Background - Historical Regulation of Medical Foods
The Orphan Drug Amendments of 1988 provided the first statutory definition of the term "medical food." Prior to 1988, FDA regulated these types of products first as drugs, then as "food for special dietary use" (i.e., "special dietary food"). By definition, medical foods are "food"; however, they differ significantly from the more conventional (and statutory) meaning of the term "food." At the same time, many medical foods also meet the criteria for being "drugs." Therefore, medical foods can be considered "drugs," "old drugs," "GRAS/E drugs," "Rx drugs," "food," and "food for special dietary use." The precise category(ies) is determined by a product's intended use as shown by the objective factors surrounding its use, and the product can be in more than one category at the same time.
Regulatory FDA Framework for "Medical Foods"
FDA published an advance notice of proposed rulemaking ("ANPRM") in 1996 to solicit comments about re-evaluating the Agency's approach to regulation of "the broad group of heterogeneous products that are marketed as medical foods." FDA explained that there was a continuum of permissible health and disease claims for particular products: conventional foods fell at one end of the spectrum, drugs at the other end of the spectrum, and medical foods "somewhere between these two points." The Agency asked for comment on its preliminary view that "the scientific standard contained in the statutory medical food definition may require some of the same types of data for medical foods as are needed to support drug claims (e.g., data from clinical investigations)." Of note, FDA provided an extensive list of types of enteral nutrition products that were then on the market and available for patients with various diseases and inborn errors of metabolism (many of which contained added amino acids, restricted quantities of certain amino acids, or altered types and quality of protein). Although this 1996 notice (along with many others) was withdrawn in 2004 because FDA no longer considered it to be a viable candidate for further Agency action, FDA specifically stated that it would continue to refer to this notice (as well as the Agency's medical food compliance program) when evaluating medical foods. In May 2007, FDA issued a revised guidance document (in the form of frequently asked questions) for medical foods.
Despite the Agency's efforts to create a well-defined category of products called "medical foods," there is still a lack of clarity and understanding about the properties and uses of medical foods that allows these products to have simultaneous status as both foods and GRAS/E Rx drugs. Although FDA recognizes the importance of medical foods, the Agency's historical regulation of these products has evolved. Congress and the Courts have attempted to balance competing Agency, consumer, and manufacturer interests in access to these items. Despite FDA's administrative shift of medical foods out of the "drug" category, FDA's actions did not remove all of the characteristics of medical foods that still make them GRAS/E Rx drug products that do not require approved NDAs.
Medical Foods as "Drugs"
FDA first regulated medical foods under the 1938 FFDCA as "drugs" on the basis that they were intended to affect the structure or function of the body, were not conventional foods, and were used to cure, mitigate, treat, and/or prevent disease. One of the first medical foods marketed was Lofenalac®, an infant formula that FDA approved as a new drug product under FFDCA §201(g)(1)(B) in 1957 for the dietary management of phenylketonuria ("PKU"). Because Lofenalac was approved prior to enactment of the Kefauver-Harris Drug Amendments of 1962 ("1962 Amendments"), it was approved on a safety-only basis.
The 1962 Amendments required that new drugs be both safe and effective. Lofenalac was one of many pre-1962 drugs that were retroactively reviewed for efficacy under FDA's Drug Efficacy Study Implementation ("DESI") program. However, in 1972 FDA stated that it would not implement the DESI report for Lofenalac and would not make a judgment about the product's efficacy because the Agency "no longer regarded [Lofenalac] as a drug"; instead, FDA characterized Lofenalac as a food for special dietary use. FDA made this change for several reasons, including fostering innovation for these types of products which were, at that time, used by a limited patient population and manufactured by relatively few reputable companies. The product's conventionality as a food was not material to the decision.
