The Human Microbiome Project (HMP) has vastly increased our knowledge about the diversity of microbiota in the human body.¹ Although significant research remains to be done to understand the role of these bacterial communities in human health and disease, the HMP has increased focus on the potential value of probiotics to provide novel, safe and low-cost therapeutic approaches to pressing public health problems.²

The public’s enthusiasm for probiotics has resulted in a worldwide market in excess of $35 billion.³ However, the plethora of untested probiotics currently in the marketplace and the lack of evidence from randomized controlled trials have led some scientists to question the benefit of the entire category.⁴ Some companies that do invest in careful classification of bacterial species and their biological effects may be deterred from promoting their findings by the perception that such promotion would automatically trigger the requirement to submit an application for new drug approval to FDA. On the whole, the industry appears not to be pursuing opportunities to develop therapeutic probiotics because of the perception that making medical claims will require outlays of funds equivalent to drug development.

Realizing the therapeutic potential of probiotics will require a clear and appropriately tailored regulatory path. While FDA’s current regulatory regime is likely more flexible and nuanced than some probiotics manufacturers may appreciate, the absence of clear agency guidance itself can deter the development of new, validated therapeutic probiotics. Furthermore, to the extent FDA’s current interpretation of its regulatory authority creates barriers to market entry, FDA should consider the applicability and appropriateness of such interpretation to all probiotics. The case of C. diff, described below, underscores the potential public health benefits of probiotics and the importance of a clear regulatory path for realizing this potential.

Probiotics are live microorganisms with the capacity to confer a health benefit when ingested in adequate amounts.⁵ While microorganisms have a long history of use in food production—for example, lactic-acid producing bacteria have been used in cheese production since ancient times—focus on their therapeutic potential has arisen more recently. The biological impact of probiotics derives not from the microbes themselves, but rather, from the chemicals—e.g., acids and enzymes—that they produce. Thus, characterizing and classifying these products and their physiological effect is paramount to the identification and development of therapeutic probiotics.

A case in point is the enzyme bile salt hydrolase (BSH), and the growing awareness of its role in preventing and treating C. diff infection.⁶ The U.S. government considers reduction of C. diff infection to be a national priority because of significant morbidity, mortality and economic costs associated with the disease.⁷ A major known cause of C. diff is antibiotic administration, which interrupts the normal transition of primary to secondary bile acids.

BSH is essential for the metabolism of primary bile acids, synthesized in the liver from cholesterol, to secondary bile acids produced in the intestines. BSH performs the initial step in this pathway, followed by 7-alpha dehydratase, also produced by normal intestinal bacteria.

Many individuals have dormant spores of C. diff in their intestines. These spores remain dormant because of the presence of the effect of secondary bile acids. Antibiotics suppress the normal bacterial enteric flora. Decreased BSH leads to a decrease of secondary bile acids and increase in primary bile acids, which stimulates the C. diff spores to transform into their vegetative state. Vegetative C. diff then produces toxins that attack the intestinal lining, causing severe inflammation.⁸ Re-establishing the normal primary/secondary bile acid ratio in the intestine reduces the inflammation, but the therapeutic approach currently available to do so is fecal microbiota transplant (FMT), which is a cumbersome, and currently investigational, procedure with potentially serious side effects.⁹

A number of probiotics are also known to produce BSH and can therefore promote the production of secondary bile acids from primary bile acids and help maintain the normal ratio in the presence of antibiotics. This mechanism is likely to be the basis for mostly anecdotal evidence that probiotics are useful for the prevention and treatment of antibiotic-associated diarrhea. A few studies actually establish an increase in BSH activity after probiotic administration.¹⁰

Oral supplementation with probiotics that produce BSH concurrently with antibiotic administration could therefore prevent the development of C. diff infection, and could also mitigate the negative effects of existing C. diff infection. Other products of the probiotic, currently less well-defined, may add to the beneficial effect. However, the daunting prospect of FDA’s “new drug" approval process may deter companies from doing the additional studies necessary to validate and promote such findings by the cumbersome prospect of FDA approval. Although new drug approval need not be the only pathway to marketing a probiotic for C. diff., uncertainty regarding the regulatory path and fear of becoming enmeshed in the drug approval process serve as a barrier to the development of a therapeutic probiotic market.

