On September 10, 2013, FDA published a new guidance document restricting the scope of research permitted for dietary supplements and medical foods without first submitting an Investigational New Drug application (“IND”). The document titled, “Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND,” is available here. FDA now incorporates all disease research into the agency’s IND application process. Because medical foods necessarily require research into disease management, the September IND guidance imposes substantial compliance costs on medical food companies, particular those companies with novel formulae or products addressing novel disease associations.
The IND Guidance:
FDA’s guidance tells clinical investigators, sponsors, sponsor-investigators, and IRBs “when research studies involving human subjects must be conducted under an investigational new drug application…” See IND Guidance at 1. FDA addressed when an IND would be required for foods, including dietary supplements and medical foods. Whether an IND is required for a dietary supplement depends upon the study objectives. In its guidance, FDA explained that an IND is not required for a dietary supplement “[i]f the clinical investigation is intended only to evaluate the dietary supplement’s effect on the structure or function of the body[.]” On the other hand, an IND is required when “the clinical investigation is intended to evaluate the dietary supplement’s ability to diagnose, cure, mitigate, treat, or prevent disease[.]” FDA illustrated these points as follows:
[A] clinical investigation designed to study the relationship between a dietary supplement’s effect on normal structure or function in humans (e.g., guarana and maximal oxygen uptake) or to characterize the mechanism by which a dietary supplement acts to maintain such structure or function (e.g., fiber and bowel regularity) would not need to be conducted under an IND. However, a clinical investigation designed to evaluate a dietary supplement’s ability to prevent osteoporosis or to treat chronic diarrhea or constipation would need to be conducted under an IND.
See Guidance, at 12. Similarly for conventional foods, a clinical investigation requires an IND if the study intends to evaluate the effect of a food on disease. FDA examines the “primary purpose” for which the consumer has ingested the food article. If the primary purpose for consumption is the product’s character as food (i.e., the product is consumed primarily for its taste, aroma, or nutritive value), an IND is not required because the product does not qualify as a “drug” under the Federal Food, Drug, and Cosmetic Act (“FDCA”). If, however, the edible product is primarily being consumed for a purpose other than taste, aroma, or nutritive value (e.g. blocking the absorption of fat), an IND is required because the product is being used a drug for a physiological effect, not as food.
Perhaps the most significant element in FDA’s new guidance is the inclusion of Medical Foods within the broader discussion of conventional foods. According to the guidance, a “clinical investigation intended only to evaluate the nutritional effects of a food (including medical foods) would not require an IND, but an investigation intended to evaluate other effects of a food on the structure or function of the body would.” FDA illustrated those points as follows:
[A] study of the effect of iron on hemoglobin levels in which subjects were fed beef or lamb as a source of iron would not require an IND, but a study of the effect of soy isoflavones on bone metabolism would. Similarly, a study of the ability of an infant formula to support growth of infants or of other nutritional properties of the formula would not require an IND. However, a study of other effects of the formula on the structure or function of the body (e.g., an investigation of the effects of docosahexaenoic acid in infant formula on visual acuity of infants) would require an IND.
A clinical investigation intended to evaluate the ingredient’s safety generally does not require an IND. The same is true for an investigation intended to evaluate the tolerability of a food in a specific subset of the population, including diseased persons (e.g., giving a novel food protein ingredient to a potentially allergic population to assess allergic reactions).
Regarding medical foods in particular, however, the guidance explains that an IND is required if the clinical investigation is intended to evaluate the medical food’s effect on disease, but not “if the medical food is simply being fed to subjects for nutritional purposes during a study examining the effects of another intervention.” Yet FDA rightly observed that the definition of a “medical food” is a food “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.” See Guidance at 13 n.21; 21 U.S.C. § 360ee(b)(3) (emphasis added). Does it seem odd that FDA would expressly apply the drug regulations in Part 312 whenever a “medical food” study explored the product’s impact on disease? A medical food by definition is intended to manage disease conditions, and by statutory definition medical foods are not drugs.
Similarly, the FDA announced that clinical investigations intended to support a new health claim (i.e., a claim characterizing the relationship between a substance and a disease or health-related condition) for a conventional food or dietary supplement, require INDs. Dietary supplements making health claims are certainly not “drugs” under the DSHEA. Yet, as with medical foods, FDA now plans to regulate the scientific support for those products through its drug regulations. That approach improperly regulates conventional foods, medical foods, and dietary supplements as “drugs.”
