Last month the FDA issued a final guidance on when an investigational new drug (IND) application is required for human research. Guidance for Clinical Investigators, Sponsors, and Institutional Review Boards on Investigational New Drug Applications–Determining Whether Human Research Studies Can Be Conducted Without an Investigational New Drug Application
An IND is required by the FDA for any human studies on drug development.
This guidance addresses what types of human studies require INDs, and relevant to this article, when the FDA sees food as a drug. According to food law in the United States, it is the intention of use that primarily drives categorization of a substance as a food or drug.
“It is important to note that the drug definition is not limited to compounds intended for a therapeutic purpose. The definition also includes compounds intended to affect the structure or function of the body, without regard to whether the compound is intended to influence a disease process. The definition also includes compounds used for research purposes in healthy subjects to blunt or provoke a physiologic response… Note, however, that … a food used as such (i.e., primarily for its taste, aroma, or nutritive value) and not for a therapeutic purpose or to affect the structure or function of the body, other than by providing nutrition, is not a drug (see section VI.D.2).” (Guidance, page 3)
For the purposes of conducting research, the FDA sees research on structure/function (with the exception of taste, aroma or nutritive value) or reduction-of-risk-of-disease (with the exception of already approved food/disease reduction relationships) endpoints as drug uses, and requires an IND. This is the case regardless of the safety or common usage of the test product.
Functional effects of foods, which go beyond nutritive value, are well known. Prunes for digestive regularity; saltine crackers for settling an upset stomach; coffee to wake you up in the morning; fiber to ‘feed’ the positive bacteria in your gut and keep you regular; probiotics to support a healthy immune system. Apparently, the FDA considers these functions to be drug functions, and according to this new guidance research to study them in the United States will need to be conducted under an IND.
‘Primarily’ vs. ‘solely’
In 1983, the United States Court of Appeals, Seventh Circuit issued a ruling in a case regarding structure/function claims for foods (NUTRILAB v. SCHWEIKER). The following quote in this decision is relevant to this discussion:
“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.” (emphasis added) http://www.leagle.com/decision/19831048713F2d335_1987
This statement clearly indicates that although food may primarily be used for taste, aroma and nutritive value, there are legitimate uses of foods which target other physiological effects. A food attorney, A. Wes Siegner, Jr. of Hyman, Phelps & McNamara summarized this point nicely at an FDA hearing in December of 2006 (Seigner 2006).
But FDA’s guidance of September 2013 does not accept this interpretation, and holds a very narrow interpretation of food uses.
What does this mean for research on probiotic foods?
This guidance is about doing human research, not about making product claims. But one thing is clear – if you can’t do the research to support a product claim, you’ll never be able to make a product claim.
Substances used to cure, treat, mitigate or prevent disease, or affect the structure/function of the human body are drugs according to Food, Drug and Cosmetic Act. But there are also exceptions for foods, i.e., that foods can reduce the risk of disease and can affect the structure/function of the body. However, this new guidance greatly restricts when these exceptions can apply to foods, at least for the purposes of research:
- FDA opinion expressed in the guidance is that the only avenue for foods to affect the structure or function of the human body is through taste, aroma or nutritive value. (Conventional foods intending to impact the structure/function of the human body through a non-nutritive function are considered to be drugs in this new guidance)
- FDA opinion expressed in the guidance is that you can do a human study on a food to support an already authorized reduction-of-risk-of-disease claim without an IND, but if you want to do research on a substance/ endpoint relationship that is not currently an approved health claim, then you have to do the study under an IND.
It seems that research, for example, to evaluate the impact of a probiotic yogurt on immune function or intestinal integrity – both structure/function endpoints – would require an IND because these are not seen as nutritive value endpoints. Also, although evidence for currently approved health claims was generated in human studies without INDs in the past, going forward it appears that won’t be allowed. Since human studies are necessary to provide substantiation for a health claim (see here), the only new health claims will be from studies already conducted or from studies conducted outside the United States.
Perhaps a more careful reading of this guidance by those qualified in legal matters will yield more optimism for the future of functional foods in the United States. But in a blog post about this new guidance, Wes Siegner & Paul M. Hyman made a chilling recommendation: 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. (Emphasis mine.) A likely outcome of this FDA policy is that research on functional foods will be shipped off-shore.Or research on physiological effects of functional foods will essentially stop, and the marketplace will contain foods with minimally substantiated claims.
