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Learn how to determine whether your project is a clinical trial, basic experimental study involving humans (BESH), or an observational study involving humans. Check what to consider when answering the four clinical trial questions, case studies, and tips for BESH investigators.
Clinical Trial
A research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.
Basic Experimental Studies Involving Humans (BESH)
Basic experimental studies involving humans (BESH) are studies in humans that have the purpose of understanding fundamental aspects of phenomena without a direct application towards clinical processes or products. We define “process or products” as the application of biomedical or behavioral research to affect a health-related outcome. Accordingly, the NIH does not consider BESH to be clinical trials (NOT-OD-26-032).
Observational Studies Involving Humans
Observational studies involving humans are studies in which data are gathered from or about human participants, but the researchers do not perform an intervention. Observational studies can be conducted with human participants in real time or can be performed retrospectively using previously gathered information.
The main sub-types of observational studies include:
- Natural History Studies: Researchers observe a cohort of participants over a long period.
- Secondary Research Studies: Researchers use existing data or biospecimens that were previously collected for a different purpose.
- Repository Studies: These involve only the collection and storage or maintenance of identifiable private information or identifiable biospecimens for secondary research.
When research involving human biospecimens is considered human subjects research (e.g., the samples are identifiable) it would also be considered an observational study involving humans. See 45 CFR 46 for more information on whether a study qualifies as human subjects research.
Observational studies involving humans are not clinical trials or BESH.
Does the study have a health-related outcome?
Under the NIH definition of a clinical trial, a health-related biomedical or behavioral outcome has the potential for direct advancement of health. Although basic science studies that produce fundamental information about biological systems might eventually inform advances in health, they do not have the immediate intention of changing clinical practice but rather aim to understand fundamental aspects of phenomena without direct clinical applications. Therefore, for the purposes of the definition of a clinical trial, such studies do not have health-related biomedical or behavioral outcomes.
Does the study use an intervention?
Interventions are manipulations of the subject or the subject’s environment that are performed for research purposes. Examples include administration of a drug, use of a behavioral manipulation, or exposure to a change in environmental conditions.
Answering the 4 Clinical Trial Questions for Basic Research Studies
There are 4 key questions that determine if a study meets the NIH definition of a clinical trial. If the answer to any one of these questions is no, then the study is not a clinical trial. Here are some specific things to consider when answering these questions in the context of basic research studies.
| Does the study involve human participants? | |
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According to 45 CFR 46, a human subject is a living individual about whom an investigator (whether professional or student) is conducting research:
For further information about whether your study qualifies as human subjects research, see 45 CFR 46. |
| Are the participants prospectively assigned to an intervention? | |
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Prospective assignment is not limited to random assignment to a manipulation or condition. "Prospectively assigned" means the experimental manipulation (intervention) is assigned per a predefined protocol. The method of prospective assignment also does not matter. Neither does the number of conditions. For more about interventions, see question #3 below. |
| Is the study designed to evaluate the effect of the intervention on the participants? | |
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Interventions are manipulations of the subject or the subject’s environment that are performed for research purposes. |
| Is the effect being evaluated a health-related biomedical or behavioral outcome? | |
| Under the NIH definition of a clinical trial, a health-related biomedical or behavioral outcome has the potential for direct advancement of health. Although basic science studies that produce fundamental information about biological systems might eventually inform advances in health, they do not have the immediate intention of changing clinical practice but rather aim to understand fundamental aspects of phenomena without direct clinical applications. Therefore, for the purposes of the definition of a clinical trial, such studies do not have health-related biomedical or behavioral outcomes. Evaluations of the safety or efficacy of drugs, behavioral intervention, or medical devices have the potential for direct advancement of health and therefore are looking at health-related biomedical or behavioral outcomes. Likewise, studies comparing the relative effectiveness of two different behavioral therapies on a mental health condition would have health-related biomedical or behavioral outcomes. |
| Human Participants? | Prospectively Assigned Intervention? | Evaluate Effect of Intervention? | Health-Related Outcome? | Study Type |
|---|---|---|---|---|
| Yes | Yes | Yes | Yes | Clinical Trial |
| Yes | Yes | Yes | No | BESH |
| Yes | No | No | Yes | Observational |
| Yes | No | No | No | Observational |
Case Studies
Case 1
The example case below uses the Stroop Effect, an established measure of executive function in which a person’s response time to name the color of words presented is measured. In the standard version of the task, the colors of words presented can be the same or different from the meaning of the word itself. The Stroop Effect is the slowing in color naming time for incongruent word presentations. Sometimes investigators modify the design, for example, to study the effect of emotional content of the words (i.e. the independent variable) on the Stroop Effect.
A group of participants with social anxiety will perform an experimentally manipulated Stroop test. In this variant of the Stroop test, the stimuli presented are varied to include emotional and neutral facial expressions presented in different colors. Participants are instructed to name the colors of the faces presented, with the expectation that they will be slower to name the color of the emotional face than the neutral face. The purpose of the study is to examine the degree to which participants with social anxiety will be slower to process emotional faces than neutral faces.
- Does the study involve human participants? Yes, participants with social anxiety will be enrolled in this study.
