FDA has recently issued two different guidance documents for medical foods in an attempt to stem the flow of these foods, which are perceived by FDA as increasingly being used to circumvent drug-into-food prohibition and to market foods with claims. The first (issued in August 2013) is the second edition of the May 2007 draft guidance document “Guidance for Industry: Frequently Asked Questions About Medical Foods” and the other (issued in September 2013) is “Guidance for Clinical Investigators, Sponsors and IRBs: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND.” Clearly, some guidance is necessary, due to the fact that the medical food category has expanded to include foods that might not meet the original intent of the category. However, FDA has overshot its mark with unrealistic restrictions on medical foods and, essentially raising the bar too high for most substances to qualify. As discussed below, the new guidance is an attempt by FDA to turn back to the clock to before 1972, when medical foods were regulated as drugs.
History of the Definition of Medical Food
Before 1972, FDA regulated products that meet the current definition of medical foods (e.g., Lofenolac, an infant formula for the dietary management of phenylketonuria) as drugs (under 201-G1B of the Federal Food, Drug, and Cosmetic Act [21 USC 321-G1B]) because of their role in mitigating serious adverse effects of the underlying disease. In 1972 FDA stated that Lofenolac would no longer be regulated as a drug, but rather as a “food for special dietary use” (37 FR 18229 to 18230; September 8, 1972), a term that was legally defined in 1977 under 21 CFR § 105.3. Three types of foods meet the regulatory definition of a food for special dietary use: (a) foods used for supplying particular dietary needs that exist by reason of physical, physiological, pathological, or other conditions, including (but not limited to) the condition of disease, convalescence, pregnancy, lactation, allergic hypersensitivity to food, underweight, and overweight; (b) foods used for supplying particular dietary needs that exist by reason of age, including (but not limited to) the ages of infancy and childhood; and (c) foods used for supplementing or fortifying the ordinary or usual diet with any vitamin, mineral, or other dietary property. Therefore, in 1977, foods for special dietary uses included dietary supplements, foods for use in people with inborn errors of metabolism or physical limitations (e.g. inability to swallow), and infant formula. While medical foods, infant formula and dietary supplements have been carved away from the “food for special dietary use” category, the category has not been eliminated by regulation.
Medical foods became an individual category of foods in 1988, when they were defined by Congress within section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) as “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.” It has been hypothesized that the definition appeared within the Orphan Drug Act because medical foods were considered “orphans” which were used to treat rare disorders affecting less than 200,000 individuals in the United States. As Congress wanted to encourage the development of medical foods beyond “orphan” status, they incorporated “medical foods” into the Nutrition Labeling Education Act of 1990 (NLEA) and exempted them from nutrition labeling, health claim prior approval requirements, and nutrient content claim requirements applicable to conventional foods. Prior to publication of the final labeling rule, FDA advised Congress to provide a statutory definition for medical foods to “narrowly constrain the types of products that can be considered to fall within this exemption”. The final rule on mandatory nutrition labeling incorporated the following statutory definition of a medical food into FDA’s regulations at 21 CFR 101.9(j)(8)):
(i) It is a 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;
(ii) It is 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;
(iii) It 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;
(iv) It is intended to be used under medical supervision; and
(v) It is intended only for a patient receiving active and ongoing medical supervision wherein the patient requires medical care on a recurring basis for, among other things, instructions on the use of the medical food.
Historically, unsubstantiated claims were allowed for medical foods because they were generally limited to ease of administration (e.g., by a nasogastric tube) or for rare diseases or conditions with distinctive nutritional requirements conditions managed by physicians. The more relaxed requirements for medical foods under the Orphan Drug Act were being permitted by FDA, rather than the more stringent requirements of 21 CFR 101.9(j)(8)). Fast forward to present day, where medical foods are increasingly being marketed to help treat or prevent diseases that do not have distinctive nutritional requirements. Conditions for which medical foods have been promoted include Alzheimer’s disease, epilepsy, osteoporosis, viral infections, lower back pain, chronic fatigue syndrome, fibromyalgia, leaky gut syndrome, metabolic syndrome, cardiovascular disease, inflammatory bowel disease, type 2 diabetes, peripheral artery disease , bariatric surgery, eczema, rhinitis, and asthma.