FDA Regulates Dietary Supplements and Medical Foods as “Drugs”:
That begs the question, if the IND application process is explicitly reserved for investigational “drugs,” and medical foods or dietary supplements with DSHEA health claims are not “drugs,” then why would FDA regulate those latter products as “drugs” under the IND regulations? After all, if FDA was concerned with protecting study subjects, one would think FDA’s Good Clinical Practices regulations would be sufficient. See, e.g., 21 CFR parts 56 and 50. Industry should recognize this maneuver for what it its: an administrative power grab intended to give FDA more control over dietary supplement and medical food research, and also place manufacturers of such products in a regulatory dilemma. There are material consequences to filing an IND application, not the least of which is an admission that the product studied is a “drug.”
The regulations in 21 CFR Part 312 are clear on their face. In an IND application, Section 312.23(a)(7)(iv)(a) requires a “description of the drug substance…” (emphasis added). The regulations pertain to “drug” products exclusively. Those regulations are tailored to the drug approval process, and the mechanisms by which companies seek drug approval, including the rigid clinical trial model involving randomized double-blinded, placebo-controlled studies. See 21 CFR 312.23(a)(7)-(8). As we have observed in other contexts, particularly for dietary supplement health claims, the FDA’s Evidence-Based Review System built on the drug model is often impractical in the food and dietary supplement context. Proving drug efficacy in an acute disease or disorder is a different matter than studying the preventative effect of certain nutrients ingested over a lifetime. To prove dietary supplement health claims through the traditional Randomized Clinical Trial (RCT) model would, therefore, be prohibitively expensive because of the long study durations and substantial population sets. FTC experts recently estimated that if forced to follow the rigid drug model a suitable RCT study for dietary supplement health claims could cost as much as $600 million, a price perhaps expected for drug products, but not dietary supplements. See FTC Initial Decision, In re POM Wonderful LLC, et al., FTC Docket No. 9344 (May 17, 2012), at 96, ¶ 650 (FTC experts “testified that studies of disease prevention should involve 10,000 to 30,000 men and that such studies are ‘incredibly expensive’ and in the range of $600 million”). Instead, dietary supplement and food studies must make use of different data sets, including animal models, meta-studies, and observational studies that can provide persuasive support at lower costs which also mirror the reduced safety concerns in foods or supplements. The IND application process does not accommodate those approaches because an IND application is in contemplation of seeking drug approval—something dietary supplement and medical food companies have no intention of pursuing.
Perhaps the most notable burden is the cost. IND applications are substantial filings that require research and development. Imagine now having to complete an IND application for a vitamin to study the risk-reductive effects of that vitamin in the development of a certain site-specific cancer. IND applications require: detailed statements of the investigative plans; an investigator’s brochure; detailed information concerning clinical protocols and investigator information; information on the composition, manufacturer, stability, and controls used for manufacturing the “drug” substance; and pharmacology & toxicology information, including prior human experience with the “investigational drug.” Moreover, once studies begin under an IND, the sponsor must maintain that IND. FDA also enforces regulations governing when and how a sponsor can charge for an investigation drug subject to FDA’s IND regulations. See 21 CFR 312.8(b)-(c).
IND applications can actually prevent dietary supplements from qualifying as a “dietary supplement” under the DSHEA definition. See 21 U.S.C. § 321(ff)(3)(B)(ii); 21 U.S.C. § 331(ll) (prohibiting the marketing of any food to which has been added a drug or biologic for which substantial clinical investigations has been made public, unless the drug or biologic was marketed in food before any substantial clinical investigations involving he drug or biologic were instituted). FDA was therefore compelled to explain in its IND Guidance that “[m]arketing the substance of interest as a dietary supplement or as a food or in food before seeking an IND or beginning any clinical investigations preserves the option to continue to market the substance in those forms after substantial clinical investigations have been instituted and their existence has been made public.” See Guidance at 11. That sounds logical, if not also entirely unnecessary if FDA had not suddenly required all foods and dietary supplements to file investigational new drug applications before researching potential associations with disease prevention.
