Clinical endpoints or clinical outcomes are outcome measures referring to occurrence of disease, symptom, sign or laboratory abnormality constituting a target outcome in clinical research trials. This duration results in enormous cost and a delay in developing newer therapies. The identification of surrogate endpoints that can replace true endpoints in clinical trials could provide an important advance for the evaluation of therapeu we use cookies to enhance your experience on our website. An fda perspective on clinical trial endpoint measurements. A regulatory authoritys opinion about surrogate endpoints. An endpoint is the primary outcome that is being measured by a clinical trial. The strength of association between surrogate end points. However, without proper validation, the use of surrogates may lead to incorrect conclusions about the efficacy and safety of treatments. American journal of respiratory and critical care medicine. However, os assessments require longterm followup and a large number of participants in clinical trials. The validation of surrogate endpoints has been studied by prentice, who presented a definition as well as a set of criteria that are equivalent if the surrogate and true endpoints are binary. Prentice fred hutchinson cancer research center, 1124 columbia street, seattle, wa 98104, u. Prentice derived operational criteria that are equivalent to.
Surrogate endpoints and fdas accelerated approval process. The surrogate is intended to predict clinical benefit from a therapeutic intervention 12. Statistical methods in surrogate marker research for clinical trials. The prentice criteria are succinctly summarized in two parts. The use of surrogate end points in oncology, particularly pfs, has grown in recent years and it is frequently the primary end point of cancer clinical trials and the basis for regulatory approval of novel agents. The quality of a surrogate endpoint is therefore determined by the extent to which a treatment effect on that surrogate corresponds. Criteria for the validation of surrogate endpoints in randomized experiments biometrics 54. Initial studies typically target surrogate endpoints, and these studies help to inform subsequent larger trials that are powered to measure more patientorientated clinical outcomes such as survival. Surrogate endpoints include a shrinking tumor or lower biomarker levels. Surrogates are those endpoints that do not directly measure how a person feels, functions or survives, but which are so closely associated with a clinically meaningful endpoint that they are taken to be a reliable substitute for them.
Randomized clinical trials that are powered based on clinical endpoints, such as. Challenges and methodologies in using progression free survival as a surrogate for overall survival in oncology volume 34 issue 3 karla hernandezvillafuerte, alastair fischer, nicholas latimer. The competing risk of death and premature assessment of neurological prognosis pose significant challenges to measuring. A causal framework for surrogate endpoints with semi. Trial endpoints should show clinically meaningful improvements in patient survival or quality of life. Pfs is one of the most commonly used surrogate endpoints in.
The first criterion is typically readily verified empirically, whereas the second, which requires the surrogate to fully mediate. At present, no theoretical basis or practical guidelines exist to help in the choice of surrogate endpoints. Pdf statistical evaluation of surrogate endpoints in clinical studies. Although in its simplest form, pfs is the time from randomization to a predefined endpoint, there are many factors that can influence the exact moment of when disease. This was followed in the 1990s by the introduction of a graded criterion for validation of surrogate endpoints using single trials, termed the. Surrogate endpoints are often used as replacements for true clinically relevant endpoints in several areas of medicine, as they enable faster and less expensive clinical trials.
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 metaanalytic framework for the evaluation of surrogate endpoints in clinical trials. Using biomarkers as surrogate endpoints often is motivated by interests to reduce the size and duration of definitive clinical trials, with the hope that this will allow more timely evaluation of the benefittorisk profile of experimental interventions, and an improved ability to offer patients another choice in their clinical care. I discuss the idea of using surrogate endpoints in the context of clinical trials to compare two or more treatments or interventions in respect to some true endpoint, typically a. Surrogate endpoints in pediatric clinical trials core. An approach is proposed here, based on three provisos which can be. Definition and operational criteria prentice, ross l. The strict, statistical definition of a surrogate requires that the effect of an intervention on the desired outcome be fully explained through the surrogate. Clinical endpoints will be distinguished from 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. Choosing primary endpoints for clinical trials of health.
Thus, clinical trials require approximately 5 to 8 years from activation to completion and analysis of outcomes. The centers for disease control and prevention and national institutes of health convened a multidisciplinary meeting to discuss surrogate markers of treatment response in tuberculosis. We urgently need new therapies to improve outcomes after cardiac arrest. This activity has largely been driven by the promise surrogate endpoints appear to hold. Biomarkers and surrogate endpoints in glaucoma clinical trials. An overview of endpoints for cystic fibrosis clinical. The datecan2 project aims at assessing the surrogate properties for os of several timetoevent endpoints through metaanalyses of completed and published randomized controlled trials. For example, serum t 3 is used as a marker of the tissue damage that thyroid hormone causes in patients with hyperthyroidism.
To date, few surrogate endpoints have been validated in digestive oncology. Statistical challenges in the evaluation of surrogate endpoints in randomized trials. The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. A large amount of research has been devoted to operational criteria to implement prentices definition in practice. Confounding factors can nullify the value of surrogate endpoints. Definition and operational criteria surrogate endpoints in clinical trials. Thus, there is a need to identify markers or surrogate endpoints that can be used in clinical trials to expedite the development of new treatments. Replacement of os by a surrogate endpoint allows to reduce trial duration. Surrogate end points and their validation in oncology. Phase 3 clinical trials, which evaluate the effect that new interventions have on the clinical outcomes of particular relevance to the patient such as death, loss of vision, or other major symptomatic event, often require many participants to be followed for a long time. There has recently been great interest in using surrogate end points, such as tumor shrinkage or changes in cholesterol. Metaanalysis for the evaluation of surrogate endpoints in.
