Analyzing multiple endpoints in clinical trials of pain. In his 2010 budget request, the director of the national cancer institute earmarked \reengineering cancer clinical trials as a research initiative. Office of biostatistics ots, cderfda dia annual meeting, boston, ma june, 20 this presentation reflects the views of the presenter and should not be construed to represent fdas views or policies. The national institutes of health usa defines surrogate endpoint as a biomarker intended to substitute for a clinical endpoint. Clinical trial design principles and endpoint definitions. The purpose of this guidance is to assist sponsors in the clinical development of drugs for the treatment of ulcerative colitis uc in adult and pediatric patients. Surrogate endpoints are most likely to be useful when the pathophysiology of the disease and the mechanism of action of the intervention are thoroughly understood. Surrogate end points and their validation in oncology. The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. For example, in clinical trials for cancer, researchers may be able to detect that a medicine is having an impact if there is a reduction in the size of a patients tumor before the disease fully manifests. In a cancer chemotherapy trial the clinical objective is usually improved survival.
Pdf surrogate outcomes in clinical trials a cautionary tale. Examples of trials in prostate cancer, breast cancer, and lung cancer will be used to illustrate the key points. While early phase conventional clinical studies demonstrate more tangible endpoints such as tumor shrinkage, later phase endpoints may evaluate prolonged survival and quality of life. Clinical trial design principles and endpoint definitions for. I primary endpoints address primary objectives of the trial. Clinical trial endpoints for oncology studies applied. Developing new clinical endpoints for immunooncology. All developments are illustrated with data from an actual clinical trial in ophthalmology section 2. Surrogate outcomes in clinical trials a cautionary tale article pdf available in jama internal medicine 1738. Proposed standardized neurological endpoints for cardiovascular clinical trials.
Accelerating therapies for rare diseases workshop, october 19, 2010 2. Surrogate endpoints in cancer clinical trials springerlink. Summer institute in statistics for clinical research biomarkers and surrogate endpoints in clinical trials july 28, 2017 thomas r. View the article pdf and any associated supplements and figures for a period of 48 hours. Evans and toshimitsu ochiai, interim evaluation of efficacy or futility in clinical trials with two coprimary endpoints, groupsequential clinical trials with multiple coobjectives, 10. Apr 27, 2020 substitute measure for a clinical endpoint. Apr 24, 2009 the identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. Burke phd, associate director for study endpoints and labeling. Endpoints we will consider the choice and interpretation of study endpoints in the context of a randomized clinical trial rct, and thus where treatment groups are being compared however, most results apply to the issue of selecting endpoints for other types of biomedical investigation, including. Patients eligible for inclusion in this study have to meet all of the following criteria. In the treatment of cancer, endpoints can be classified into two categories. Criteria for the validation of surrogate endpoints in randomized experiments biometrics 54. Clinical trial endpoints for the approval of non small cell.
Key multiplicity concepts and principles addressed in the. Appropriate endpoints are those of efficacy and toxicity under reallife conditions. Recommended timing of clinical and imaging evaluations. There exists a need for standardized acquisition pulse sequences and analysis 14 techniques for mr imaging biomarker studies. The extent of atherosclerosis is the primary determinant of the risk of myocardial. National institutes of health nih issued a final policy establishing the expectation that every clinical trial funded in whole or in part by nih is registered on clinicaltrials. For example, in hivrelated clinical trials, hiv viral load vl and cd4 t lymphocyte cd4 count are surrogate endpoints for hiv disease. The incidence of coronary artery disease is a function of 3 pathophysiologic processes. Clinical win criteria with primary endpoints i win criteria are also called \ clinical decision rules for determining clinically meaningful treatment e cacy. Design of clinical trials with failuretime endpoints and interim analyses. In this paper, we highlight several important aspects related to study design and statistical analysis for clinical research incorporating biomarkers. The purpose of this paper is to discuss the role of surrogate endpoints in cancer clinical trials, including prevention, screening, and therapeutic trials. These endpoints may be measured objectively or subjectively, and are either i reported by clinicians clinro, which involves judgement or interpretation of clinical signs or events such as stroke, myocardial infarct or cancer remission, ii assessed by standardised performance.
Clinical trial endpoints friends of cancer research. The following table shows a number of efficacy endpoints. The endpoints or outcomes, determined for each study participant, are the quantitative measurements required by the objectives. Clinically meaningful endpoints relate to outcomes which capture how a person feels, functions or survives. Design of clinical trials with failuretime endpoints and. Developing new clinical endpoints for immunooncology studies. Di erent types of endpoints clinical trials generally classify the endpoints into primary, secondary and exploratory types. We first recall prentices definition and operational criteria for the validation of surrogate endpoints section 3. Chapter 4 analysis of multiple endpoints in clinical trials. While some guidelinessuch as the guidance on trial design in the international conference on harmonization guideline for good clinical practice generally prefer a primary endpoint based on a single outcome that will be defined before the study begins, many recent studies include multiple outcomes as part of a composite. The national institutes of health usa defines surrogate endpoint as a biomarker intended to substitute for a clinical endpoint surrogate markers are used when the. The unique mechanism of action of immunooncology treatments necessitates rethinking of traditional clinical trial endpoints.