Another negative outcome from requiring an IND for functional food research is that it will prevent independent researchers from studying functional foods. If a product is making a claim, independent researchers should be able to conduct and publish independent evaluations of the products. However, input from the product manufacturer is required to complete an IND; if the product manufacturer doesn’t want its product evaluated independently, it can simply refuse to provide the information.
It is noteworthy that a group at the University of Maryland has proposed an abbreviated IND process, which could make it much easier for probiotic research to be conducted under an IND. A Policy Forum article in Science summarizes this process, Probiotics: Finding the Right Regulatory Balance.
Foods cannot contain drugs: FDA Amendment Act of 2007
This insistence that most conceivable research on humans turns a food into a drug has some potential implications for future marketing of a food product. The FDA Amendments Act (FDAAA, 2007) says, in short, that foods cannot contain drugs. From Carvajal and McColl (2009):
“With certain limited exceptions, FDCA section 301(ll) prohibits the marketing of food to which has been added an approved drug, a licensed biological product, or a “drug” or “biological product” for which substantial clinical investigations have been instituted and their existence made public. Depending on how it is implemented, section 301(ll) could adversely affect development of novel food and dietary ingredients.”
So does this mean that if you conduct your human research under an IND on a substance you intend to market as a food, will this constitute “substantial clinical investigations” as a drug and therefore will you be precluded from marketing it as a food?
The FDAAA does have a ‘first-to-market’ exception that allows the addition of a drug or biological product to food if that drug or biological product was first “marketed in food”. But exactly what that means is not clear:
- It is unclear what ‘marketed in food means’ (is just being present as an ingredient sufficient, or does the presence of the ingredient need to be called out in a label?)
- It is unclear if this includes dietary supplements or not (in one place in the Act, dietary supplements are included in another they are not)
- It is unclear what is meant by ‘drug’ – in US law, the concept of ‘drug’ is tied to manifestation of intent – regardless of identity of the substance – so is it even possible to lawfully market a drug as part of a food?
- It is unclear what ‘substantial’ means with regard to ‘substantial clinical investigations.’
Is there hope for dietary supplement research?
The Dietary Supplement Health and Education Act specifically states that dietary supplements can impact the structure/function of the human body. In this regard, human research on a dietary supplement form of a probiotic may be able to proceed without an IND.
From the guidance: “Note, however, that (1) a dietary supplement intended only to affect the structure or function of the body and not intended for a therapeutic purpose is not a drug…”
This guidance, unlike previous draft guidances on INDs for human research, was issued by all three centers, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research and Center for Food Safety and Applied Nutrition. This suggests harmonization on this issue among all three centers.
The opinions expressed in this FDA guidance document did not go through the more official FDA process of rulemaking. Therefore it does not carry the force of law; it only provides insight into FDA’s thinking.
A search of www.clinicaltrials.gov, a service of the U.S. National Institutes of Health, lists 222 open studies on probiotics registered with this site, of which 21% are being conducted in the United States. A similar search for studies on antibiotics shows that 42% of all open studies are being conducted in the United States. This suggests disproportionately fewer studies are being conducted in the United States on probiotics.
At a time when health care costs are climbing, the population is aging and morbidity due to chronic diet-related diseases is at an all-time high, the FDA’s unwillingness to consider that foods may have functions that can promote health beyond nutrition seems unfathomable.
If Americans care about what foods may promote their health, or that functional food research will be shipped off-shore to the detriment of researchers in the United States, they should ask the FDA to justify this restrictive policy and modify it to the extent allowable by law. If not, our next generation foods may taste good, but we’ll know nothing about their possible positive effects on our health.
Update January 18, 2014: The FDA has agreed to re-open the comment period on this guidance.
Carvajal R.,McColl D. FDA’S Implementation of FDAAA’S Food-Related Provisions: A Work in Progress. Food and Drug Law Journal, Jan/Feb:6-9.
Functional Foods Expert Report: Opportunities and Challenges March 24, 2005. IFT Expert Report, Panel Chair: Fergus Clydesdale.
Siegner, A.W. Jr., Conventional Foods Being Marketed As Functional Foods. Summary Of Oral Presentation to FDA Public Hearing, December 5, 2006.
Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims January 2009