The landscape for nutritional products has changed dramatically over the past few years. Consumers are attuned to and taking more responsibility for their healthcare. A driver of this change is a more educated consumer with higher expectations.

Healthcare practitioners are also supporting nutritional interventions for many health issues. The importance of meaningful claims supported by strong clinical research has never been higher. The development of new products must be attuned to the new marketplace. The first step in this process is to help optimize product positioning and targeted indication(s). The goal is to refine product claims backed with clinical substantiation.

Regulatory Categories, Claims & Substantiation 
The following section summarizes U.S. regulatory requirements for the types of claims and required substantiation. The Federal Food and Drug Administration (FDA) identifies four types of food products for which claims can be made:

• Conventional food
• Dietary supplements
• Food for special dietary uses
• Medical foods

This is the FDA definition of conventional foods: “Items used for food or drink or components of any of these items (i.e., food ingredients, food additives, GRAS substances, and processing aids),” (§ 201(f) of the FFDCA [21 USC § 321(f)]).

The FDA defines dietary supplements as items that are, “intended to supplement the diet and contain[s] one or more of the following: a vitamin; mineral; herb or other botanical; amino acid; dietary substance for use to supplement the diet by increasing total dietary intake; or a concentrate, metabolite, constituent, extract or combination of any the aforementioned; is intended for ingestion as a tablet, capsule, powder, softgel, gelcap, or liquid form, or if not intended for ingestion in such a form, is not represented as conventional food and is not represented for use as a sole diet,” (21 U.S.C. §321(ff).

Both structure/function and health claims can be made for conventional food (with restrictions) and dietary supplements. Structure/function claims define how the compound affects the structure or function of the human body or characterize the documented mechanism by which the nutrient acts to maintain such structure or function. But structure/function claims must not claim to “diagnose, mitigate, treat, cure, or prevent a specific disease or class of diseases,” (21 U.S.C.A. § 343).

Health claims describe the relationship between a compound and reduced risk of a disease or health-related condition. The FDA must approve a health claim by regulation or an agency letter.

Foods for special dietary use (FSDU) are included within the category of conventional foods. This subcategory includes the use of food to fulfill a dietary need that exists due to any of the following: “A physical, physiologic, pathologic, or other condition including, but not limited to, diseases, convalescence, pregnancy, lactation, allergen hypersensitivity, underweight, or overweight, age, and used for supplementing or fortifying the ordinary or usual diet with any vitamin, mineral, or other dietary property, and are intended for persons who otherwise can consume a normal diet containing a normal range of nutrient intakes to meet their physiological needs,” [Title 21 Code of Federal Regulations (21 CFR) § 105.3]. Foods for special dietary use do not require the supervision of a physician.

Medical foods, unlike FSDU, must be used under the supervision of a physician. Medical foods are specifically defined and constrained by the following mandated conditions:

• “… specially formulated and processed product (as opposed to a naturally occurring foodstuff used in its natural state) for the partial or exclusive feeding of a patient by means of oral intake or enteral feeding by tube”;
• “… intended for the dietary management of a patient who, because of therapeutic or chronic medical needs, has limited or impaired capacity to ingest, digest, absorb or metabolize ordinary foodstuffs or certain nutrients, or who has other special medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone”;
• “… provides nutritional support specifically modified for the management of the unique nutrient needs that result from the specific disease or condition, as determined by medical evaluation”; and are
• “… intended to be used under medical supervision.”

The concept of distinctive nutritional requirements is integral to the definition of medical foods. Distinctive is interpreted as the difference in requirements, expressed in grams/day, between the normal healthy physiological state and the disease state or condition (21 U.S.C. 360ee (b) (3)).  

Safety and Quality
Safety and quality standards for a product are also critical to consumers, practitioners, and regulatory agencies. The FDA requires that food ingredients are:

• Approved by the FDA as a food additive or color additive;
• Be prior sanctioned by the regulatory agency; or
• Be Generally Recognized As Safe (GRAS) either by the FDA or self-determined by a panel of experts qualified by training and experience (21 CFR 170). 

