Biotechnology Regulations and Ethics

FDA Regulation of Probiotics

One of the most significant implications of the Human microbiome project (HMP) is the expansion of number of probiotic products available on the commercial market. As, it is new area of study, new claims are being made about the role and the value of probiotics in promoting human health and well-being. However there is some uncertainty about the how these products should be regulated. The Goal of this paper is to discuss the current legal and regulatory issues raised by probiotics and to determine whether the current regulatory framework is a good fit for the products that are available on the market which may be developed in the future as a result of HMP. This paper discusses the current regulatory structure of probiotics, issues, concerns and broad recommendations.

According to the Joint Food and Agriculture Organization/World Health Working group, probiotics are defined as “live microorganisms which, when administered in adequate amounts, confer a health benefit in the host”. However no legal definition of probiotics exists, in the U.S or in other countries which allows the marketing of products labelled as “probiotics” that do not meet the fundamental criteria stipulated in the scientific definition. Probiotics are live nonpathogenic microorganisms administered to improve microbial balance, particularly in the gastrointestinal tract. They consists of Saccaromyces boulardii yeast or lactic acid bacteria, such as Lactobacillis and Bifidobacterium species, and are regulated as dietary supplements and foods. There are available commercially in many products but primarily as foods and dietary supplements. However a wider variety of probiotic strains, either singly or in combination, is used in supplements than in foods. Supplement formulations may also contain other active components, including vitamins and prebiotics [1]. Probiotics in the form of clinical therapeutics and diagnostics are currently under development. As with any health related product, it is important that probiotics be safe and effective. Moreover, probiotics must be prepared in such a way that the beneficial effects persist throughout the supply chain of the consumer and also through the expiration of the product. As probiotics begin to proliferate in the market, there is a need to consider the regulatory structure that is fits more suitably for the current situation because the current regulatory environment of the probiotics is unclear. According to me, the regulatory structure should account for the risks of probiotics as well as the accuracy of the claims of effectiveness is necessary to protect and guide the consumers who may use or recommend their use. Additionally, the regulatory structure needs to be flexible enough to allow research on the future probiotic products that may have therapeutic benefits.

The main fundamental issue surrounding probiotics is to identify whether there have intrinsic and distinct characteristics that are important in considering how they should be regulated. Unlike chemicals, by nature probiotics are live organisms that are dynamic. Probiotics may degrade and lose their viability under certain circumstances, as a result, probiotic research and production involves a greater number of variables than research with many other substances, which includes the environment on the effectiveness and viability of the probiotic; the interaction with the human genome and human microbiota and triggers within the human body they may activate or deactivate the probiotic. Thus, Quality control is essential otherwise, certain probiotics may lose the properties that once formed their selection and isolation criteria. The role of animal models may be of limited use in probiotic research because the human microbiome is highly complex and differs significantly when compared to animal microbiomes. For example as with botanicals, there are differences that appear from batch to batch when manufacturing probiotics. Also, many probiotics are consumed as foods. Finally, unlike other products regulated by the FDA, probiotics are often derived from microbes living in humans. Given these differences, probiotics raise some unique and potentially problematic questions of dosing for therapeutic purposes, manufacture, storage and shelf life. These intrinsic characteristics may be difficult to translate into regulatory processes. In addition to these characteristics, probiotics as live microorganisms that differentiate them from most other health related products, another unique feature of probiotics is that they are intended to promote wellness and balance. Although the HMP and its related research are likely to lead clinical therapeutic (drugs) uses for certain probiotics, most stakeholders in the world of probiotics understand that most of these products play a role that is unlike that of drugs. As a result most of the probiotics products are sold as food and dietary supplements. Studies have shown that probiotics to some extent contemplate the role of foods in preventing or reducing illness and disease. This very concept of promoting balance in body systems is not the part of disease paradigm that has governed regulation of health related products in this country for years. Broadly speaking, under the disease paradigm, humans are healthy unless they have illness that must be diagnosed and treated. Under the current law, any article that is used for “diagnosis, cure, mitigation, treatment or prevention” of disease or “intended to affect the structure or any function of the body of man or other animals” is a drug. This definition sweeps into it any products, including foods that have a role in treating or curing the disease, except in the case of foods and dietary supplements which make claims regarding the effect of the product on the structure or function of the body. It is important to note that the traditional definition of the drug does not consider the use of the products to promote a healthy balance of microflora, the role of such products in healthy individuals or in promoting health. By taking all these into consideration, it is better to consider an alternative wellness paradigm would be a useful response for current probiotic research which is revealing the role of probiotics in keeping healthy people healthy and preventing or reducing the risk of illness. Another unique feature of probiotics is their potential effect on the environment. The effects of probiotics released into the environment, their ability to multiply and the possibility that they may have adverse environmental effects, have not been studied adequately. This is particularly important in case of research in genetically engineered bacteria. As we have already discussed the variation of probiotics with other products, let us discuss about the regulation of probiotics by FDA.

