Perspectives on Biomarker and Surrogate Endpoint Evaluation Discussion Forum Summary (2011) / Chapter Skim
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2 Committee Findings and Recommendations
2 Committee Findings and Recommendations
Pages 3-28
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From page 3... ...
These FDA centers expressed concern regarding the limited number of surrogate endpoints available, the high cost of evaluating possible surrogate endpoints, and the absence of an agreed-upon, systematic, and transparent process for biomarker evaluation. They also wished to learn whether principles of biomarker qualification or evaluation learned in the drug development setting could be applied in other FDA-regulated product categories, such as foods.
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From page 4... ...
4. Make ancillary recommendations for the application, enhanced de velopment, and use of risk biomarkers and surrogate endpoints in chronic disease.2 On the basis of this statement of task, the committee undertook its work to address these charges as ensured by the IOM external review process, said committee chair John R
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From page 5... ...
This framework and additional supporting recommendations were introduced in the workshop's first session, following the definition of a series of terms relevant to biomarker evaluation and application. This session also reviewed examples of biomarker case studies to which the committee applied their evaluation framework.
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Two key successes are blood pressure as a surrogate endpoint for CVD clinical endpoints, and HIV-1 RNA as an indicator of complete viral suppression for HIV interventions. By contrast, arrhythmia suppression proved a fail
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Dr. Wagner said that the first two pieces of the framework, analytical validation and qualification, are already commonly accepted; on the other hand, he noted, "the addition of utilization is a little bit more controversial, but nonetheless extremely useful." He added that the committee envisioned all three elements of biomarker evaluation as interdependent components of an iterative cycle, as illustrated in Figure 2-1.
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Utilization, a concept subsumed under qualification in some previous biomarker evaluation frameworks, is a distinct process in the committee's evaluation framework because it represents a subjective and contextual analysis -- as contrasted with the objective analyses in the analytical vali dation and qualification steps -- specific to the use of a given biomarker or surrogate endpoint, Dr. Wagner said.
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COMMITTEE FINDINGS AND RECOMMENDATIONS BOX 2-1 Recommendations The Evaluation Framework 1. he biomarker evaluation process should consist of the following three T steps: 1a.
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From page 10... ...
Further, different contrast agents and different protocols may be used, all of which affect measurement precision. Thus, he concluded, "analytical validation of tumor size is complicated by mul tiple imaging platforms and other assay performance issues." CRP and Qualification Biomarker qualification requires analysis of the nature and the strength of evidence for the relationship between a given biomarker and a diseaseassociated biologic pathway, and of evidence that interventions targeting the biomarker affect the clinical endpoints of interest, Dr.
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. Beta-Carotene and the Biomarker Evaluation Process The committee's second recommendation (see Box 2-1)
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LDL and HDL Case Study Committee member Ronald Krauss, director of atherosclerosis research and senior scientist at the Children's Hospital Oakland Research Institute, presented an in-depth analysis of the committee's fifth case study, LDLand HDL-cholesterol as biomarkers for cardiovascular risk, to illustrate the application of the biomarker evaluation framework (see also pages 159–168 in IOM, 2010)
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From page 13... ...
NOTE: HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipopro tein cholesterol; mg/dL = milligrams per deciliter; RR = relative risk; Y = years. SOURCE: Castelli, 1988.
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From page 14... ...
"Fortunately," he continued, "a number of people in the field held out for clinical trials, and some major clinical trials demon strated that HRT had no benefit on CVD incidence in healthy women, and actually increased mortality in the first year of treatment in women with preexisting cardiovascular disease and increased the risk for throm boembolic events." Dr. Krauss summarized the conclusions of the committee's case study of LDL-C as a biomarker of CVD risk as follows:
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From page 15... ...
? " Thus, he concluded, "there is as yet no conclusive evidence in humans for an independent benefit of HDL increase on CVD outcomes, in large measure because trials aimed at raising HDL almost always have concordant effects on other cardiovascular risk markers that cannot easily be teased apart." As an example of these findings, Dr.