Updated FDA Guidance on Medical Foods
The updated draft “Guidance for Industry: Frequently Asked Questions About Medical Foods” provides more clarity about what FDA currently considers a medical food. FDA has melded the definition of medical food as defined in section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)) with the definition as defined in 21 CFR 101.9(j)(8), to emphasize that a medical food is a food that is formulated to be consumed or administered enterally under the supervision of a physician and 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 (from the Orphan Drug Act) for a patient who, because of therapeutic or chronic medical needs, has a 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 (from 21 CFR 101.9(j)(8)(ii)). FDA is enforcing the new guidance as evidenced by the disallowance on August 13, 2013 of 14 Metagenics products as medical foods.
It is clear that some medical food manufacturers market their products for dietary management of disease or conditions that do not have distinct nutritional requirements. For every one of the Metagenics products considered as violative, FDA stated: “FDA is not aware of any distinctive nutritional requirement for patients with (disease name), nor is FDA aware of any evidence that patients with (disease name) have a limited or impaired capacity to ingest, digest, absorb, or metabolize any specific nutrients.” From the Metagenics warning letter, it is obvious that FDA also does not consider chronic fatigue syndrome, fibromyalgia, leaky gut syndrome, metabolic syndrome, cardiovascular disease, inflammatory bowel disease, bariatric surgery, peripheral artery disease, eczema, rhinitis or allergy-responsive asthma to be diseases for which there are distinct nutritional requirements. FDA also does not consider diabetes, pregnancy or diseases resulting from essential nutrient deficiencies (e.g., scurvy, pellagra) to be diseases for which a medical food could be labeled and marketed, because the nutritional requirements of people with these conditions can be managed through dietary modification alone.
Historically, FDA generally considers inborn errors of metabolism (IEMs) to be diseases or conditions that a medical food could be used to manage.1 IEMs include inherited biochemical disorders in which a specific enzyme defect interferes with the normal metabolism of protein, fat, or carbohydrate. Currently, the majority of U.S. medical food products (51 of 82) on the market are for metabolic diseases. Protein-based medical foods are the most common. Nutrients such as omega 3s, isoflavones, vitamin D, chelated zinc, flavonoids (e.g., baicalin, catechin, pterostilbene), chromium picolinate, phytosterols and L-arginine are other leading ingredients used in medical foods, along with other vitamins and minerals such as pyridoxine, thiamine and folic acid, which are being used in combination. Unless manufacturers can determine that these (or other such substances promoted for use in medical foods) are consumed for the dietary management of diseases or conditions which have distinctive nutritional requirements, they will not be permitted in medical foods.
The Council for Responsible Nutrition (CRN) has commented on the draft guidance, stating that FDA’s conclusion that medical foods may be marketed only for diseases or conditions the “dietary management of which cannot be achieved by modification of the normal diet alone” (as stated in 21 CFR 101.9(j)(8)(ii)), is unduly restrictive, not in the best interest of public health and inconsistent with the statutory definition of medical foods. Companies and trade associations have commented that FDA lacks authority to redefine medical foods, specifically adding new criteria that would prohibit the marketing of medical foods to diabetic because the disease can be managed through changes in the normal diet. It will be interesting to see if the “modification of the normal diet alone” stipulation is removed from the final guidance in response to comments from stakeholders. Others have commented that the emphasis on medical supervision implies that the products should be distributed by physicians and should not be available in stores. This would severely restrict the sale of medical foods like Ensure® and Pedialyte®, which have been available on the supermarket shelf for decades. Imagine the consequences of making products like Pedialyte® only available through a doctor’s office! This will only lead to higher prices and reduced access for a safe product that has benefitted millions of children.
