By Wes Siegner & Paul M. Hyman –
The term “medical food” was first defined by statute in the Orphan Drug Act Amendments of 1988. The medical food category is closely related to the already existing category of “foods for special dietary use,” authorized by the Federal Food, Drug, and Cosmetic Act (FDC Act), section 403(j). In very simplified terms, medical foods and foods for special dietary use are foods that are formulated to meet the needs of individuals with diseases or conditions that may benefit from ingestion and/or clinical management by specialized foods. Unlike most other foods, the labeling for foods that fall in these categories may legally mention the disease or condition for which they are intended. As our understanding of nutrition and its role in both normal and disease processes of the human body advances, many diseases and conditions that could only be addressed through drug therapies are now being improved by combination drug/food therapies. Access to and development of medical foods is, therefore, of enormous potential importance to public health, both because of the potential for improved health as well as the opportunity to reduce healthcare costs.
Within the last month, FDA has issued a draft medical food Q&A guidance and a final guidance on INDs that will dramatically impact the availability and development of medical foods. Previous blogposts on these guidance documents can be viewed here and here. These guidances also further illustrate the FDA trend of issuing important and controversial policy decisions through legally “non-binding” guidance (see our previous post here), which short-cuts the notice and comment rulemaking process, deprives stakeholders of a meaningful opportunity to change FDA policy, and makes legal challenge to these new policies problematic at best.
Regardless, it is essential for patient groups, physicians, academic researchers, and the industries that these guidances will negatively impact to make their voices heard.
FDA’s Draft Medical Food Q&A
Medical foods help to manage a disease or condition by meeting the “distinctive nutritional requirements” that the disease or condition creates. As FDA points out in its medical food draft guidance, certain rare inborn errors of metabolism (“IEMs”) such as phenylketonuria (“PKU”) require careful manipulation of the diet to avoid certain nutrients (phenylalanine in the case of PKU). Failure to do so can lead to serious medical consequences, including death. It is difficult, but not impossible, for individuals with these diseases to accomplish the necessary dietary manipulation without medical foods that are specially formulated to help manage the disease. In FDA’s view, “[m]edical foods become indispensable for individuals with these IEMs in order to meet the daily requirements of essential nutrients and to limit the metabolic disturbances associated with the particular IEM.” Q&A 17.
However, there is a growing recognition that medical foods can also play important disease management roles in a much broader array of diseases where distinctive nutritional requirements have been established, including cancer, AIDS, arthritis, heart disease, osteoporosis, and gastrointestinal diseases, among others. As new research into disease, nutrition, and health shows better ways to manage disease through nutrition, medical foods, which are inherently safe and do not therefore require years of costly product safety and efficacy testing and FDA premarket approval, are increasingly becoming a cost-effective component of disease management.
FDA’s new draft Q&A, as well as a number of recent warning letters to medical food marketers, indicate that FDA is determined to narrowly interpret the definition of “medical food” and prohibit the marketing of many novel products that might fit into this category and benefit patient health. One of FDA’s primary tools in restricting access to the medical food market is a criterion that FDA promulgated in a medical food labeling regulation, 21 C.F.R. §101.9(j)(8), but that does not exist in the statutory definition. This regulation requires that, to qualify for an exemption for medical foods from otherwise applicable food labeling requirements, the food must supply “medically determined nutrient requirements, the dietary management of which cannot be achieved by the modification of the normal diet alone.” This concept is nowhere implied in the statutory definition, and it makes no sense from a medical perspective in the context of addressing the management of a patient’s disease or condition.
FDA’s draft medical food Q&A guidance relies particularly on that restriction in an attempt to eliminate what is likely the largest potential patient base for medical food products, patients with diabetes. FDA recognizes that there are distinctive nutritional requirements that are critical to the health of all individuals with diabetes mellitus (“DM”), but nonetheless answers “No” to the following question – “Does FDA consider type 1 or type 2 DM to be conditions for which a medical food could be labeled and marketed?” Draft medical food guidance, Q&A 22 and 23. What is FDA’s explanation? “Diet therapy is the mainstay of diabetes management. A regular diet can be modified to meet the needs of an individual affected by either type of DM.”
