The most important requirement for a clinical trial endpoint is clinical relevance, or what the effect means to the patient. Appropriate measurement or detection of a clinical endpoint is secondary to the appropriate selection of a clinically relevant endpoint; measuring an endpoint well means nothing to the patient if the endpoint has poor clinical relevance. In addition to clinical relevance, trial endpoints should reflect the research question, the drug’s mechanism (or mechanisms) of action and patient well-being. In phase I clinical studies, safety is the primary endpoint; in phase II clinical studies, a measure of efficacy is the primary endpoint. Quality of life (QOL) is becoming an increasingly important endpoint in chronic or terminal conditions, including cancer.
Clinical trials should have only one primary endpoint — hence the “primary” designation. The primary endpoint should be the most meaningful result in a clinical trial. An example of a primary endpoint in cancer clinical trials is survival. Survival has long been considered the “gold standard” endpoint for cancer therapies, based on the importance of survival to cancer patients. Other results that contribute to the interpretation of the clinical trial are then considered “secondary endpoints.” A clinical trial can have, and often does have, many secondary endpoints. Still, when a clinical trial attempts to capture too many endpoints, complications can arise that impede the critical goal of answering a primary question. If multiple endpoints yield conflicting results, the study cannot be interpreted meaningfully. Multiple endpoints also increase the chance of a Type 1 error (when a difference is shown when there is no actual difference).
Composite endpoints
Composite endpoints are used in studies of diseases that occur rarely or in studies that may require a sample size so large that the studies cannot be completed in a reasonable amount of time. A combination of measurements can be examined and assigned as “an” endpoint. Components of the composite endpoint must be related to a common pathophysiology and be closely related in the degree of severity. For example, a composite endpoint in cardiovascular disease can include all-cause mortality, fatal coronary heart disease and non-fatal myocardial infarction; all of these components are considered closely related in the degree of severity, such that an occurrence of one or more of these component endpoints is as serious as death (mortality). Composite endpoints can sometimes yield conflicting results that complicate interpretation of the study. For example, if one treatment group has a higher event rate in one component but another treatment group shows a higher event rate in another component, the interpretation of the study becomes less clear-cut than comparing singular endpoints between treatment groups.
Quality of life endpoints may be considered “missed opportunities” in clinical trials, but QOL endpoints are not often used because defining QOL parameters can be a challenge. In addition, assessment by patients is subjective (one can debate that the patients’ opinions are ultimately what matter). Quality of life may capture perceptions that are not always study-related, and can affect the results of a study (for example, a life-changing event can affect a patient on many physiological and psychological levels). Still, QOL is especially relevant in therapies that can be toxic, such as cancer therapies. I remember reading a story from the husband of a cancer patient: His wife fell into a coma as a result of the toxicities of a treatment, but did not die until many months later. This patient was considered a statistical “success story” based on survival, yet this example begs the question of whether survival with poor QOL is better than death without suffering.
Surrogate endpoints are increasingly used in lieu of the “true” endpoints of disease eradication or survival, and the role of surrogate endpoints in clinical trials is a controversial subject. Disease eradication and survival can take years to prove. Surrogate endpoints in clinical trials lead not only to shorter clinical trial timelines, but also to less cost. Surrogate endpoints also reduce follow-up lapses that can be common in long-term studies: Patients may miss visits and not follow up, which leads to missing data and suboptimal study analysis. Examples of surrogate endpoints are blood pressure effects or prostate-specific antigen levels. The use of surrogate endpoints in clinical trials requires researchers to identify the appropriate surrogate markers, which is not an easy task. Surrogate endpoints are useful if they can be easily measured and are highly correlative with direct endpoints of clinical relevance. Surrogate endpoints are usually closer to the biology of the disease and may not always correlate with clinical outcomes.