Medical foods have it even worse. As explained above, “medical foods” cannot qualify for the statutory definition in Section 360ee without first having scientific evidence to support the product’s use in dietary management of disease. Under FDA’s new IND guidance, however, medical food manufacturers must file an IND application before investigating the disease relationship. So before the medical food can even become a “medical food,” it must first become a “drug” under FDA regulations, even though Congress expressly permitted “medical foods” to be associated with diseases without actually becoming drug products.
FDA’s IND guidance does not account for that discrepancy, nor does FDA explain the significance an IND designation might have on medical food products in development. FDA buried this sweeping change within a separate discussion of conventional foods. A company that first files an IND on a medical food formula might later discover that it cannot pursue medical food status because of the apparent drug purpose memorialized in the IND application. Moreover, that same company cannot now protect marketability by arguing that its product was first marketed as a food or dietary ingredient, because FDA could find that the product fails the “medical food” definition for a different reason. Under another recent draft guidance, FDA determined that medical foods cannot be marketed for diseases or conditions which can be managed through changes to the normal diet alone. See Our Prior Blog Post here (a medical food must now be “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”) (emphasis added).
So if a company claims that its “medical food” was previously marketed as a conventional food or dietary supplement, then FDA could theoretically conclude that changes to diet alone are available to the patient which would obviate the need for a “medical food.” Yet if the sponsoring company first filed an IND application to study the required connection with disease management, FDA could theoretically prevent the product from being sold as a “medical food” because it was studied first as a drug ingredient. We assume FDA would not wield its authority so capriciously, but the IND Guidance should have devoted more explanation to these conflicts. Instead it raised many unanswered questions.
In the realm of FDA regulated products, the FDA survives on its categorical distinctions between products like cosmetics, drugs, biologics, dietary supplements, etc. Everything FDA handles is built into that system of classification-first, regulation-second. The exact same molecular formula can be a drug, dietary supplement, cosmetic, or food, all depending on the product’s intended use. In the IND Guidance the FDA should have focused on the intended use of the test article. If an article is investigated for a non-drug use, then FDA has no authority to regulate the article as a drug during the research stage or at any stage thereafter. After all, completion of successful testing does not make the medical food a “drug” simply because that testing investigated the product alongside disease. A dietary supplement with an approved health claim does not become a “drug” simply because scientific studies explored the product’s relationship with the risk-reductive effect of certain diseases. Dietary supplements do not become drugs just because the manufacturer relies on clinical intervention studies that tested against disease conditions, particularly when those studies also support the product’s use in maintaining a structure or function of the body. Product characterizations should be established based on intended use in commerce, not scientific research into potentially non-drug or disease endpoints.
For years, FDA has made public its disdain for dietary supplements and medical food products, mostly because, unlike drugs and devices (i.e., products with user fees), FDA cannot exercise strict premarket control over products like dietary supplements. This is not the first time FDA attempted to increase oversight of foods and supplements through controversial guidance documents. In July 2011, the FDA published a draft NDI (New Dietary Ingredient) guidance document interpreting Section 350b of the FDCA. That guidance imposed new and burdensome compliance measures on dietary supplement companies, measures designed to substantially increase the amount of premarket “notifications” filed by dietary supplement companies. FDA’s instant IND Guidance has the same effect by requiring dietary supplement and medical food companies to submit extensive information before beginning valuable scientific research.
Particularly as applied to medical foods and dietary supplements seeking health claims, the FDA’s September IND guidance is arbitrary and capricious, and in conflict with the FDA’s enabling act. The Federal Food, Drug, and Cosmetic Act as amended by the DSHEA and the Orphan Drug Act carefully preserved the distinctions between dietary supplements, medical foods, and drugs. FDA acts arbitrarily and capriciously when it directly regulates all of those products under the drug regulations solely because certain research might involve an exploration of disease conditions. The FDA IND guidance therefore substantially changes the substantive legal obligations of those dietary supplement and medical food manufacturers that would otherwise seek to support their products through scientific research. The guidance therefore sets new rules that should not have been implemented through guidance documents. As applied to medical foods, and particularly on the heels of FDA’s September 2013 revisions to the Medical Food Guidance, FDA should have given more attention to its discussion of “medical foods” in this IND Guidance.