Surrogate endpoints in clinical trials definition and operational criteria pdf
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Cancer is a major public health problem in the United States and worldwide.
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. 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 primary endpoint is undesired e. The FDA and other regulatory agencies will often accept evidence from clinical trials that show a direct clinical benefit to surrogate markers. Surrogate endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or biomarkers from Electroencephalography qEEG , MRI , PET , or biochemical biomarkers.
A correlate does not make a surrogate. It is a common misconception that if an outcome is a correlate that is, correlated with the true clinical outcome it can be used as a valid surrogate end point that is, a replacement for the true clinical outcome. However, proper justification for such replacement requires that the effect of the intervention on the surrogate end point predicts the effect on the clinical outcome—a much stronger condition than correlation.
The term "surrogate" should not be used in describing end points. Instead, descriptions of results and interpretations should be formulated in terms that designate the specific nature and category of variable assessed. A surrogate endpoint of a clinical trial is a laboratory measurement or a physical sign used as a substitute for a clinically meaningful endpoint that measures directly how a patient feels, functions or survives.
Changes induced by a therapy on a surrogate endpoint are expected to reflect changes in a clinically meaningful endpoint. A commonly used example is cholesterol. While elevated cholesterol levels increase the likelihood for heart disease , the relationship is not linear - many people with normal cholesterol develop heart disease, and many with high cholesterol do not.
A clinical trial may show that a particular drug for example, simvastatin Zocor is effective in reducing cholesterol, without showing directly that simvastatin prevents death. Proof of Zocor's efficacy in reducing cardiovascular disease was only presented five years after its original introduction, and then only for secondary prevention. The company countered that rosuvastatin had been tested on larger groups of patients than any other drug in the class, and that its effects should be comparable to the other statins.
Progression Free Survival is a prominent example in Oncology contexts. There are examples of cancer drugs approved on the basis of progression-free survival failed to show subsequent improvements in overall survival in subsequent studies. In breast cancer, Bevacizumab Avastin initially gained approval from the Food and Drug Administration , but subsequently had its license revoked.
There have been a number of instances when studies using surrogate markers have been used to show benefit from a particular treatment, but later, a repeat study looking at endpoints has not shown a benefit, or has even shown a harm.
From Wikipedia, the free encyclopedia. Controlled Clinical Trials. Annals of Internal Medicine. Statistics in Medicine. A regulatory authority's opinion about surrogate endpoints. Clinical Measurement in Drug Evaluation. New York: Wiley; McKillop T November 1, European Journal of Cancer. British Journal of Cancer. Clinical research and experimental design. Clinical trial Trial protocols Adaptive clinical trial Academic clinical trials Clinical study design.
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Surrogate Endpoints in Cancer Clinical Trials
November , Volume Number 11 , page 1 - 2 [Free]. Join NursingCenter to get uninterrupted access to this Article. The critical importance of a systematic review protocol for the conduct of the systematic review has been highlighted previously in this journal. It is fundamental that reviewers understand the differences between "surrogate" outcomes and those that are not, and select and justify the outcomes proposed for their review based on sound understanding of their review topic and reasoning. The purpose of this editorial is to touch upon some of these issues by defining "surrogate" outcomes, providing examples, and reflecting on the importance of these types of outcomes for the conduct of systematic reviews.
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. 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 primary endpoint is undesired e. The FDA and other regulatory agencies will often accept evidence from clinical trials that show a direct clinical benefit to surrogate markers. Surrogate endpoints can be obtained from different modalities, such as, behavioural or cognitive scores, or biomarkers from Electroencephalography qEEG , MRI , PET , or biochemical biomarkers. A correlate does not make a surrogate.
Not a MyNAP member yet? Register for a free account to start saving and receiving special member only perks. Many medical or lifestyle interventions, indispensible to modern medical care, can induce changes in biomarkers. In order for consumers, physicians, drug developers, and policy makers to make informed decisions based on biomarkers, it is important to understand the amount, strength, and quality of data supporting the use of any specific biomarker to direct decisions in clinical care, drug development, public health, and health policy decisions. Even this fairly simple example of a biomarker highlights some of the issues associated with their use. For example, the method used to measure body temperature matters. Using a thermometer is a more accurate approach than a hand to the forehead.
This criterion essentially requires the surrogate variable to 'capture' any relationship between the treatment and the true endpoint, a notion that can be.
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Felipe A. With the recent progress in imaging technologies for assessment of structural damage in glaucoma, a debate has emerged on whether these measurements can be used as valid surrogate endpoints in clinical trials evaluating new therapies for the disease. A discussion of surrogates should be grounded on knowledge acquired from their use in other areas of medicine as well as regulatory requirements. This article reviews the conditions for valid surrogacy in the context of glaucoma clinical trials and critically evaluates the role of biomarkers such as IOP and imaging measurements as potential surrogates for clinically relevant outcomes.
Ross L. Outcome events that are more frequent in occurrence and more proximate in time, compared with customary disease-specific mortality or incidence outcomes, could give answers that are based on smaller trials of shorter duration. However, reliance on surrogate outcomes is justifiable only if treatment comparisons that are based on a surrogate are a faithful reflection of comparisons that are based on the true endpoint.
A common problem of interest within a randomized clinical trial is the evaluation of an inexpensive response endpoint as a valid surrogate endpoint for a clinical endpoint, where a chief purpose of a valid surrogate is to provide a way to make correct inferences on clinical treatment effects in future studies without needing to collect the clinical endpoint data. We discuss CEP-based criteria for a useful surrogate endpoint, including 1 the meaning and relative importance of proposed criteria including average causal necessity ACN , average causal sufficiency ACS , and large clinical effect modification; 2 the relationship between these criteria and the Prentice definition of a valid surrogate endpoint; and 3 the relationship between these criteria and the consistency criterion i. This includes the result that ACN plus a strong version of ACS generally do not imply the Prentice definition nor the consistency criterion, but they do have these implications in special cases. Moreover, the converse does not hold except in a special case with a binary candidate surrogate. The results highlight that assumptions about the treatment effect on the clinical endpoint before the candidate surrogate is measured are influential for the ability to draw conclusions about the Prentice definition or consistency. In addition, we emphasize that in some scenarios that occur commonly in practice, the principal strata subpopulations for inference are identifiable from the observable data, in which cases the principal stratification framework has relatively high utility for the purpose of effect modification analysis and is closely connected to the treatment marker selection problem. The results are illustrated with application to a vaccine efficacy trial, where ACN and ACS for an antibody marker are found to be consistent with the data and hence support the Prentice definition and consistency.
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