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Critical Markers for Healthy Endpoints

Healthy diets, unhealthy lipid levels, heart-healthy foods … these are some of the myriad descriptors associated with food products and lifestyles that attempt to communicate evidence-based outcomes which suggest improved health. In the world of regulations, “healthy” refers to five fundamental criteria. These criteria are based on total fat, saturated fat, cholesterol, sodium, and specific nutrient (vitamin A, vitamin C, calcium, iron, protein, and fiber) content. Yet, there remains confusion among the general public who purchase and consume these foods, as well as clinicians, dietitians, nutritionists, food scientists, and food technologists involved with clinical evaluation, recommendations, and design of foods that meet specific “healthy” guidelines. Food manufacturers, in their attempt to gain a “healthy” edge, often launch products that tout unauthorized health claims, unauthorized nutrient content claims, and unauthorized use of this word “healthy.” Yet, many companies provide legitimate, strong evidence that support their “healthy” position, despite current regulatory restrictions. At the same time, front-of-package labeling has received considerable attention by regulatory agencies, and the Institute of Medicine (see HR 1105; the Omnibus Appropriations Act of 2009).

For nearly two decades, clinically-relevant biomarkers or indicators of normal biological or pathogenic processes have been narrowly accepted. The most common of these are LDL-cholesterol, HDL-cholesterol, and blood pressure. Surrogate biomarkers, such as C-reactive protein (inflammation), flow mediated dilatation (possible through some polyphenols), and prostate specific antigen (indicator of prostate “health” status) have not been permitted, at least as part of the communication to potential health benefits of a food or food components.

On May 12, 2010, the Institute of Medicine released an important report entitled, “Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.” The development of this report reflects many years of clinical investigations and hundreds of food health claims that included clinical endpoints other than those currently accepted by the FDA. In an attempt to evaluate biomarkers, numerous experts, agencies, and committees convened to examine the strength of the evidence or the absence thereof.

This 267-page, five-chapter report discusses the framework of potential biomarker assessment, including analytical validation, qualification, and utilization and their regulatory implications. While these are important steps, the regulatory impact of identified biomarkers was deferred to another expert panel, and the practical application of these biomarkers will be addressed on a case-by-case basis.

Citing many examples of surrogate biomarkers, challenges include an improved understanding of normal biodiversity and inconsistent responses within the population, and the clinical significance of the proposed indicators of health. For example, as noted by Clemens and Pressman in their October 2005 Food, Medicine & Health column and reinforced in this IOM report, C-reactive protein is a non-specific marker of acute systemic inflammation. Of course, there are many other inflammatory reactants, such as cytokines, high-sensitivity CRP, and serum amyloid A, that deserve consideration, the usefulness of which depends on the quality steps previously mentioned. Critical to these assessments is our understanding of CRP in the disease processes, particularly its role in the progressive complexities of cardiovascular disease (CVD). The inconsistencies of CRP levels among populations presenting CVD cast doubt to their clinical relevance as a clinical endpoint, practical predictor of disease risk, useful biomarker, and to a lesser degree, as an indicator for rulemaking. Similar assessments of β-carotene keep the utilitarian application of serum levels of this vegetable-derived carotenoid for disease risk reduction in question.

The validation, qualification, and utilization of surrogate biomarkers have their foundation in clinical investigations, most of which were associated with pharmacological interventions. In January 2008, Clemens and Pressman commented that the food industry, in its effort to provide more-healthful choices in the functional foods arena, must consider more illuminating biomarkers that punctuate the much larger and exquisitely complex constellation of factors representing our emerging knowledge of the progression of disease states. The 2010 IOM report provides an important framework for biomarkers and surrogate clinical endpoints upon which the food industry, in collaboration with research organizations, can validate and qualify useful and credible biomarkers of disease risk reduction through foods, food components, and lifestyle. These efforts will assist in substantiating persuasive health claims for the future.

Roger ClemensRoger Clemens
Associate Director, Regulatory Science
University of Southern California

One Response

  1. Very useful information and comment. Thanks Roger.

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