The FDA’s Final IND Guidance – A Bitter Pill for Food and Nutrition Research

“Let food be thy medicine and medicine be thy food.” So Hippocrates, the father of medicine, stated. Unfortunately, the Food and Drug Administration (FDA) has taken Hippocrates too literally, with immediate and severe consequences to food and nutrition research in the United States.

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In September, FDA issued a final Guidance for Clinical Investigators, Sponsors, and IRBs – Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without An IND. This Final Guidance is intended to assist clinical investigators, pharmaceutical sponsors, and Institutional Review Boards (IRBs) in determining when clinical research with human subjects must be conducted under an investigational new drug application (IND). Based upon the Draft Guidance proposed in October 2010, there was no reason to believe that FDA’s drug and biological product IND regulations in 21 C.F.R. Part 312 had any relevance for food and nutrition research conducted every day.

Then, FDA issued the Final Guidance and suddenly conventional foods and medical foods (collectively “food”) were thrown into the same Part 312 regulations that govern human clinical research of immunosuppressants, antivirals, and other drugs. FDA announced this dramatic change in a Final Guidance with no notice or opportunity for comment; the agency offered no public health or patient safety justification for the change. Now, just as with drugs, virtually all food investigations in humans are required to have an IND.

Four months later, it is clear that what might have worked for Hippocrates’ patients is not working for modern U.S. food and nutrition research.

FDA’s IND requirements explained

It is a violation of the Federal Food, Drug and Cosmetic Act (FDC Act) to ship an unapproved drug in interstate commerce. 21 U.S.C. § 355(a). The IND application is FDA’s legal mechanism which gives a drug sponsor permission to ship an unapproved drug to clinical investigators for administration to human research subjects.

A typical IND under 21 C.F.R. Part 312 is a substantial and costly submission that must include, among other things:

  • General investigational plan;
  • Information and completed forms about the investigators and the Investigator’s brochure;
  • Study protocols;
  • Chemistry, manufacturing and controls (CMC) information about the drug substance and the drug product; and
  • Animal pharmacological and toxicological studies and any prior human experience.

Once the IND is submitted, the sponsor must report changes to the protocols and other information amendments, report adverse events, and make an annual report to the agency.

The Final Guidance described

The Final Guidance extends these requirements to most human research in foods. To do so, FDA reaches into the definition of “food” and “drug” in the FDC Act. First, any food that is “intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease,” is already regulated as a drug and requires an IND. 21 U.S.C. § 321(g)(1)(B) (definition of “drug”). This part isn’t new; the change is that now FDA is asserting that studying dietary management of patients with a disease or condition or looking at biologic effects of compounds providing nutritive value on endpoints other than safety, tolerance, or organoleptic properties would require an IND. Therefore, FDA concludes, clinical investigations intended to evaluate the effect of a food, including a medical food, on the signs and symptoms of disease, require an IND. Final Guidance at 13.

The Final Guidance does not stop there. A drug is also, under the FDC Act, an “article[] (other than food) intended to affect the structure or any function of the body.” 21 U.S.C. § 321(g)(1)(C) (definition of “drug”). Relying upon a 30-year old court decision interpreting what “other than food” means, FDA concludes that conventional foods (including infant formula and medical foods) that are intended to affect the structure or function of the body are foods only if the intended structure or function effect derives from the product’s “taste, aroma, or nutritive value.” FDA explains:

However, if an edible product that might otherwise be a conventional food is intended for a use other than providing taste, aroma, or nutritive value, such as blocking the absorption of carbohydrates in the gut, the product becomes a drug because the primary purpose of consuming it has changed. In other words, the product is no longer being consumed as a food — primarily for taste, aroma, or nutritive value — but used as a drug for some other physiological effect.

Final Guidance at 13 (emphasis supplied).

Consequently, “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.” Id..

