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3 The Biomarker Evaluation Process
Pages 97-130

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From page 97...
... analytical validation of relevant biomarker tests; (2) qualification, a description of the evidence relating to the biomarker in question -- as measured using validated tests -- to the intervention and disease outcome; and (3)
From page 98...
... data; the committee's framework explicitly includes such a process, while allowing for timely, reliable, and effective decision making. The evaluation framework is intended to be applicable across a wide range of biomarker uses, from exploratory uses for which less evidence is required to surrogate endpoint uses for which compelling evidence is required.
From page 99...
... In addition, the circle in the center signifies ongoing processes that should continually inform 1, editable biomarker evaluation process. Figure each step in the panels of biomarkers in addition to single biomarkers and for both circulating and imaging biomarkers.
From page 100...
... This includes a determination of whether the validation and qualification conducted provide sufficient support for the use proposed. The committee recognizes that including analytical validation in the evaluation framework and separating the evidentiary assessment from the utilization analysis is a departure from many previous attempts to develop biomarker evaluation systems, but found that these processes, although distinct, are interwoven in such a way that it is impossible to responsibly consider one without also considering the others.
From page 101...
... Also, decisions made during the evaluation process are based on probabilistic rather than deterministic reasoning. Probabilistic reasoning emphasizes epidemiological and statistical relationships and acknowl edges that the biology is not fully understood.
From page 102...
... The terminology used in the recommendation, analytical performance, is not meant to describe how well a biomarker correlates with the clinical outcomes of interest. Instead, analytical validation of an assay includes the biomarker's limit of detection, limit of quantitation, reference (normal)
From page 103...
... . It resulted in a validation approach for laboratory biomarker assays in support of drug development.
From page 104...
... Though these background fluctuations affect TABLE 3-1 Sources of Variability in Biomarker Measurements Preanalytical Sources of Variability Analytical Sources of Variability Biological Sample Collection Sociodemographics Mislabeling Purity of reference (including age and Duration of tourniquet standards gender) application Lot-to-lot variation in Posture Strength of collection reagents Exercise vacuum Antibody crossreactivity Meals/fasting status Size of needle gauge Loss during extraction Diet Dead volume in Mislabeling of Diurnal biorhythm catheters/collection processing tubes Seasonal biorhythm tubes Pre-assay incubation Concurrent diseases Anticoagulants time and temperature Concurrent medications Local effects of Pre-assay amplifications Overall health/ indwelling catheter Chemical interference preexisting disease Time and temperature by endogenous Gastrointestinal motility prior to compounds Anesthesia/surgical centrifugation Chemical interference by intervention Centrifugation drugs Stress speed, duration, Analyte or reagent Pregnancy temperature instability in light Menstrual cycle Evaporation/biomarker Time between Dehydration volatility intermediate steps Kidney function Preservatives/biomarker Fluctuations in Body composition instability instrument (obesity)
From page 105...
... Box 3-2 introduces the case study exemplifying the issues found in analytical validation. Further detail can be found in Chapter 4.
From page 106...
... for cutoff identification of limiting plasma and whole blood A negative QC sample to substrates measurements monitor baseline drift Linearity of signal Influence of gel separator Calibration frequency to be Reactivity to various plasma tubes determined based on the biomarker forms (degree Time and speed (relative imprecision and drift of equimolarity) centrifugal force)
From page 107...
... evaluating the nature and strength of evidence about whether the biomarker is on a causal pathway in the disease pathogenesis, and (2) gathering available evidence showing that interventions targeting the biomarker in question impact the clinical endpoints of interest.
From page 108...
... . Given that biomarkers are "indicators" -- in that they are not necessarily causal -- and that an abnormal value or a gradient in level over time is not necessarily informative or predictive depending on the clinical situa tion, the committee instead used these criteria as a structure for assessing the prognostic value of the biomarker for the clinical outcomes of interest.
From page 109...
... Evidence That Interventions Impacting the Biomarker Impact the Clinical Endpoint For the second part of qualification -- for surrogate endpoints, that is -- prognostic value is a necessary but not sufficient criterion for the evaluation. Interventions targeting the biomarker in question should impact the clinical endpoints of interest.
From page 110...
... . In the description of evidence about the biomarker, populations and conditions to which the assessment applies need to be articulated so they can be considered in the utilization step of the biomarker evaluation framework.
From page 111...