The statistical evaluation of surrogate endpoints in. Definition and operational criteria surrogate endpoints in clinical trials. Nov 10, 2012 the second clinical setting where considerable biological insights as well as data intensive approaches are needed to justify effective implementation of biomarkers is their use as replacement or surrogate endpoints for clinical efficacy measures in clinical trials intended to provide a definitive assessment of the benefittorisk profile of an. Policies nih policy on registration and results submission of nihfunded clinical trials.
Clinical trial endpoints for the approval of cancer drugs and biologics for a detailed discussion on general endpoint and respective trial design considerations. Innovative clinical trial endpoints are intended to evaluate potential new cancer treatments. 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. 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. For example, in hivrelated clinical trials, hiv viral load vl and cd4 t lymphocyte cd4 count are surrogate endpoints for hiv disease progression.
Although overall survival remains the most compelling primary endpoint, achieving it requires years of study and would delay the approval of lifesaving or extending treatments. Interpretation of the definition of noninterventional. 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. Commonly used efficacy endpoints in oncology clinical trials. Metaanalysis for the evaluation of surrogate endpoints in. Each of these endpoints is associated with certain advantages and limitations. Because it can be difficult to measure clinical endpoints in studies running for several years, researchers often use surrogate endpoints as substitute measures for clinical endpoints.
In addition to endpoints used in trials of systemic therapy. For example, for a clinical trial of a prostate cancer drug employing os or cancerspecific survival as an endpoint. Endpoints serve as a standard for measuring clinical research outcomes. 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 disease occurrence. Biomarkers and surrogate endpoints in clinical trials. Specific symptom endpoints time to progression of cancer symptoms, an endpoint similar to ttp, is a direct measure of clinical benefit rather than a potential surrogate problems in measuring progression e. For instance, smoking causes lung cancer, and a trial of the benefit of education in preventing lung cancer might use smoking as a surrogate endpoint. Development and validation of measures to support claims in labeling presented by laurie b. We should not assume anything but should discover and adjust for differences. The challenges in defining clinical endpoints presented by the mechanism of action of immunotherapeutic agents differentially affects early and late phase studies. A surrogate endpoint is a laboratory measure or a physical sign that is intended to be used as a substitute for a clinically meaningful endpoint. Appropriate endpoints are measures of drug disposition and target inhibition.
Patient is currently enrolled in a novartis gdd or gmasponsored or incytesponsored clinical study where incyte can delegate the sponsorship to a preferred cro, if applicable that is approved to enroll into this rollover study, and are receiving either ruxolitinib. 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. Definition and operational criteria prentice, ross l. Surrogate endpoints in clinical trial linkedin slideshare. A practical guide to design, analysis and reporting. 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. Criteria for the validation of surrogate endpoints in. First, and most important, is the development and progression of atherosclerosis. Choosing primary endpoints for clinical trials of health. This figure provides recommended and optional assessments for each time point. I then discuss this operational criterion in the examples of the accompanying papers and in the setting of trials aimed at the primary and. The use of surrogate endpoints can accelerate drug development and considerably shorten the time required for fda approval.
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. Need to evaluate multiple endpoints to establish effectiveness for approval wish to evaluate multiple endpoints to provide additional effectiveness information composite endpoints 12. Recently, metaanalytic methods for evaluating potential surrogates. Jul 19, 2001 a man, aged 50, has about a 50% risk and a 50yearold woman a 35% risk of having a myocardial infarction during their lifetime. I they are usually few but are clinically most relevant to the disease and the treatment under study. We will be unable to substantially reduce the lifetime risk of coronary artery disease without primary prevention of atherosclerosis. Endpoints are measurable clinical and biological findings that are used for the development and assessment of treatment options. The extent of atherosclerosis is the primary determinant of the risk of myocardial infarction. In addition, biomarkers are widely expected to be used as a tool for disease diagnosis, personalized medication, and surrogate endpoints in clinical research. The meaning of the endpoints in the clinical trials described here go as follows.
Patient is currently enrolled in a novartis gdd or gmasponsored or incytesponsored clinical study where incyte can delegate the sponsorship to a preferred cro, if applicable that is approved to enroll into this rollover study, and are receiving either ruxolitinib or combination of. Clinical trial endpoints an endpoint is the primary outcome that is being measured by a clinical trial. 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. 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. In the dansinger weight loss study, the primary endpoint was identified to be mean absolute change from baseline weight at 1 year. Common definition for categories of clinical research. An update after fteen years pei hea, tze leung laib, and zheng suc agenentech inc. The food and drug administration fda or agency is announcing the availability of a draft guidance for industry entitled ulcerative colitis. The statistical evaluation of surrogate endpoints in clinical trials geert molenberghs geert. The second clinical setting where considerable biological insights as well as data intensive approaches are needed to justify effective implementation of biomarkers is their use as replacement or surrogate endpoints for clinical efficacy measures in clinical trials intended to provide a definitive assessment of the benefittorisk profile of an. Trials in which a usually low dose of a drug is given.
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