In any regulatory analysis, the initial question which should be addressed is what regulatory structure is already in place and does the new product fit within that existing regulatory structure, or does it raise concerns that require a new or revised regulatory framework. An insight of the current regulatory framework is mentioned below.

It is often misstated that probiotic products are unregulated. Clearly, the FDA has regulatory authority over probiotic products. In the United States probiotics are sub categorized as dietary supplements/drugs/live bio therapeutic agents/medical food. They are regulated on their intended use. Largely, probiotics have been under the conventional foods or biological product categories. The reason behind regulations and the purpose of the FDA is to protect the public health (FDA, 2011). Biological products containing whole, live microorganisms are regulated under section 351 of the Public Health Service Act of 1944 (PHS Act), 42 U.S.C. 262. A biological product is defined as:

“a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.” (42§262)

Requirements are that the “biologic product that is the subject of the application is safe, pure, and potent”, the manufacturing facility meets these standards, and an inspection of the facility is conducted (42 USC 262). A Biologics License Application (BLA) is submitted through the Center for Biologics Evaluation and Research (CBER) to gain approval to market a Live Biotherapeutic Product (LBP). This is done when the LBP is intended for the use of preventing or treating a disease, and requires clinical trial results from an Investigational New Drug (IND) Application (21 CFR part 312). The requirements and fees for INDs are steep, and include (i) a description of the composition, manufacturing process, and control testing of the drug substance and drug product, (ii) pharmacological and toxicological studies of the drug in vitro or in animal models to support the proposed clinical investigation, (iii) previous human experience, if any, (iv) proposed clinical study protocol, and (v) any other information deemed relevant for review. Filing costs for applications requiring clinical data are over $1.8 million, or over $0.9 million when not requiring clinical data (Federal Register 76:147, 2011).

However, recently there has been active interest across many medical disciplines in the use of probiotics for a myriad of clinical indications meet the definition of a drug per the Food, Drug, and Cosmetic Act of 1938. In addition to these, the FDA Office of Combination Products (OCP) responds both formally and informally about industry inquiries about which FDA center should regulate a particular product. The OCP divided the regulatory responsibilities for products combining elements of drugs, devices and biologics among relevant centers---CDER, CDRH and CBER. Where a product contains a drug and a medical device, a drug and a biologic, a medical device and a biologic, or all three, it is termed a “combination product” and regulated according to the primary mode of action.

As discussed earlier, FDA places products in categories by their intended use, as the intended use of the product is based on the claims made by the manufacturer rather than the ingredients or other characteristics, the statutory definitions of the FDA product categories are important to note, as they relate to the category into which a probiotic product might fit and which FDA center will regulate it. Particularly relevant to the regulation of probiotics are the definitions of food, components of food, dietary supplements, cosmetics, and drugs:

1) Conventional foods are articles used for food or drink for humans and animals. Within this broad category are subcategories mainly

Food addictive: any substance the intended use of which results or can reasonably expected to result, directly or indirectly, in its becoming a component or otherwise affecting the characteristics of food unless the substance is generally recognized as safe (GRAS).

