Surrogate endpoints in medicinedownloads.hindawi.com/journals/dm/2002/182186.pdfDisease Markers 18...
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Disease Markers 18 (2002) 39–40 39 IOS Press Foreword Surrogate endpoints in medicine Sudhir Srivastava a and John A. Wagner b a Cancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 Executive Plaza North, Suite 3142, Bethesda, MD 20892, USA b Department of Clinical Pharmacology, Merck Research Laboratories, Rahway, NJ, USA A surrogate endpoint is defined as a biomarker in- tended to substitute for a clinical endpoint, such as an incidence, or mortality. The evidence supporting the linkage of a biomarker to accurately substitute for a clinical endpoint may be derived from epidemiologic studies, clinical trials, in vitro analysis, animal mod- els, and simulated biologic systems. Analytical epi- demiological studies of the relationship between puta- tive intermediate endpoints and disease help postulate the nature of the interrelationship among epidemiolog- ical risk factors, intermediate endpoints, and disease. This presents problems in a system where more than one causal path exists. Adjustment for the presence of standard epidemiological factors may have different interpretations. Specifically, the disappearance of an association between a putative intermediate endpoint and disease after adjustment for the presence of some epidemiological risk factors may have opposing inter- pretations: either the intermediate endpoint is causal, related to disease and mediates the effects defined by the epidemiologic risk factor or it has nothing to do with disease in a causal sense. Several contributors throughout this issue have de- scribed and used a variety of biomarkers in treatment trials. Selected biomarkers may be proposed as po- tential surrogate endpoints, however, relatively few are likely to achieve this status because of the complexity of disease mechanisms and the limited capability of a single biomarker to reflect the collective impact of mul- tiple chemopreventive and therapeutic effects on out- come. It is likely that the future studies would employ a panel of biomarkers as a surrogate endpoint, which would require additional biologic studies and insights. A biomarker does not have to be causally related to a disease to play a valuable role in early detection and intervention of that disease. However, causally related biomarkers, i.e., surrogate endpoints, if measured with precision, are likely to have the strongest association with disease. Biologic characteristics of surrogate endpoints At least three elements are necessary to use biomark- ers as surrogate outcomes: (1) the proper definition of the risk factor and how to detect it, (2) the proper description of the definitive outcome of interest and a procedure on how to assess it, and (3) knowledge of the strength and direction of the relationship between the surrogate outcome and the definitive outcome over a specified time interval. For a risk factor to be a useful surrogate outcome it must be strongly connected to the definitive outcome and the probability and direction of the relationship must be known. Surrogate outcomes do not shorten the first investigation because the rela- tionship between the risk factor and the true outcome must be known prior to using the risk factor as a surro- gate outcome. Several basic criteria must be met before the potential markers could serve as adequate surrogate endpoints either for risk or clinical outcome: (1) Is the surro- gate biomarker differentially expressed in normal and high-risk tumor tissues? (2) At what stage of carcino- genesis does the marker appear? (3) Does the marker, and its assay, provide acceptable sensitivity, specificity and accuracy, and (4) How easily can the marker be measured? For surrogate biomarkers to serve as in- termediate endpoints, it would be desirable to satisfy additional criteria: (1) Can the marker be modulated by chemopreventive agents? and (2) Does modulation of the marker correlate with a change in disease rate? ISSN 0278-0240/02/$8.00 2002 – IOS Press. All rights reserved
Transcript of Surrogate endpoints in medicinedownloads.hindawi.com/journals/dm/2002/182186.pdfDisease Markers 18...
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Disease Markers 18 (2002) 39–40 39IOS Press
Foreword
Surrogate endpoints in medicine
Sudhir Srivastavaa and John A. WagnerbaCancer Biomarkers Research Group, Division of Cancer Prevention, National Cancer Institute, 6130 ExecutivePlaza North, Suite 3142, Bethesda, MD 20892, USAbDepartment of Clinical Pharmacology, Merck Research Laboratories, Rahway, NJ, USA
A surrogate endpoint is defined as a biomarker in-tended to substitute for a clinical endpoint, such as anincidence, or mortality. The evidence supporting thelinkage of a biomarker to accurately substitute for aclinical endpoint may be derived from epidemiologicstudies, clinical trials,in vitro analysis, animal mod-els, and simulated biologic systems. Analytical epi-demiological studies of the relationship between puta-tive intermediate endpoints and disease help postulatethe nature of the interrelationship among epidemiolog-ical risk factors, intermediate endpoints, and disease.This presents problems in a system where more thanone causal path exists. Adjustment for the presenceof standard epidemiological factors may have differentinterpretations. Specifically, the disappearance of anassociation between a putative intermediate endpointand disease after adjustment for the presence of someepidemiological risk factors may have opposing inter-pretations: either the intermediate endpoint is causal,related to disease and mediates the effects defined bythe epidemiologic risk factor or it has nothing to dowith disease in a causal sense.