Several parenteral products containing protein hydrolysates were reviewed under the DESI program. Many of these products contained amino acids and short-chain peptides from natural sources (e.g., fibrin, casein) for use as a dietary supplement of protein. FDA determined that the majority of these products were effective as adjuncts to prevent the loss of nitrogen or to treat negative nitrogen balance in some patient populations, including those people with certain alimentary tract dysfunctions, impaired GI protein absorption, and for whom "metabolic requirements for protein are substantially increased, as with excessive burns." Furthermore, FDA stated that the label must contain the statement, "Caution: Federal law prohibits dispensing without prescription." These Agency conclusions are significant because they illustrate FDA's awareness of the physiological importance of medical nutrition/food and that certain medical conditions have a unique amino acid or protein requirement for effective treatment. Furthermore, parenteral products intended for intravenous use are regulated as new drugs under approved NDAs because of concern about plastic leaching and migrating into the drug product, and the plastic container absorbing and the drug product. They are not new drugs because of their intended medical/nutritional use.
Medical Foods as "Food for Special Dietary Use"
By moving Lofenalac from the "drug" category to the "food for special dietary use" category, FDA recognized that medical foods do not require the adequate and well-controlled clinical investigations of substantial effectiveness that new drugs require. This administrative transfer of medical foods from one category to another was the first of many regulatory overlaps between drugs and foods. The ultimate effect of this product transfer, along with other statutory and regulatory changes in the ensuing years, was to make medical foods simultaneously both foods and old or GRAS/E Rx drugs - but not "new drugs." This decision has been consistently applied for almost forty years.
The phrase "special dietary use" was included in the misbranded food provision of the 1938 FFDCA, although the phrase "food for special dietary use" did not appear in FDA's regulations until 1941. In 1962, the Agency proposed changes to its food for special dietary use regulations because of "many advances in the science of nutrition and its commercial applications to products that are represented or which purport to be foods for special dietary uses." Although the changes became final in 1966, FDA issued a stay and held a hearing on several issues related to the new regulations, including whether "special dietary use" should be defined in order to inform purchasers of the value of these foods. After the hearing and the issuance of a tentative order, FDA issued a final order (and lifted the stay on the 1966 final regulations) in August 1973, concluding that it was reasonable to define this term. The issues raised were complex, however, because the hearing involved regulations not only for food for special dietary use, but also food with added artificial sweeteners and dietary supplements containing vitamins and minerals.
The evolution of the "special dietary use" regulations was only the beginning of a continuing battle between FDA, which wanted to limit the use of these products, and those people advocating for consumers' unfettered use of vitamin- and mineral-containing products. Following FDA's 1973 final order referenced above, many statutory and regulatory changes continued to take place. There were Court challenges, FDA's consolidation of regulations, and Congress' enactment of The Health Research and Health Services Amendments of 1976 ("Proxmire Amendments"). The Proxmire Amendments represented Congress' first attempt to restrict the Agency's ability to limit the inclusion of ingredients or set a maximum potency of vitamins and minerals in dietary supplements that are safe for use by adults (other than pregnant or lactating women). Simply stated, "[t]he underlying purpose of this amendment involves the promotion of concentrated vitamins to help supplement peoples' diets."
The enactment of the Proxmire Amendments created problems for FDA, however, because the legislation added a statutory definition for "special dietary use" that differed from FDA's 1973 final regulations. (Until 1976, the only definition for "special dietary use" was in FDA's regulations, not the FFDCA.) Although the definition in the Proxmire Amendments applied only to vitamin and mineral preparations that were the subject of the legislation, FDA decided to apply the new statutory definition to all foods that were governed by 21 C.F.R. Part 125 (label statements concerning dietary properties of food purporting to be or represented for special dietary uses). Additional litigation was followed by the 1979 publication of a regulation defining "special dietary use" that was nearly identical to the original 1941 definition.
It is clear that both Congress and FDA have struggled with how to appropriately regulate medical foods, food for special dietary use, dietary supplements, and various vitamin and mineral preparations. Congress has tried to balance the often competing interests of FDA, consumers, and industry by trying to moderate between any extreme positions.
Medical Foods as "Foods"
Subsequent legislation, the Dietary Supplement Health and Education Act of 1994 ("DSHEA"), provided the first statutory definition of a "dietary supplement" in the FFDCA. DSHEA was intended to balance FDA's authority over unsafe or adulterated dietary supplement products with the need for consumer access to safe products and accurate information about them. Furthermore, Congress noted that "a rational Federal framework must be established to supersede the current ad hoc, patchwork regulatory policy on dietary supplements." Among the changes that DSHEA made to the FFDCA was the addition of specific requirements for dietary supplement product labeling and ingredient declaration. The Agency's proposed and final rules that implemented DSHEA again amended 21 C.F.R. §101.36.
