Medical Foods: Creating a Successful GRAS Notification

Photo © iStockphoto.com/Imre Cikajlo, edited by Quinn Williams

By Ginny Bank and Cheryl Dicks, MS, RAC, GRAS Associates

Medical food is a growing specialty product category that gives food and dietary supplement manufacturers interesting business opportunities for expanding the market of an ingredient or final product. But marketing a medical food is not always simple given the “gray zone” of FDA regulation and guidance for medical foods. In addition, marketers in general are often confused over what separates a medical food from a conventional food.

First off, medical foods must comply with all applicable food-manufacturing requirements. Ingredients used in medical foods must be Generally Recognized as Safe (GRAS) as approved food additives, or, if the ingredients are not already GRAS affirmed, they must be the subject of exemption for investigational use (21 U.S.C. 321 and 348). If your ingredient has already completed a FDA GRAS notification for conventional foods and you would like to add medical foods as an intended use, you may submit an amendment to the original GRAS dossier to cover its use in medical foods. Many GRAS notifications include both conventional foods and medical foods as their intended use.

What is the best way to ensure a GRAS notification for an ingredient’s use in medical foods will receive a “No Questions” letter from FDA? One way is to better understand FDA’s viewpoint of medical foods by reviewing GRAS notifications for which the agency has already issued “No Questions” responses. Ahead, we take a look at some of these notifications and how the notifiers describe their ingredient’s use in medical foods.

FDA Medical Foods Regulation Overview

It is first helpful to understand what a medical food is. A “medical food” is defined in section 5(b)(3) of the 1988 Orphan Drug Act (ODA) (21 U.S.C. 360ee(b)(3)). The definition is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation.”

In 2013, FDA published a revised version of its 2007 draft guidance for medical foods, Draft Guidance for Industry: Frequently Asked Questions about Medical Foods, Second Edition. Following that, FDA recently published Final Guidance on Frequently Asked Questions about Medical Foods. This guidance reflects FDA’s viewpoint that the statutory definition of medical food is narrowly constrained to the types of products that fit within this category of food. According to the final guidance, a medical food:

• Provides distinctive nutritional requirements not met by alteration to normal diet
• Can be food intended for persons not able to ingest food in certain physical forms (i.e., partial or exclusive oral intake or enteral tube feeding)
• Is an integral part of the patient’s clinical management under medical supervision
• Is intended for the “specific dietary management” of a disease or condition
• Is a food that is processed or specially formulated and not in its “natural” state

Among industry, there is still much confusion around what type of food or dietary ingredient qualifies as a medical food. It is important to note that medical foods are not foods used in their “natural state,” nor are they dietary supplements simply recommended by a physician as part of an overall diet to manage the symptoms or reduce the risk of a disease or condition. What’s more, not all foods fed to sick patients are medical foods. Medical foods are foods that are specially formulated and processed for a patient who is seriously ill or who requires use of the product for dietary management that cannot be achieved by changes to a normal diet.

GRAS Notifications and Medical Foods

A number of companies have notified FDA of GRAS determinations for ingredients with an intended use in medical foods. A summary of these ingredients can be found here. Our review investigated whether these GRAS notifications treated the intended use of an ingredient in medical foods differently than the ingredient’s intended use in conventional foods.

One thing we looked at is how specifically these notifications described just how an ingredient would be used in a medical food. While some GRAS notifications definitively outlined the intended use of an ingredient in medical foods, others did not. All of the notifications described herein reflect notifications that received “No Questions” letters from FDA.

Getting Specific about Medical Foods

Here are some GRAS notifications that made more-specific mentions of their ingredient’s intended uses within the medical foods framework.

A GRAS notification for the use of palm oil–derived carotenoids¹ noted a specific medical food use for the treatment of erythropoietic protoporphyria, a metabolic disorder that can manifest in
skin hypersensitivity.

The medical food use of selenium² received a “No Questions” response from FDA for use to “facilitate avoidance of selenium deficiency to this essential micronutrient.” The notification proposed that the medical food uses would replace 20 servings per day of traditional foods and further noted that the medical food use is to be under the supervision of a physician and that intake of the ingredient would be monitored to ensure safe use.

A second notification for selenium³ also described the use of medical foods as a supplement to the typical diet (when the medical food is not the sole source of the diet). This notification added that because medical foods are administered under physician supervision, it is “likely that the physician is cognizant of the need for adequate amounts of selenium and the possible overdosing of selenium and, therefore, will advise the patient to avoid other dietary sources rich in selenium.” In addition, the submission included a detailed description of the definition and categories of medical foods, as well as medical conditions for which medical foods are used (renal disease, hypermetabolic states, and malabsorption). Although the notifier did not specifically state that the ingredient would be used in medical foods to treat these conditions, this is certainly inferred.

GRAS notifications for dietary sources of omega-3 fatty acids DHA and EPA, including krill oil⁴, phosphatidylserine from fish⁵, and phosphatidylserine from krill⁶, pointedly separated medical food uses from the other food categories by noting a much higher dosage rate if used in medical foods, and  including a brief definition of the Orphan Drug Act.

