We use the clinical outcome term on a daily basis in our work in clinical research but how precise are we with the definitions and the specific requirements of each of those? Before we enter the complex world of clinical endpoint adjudication let’s take one more look at these basic notions that drive clinical trials and ultimately define the marketing authorization of our drugs.
Clinical Outcomes
Clinical outcomes are measurable changes in health, function or quality of life that result from giving care to patients. Clinical outcomes can be measured by activity data such as hospital re-admission rates, or by agreed scales and other forms of measurement (1).
The term “outcome” in clinical trials refers to a measured variable (e.g., peak volume of oxygen or PROMIS Fatigue score). The term is well described in the following quotes:
“Improvement in clinical outcome was seen only in patients with major depressive disorder who were receiving doses of antidepressant [...]”
“...delay between presentation and therapy increases the risk of a poor outcome...”
Endpoints
An endpoint refers to the analyzed parameter (e.g., change-from-baseline at 6 weeks in mean PROMIS Fatigue score). A clinical endpoint generally refers to one of the target outcomes of the trial, but may also refer to any disease or sign that strongly motivates the withdrawal of the patient from the trial, then often termed humane (clinical) endpoint.
Target outcomes and primary endpoint
Like all scientific investigations, clinical trials seek to confirm or reject a hypothesis (generally the hypothesis that a new drug is efficient and safe at the selected doses in fighting a given disease). In order to conduct such investigation, we must select the most representative outcome, agree on the target value (endpoint) and calculate the size of the sample allowing a reasonable estimation of the true effect (power of the trial). It is good scientific practice to only ask one question at a time, therefore a single primary endpoint should be selected whenever possible.
Primary and secondary endpoints
All drugs have safety risks. Therefore, the only reason that a patient would want to take a drug would be if the drug i) improved survival, ii) resulted in a benefit that was detectable by the patient (improvement in symptoms, improvement in functional capacity), or iii) decreased the chances of developing a condition or disease complication that is itself apparent to the patient and is undesirable (e.g. stroke).
Therefore, a primary endpoint should be a direct measure of one of these. A primary endpoint should generally not be a measure of something that is not important to the patient.
Secondary endpoints are endpoints for which the trial may not be powered nor randomized.
Secondary endpoints align with secondary questions and need to be clearly defined up front, but allow to dig more deeply into the more subtle information provided by the trial that may or may not provide definitive conclusions, but might dictate the direction of future studies (2).
Direct and surrogate endpoints
A direct endpoint is a clinically meaningful outcome (endpoint) that directly measures how a patient feels, functions, or survives. Direct endpoints in themselves represent or characterize the clinical outcome of interest
– Objective: survival, disease exacerbation, clinical event (e.g. MI, stroke), etc.
– Subjective: symptom score, “health related quality of life” (validated instrument), etc.
A surrogate endpoint is an indicator or sign used in place of another to tell if a treatment works. Surrogate endpoints include a shrinking tumor or lower biomarker levels. They may be used instead of stronger indicators, such as longer survival or improved quality of life, because the results of the trial can be measured sooner. The use of surrogate endpoints in clinical trials may allow earlier approval of new drugs to treat serious or life-threatening diseases, such as cancer. Surrogate endpoints are not always true indicators or signs of how well a treatment works .
Endpoints that need independent adjudication
Certain Clinical Outcomes (endpoints) such as the diagnosis of refractory angina pectoris or myocardial infarction are subject to considerable inter-individual variability of the treating physicians/investigators. In order to get unbiased event documentation, it is strongly recommended to establish blinded event adjudication committees for the additional verification of such events.
(1) Peter R. Nelson. Clinical Trials Design in Operative and Non-Operative Invasive Procedures.
(2) NIH, NCI Dictionary of Cancer Terms
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