www.fda.gov Guidance Snapshots are a communication tool and are not a substitute for the guidance 

document. To learn more about enhancing the diversity of clinical trials, read the guidance. 

Adjusting for Covariates in Randomized Clinical Trials

for Drugs and Biological Products

Final Guidance

A final guidance has been issued

providing recommendations on adjusting

for covariates in randomized clinical trials to improve

statistical power and the precision of treatment effect 

estimates.

Covariate adjustment refers to the use 

of information measured on a subject 

before the time of randomization (e.g., demographic 

factors, disease characteristics) for estimating and 

testing treatment effects between randomized groups.

It is desirable to study a population 

in clinical trials that reflects the 

variability of the target population, but doing so may 

make it harder to detect a treatment effect. Covariate 

adjustment allows for incorporation of prespecified 

prognostic factors in the statistical analysis and can 

result in narrower confidence intervals and a greater 

statistical power to detect treatment effects.

What is covariate 

adjustment? 

Why is covariate 

adjustment helpful? 

What is recommended

in the guidance?

Guidance Snapshot 

BASELINE COVARIATES

Sponsors should adjust for

baseline covariates that are

strongly associated with an

outcome in a clinical trial

population.
www.fda.gov

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

To learn more about adjusting for covariates, read the guidance.

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

Speaker: Dr. Dan Rubin, Statistician in the Center for Drug Evaluation and Research’s 

Office of Biostatistics

Click here to listen Click here to read transcript

Guidance Recap Podcast - 

Hear Highlights Straight from FDA Staff

What to submit when adjusting for covariates?

Sponsors should prospectively specify the covariates and the mathematical

form of the covariate adjusted estimator in the protocol or statistical

analysis plan. The prespecified primary analysis will be emphasized in

review rather than post-hoc analyses using different models or covariates.

If the number of covariates is large relative to the sample size or covariates

are adaptively selected, sponsors should discuss the method of adjustment

with the FDA during review of the protocol or statistical analysis plan.

Drug Development Timeline

* When to Apply the Guidance Recommendations

BASIC 

RESEARCH

PROTOTYPE 

DESIGN OR 

DISCOVERY

FDA 

FILING & 

APPROVAL

PRECLINICAL 

DEVELOPMENT

POSTMARKET OR 

POSTAPPROVAL 

CLINICAL DEVELOPMENT* STUDIES

During Clinical Development: FDA strongly recommends that sponsors considering use of covariate 

adjustment in a primary analysis prespecify the details of the proposed analysis in the study protocol or 

statistical analysis plan. In general, sponsors should use existing pathways for interacting with the FDA during 

the course of the clinical development program, including Type A, Type B, Type B end-of-phase, and Type C 

meetings, as well as the IND amendment review process.

PHASE 1 PHASE 2 PHASE 3