Substances recognized as safe: substances added to food that are generally recognized, among qualified experts, as having been adequately shown to be safe under the conditions of their intended use. A food substance may be established as GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on

Common use in food.

Medical Food: 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.

Foods for special dietary use: a narrow category of foods that FDA defines as “foods that are specially formulated to meet a special dietary need, such as a food allergy or difficulty in swallowing, but that provide nutrients intended to meet ordinary nutritional requirements.” By regulation, FDA has approved label statements for three categories of foods for special dietary use – hypoallergenic foods, infant foods and food “that purports to be or is represented for special dietary use because of usefulness in reducing or maintaining body weight.

Cosmetic: a product, except soap, intended to be applied to the human body for cleansing, beautifying, promoting attractiveness, or altering the appearance

Dietary supplement: a product that is intended to supplement the diet and contains any of the following dietary ingredients: a vitamin; a mineral; an herb or other botanical; an amino acid; or a concentrate, metabolite, constituent, or extract; or combination of any of the above. The product must be a substance historically used by man to supplement the diet; intended for ingestion in pill, capsule, tablet, powder or liquid form; not represented for use as a conventional food or as the sole item of a meal or diet; and labeled as a “dietary supplement”

2) Drugs: an article that is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or in other animals.

Cosmetic Drugs: – a product can be both a “cosmetic” and a “drug” depending on the nature of the claims. There is no statutory category for, or definition of, cosmetic drugs. A product can be both if it claims to both cleanse or beautify (a cosmetic) and makes a drug claim. For regulatory purposes, the FDA treats such dual status products as drugs and subjects them to drug safety, efficacy, labeling, and manufacturing requirements.

How regulation works

The Food, Drug and Cosmetic (FDC) Act lays out a highly varied legal framework that governs a wide array of products. The system of regulation delineated in the FDC Act is anything but the one size fits all approach. Under the regulatory system laid out in the FDC Act, the nature of the restraint that can be imposed on a given product hinges, in large part, on how the product is categorized. Specifically, how a product is categorized under this act governs the regulatory and evidentiary burdens that the manufacturer and the FDA have with respect to demonstration of the lawfulness of a given product. For instance, if the product falls within the definition of the food addictive, new drug or a biological product, an evidentiary burden is placed on the manufacturer to demonstrate the propriety of the product before marketing. Conversely, other product categorizations under the FDC Act result the regulation under post market systems which permit the manufacturer to place a product without seeking any approval from the FDA which in turn places an evidentiary burden on the FDA to take action against the product. If the FDA has regulatory concern about a marketed product, then it may look for ways to categorize that product so that it is subjected to premarket, as opposed to post market controls, which substantially reduces the regulatory and evidentiary burden on the FDA with regard to restricting the marketing of the product.

One general point needs to be addressed regarding the categorization; regarding matters deemed by the FDA to present meaningful public health benefits, where there has been certain tension about how FDA opts to administer and apply the FDC Act whether the FDA should opt to foster restraint or to foster innovation. The FDA’s decision on regulation of botanicals provides a relatively recent and clear example to choose the latter (innovation). In doing so, the FDA considered the promising potential of the technology to yield a safe and abundant food supply and opted to pursue regulatory pathways and categorizations that are tailored, in part to encourage innovation. Nevertheless, it should keep in mind that, as a matter of routine, the FDA, as public health protector, is naturally inclined to favor restraint in its efforts to ensure the public health.

