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Experimental studies are research designs that involve the manipulation of variables to determine their effects on certain outcomes, primarily used in epidemiology to establish causal relationships. These studies typically involve randomization, control groups, and interventions, allowing researchers to evaluate the effectiveness of treatments or interventions in preventing or controlling diseases.

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5 Must Know Facts For Your Next Test

• Experimental studies are considered the gold standard in research because they allow for the establishment of cause-and-effect relationships through manipulation of independent variables.
• Randomization is a key feature of experimental studies, as it helps to ensure that the groups being compared are similar at baseline, reducing confounding variables.
• Control groups play a crucial role in experimental studies by providing a baseline against which the effects of the intervention can be compared.
• Blinding, where participants and/or researchers are unaware of group assignments, helps minimize bias in the results of experimental studies.
• The results from experimental studies can directly inform public health interventions and policies by providing evidence for effective strategies to prevent and control diseases.

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• Experimental studies contribute to establishing causality by manipulating independent variables and observing the resulting changes in dependent variables. By randomizing participants into treatment and control groups, researchers can control for confounding factors and isolate the effects of the intervention. This methodological rigor allows for stronger conclusions about the relationships between exposures and outcomes, making these studies crucial for informing public health decisions.
• The key differences between experimental studies and observational studies lie in how they handle variable manipulation and control. In experimental studies, researchers actively manipulate independent variables and randomize participants, enabling them to establish causal relationships. In contrast, observational studies merely observe existing conditions without intervention, making it difficult to determine causality. This distinction impacts how findings are interpreted and applied in public health practice.
• Conducting experimental studies in public health settings involves several ethical considerations, including informed consent, participant safety, and the potential for harm versus benefits. Researchers must ensure that participants are fully aware of the nature of the study and any risks involved before consenting to participate. Additionally, it is crucial to have appropriate oversight mechanisms to monitor participant safety throughout the study. Balancing these ethical obligations with the pursuit of knowledge is essential for maintaining public trust and integrity within research practices.

Related terms

Randomized Controlled Trial (RCT) : A type of experimental study where participants are randomly assigned to either a treatment group or a control group, helping to eliminate bias and establish causality.

Cohort Study : An observational study design where a group of individuals is followed over time to see how certain exposures affect the incidence of specific outcomes.

Placebo Effect : A phenomenon in which participants in a study experience perceived or actual improvements in their condition after receiving a placebo treatment, highlighting the importance of control groups in experimental studies.

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What Are Clinical Trials and Studies?

On this page:

What is clinical research?

Why participate in a clinical trial, what happens in a clinical trial or study, what happens when a clinical trial or study ends, what are the different phases of clinical trials, questions to ask before participating in clinical research, how do researchers decide who will participate, clinical research needs participants with diverse backgrounds.

By participating in clinical research, you can help scientists develop new medications and other strategies to treat and prevent disease. Many effective treatments that are used today, such as chemotherapy, cholesterol-lowering drugs, vaccines, and cognitive-behavioral therapy, would not exist without research participants. Whether you’re healthy or have a medical condition, people of all ages and backgrounds can participate in clinical trials. This article can help you learn more about clinical research, why people choose to participate, and how to get involved in a study.

Mr. Jackson's story

Mr. Jackson is 73 years old and was just diagnosed with Alzheimer’s disease . He is worried about how it will affect his daily life. Will he forget to take his medicine? Will he forget his favorite memories, like the births of his children or hiking the Appalachian Trail? When Mr. Jackson talked to his doctor about his concerns, she told him about a clinical trial that is testing a possible new Alzheimer’s treatment. But Mr. Jackson has concerns about clinical trials. He does not want to feel like a lab rat or take the chance of getting a treatment that may not work or could make him feel worse. The doctor explained that there are both risks and benefits to being part of a clinical trial, and she talked with Mr. Jackson about research studies — what they are, how they work, and why they need volunteers. This information helped Mr. Jackson feel better about clinical trials. He plans to learn more about how to participate.

Clinical research is the study of health and illness in people. There are two main types of clinical research: observational studies and clinical trials.

Observational studies monitor people in normal settings. Researchers gather information from people and compare changes over time. For example, researchers may ask a group of older adults about their exercise habits and provide monthly memory tests for a year to learn how physical activity is associated with cognitive health . Observational studies do not test a medical intervention, such as a drug or device, but may help identify new treatments or prevention strategies to test in clinical trials.

Clinical trials are research studies that test a medical, surgical, or behavioral intervention in people. These trials are the primary way that researchers determine if a new form of treatment or prevention, such as a new drug, diet, or medical device (for example, a pacemaker), is safe and effective in people. Often, a clinical trial is designed to learn if a new treatment is more effective or has less harmful side effects than existing treatments.

Other aims of clinical research include:

• Testing ways to diagnose a disease early, sometimes before there are symptoms
• Finding approaches to prevent a health problem, including in people who are healthy but at increased risk of developing a disease
• Improving quality of life for people living with a life-threatening disease or chronic health problem
• Studying the role of caregivers or support groups

Learn more about clinical research from MedlinePlus and ClinicalTrials.gov .

People volunteer for clinical trials and studies for a variety of reasons, including:

• They want to contribute to discovering health information that may help others in the future.
• Participating in research helps them feel like they are playing a more active role in their health.
• The treatments they have tried for their health problem did not work or there is no treatment for their health problem.

Whatever the motivation, when you choose to participate in a clinical trial, you become a partner in scientific discovery. Participating in research can help future generations lead healthier lives. Major medical breakthroughs could not happen without the generosity of clinical trial participants — young and old, healthy, or diagnosed with a disease.

Where can I find a clinical trial?

Looking for clinical trials related to aging and age-related health conditions? Talk to your health care provider and use online resources to:

• Search for a clinical trial
• Look for clinical trials on Alzheimer's, other dementias, and caregiving
• Find a registry for a particular diagnosis or condition
• Explore clinical trials and studies supported by NIA

After you find one or more studies that you are interested in, the next step is for you or your doctor to contact the study research staff and ask questions. You can usually find contact information in the description of the study.

Let your health care provider know if you are thinking about joining a clinical trial. Your provider may want to talk to the research team to make sure the study is safe for you and to help coordinate your care.

Joining a clinical trial is a personal decision with potential benefits and some risks. Learn what happens in a clinical trial and how participant safety is protected . Read and listen to testimonials from people who decided to participate in research.

Here’s what typically happens in a clinical trial or study:

• Research staff explain the trial or study in detail, answer your questions, and gather more information about you.
• Once you agree to participate, you sign an informed consent form indicating your understanding about what to expect as a participant and the various outcomes that could occur.
• You are screened to make sure you qualify for the trial or study.
• If accepted into the trial, you schedule a first visit, which is called the “baseline” visit. The researchers conduct cognitive and/or physical tests during this visit.
• For some trials testing an intervention, you are assigned by chance (randomly) to a treatment group or a control group . The treatment group will get the intervention being tested, and the control group will not.
• You follow the trial procedures and report any issues or concerns to researchers.
• You may visit the research site at regularly scheduled times for new cognitive, physical, or other evaluations and discussions with staff. During these visits, the research team collects data and monitors your safety and well-being.
• You continue to see your regular physician(s) for usual health care throughout the study.

How do researchers decide which interventions are safe to test in people?

Before a clinical trial is designed and launched, scientists perform laboratory tests and often conduct studies in animals to test a potential intervention’s safety and effectiveness. If these studies show favorable results, the U.S. Food and Drug Administration (FDA) approves the intervention to be tested in humans. Learn more about how the safety of clinical trial participants is protected.

Once a clinical trial or study ends, the researchers analyze the data to determine what the findings mean and to plan the next steps. As a participant, you should be provided information before the study starts about how long it will last, whether you will continue receiving the treatment after the trial ends (if applicable), and how the results of the research will be shared. If you have specific questions about what will happen when the trial or study ends, ask the research coordinator or staff.

Clinical trials of drugs and medical devices advance through several phases to test safety, determine effectiveness, and identify any side effects. The FDA typically requires Phase 1, 2, and 3 trials to be conducted to determine if the drug or device can be approved for further use. If researchers find the intervention to be safe and effective after the first three phases, the FDA approves it for clinical use and continues to monitor its effects.

Each phase has a different purpose:

• A Phase 1 trial tests an experimental drug or device on a small group of people (around 20 to 80) to judge its safety, including any side effects, and to test the amount (dosage).
• A Phase 2 trial includes more people (around 100 to 300) to help determine whether a drug is effective. This phase aims to obtain preliminary data on whether the drug or device works in people who have a certain disease or condition. These trials also continue to examine safety, including short-term side effects.
• A Phase 3 trial gathers additional information from several hundred to a few thousand people about safety and effectiveness, studying different populations and different dosages, and comparing the intervention with other drugs or treatment approaches. If the FDA agrees that the trial results support the intervention’s use for a particular health condition, it will approve the experimental drug or device.
• A Phase 4 trial takes place after the FDA approves the drug or device. The treatment’s effectiveness and safety are monitored in large, diverse populations. Sometimes, side effects may not become clear until more people have used the drug or device over a longer period of time.

Clinical trials that test a behavior change, rather than a drug or medical device, advance through similar steps, but behavioral interventions are not regulated by the FDA. Learn more about clinical trials , including the types of trials and the four phases.

Choosing to participate in research is an important personal decision. If you are considering joining a trial or study, get answers to your questions and know your options before you decide. Here are questions you might ask the research team when thinking about participating.

• What is this study trying to find out?
• What treatment or tests will I have? Will they hurt? Will you provide me with the test or lab results?
• What are the chances I will be in the experimental group or the control group?
• If the study tests a treatment, what are the possible risks, side effects, and benefits compared with my current treatment?
• How long will the clinical trial last?
• Where will the study take place? Will I need to stay in the hospital?
• Will you provide a way for me to get to the study site if I need it, such as through a ride-share service?
• Will I need a trial or study partner (for example, a family member or friend who knows me well) to come with me to the research site visits? If so, how long will he or she need to participate?
• Can I participate in any part of the trial with my regular doctor or at a clinic closer to my home?
• How will the study affect my everyday life?
• What steps are being taken to ensure my privacy?
• How will you protect my health while I participate?
• What happens if my health problem gets worse during the trial or study?
• Can I take my regular medicines while participating?
• Who will be in charge of my care while I am in the trial or study? Will I be able to see my own doctors?
• How will you keep my doctor informed about my participation?
• If I withdraw from the trial or study, will this affect my normal care?
• Will it cost me anything to be in the trial or study? If so, will I be reimbursed for expenses, such as travel, parking, lodging, or meals?
• Will my insurance pay for costs not covered by the research, or must I pay out of pocket? If I don’t have insurance, am I still eligible to participate?
• Will my trial or study partner be compensated for his or her time?
• Will you follow up on my health after the end of the trial or study?
• Will I continue receiving the treatment after the trial or study ends?
• Will you tell me the results of the research?
• Whom do I contact if I have questions after the trial or study ends?

