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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary 6 Public Health, Consumer, and Consulting Organization Perspectives Speakers from the American Dietetic Association (ADA), the Center for Science in the Public Interest (CSPI), and Johnson Nutrition Solutions, LLC, discussed their views on the committee’s recommendations and report. These speakers were also asked to answer the same series of questions posed to representatives from stakeholder industries: How do biomarkers affect patients, consumers, or clients in your industry stakeholder group? How does the recommended biomarker evaluation framework relate to biomarker evaluation processes currently in use with your industry or stakeholder? Will a prospective biomarker evaluation process add clarity to product development and consumer understanding? To the degree it is possible to respond, if at all, what are your key concerns for implementation of the recommendations? To the degree it is possible to respond, if at all, which recommendations of the report are the most useful or important? PRESENTATION BY GUY JOHNSON, JOHNSON NUTRITION SOLUTIONS, LLC Guy Johnson said that his remarks did not represent any specific group but derived from his extensive experience with biomarkers as applied in such contexts as health claim substantiation.
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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary He began by stating that the report outlines clearly “all of the factors and potential pitfalls” involved in determining what he called a “rock star biomarker.” Calling the three-step framework comprehensive, Dr. Johnson agreed that biomarker use demands analytical rigor, and he assessed the qualification phase as feasible based on prospective epidemiological studies. However, he added, “the rub comes in determining the clinical outcome of an intervention where you change just the biomarker and nothing else, and then wait to see what happens in a group of healthy people.” The report conveys the message that there are no shortcuts to a surrogate endpoint, he said. Nevertheless, Dr. Johnson emphasized that biomarkers offer an important means to communicate useful information to companies and other organizations and to inform research. He expressed hope that the report can be used to “provide some structure around how that information can be communicated.” Such communication could happen during the utilization step, by distinguishing between predictive biomarkers, for which there is evidence of an association with a clinical endpoint (for example, C-reactive protein [CRP]) that could be used to inform less rigorous claims, from probable biomarkers for which validity is clearly established. “It is possible that there could be some kind of regulatory language that would allow information on those less-than-rock-star biomarkers to be communicated,” he suggested. “I don’t think the committee’s intent was to tell clinicians they can’t measure CRP because it hasn’t been fully established as a biomarker,” he said; rather, there need to be guidelines for how to make use of information from biomarkers that are not surrogate endpoints. “That’s where I think the real opportunity of this report is,” he said. Having the same standards of scientific rigor for biomarkers used in foods and drugs makes perfect sense, Dr. Johnson said. However, there are inherent differences between the process one might use to determine the effect of a food on a biomarker and the effect of a drug on the same biomarker. For example, he continued, “it’s tough to do a randomized double-blind placebo-controlled trial with pomegranate juice [so that] … people don’t know that they are eating it.” The report presents an opportunity to communicate information to consumers, as do biomarkers themselves, Dr. Johnson said. “Frankly, there’s a danger in not communicating information to consumers,” he said. On the other hand, he hoped that the report was not viewed as the “kiss of death” for a variety of biomarkers, such as low-density lipoprotein cholesterol (LDL-C). Dr. Johnson also asked, in light of the report’s recommendations, whether the Food and Drug Administration (FDA) would need to convene a panel to examine the blood pressure/sodium biomarker. “There are no clinical trials that show that reducing sodium, and therefore blood
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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary pressure, in the population results in a clinical benefit,” he said, “and there are suggestions that there could be unanticipated consequences [of sodium level reduction]. So if you apply the standards in this report, somebody has to take a look at that in a very rigorous way.” PRESENTATION BY MARY HAGER, AMERICAN DIETETIC ASSOCIATION Mary Hager, director of regulatory affairs at the ADA, presented the association’s viewpoints on the report. She noted that the ADA has more than 70,000 members, the majority of whom are registered dieticians who work in facilities and outpatient care. Biomarkers are part of the process by which these professionals make recommendations for changes in dietary regimens. In addition, registered dieticians also conduct research on nutrition, provide consumer education, and monitor the nation’s health through such programs as the NHANES. The ADA is known for its innovative evidence analysis library and for its systematic review of the literature, the results of which are archived transparently, she said. Nutritional intake and health status relate to chronic disease in terms of risk and disease progression, Dr. Hager stated. The ADA “recognizes that validated biomarkers are important to identifying estimates of optimal dietary nutrient needs and are important in determining dietary reference intakes,” she said. In the past, when food was in shorter supply, research was conducted on the effects of an exposure to a nutrient in hopes of eliminating deficiency diseases, she explained. The abundance of calories in the current American diet does not guarantee nutrient sufficiency, let alone the optimal or ideal intake of particular nutrients, she said. “Biomarkers of nutritional status as they relate to health are very important, and understanding the interplay between the nutrient intake and the development and progression of these chronic diseases is very important for individuals and consumers at large,” Dr. Hager emphasized. For these reasons, the ADA supports the committee’s recommendation that the FDA employ the same degree of scientific rigor in evaluating biomarkers across all of its regulatory areas. “Knowing with confidence the effect of a nutrient on an individual’s or a population’s risk for a disease or nutrition disorder would allow for more effective interventions,” she said. Dr. Hager also raised a topic of concern for the ADA regarding the use of genetic biomarkers in tests that she said she believed “are probably not approved or reviewed, and are … being used by individuals and by consumers … to diagnose allergies or disease.” This phenomenon concerns many health care practitioners who are ADA members, she said, and expressed hope that the FDA “can have the authority to vali-
