In a clinical research trial, a clinical endpoint generally refers to occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial, but may also refer to any such disease or sign that strongly motivates the withdrawal of that individual or entity from the trial, then often termed humane (clinical) endpoint.[clarification needed]
The primary endpoint of a clinical trial is the endpoint for which subjects are randomized and for which the trial is powered. Secondary endpoints are endpoints that are analyzed post hoc, for which the trial may not be powered nor randomized.
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 to prevent heart attack 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, 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 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 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.
In clinical cancer research, 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 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 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.
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 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.
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), 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.
A surrogate endpoint (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 (USA) define surrogate endpoint as "a biomarker intended to substitute for a clinical 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, 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.
Each trial 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. (e.g. see Response Evaluation Criteria in Solid Tumors, and Small-cell carcinoma treatment, and for immunotherapies, Immune-Related Response Criteria).
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.
- "median overall survival". NCI Dictionary of Cancer Terms. National Cancere Institute. Retrieved 4 December 2014.
- Humane Endpoints Archived 2010-08-27 at the Wayback Machine From Netherlands Association for Laboratory Animal Science (NVP). Retrieved April 2011.
- Controlled Clinical Trials 22:485–502 (2001))
- Cohn JN (2004). "Introduction to Surrogate Markers". Circulation. American Heart Association. 109 (25 Suppl 1): IV20–1. doi:10.1161/01.CIR.0000133441.05780.1d. PMID 15226247.
- Handforth C, Hall P, Marshall H, Seymour M. "Overall treatment utility: A novel outcome measure to convey the balance of benefits and harms from cancer treatment". journal of geriatric oncology.
- "The CROWN Initiative: journal editors invite researchers to develop core outcomes in women's health". Human Reproduction Update. 20 (4): 465–466. 2014. doi:10.1093/humupd/dmu029. ISSN 1355-4786. PMC 4102731.
- AR Waladkhani. (2008). Conducting clinical trials. A theoretical and practical guide. ISBN 978-3-940934-00-0
- Progression-free survival (PFS) and time to progression (TTP) as surrogate endpoints for median overall survival (mOS) in metastatic colorectal cancer (MCRC): Analysis from 34 randomized controlled trials (RCTs) of first-line chemotherapy
- Clinical trial endpoints at the Wayback Machine (archived October 5, 2011)
- Endpoints: How the Results of Clinical Trials are Measured