In sum, Congress created a consistent labeling procedure for products that require use under a physician's supervision (i.e., the Rx legend). For over-the-counter ("OTC") drugs, foods, and dietary supplements, if labeling for the layman can be written, then the product should be directly sold to the consumer. When labeling cannot be written for the layman, the product is exempt from such labeling, requires the Rx legend, and must be dispensed only under the supervision of a physician. This is the case with medical foods. The identical nature of the regulatory scheme provides evidence of the congruency of at least some medical foods and Rx drugs, as we address in greater detail below.
Medical Foods as "Drugs" in Medical Practice
Historically, FDA approved medical foods as drugs under the 1938 FFDCA. When FDA administratively moved these products from the "drug" to the "food for special dietary use" category, it did so to stimulate innovation of medical food products - not because the products no longer met the "drug" definition. This administrative change did not cause medical foods to lose the characteristics that led FDA to categorize them as drugs in the first place. Despite Congress' and FDA's repeated efforts to disentangle the categories of products known as drugs, dietary supplements, foods, and medical foods, these attempts have fallen short. Statutory and regulatory overlap between these product categories remains today.
For example, the Courts have spent decades trying to precisely determine the regulatory boundaries of a "food." Despite the fact that the statutory definition of "food" uses the term itself in the definition, it has been held that Congress intended that term to refer to the "common sense" meaning of food, including articles used primarily for taste, aroma, or nutritive value. As one Magistrate Judge concluded and as the U.S. District Court for the Eastern District of New York affirmed, the "common sense and scientific definitions of 'food'" includes two elements: (1) intake of nutrients; and (2) enteral nutrient administration (i.e., ingestion into the GI tract). Furthermore, the definition of "food" contains no reference to the manufacturer's intent for the product's use - unlike the statutory definitions of both "drug" (which contains references to the manufacturer's intention for the product's uses or actions) and "medical food" (which states that the product must be "intended for the specific dietary management of a disease or condition"). But "a manufacturer cannot avoid the reach of the FDA by claiming that a product which looks like food and smells like food is not food because it was not intended for consumption."
By their definitions, foods for special dietary use, dietary supplements, and medical foods (as well as infant formulas) are all "food." Products in these categories come in numerous forms, strengths, and textures. Therefore, the broad umbrella term "food" actually includes products that have very little practical relationship to the "common sense" understanding of that word. These multiple meanings for the single term "food" perpetuate the regulatory confusion that has existed for decades. The Courts have continued to ponder the legal distinctions between these product categories, often noting the legal overlap that exists between dietary supplements and drugs; dietary supplements and food; food and drugs; and medical foods, foods, and drugs.
Medical foods are unique among the broader category of food products in that they require physician oversight and are used for specific dietary needs relative to a medical disease or condition. Medical foods clearly function more as drugs than as conventional foods in actual medical practice because they are used for the dietary management of a disease or condition. In the case of conventional foods, the food components provide a technical function. For medical foods, that technical function is a drug-like therapeutic function that requires a physician's intervention. The therapeutic function of a medical food is, therefore, its effectiveness.
Although there have been few legal cases involving medical foods, one Court correctly noted that "medical foods continue to occupy a regulatory loophole exempt from both nutrition-nutrient labeling requirements applicable to most foods, as well as the labeling and testing requirements applicable to drugs," which is the congruent requirement for Rx drugs. Only by classifying medical foods as both foods and GRAS/E Rx drugs that do not require FDA preapproval can this class of products fit within the legal scheme that has resulted from a century's-worth of statutory amendments.
Requirement for Professional Medical Oversight
Appropriate use of a medical food requires a physician's oversight to establish the presence of the disease or condition and to monitor product use. Physician involvement is therefore central to diagnosis and treatment with a medical food. FDA recognizes that medical foods are not appropriate for the general population because they are specially formulated. As a result, there is a distinct patient population for whom medical foods are therapeutically appropriate.