As science and technology develop, new and unanticipated challenges face the FDA in terms of safety and efficacy. Regulations are created to broadly cover different product in response to the uncertainty of future needs. Depending on the intended use of a probiotic, whether as a drug or a dietary supplement, regulatory requirements differ. If a probiotic is intended for use as a drug, then it must undergo the regulatory process as a drug, which is similar to that of any new therapeutic agent. An Investigational New Drug application must be submitted and authorized by FDA before an investigational or biological product can be administered to humans. The probiotic drug must be proven safe and effective for its intended use before marketing. After a manufacturer completes this extensive testing, the FDA reviews the application. If approved, the drug may be marketed as safe and effective for its intended use. This process takes several years. As of this writing, the FDA has not approved any probiotics to be marketed as drugs. One serious problem with conducting research on efficacy of probiotics is the FDA definitional structure. Probiotics are, by definition, safe. This allows them to be sold as food, dietary supplement or food additive. Hence, they cannot be drugs because drugs are unsafe. Nevertheless, claiming that the probiotic is effective in alleviating a symptom or disease is making a drug claim which requires the product to be evaluated as drug. For instance, Lactobacillus GG is currently approved as food additive that is safe for use in infant formulas. To access its efficacy in addressing the symptoms, the product must go through all of the same multiple level tests and approvals that would apply to introducing a new chemotherapy drug. Thus, the presumption that drugs are dangerous and foods are not, coupled with extensive review and research process by an FDA NDA, which has created an environment in which the manufacturers are reluctant to gather evidence on the efficacy of their probiotic product. Instead, they market the products as foods or dietary supplements and forgo learning whether or not they are effective. So long as manufacturers find a market for their probiotics without proving their efficacy, they would avoid clear claims about their function.

In contrast to drugs, dietary supplements do not need FDA approval before being marketed. However, manufacturers need to notify FDA before marketing a product. According to DSHEA, the manufacturer is responsible for determining that the dietary supplements that it manufactures or distributes are safe and that any representations or claims made about them are substantiated by adequate evidence to show that they are not false or misleading; the manufacturers need not provide FDA with evidence that substantiates the safety or purported benefits of their products, either before or after marketing. If a dietary supplement contains a new dietary ingredient that was not sold before October 15, 1994, then the manufacturer is required to notify FDA and demonstrate to FDA before marketing why the ingredient is reasonably expected to be safe for use in a dietary supplement. On June 22, 2007, FDA announced a final rule establishing Current Good Manufacturing Practice requirements for dietary supplements. To ensure the identity, purity, quality, strength, and composition of dietary supplements, those who manufacture, package, or hold dietary supplements must follow these regulations. Also, since the implementation of the Dietary Supplement and Nonprescription Drug Consumer Protection Act in 2006, manufacturers and distributors of dietary supplements have been required to record and forward to FDA any directly received reports of serious adverse events associated with use of their products.

Claims and labeling

In part, the regulations that apply to a product are related to kinds of claims that a manufacturer makes about its contents, intended use and efficacy. Both the FDA and FTC regulate the claims in probiotics. In general, the FTC gives great deference to an FDA determination of any claim. The federal trade and commission (FTC) and the FTC Act, sections 5 and 12, also regulates the kinds of claims that may be made about products, including claims related to the over the counter drugs, food, devices and cosmetics. Section 5 of FTC Act prohibits unfair or deceptive acts in affecting commerce. Section 12 prohibits disseminating or causing dissemination of a false advertisement in commerce for the purpose of inducing, the purchase of food, drug, device or cosmetics. One major concern is what claims can be made about the probiotic products and the substantiation required for each type of claim. This is particularly completed in the area of probiotics because most probiotics appear in foods and dietary supplements and making health or disease claims may risk the products pushing towards the drug category. This is further complicated by the fact that the approved health claims are not regarded as better than structure/function claim [2]. Thus, product development of probiotics may be stifled because there appears to be little return of investment for a food company to go through the costly and lengthy process to gain an approved health claim. In fact, very few manufacturers have availed themselves for the process in place for approval and authorization of qualified health claims because of the amount of time and also lack of understanding of FDA guidance in this area. Although the FDA had issued detailed regulations and guidance on these claims which attempts to distinguish between claims for foods and dietary supplements, the guidance has not always been helpful. For health related products, both the FDA and FTC regulate what manufacturers say about the product. Furthermore, the claims a manufacturer makes about a product also relate to how the product is regulated by the FDA. The issue of how the claims are regulated is very complex because different FDA regulatory categories require different degree of scientific substantiation.