To be eligible to participate, you may need to have certain characteristics, called inclusion criteria. For example, a clinical trial may need participants to have a certain stage of disease, version of a gene, or family history. Some trials require that participants have a study partner who can accompany them to clinic visits.

Participants with certain characteristics may not be allowed to participate in some trials. These characteristics are called exclusion criteria. They include factors such as specific health conditions or medications that could interfere with the treatment being tested.

Many volunteers must be screened to find enough people who are eligible for a trial or study. Generally, you can participate in only one clinical trial at a time, although this is not necessarily the case for observational studies. Different trials have different criteria, so being excluded from one trial does not necessarily mean you will be excluded from another.

When research only includes people with similar backgrounds, the findings may not apply to or benefit a broader population. The results of clinical trials and studies with diverse participants may apply to more people. That’s why research benefits from having participants of different ages, sexes, races, and ethnicities.

Researchers need older adults to participate in clinical research so that scientists can learn more about how new drugs, tests, and other interventions will work for them. Many older adults have health needs that are different from those of younger people. For example, as people age, their bodies may react differently to certain drugs. Older adults may need different dosages of a drug to have the intended result. Also, some drugs may have different side effects in older people than in younger individuals. Having older adults enrolled in clinical trials and studies helps researchers get the information they need to develop the right treatments for this age group.

Researchers know that it may be challenging for some older adults to join a clinical trial or study. For example, if you have multiple health problems, can you participate in research that is looking at only one condition? If you are frail or have a disability, will you be strong enough to participate? If you no longer drive, how can you get to the research site? Talk to the research coordinator or staff about your concerns. The research team may have already thought about some of the potential obstacles and have a plan to make it easier for you to participate.

Read more about diversity in clinical trials .

You may also be interested in

• Learning more about the benefits, risks, and safety of clinical research
• Finding out about participating in Alzheimer's disease research
• Downloading or sharing an infographic with the benefits of participating in clinical research

Sign up for email updates on healthy aging

For more information about clinical trials.

Alzheimers.gov www.alzheimers.gov Explore the Alzheimers.gov website for information and resources on Alzheimer’s and related dementias from across the federal government.

Clinical Research Trials and You National Institutes of Health www.nih.gov/health-information/nih-clinical-research-trials-you

ClinicalTrials.gov www.clinicaltrials.gov 

This content is provided by the NIH National Institute on Aging (NIA). NIA scientists and other experts review this content to ensure it is accurate and up to date.

Content reviewed: March 22, 2023

nia.nih.gov

An official website of the National Institutes of Health

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10 Experimental research

Experimental research—often considered to be the ‘gold standard’ in research designs—is one of the most rigorous of all research designs. In this design, one or more independent variables are manipulated by the researcher (as treatments), subjects are randomly assigned to different treatment levels (random assignment), and the results of the treatments on outcomes (dependent variables) are observed. The unique strength of experimental research is its internal validity (causality) due to its ability to link cause and effect through treatment manipulation, while controlling for the spurious effect of extraneous variable.

Experimental research is best suited for explanatory research—rather than for descriptive or exploratory research—where the goal of the study is to examine cause-effect relationships. It also works well for research that involves a relatively limited and well-defined set of independent variables that can either be manipulated or controlled. Experimental research can be conducted in laboratory or field settings. Laboratory experiments , conducted in laboratory (artificial) settings, tend to be high in internal validity, but this comes at the cost of low external validity (generalisability), because the artificial (laboratory) setting in which the study is conducted may not reflect the real world. Field experiments are conducted in field settings such as in a real organisation, and are high in both internal and external validity. But such experiments are relatively rare, because of the difficulties associated with manipulating treatments and controlling for extraneous effects in a field setting.

Experimental research can be grouped into two broad categories: true experimental designs and quasi-experimental designs. Both designs require treatment manipulation, but while true experiments also require random assignment, quasi-experiments do not. Sometimes, we also refer to non-experimental research, which is not really a research design, but an all-inclusive term that includes all types of research that do not employ treatment manipulation or random assignment, such as survey research, observational research, and correlational studies.

Basic concepts

Treatment and control groups. In experimental research, some subjects are administered one or more experimental stimulus called a treatment (the treatment group ) while other subjects are not given such a stimulus (the control group ). The treatment may be considered successful if subjects in the treatment group rate more favourably on outcome variables than control group subjects. Multiple levels of experimental stimulus may be administered, in which case, there may be more than one treatment group. For example, in order to test the effects of a new drug intended to treat a certain medical condition like dementia, if a sample of dementia patients is randomly divided into three groups, with the first group receiving a high dosage of the drug, the second group receiving a low dosage, and the third group receiving a placebo such as a sugar pill (control group), then the first two groups are experimental groups and the third group is a control group. After administering the drug for a period of time, if the condition of the experimental group subjects improved significantly more than the control group subjects, we can say that the drug is effective. We can also compare the conditions of the high and low dosage experimental groups to determine if the high dose is more effective than the low dose.

Treatment manipulation. Treatments are the unique feature of experimental research that sets this design apart from all other research methods. Treatment manipulation helps control for the ‘cause’ in cause-effect relationships. Naturally, the validity of experimental research depends on how well the treatment was manipulated. Treatment manipulation must be checked using pretests and pilot tests prior to the experimental study. Any measurements conducted before the treatment is administered are called pretest measures , while those conducted after the treatment are posttest measures .

Random selection and assignment. Random selection is the process of randomly drawing a sample from a population or a sampling frame. This approach is typically employed in survey research, and ensures that each unit in the population has a positive chance of being selected into the sample. Random assignment, however, is a process of randomly assigning subjects to experimental or control groups. This is a standard practice in true experimental research to ensure that treatment groups are similar (equivalent) to each other and to the control group prior to treatment administration. Random selection is related to sampling, and is therefore more closely related to the external validity (generalisability) of findings. However, random assignment is related to design, and is therefore most related to internal validity. It is possible to have both random selection and random assignment in well-designed experimental research, but quasi-experimental research involves neither random selection nor random assignment.

Threats to internal validity. Although experimental designs are considered more rigorous than other research methods in terms of the internal validity of their inferences (by virtue of their ability to control causes through treatment manipulation), they are not immune to internal validity threats. Some of these threats to internal validity are described below, within the context of a study of the impact of a special remedial math tutoring program for improving the math abilities of high school students.

History threat is the possibility that the observed effects (dependent variables) are caused by extraneous or historical events rather than by the experimental treatment. For instance, students’ post-remedial math score improvement may have been caused by their preparation for a math exam at their school, rather than the remedial math program.

Maturation threat refers to the possibility that observed effects are caused by natural maturation of subjects (e.g., a general improvement in their intellectual ability to understand complex concepts) rather than the experimental treatment.

Testing threat is a threat in pre-post designs where subjects’ posttest responses are conditioned by their pretest responses. For instance, if students remember their answers from the pretest evaluation, they may tend to repeat them in the posttest exam.

Not conducting a pretest can help avoid this threat.

Instrumentation threat , which also occurs in pre-post designs, refers to the possibility that the difference between pretest and posttest scores is not due to the remedial math program, but due to changes in the administered test, such as the posttest having a higher or lower degree of difficulty than the pretest.

Mortality threat refers to the possibility that subjects may be dropping out of the study at differential rates between the treatment and control groups due to a systematic reason, such that the dropouts were mostly students who scored low on the pretest. If the low-performing students drop out, the results of the posttest will be artificially inflated by the preponderance of high-performing students.

Regression threat —also called a regression to the mean—refers to the statistical tendency of a group’s overall performance to regress toward the mean during a posttest rather than in the anticipated direction. For instance, if subjects scored high on a pretest, they will have a tendency to score lower on the posttest (closer to the mean) because their high scores (away from the mean) during the pretest were possibly a statistical aberration. This problem tends to be more prevalent in non-random samples and when the two measures are imperfectly correlated.

Two-group experimental designs

Pretest-posttest control group design . In this design, subjects are randomly assigned to treatment and control groups, subjected to an initial (pretest) measurement of the dependent variables of interest, the treatment group is administered a treatment (representing the independent variable of interest), and the dependent variables measured again (posttest). The notation of this design is shown in Figure 10.1.

Statistical analysis of this design involves a simple analysis of variance (ANOVA) between the treatment and control groups. The pretest-posttest design handles several threats to internal validity, such as maturation, testing, and regression, since these threats can be expected to influence both treatment and control groups in a similar (random) manner. The selection threat is controlled via random assignment. However, additional threats to internal validity may exist. For instance, mortality can be a problem if there are differential dropout rates between the two groups, and the pretest measurement may bias the posttest measurement—especially if the pretest introduces unusual topics or content.

Posttest -only control group design . This design is a simpler version of the pretest-posttest design where pretest measurements are omitted. The design notation is shown in Figure 10.2.

The treatment effect is measured simply as the difference in the posttest scores between the two groups:

The appropriate statistical analysis of this design is also a two-group analysis of variance (ANOVA). The simplicity of this design makes it more attractive than the pretest-posttest design in terms of internal validity. This design controls for maturation, testing, regression, selection, and pretest-posttest interaction, though the mortality threat may continue to exist.

Because the pretest measure is not a measurement of the dependent variable, but rather a covariate, the treatment effect is measured as the difference in the posttest scores between the treatment and control groups as:

Due to the presence of covariates, the right statistical analysis of this design is a two-group analysis of covariance (ANCOVA). This design has all the advantages of posttest-only design, but with internal validity due to the controlling of covariates. Covariance designs can also be extended to pretest-posttest control group design.

Factorial designs

Two-group designs are inadequate if your research requires manipulation of two or more independent variables (treatments). In such cases, you would need four or higher-group designs. Such designs, quite popular in experimental research, are commonly called factorial designs. Each independent variable in this design is called a factor , and each subdivision of a factor is called a level . Factorial designs enable the researcher to examine not only the individual effect of each treatment on the dependent variables (called main effects), but also their joint effect (called interaction effects).