Several contributors throughout this issue have de-scribed and used a variety of biomarkers in treatmenttrials. Selected biomarkers may be proposed as po-tential surrogate endpoints, however, relatively few arelikely to achieve this status because of the complexityof disease mechanisms and the limited capability of asingle biomarker to reflect the collective impact of mul-tiple chemopreventive and therapeutic effects on out-come. It is likely that the future studies would employa panel of biomarkers as a surrogate endpoint, whichwould require additional biologic studies and insights.A biomarker does not have to be causally related to adisease to play a valuable role in early detection and
intervention of that disease. However, causally relatedbiomarkers, i.e., surrogate endpoints, if measured withprecision, are likely to have the strongest associationwith disease.
Biologic characteristics of surrogate endpoints
At least three elements are necessary to use biomark-ers as surrogate outcomes: (1) the proper definitionof the risk factor and how to detect it, (2) the properdescription of the definitive outcome of interest and aprocedure on how to assess it, and (3) knowledge ofthe strength and direction of the relationship betweenthe surrogate outcome and the definitive outcome overa specified time interval. For a risk factor to be a usefulsurrogate outcome it must be strongly connected to thedefinitive outcome and the probability and direction ofthe relationship must be known. Surrogate outcomesdo not shorten the first investigation because the rela-tionship between the risk factor and the true outcomemust be known prior to using the risk factor as a surro-gate outcome.
Several basic criteria must be met before the potentialmarkers could serve as adequate surrogate endpointseither for risk or clinical outcome: (1) Is the surro-gate biomarker differentially expressed in normal andhigh-risk tumor tissues? (2) At what stage of carcino-genesis does the marker appear? (3) Does the marker,and its assay, provide acceptable sensitivity, specificityand accuracy, and (4) How easily can the marker bemeasured? For surrogate biomarkers to serve as in-termediate endpoints, it would be desirable to satisfyadditional criteria: (1) Can the marker be modulatedby chemopreventive agents? and (2) Does modulationof the marker correlate with a change in disease rate?
ISSN 0278-0240/02/$8.00 2002 – IOS Press. All rights reserved
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40 S. Srivastava and J.A. Wagner / Foreword
Laboratory characteristics of surrogate endpoints
A surrogate endpoint or biomarker must be quantifi-able in an appropriate biologic specimen and indica-tive of pharmacologic response to a chemopreventiveor therapeutic agents. These must meet the followingcriteria: (1) the biomarker must be stable, and in case ofadducts as biomarkers, must have a longer half-life, (2)the assay for biomarkers must be reproducibleand musthave high sensitivity and specificity, (3) must have min-imum diurnal variations and (4) the modulation prefer-ably be consistent, at least with the same class of thechemopreventive or therapeutic agents.
Interventional assessment of surrogate endpoints
The surrogate endpoint must be assessed for its ef-ficacy. The recently established NCI Early Detec-
tion Research Network (http://www.cancer.gov/edrn)has undertaken a major step in developing and validat-ing biomarkers for evaluating cancer risk and detectingearly cancer. The Network links centers of expertisein tumor biology, diagnostic technologies, and clinical-trials methodology in academia and industry to develophigh-throughput assays suitable for clinical applica-tion. These laboratories/centers cover a range of studydesigns, technology developments, and innovative ap-proaches from genomics to proteomics in pursuit of de-veloping molecular, genetic and biologic markers forearlier cancer detection and identification of high-risksubjects, which will provide powerful tools for identi-fying suitable cohorts for chemoprevention studies inthe future.
Finally, the special issue ofDisease Markers “Sur-rogate Endpoints in Medicine” provides a valuable re-source for researchers engaged in clinical trials.
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