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

To learn more about drug-drug interaction assessment for therapeutic proteins, read the guidance.

www.fda.gov 1

What is recommended 

in this guidance?

This final guidance provides recommendations on 

evaluating the drug-drug interaction (DDI) potential 

for an investigational therapeutic protein (TP). This 

guidance focuses on when TP DDI studies could be 

warranted and the relevant study type and study 

design. The DDI evaluation for antibody-drug 

conjugates is covered by a separate guidance: 

Clinical Pharmacology Considerations for 

Antibody-Drug Conjugates (February 2022).1

1 We update guidances periodically. For the most recent 

version of a guidance, check the FDA guidance web page.

Drug-Drug Interaction Assessment 

for Therapeutic Proteins

Final Guidance for Industry

Why is this 

guidance important?

Patients frequently use more than one medication 

at a time. Unanticipated, unrecognized, or

mismanaged DDIs could lead to increased 

adverse events or decreased efficacy associated 

with prescription TP use. The guidance provides 

recommendations for evaluating DDIs during TP 

development and outlines when and how TP 

DDIs should be evaluated.

What are TPs?

TPs are large, complex amino acid-based 

molecules derived from living cells. Currently, 

FDA defines the term “protein” as any alpha amino 

acid polymer with a specific defined sequence 

that is >40 amino acids in size. TPs include purified 

monoclonal antibodies, cytokines, enzymes, and 

other novel proteins. They are usually administered 

through intravenous, subcutaneous, or 

intramuscular injection.

Guidance Snapshot
www.fda.gov 2

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

To learn more about drug-drug interaction assessment for therapeutic proteins, read the guidance.

 Mechanisms Related to 

Proinflammatory Cytokines

 TPs that are proinflammatory cytokines 

or that cause increases in proinflammatory 

cytokine levels can downregulate cytochrome 

P450 (CYP) enzymes that metabolize 

certain drugs

 TPs that reduce cytokine levels can also 

impact CYP activity, but background levels of 

proinflammatory cytokines differ by disease 

and can influence the magnitude of effect

2

 This is an emerging area, and sponsors are encouraged to discuss the proposed approach with FDA.

 In Vitro and Animal studies: may help 

provide mechanistic information

 Clinical Studies

 Parallel Design: might be appropriate 

when evaluating the effect of other drugs on a 

TP and when the TP has a long half-life.

 Single Sequence Crossover: can evaluate 

the effect of the TP on other drug(s)

 Mechanisms Unrelated to 

Proinflammatory Cytokines

 TPs that affect physiological processes 

(e.g., delayed gastric emptying)

 TP disposition, distribution, or binding 

interactions can be impacted by concomitantly 

administered medications or other TPs

 Concomitantly administered immunosuppressors can affect the immunogenicity 

and pharmacokinetics of a TP

 Population PK Modeling: pprospective 

designs can assess the effect of other drugs on 

a TP, or the effect of a TP on other drugs if 

necessary data 

are collected

 Other Modeling 

Approaches (e.g.,

physiologically 

based PK modeling)2

Example scenarios in which DDI studies could be warranted:

Types of DDI assessments 

Background About the Guidance

With the continued market growth and increased clinical use of 

TPs, it is important to understand the nature of and the potential 

for DDIs with these products. This guidance supplements 

the final FDA guidances for industry In Vitro Drug Interaction 

Studies–Cytochrome P450 Enzyme- and Transporter-Mediated 

Drug Interactions (January 2020) and Clinical Drug Interaction 

Studies–Cytochrome P450 Enzyme- and Transporter-Mediated Drug 

Interactions (January 2020) by providing a systematic, risk-based 

approach to determining the need for DDI studies for TPs. Although 

this guidance applies to TPs, the general concepts could be applicable to 

other biological products, including biological products regulated by CBER 

such as cellular and gene therapies.
www.fda.gov

Guidance Recap Podcast

Hear highlights from FDA staff

Click here to listen Click here to 

read transcript

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

To learn more about drug-drug interaction assessment for therapeutic proteins, read the guidance. 

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

3

Speaker(s): Elimika Pfuma Fletcher, PhD, and Qin Sun, PhD, 

Policy Leads in the Center for Drug Evaluation and Research, Office of Clinical Pharmacology

Drug Development Timeline

When to Apply the Guidance Recommendations

Sponsors should consider the DDI risk of their TPs 

early in clinical development and summarize their DDI 

evaluation program at milestone meetings with the 

FDA. Potential discussion topics at these meetings 

include the need for and planning, timing, and study 

PHASE 2* PHASE 3*

FDA 

FILING & 

APPROVAL

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

PRECLINICAL 

DEVELOPMENT

POSTMARKET OR 

POSTAPPROVAL 

STUDIES

CLINICAL 

DEVELOPMENT*

PHASE 1*

design of DDI evaluations for the investigational 

TP. Currently in vitro or animal data have not been 

predictive of the potential for clinical DDI with TPs, 

although some data could provide mechanistic 

understanding of the DDI potential of a TP. 

Apply to Clinical Development Phases 1 through 3: 

Labeling Recommendations 

Prescribing Information must include a summary of essential DDI information needed for the safe and effective 

use of the drug by the health care provider. For specific requirements and recommendations regarding how to 

incorporate DDI information in labeling, refer to 21 CFR 201.57 and the following FDA guidances: 

Labeling for Human Prescription Drug and Biological Products – Implementing the PLR Content and Format 

Requirements (February 2013) 

 Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling for Human Prescription 

Drug and Biological Products — Content and Format (October 2011) 

 Clinical Pharmacology Section of Labeling for Human Prescription Drug and Biological Products — Content and 

Format (December 2016) 

Patient Counseling Information Section of Labeling for Human Prescription Drug and Biological Products — 

Content and Format (December 2014)