The Final Guidance immediately and severely impacts food research

In our experience, studies undertaken to support health claims and health claim petitions pursuant to the 1990 Nutrition Labeling and Education Act (NLEA) have typically not been conducted with an IND in place. There was no reason, for instance, to assume that it was necessary to submit an IND before researching the relationship between dietary fats and cancer. See 21 C.F.R. § 101.73 (FDA-approved health claim for dietary lipids and reduction in risk of cancer). No researcher sought, no IRB expected, and no FDA inspector ever demanded an IND before moving apples in interstate commerce to investigate their effectiveness in reducing coronary heart disease (See 21 C.F.R. § 101.77 (FDA-approved health claim for fiber-containing fruits, vegetables, grains and reduction in risk of coronary heart disease).

The effects extend far beyond food manufacturers’ ongoing food research. Many governmental institutions also investigate the nutritional benefits of foods. Agencies within the U.S. Department of Agriculture (USDA), including the National Institute for Food and Nutrition, Economic Research Service, and the Agricultural Research Service undertake significant food and nutrition research. The founding of land-grant universities was predicated upon, among other things, pursuing an agriculture research agenda. This food and agricultural research is varied and vast and IRBs will not approve these investigator-initiated studies without INDs.

Food companies and clinical researchers will be engaging in months of costly work to develop and submit INDs to FDA, even assuming they can be submitted at all. IRB approval of a clinical study is essential to the conduct of any food research in academic and institutional settings. Even though FDA is careful to state that the Final Guidance is not legally enforceable, IRBs are concluding that basic food and nutrition research must be subject to an IND and are refusing to approve new food research.

Food research is incompatible with IND requirements

Foods simply do not expose humans to the risks that justify their tight control and monitoring under an IND. The human safety concerns that new drug compounds pose are inapplicable to food that is already being consumed. Submission of animal, pharmacological and toxicological studies to FDA is not generally warranted by the risks common, conventional foods and GRAS substances pose. Moreover, in the case of academic and other investigator-initiated studies, the researcher may not even know or have access to the CMC information in order to submit an IND. From a purely practical standpoint, most foods (whether natural or formulated) are complex mixtures of innumerable compounds that would be virtually impossible to characterize in the detailed way that FDA expects for drug products (which typically only consist of a single active compound and a few other well characterized compounds).

Ironically, the IND requirements for already approved drugs being investigated for new uses appear more lenient than those now applicable by operation of the Final Guidance to marketed foods. 21 C.F.R. § 312.2(b) exempts from an IND the “clinical investigation of a drug product that is lawfully marketed in the United States” if other conditions are met, e.g., the investigation is not intended to be reported to FDA, does not involve a change that significantly increases patient risk, etc. As a food is not a “drug product that is lawfully marketed in the United States,” it would seem to be ineligible for this important exemption from an IND.

Further, FDA’s current good manufacturing practice (cGMP) regulations in 21 C.F.R. Parts 210 and 211 apply to drugs in Phase II and Phase III clinical trials, 21 C.F.R. § 210.2(c). Pursuant to FDA Guidance, modified cGMPs are applicable to unapproved, investigational drugs in Phase I clinical trials. It would seem, therefore, that foods that become drugs by operation of the Final Guidance would have to comply with the drug cGMPs.

The Final Guidance is (unlawfully) altering something that no one thought was broken

There is no indication whatsoever that food and nutrition research was posing any hazards to patients and consumers that necessitated closer FDA oversight through the IND process. If food and nutrition research were risking consumer health, there have been many vehicles for remedying the problem. Food and drug safety have been subject to intense Congressional scrutiny. With the Food Safety Modernization Act, signed into law in January 2011, Congress enacted the most sweeping reforms to food safety in 70 years. The Food and Drug Administration Safety and Innovation Act, passed in 2012, and the Drug Quality and Security Act, passed in 2013, both instituted significant changes to FDA’s oversight of, and authority over drugs. If Congress believed food and nutrition research warranted drug-level controls, it has had ample opportunity to make those changes to the FDC Act.

Moreover, it seems FDA struck out utterly on its own and without the benefit of stakeholder input. The agency did not propose these changes in the draft Guidance it issued in October 2010; they appeared for the first time in the Final Guidance and though characterized as “guidance,” they may have the effect of being a legal requirement. As such, the Final Guidance may not have been promulgated in compliance with procedural protections that may be applicable, including: 21 U.S.C. § 371(h) and the implementing Good Guidance Practices regulation, 21 C.F.R. § 10.115; the Administrative Procedure Act, 5 U.S.C. §§ 553, 706; and the Regulatory Flexibility Act and Paperwork Reduction Act.