- Are the participants prospectively assigned to an intervention? Yes, the participants will be prospectively assigned to perform a modified Stroop test using different colored emotional/neutral faces to explore emotional processing in people with social anxiety.
- Is the study designed to evaluate the effect of the intervention on the participants? Yes. Participants are shown cards with different faces on them.
- Is the effect being evaluated a health-related biomedical or behavioral outcome? No, the study is designed to measure the effect of emotional valence (i.e. emotional faces) on participant response time to name colors. The purpose is to determine whether the response time to emotional faces is exaggerated for people with social anxiety as compared to neutral faces. The results of this study are intended to better understand fundamental phenomena rather than to directly advance health. Although this information could eventually be useful in developing therapies for social anxiety, because the study is designed to gain fundamental insights into behavior and the brain, it is considered basic research.
This study is a basic experimental study involving humans (BESH) and is not considered a clinical trial by the NIH.
Case 2
Investigators sequence Cytochrome P450 genes from human volunteers. They randomly assign these volunteers to different groups and give each group a different non-toxic chemical compound that is metabolized in the liver. They collect blood and urine from the volunteers at different times and measure the levels of the compounds and their metabolites. Their goal is to better understand the functions and mechanisms of human Cytochrome P450s and how genotypes affect their activities.
- Does the study involve human participants? Yes.
- Are the participants prospectively assigned to an intervention? Yes.
- Is the study designed to evaluate the effect of the intervention on the participants? Yes. Participants are given non-toxic chemical compounds in order to observe how they are metabolized.
- Is the effect being evaluated a health-related biomedical or behavioral outcome? No, the study is designed to better understand the functions and mechanisms of human Cytochrome P450s and how genotypes affect their activities rather than to directly advance health.
Because an intervention is conducted and participants prospectively assigned to it but there is no health-related biomedical or behavioral outcome being evaluated, this study is a basic experimental study involving humans (BESH) and is not considered a clinical trial by the NIH.
Case 3
Researchers are comparing the efficacy of two different behavioral therapy approaches in ameliorating addictive behaviors. Patient volunteers in an addiction clinic are randomly assigned to one or the other intervention. The researchers compare measures of mental health and addictive behaviors in the two groups over time. The goal of the study is to determine which, if either, behavioral therapy produces more effective results in reducing addictive behaviors.
- Does the study involve human participants? Yes.
- Are the participants prospectively assigned to an intervention? Yes.
- Is the study designed to evaluate the effect of the intervention on the participants? Yes. The study participants are given behavioral therapy designed to improve addictive behaviors and other mental health conditions.
- Is the effect being evaluated a health-related biomedical or behavioral outcome? Yes. The study is designed to test the relative efficacy of two different behavioral therapies in reducing addictive behaviors. The results could immediately inform clinical practice.
This study is a clinical trial as it meets all four required components of the NIH clinical trial definition.
Case 4
Researchers are using existing patient electronic health records from several medical centers to look for factors that predict the onset of sepsis in hospitalized patients as well as their eventual outcomes. The researchers use artificial intelligence to scan the records to find patterns and to produce a tool that will help predict whether a patient is likely to develop sepsis. They are also trying to establish whether particular health factors or treatments lead to better outcomes in patients who develop sepsis.
- Does the study involve human participants? Yes.
- Are the participants prospectively assigned to an intervention? No. The researchers are using retrospective records.
- Is the study designed to evaluate the effect of the intervention on the participants? No. There is no intervention. The researchers are using retrospective data.
- Is the effect being evaluated a health-related biomedical or behavioral outcome? Yes. The study is designed to look for factors that predict the onset of sepsis and the likely outcome when it develops. This information could inform clinical practice.
This study is an observational study involving humans.
Case 5
Researchers are developing a new technology for high-resolution imaging of blood vessels in humans. They test prototypes by placing healthy volunteers in the device and creating images of their peripheral blood vessels. They use this information to test the theory behind the technology and to refine the design of the prototype to improve the resolution of the images and reduce the time required to make them.
- Does the study involve human participants? Yes.
- Are the participants prospectively assigned to an intervention? Yes. The researchers use healthy volunteers to test and refine their prototypes.
- Is the study designed to evaluate the effect of the intervention on the participants? No. The study is designed to test and refine the prototype devices not to evaluate an effect on the participants. If the study was designed to detect clinically-relevant anomalies in the participants, then the answer would be yes.
- Is the effect being evaluated a health-related biomedical or behavioral outcome? No. The researchers are conducting early-stage technology research and development. They are using the information in the study to test the theory behind the technology and to refine the prototypes rather than to evaluate the efficacy of the device for clinical applications. If the reseachers were trying to assess the efficacy of the final version of the device in detecting clinically-relevant anomalies in blood vessels, then the answer would have been yes.
This study is a basic experimental study involving humans (BESH) and is not considered a clinical trial by the NIH.
Tips for BESH Investigators
Talk to a Program Official: All applicants are strongly encouraged to talk with a Program Official before submitting an application. Program Officials can help determine the right funding opportunity for your specific research. If you are unsure who the right Program Official is, try out our Matchmaker Tool.
Get to know the Human Subjects & Clinical Trial Information Form: Take a video tour of the application form to familiarize yourself with how this information is collected.