Labeling:

The FDA has the responsibility for administering federal food labeling requirements in accordance with the FDCA. The Act prohibits labeling that is false and misleading. The Dietary supplement Health and Education Act (DHSEA) amended the FDCA by defining dietary supplements and adding specific labeling requirements, as well as optional labeling statements. Labeling for drugs differs from that of a food and dietary supplements. Currently, probiotic manufacturers do not have to specify on their product labels the strains they use in probiotic products or specify the number of live microbes of each strain that the products deliver through the end of the shelf life. However some manufacturers refuse to divulge this information by claiming them as proprietary information.

In sum, current regulatory structure has no clear and useful mechanism to require systemic scientific study of probiotics and their effect on human microbiome. On the other hand, the current regulatory structure allows manufacturers to market their products without providing either physicians or consumers with the research data to support claims about their efficacy. Thus, manufacturers who have established a market for their products have no incentive to conduct studies that might demonstrate that their products are less effective than consumers believes them to be. Other than this, probiotic manufacturers are developing new functional products where labeling of the product with health claim is important. This plays an important role in marketing of the new product, with appropriate labeling. Any petition to a regulatory agency for a health claim will have to name or describe the active ingredients in the product to be approved and provide evidence of efficacy. Companies seeking approved label health claims for probiotics may find this somewhat problematic. For example, definitive identification of the microorganisms contained in the probiotic product often requires rigorous molecular biology and informatics techniques [3]. Polyphasic characterization combining phenotypic, biochemical, genotypic, and sequencing results is now being used to reliably identify bacteria to the strain level [4]. This is particularly important because it is now evident that even closely related bacterial species can have different properties. Properties such as pH sensitivity and resistance to bile salts or other characteristics may affect their ability to survive in the gastrointestinal (GI) tract and exert their beneficial effects [5, 6]. It is therefore, essential that the bacteria included in a probiotic be identified to the species or subspecies level. In some cases, the bacterial strain used is proprietary, which can make verification of its identity by regulatory agencies more difficult. To obtain a health claim for a probiotic product, food manufacturers will have to precisely define their microorganism.