The Final Guidance too narrowly construes what “food” is

The Final Guidance assumes, erroneously, that a food becomes a drug subject to an IND because a clinical trial might explore how its components affect the structure or function of the body. FDA assumes that the food is no longer a food “because the primary purpose of consuming it has changed” as it is no longer being consumed “primarily for taste, aroma, or nutritive value.” Final Guidance at 13.

FDA provides no support for this very flawed reasoning. Though food research routinely investigates the benefits foods provide apart from their nutritive value, the research undertaken does not change the primary reason for which food is consumed. A researcher could investigate how diindolylmethane-containing cruciferous vegetables might modulate immune response. However, even assuming such a hypothesis was demonstrated, it does not follow that the primary purpose of broccoli on grocery store shelves changes. Food companies would continue to market broccoli and consumers would continue to buy and eat broccoli primarily because it’s “good for you” and consumers like to eat it steamed and in salads and stir fries. The food researched is still intended to be, and will be, consumed, primarily for the conventional taste, aroma and nutrition it provides the consumer.

Knowing how foods, routinely enjoyed primarily for their taste, aroma and/or nutritive value, may also provide additional health benefits will not alter the reasons consumers eat these foods. More information about the benefits of certain foods may encourage consumers to eat more of them and to substitute to them for other foods as a more healthful option. The IND requirement chills the basic research that is conducted to understand food better.

The Final Guidance creates perverse incentives

The Final Guidance actually discourages the development of good clinical data about foods. First, given the onerous requirements for an IND, it is likely that researchers will take their investigations outside the U.S., an outcome that is undesirable for FDA, patients, consumers, and food companies, and will likely harm the overall U.S. research establishment.

Second, the Final Guidance encourages marketing of foods without prior adequate clinical research into their effects. The Final Guidance makes this recommendation because conducting substantial clinical investigations under an IND for a new dietary ingredient would preclude the ingredient from later being marketed in or as a food or dietary supplement. Final Guidance at 11 (citations and quotations omitted).

Medical foods are also in a quandary. A medical food 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.” 21 U.S.C. 360ee (b)(3). Therefore, by definition, a medical food must have scientific evidence demonstrating its efficacy in the dietary management of disease. Yet, the Final Guidance now requires a medical food to be covered by an IND before the manufacturer can develop the scientific evidence supporting how the food aids in the management of the disease. The Final Guidance seems to have made medical foods indistinguishable from drugs and written medical foods out of the FDC Act.

Unanswered questions remain

In addition to the previously mentioned problems, other difficulties abound, including:

  • Did FDA intend to apply all drug standards to foods, including cGMPs, labeling, promotional restrictions, adverse event and annual reporting, protocol and information amendments, and other regulations and guidances, including International Conference on Harmonisation standards?
  • Is FDA prepared to commit the staff and resources to the review of thousands of food INDs that may, theoretically, pour into the agency? Is FDA staff trained in the differences between foods and drugs?
  • Are foods bearing well-substantiated and common structure-function claims now drugs because similar claims, in the future, would have to be investigated under an IND?

Hippocrates was on to something useful – good nutrition is an important part of good health. However, another adage attributed to Hippocrates is even more pertinent – “first, do no harm.” Sweeping all food and nutrition research into the IND rubric is decidedly harmful to public health. The Final Guidance increases costs, increases confusion, drives research outside the U.S., discourages scientific development, and perversely encourages the marketing of products without adequate clinical investigation. The Final Guidance’s effects upon food and nutrition research are so counter to the public interest and so legally suspect, we believe the only recourse is for FDA to withdraw the Final Guidance and re-promulgate it with the food regulation section omitted. If FDA believes that current practice in food and nutrition research is not sufficiently protecting patient health, the agency must gather that record and promulgate regulation and guidance in accordance with applicable requirements and procedures.

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