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

about the multiple endpoints in clinical trials, read the guidance: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-endpoints-clinical-trials-guidance-industry

www.fda.gov

Multiple Endpoints in Clinical Trials 

Guidance for Industry

The Hierarchy of Families of Endpoints

Because diseases may have multiple clinical manifestations, studies may sometimes use multiple endpoints or endpoints 

that incorporate multiple aspects of the disease to establish efficacy. 

Endpoints in adequate and well-controlled drug trials are usually grouped hierarchically in the following categories 

according to their clinical importance. Each category in the hierarchy may contain a single endpoint or a family of endpoints.

PRIMARY ENDPOINTS

• Establish the effect(s) of the drug

• Are the basis for concluding that the study meets its objectives

SECONDARY ENDPOINTS 

• May extend understanding of an effect related to the primary endpoint or

provide evidence of a distinct clinical benefit

• Should be included in the prospective statistical analysis plan if they provide

evidence of additional effects of the drug

EXPLORATORY ENDPOINTS

• Generally not used to support definitive conclusions, so

multiplicity adjustment not needed

What is multiplicity?

Multiplicity is the existence 

of many comparisons in a 

clinical trial which, without 

appropriate statistical 

adjustments, can lead to a 

higher-than-intended rate 

of making false conclusions 

about a drug’s effect. A focus of 

this guidance is the appropriate 

planning of primary and secondary 

endpoints of a clinical trial to ensure 

that the major findings of a clinical 

trial are well supported.

What Is Covered in This Guidance?

This guidance reflects FDA’s thinking about analysis, interpretation, and management of issues 

related to the use of multiple endpoints in clinical trials. Strategies for grouping and ordering 

endpoints for analysis of a drug’s effects and statistical methods to control the chance of 

making erroneous conclusions about drug effects are discussed.

Why is this guidance important?

Most clinical trials in drug development contain multiple endpoints to document the ability of the 

drug to affect one or more disease characteristics. When more than one endpoint is analyzed in 

a clinical trial without appropriate adjustment, the likelihood of making false conclusions about 

a drug’s effects may be increased. This guidance recommends strategies that will allow for 

appropriate assessments of drug effects when multiple endpoints are used.
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. To learn more 

about the multiple endpoints in clinical trials, read the guidance: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-endpoints-clinical-trials-guidance-industry

www.fda.gov

Used when a treatment effect on all of two or 

more clinical features is critically important 

to demonstrate efficacy

• The chance of making an erroneous conclusion

of efficacy based on co-primary endpoints is

reduced compared to the use of any single

endpoint.

• The chance of failing to detect beneficial effects

may be increased

CO-PRIMARY ENDPOINTS

Important clinical outcomes are combined into 

a single primary endpoint

• When a single statistical test is performed on the

composite endpoint, there is no multiplicity problem

• Choice of, and effects on, the components should be

examined with care

» Clinical importance of components may be

substantially different

» There is a possibility that there can be an effect

on a composite endpoint when there is no effect

on the most important components but there is

a large effect on less important components

» Overall outcome may have a favorable result

even with adverse effects on an important

component

» Assessment of clinical meaningfulness may be

important

» Pre-specification and multiplicity adjustment

is important to support conclusions about

treatment effect on specific components

COMPOSITE ENDPOINTS

Multiple Primary Endpoints where a treatment 

effect on any one of these endpoints is sufficient 

to support a conclusion of effectiveness

• It is critical to develop a prospective plan to

address the chance of erroneously detecting an

effect that is not present.

• A variety of approaches to address multiplicity

are described in the guidance

MULTIPLE PRIMARY ENDPOINTS 

Circumstances for Using Different Types of 

Multiple Primary Endpoints

Within-patient combination of two or more 

components

• Each patient gets an overall rating based

on observation of all specified components

according to specified rules

• May be efficient if within-subject component

effects generally trend in the same direction

• The chance of detecting a beneficial effect

may be adversely affected if there is limited

concordance among component endpoints

• Evaluation of components involves similar

considerations as for composite endpoints

MULTI-COMPONENT ENDPOINTS
Guidance Snapshots are a communication tool and are not a substitute for the guidance document. To learn more about 

multiple endpoints in clinical trials, read the guidance: 

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/multiple-endpoints-clinical-trials-guidance-industry

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

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

www.fda.gov

Guidance Recap Podcast – Hear Highlights Straight From FDA Staff

Speaker: John Lawrence, PhD, statistician in CDER’s Office of Biostatistics

Background About the Guidance 

The ICH guidance for industry E9 Statistical 

Principles for Clinical Trials (September 1998) 

is a broad guidance that includes discussion 

of multiple endpoints. This guidance provides 

greater detail on this topic and corresponds with 

an FDA commitment under the Food and Drug 

Administration Amendments Act (FDAAA) of 2007.

Guidance Recommendations Apply Throughout the Drug Development Timeline 

During Clinical Development: FDA recommends that sponsors considering the use of multiple endpoints 

should prospectively specify all planned endpoints, time points, analysis populations, and analyses in the 

study protocol or statistical analysis plan. Sponsors should consider the variety of methods available to 

control the likelihood of making false conclusions about drug effects and in the prospective analysis plan 

select the most powerful method that is suitable for the design and objective of the study.

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