Probiotics: The Claimed Effect Decides the Regulatory Path

The addition of probiotics to consumer products is gaining popularity over a wide range of different disciplines and industry sectors, but the term itself may mean different things to different people, depending on their viewpoint and the regulatory climate that governs their industry. Although there is no one definition agreed upon by regulatory agencies worldwide, in 2001 the Food and Agriculture Organization (FAO) of the World Health Organization (WHO) defined probiotics as “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host."¹ The International Scientific Association for Probiotics and Prebiotics reevaluated the definition and confirmed the definition to be consistent with scientific studies on probiotics. However, the amount of “health benefit" that is indicated by claims associated with the probiotic may, in the regulatory world, define the probiotic as either a food, dietary supplement or drug.

Scientific studies have found that certain bacteria in the intestinal tract can have a beneficial effect on human physiology, helping in the development of a healthy immune system and maintenance of the intestinal function, and working to limit growth of pathogenic or opportunistic bacteria.² Historically, intentional consumption of bacteria has been through the addition of bacteria to foods to produce fermented products, a form of food preservation. In time, the fermented products were found to have beneficial effects on the body and have been marketed as “functional food" products (i.e., foods providing a positive benefit beyond the basic nutritive value).³

In the United States, the described benefit of a substance impacts how it is regulated. In the case of beneficial bacteria (i.e., probiotics), if the probiotic is added to food “primarily for taste, aroma or nutritive value" but also providing an added beneficial effect to a healthy individual, the probiotic will be regulated as a food.⁴ If the probiotic is marketed to help maintain the structure or function of the body and to “supplement" the diet, the probiotic will generally be considered a dietary supplement (when labeled according to dietary supplement labeling regulations) and the associated claim is termed a “structure/function" claim. A structure/function claim does not need pre-market approval, but does need to be substantiated with “competent and reliable" scientific evidence proving the claim is “truthful and not misleading."⁵ Recent claims indicate a wide variety of effects of consumed probiotics on the body, including effects on the skin that consumers regard as a “cosmetic" effect.⁶ Probiotics have also been added directly to cosmetic products to modulate the cutaneous microbiota.⁷ However, cosmetic manufacturers must keep in mind that any product that affects the structure or function of the body when applied to the skin is considered a drug, and therefore claims for cosmetics must be limited to the beautifying or attractiveness effects.⁸ In general, claims for foods and dietary supplements that discuss the nutritive value or maintenance of the body do not need pre-market approval, but claims that relate a food or dietary supplement ingredient to the reduction in risk of a disease, termed “health claims," do require pre-market approval by FDA, which regulates claims stated on food and dietary supplement labels.

However, if a probiotic is claimed to “prevent, treat, cure or mitigate" disease, the probiotic will be regulated as a drug and the associated claim is a drug claim. Even if a probiotic is added to a food product or dietary supplement, but the claims on the packaging (or other media such as websites or social media) state the probiotic prevents or treats disease or symptoms characteristic of a disease, then FDA or FTC, the latter of which has jurisdiction over advertisements for food, drugs and medical devices, would consider the probiotic a “biologic" drug, and therefore misbranded as a food or dietary supplement.

Animal feed, which falls under the regulatory guidance of FDA’s Center for Veterinary Medicine (CVM), may also contain probiotics (typically termed “direct-fed microbials"), but the beneficial effect can only be for nutritive value; a probiotic added to feed and claimed to help in the digestion of complex carbohydrates for the better use of carbohydrate calories would be an appropriate animal feed ingredient. However, if a probiotic claims to affect the structure or function of the animal (other than through nutritive value) such that the probiotic prevents, cures or treats disease or increases weight gain (e.g., increases the “performance" of the animal), the probiotic would be considered a drug and would need to obtain pre-market approval through the drug approval process.

Regardless of the type of claim for foods or dietary supplements, scientific evidence that substantiates the claim is truthful must be compiled prior to use of that claim on food or dietary supplement labels or advertising. Various types of scientific evidence may be used to substantiate claims, but FDA regards randomized, placebo-controlled clinical trials as the “gold standard" for substantiating health claims, as long as the clinical trial shows a statistically significant effect and the clinical trial has been conducted in a healthy population. FDA has indicated clinical trials conducted in people that are ill or suffering from a disease showing a beneficial outcome by consumption of a probiotic show that the probiotic treats the disease, suggestive of a drug claim.⁹ The substantiation of structure/function claims is not as rigorous as substantiation for health claims, and can use preclinical trials in laboratory animals, as long as the mechanism of action of the probiotic has been shown to be similar between laboratory animals and humans.

