Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

symptom Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showi ...

sign A sign is an Physical object, object, quality (philosophy), quality, event, or Non-physical entity, entity whose presence or occurrence indicates the probable presence or occurrence of something else. A natural sign bears a causal relation to ...

or laboratory abnormality constituting a target outcome in clinical research trials. The term may also refer to any disease or sign that strongly motivates withdrawal of an individual or entity from the trial, then often termed a ''humane (clinical) endpoint''. The primary endpoint of a clinical trial is the endpoint for which the trial is powered. Secondary endpoints are additional endpoints, preferably also pre-specified, for which the trial may not be powered.

Surrogate endpoints In clinical trials, a surrogate endpoint (or surrogate marker) is a measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of H ...

are trial endpoints that have outcomes that substitute for a clinical endpoint, often because studying the clinical endpoint is difficult, for example using an increase in blood pressure as a surrogate for death by cardiovascular disease, where strong evidence of a causal link exists.

Scope

In a general sense, a clinical endpoint is included in the entities of interest in a trial. The results of a clinical trial generally indicate the number of people enrolled who reached the pre-determined clinical endpoint during the study interval compared with the overall number of people who were enrolled. Once a patient reaches the endpoint, he or she is generally excluded from further experimental intervention (the origin of the term ''endpoint''). For example, a clinical trial investigating the ability of a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy ( pharmacotherapy) is an important part of the medical field an ...

to prevent

heart attack A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which m ...

might use ''chest pain'' as a clinical endpoint. Any patient enrolled in the trial who develops chest pain over the course of the trial, then, would be counted as having reached that clinical endpoint. The results would ultimately reflect the fraction of patients who reached the endpoint of having developed chest pain, compared with the overall number of people enrolled. When an experiment involves a

control group In the design of experiments, hypotheses are applied to experimental units in a treatment group. In comparative experiments, members of a control group receive a standard treatment, a placebo, or no treatment at all. There may be more than one t ...

, the proportion of individuals who reach the clinical endpoint after an intervention is compared with the proportion of individuals in the control group who reached the same clinical endpoint, reflecting the ability of the intervention to prevent the endpoint in question. A

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

will usually define or specify a ''primary endpoint'' as a measure that will be considered success of the therapy being trialled (e.g. in justifying a marketing approval). The primary endpoint might be a

statistically significant In statistical hypothesis testing, a result has statistical significance when it is very unlikely to have occurred given the null hypothesis (simply by chance alone). More precisely, a study's defined significance level, denoted by \alpha, is the p ...

improvement in ''overall survival'' (OS). A trial might also define one or more ''secondary endpoints'' such as '' progression-free-survival'' (PFS) that will be measured and are expected to be met. A trial might also define ''exploratory endpoints'' that are less likely to be met.

Examples

Clinical endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or

biomarker In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...

s from

Electroencephalography Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocor ...

( qEEG), MRI,

PET A pet, or companion animal, is an animal kept primarily for a person's company or entertainment rather than as a working animal, livestock, or a laboratory animal. Popular pets are often considered to have attractive appearances, intelligence ...

, or biochemical biomarkers. In clinical

cancer research Cancer research is research into cancer to identify causes and develop strategies for prevention, diagnosis, treatment, and cure. Cancer research ranges from epidemiology, molecular bioscience to the performance of clinical trials to evaluate a ...

, common endpoints include discovery of local recurrence, discovery of regional metastasis, discovery of distant metastasis, onset of symptoms, hospitalization, increase or decrease in pain medication requirement, onset of toxicity, requirement of salvage chemotherapy, requirement of salvage surgery, requirement of salvage radiotherapy, death from any cause or death from disease. A cancer study may be powered for overall survival, usually indicating time until death from any cause, or disease specific survival, where the endpoint is death from disease or death from toxicity. These are expressed as a period of time (survival duration) e.g., in months. Frequently the median is used so that the trial endpoint can be calculated once 50% of subjects have reached the endpoint, whereas calculation of an

arithmetical mean In mathematics and statistics, the arithmetic mean ( ) or arithmetic average, or just the ''mean'' or the ''average'' (when the context is clear), is the sum of a collection of numbers divided by the count of numbers in the collection. The colle ...

can only be done after all subjects have reached the endpoint.

Disease free survival

The disease free survival is usually used to analyze the results of the treatment for the localized disease which renders the patient apparently disease free, such as surgery or surgery plus adjuvant therapy. In the disease-free survival, the event is relapse rather than death. The people who relapse are still surviving but they are no longer disease-free. Just as in the survival curves not all patients die, in "disease-free survival curves" not all patients relapse and the curve may have a final plateau representing the patients who didn't relapse after the study's maximum follow-up. Because the patients survive for at least some time after the relapse, the curve for the actual survival would look better than disease free survival curve.