FDA’s regulatory approach is category-driven. The agency’s governing statute specifies categories of products and the requirements that must be met to manufacture and distribute them. FDA determines the relevant regulatory category based on a product’s “intended use," and generally looks to the manufacturer’s labeling, including promotional claims, to determine the intended use. Of significance here, a product containing the same ingredients may be assigned different categories based solely on the claims made, and not based on any substantive difference in the product.

FDA regulates, among other product categories, “food" and “drugs."  The statutory category of “food" comprises “articles" that are “used for food and drink," and, in practice, has been interpreted to include products that are consumed for their taste, aroma or nutritional value.

Within the broader category is the subcategory of “dietary supplement," which is a product that is intended for ingestion for the purpose of supplementing the diet, and that contains a vitamin or mineral, an herb, other botanical, or amino acid and/or a “dietary substance" (described as something  “used to supplement the diet by increasing total dietary intake"). A dietary supplement manufacturer may not represent the product as being for use as a “conventional food" or as the “sole item of a meal or the diet."

Manufacturers of conventional foods and dietary supplements are not required to seek FDA approval prior to marketing their products. Both must follow specified labeling, manufacturing and record-keeping requirements. If a dietary supplement contains an ingredient that was not on the market prior to 1994, the manufacturer must first make a new dietary ingredient notification (NDIN) to FDA that includes the basis for the manufacturer’s conclusion that the dietary supplement will be safe under the labeled conditions of use.

Both conventional foods and dietary supplements are permitted to make “structure/function" claims, which are claims that describe the effect of the product on a structure or function of the body. They are also permitted to make certain “health claims," which are claims describing the relationship between a food substance and reduced risk of a disease or health-related condition. A health claim may be made if (1) FDA issues a regulation authorizing the claim, either on its own initiative or based on a petition or (2) a specified scientific body has issued an authoritative statement supporting the claim. FDA requires there be “significant scientific agreement" supporting the claim in order to issue a health claims regulation. However, manufacturers may seek FDA permission to make “qualified health claims" based on a lower level of supporting evidence (“credible evidence"), provided the claim also includes a disclaimer or other qualifying language to accurately communicate to consumers the level of scientific evidence supporting the claim.

A product that does not meet the definition of a food or dietary supplement but that is intended to affect a structure or function of the body is subject to regulation as a “drug." The category of drugs also comprises articles “intended for use in diagnosing, treating, curing, preventing, or mitigating a disease or condition."  Drugs that are classified as “new drugs" require prior approval by FDA, and such approval may be granted following the submission of an application for new drug approval (NDA) demonstrating the drug is safe and effective for its intended use. Efficacy must be demonstrated based on evidence from adequate and well-controlled clinical investigations. With few exceptions, a drug is considered a “new drug" and requires approval if (1) it was not marketed prior to 1962, and (2) does not fall within an existing over-the-counter (OTC) drug “monograph."

Applying FDA’s category-based regulatory approach, a probiotic could be regulated as a dietary supplement if its intended use was to increase total dietary intake. Under these circumstances, the manufacturer would be permitted to make claims about the effect of the probiotic on a structure or function of the body. A probiotic manufacturer could also petition FDA to make a health claim regarding the relationship of the probiotic to reduced risk of a disease or health-related condition, provided the claim was supported by credible evidence and appropriate qualifying language was used, where necessary.

A probiotic intended to treat, mitigate or cure a disease (and, in the absence of health claim authorization, to prevent a disease), would be subject to regulation as a drug. Furthermore, since probiotics are not addressed in any OTC drug monograph, and since presumably the products do not have a marketing history prior to 1962, probiotics claiming this would likely be classified as “new drugs" and would be subject to NDA standards.