In a factorial design, a main effect is said to exist if the dependent variable shows a significant difference between multiple levels of one factor, at all levels of other factors. No change in the dependent variable across factor levels is the null case (baseline), from which main effects are evaluated. In the above example, you may see a main effect of instructional type, instructional time, or both on learning outcomes. An interaction effect exists when the effect of differences in one factor depends upon the level of a second factor. In our example, if the effect of instructional type on learning outcomes is greater for three hours/week of instructional time than for one and a half hours/week, then we can say that there is an interaction effect between instructional type and instructional time on learning outcomes. Note that the presence of interaction effects dominate and make main effects irrelevant, and it is not meaningful to interpret main effects if interaction effects are significant.

Hybrid experimental designs

Hybrid designs are those that are formed by combining features of more established designs. Three such hybrid designs are randomised bocks design, Solomon four-group design, and switched replications design.

Randomised block design. This is a variation of the posttest-only or pretest-posttest control group design where the subject population can be grouped into relatively homogeneous subgroups (called blocks ) within which the experiment is replicated. For instance, if you want to replicate the same posttest-only design among university students and full-time working professionals (two homogeneous blocks), subjects in both blocks are randomly split between the treatment group (receiving the same treatment) and the control group (see Figure 10.5). The purpose of this design is to reduce the ‘noise’ or variance in data that may be attributable to differences between the blocks so that the actual effect of interest can be detected more accurately.

Solomon four-group design . In this design, the sample is divided into two treatment groups and two control groups. One treatment group and one control group receive the pretest, and the other two groups do not. This design represents a combination of posttest-only and pretest-posttest control group design, and is intended to test for the potential biasing effect of pretest measurement on posttest measures that tends to occur in pretest-posttest designs, but not in posttest-only designs. The design notation is shown in Figure 10.6.

Switched replication design . This is a two-group design implemented in two phases with three waves of measurement. The treatment group in the first phase serves as the control group in the second phase, and the control group in the first phase becomes the treatment group in the second phase, as illustrated in Figure 10.7. In other words, the original design is repeated or replicated temporally with treatment/control roles switched between the two groups. By the end of the study, all participants will have received the treatment either during the first or the second phase. This design is most feasible in organisational contexts where organisational programs (e.g., employee training) are implemented in a phased manner or are repeated at regular intervals.

Quasi-experimental designs

Quasi-experimental designs are almost identical to true experimental designs, but lacking one key ingredient: random assignment. For instance, one entire class section or one organisation is used as the treatment group, while another section of the same class or a different organisation in the same industry is used as the control group. This lack of random assignment potentially results in groups that are non-equivalent, such as one group possessing greater mastery of certain content than the other group, say by virtue of having a better teacher in a previous semester, which introduces the possibility of selection bias . Quasi-experimental designs are therefore inferior to true experimental designs in interval validity due to the presence of a variety of selection related threats such as selection-maturation threat (the treatment and control groups maturing at different rates), selection-history threat (the treatment and control groups being differentially impacted by extraneous or historical events), selection-regression threat (the treatment and control groups regressing toward the mean between pretest and posttest at different rates), selection-instrumentation threat (the treatment and control groups responding differently to the measurement), selection-testing (the treatment and control groups responding differently to the pretest), and selection-mortality (the treatment and control groups demonstrating differential dropout rates). Given these selection threats, it is generally preferable to avoid quasi-experimental designs to the greatest extent possible.

In addition, there are quite a few unique non-equivalent designs without corresponding true experimental design cousins. Some of the more useful of these designs are discussed next.

Regression discontinuity (RD) design . This is a non-equivalent pretest-posttest design where subjects are assigned to the treatment or control group based on a cut-off score on a preprogram measure. For instance, patients who are severely ill may be assigned to a treatment group to test the efficacy of a new drug or treatment protocol and those who are mildly ill are assigned to the control group. In another example, students who are lagging behind on standardised test scores may be selected for a remedial curriculum program intended to improve their performance, while those who score high on such tests are not selected from the remedial program.

Because of the use of a cut-off score, it is possible that the observed results may be a function of the cut-off score rather than the treatment, which introduces a new threat to internal validity. However, using the cut-off score also ensures that limited or costly resources are distributed to people who need them the most, rather than randomly across a population, while simultaneously allowing a quasi-experimental treatment. The control group scores in the RD design do not serve as a benchmark for comparing treatment group scores, given the systematic non-equivalence between the two groups. Rather, if there is no discontinuity between pretest and posttest scores in the control group, but such a discontinuity persists in the treatment group, then this discontinuity is viewed as evidence of the treatment effect.

Proxy pretest design . This design, shown in Figure 10.11, looks very similar to the standard NEGD (pretest-posttest) design, with one critical difference: the pretest score is collected after the treatment is administered. A typical application of this design is when a researcher is brought in to test the efficacy of a program (e.g., an educational program) after the program has already started and pretest data is not available. Under such circumstances, the best option for the researcher is often to use a different prerecorded measure, such as students’ grade point average before the start of the program, as a proxy for pretest data. A variation of the proxy pretest design is to use subjects’ posttest recollection of pretest data, which may be subject to recall bias, but nevertheless may provide a measure of perceived gain or change in the dependent variable.

Separate pretest-posttest samples design . This design is useful if it is not possible to collect pretest and posttest data from the same subjects for some reason. As shown in Figure 10.12, there are four groups in this design, but two groups come from a single non-equivalent group, while the other two groups come from a different non-equivalent group. For instance, say you want to test customer satisfaction with a new online service that is implemented in one city but not in another. In this case, customers in the first city serve as the treatment group and those in the second city constitute the control group. If it is not possible to obtain pretest and posttest measures from the same customers, you can measure customer satisfaction at one point in time, implement the new service program, and measure customer satisfaction (with a different set of customers) after the program is implemented. Customer satisfaction is also measured in the control group at the same times as in the treatment group, but without the new program implementation. The design is not particularly strong, because you cannot examine the changes in any specific customer’s satisfaction score before and after the implementation, but you can only examine average customer satisfaction scores. Despite the lower internal validity, this design may still be a useful way of collecting quasi-experimental data when pretest and posttest data is not available from the same subjects.

An interesting variation of the NEDV design is a pattern-matching NEDV design , which employs multiple outcome variables and a theory that explains how much each variable will be affected by the treatment. The researcher can then examine if the theoretical prediction is matched in actual observations. This pattern-matching technique—based on the degree of correspondence between theoretical and observed patterns—is a powerful way of alleviating internal validity concerns in the original NEDV design.

Perils of experimental research

Experimental research is one of the most difficult of research designs, and should not be taken lightly. This type of research is often best with a multitude of methodological problems. First, though experimental research requires theories for framing hypotheses for testing, much of current experimental research is atheoretical. Without theories, the hypotheses being tested tend to be ad hoc, possibly illogical, and meaningless. Second, many of the measurement instruments used in experimental research are not tested for reliability and validity, and are incomparable across studies. Consequently, results generated using such instruments are also incomparable. Third, often experimental research uses inappropriate research designs, such as irrelevant dependent variables, no interaction effects, no experimental controls, and non-equivalent stimulus across treatment groups. Findings from such studies tend to lack internal validity and are highly suspect. Fourth, the treatments (tasks) used in experimental research may be diverse, incomparable, and inconsistent across studies, and sometimes inappropriate for the subject population. For instance, undergraduate student subjects are often asked to pretend that they are marketing managers and asked to perform a complex budget allocation task in which they have no experience or expertise. The use of such inappropriate tasks, introduces new threats to internal validity (i.e., subject’s performance may be an artefact of the content or difficulty of the task setting), generates findings that are non-interpretable and meaningless, and makes integration of findings across studies impossible.

The design of proper experimental treatments is a very important task in experimental design, because the treatment is the raison d’etre of the experimental method, and must never be rushed or neglected. To design an adequate and appropriate task, researchers should use prevalidated tasks if available, conduct treatment manipulation checks to check for the adequacy of such tasks (by debriefing subjects after performing the assigned task), conduct pilot tests (repeatedly, if necessary), and if in doubt, use tasks that are simple and familiar for the respondent sample rather than tasks that are complex or unfamiliar.

In summary, this chapter introduced key concepts in the experimental design research method and introduced a variety of true experimental and quasi-experimental designs. Although these designs vary widely in internal validity, designs with less internal validity should not be overlooked and may sometimes be useful under specific circumstances and empirical contingencies.

Social Science Research: Principles, Methods and Practices (Revised edition) Copyright © 2019 by Anol Bhattacherjee is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License , except where otherwise noted.

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• J Am Assoc Lab Anim Sci
• v.50(5); 2011 Sep

Administration of Substances to Laboratory Animals: Routes of Administration and Factors to Consider

Patricia v turner.

1 Department of Pathobiology, University of Guelph, Guelph, Canada

2 Department of Comparative Medicine, School of Medicine, University of Washington

Cynthia Pekow

3 Research and Development, Veterans Affairs Puget Sound Health Care System, Seattle, Washington

Mary Ann Vasbinder

4 Platform, Technology and Sciences, Quality and Risk Management,Glaxo Smith Kline, Research Triangle Park, North Carolina

Administration of substances to laboratory animals requires careful consideration and planning to optimize delivery of the agent to the animal while minimizing potential adverse experiences from the procedure. For all species, many different routes are available for administration of substances. The research team and IACUC members should be aware of reasons for selecting specific routes and of training and competency necessary for personnel to use these routes effectively. Once a route is selected, issues such as volume of administration, site of delivery, pH of the substance, and other factors must be considered to refine the technique. Inadequate training or inattention to detail during this aspect of a study may result in unintentional adverse effects on experimental animals and confounded results.

Administration of substances to laboratory animals is often a critical component of experimental design. Administered substances may include: infectious disease agents; various therapeutics, such as vaccinations, antimicrobials, pharmacologic agents, anesthetics, and analgesics; chemical test agents; radiocontrast agents; electrolytes and other fluids; and nutritive support. Because substances may be administered repeatedly to the same animal or to multiple animals on the same study, the dosing methodology is an important consideration when planning an experiment and during protocol review by animal care and use committees and represents an essential opportunity for refining treatment of research subjects. Specific considerations for delivery of substances to animals are numerous and include factors such as absorption, distribution, metabolism and excretion of therapeutic or chemical agents; route, volume, and frequency of administration; duration of treatment; pH, stability, homogeneity, and osmolality of the substance to be administered; selection of vehicle or solvent for delivering substances that cannot be administered in a solid or particulate state; solution preparation, including considerations for sterility if the substance is being administered parenterally; and dosing apparatus and animal restraint necessary for specific routes of delivery. In addition, research teams should be aware of potential adverse effects related to substance administration to avoid confounding effects with other aspects of study design and to permit accurate interpretation of research findings.

