In this paper, we highlight several important aspects related to study design and statistical analysis for clinical research incorporating biomarkers. Summer institute in statistics for clinical research biomarkers and surrogate endpoints in clinical trials july 28, 2017 thomas r. Recommended timing of clinical and imaging evaluations. I primary endpoints address primary objectives of the trial.
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. 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. The challenges in defining clinical endpoints presented by the mechanism of action of immunotherapeutic agents differentially affects early and late phase studies. Clinical trial design principles and endpoint definitions. For example, for a clinical trial of a prostate cancer drug employing os or cancerspecific survival as an endpoint. Each of these endpoints is associated with certain advantages and limitations. Metaanalysis for the evaluation of surrogate endpoints in. Design of clinical trials with failuretime endpoints and interim analyses. Analyzing multiple endpoints in clinical trials of pain.
Criteria for the validation of surrogate endpoints in randomized experiments biometrics 54. Di erent types of endpoints clinical trials generally classify the endpoints into primary, secondary and exploratory types. 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. Proposed standardized neurological endpoints for cardiovascular clinical trials. 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. 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. Design of clinical trials with failuretime endpoints and. Endpoints serve as a standard for measuring clinical research outcomes. Clinical trial endpoints for the approval of cancer drugs and biologics for a detailed discussion on general endpoint and respective trial design considerations. The endpoints or outcomes, determined for each study participant, are the quantitative measurements required by the objectives. Apr 27, 2020 substitute measure for a clinical endpoint. 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. The meaning of the endpoints in the clinical trials described here go as follows. 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.
I then discuss this operational criterion in the examples of the accompanying papers and in the setting of trials aimed at the primary and. Biomarkers and surrogate endpoints in clinical trials. We will be unable to substantially reduce the lifetime risk of coronary artery disease without primary prevention of atherosclerosis. In his 2010 budget request, the director of the national cancer institute earmarked \reengineering cancer clinical trials as a research initiative. In the treatment of cancer, endpoints can be classified into two categories. Examples of trials in prostate cancer, breast cancer, and lung cancer will be used to illustrate the key points. Commonly used efficacy endpoints in oncology clinical trials. Trials in which a usually low dose of a drug is given. Innovative clinical trial endpoints are intended to evaluate potential new cancer treatments. Common definition for categories of clinical research.
We should not assume anything but should discover and adjust for differences. Surrogate endpoints in clinical trial linkedin slideshare. A practical guide to design, analysis and reporting. Surrogate endpoints in cancer clinical trials springerlink. In a cancer chemotherapy trial the clinical objective is usually improved survival. Appropriate endpoints are those of efficacy and toxicity under reallife conditions. 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. The identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. 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. 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. Appropriate endpoints are measures of drug disposition and target inhibition. Key multiplicity concepts and principles addressed in the. 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.
First, and most important, is the development and progression of atherosclerosis. The statistical evaluation of surrogate endpoints in. 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. Definition and operational criteria surrogate endpoints in clinical trials. There exists a need for standardized acquisition pulse sequences and analysis 14 techniques for mr imaging biomarker studies. The following table shows a number of efficacy endpoints. Clinically meaningful endpoints relate to outcomes which capture how a person feels, functions or survives. In addition, biomarkers are widely expected to be used as a tool for disease diagnosis, personalized medication, and surrogate endpoints in clinical research. Developing new clinical endpoints for immunooncology studies. An update after fteen years pei hea, tze leung laib, and zheng suc agenentech inc. Clinical trial endpoints for oncology studies applied. Accelerating therapies for rare diseases workshop, october 19, 2010 2. 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.
Choosing primary endpoints for clinical trials of health. Pdf surrogate outcomes in clinical trials a cautionary tale. We first recall prentices definition and operational criteria for the validation of surrogate endpoints section 3. 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. Clinical trial design principles and endpoint definitions for. The use of surrogate endpoints can accelerate drug development and considerably shorten the time required for fda approval. View the article pdf and any associated supplements and figures for a period of 48 hours. The statistical evaluation of surrogate endpoints in clinical trials geert molenberghs geert. Criteria for the validation of surrogate endpoints in. Burke phd, associate director for study endpoints and labeling. 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. I they are usually few but are clinically most relevant to the disease and the treatment under study.
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. 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. 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. Interpretation of the definition of noninterventional. 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. 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. This figure provides recommended and optional assessments for each time point. 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. Prentice fred hutchinson cancer research center, 1124 columbia street, seattle, wa 98104, u. Development and validation of measures to support claims in labeling presented by laurie b. Recently, metaanalytic methods for evaluating potential surrogates. The incidence of coronary artery disease is a function of 3 pathophysiologic processes. Patients eligible for inclusion in this study have to meet all of the following criteria. The food and drug administration fda or agency is announcing the availability of a draft guidance for industry entitled ulcerative colitis.
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. In the dansinger weight loss study, the primary endpoint was identified to be mean absolute change from baseline weight at 1 year. Chapter 4 analysis of multiple endpoints in clinical trials. Clinical trial endpoints friends of cancer research.
Policies nih policy on registration and results submission of nihfunded clinical trials. 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. Clinical win criteria with primary endpoints i win criteria are also called \ clinical decision rules for determining clinically meaningful treatment e cacy. Definition and operational criteria prentice, ross l. Clinical trial endpoints for the approval of non small cell. 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.
Although the endpoint definitions provided here are from fda guidance, please note that individual clinical trials may use different definitions. All developments are illustrated with data from an actual clinical trial in ophthalmology section 2. In addition to endpoints used in trials of systemic therapy. 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. For example, in hivrelated clinical trials, hiv viral load vl and cd4 t lymphocyte cd4 count are surrogate endpoints for hiv disease. 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 24, 2009 the identification and validation of putative surrogate endpoints in oncology is a great challenge to medical investigators, statisticians, and regulators. 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. The extent of atherosclerosis is the primary determinant of the risk of myocardial. The unique mechanism of action of immunooncology treatments necessitates rethinking of traditional clinical trial endpoints. For example, in hivrelated clinical trials, hiv viral load vl and cd4 t lymphocyte cd4 count are surrogate endpoints for hiv disease progression.
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