... . In drug development, for example, there is a continuum of uses from early trials on one end to surrogate endpoints on the other end.
From page 112...
... What is the biomarker's For biomarkers that are likely to purpose with respect to be used in a regulatory submission phase of development in or as evidence supporting clinical trials? statements regulated by the FDA, consideration should be given to the need for additional data collection.
From page 113...
... Likewise, an intervention meant to treat a rare but life-threatening disease may permit more tolerance of risk than an intervention meant to treat a more common but less serious disease. So, it may be easier to defend use of a surrogate endpoint for trials of rare and life-threatening diseases than for trials of primary prevention interventions for common but less serious or life-threatening diseases.
From page 114...
... The committee did not explicitly include analysis of a biomarker test's or intervention's cost effectiveness in the evaluation framework. Cost effectiveness is important for a subset of biomarker uses, particu larly those involving changing the clinical practice of medicine.
From page 115...
... Evaluation of a Biomarker as a Surrogate Endpoint In the case of chronic disease, where there are multiple pathogenetic pathways leading to development of clinical outcomes and multiple manifestations of disease, the probabilistic nature of predictions made using biomarker data means that no biomarker can give absolute certainty of an event's future occurrence nor absolute certainty of the timing of the pre dicted event. Nonetheless, there are situations in which use of a biomarker as a surrogate endpoint in situations with regulatory impact may be sup ported, such as in situations where the need for interventions is urgent or where studies including clinical endpoints are not feasible because of technical or ethical reasons.
From page 116...
... Finally, it is essential to remember that the information that an individual surrogate endpoint or clinical endpoint can give is inherently limited; as a result, it is important to emphasize the need to evaluate data relating to adverse events and unintended effects of biomarker use. The committee does not intend to imply that selection of endpoints for clinical trials would be simple or risk free if investigators were sim ply to avoid surrogate endpoints.
From page 117...
... 2c. The expert panels should reevaluate analytical validation, quali fication, and utilization on a continual and a case-by-case basis.
From page 118...
... Direct engagement by the FDA in the process of biomarker evaluation for regulatory decision making may be helpful. Because of the substantial expense, resources, and time that will be needed to qualify new biomarkers, particularly as surrogate endpoints, prospective and specific guidance on the potential or actual acceptance of biomarkers on the part of regula tory agencies for different purposes, and the agencies' regulatory risk tol erance in qualifying biomarkers for each new use, would also be helpful.
From page 119...
... The expert panel for biomarker evaluation should be formulated with due attention to the 2009 IOM recommendations. The biomarker evaluation process inevitably requires judgments to be made by the expert panel; these judgments must be known to be made in good faith and without undue influence.
From page 120...
... was found to generally remain the same. These findings could be cause for reevaluation of the analytical validation step of the biomarker evaluation framework.
From page 121...
... The reappraisal process need not consider the biomarker as though no previous evaluation had occurred. The monetary and opportunity costs of this kind of de novo evaluation would render such analyses prohibitive.
From page 122...
... take a few common drugs. About 184 million people drank fluoridated water in the United States in 2006, about 62 percent of the entire popu lation (CDC, 2006)
From page 123...
... In the case of foods and supplements, for example, this may require Congress to enact legislation to allow the FDA to compel companies to gather and submit data relating to the safety and efficacy of proposed products and health claims, based on both the nutrients of interest alone and on the whole products within which they are contained.
From page 124...
... The committee concluded that for the utilization step of the biomarker evaluation framework, it is necessary to evaluate the bio marker's proposed use in terms of the entire product in all situations. In addition, the committee concluded that it is important to evaluate efficacy as well as safety of proposed biomarker uses.
From page 125...
... Determining that a biomarker has prognostic value and a well-defined scientific basis, however, is distinct from knowledge that modifying the biomarker will bring about clinical benefit or harm. Utilization, the process of making assessments of whether a proposed biomarker is fit for the purpose for which it is being proposed, is the third essential component of the biomarker evaluation process.
From page 126...
... 2005. Surrogate endpoints and the FDA's accelerated approval process.
From page 127...
... 2005. Method validation and measurement of biomarkers in nonclinical and clinical samples in drug development: A conference report.
From page 128...
... 2007. Surrogate endpoints and emerg ing surrogate endpoints for risk reduction of cardiovascular disease.
From page 129...
... 2008. National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine practice guidelines: Analytical issues for biomarkers of heart failure.


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