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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary date and enforce surveillance of these … so-called diagnostic kits in the marketplace.” “I believe, and so do most of our members, that consumers will greatly benefit from the FDA having improved authority to test and to require valid data to support health claims, resulting in enhanced consumer confidence in selecting products that are best suited for their individual needs,” Dr. Hager said. Regarding the committee’s recommendations to this effect, she (like several other speakers) expressed concern that the necessary research would be difficult to fund, given thin profit margins associated with nutrients and foods as compared with pharmaceuticals. She also noted that the FDA will have to obtain “additional legal authority to request studies and sufficient authority to act on the results of the stud[ies] related to consumer understanding of claims on foods and dietary supplements.” PRESENTATION BY ILENE HELLER, CENTER FOR SCIENCE IN THE PUBLIC INTEREST Ilene Heller, senior staff attorney at the Center for Science in the Public Interest, emphasized the importance of scientifically valid information on food labels that allow consumers to choose healthy foods and reduce their risk of diet-related diseases. According to Ms. Heller, the lack of consistent, reliable information on food labels necessitates more stringent standards for all health-related claims on foods. “For consumers, the most important recommendations to come out of the … report are the need for all health-related claims to be based on stringent standards and allowing claims to appear only on products that are part of a healthy diet,” she observed. Ms. Heller described three categories of health-related claims: authorized health claims, which require significant scientific agreement; qualified health claims, which are based on credible evidence; and structure–function claims, which merely associate a nutrient contained in the food with a health benefit. Health claims are the gold standard, Ms. Heller said. “They require notice and comment rulemaking,” she noted, and the foods to which they apply must contain a minimum level of nutrients prior to fortification (which is known as the “Jelly Bean Rule,” because you can’t fortify a jelly bean and call it healthy). Foods with health claims cannot exceed disqualifying levels for nutrients that need to be limited, such as sodium, cholesterol, or fat, and the health claims “must state that a disease depends on many factors, and that the nutrient must be eaten as part of a healthy diet.” Some health claims state how much nutrient is needed to achieve the purported benefit, as well as how much of that nutrient is present in the food.
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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary According to Ms. Heller, a problem that is occurring with increasing frequency—as typified by the Cheerios box that figured prominently in workshop discussion—is that health claims are being overshadowed by lesser claims (for example structure–function and qualified health claims) displayed in large print on the front of packages. Since 2003, qualified health claims—a category originally applied only to dietary supplements—has been used for foods that attain the standard of credible evidence, said Ms. Heller. “Qualified health claims can even be made when the FDA thinks such claims are unlikely to be valid,” she noted. For example, she quoted the language of the qualified health claim for green tea and cancer that was accepted by the Center for Food Safety and Applied Nutrition (CFSAN): “Two studies do not show that drinking green tea reduces the risk of breast cancer in women, but one weaker, more limited study suggests that drinking green tea may reduce this risk. Based on these studies, FDA concludes that it is highly unlikely that green tea reduces the risk of breast cancer” (FDA, 2009). Qualified health claims are “pretty clumsy” and therefore not widely used on food labels—except for nearly half of all nuts—but they do “stimulate misleading advertising and public relations campaigns,” said Ms. Heller. She also noted the results of two FDA studies conducted in 2005 and 2007 (which CSPI obtained by filing a Freedom of Information Act petition) suggested that consumers cannot distinguish between qualified health claims and “gold standard” health claims. The most prolific type of health-related claim is the structure–function claim, Ms. Heller said. “That is not surprising … it is short and sweet, and it doesn’t mention a disease. It is a lot more interesting for consumers and a lot more pleasant to see it on a cereal box than talk of cancer and heart disease.” Moreover, no prior approval is needed to make such claims, nor do they require minimum or maximum nutrient levels. Often, if a company cannot make a qualified health claim for a product because it has too much fat, they make a structure–function claim instead,” she observed. While structure–function claims for foods cannot be false or misleading, the FDA has admitted to the Government Accountability Office (GAO) that the agency can’t prosecute breaches of structure–function claims because it lacks resources for conducting research necessary to mount such a legal challenge (GAO, 2000), Ms. Heller said. However, the City of San Francisco successfully challenged a false immunity claim displayed on Cocoa Krispies boxes, as did the Federal Trade Commission, while the FDA did not. Recently, the FDA sent a warning letter to the makers of Juicy Juice regarding its structure–function claim linking docosahexaenoic acid (DHA, an omega-3 fatty acid) with brain health, she said, but only on the grounds that such claims cannot be made on products marketed to children under 2 years of age.
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Perspectives on Biomarker and Surrogate Endpoint Evaluation: Discussion Forum Summary CSPI’s conclusions regarding these matters are simple, Ms. Heller said: “Consumers can’t tell one type of claim from another. Therefore, the same evidentiary and eligibility standards should apply to all categories of claims.” To those who would argue that it would be too difficult to change the standards for all claims, she insisted this was not the case. “It is not going to be burdensome at all,” she said. “There are well-established claims, like ‘calcium builds strong bones,’ that could form a category of claims to be included in a safe harbor or a positive list, as it is known in the European Union.” In addition, health claims could be rephrased as structure–function claims, provided structure–function claims meet the minimum and maximum nutrient levels currently demanded by health claims. The FDA could also consider the structure–function claims approved by the European Food Safety Authority, she added. While CSPI delivered these recommendations to the FDA in 2008 and 2009, she said, the agency has yet to take action on them. CSPI’s recommendations are consistent with the committee’s Recommendations 3 and 4, Ms. Heller noted, “because they are based on the premise that all claims should be based on stringent scientific standards and should only appear on products that are part of a healthful diet.”