FDA has never waivered in its belief that the appropriate use of a medical food requires a physician's intervention. In 1988, the Orphan Drug Amendments codified a definition of medical food that included the requirement for physician involvement and oversight, which was based on the historical use of these types of products. Following the enactment of the NLEA in 1990, FDA's amended regulations at 21 C.F.R. §101.9 exempted medical foods from nutrition labeling requirements if, among other criteria, they were used under medical supervision. FDA further clarified that the phrase "under the supervision of a physician" indicates that "the intended use of a medical food is for the dietary management of a patient receiving active and ongoing medical supervision (e.g., in a health care facility or as an outpatient)." The Agency continued to support this position in the 1996 ANPRM for medical foods, adding that "medical foods are foods that are an integral component of the clinical management of a patient." In 2006, FDA noted that the fact that medical foods must be used under medical supervision distinguishes them from the "broader category" of food for special dietary use, as well as from foods making health claims (e.g., dietary supplements). The need for physician oversight is also stressed in FDA's medical food guidance, as well as in international documents addressing foods for special medical purposes.
Because medical foods require physician oversight and Congress has determined that physician oversight and "Rx only" are synonymous, the "Rx only" legend is clearly appropriate on medical food labeling. The Rx status of medical foods protects consumers, and a medical food without the "Rx only" legend would be deemed misbranded because a product that requires the Rx labeling is misbranded without the legend. Medical foods are not intended for lay use as normal dietary foodstuffs, and they "are generally not available on the retail shelf." These distinguishing features make medical foods different from other types of foods such as dietary supplements and food for special dietary use. The need for physician oversight, as well as the dosage form, functions, and intended uses of medical foods are all indicia of Rx drugs rather than indicia of conventional foods. Therefore, the requirement for the "Rx only" legend on a medical food product supports the fact that these products were, and continue to be, regarded in medical practice as "GRAS/E Rx drugs."
Amino Acids and Drugs
As early as 1945, FDA issued trade correspondence to address the use of amino acids in foods and drugs. The Agency concluded that amino acids for oral use were food for special dietary use but could, in certain instances, also be subject to regulation as a drug. Amino acids in parenteral products were regulated as new drugs. FDA recognized that synthetic amino acids and/or protein hydrolysates could supply an individual's protein requirements if they cannot consume or digest protein found in "ordinary food." Such preparations containing either amino acids or protein hydrolysates were subject to the DESI review for effectiveness, including Lofenalac. Protein hydrolysate parenteral products were also part of the DESI review, and FDA ultimately found that the majority of these products were appropriate for several uses, including when "metabolic requirements for protein are substantially increased, as with extensive burns." For these fundamental medical nutritional/medical food claims, the Agency treated "amino acids" as a generic term referring to essential and non-essential amino acids.
Amino acids have also been included in OTC and Rx drug preparations. In 1979, FDA published the report of the Advisory Review Panel on OTC Vitamin, Mineral, and Hematinic Drug Products in the form of a proposed rule which the Agency planned to use to establish an OTC monograph for vitamin and mineral drug products. The panel noted that amino acids or peptides added to such products "make no significant contribution to the vitamin or mineral content or utilization of these products." (FDA's proposed rule was later withdrawn and no monograph was ever created for this category of OTC drugs.) Importantly, the panel did not conclude that amino acids were unsafe or ineffective; it merely questioned their value when used in combination with vitamins and minerals. The panel also did not conclude that they were unapproved new drugs.
A different panel, the Advisory Review Panel on OTC Miscellaneous Internal Drug Products, also considered the addition of vitamins and minerals to weight control drug products. Like the panel referred to above, this panel found that the addition of vitamins and minerals to OTC weight control drug products "serve[d] no useful purpose for those following a well balanced diet," and that they should therefore not be included in these types of OTC drugs. FDA later stated, however, that it agreed with public comment that it may be difficult for a person taking a weight control drug product to consume the appropriate amount of vitamins and minerals in their diet, and "that it would be reasonable to allow such nutrients to be combined with an active weight control drug." FDA clarified that its proposed rule for OTC weight control drug products did not apply to food for special dietary use regulated under 21 C.F.R. Part 105. Therefore, even though there was doubt about the importance of adding additional components to OTC weight loss drugs, this is a separate inquiry from whether or not amino acids, vitamins, or minerals are beneficial for addition to food for special dietary use or any other product category, especially under the supervision of a physician.
