

To learn more about assessing the bioavailability studies submitted in NDAs or INDs, read the guidance:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/bioavailability-studies-submitted-ndas-orinds-general-considerations

To see additional Guidance Snapshots, check out the pilot program: 

https://www.fda.gov/drugs/guidances-drugs/guidance-snapshot-pilot 

www.fda.gov