Although understanding the basic pharmacology of any administered therapeutic or chemical agent is important for experimental planning, it is beyond the scope of this article to review principles of pharmacokinetics and pharmacodynamics, and readers are referred to several excellent texts dealing with these subjects. 22 , 102 , 106 This article is the first of a 2-part review of substance delivery to laboratory animals and summarizes recommended practices for various routes of administration to a range of species and factors to consider during experimental planning. The second part of this review examines dosing equipment and apparatus needed for substance delivery, considerations for selecting vehicles, and solute preparation and handling. 134

Routes of Administration

Selection of a route..

Substances are administered to laboratory animals by a wide variety of routes. A key factor determining the route selected is whether the agent is being administered for a local or systemic (either enteral [through the digestive tract] or parenteral [outside the digestive tract]) effect. Parenteral administration methods typically produce the highest bioavailability of substances because these methods avoid the first-pass effect of hepatic metabolism, which occurs commonly with orally administered chemicals and therapeutics. Parenteral routes also circumvent some of the unpredictability associated with enteral absorptive processes. Furthermore, regulatory requirements may influence the selection of a particular route, depending on the purpose of the study (for example, nonclinical safety testing, in which the route of delivery to animals should closely resemble the projected route of administration to humans). 37 , 38

A substance may be given into the mouth (orally) or delivered directly into the stomach (gastric gavage); delivered into a blood vessel (intravenous); delivered onto, into, under, or across the skin or into a muscle (epicutaneous, intradermal, subcutaneous, transdermal, and intramuscular administration, respectively); instilled onto or into the eye (transcorneal or intraocular, respectively); into the brain (intracerebral) or the space surrounding the dura mater or that surrounding the distal spinal cord (epidural and intrathecal, respectively); administered into the peritoneal cavity (intraperitoneal), directly into the marrow cavity (intraosseous); sprayed into the nose for absorption across the nasal mucous membranes or into the lungs (intranasal) or delivered into the lungs by direct tracheal instillation (intratracheal) or inhalation; or administered by a range of less common routes using other body orifices, surgical exposures, and species-specific anatomic features (for examples, see references 16 , 41 , 60 , 64 , 73 , 91 , and 127 ).

In laboratory species, many of the commonly used methods of delivery require restraint, sedation, or general anesthesia. The use of such manipulations should be considered when selecting the administration route to refine procedures so that they are less invasive or aversive to the animals. In addition, each route has advantages and disadvantages that should be considered depending on the final effect to be achieved, and ultimately the route selected will markedly affect the pharmacokinetics of the substance. This pharmacokinetic effect of route of administration is exemplified by naloxone, a potent opioid antagonist. Given intravenously, naloxone rapidly reverses opioid-induced central nervous system depression, 28 but when given enterally, the drug can be used to treat opioid-induced bowel stasis without antagonism of the analgesic effects of systemically administered opioids. 52 Another consideration regarding once-daily administration of substances to animals is their chronobiology or circadian rhythm. Depending on the aims and objectives of the experiment, the timing of substance administration may need to be considered carefully, for example, to administer a therapeutic when an animal's system is most or least metabolically active to induce or minimize toxicity. 119

Enteral administration.

Administration of substances directly into the mouth, admixed in diet or other foodstuffs, or by orogastric or nasogastric gavage is common in laboratory animal medicine and research. Per rectum administration of substances by enema or suppository is less common in animals than in humans. The oral route is economical, convenient, relatively safe, and some animals can be trained to cooperate voluntarily, depending on the compound being administered ( Figure 1 A through C ). Although voluntary consumption of the material being administered is ideal, this dosing technique may not be reliable in all animals or dose groups or for long-term studies, because of individual preferences for flavors, palatability issues, and changes in behavior over time. For substances being tested for safety, oral dosing mimics the most commonly used mode of administration of substances to humans. When placing substances directly into the mouth, it is important to ensure that tablets or gelatin capsules containing test material are placed far back in the mouth and that the animal swallows, to ensure receipt of the full dose. The number and size of capsules or tablets administered should be proportional to the size of the animal being dosed, to minimize regurgitation. Gavage (esophageal or gastric) is often used in research settings, instead of mixing substances in water or food, to ensure precise and accurate dosing of animals ( Figure 1 D ).

(A) Rat voluntarily consuming nutritional supplement from a syringe. Photo courtesy of Colette Wheler. (B) Macaque voluntarily drinking medication from a syringe. Photo courtesy of Andrew Winterborn. (C) Pig voluntarily accepting medication when administered in a marshmallow. (D) Oral gavage of fish. Photo courtesy of Gerald Johnson.

Selection of appropriate tubing size for orogastric or nasogastric gavage is important to minimize discomfort while optimizing delivery of substances. Nasogastric tubes are used commonly in rabbits for enteral nutrition and in nonhuman primates for dose administration and typically comprise 3- to 8-French soft rubber pediatric feeding tubes. 18 , 104 Tubing is measured from the external nares to the last rib and marked. To minimize discomfort, a small amount of xylocaine jelly can be placed on the end of the tubing or a drop of 0.5% proparicaine hydrochloride ophthalmic solution is placed directly in the nares prior to introducing the tubing into the ventromedial meatus ( Figure 2 ).

Chronic nasogastric catheter placement in a rabbit for enteral nutrition. Photo courtesy of Colette Wheler.

Except when given in the diet or admixed with food, oral administration of substances typically requires some form of restraint. In many species, including rodents and nonhuman primates, restraint can be the greatest adverse effect of a procedure. 25 , 78 , 135 Habituation or positive reinforcement training to restraint may reduce the stress associated with the procedure. 1 , 107 , 120 In addition, the administration of large volumes of substances by orogastric or nasogastric gavage may cause stress due to gastric distension in species that are unable to vomit, such as rodents. 21 Therefore, using the smallest volume possible is recommended for the oral route of administration, optimally 5 mL/kg for all species ( Table 1 ). When rats underwent gavage at this volume, no difference was noted between the stress induced by gavage compared with that induced by restraint alone. 135 When large volumes must be administered by gavage, a slower delivery rate may be better tolerated by animals.

Recommended volumes and sites of Administration of substances to laboratory animals

The physicochemical properties of the substance to be administered will markedly affect the volumes that are tolerated. For example, lower volumes than those listed in this table may need to be used for highly viscous or irritating substances.

Limitations of oral dosage may include a slower onset of action compared with parenteral delivery, a potentially significant first-pass effect by the liver for those substances metabolized through this route with reduced efficacy, lack of absorption of substances due to chemical polarity or interference with absorption by ingesta, poor compliance with voluntary consumption because of poor palatability or local irritation, lack of systemic absorption from the digestive tract, degradation of substances by digestive enzymes and acid, and inability to use this route in animals that are unconscious or have clinically significant diarrhea or emesis. 11 Oral gavage requires moderate technical skill and confidence. Research personnel should have training and practice prior to study initiation to minimize adverse events associated with the technique and to ensure that it is performed accurately, rapidly, and humanely in experimental animals.

Intravenous administration.

The intravenous route of delivery is the most efficient means of delivering substances to animals because it bypasses the need for solute absorption. With this method, substances are administered as a bolus or infusion directly into blood vessels on either an acute or chronic basis ( Figure 3 ). Precision electronic infusion pumps equipped with alarms to indicate flow interruptions and microdrop infusion sets are used to ensure accurate chronic intravenous delivery of many substances; however, less expensive precision and spring-operated disposable pumps have become available for this purpose in recent years and may represent a more economical alternative for experimental intravenous substance delivery, depending on the nature of the material to be administered and the duration of treatment. 2 , 32 , 117

Different routes of skin administration of substances. Depicted are intramuscular (IM), intravenous (IV), subcutaneous (SC), and intradermal (ID) routes. Illustration courtesy of Gianni Chiappetta.

Although fluids and parenteral nutrition typically are infused on a continuous basis over several hours or days, the decision to administer other substances by the intravenous route often depends on the pharmacokinetics of the substance, as well as the maximum tolerated dose, the time interval over which delivery is required (referred to as dosing intensity), and the need to minimize variations in peak and trough blood levels in the substance being administered. The actual technique involves aseptic preparation of skin for percutaneous venous injection or surgical exposure of blood vessels for substance administration. Intentional intraarterial administration of substances should be avoided routinely and used only for specific experimental conditions, because of the potential for severe complications with this route, including blindness, cerebrovascular stroke, permanent motor deficits, and limb gangrene. 75 , 114 , 116 , 142 Suggested sites and volumes for intravenous injection and infusion of substances are given in Table 1 .

Researchers designing experiments requiring single or repeated intravenous treatments should consider technique refinements that may enhance animal comfort, including the use of the smallest needle or catheter size possible to minimize injection trauma, butterfly needles for single injections to minimize perivascular trauma, indwelling catheters and vascular access ports for animal comfort and locomotor freedom, topical anesthetic creams and ointments prior to needle placement to minimize injection pain, and external pump packs to minimize the restriction of animal movement associated with tethering. Excellent recent reviews of techniques, equipment, and refinements for using catheters and vascular access ports in animals have been published. 16 , 53 , 89 , 124 , 125 , 128 A more detailed discussion of dosing equipment for intravenous delivery can be found in the companion article to the current work. 134

Intraosseous administration of substances, particularly crystalloid fluids, is used in human pediatric medicine and emergency avian and rabbit medicine as an alternative for the intravenous route in hypovolemic patients with inaccessible or collapsed veins. 31 , 80 , 129 The medullary cavity contains noncollapsing venous sinuses that directly enter into the central venous circulation and substances administered intraosseously are generally detectable immediately after administration. The technique is difficult to perform without advanced training and is potentially invasive, with considerable risk for postprocedural osteomyelitis, fat embolization, iatrogenic fracture and growth plate injury, and pain. Intraosseous administration typically is conducted in fully anesthetized animals.

Substances administered intravenously or intraosseously must be delivered aseptically and should be sterile; free of particulates that may induce foreign body emboli; and minimally irritating to vascular endothelia, to prevent vasculitis and thrombosis, and to erythrocytes, to minimize lysis. Certain oily substances, such as cremaphor, and various alcohols, surfactants, and other vehicles and excipients may induce hemolysis when introduced intravenously; these substances should be avoided, whenever possible, or first evaluated in vitro for safety. 4 , 79 , 90 The intravenous route of substance delivery, although efficient, can be risky in animals, and persons conducting this technique require training and practice to ensure competency. Careful control of hemostasis must be instituted when the catheter or needle is removed, to minimize blood loss and painful hematoma formation. When fluids or infusions are administered chronically, animals should be monitored closely for signs of fluid overload and pulmonary edema, such as dyspnea and cyanosis. 77 Chronically implanted catheters and vascular access ports require regular cleaning and maintenance to ensure patency and prevent infection.

