Perspectives on Biomarker and Surrogate Endpoint Evaluation Discussion Forum Summary (2011) / Chapter Skim
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3 FDA Perspectives
3 FDA Perspectives
Pages 29-42
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Speakers representing three FDA centers involved in using biomarkers in regulatory decision making -- Center for Food Safety and Applied Nutrition (CFSAN) , Center for Drug Evaluation and Research (CDER)
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Speaker Paula Trumbo, supervisory biologist at CFSAN, replied, "risk biomarkers can be surrogate endpoints, but not all risk biomarkers are surrogate endpoints." This exchange prompted Thomas Fleming to ask whether CFSAN's goal was to be able to determine whether a given biomarker is a reliable way to assess the level of risk a patient has for a certain event, or whether they seek biomarkers that can represent reliably whether a treatment will alter a patient's risk for such an event, and can therefore serve as a surrogate endpoint. "The former [case]
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Fleming, biological plausibility is particularly critical to formulating a hypothesis regarding a putative surrogate endpoint; thereafter, prospec tive trials are needed to validate the effect of an intervention on the bio marker as compared to a clinical endpoint. "Now, in that validation trial, I will also have had prespecified biological mechanisms that will be key supportive endpoints, and those can, in fact, be more readily interpreted as confirmatory," he explained, "yet I'll explore the data even in those trials … but those additional exploratory analyses of biological mecha nism have to be viewed with great caution." Committee member Victor De Gruttola, professor and chair of the Department of Biostatistics at Harvard School of Public Health, noted that the association between a given surrogate and a clinical endpoint may be confounded.
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More often, however, CFSAN must evaluate evidence for health claims based on observational studies involving surrogate endpoints. "For instance, one of our qualified health claims is on monounsaturated fats and olive oil, and another one … [is for]
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PRESENTATION By kATHLEEN ELLWOOD, CFSAN Kathleen Ellwood, director of nutrition programs staff in the Office of Nutrition, Labeling, and Dietary Supplements in CFSAN, further outlined the challenges that led to CFSAN's request for the IOM study. She noted that there are few known "validated modifiable risk biomarkers for chronic disease risk," and "not all risk biomarkers are surrogate endpoints." In particular, she said, many chronic diseases lack surrogate endpoints.
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So what would it take for HDL, then, to be considered a surrogate endpoint for a chronic disease? " CFSAN's objective in requesting that the IOM recommend a framework and demonstrate its use through case studies was "to assist FDA in developing a framework for the evidentiary standards for the qualification of biomarkers as potential surrogate endpoints of chronic disease risk." PRESENTATION By MARC WALTON, CDER CDER's interest in biomarkers rests primarily in their ability to improve drug development and to improve CDER review decision making.
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In addition, Dr. Walton noted that CDER has established the Biomarker Qualification Process, which has been in development and slowly maturing over the past couple of years.
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In addition, as with all guidances that FDA publishes, this allows for public comment regarding specific biomarkers and CDER's evaluation process. Regarding the committee's recommended biomarker evaluation framework, Dr.
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may have adequate sensitivity, and for other purposes, it may not be adequately sensitive." Therefore, "the validity of the method and its performance characteristics have to be thought about with the context of use in mind." PRESENTATION By FEDERICO gOODSAID, CDER Federico Goodsaid, chemist at CDER, began by echoing Dr. Walton's emphasis on context, as well as remarks by Dr.
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(Dieterle et al., 2010) , based on the submission of drug toxicity studies and analyses of biomarker performance from the Predic tive Safety Testing Consortium (PSTC)
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In response to an audience question, Dr. Becker noted that biomarker tests can also be approved through another pathway defined by the Clinical Laboratory Improvement Amendments (CLIA)
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; • Sample type/matrix; • Sample preparation/conditions; • Performance around the cutoff; and • Potential for carryover, cross-hybridization. The steps CDRH takes to conduct analytical validation of a biomarkerbased device vary according to the technologies involved, said Dr.
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Dr. Becker pointed out that these devices may operate in a range of medical contexts that include risk estimation, screening, diagnosis, residual or refractory disease, recurrent disease, monitoring, prognosis, and pre diction of therapeutic response.
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Becker offered further explanation of considerations regarding "follow-on" tests based on biomarkers. HER2 is expressed at a variety of levels that can be assessed from the perspective of either biochemistry or cellular physiology, with one method measuring the HER2 protein itself while the other method relies on reversetranscriptase polymerase chain reaction (RT-PCR)
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