This new policy position ignores the essential role that food convenience plays in compliance with the often difficult dietary manipulations that are needed in a variety of diseases and conditions, including diabetes. Why should FDA want to make it difficult for patients to comply with diets that are essential to the management of serious, life-threatening diseases? The new policy position is also arbitrary, as FDA recognizes that medical foods are essential to the management of certain genetic diseases, such as PKU, where dietary manipulation is also difficult but still possible, but not others, such as diabetes. FDA’s draft guidance is internally inconsistent on this point (see Q&A 17) and raises the question, just how difficult does dietary manipulation have to be for FDA to permit a medical food to be marketed? As medical foods are inherently safe, it would appear that the question of whether dietary compliance, and therefore patient health, will benefit from a medical food should be left to the medical community, not to FDA.
Indeed, this approach amounts to FDA’s dictating the therapeutic regimen for these patients, substituting the agency’s judgment for that of the clinician. No one would stand for FDA’s allowing only one drug or course of therapy to be used for a patient, despite the availability of other effective measures. Yet FDA here essentially would do just that – prohibit the use of available, safe and effective agents of dietary management of the patient’s disease if, in FDA’s view, management might be accomplished by modification of the diet, regardless of how impractical that might be.
FDA’s draft guidance also leaves open the question of whether there might be medical foods appropriate for pregnant women, as well as the question of whether medical foods intended to manage the wide variety of diseases and conditions that are not “inborn errors of metabolism” would qualify for medical food status. However, FDA’s draft Q&A combined with a recent increase in FDA warning letters suggests that the entire medical food category is under increased scrutiny and risk of FDA enforcement. The impact, if the guidance is not revised, will be to stifle creative and cost-effective use of nutrition to improve patient health through use of medical foods.
FDA’s Final IND Guidance
FDA’s final IND guidance potentially will require FDA approval of an investigational new drug application (“IND”) for most, if not all, clinical studies intended to support the benefits of any medical food. The “non-binding” medical food IND requirement was inserted into the final guidance in a new section D.2., titled “Conventional Food,” even though there was no such provision in the draft guidance FDA issued in 2010, thereby making any comment on this new policy impossible before FDA issued the final guidance.
The new requirement poses significant challenges to clinical studies into disease management:
- The final IND guidance attempts to distinguish between medical food studies that do not require an IND – safety studies and studies of the taste, aroma, or nutritive value of a medical food – and those that do require an IND – studies into how the medical food might affect the structure or function of the body in ways that do not derive from “nutritive value,” however FDA might interpret that term. As set forth by FDA, this distinction is difficult if not impossible to comprehend. The guidance is intended to affect the behavior of institutional review boards ("IRBs") that are not usually willing to second-guess FDA policy. Therefore, IRBs are likely to require INDs unless FDA is willing to agree that an IND is not needed, which FDA is unlikely to do.
- The need to conduct studies under an IND will put many novel medical foods in a quandary, as FDC Act §301(ll) potentially prohibits the marketing of a food where the food is first studied under an IND, even if the study is ultimately intended to support food rather than drug use. Medical food companies might attempt to avoid the prohibition by marketing products as foods or dietary supplements prior to conducting medical food studies, or by using only ingredients already widely consumed as food, but this strategy increases the risk that FDA will challenge the medical food on the basis that the nutritional requirement can be met by modification of the normal diet. Whether this conundrum is deliberate or is a result of FDA’s failure to think through its new policy, first announced in FDA’s final guidance, is unclear. Regardless, because IRBs will take FDA’s guidance and gospel, the final guidance will restrict medical food development and research into the understanding of nutrition and disease generally.
In order to create the requirement for an IND for medical food studies, FDA’s IND guidance reverts to a legal theory for regulating structure/function claims for foods that we believed (or hoped) the agency had long ago abandoned.
Consistent with case law interpreting the “other than food” exception as applying to articles consumed primarily for taste, aroma, or nutritive value, FDA regulates conventional foods (including infant formula) that are intended to affect the structure or function of the body as foods, not drugs, as long as the intended structure or function effect derives from the product’s character as a food — its taste, aroma, or nutritive value.
IND Guidance at 13 (citing Nutrilab v. Schweiker, 713 F.2d 335 (7th Cir. 1983)). FDA then goes on to narrowly construe the term “nutritive value” by stating, as an example of a food study that would require an IND, that “a study of the effect of soy isoflavones on bone metabolism would [require an IND].” Id.