FDA Guidance on Clinical Trials in Humans
Another means by which FDA is curtailing the medical food category as a viable category for functional foods is via the issuance of new guidance on clinical trials in humans. The guidance states that clinical investigations intended only to evaluate the nutritional effects, tolerability or safety of a food (including medical foods) would not require an Investigational New Drug (IND) application, but investigations intended to evaluate other effects of a food on the structure or function of the body would require one. The guidance further states that diseased patients may be used in studies to assess safety or tolerability in a susceptible population, but “an investigation intended to evaluate the effects of a medical food on a disease would require an IND.” Thus, the guidance contains conflicting statements about medical foods and INDs. By definition, medical foods are intended for the specific dietary management of a disease or condition and are considered foods. In order to show that a medical food is effective for specific dietary management of a disease or condition, clinical studies must be performed in people that have the disease or condition. By requiring INDs for such studies, FDA is forcing all new medical foods that have not yet been tested in humans as drugs, even though they also state in the guidance that clinical investigations intended to evaluate the nutritional effects of a food (including medical foods) would not require an IND. So, even though regulations permit medical foods to be used for diseases without being classified as drugs, FDA, by virtue of the guidance, has decreed that medical foods are drugs. Medical foods will be branded as drugs as soon as the IND (Investigational New Drug) application is filed.
FDA is clearly overstepping its authority by requiring INDs for clinical studies performed on medical foods, and should revise the guidance to be in accordance with section 5(b)(3) of the Orphan Drug Act (21 U.S.C. 360ee(b)(3)). Perhaps the intent of the guidance was to prohibit use of medical foods for diseases other than the disease that requires the nutritive benefit from the medical food; if so, the guidance should be revised to read “an investigation intended to evaluate the effects of a medical food on a disease would require an IND (other than the disease which would require the nutritive benefit from the medical food).” This would limit the use of the medical food to a specific condition and curb off-label use for other conditions. Revising the document to state “an investigation intended to evaluate the effects of a food on a disease (other than a medical food) would require an IND,” also makes sense, based on the regulatory definitions of food, medical foods and drugs. Unfortunately, since this guidance document has been finalized it cannot be easily changed. So, we are left with a guidance document that, if enforced, will severely limit development of new foods and availability of medical foods that are currently on the market.
To better regulate the medical food category, FDA is taking a proactive stance, in addition to its usual reactive policy of issuing warning letters. By requiring submission of an IND for clinical investigations on the structure or function of the body, it effectively channels all studies for medical foods designed to be used for purposes other than nutrition into the drug category, branding them as drugs. A central theme to the new guidance is “intent” or purpose. If the purpose of the study is to examine the safety or nutritive value of a food ingredient, then an IND is not required. So, in order to conduct clinical trials without an IND, design clinical studies on medical foods with these caveats in mind. Developers of functional foods should consider whether their food could fall under the definition of a food for special dietary use, as this definition has not been officially declared extinct by either Congress or FDA. The medical food arena will no longer be an option unless FDA revises their definition of a medical food.
 FDA (2013). Draft Guidance for Industry: Frequently Asked Questions About Medical Foods; Second Edition. Available at http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/MedicalFoods/ucm054048.htm, site visited March 4, 2014.
 FDA (2013). Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs)-Determining Whether Human Research Studies Can Be Conducted Without an IND. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM229175.pdf, site visited March 4, 2014.
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 Council for Responsible Nutrition (CRN) (2013). Response Letter to Docket No. FDA-2013-D-0880, Draft Guidance for Industry, Frequently Asked Questions About Medical Foods; Second Edition, October 31, 2013. Available at http://crnusa.org/pdfs/CRN-Comments-MedicalFoodGuidance103113.pdf, site visited March 4, 2014.
 Murphy, J. (2014). FDA medical food guidance should be withdrawn, attorneys for industry say. Food Chemical News, January 3, 2014.
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