In its July 1992 report on the "Safety of Amino Acids Used as Dietary Supplements," the Life Sciences Research Office ("LSRO") of the Federation of American Societies for Experimental Biology ("FASEB") listed a number of Rx and OTC drugs containing amino acids ("LSRO 1992 Report"). Today, the amino acid glycine is found in the OTC monograph for antacid drug products as a GRAS ingredient, and there is a small number of approved NDAs for drug products containing individual amino acids when intended for narrow, precise therapeutic uses. Furthermore, every amino acid is found in the United States Pharmacopeia-National Formulary ("USP-NF") in either a USP, NF, and/or dietary supplement monograph.
Finally, FDA has determined that injectable animal products containing amino acids are new animal drugs. In 1987, the Agency published a response to a Citizen Petition filed by a company that had entered into a consent decree with the government over seized articles containing amino acids (Aminoplex solution; Aminoplex C solution). The Aminoplex products contained amino acids, vitamins, minerals, electrolytes, and dextrose. FDA stated that such components, either alone or in combination, were historically "regarded as drugs by the medical profession, by FDA, and by the regulated industry for more than 40 years" (i.e., since the mid-1940's). The Agency supported this contention with references to a number of supportive documents. For example, FDA referenced the results of a 1977 "Symposium on Clinical Nutrition Update: Amino Acids" sponsored by the American Medical Association and the American Academy of Pediatrics. In addition, FDA cited the USP, which contained a monograph for "protein hydrolysate injection," composed of amino acids and short-chain peptides, which was "in many ways similar to Aminoplex." The Agency also noted that various pharmacology and therapeutics texts address products containing injectable amino acids, and concluded that "[a]n article which is discussed in such texts is generally regarded as a drug." Finally, FDA cited its 1945 Trade Correspondence for the conclusion that "[a]mino acid preparations offered for parenteral use fall in the category of New Drugs." FDA ultimately concluded that the Aminoplex injectable animal products were new animal drug products - not veterinary food or GRAS/E drugs for animal use, as asserted by the manufacturer.
Amino Acids and Foods/Food for Special Dietary Use
FDA's 1945 trade correspondence stated that there is no prohibition against adding amino acids to foods that have no definitions and standards other than pertain to misbranding, and a food that includes added amino acids "will be regarded as a food for special dietary use." The Agency also stated that although there was "insufficient information to provide a basis for setting standards for amino acid dosage," formulations containing amino acids that are intended to supply food needs must supply the amino acids "in substantial quantities."
FDA subsequently published a 1972 proposed rule that made two changes to its regulations. First, the Agency proposed to delete the amino acids that were listed in 21 C.F.R. § 121.101(d)(5) and included in "nutrients and/or dietary supplements" as GRAS with no further limitation. FDA made this proposal because "the mere natural presence of an amino acid in unprocessed foods in free or combined (as protein) form does not qualify it as safe for addition in a pure form as a component of a formulated or processed food." Second, FDA proposed to add a new regulation at 21 C.F.R. § 121.1002 that established limitations on the safe and "nutritionally significant use in human food of amino acids of specified stereochemical configuration for nutritive purposes only." FDA stated that the proposed rule would not cover amino acids in foods that do not also include original intact protein.
The 1973 final rule clarified that it is not appropriate to apply limitations on amino acid fortification of protein in regular diets to special foods for controlled diets. According to the Agency:
Such foods [special foods for controlled diets] are intended for use solely under medical supervision to meet nutritional requirements in specific medical conditions. The quality and usefulness of these products must be determined on an individual product basis because of special nutritional needs dictated by the pathophysiologic conditions of a particular patient. The amino acids used in such products must be safe and of food grade, but it is inappropriate that the limitations relating to the amino acid fortification of protein in regular diets apply to them (emphasis added).
Therefore, the final regulation for amino acid fortification exempted food for special dietary use from certain provisions. Today this statement is found at 21 C.F.R. § 172.320(f), and amino acids added as nutrients in special dietary foods that are only intended for use "under medical supervision" for the nutritional requirements of specific medical conditions are exempted from certain quantity limitations on the added amino acids. However, the levels must not exceed GMPs, and the special dietary food must meet the requirements of 21 C.F.R. Part 105.