Although probiotics are, from a regulatory perspective, “new," there may be existing information about their safety and effectiveness that can be leveraged to streamline and expedite the drug approval process. For example, FDA has the authority to waive any component of the preclinical or clinical requirements for drug approval if the agency determines the requirement is not needed in order for FDA to evaluate the product. For probiotics that have an established history of human use, or for which there is other evidence that they are GRAS (generally recognized as safe), FDA could potentially waive many of the NDA requirements pertaining to establishing safety.

Similarly, while historically FDA has required two adequate and well-controlled clinical investigations to support drug efficacy, the statute gives FDA the authority to approve a drug based on one study plus confirmatory evidence from other sources. FDA also has the authority to approve drugs intended to treat certain serious or life-threatening conditions based on effect on a “surrogate endpoint"—which may be a nonclinical or clinical endpoint, depending on the circumstances—provided the sponsor verify the clinical efficacy of the drug postmarket.

While these regulatory mechanisms already exist, they have not historically been applied to new probiotics. FDA could, through the issuance of guidance documents and other public statements, encourage research and development (R&D) of validated, well-characterized probiotics. Such guidance would clarify the applicability of existing pathways for streamlining and expediting drug approval to therapeutic probiotics, and expand on any probiotic-specific issues that manufacturers need to address in their applications.

To build agency and public confidence in this class of products, probiotics manufacturers should commit to the adoption of industry “best practices," such as those established by the Council for Responsible Nutrition (CRN) and the International Probiotics Association (IPA).¹¹ FDA should prioritize inspection of manufacturers who cannot establish that they have properly implemented and comply with these best practices.

Realizing the therapeutic potential of probiotics requires a greater understanding by probiotics manufacturers of the nuances of the FDA regulatory framework and the multiple pathways to market probiotics to ameliorate public health threats such as C. difficile. This understanding, in turn, would be facilitated by clear and appropriately tailored guidance from FDA encouraging the development of new therapeutic probiotics. Just as the HMP, now in its second phase, aims to create new scientific tools to facilitate discovery of the microbiome’s impact on human health and disease, FDA must ensure the appropriate regulatory tools are available to enable the translation of these findings into new, validated therapeutic products for the benefit of the public’s health.

Editor’s Note: The authors would like to thank Miriam Guggenheim, Esq., for her helpful comments on earlier drafts of this article, and acknowledge any errors are solely their own.

Gail H. Javitt is a member of the Washington office of Epstein Becker Green in the firm’s Health Care and Life Sciences practice.

Norman B. Javitt, M.D., Ph.D., is a research professor for the Department of Medicine and Department of Pediatrics at New York University Medical Center.

References

1. National Institutes of Health, Human Microbiome Project, https://commonfund.nih.gov/hmp/ (last reviewed May 19, 2017).

2. Id.

3. U.S. Pharmacopeial Convention, USP Global Public Policy Position, Ensuring the Quality of Dietary Supplements (Feb. 2016). http://www.usp.org/sites/default/files/usp/document/about/public-policy/public-policy-dietary-supplements.pdf.

4. Id.; See also Kristensen NB et al. “Alterations in fecal microbiota composition by probiotic supplementation in healthy adults: a systematic review of randomized controlled trials." Genome Medicine. 2016;8:52.

5. International Probiotics Association, Best Practices Guidelines for Probiotics (Jan. 9, 2017). http://internationalprobiotics.org/resources/guidelines/2017-best-practices-guidelines/.

6. Spinler JK, Ross CL, Savidge TC. “Probiotics as adjunctive therapy for preventing Clostridium difficile infection – What are we waiting for?" Anaerobe. 2016;41:51-57.

7. Winston JA, Theriot CM. “Impact of microbial derived secondary bile acids on colonization resistance against Clostridium difficile in the gastrointestinal tract." Anaerobe. 2016;41:44-50.

8. Id. at 4.

9. Spinler, supra note 6, at 2.

10. Winston, supra note 7, at 3.

11. Supra note 5, at 2-4.