Administration to skin and muscle.

Some substances can be administered directly to the skin surface (epicutaneous administration) for a topical affect. The extent of absorption of materials through the skin and into the systemic circulation (that is, percutaneous or transdermal delivery) depends on: the surface area over which the substance is applied; the concentration of the substance administered; the lipid solubility of the material or vehicle; whether the skin surface is intact; the skin thickness at the site of application; the length of time that the material is in contact with the skin surface; and the degree of skin hydration and surface occlusion, in that covered and well-hydrated skin absorbs substances faster than does uncovered or dry skin. 87 For fish, specialized chambers can be constructed to expose the skin or gills specifically to test substances. 16 , 53 When administering substances topically to the skin of mammals, overlying hair is clipped to minimize matting and maximize contact with the material to be applied, and the skin surface is cleaned prior to application. Absorption of substances across the epidermis occurs through paracellular and transcellular mechanisms into the stratum corneum, to the stratum spinosum, and then to the basal layers of the skin and later, the dermis, as well as into the subcutaneous space through hair follicles and accessory glands. 42 , 93

Caution must be exercised to avoid applying caustic or irritating material directly onto the skin, and some substances may induce local sensitization reactions. Consideration should be given to the potential for systemic toxicity when administering substances topically, particularly if the site is readily accessible for grooming. 46 Application of thin layers of cream or ointment to the skin at more frequent intervals may be more efficacious with less potential for systemic toxicity than is less frequent application of thicker layers.

Transdermal or percutaneous delivery represents a similar route of administration except that materials are applied to the skin surface deliberately, usually by means of a patch, for absorption across the epithelial barrier into the systemic circulation. Typically, this method produces very constant blood levels of the substance being administered. Percutaneous delivery is an attractive alternative to other parenteral routes, avoiding the need for repeated animal restraint, painful injections, and sharps hazards. In addition, materials can readily be removed from the skin surface if dosing needs to be interrupted or if adverse effects are noted. Transdermal delivery of substances may be acute or chronic, and current techniques for delivering substances by this route have been reviewed recently. 7 , 45 , 100 The skin is prepared as for topical delivery. When a transdermal delivery system will be used, the agent and delivery system (for example, patch) must be applied in advance of when the desired effect needs to occur, based on the pharmacokinetics of substance absorption. The product should be applied in such a way to protect it from ingestion and contamination, and the signs of toxicity after inadvertent ingestion by the animal should be known. Commercially available human transdermal products can be difficult to use in animals because of the much larger doses of substances impregnated into products intended for adult human use. Cutting transdermal patches to scale-down the dose being administered is not recommended; however, covering a portion of the patch to limit substance administration may be used. Animals should be observed closely for toxicity, and as for topical delivery methods, skin sensitization may occur over time with transdermal product use. 84 Animals must be prevented from removing and ingesting patches.

Nonirritating substances may be given subcutaneously, which represents a rapid, inexpensive, and simple method of parenteral substance administration ( Figure 3 ). Substances administered subcutaneously often are absorbed at a slower rate compared with other parenteral routes, providing a sustained effect. The exact mechanism of absorption is unknown but is thought to be due to uptake of macromolecules within the subcutis by small capillaries underling the skin, with minimal lymphatic absorption. 56 Substances delivered subcutaneously can be aqueous or oily fluids, depots of oily materials for slow absorption, solid pellets, or injected into suitably sized osmotic minipumps or other implantable pumps, which subsequently are surgically inserted into a subcutaneous pocket. Because the subcutaneous space is largely a virtual space, it can be an excellent site for large volume fluid delivery in small or dehydrated animals, avoiding technical difficulties and problems sometimes seen with direct intravenous administration, such as fluid overload and pulmonary edema, because excess subcutaneous fluid is excreted rapidly by the kidneys. Compared with intravenous delivery, the subcutaneous route is a simple one to master; however, training and competency of personnel should be monitored to ensure that substances are delivered accurately and that inadvertent intravenous injection is avoided. Careful consideration should be given to using an appropriately sized needle, and humane and aseptic periinjection techniques. The skin overlying the site selected for injection should be loose to minimize discomfort, and the needle should be inserted at a shallow angle to minimize damage to underlying tissues. Passing a small-gauge needle through a thick rubber stopper to fill an attached syringe prior to injection may dull the needle point, enhancing injection discomfort. Contaminated substances injected subcutaneously typically will result in abscess formation. Recommended volumes and locations for subcutaneous injections are presented in Table 1 . Inadvertent subcutaneous administration is a common complication of intradermal injections, and small, sharp needles are required for success with intradermal delivery. 82

Intramuscular administration of substances is a common parenteral route in large animals and humans but often is avoided in smaller species because of the reduced muscle mass. Generally, intramuscular injections result in uniform and rapid absorption of substances, because of the rich vascular supply ( Figure 3 ). Smaller volumes are administered intramuscularly than for subcutaneous delivery ( Table 1 ). The intramuscular technique requires more skill than does subcutaneous injection and should be conducted only by well-trained personnel. Intramuscular injection of irritating substances or inadvertent injection of nerves may result in paresis, paralysis, muscle necrosis, and localized muscle sloughing. 103 Repeated injections may result in muscle inflammation and necrosis. 30 Other considerations and cautions for using the intramuscular route for substance delivery are similar to the subcutaneous route.

Epidural and intrathecal administration.

For rapid effects of substances on cerebrospinal tissues or meninges, substances can be administered into the epidural or subarachnoid (intrathecal) space of the spinal cord ( Figure 4 , Table 1 ). This technique avoids absorptive problems otherwise presented by the blood–brain barrier. The route is used commonly to induce spinal anesthesia or to introduce contrast media for visualizing vertebral bodies or the spinal cord of large animal species. The technique requires animals to be sedated heavily and given a local anesthetic block over the spinal needle insertion site; alternatively animals can undergo general anesthesia prior to implementation. 23 , 138 Aseptic preparation of the skin overlying the injection site and use of sterile technique for needle insertion are critical for success and animal recovery. The exact location of needle insertion and volume of injectate will vary between species and for intrathecal compared with epidural administration, and several factors contribute to procedural success (see reference 138 for review). Epidural fat, lipophilicity of the substance being administered, leakage of injectate through intervertebral spaces, and pronounced meningovertebral ligaments all will limit or alter the spread of material being introduced by epidural or intrathecal routes. 58 This limitation may be problematic, in that increased quantities of substances may need to be administered for effect, with the possibility of spill-over into systemic circulation, resulting in adverse effects, such as profound respiratory depression requiring prolonged ventilation. Visualization of cerebrospinal fluid after spinal needle insertion confirms intrathecal placement of the needle. If this fluid is noted when attempting an epidural injection, the needle should be withdrawn and repositioned, or the dose of the substance administered should be reduced, because the kinetics of substance absorption from epidural compared with intrathecal delivery can be markedly different. 138

Epidural (ED) compared with intrathecal (IT) injections in the distal lumbar spine. Illustration courtesy of Gianni Chiappetta.

Intrathecal or epidural administration of substances requires considerable technical skill and in-depth knowledge of anesthesia, analgesia, and spinal cord and vertebral column anatomy. These techniques should be performed only by well-trained personnel. Adverse events associated with epidural administration of substances to small animals include prolonged time for hair regrowth over the injection site, pruritus, urinary retention, nausea, vomiting, and prolonged and severe respiratory depression. 132

Intraperitoneal administration.

Injection of substances into the peritoneal cavity is a common technique in laboratory rodents but rarely is used in larger mammals and humans. Intraperitoneal injection is used for small species for which intravenous access is challenging and it can be used to administer large volumes of fluid safely ( Table 1 ) or as a repository site for surgical implantation of a preloaded osmotic minipump. Absorption of material delivered intraperitoneally is typically much slower than for intravenous injection. Although intraperitoneal delivery is considered a parenteral route of administration, the pharmacokinetics of substances administered intraperitoneally are more similar to those seen after oral administration, because the primary route of absorption is into the mesenteric vessels, which drain into the portal vein and pass through the liver. 74 Therefore substances administered intraperitoneally may undergo hepatic metabolism before reaching the systemic circulation. In addition, a small amount of intraperitoneal injectate may pass directly across the diaphragm through small lacunae and into the thoracic lymph. 3

In mammals, intraperitoneal administration typically is conducted in conscious animals by using firm manual restraint, with the head and body tipped downward to move viscera away from the surface of the ventral abdomen. Injections in rodents are made in the lower right abdominal quadrant away from the midline to avoid inadvertent injection into the urinary bladder or cecum. 26 The syringe plunger may be withdrawn prior to injection, specifically looking for urine, blood, or digesta in the needle hub; if these fluids are seen, the needle should be withdrawn, replaced, and repositioned prior to injection. The most common mistake is to puncture the skin at too acute an angle, resulting in subcutaneous rather than intraperitoneal administration. For intraperitoneal injections in fish, the animals are restrained on their side on a flat surface, and the needle should enter along the midline, just anterior to the pelvic fins. Larger fish may require sedation or light anesthesia for appropriate restraint. 16

Materials injected intraperitoneally should be sterile, isotonic, and nonirritating. Irritating substances injected intraperitoneally may induce painful ileus and peritonitis in rodents, with subsequent adhesions. 43 This drawback is typified by the effects of undiluted chloral hydrate when administered intraperitoneally in rats. 36 Injections of identical doses of chloral hydrate in less concentrated solutions may avoid peritoneal irritation, 137 and this technique may be used for other potentially irritating substances. Although technically a simple procedure to perform, training and competency of personnel should be monitored to ensure that substances are delivered accurately and that inadvertent intracecal or intracystic injections are avoided.

Intranasal, intratracheal, and inhalational administration.

In research settings, animals generally are sedated or anesthetized 47 for the intranasal and intratracheal routes of delivery, to minimize struggling and sneezing. Volumes administered intranasally are small compared with those of other routes ( Table 1 ), to minimize the potential for suffocation and death. The technique may not be useful in animals with signs of rhinitis or conjunctivitis. Intranasal delivery is readily taught and simple to perform in an anesthetized animal. Substances administered by this route should be nonirritating to minimize sneezing, posttreatment rhinitis, and epistaxis.