As noted in 21 C.F.R. Part 170 (food additives), among the list of "physical or technical functional effects for which direct human food ingredients may be added to foods" are nutrient supplements, defined as "substances which are necessary for the body's nutritional and metabolic processes." For a food additive to be eligible for GRAS status, experts qualified by scientific training and experience may determine an ingredient to be GRAS based on scientific procedures or through experience based on common food use if the substance was used in food prior to January 1, 1958. No specific, independent review process is required. Affirmation of the GRAS status of food and food additives is found in 21 C.F.R. Parts 170-190. For these products, an independent review process has been performed. FDA's regulations also contain multiple additional references to permitted food and food additive uses for amino acids or their derivatives, including 21 C.F.R. Part 172 (food additives permitted for direct addition to food for human consumption); 21 C.F.R. Part 182 (GRAS substances); and 21 C.F.R. Part 184 (direct food substances affirmed as GRAS).
These regulations Trade Correspondence TC 2-A, "Amino Acids," in Federal Food, Drug, and Cosmetic Act Judicial Record, 1938-1964 (Food and Drug Law Institute, Washington, D.C., 1978), 748-750. illustrate that amino acids may be used in food products and have long been recognized for such use. This conclusion is supported by the fact that the infant formula Lofenalac, which contained amino acids, was approved in 1957 - prior to the January 1, 1958 date cited in the regulations. These facts are indicative of the GRAS status of amino acids as used in food products. In the nutritional/medical food context, GRAS is independent legal status made by producers which can be affirmed by third parties.
Amino Acids and Dietary Supplements
Before the enactment of DSHEA in 1994, the LSRO 1992 Report addressed the use of amino acids as dietary supplements and noted their regulatory overlap with food use. (The concentrations of the amino acids in these products are significantly higher than those used in medical food products, by at least an order of magnitude.) Among other conclusions, the authors of the LSRO 1992 Report stated that there is a lack of data on safe consumption of amino acids as dietary supplements either alone or in mixtures, but that it could not identify a safe upper level of intake of amino acids as dietary supplements. Moreover, the authors specifically noted that certain patient populations should only consume dietary supplements containing amino acids "under responsible medical supervision," including (1) women of childbearing age (especially those who are pregnant or lactating); (2) individuals with certain diseases or disorders (e.g., diabetes or chronic liver disease); (3) individuals using OTC drugs or Rx drugs; and (4) individuals with inborn errors of metabolism. The authors also concluded that products should be accurately labeled; additional information is needed on using amino acids as dietary supplements; and that a "systematic evaluation of the safety of all amino acids should be undertaken." Thus, only at high oral concentrations of amino acids have questions ever been raised.
DSHEA added the first statutory definition for a "dietary supplement," which is defined in part as a product that bears or contains one or more substances, including amino acids, which are used to supplement the diet by increasing total dietary intake. Therefore, Congress clearly intended that amino acids can be constituents of dietary supplements. Of particular note, for dietary supplement use, the concentrations of amino acids are much higher than the normal dietary concentration, and they must be intended for use in healthy individuals or for claims that promote health. Claims for the treatment of a disease at these levels without the supervision of a physician are drug claims (e.g., intended to treat a specific disease) that require approved NDAs.
Amino Acids and Medical Foods
Amino acids have clearly been used in products that are considered to be medical foods, beginning with FDA's approval of Lofenalac. The LSRO 1992 Report cites a number of medical foods that were listed in the 1992 Physicians' Desk Reference ("PDR"), including Saave+® (DL-phenylalanine; L-glutamine) and Tropamine+® (DL-phenylalanine; L-tyrosine; L-glutamine), both for "nutrient imbalances." FDA's 1996 ANPRM for medical foods also lists numerous disease states and associated patient populations, product characteristics, and product claims for which enteral nutrition products are available, including those marketed with adjusted types or quality of protein, or adjusted amino acid content.
Today, the number of chronic diseases with established increased nutritional requirements have proliferated, generating many different purported medical foods on the market. These non-parenteral products are intended for nutritional management of disease under the supervision of a physician. These claims are consistent with the historical understanding of a medical food.