Efficacy endpoints are measures designed to reflect the intended effects of a drug. They include assessments of clinical events (e.g., mortality, stroke, pulmonary exacerbation, venous thromboembolism), symptoms (e.g., pain, dyspnea, symptoms of depression), measures of function (e.g., ability to walk or exercise), or surrogate endpoints that are reasonably likely or expected to predict a clinical benefit.
Because most diseases can potentially cause more than one clinical event, symptom, and/or altered function, many trials are designed to examine the effect of a drug on more than one aspect of the disease.
In some cases, efficacy cannot be adequately established based on a single disease aspect, and the study should use either an endpoint that incorporates multiple aspects of the disease into a single endpoint or effects should be demonstrated on multiple endpoints. In other cases, an effect on any of several endpoints could be sufficient to support approval of a marketing application.
Failure to account for multiplicity when there are several endpoints evaluated in a study can increase the chance of false conclusions regarding the effects of the drug.
The regulatory concern regarding multiplicity arises principally in the evaluation of clinical trials intended to demonstrate effectiveness supporting drug approval and claims in FDA-approved labeling; however, this issue is important for trials throughout the drug development process.
For instance, if safety outcomes are to be assessed via hypothesis testing, they would be subject to the multiplicity considerations described in this guidance.
Multiplicity problems for safety analyses that are not part of a prespecified set of hypotheses for formal statistical testing are outside the scope of this guidance.
Hypothesis testing is commonly used to address the uncertainty in the assessment of a treatment effect on a chosen endpoint. This approach begins with stating the relevant hypotheses for a chosen endpoint. In the simplest situation where the aim is to demonstrate the superiority of a test drug over control, two mutually exclusive hypotheses are specified for the endpoint in advance of conducting a clinical trial:
- One hypothesis, the null hypothesis, states that there is no treatment effect on the chosen endpoint.
- The other hypothesis is called the alternative hypothesis and posits that there is at least some treatment effect of the test drug.
In the following sections, the issues of multiple endpoints and methods to address them are discussed.
The issues of multiplicity and methods that apply to multiple endpoints also generally apply to other sources of multiplicity, including other estimand attributes (e.g., multiple doses, time points, or study population subgroups); however, these other sources of multiplicity will not be specifically addressed in this guidance.
Furthermore, there may be different considerations related to multiplicity in certain unique settings, such as the evaluation of multiple different drugs for a single disease in a master protocol, that are not addressed in this guidance.
This guidance focuses on the analysis and interpretation of multiple endpoints within a single clinical trial.