Intranasal techniques may be used for either local (for example, vaccinations or decongestant sprays) or systemic delivery of substances. The nasal mucosa lines the nasal cavity and is richly supplied with blood vessels, potentially resulting in rapid substance absorption and subsequent systemic effects, avoiding the hepatic first-pass effect seen with oral delivery. Blood drug levels of substances administered intranasally may approach those seen after intravenous administration, and small, lipophilic molecules are absorbed more rapidly by this route than are large molecular weight or highly polar substances. 54

The lung has a large surface area, which is supplied by a dense capillary network, making absorption from this site rapid. Intrapulmonary delivery is the most common route by which substances are administered to fish. With this method, substances are dissolved in a static or flow-through aquatic system into which fish are placed. Material is absorbed rapidly across the gills, which are richly supplied with capillaries, resulting in systemic uptake. Because the entire fish is submerged in the tank, the dissolved substance should not be corrosive or irritating to minimize skin and ocular damage ( Figure 5 A and B ).

(A) Deep anesthesia of a fish with tricaine methane sulfonate (MS222), achieved by immersion in aqueous solution with the drug. Drug is taken up across the gills during respiration and, to a lesser extent, across the skin. Photo courtesy of Gerry Johnson. (B) Amphibians may be similarly dosed in aqueous chambers as in the Xenopus laevis depicted; however, substance uptake is solely through trancutaneous absortion.

Intrapulmonary delivery to other species is accomplished by either intratracheal instillation or inhalation. Intratracheal instillation is an easier delivery method requiring less specialized equipment and knowledge; however, this route typically is not as effective as are inhalational techniques in ensuring even pulmonary exposure to a substance. Intratracheal instillation involves injecting small volumes of solutions directly into the trachea of anesthetized animals and results in rapid but localized and uneven distribution of material over a relatively small volume of the lung. Volumes administered by the intratracheal route must be small to avoid suffocation. Those performing the intratracheal technique should be competent at intubating the species being treated, or a surgical cutdown can be used to expose the trachea for direct injection.

Inhalational delivery typically uses vapors (for example, volatile anesthetic gases) or aerosols of nebulized particles in solution. Animals are conscious with this delivery method and are restrained with or without a specialized nose mask to optimize delivery. Substances administered by aerosol are deposited by gravitational sedimentation, inertial impaction, or diffusion. As a rule of thumb, larger particles are deposited in the airways by gravitational sedimentation and inertial impaction, whereas smaller particles make their way into distal alveolar spaces by diffusion. Particles less than 3 µm in diameter penetrate the alveoli, and those that are 3 to 5 µm in diameter distribute uniformly throughout the lung. Materials deposited in the oropharynx, proximal trachea, or airways will be transported up the trachea by the mucociliary apparatus, into the mouth, and swallowed with subsequent first pass-effect after absorption. 95 In addition, solvent and propellant effects must be taken into account, because evaporation may cause particles to change in size.

Inhalational administration is a highly complex technique requiring specialized equipment and knowledge, and it is beyond the scope of this article to discuss this methodology in further detail (for more information, see references 99, 113, and 140). Substances administered by this route should be nonirritating to minimize pharyngeal edema, bronchial spasm, anaphylaxis, peracute death, and chronic pulmonary fibrosis. Animals should be conditioned to restraint devices and nose masks prior to experimental initiation.

Factors to Consider for Substance Administration

There are a number of factors to consider to optimize substance delivery to animals and to minimize complications associated with delivery. Complications may arise from the method of delivery as well as those associated with volume of substance administered, rate of administration, temperature of substance, fasting state, and subject age. Checklists may be developed for use in experimental planning to ensure that all factors have been considered adequately; these factors should also be considered during ethical review of study protocols. 82

Adverse effects associated with dosing route.

Any method of substance administration has inherent potential side effects. For enteral administration, complications depend on the delivery method: force feeding, pilling, delivery in food, or gavage. Oral gavage can result in passive reflux if the stomach is overfilled, aspiration pneumonia, pharyngeal, esophageal, and gastric irritation or injury with stricture formation, esophageal and gastric rupture ( Figure 6 ), and stress. 17 , 21 , 40 , 85 Even when small volumes are used, microaspiration has been suggested to occur in as many as one third of gavaged mice, resulting in detection of radiolabeled particles outside the gastrointestinal tract. 27 Highly viscous substances can affect both the risk of aspiration and the systemic stress response to the gavage procedure, and oily vehicles increase the likelihood of both. 21 Highly viscous substances are difficult to deliver through a small-diameter dosing needle or catheter and should be diluted, whenever possible, for ease of administration.

Inadvertent esophageal rupture (arrows) with food contamination and local cellulitis after oral gavage in a mouse. Photo courtesy of David Hobson.

Habituation to restraint and gavage may reduce struggling and the risk of associated injuries. Without habituation, rats and mice have increased blood pressure and heart rate for as long as 1 h after gavage, as well as higher serum corticosterone levels. 5 , 17 , 51 Repeated periods of brief restraint in the week before experimental gavage reduce physiologic responses to the gavage procedure in rats. 135 Generally, rodents adjust quickly to repeated gavage, and corticosterone levels return to baseline after the second day of gavage in mice. 51 Heart rate and blood pressure return to normal by the third day of oral gavage in rats. 92 In addition, elevations in corticosterone levels in mice can be mitigated by dipping the gavage needle in a sucrose solution prior to gavage. 51 Adverse effects may also be reduced by using soft gavage tubing. In rats, changes in heart rate and blood pressure were reduced if soft gavage tubes (Teflon) were used in place of stainless steel dosing needles. 92 , 141 A potential drawback of soft tubing for oral gavage is the possibility that an animal may bite through the tube. Sedation prior to gavage is not necessarily a refinement and may interfere with pharmacokinetic measurement. Prolonged gastric retention occurred in rats that were anesthetized briefly with halothane for oral gavage. 85 Although not clinically significant in the cited study, 27 incomplete gastric retention of substances can result in variable rates of absorption and immune stimulation, thereby affecting study outcome.

Other methods of enteral administration include sprinkling or mixing the substance with food, food treats, or water, and introducing substances directly into the mouth by using a syringe or pill. When substances are mixed with food or water, dehydration, weight loss, and inefficient drug administration can occur if palatability is poor or if taste aversion develops. 5 , 82 In addition, gingivitis, tooth decay, and tooth overgrowth can result from diets high in sugar or after the addition of diet softeners, such as polyethylene glycol. 19 , 62 , 86 , 105 , 122 , 131 Finally, marked species-, breed-, strain-, and stock-associated variations in food and water consumption exist, so caution must be applied when using standard estimates of consumption of test substance in food or water, to avoid over- or under-dosing animals. 6 , 35 , 68 , 69 , 70 , 94 Obtaining accurate body weights prior to dosing and throughout the study is critical.

Syringe feeding or feeding by dropper requires training and timing with relation to natural feeding. This technique can be time-consuming, particularly with studies of more than 20 animals. 5 Not all animals readily acclimate to this method of delivery, and it may not be possible to use this method in studies in which strict accuracy of animal dosing is required. Palatability and taste aversion both can affect this type of delivery, similar to mixing substances into food or water. Absorption directly across the oral mucosa can affect substance pharmacokinetics, an effect that should be considered when oral routes of delivery are employed. 5

With common parenteral routes of administration complications associated with substance administration include local irritation, pain, infection, and damage to the surrounding tissue depending on the species, method of restraint, route, volume, and substance administered. Generally, administering smaller volumes over multiple injection sites will minimize adverse reactions and can be used for subcutaneous, intramuscular, or intradermal delivery. 82 , 143 Some substances cause species-specific complications. For example, complete Freund adjuvant can result in pulmonary granulomata in rodents, irrespective of the site of administration. 97 The mechanism underlying this reaction is unknown.

Different routes of parenteral administration may be associated with specific inherent complications. Intramuscular injections can cause muscle necrosis or inflammation of the nerves, resulting in lameness and self-mutilation of the affected area. Pain, necrosis, and self-mutilation of the feet have been reported in response to intramuscular injection in rabbits, rodents, and other species. 14 , 39 , 63 , 118 , 123 , 136 With intranasal injections, aspiration pneumonia and suffocation can occur, depending on the volume and formulation of the compound administered. 48 Dosing can be inaccurate, because animals often sneeze in response to intranasal administration. Deep sedation or light anesthesia can be useful adjuncts to this procedure to ensure dosing accuracy.

Intraperitoneal delivery represents a theoretically easy method of introducing material into rodents, but the associated accuracy can be questionable. In one study in rats, 19.6% of intraperitoneal injections conducted by competent staff resulted in the material being injected in the gastrointestinal tract, subcutaneously, retroperitoneally, or into the urinary bladder. 67 In addition, the true prevalence of associated complications likely is underestimated, given that many animals are not necropsied after injection. Potential complications include infection, pain, local irritation and chemical peritonitis, formation of fibrous tissue and adhesions within the abdominal cavity, perforation of an abdominal organ, hemorrhage, and respiratory distress or discomfort from administration of too large a volume. Repeated administration can result in a cumulative irritant effect and needle-induced damage. 82

Complications associated with intravenous delivery methods are more readily apparent than after intraperiotenal delivery. Asepsis is critical, as intravenous administration of contaminated material can result in bacteremia and septicemia ( Figures 7 and ​ and8). 8 ). Extravascular delivery of compounds that are irritating may result in local soft tissue damage, infection, pain, and tissue sloughing. In all species, injection of compounds that contain particulate material or are of low pH that precipitate when mixed with blood can result in vascular occlusion, emboli, and thrombosis of local and distant capillary beds such as those found in the ears, tail, toes, or lungs. 8 , 50 , 61 , 81 , 98 , 126 Substances also may induce hemolysis, coagulation, or anaphylaxis when administered intravenously, and these complications may vary depending on the species and the nature of the material being administered. For example, the vehicle Tween 80 causes anaphylaxis when administered intravenously to dogs but not rodents. 44 , 130 For studies involving multiple venipunctures and injections, those evaluating histologic sections should remember that pulmonary microthrombi or foreign-body granulomas related to shedding of catheter materials or hair fragments are not uncommon histologic findings in chronic infusion studies ( Figure 9 A and B ). 24 , 34 , 81 , 98

Photomicrograph of atrial thrombosis with secondary bacterial infection and myocarditis in a rat with a chronic indwelling jugular vein catheter. A large septic thrombus (T; bacterial colonies indicated by arrows) is firmly adherent to the endocardium and there is significant infiltration of the myocardium (C) with neutrophils. The thrombus has not entirely occluded the atrium, as a small lumen (L) is present. Hematoxylin and eosin stain; magnification, ×40.

Photomicrograph demonstrating multifocal suppurative encephalitis with perivascular neutrophilic cuffing (arrows) after inadvertent contamination of an indwelling jugular vein catheter in a rat. Hematoxylin and eosin stain; magnification, ×40. Photo courtesy of Leah Schutt.