In addition to this, the definition of probiotic emphasizes that the organism must be taken in adequate amounts to be effective. To support a health claim, it is thus imperative that the product manufacturer provides data about the total number of live microorganisms in the product when consumed as well as methodology that can be used to verify these values. To the consumer, “more is better,” and so efforts are often made by food manufacturers to highlight the large numbers of bacteria in their product. Enumerating bacteria or other microorganisms in a food matrix is not easy [7], and if the product contains more than 1 microorganism, individual methods may have to be used to enumerate each microorganism. Although there are accepted methods for the counting and reporting of pathogenic and spoilage organisms in food, such universally accepted methods do not exist for probiotic bacteria. Stating the type, viability, and number of bacteria contained in a probiotic product is important to both the consumer and health regulatory officials. At the present time, there is little incentive for manufacturers to include this information on their product; the costs for such quality assurance would be high. As regulations become clearer as they relate to probiotics, manufacturers can expect that they will be required to state this information. Moreover, the experimental evidence to identify probiotic microorganisms and to demonstrate their efficacy in clinical trials is more challenging when compared to other potential functional foods because effects are mediated by living microorganisms and may therefore be influenced by the status of these microorganisms. Mechanisms are seldom known, markers are generally not available, and matrix effects may be pronounced. Because of the lack of well-controlled studies in humans, health regulatory officials in most jurisdictions have not yet been convinced that there are sufficient consistent data to support health claims for probiotics, and so very few approved health claims on probiotic food products have been granted to date.
Probiotics have been tested on a long list of diseases and conditions, and it appears that a scientific consensus is approaching for the use of certain probiotics for lactose intolerance and rotavirus diarrhea. Claims related to these benefits may be the first to be accepted in many jurisdictions. Before other claims are approved, manufacturers will have to invest considerable time and money to obtain data to show the efficacy and safety of their probiotic product. The data and documentation required to obtain a label health claim will be different in different jurisdictions because of differences in legislation. These discrepancies will add to the challenges faced by probiotics producers and consumers.
In terms of efficacy no single biomarker has been identified that applies to all clinical trials involving probiotics because of the wide variety of diseases and conditions that have been studied. The efficacy of probiotics has been studied for a variety of diseases and metabolic problems including Crohn's disease [8], irritable bowel syndrome [9], cholesterol metabolism [10], anticancer properties [11], and diverticulitis [12]. However, that the degree of success that has been obtained for these conditions/diseases in probiotic feeding trials has not been uniform and it would be wrong to assume that there exists good evidence to suggest that all of these conditions may be improved with probiotics. In many cases the GI tract has been the primary target [13], but it is becoming evident that other conditions including allergies, obesity, and urogenital infections not initially associated with the gut microbiota might also be affected [14]. A variety of mechanisms have been proposed to explain the responses to probiotics, including production of organic acids, production of bacteriocins (bacterial substances produced by a strain of certain bacteria and harmful to another strain within the same family), and reduction of toxin-producing organisms [15] as well as effects on the mucosal epithelium and the gut-associated lymphoid tissue [16]. The suggestion that probiotics may be stimulating the immune system has generated a great deal of interest because of possible consequences to health and metabolism. However, studies are not often replicated, and therefore, efficacy is hard to establish. Some articles often lacked details such as the bacterial strain fed, the numbers of live bacteria consumed, or the timing of the consumption, e.g., with or without other foods, which limits their usefulness to prove efficacy. Despite the long list of conditions that have been tested with various probiotic products, very few health/metabolism conditions have been studied enough to obtain a label health claim. Efficacy experiments must be replicated and have appropriate numbers of subjects to achieve scientific consensus. The claim of efficacy will be greatly enhanced if a plausible mechanism can be suggested, or demonstrated, that explains the beneficial effect.
A microbial strain has to fulfill a number of specific properties or criteria for it to be regarded as probiotic. These criteria are classified to safety, performance and technological aspects (Gibson & Fuller, 2000). The criteria are further dependent on specific purpose of the strain and on the location for the expression of the specific property. With regards to safety, the probiotic strain must be of human origin, isolated from the gastrointestinal tract (GIT) of healthy individuals. They should possess GRAS (generally regarded as safe) status, be non-pathogenic, and without previous association with diseases such as infective endocarditis or gastrointestinal disorders. Probiotic strains must not deconjugate bile salts and they should carry no antibiotic resistance genes that can be transferred to pathogens (Collins et al., 1998; Saarela et al., 2000). The available literature regarding strains indicates that the safety evaluations of probiotics should consider pathogenicity, infectivity, virulence factors, toxicity, metabolic activity and intrinsic properties of microbes. While some strains are safe for human use, for others there is a limited data on safety. One issue of concern relating to the safety of probiotics is the potential for lateral/horizontal gene transfer which means exchange gene exchange from parental generation to offspring. Lateral gene transfer is the mechanism of gene exchange that happens independently of reproduction and is of the mechanisms for bacterial antibiotic resistance [17]. In an ever changing environment such as GI tract, introduction of new organisms such as probiotics may eventually lead to lateral gene transfer. Traditionally, the gold standard for determining the safety and efficacy of new drugs is the randomized placebo controlled clinical trial. Such trials however present some challenges on food safety. The randomized clinical trials are designed primarily to address efficacy, although it may also provide safety information through post market research. When it comes to safety, it can be determined by its history of safe use of the product without significant adverse events. This concept is adopted by the FDA and other regulatory bodies. For instance, a food substance may be established as GRAS (if used before 1958). Under 21 C.F.R. 170. 30( c) and 170. 3 (f) general recognition of safety through experience based on common use in foods requires, among other things, a substantial history of consumption of substance for food use by significant number of consumers. The FDA has approved a number of microorganisms and microbial derived ingredients that are used in food as GRAS [18]. The challenge of conducting clinical food safety studies had a major impact on the most extensive review of probiotic safety till date. On July 2011, the FDA released draft guidance in the area of NDI regulation. The guidance was met with widespread concern by probiotic industry because although it does not refer to probiotics specifically it used the term microorganisms and says that not all microorganisms are dietary supplements. As noted above, probiotic manufacturers usually do not want their products placed in the drug category because of the additional regulatory burdens and the cost of development of drugs. Therefore manufacturers who are contemplating adding new or different probiotics to a dietary supplement want the new addition to be considered as a dietary ingredient rather than a non-dietary microorganism that might require the product to be regulated as biologic or drug. However in June 2012, FDA indicated that it would revisit the controversial new IND guidance [19].