Alternatively, an endpoint can be a validated surrogate for such an outcome measure. This criterion essentially requires the surrogate variable to capture any relationship between the treatment and the true endpoint, a notion that can be. Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. Recently, metaanalytic methods for evaluating potential surrogates. During clinical trials, endpoints should be used, unless a biomarker. When can intermediate outcomes be used in clinical trials. In clinical trials, the clinical endpoint is often replaced by an intermediate endpoint, known in some instances as a surrogate endpoint. The goals were to assess recent surrogate marker research and to provide specific recommendations for 1 the qualification and validation of biomarkers of treatment outcome. Clinical trial endpoints friends of cancer research. The aim of this study was to draw up an ordered list of potential surrogate endpoints for os in digestive cancer trials, by way of a survey. Several frameworks have been used to describe the validation of a surrogate. Outcomes and endpoints in trials of cancer treatment. In clinical trials, an indicator or sign used in place of another to tell if a treatment works. Developing a definition of a valid surrogate endpoint and operational criteria to assess a proposed surrogate were needed.
Biomarkers and surrogate endpoints in clinical trials. A cancer drug, for example, might use survival as an endpoint, comparing the fiveyear survival rate of patients using an experimental therapy against the fiveyear survival rate of patients using another treatment or a placebo a clinical trial might use a clinical endpoint or a surrogate endpoint. Surrogate endpoints for overall survival in advanced. A putative surrogate endpoint must be validated at both individuallevel and triallevel before it can be used to replace the clinical endpoint in a future clinical trial. Progressionfree survival pfs is increasingly used as an important and even a primary endpoint in randomized cancer clinical trials in the evaluation of patients with solid tumors for both practical and clinical considerations. Surrogate endpoints have therefore been used to shorten the assessment time of new agents and reduce costs.
Surrogate endpoints may be used instead of clinical outcomes in some clinical trials. An even larger amount of research has been devoted to a different approach based on statistical associations between the endpoints surrogate and true, and between treatment effects on these endpoint. A surrogate endpoint is an outcome measure used as a substitute for a clinically meaningful endpoint changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint 9. Description usage arguments details value authors references examples. Identifiability and exchangeability of direct and indirect effects. For example, surrogate endpoints are used when the clinical outcomes, like strokes, might take a very long. For a valid surrogate, the treatment effect on the clinical outcome must also be entirely explained by the treatment effect on the surrogate, a criterion known as the capture criterion. Schatzkin, statistical validation of intermediate endpoints for. The reasons for the substitution are often both practical and financial. Evaluation of surrogate endpoints in clinical trials. Augmented designs to assess immune response in vaccine trials. Overall survival os is the gold standard for the demonstration of a clinical benefit in cancer trials. Considerations in the evaluation of surrogate endpoints in clinical trials. Journal of statistical planning and inference 8, 432449.
A validated surrogate is one which reliably captures a treatment effect against one or more clinically meaningful endpoints, bearing in mind that the strength of this association may be context dependent, and reliability cannot be inferred unless there are multiple randomised, controlled trials of interventions that have the same or similar. Disease definition explicit and specific to targeted clinical trial population matches the inclusionexclusion criteria disease severity demographics other important aspects of heterogeneity more detailed than diagnostic or stratification criteria may vary by subgroup e. In clinical trials, a surrogate endpoint or surrogate marker is a measure of effect of a specific. This also raises the question of whether more than one surrogate endpoint should be used in clinical trials. In 1989, prentice 16 proposed the first formal method for testing the statistical validity of a surrogate endpoint using a single trial, which relied on an all or nothing criteria in terms of validation. Researchers in cardiovascular drug development have access to clearly defined and rigorously validated biomarkers, surrogate endpoints, and clinical endpoints. We consider here the definition but not published operational criteria. However, determining whether an end point is a reliable triallevel surrogate based on results of previous trials is not straightforward. Ability to conduct normal activities ability to walk, ability to engage in recreational activities, ability for self care, risk of syncope time in hospital or missing school overall, or cause specific. Surrogate endpoints and risk adaptive strategies in. Alternative endpoints such as progressionfree survival, diseasefree survival, and objective response rate have been used to identify benefit earlier, but their true validity as surrogate endpoints is. Cancer treatment should allow patients to live better or longer lives, and ideally, both. The advantages and limitations of current endpoints will be identified, and the potential role for chest ct and newer imaging modalities discussed in this context. A triallevel surrogate end point for a randomized clinical trial may allow assessment of the relative benefits of the treatment to be performed at an earlier time point and potentially with a smaller sample size.
Variability of definitions for survival endpoints and. There are a number of other important concepts to understand when considering surrogate endpoints. Biomarkers and surrogate endpoints in clinical drug. Definition of surrogate endpoint nci dictionary of. Considerations for development of surrogate endpoints for. The definitive end point for randomized phase iii clinical trials in oncology is survival. Does the prentice criterion validate surrogate endpoints. Surrogate endpoints and competing risk of death in cardiac. By continuing to use our website, you are agreeing to our use of cookies. Infarct volume as a surrogate or auxiliary outcome measure. 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.
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