Photomicrographs demonstrating incidental findings. (A) Raft of epithelial cells (arrows) forming microthrombus within a pulmonary vessel of a chronically infused rat. Hematoxylin and eosin stain; magnification, ×200. Photo courtesy of Igor Mikaelian. (B) Hair shaft embedded centrally within pulmonary microthrombus of rat receiving a bolus IV injection. Hematoxylin and eosin stain; magnification, ×400. Photo courtesy of Heather Workman.

For continuous infusion studies, the nature of the catheter material may affect irritation at the site of catheterization, and this consideration is important when catheters will be in place long term (see Table 2 of reference 134). 134 In long-term continuous infusion studies, the local concentration of the substance in the cannulated vessel can be higher close to the catheter insertion site for a longer period of time when low flow rates are used. In combination with the mild local inflammation that is typically associated with the implanted catheter, this higher concentration may result in phlebitis and vascular thrombosis. 49 Even substances that do not induce phlebitis when given as a rapid intravenous bolus may cause irritation when given by continuous infusion, because of the background inflammation in catheterized vessels. 49

Considerations for administration volumes.

The volume of solution that can be given varies with species, strain, route, frequency of administration, speed of administration, and composition of the solution. For example, gavage administration of large volumes (20 mL/kg or more) of oil-based formulations is associated with greater toxicity than are aqueous-based formulations. 21 Large volumes (10 mL/kg or more) administered by oral gavage can result in absorption changes associated with rapid shunting of the compounds to the duodenum 88 , 133 , 144 or aspiration pneumonia associated with passive reflux of the material into the esophagus. 21 Large volumes given subcutaneously, intramuscularly, and intradermally can result in pain, necrosis, and changes in absorption as well as leakage from the site of injection. Volume of administration also influences the absorption of substances given intraperitoneally, 9 , 20 , 33 and larger volumes can result in pain and respiratory distress. 82

The volume of substances given intravenously should be calculated carefully, because large volumes can result in immediate distress, pulmonary and cardiac abnormalities, and death. The maximum volume of substances that can be administered depends on dosing rate, in which smaller total volumes should be given for bolus administration (over 1 min or less) than for slow infusion (5 to 10 min) or chronic (continuous) infusion. In rats, large volumes (40 mL/kg or greater) of fluid given as a slow infusion (1.0 mL/min) induce clinical signs of distress, including tachypnea and porphyrin pigment staining, as well histologic evidence of pulmonary changes. 81 Large volumes of substances given by bolus administration caused increased central venous pressure, hemodilution, acid–base disturbances, and diuresis. 30 , 6 , 82

Generally, best practices for intravenous substance delivery suggest that the blood volume should not acutely be increased more than 4%. 82 Special practices may require larger volumes, such as in hydrodynamic gene delivery, in which volumes ranging from 25% to more than 100% of the circulating blood volume are administered to deliver genes to the liver. 111 In rodents, volumes of 80 to 100 mL/kg body weight typically are injected into the tail vein over 5 s, resulting in expression levels of reporter genes in approximately 40% of the hepatocytes without the use of viral vectors or other carriers (for review, see reference 111). Similar methods attempted in other species have been less successful. 111 Hydrodynamic gene delivery results in swelling of the liver and outflow obstruction, which is believed to be critical to the gene delivery. Although rodents generally survive, this delivery method has considerable side effects. Blood pressure and heart rate drop dramatically (in mice, from 500 to 200 beats per minute), and cardiac electrical abnormalities are observed. 110 , 145 Other approaches have been used to minimize some of these generalized effects and include inferior vena cava delivery and regional methods, such as delivery directly to particular lobes of the liver or isolated muscle groups. 57 , 111 , 112

With slow or chronic infusion, the composition of the compound, the type of excipient 134 and the age, size, and sex of the recipient can induce potential complications. 134 For example, a chronic infusion rate of 2 to 3 mL/kg/h usually is well tolerated in rats; however, increased fetal toxicity has been reported in pregnant rats at infusion rates exceeding 1 mL/kg/h. 49 In general, chronic infusion results in decreased water consumption and weight loss. Higher rates of slow or chronic infusion (greater than 1 to 1.5 times the total circulating blood volume per 24 h) can result in hemodilution and diuresis. 49

Considerations for substance temperature during administration.

Substances given at or near body temperature will have fewer side effects in animals. The administration of large volumes of cold substances (below body temperature) intraperitoneally or intravenously can induce distress and hypothermia. 96 , 115 Local absorption rate can be influenced by the temperature of substances administered intraperitoneally. 13 , 55

The effect of feeding and fasting prior to substance delivery.

The timing of dosing related to the diurnal rhythm of various species may affect absorption and toxicity in animals and introduce unwanted variability, regardless of the route of administration. 12 , 66 For example, the activity of several hypnotic drugs including ketamine, pentobarbital, propofol, midazolam, and ethanol was tested at different times of the photoperiod, and longer periods of sleeping and anesthesia were observed when drugs were administered in the early active phase (early in the dark phase) as compared with during the early inactive period (early light phase). 109 Aminoglycosides have greater toxicity when administered during the resting period than during the active period. 10

In addition, fasting and water deprivation affect the absorption of many substances. 29 , 65 , 108 , 139 Duration of fasting will vary with the species involved, in that gastric emptying times vary considerably across species, with mice and rats having significantly shorter gastric emptying times than those of larger animals. 139

Considerations for subject age when administering substances.

Neonatal animals that receive experimental manipulations may undergo maternal rejection. Important techniques to minimize rejection and cannibalism include wearing gloves to mask hand odors, handling all young in a litter, and ensuring that pups are rewarmed before returning them to their dams. 71 Neonatal stress associated with maternal separation for experimental purposes can profoundly affect behavioral indices later in life. 72 However, when care is given to use volumes appropriate for the size, species, and route, neonatal animals can be dosed at early time points. Because they are undergoing rapid growth, establishing accurate body weights prior to administering substances is critical. In rodents, oral gavage can be administered as early as postnatal day 1, although waiting until postnatal day 4 is more common. 83 In neonates, esophageal tissues are very thin, and care must be taken to use appropriately sized equipment and correct technique. Typically for oral gavage of rodent pups, a 30-gauge needle attached to size 10 polyethylene tubing is used. The end is lubricated, and a small amount (up to 10%) of food coloring may be added to the material to be gavaged (typically 0.05 mL for mouse pups) to permit immediate visualization of the substance within the stomach (through the body wall) after administration. 101 Intravenous injections can be started at postnatal day 3 for rodents, and the external jugular and superficial temporal veins are readily accessible sites. 59 Intraperitoneal and subcutaneous injections can be given early, although careful attention to volume is required and intraperitoneal injections are more difficult due to limited space in the abdomen. Administration of irritating substances or large volumes that result in discomfort may influence the outcome of the study significantly, in that either of these properties could affect the nursing behavior of the pups, causing them to go off feed. 15 In many species, dams lick and consume the feces and urine of their litters, and consideration should be given to the effects on the dam of any test substance or its metabolites that are excreted by the pups.

The administration of substances to animals is a key component of many scientific projects. There are many factors that must be considered by the research team, veterinarian, institutional animal caregivers, and animal ethics committee members to ensure that studies involving experimental administration of substances to animals are planned and conducted appropriately. Careful attention to detail and consideration of the route of administration will contribute to experimental refinement and minimize adverse effects on animals.

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This page provides information, tools, and resources about the definition of a clinical trial. Correctly identifying whether a study is considered by NIH to be a clinical trial is crucial to how you will:

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In 2016, NIH launched a multi-faceted effort to enhance its stewardship over clinical trials. The goal of this effort is to encourage advances in the design, conduct, and oversight of clinical trials while elevating the entire biomedical research enterprise to a new level of transparency and accountability. The NIH definition of a clinical trial was revised in 2014 in anticipation of these stewardship reforms to ensure a clear and responsive definition of a clinical trial. Learn more about why NIH has made changes to improve Clinical Trial Stewardship .

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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 .

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Experimental methods of ethanol administration

Affiliation.

• 1 Section of Liver Disease and Nutrition, Bronx Veterans Administration Medical Center, New York 10468.
• PMID: 2673971
• DOI: 10.1002/hep.1840100417

Techniques are reviewed for the experimental feeding of alcohol, including a liquid diet procedure invented 25 years ago. This technique results in much higher ethanol intake than with other approaches. As a consequence, various complications observed in alcoholics can be reproduced in animal models. These include fatty liver, hyperlipemia, various metabolic and endocrine disorders, tolerance to ethanol and other drugs, physical dependence and withdrawal and, in the baboon, liver fibrosis and cirrhosis. Variations of the liquid diet formulation are compared, and adequacy of nutrition in terms of minerals, vitamins, lipotropes, carbohydrates and proteins is discussed. The importance of selecting proper controls is emphasized. The respective advantages of three standardized basic rat formulas are reviewed: (i) an all-purpose (35% fat) diet, comparable to the diet previously referred to as the "Lieber-DeCarli formula" and suitable for most experimental applications, particularly those intended to mimic the clinical situation in which the various effects of alcohol occur in the setting of hepatic changes characterized by a fatty liver; (ii) a low-fat diet comparable in all respects to the preceding diet but with a lower fat content, intended to minimize the hepatic changes, and (iii) a high-protein formula particularly useful in those circumstances in which an oversupply of dietary protein might be recommended (i.e. pregnancy). Variations of this technique, including continuous intragastric infusion, are also discussed. It is concluded that, for most experimental studies of chronic alcohol consumption, the liquid diet technique provides one of the most efficient tools to study the effects of ethanol under controlled nutritional conditions because it allows for alcohol consumption of clinical relevance and offers flexibility to adjust to special experimental or physiologic needs by allowing for various substitutions required for a particular experimental design, including changes in lipids, proteins or other dietary constituents. The technique also facilitates the comparison with controls by simplifying the pair feeding and is the best procedure available for the study of the toxic effects of alcohol and their interactions with deficiency or excess of various nutrients.

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• Clinical Trials: What Patients Need to Know

Basics About Clinical Trials

What are clinical trials.

Clinical trials are research studies in which people volunteer to help find answers to specific health questions. When carefully conducted, they are the safest and fastest way to find new treatments and ways to improve health.

Clinical trials are conducted according to a plan, called a protocol, which describes:

• the types of patients who may enter the study
• the schedules of tests and procedures
• the drugs involved
• the dosages, or amount of the drug
• the length of the study
• what the researchers hope to learn from the study.

Volunteers who participate in the study must agree to the rules and terms outlined in the protocol. Similarly, researchers, doctors, and other health professionals who manage the clinical trials must follow strict rules set by the FDA. These rules make sure that those who agree to participate are treated as safely as possible.