Whether for food or for dietary supplements, probiotics must provide the intended function throughout the proposed product shelf life, which may be difficult for live microorganisms. Therefore, shelf-life studies must be conducted that mimic storage and retail conditions to confirm the label statements on the packaging are truthful and the probiotic is viable throughout the shelf life of the product.¹⁰ The general regulatory conditions that apply to any food or dietary supplement ingredient also apply to probiotics: the specific probiotic must be determined safe and be approved as a food additive by FDA, if it has not previously been determined GRAS (generally recognized as safe) for its intended use in food. For use in dietary supplements, the probiotic must be notified to FDA as a new dietary ingredient (NDI) for use in dietary supplements, if the specific microorganism was not used in dietary supplements prior to Oct. 15, 1994, per the Dietary Supplement Health and Education Act (DSHEA).¹¹

Probiotics have been found through scientific study and through history of use to provide benefits to the host, but manufacturers must be careful when stating claims for these probiotics, as the statements made on a food or dietary supplement may indicate a product previously considered a food or dietary supplement is being promoted for a drug effect. Probiotics added to foods or dietary supplements may be consumed for nutritive value or to help maintain the function of a healthy body, which has been the historic role of probiotics found in food products. And although new beneficial effects of probiotics are increasingly being found through research, the probiotics must be regulated for use in food or dietary supplements. For any type of claim stated, the beneficial effects of a probiotic must be appropriately substantiated prior to any claims stated on food or dietary supplement products or in advertising.

Ray A. Matulka, Ph.D., is the director of toxicology at Burdock Group (burdockgroup.com), bringing more than a decade of experience in the analysis of toxicity data and conducting safety and risk assessments. He earned a doctorate in toxicology from the Medical College of Virginia, and has post-doctoral experience at both Boston University School of Medicine and the University of North Carolina.

References

1. Joint FAO/WHO Working Group Report on Drafting Guidelines for the Evaluation of Probiotics in Food. London, Ontario, Canada. April 30 and May 1, 2002.

2. Caricilli AM et al. “Intestinal barrier: A gentlemen’s agreement between microbiota and immunity." World J Gastrointest Pahtophysiol. 2014;5(1):18-32.

3. Weiner K, Will C. “Materiality matters: Blurred boundaries and the domestication of functional foods." BioSocieties. 2015;10:194–212.

4. Nutrilab, Inc. v. Schweiker, 713 F.2d 335, 338 (7th Cir. 1983). 

5. U.S. Food and Drug Administration, Guidance for Industry: Substantiation for Dietary Supplement Claims Made Under Section 403(r) (6) of the Federal Food, Drug, and Cosmetic Act; http://www.fda.gov/food/guidanceregulation/guidancedocumentsregulatoryinformation/dietarysupplements/ucm073200.htm; site last accessed Dec. 22, 2015.

6. Probiotic products gaining traction in the anti-aging marketplace; http://www.cosmeticdesign.com/content/view/print/1082870; site last accessed Dec. 21, 2015.

7. Huang MJ, Tang J. “Probiotics in personal care products." Microbiology Discovery. 2015;3(5):1-9. 

8. U.S. Food and Drug Administration, Guidance for Industry: Is It a Cosmetic, a Drug, or Both? (Or Is It Soap?); http://www.fda.gov/Cosmetics/GuidanceRegulation/LawsRegulations/ucm074201.htm; site last accessed Dec. 22, 2015.

9. U.S. Food and Drug Administration, Guidance for Industry: Evidence-Based Review System for the Scientific Evaluation of Health Claims – Final;   http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm073332.htm; site last accessed Dec. 22, 2015.

10. U.S. Food and Drug Administration, Guidance for Industry: Enzyme Preparations: Recommendations for Submission of Chemical and Technological Data for Food Additive Petitions and GRAS Notices; http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm217685.htm; site last accessed Dec. 22, 2015. 

11. U.S. Food and Drug Administration, Draft Guidance for Industry: Dietary Supplements: New Dietary Ingredient Notifications and Related Issues; http://www.fda.gov/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/ucm257563.htm; site last accessed Dec. 22, 2015.