A GRAS notification for long-chain inulin⁷ likewise provided a very detailed intended-use description for medical foods. The notifier indicated that the intended uses for this long-chain inulin do not include conventional foods; only medical foods and infant and toddler formulas. This submission noted that medical foods are used under physician supervision as supplemental or sole source of nutrition for those “who are unable to ingest sufficient nutrition from conventional foods.” Medical food uses included nutritionally incomplete oral products, nutritionally complete oral products, tube feedings, and pediatric nutritionals. Each of these categories was described in detail, with examples of conditions the medical food addressed.

Less Specific

On the other end of the spectrum, some GRAS notifications did not directly state the intended use and usage levels of their ingredient in medical foods; instead, they alluded to medical food use by referencing all or some part of the medical food definition.

For example, although some GRAS notifications for dietary fiber provided very little detail about the ingredient’s specific use in medical foods and did not discuss the difference between the ingredient’s intended use in medical foods versus conventional foods, they did allude to medical food use by pointing out that applications in medical food are monitored by the healthcare provider, or they “estimated” the use rate of medical foods based on the number of average servings of a medical food.

Whether submitted to FDA or done via self-determination, a GRAS notification should clearly define the intended use and use levels in a medical food.

FDA: Few Mentions of Medical Food Except in Warning Letters

As mentioned, all of the GRAS notifications described previously did receive “No Objections” letters from FDA. How specific does FDA itself get when referring to medical foods in GRAS responses?

In fact, FDA made little mention of medical foods when responding to these notifications. In its response letters to these GRAS notifications, FDA made no reference to medical foods other than to include a detailed definition of a medical food per the Orphan Drug Act.

What’s more, FDA said the agency’s response had no bearing on whether a finished product would legally be considered a medical food. As the letters stated, FDA’s response “does not address the question of whether any particular food product that contains (the ingredient name) would be a medical food within the meaning of section 5(b) of the Orphan Drug Act, and thus would be exempt from the requirements for nutritional labeling, nutrient content claims, and health claims.” Rather, it is up to marketers to correctly sell these products within the confines of medical food regulations.

In warning letters, however, FDA did provide some insight on when products are not considered medical foods. A search of FDA warning letters using the term medical foods returned 10 letters sent between 2006 and 2013. Most of these warning letters appear to have been sent because companies were attempting to market products that are clearly dietary supplements as medical foods.

In each letter, FDA informed each manufacturer that its product was misbranded. “Because these products are intended to support diseases or conditions that do not have distinct requirements for certain nutrients, these products do not meet the statutory definition or regulatory criterion for medical foods set forth in 21 CFR 101.9(j)(8)(ii),” it said. In addition, FDA informed manufacturers that because they were making disease claims, their products were also considered “new unapproved drugs.” FDA then requested prompt action to correct the violations.

Industry Takeaways

Despite haziness around the regulations for medical foods, marketers can glean some key insight about what FDA views as permissible for medical foods based on the agency’s “No Objections” to GRAS notifications as well as its warning letters.

First and foremost, it is clear that it would be difficult for any ingredient that is not a well-recognized nutrient to get through the notification process unless it has very specific use for a condition as defined in the Orphan Drug Act and meets the criteria FDA laid out in the revised guidance.

While some GRAS notifications supplied very little detail on the use of the ingredient in medical foods, most included some simple elements to assure FDA that the notifier is aware that the use of the ingredient in medical foods requires meeting certain requirements. We recommend that the following elements be included in any GRAS notification for use in medical foods:

• Detailed definition of medical foods as per the Orphan Drug Act
   
• A separate calculation of estimated dietary exposure in medical foods. This provides additional evidence that the manufacturer perceives the use of the ingredient in medical food as either a replacement of conventional food servings and/or for use by only a small population of individuals (e.g., those with genetic disorders)
   
• Convey awareness that medical foods require physician supervision, which helps eliminate concerns of exceeding maximum use levels
   
• A statement that the intended use of the ingredient in medical foods will follow all applicable regulations
   
• In cases in which a deficiency of the nutrient ingredient causes no specific disease or syndrome, a statement that the ingredient will be used only in foods already determined to be medical foods

It is also important to have on hand substantial clinical support to demonstrate the efficacy and nutrient requirement of the medical food use through the “gold standard” of clinical trials (double-blind, randomized trials) that address nutrient deficiency and effect on targeted disease. This information should be part of a comprehensive product-development plan, creating a synergistic strategy for market placement and regulatory compliance for your medical food.

References:

[1] GRN 320

[2] GRN 260

[3] GRN 353

[4] GRN 242 and GRN 371

[5] GRN 279

[6] GRN 311

Ready to seek GRAS status for your medical food ingredient? Ginny Bank (associate) and Cheryl Dicks (senior regulatory affairs scientist) support GRAS Associates (Bonita Springs, FL), which has extensive experience in medical food compliance, as well as the submission of GRAS notifications to the FDA.

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