Contrary to FDA’s assertion that its interpretation is “consistent with case law,” FDA’s reliance on Nutrilab for the agency’s narrow interpretation of the “other than food” provision of the FDC Act is in direct conflict with the opinion of the Seventh Circuit as well as subsequent case law that relied on Nutrilab. That case law establishes that, in the view of the courts, a “food” may properly make any claim in labeling that is truthful and nonmisleading about a “physiological effect” of the food, including a physiological effect of a component of the food, on the structure or function of the human body, provided that the claim does not represent that the product is intended to cure, treat, mitigate, or prevent disease (which would create “drug” status for the product), and does not “characterize the relationship” between a “substance” and “disease,” “damage,” or “dysfunction” of the body (which would meet the definition of a “health claim” and create separate requirements. 713 F.2d at 338 (“To hold as did the district court that articles used as food are articles used solely for taste, aroma or nutritive value is unduly restrictive since some products such as coffee or prune juice are undoubtedly food but may be consumed on occasion for reasons other than taste, aroma, or nutritive value.”); American Health Products Co., Inc. v. Hayes, 574 F. Supp. 1498, 1507 (S.D.N.Y. 1983), aff’d, 744 F.2d 912 (2d Cir. 1984) (“[I]f an article affects bodily structure or function by way of its consumption as a food, the parenthetical [i.e., the ‘(other than food)’provision in 21 U.S.C. §321(g)(1)(C)] precludes its regulation as a drug notwithstanding a manufacturer's representations as to physiological effect . . . . The presence of the parenthetical in [21 U.S.C. §321(g)(1)(C)] suggests that Congress did not want to inhibit the dissemination of useful information concerning a food’s physiological properties by subjecting foods to drug regulation on the basis of representations in this regard.”)
FDA’s IND guidance is yet another example of the agency, contrary to law, “subjecting foods to drug regulation” by requiring any study of the physiological effect of a food that does not derive from “nutritive value” to first be approved as a drug study through FDA’s IND approval process. As FDA’s isoflavone example illustrates, perhaps intentionally, FDA has so muddled the picture as to what effects of food derive from “nutritive value” and which do not, that even experts will find it difficult to advise clients or, more important, IRBs, when an IND is required. This will predictably lead IRBs to either require INDs for virtually all clinical studies that examine structure/function effects or any beneficial effects of foods, or to require that FDA’s drug center be consulted before conducting such studies, which will likely yield the same result.
Oddly, according to FDA’s IND guidance, it appears that if the same isoflavone study on bone metabolism were conducted as a dietary supplement study rather than a conventional food study, no IND would be required, since “a dietary supplement is not considered a drug and is not subject to the premarket approval requirements for drugs if the intended use for which it is marketed is only to affect the structure or any function of the body (i.e., not intended to be used for a therapeutic purpose).” IND Guidance at 12.
What Should Be Done?
The question for patients, physicians, academic researchers and industry is “now what?” Some short term measures may bring temporary results, including:
- File comments – FDA has withdrawn and/or rewritten controversial draft and final guidance in the past in response to negative comments. Given the important medical, research, and patient health implications of FDA’s recent guidances, comment from patients, researchers, and medical specialty associations will be important to a change of FDA’s course.
- Enlist the help of Congress – congressional representatives can effectively influence FDA’s course through letters, hearings, and other measures.
- Some companies in the medical food arena may qualify as small businesses, which may make it possible to engage the Small Business Administration (“SBA”). SBA has been an effective advocate for small business in other flawed FDA initiatives.
- Carefully design study protocols to avoid IND implications, or if that is not possible, conduct studies that IRBs and FDA will not permit in the U.S. without an IND in Canada or Europe.
A longer-term industry strategy is also needed. It is clear that FDA is determined to severely restrict both access to and research on medical foods in the U.S., regardless of the potential importance of such products to public health and the effect on the cost of medical treatment. Currently, there is no trade association devoted to protecting the interests of the medical food industry, but it appears that the time has arrived for one to be created. A trade association could help the industry interact more consistently with FDA, would help develop long-term allies in Congress, and provide industry with the necessary resources to litigate critical issues if necessary.