Progression free survival

The

Progression Free Survival Progression-free survival (PFS) is "the length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse". In oncology, PFS usually refers to situations in which a tumor is p ...

is usually used in analysing the results of the treatment for the advanced disease. The event for the progression free survival is that the disease gets worse or progresses, or the patient dies from any cause. ''Time to Progression'' is a similar endpoint that ignores patients who die before the disease progresses.

Response duration

The response duration is occasionally used to analyze the results of the treatment for the advanced disease. The event is progression of the disease (relapse). This endpoint involves selecting a subgroup of the patients. It measures the length of the response in those patients who responded. The patients who don't respond aren't included.

Overall survival

Overall survival is based on death from any cause, not just the condition being treated, thus it picks up death from side effects of the treatment, and effects on survival after relapse.

Toxic Death Rate

Unlike overall survival, which is based on death from any cause or the condition being treated, the toxic death rate picks up just the deaths that are directly attributable to the treatment itself. These rates are generally low to zero as clinical trials are typically halted when toxic deaths occur. Even with chemotherapy the overall rate is typically under a percent. However the lack of systematic autopsies limits our understanding of deaths due to treatments.

Percent serious adverse events

The percentage of treated patients experiencing one or more serious adverse events. Serious adverse events are defined by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

as "Any AE occurring at any dose that results in any of the following outcomes: * Death * Life-threatening adverse drug experience * Inpatient hospitalization or prolongation of existing hospitalization * Persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions * Congenital anomaly/birth defect * Important medical events (IME) that may not result in death, be life-threatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition."

Humane endpoint

A humane endpoint can be defined as the point at which pain and/or distress is terminated, minimized or reduced for an entity in a trial (such as an

experimental animal Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...

), by taking action such as killing the animal humanely, terminating a painful procedure, or giving treatment to relieve pain and/or distress. The occurrence of an individual in a trial having reached may necessitate withdrawal from the trial before the target outcome of interest has been fully reached.

Surrogate endpoint

surrogate endpoint In clinical trials, a surrogate endpoint (or surrogate marker) is a measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but does not necessarily have a guaranteed relationship. The National Institutes of ...

(or ''marker'') is a measure of effect of a specific treatment that may correlate with a ''real'' clinical endpoint but doesn't necessarily have a guaranteed relationship. The

National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government The federal government of the United States (U.S. federal government or U ...

(USA) define surrogate endpoint as "a biomarker intended to substitute for a clinical endpoint".

Combined endpoint

Some studies will examine the incidence of a ''combined endpoint'', which can merge a variety of outcomes into one group. For example, the heart attack study above may report the incidence of the ''combined endpoint'' of chest pain,

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ...

, or death. An example of a cancer study powered for a combined endpoint is disease-free survival (DFS); trial participants experiencing either death or discovery of any recurrence would constitute the endpoint. Overall Treatment Utility is an example of a multidimensional composite endpoint in cancer clinical trials. Regarding humane endpoints, a combined endpoint may constitute a threshold where there is enough cumulative degree of disease, symptoms, signs or laboratory abnormalities to motivate an intervention.

Response rates

The response rate is the percentage of patients on whom a therapy has some defined effect; for example, the cancer shrinks or disappears after treatment. When used as a clinical endpoint for trials of cancer treatments, this is often called the ''objective response rate'' (ORR).Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics
FDA The

FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...

definition of ORR in this context is "the proportion of patients with tumor size reduction of a predefined amount and for a minimum time period." Each trial, for whatever illness or condition, may define what is considered a ''complete response'' (CR) or ''partial response'' (PR) to the therapy or intervention. Hence the trials report the complete response rate and the ''overall response rate'' which includes CR and PR. (See e.g. Response evaluation criteria in solid tumors, and Small-cell carcinoma treatment, and for immunotherapies,

Immune-related response criteria The immune-related response criteria (irRC) is a set of published rules that define when tumors in cancer patients improve ("respond"), stay the same ("stabilize"), or worsen ("progress") during treatment, where the compound being evaluated is an i ...

Consistency

Various studies on a particular topic often do not address the same outcomes, making it difficult to draw clinically useful conclusions when a group of studies is looked at as a whole. The Core Outcomes in Women's Health (CROWN) Initiative is one effort to standardize outcomes.

References

External links

Endpoints: How the Results of Clinical Trials are Measured
{{Medical research studies Clinical research Clinical trials Medical statistics