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"We now know that there are off-target effects of this drug on cardiovascular disease itself, not manifested by any biomarker yet that we clinically use, that could have accounted for the adverse effect." Dr. Krauss then discussed the committee's case study of LDL and HDL as CVD biomarkers in the context of a well-established paradigm for evaluating relationships between disease and intervention, surrogate endpoints, and clinical outcome, devised by committee member David DeMets, professor of biostatistics and medical informatics at the University of Wisconsin, and Thomas Fleming, who gave an overview presenta tion later in the discussion forum (see Chapter 7 in this volume)
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Ball learned, however, "it depends." Red wine, he said, may be "good for the plumb ing, the coronary arteries, apparently, but it was not so good for my pacemaker, the electrical system." Similarly, he observed, sometimes an intervention affects biomarkers, sometimes it affects the disease itself, and sometimes it doesn't have an effect -- or it has a negative effect -- on clinical outcomes. These circumstances, he said, led the committee to devise the three-part biomarker evaluation framework comprising analytic vali dation, qualification, and utilization, depending on context of use.
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In other words, a surrogate endpoint may not be on the causal pathway of the disease process and a substance or intervention may have mechanisms of action independent of the disease process. Dotted lines indicate possible pathways.
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The committee's task was to identify criteria to be used for judging whether a given surrogate endpoint represents an appropriate way to monitor a specific disease or biological process, according to committee member Jennifer Van Eyk, professor in the departments of medicine and biological chemistry at Johns Hopkins University. The committee was not focused on the various entities that a biomarker or surrogate endpoint may be used to test, she said; instead, they considered the criteria by which surrogate endpoints should be judged and the challenges of developing surrogate endpoints that can be used throughout the regulatory process.
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Wagner added. The analytical validation and qualification requirements for a particular biomarker used in research would not be the same if that biomarker was to be used for a regula tory purpose; for example, although there are qualification issues with tumor size as a biomarker in oncology, it would be appropriate for use as a biomarker for evaluating a candidate anticancer agent under certain circumstances, especially given the dearth of cancer biomarkers.
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for stroke based on [its] effect on blood pressure." Thus, he concluded, in the utilization step, one takes "the totality of the data from the analytical validation and the critically important qualification steps into a real-world setting to [ask]
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This viewpoint prompted considerable discussion. Presenter Stephen Williams, chief medical officer of SomaLogic, Inc., noted that analytical validation and qualification of biomarkers can always be improved, and the consequences of error are uncertain, and asked, "how good is good enough?
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Ness introduced the committee's ancillary recommendations intended to support the implementation of the biomarker evaluation framework across all areas regulated by the FDA (see Recommendations 5 and 6 in Box 2-1)
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The committee determined that surveillance of biomarker-based food health claims is needed, she said, because it is important to understand the impact of the actual foodstuffs on consumers. "When surrogate endpoints are used in product or claim approvals, data collection is needed to link the product or claim to health outcomes experienced by patients and consumers, whether for drugs, biologics, devices, foods, or supplements," she said.
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From page 25... ...
," Dr. Ball concluded, "but at the same time … when a claim is made on the basis of surrogate endpoints, there needs to be follow-up, because there can be unintended consequences of the claim." Given the committee's position regarding the need for studies of food health claims based on surrogate endpoints, audience member Chor San Khoo, vice president of global nutrition and health at Campbell Soup Company, Inc., wondered whether the committee would recommend similar evaluation of diets.
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This tendency has been reflected in research that further suggests that consumers have difficulty distinguishing among the various evidentiary levels of health claims on food labels and understanding the qualifying language that these claims frequently contain. The committee therefore concluded that the FDA needs the authority to request and require studies of consumer understanding and to make changes or remove claims that are misunderstood by consumers.
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From page 27... ...
To this end, she noted that the FDA has been building a program known as the Sentinel Initiative,3 a national electronic system for the postmarket safety tracking of drugs, biologics, medical devices, and eventually, all FDA-regulated products. She observed that ClinicalTrials.gov, which provides publicly accessible information about clinical trials, could provide "important guidance for biomarker data collection efforts" as well.
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