Clinical endpoint
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Clinical endpoints or clinical outcomes are
The primary endpoint of a clinical trial is the endpoint for which the trial is
Surrogate endpoints 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 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
A
Examples
Clinical endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or
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
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.
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.[2]
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 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."[3]
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
Surrogate endpoint
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".[5][6][7]
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, 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.[8]
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.[citation needed]
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.[9]
When used as a clinical endpoint for trials of cancer treatments, this is often called the objective response rate (ORR).
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.)
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.[13]
See also
References
- ^ "median overall survival". NCI Dictionary of Cancer Terms. National Cancere Institute. Retrieved 4 December 2014.
- PMID 22677904.
- ^ "CFR - Code of Federal Regulations Title 21". www.accessdata.fda.gov. April 1, 2020. Retrieved 9 January 2021. This article incorporates text from this source, which is in the public domain.
- ^ Humane Endpoints Archived 2010-08-27 at the Wayback Machine From Netherlands Association for Laboratory Animal Science (NVP). Retrieved April 2011.
- S2CID 288484.
- PMID 11578783.
- PMID 15226247.
- .
- ^ "NCI Dictionary of Cancer Terms". National Cancer Institute. Retrieved 5 June 2016.
- ^ a b Guidance for Industry Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics FDA
- ^ Objective tumor response and RECIST criteria in cancer clinical trials
- ^ "Understanding a Cancer Research Study | OncoLink". www.oncolink.org. Retrieved 10 September 2023.
- PMID 25045427.
Further reading
- Spiegelhalter, David J.; Abrams, Keith R.; Myles, Jonathan P. (2004). "Randomised Controlled Trials". Bayesian Approaches to Clinical Trials and Health-Care Evaluation. Chichester: John Wiley & Sons. pp. 181–249. ISBN 0-471-49975-7.
- Chin, Jane Y. (1 August 2004). "The Clinical Side: Clinical trial endpoints". Pharmaceutical Representative. Archived from the original on 5 October 2011.