A dossier regarding the safety of the ingredients, separate from the review of regulatory requirements and product claims, should be prepared prior to commercial introduction of any new ingredients.

A supplement is considered safe if it does not present a significant or unreasonable risk of illness or injury under conditions of use recommended or suggested in labeling, or under ordinary conditions of use (21 U.S.C. §342, 21 CFR 190.6).

Historically, the determination of safety for both food and supplement ingredients has been achieved through GRAS determinations. The GRAS self-affirmation process can be used for determining the safety and regulatory acceptability of food ingredients and for determining safe use of supplement ingredients.

Regarding dietary ingredient intake, the standard of safety in the Dietary Supplement Health and Education Act (DSHEA) is linked to the conditions of use listed in the supplement labeling. On the other hand, the common use procedure employed in GRAS determinations are like those used to support New Dietary Ingredient (NDI) use. However, GRAS determination uses the common use approach (the ingredients must have been used before 1958), whereas the FDA considers daily, chronic use (in large population groups) for a period of 25 years or more as a qualification for a history of safe use, thus supporting the safety of the NDI in supplements. DSHEA directs the FDA to consider history of use and actual product use (as defined in labeling).

As defined in 21 CFR §170.3, the eligibility for classification as GRAS can be determined through two approaches: scientific procedures and/or common use.  

The scientific procedures approach requires the same quantity and quality of evidence as that required for a food additive petition. The common use approach is used for substances with a widespread history of use in food prior to Jan. 1, 1958, through experience based on common use in food (21 CFR 170.30).

Supporting Strong Claims
Claims that address unmet needs and have high potential for regulatory approval are more likely to achieve commercial success. This is not limited to any one regulatory category; however, a major benefit of products classified as medical foods is that they are permitted to make claims for the dietary management of a disease/health condition. Medical food claims are said to lend significant credibility to products, specifically in the health practitioner channel.

Products designated as medical foods are also often distributed through healthcare institutions and recommended by practitioners because the designation allows a pathway for third-party reimbursement. Among other requirements, the FDA requires that a product meet the following three characteristics to be categorized as a medical food:

1. Is the product Generally Recognized As Safe (GRAS)? GRAS status depends either on a long history of safe use or self-affirmation of GRAS status based on use, usual intake, and target population, based on availability of accepted scientific data agreed on by a panel of experts.
2. Is there a scientifically recognized distinct nutritional requirement (DNR)? A DNR is a proven clinical need for a specific nutritional intake different from that provided by the intake of healthy populations, A DNR arises from abnormal physiology imposed by a disease or condition. Thus, if clinical research on a product has an endpoint that demonstrates a therapeutic benefit, it is likely considered a drug. This criterion is often the major hurdle preventing a product from obtaining medical food status.
3. Are claims for the product supported by sufficient credible research? Claims must be supported with findings from well designed and executed preclinical and clinical trials. It is commonly accepted that the scientific studies supporting medical food claims be more rigorous in demonstrating the need for distinctive nutritional requirements that cannot be met by modifying the diet alone, although the FDA has not yet specified this in writing.

Preclinical research is done in vitro and in vivo to show proof of principle, mechanism of action, and to provide a foundation on which to base larger studies. Clinical research assessing outcomes is ideally done with the product in question in the intended population. At the very least, human trial results are needed for the ingredient in question.

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About the Author: Greg Stephens, RD, is president of Windrose Partners, a company serving clients in the the dietary supplement, functional food and natural product industries. Formerly vice president of strategic consulting with The Natural Marketing Institute (NMI) and Vice President of Sales and Marketing for Nurture, Inc (OatVantage), he has 25 years of specialized expertise in the nutritional and pharmaceutical industries. His prior experience includes a progressive series of senior management positions with Abbott Nutrition (Ross Products Division of Abbott Laboratories), including development of global nutrition strategies for disease-specific growth platforms and business development for Abbott’s medical foods portfolio. He can be reached at 267-432-2696; E-mail: gregstephens@windrosepartners.com.