Learn more about the basics of clinical trial participation, read first hand experiences from actual clinical trial volunteers, and see explanations from researchers at the NIH Clinical Research Trials and You Web site.

Why are clinical trials done?

Clinical trials are conducted for many reasons:

• to determine whether a new drug or device is safe and effective for people to use.
• to study different ways to use standard treatments or current, approved treatments so that they will be more effective, easier to use, or decrease certain side effects.
• to learn how to safely use a treatment in a population for which the treatment was not previously tested, such as children.

Who should consider clinical trials and why?

Some people participate in clinical trials because none of the standard (approved) treatment options have worked, or they are unable to tolerate certain side effects. Clinical trials provide another option when standard therapy has failed. Others participate in trials because they want to contribute to the advancement of medical knowledge.

Ensuring people from diverse backgrounds join clinical trials is key to advancing health equity. Participants in clinical trials should represent the patients that will use the medical products. This is often not the case—people from racial and ethnic minority and other diverse groups are underrepresented in clinical research. This is a concern because people of different ages, races, and ethnicities may react differently to certain medical products. Learn more about the clinical trial diversity initiative from the Office of Minority Health and Health Equity.

All clinical trials have guidelines, called eligibility criteria, about who can participate. The criteria are based on such factors as age, sex, type and stage of disease, previous treatment history, and other medical conditions. This helps to reduce the variation within the study and to ensure that the researchers will be able to answer the questions they plan to study. Therefore, not everyone who applies for a clinical trial will be accepted.

It is important to test drugs and medical products in the people they are meant to help. It is also important to conduct research in a variety of people, because different people may respond differently to treatments.  FDA seeks to ensure that people of different ages, races, ethnic groups, and genders are included in clinical trials. Learn more about FDA’s efforts to increase diversity in clinical trials .

Where are clinical trials conducted?

Clinical trials can be sponsored by organizations (such as a pharmaceutical company), Federal offices and agencies (such as the National Institutes of Health or the U.S. Department of Veterans Affairs), or individuals (such as doctors or health care providers). The sponsor determines the location(s) of the trials, which are usually conducted at universities, medical centers, clinics, hospitals, and other Federally or industry-funded research sites.

Are clinical trials safe?

FDA works to protect participants in clinical trials and to ensure that people have reliable information before deciding whether to join a clinical trial. The Federal government has regulations and guidelines for clinical research to protect participants from unreasonable risks. Although efforts are made to control the risks to participants, some may be unavoidable because we are still learning more about the medical treatments in the study.

The government requires researchers to give prospective participants complete and accurate information about what will happen during the trial. Before joining a particular study, you will be given an informed consent document that describes your rights as a participant, as well as details about the study, including potential risks. Signing it indicates that you understand that the trial is research and that you may leave at any time. The informed consent is part of the process that makes sure you understand the known risks associated with the study.

What should I think about before joining a clinical trial?

Before joining a clinical trial, it is important to learn as much as possible. Discuss your questions and concerns with members of the health care team conducting the trial. Also, discuss the trial with your health care provider to determine whether or not the trial is a good option based on your current treatment. Be sure you understand:

• what happens during the trial
• the type of health care you will receive
• any related costs once you are enrolled in the trial
• the benefits and risks associated with participating. 

What is FDA’s role in approving new drugs and medical treatments?

FDA makes sure medical treatments are safe and effective for people to use. We do not develop new therapies or conduct clinical trials. Rather, we oversee the people who do. FDA staff meet with researchers and perform inspections of clinical trial study sites to protect the rights of patients and to verify the quality and integrity of the data.

Learn more about the Drug Development Process .

Where can I find clinical trials?

One good way to find out if there are any clinical trials that might help you is to ask your doctor. Other sources of information include:

• FDA Clinical Trials Search. Search a database of Federally and privately supported studies available through clinicaltrials.gov. Learn about each trial’s purpose, who can participate, locations, and who to contact for more information.
• Clinicaltrials.gov. Conduct more advanced searches
• National Cancer Institute or call 1–800–4–CANCER (1–800–422–6237). Learn about clinical trials for people with cancer.
• AIDS Clinical Trials and Information Services (ACTIS) or call 1–800–TRIALS–A (1–800–874–2572). Locate clinical trials for people with HIV.
• AIDSinfo. Search a database of HIV/AIDS trials, sponsored by the National Institutes of Health’s National Library of Medicine.

What is a placebo and how is it related to clinical trials?

A placebo is a pill, liquid, or powder that has no treatment value. It is often called a sugar pill. In clinical trials, experimental drugs are often compared with placebos to evaluate the treatment’s effectiveness.

Is there a chance I might get a placebo?

In clinical trials that include placebos, quite often neither patients nor their doctors know who is receiving the placebo and how is being treated with the experimental drug. Many cancer clinical trials, as well as trials for other serious and life-threatening conditions, do not include placebo control groups. In these cases, all participants receive the experimental drug. Ask the trial coordinator whether there is a chance you may get a placebo rather than the experimental drug. Then, talk with your doctor about what is best for you.

How do I find out what Phase a drug is in as part of the clinical trial?

Talk to the clinical trial coordinator to find out which phase the clinical trial is in. Learn more about the different clinical trial phases and whether they are right for you.

What happens to drugs that don't make it out of clinical trials?

Most drugs that undergo preclinical (animal) research never even make it to human testing and review by the FDA. The drug developers go back to begin the development process using what they learned during with their preclinical research. Learn more about drug development .

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Plans + pricing, take a guided tour, watch a demo, solution finder, call us today:, floating holidays: definition, overview and benefits.

Last Updated: September 24, 2024 | Read Time: 9 min

One-Minute Takeaway

• A floating holiday is a paid day off that employees can use at their discretion. It is separate from paid holidays or paid time off.
• Giving employees a floating holiday yields several benefits, including enhancing employee satisfaction, increasing productivity and promoting an inclusive workplace.
• Before implementing a floating holiday, employers need to draft a floating holiday policy that outlines the process and rules for using floating holidays.

Most employers build their holiday schedule in accordance with designated federal holidays , such as New Year’s Day, Veterans Day and Thanksgiving. But as the workforce diversifies and HR departments launch diversity, equity and inclusion (DEI) initiatives, floating holidays provide a good way for benefits leaders to give employees a day off to spend how they would like, whether for religious/cultural observances or a mental health day at home.

While offering a floating holiday is a welcome addition to your employee benefits package, you should understand the concept fully, including its benefits and common rules or restrictions.

What is a Floating Holiday?

A floating holiday is a paid day off that workplaces give their employees in addition to paid public holidays and their PTO accrual. As the name suggests, employees may use this day at their discretion, meaning it can float to any day.

How Does a Floating Holiday Work?

Companies that choose to offer a floating holiday need to clearly define their floating holiday policy, which may differ from employer to employer. Factors to consider include:

• How many floating days to offer
• Eligibility requirements
• Restrictions on usage

Floating holidays are often granted at the beginning of the year or after a certain period of employment. Employees can use their floating holidays at their discretion, provided they follow the company’s request procedures.

What are the Benefits of Offering Floating Holidays?

Implementing a floating holiday offers the following advantages:

• Enhances employee satisfaction : Providing floating holidays allows employees to take time off when they need it most, whether for personal reasons, cultural observances or mental health days. This flexibility leads to higher job satisfaction.
• Promotes inclusion: Floating holidays enable employees to observe their own cultural or religious traditions, aligning with DEI initiatives and supporting a diverse workforce .
• Gives a competitive edge for recruitment: The floating holiday is an underutilized benefit, with more than half of respondents to American Society of Employers’ annual Holiday Schedule & Practices Survey saying they don’t offer it. Providing this benefit could differentiate your company from its competitors.
• Increases productivity : Empowering employees to take time off when they need it helps them return to work refreshed and motivated, which increases productivity and reduces burnout.

And for employees, a floating holiday offers flexibility and autonomy to manage their personal and cultural needs more effectively.

Building a Company Policy + Implementing Floating Holidays

Follow these steps to build a company floating holiday policy.

1. Policy Drafting

First, begin by drafting a policy for how your company plans to handle floating holidays. Consider all the questions employees might have about floating holidays, including:

• How do floating holidays differ from vacation days or paid holidays?
• Can unused floating holidays be rolled into the next year?
• Who is eligible for a floating holiday?
• Are there any restrictions or blackout dates?
• How does an employee request off their chosen floating holiday?

Include the answers to those common questions as well as any rules you want to impose on your floating holiday allowance. Some common rules and restrictions associated with floating holidays include:

• Use it or lose it : Most companies require employees to use floating holidays within the calendar year or forfeit them.
• Advance notice : Employers typically ask for advance notice of an employee’s floating holiday. Two weeks is common.
• Manager approval : While the floating holiday can be taken at the employee’s discretion, it’s still a best practice to require employees to request their floating holiday as they would PTO. This includes submitting the days for manager approval.

2. Legal Review

Once the policy is drafted, run it by legal counsel to ensure it complies with local, state and federal labor laws. Better yet, use a benefits management platform that stays up to date on labor and payroll regulations to ensure compliance. This mitigates potential legal issues and ensures the policy is fair and equitable for all employees.

3. Training

Train HR staff and managers on the new floating holiday policy. Ensure they understand the policy details, including the procedures for approving floating holiday requests and how to communicate the policy to employees.

4. Communication

Next, communicate the policy companywide. Use multiple channels such as email, the company intranet and team meetings to reach employees where they are and inform them of the new benefit. Provide clear instructions on how to request a floating holiday and tell employees where to go if they have any questions.

5. Implementation

Finally, roll out your new benefit at a time that makes sense for your company, whether the start of a calendar year or fiscal year. Update the employee handbook, onboarding paperwork and recruitment materials to include mention of the floating holiday benefit. Also, ensure the infrastructure is in place for employees to request their floating holiday off.

6. Evaluation

As with all benefits, evaluate its effectiveness during your annual benefits review. Keep track of how many employees utilize their floating holiday and solicit feedback from employees, whether they take advantage of the benefit or not.  

Review productivity and employee satisfaction metrics to find any changes or patterns correlating with the use of floating holidays. Use the insights gained from this review to make any necessary adjustments to the policy to ensure it continues to meet the needs of the organization and its employees.

How Paycor Helps

From floating holidays to FSAs, a strong benefits package helps employees feel valued. And happy employees are productive employees. Paycor streamlines benefits administration, allowing HR leaders to focus efforts on recruiting and retaining the best talent.

Take a guided tour of Benefits Advisor to learn how Paycor reduces tedious administrative work and maximizes the power of a benefits program.

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