Issues of concern
While probiotics come fall into virtually every product category regulated by the FDA, to date, the FDA does not have a central pathway that deals specifically with probiotics. Nor it has a regulatory definition for probiotics. Probiotics are regulated based on product category they fall. I.e. food, food additive, cosmetic, dietary supplement or drug. When question arises into which category a probiotic belongs, the answer would be determined on case by case analysis. Moreover although many are sold as dietary supplements, probiotics are not specifically listed under the definition of dietary supplements, which specifically lists, vitamins, amino-acids etc.. The main concern here is, because probiotics falls into multiple categories, lack of expertise among the products, spread unevenly in multiple centers at the FDA without a single authoritative agency voice on any issue. This in turn led to inter center inconsistencies in interpretation and application of regulations, data requirements, and the content of potentially relevant documents. Furthermore, in the absence of a clear FDA position on regulation of probiotics, CBER may act like the default center to review any probiotic where there is a question about whether the product requires IND given that recent CBER guidance implies that probiotics are live bio therapeutics. This issue is of great concern because; CBER may not be the most appropriate center to regulate probiotics. In addition to this, the current regulatory framework does not properly address the role of foods in preventing disease, improving health, or treating a disease. For instance, although there is a statutory category for medical foods ( 21 C.F.R 101 J8) the FDA has not promulgated regulations or issued guidance clarifying the category could include probiotics. Probiotic foods and dietary supplements that attempt to take on the role of improving health or treating a disease are directly placed under the drug category. A related concern is that once a manufacturer pursues an IND for a probiotic product, it will get locked under the drug category. Section 912 of the FDA Amendments Act of 2007 added sub section 301(11) to the FDCA, which prohibits the sale of food to which a drug, licensed biological product, for which substantial clinical investigations have been instituted has been added. From a historical perspective, this marks a significant change in the regulation of food and drugs. Prior to the advent of the subsection 301 (11), there was considerable flexibility in the regulatory categorization of a substance as a food, a drug, or both. This in fact inhibits manufacturers and researchers from pursuing research that studies the role of foods in preventing disease, improving health, or in the treatment of the disease as the FDA considers probiotics to be biological products. This would become a problem if the manufacturers prefer to market their product as a food for general consumption rather than as a drug with a more limited distribution.
However, according to my opinion, the current FDA regulatory framework provides a comprehensive and potential flexibility for regulating probiotic products and is able to incorporate probiotics as it has incorporated other new types of products. More-over, the regulatory framework clearly indicates that the intended use of a probiotic product should govern the regulatory category into which the product will fall and accordingly, the regulatory requirements the product must meet. This kind of regulatory framework offers enormous pathways for marketing and also issues concerning research could also be addressed by ensuring that the product is placed in a particular regulatory pathway.

With the advent of the HMP, research relating to probiotics has increased in the last decade resulting in numerous research concerns. At the root of these concerns is that the researchers and manufacturers would like to conduct research on probiotics in a manner that is safe and appropriate but not be subjected to research regulations for drugs as they may not be applicable to certain commonly used probiotics, in particular, foods.

This would lead us to IND where a request for authorization from the FDA to administer an investigational drug or biological product to humans is placed. Such authorization must be sought prior to interstate shipment and administration of any new drug or biological product that is not subject of an approved New Drug Application or Biologics/Product License Application (21 C.F.R 312. 40). An IND is required for a clinical study if it is intended to support a new indication of a drug, a change in the approved route of administration of dosage, a change in approved patient population or a significant change in the promotion of an approved drug (21 C.F.R 312.2). There are two main categories of IND: investigator initiated and sponsor initiated. Investigator initiated IND’s are used when an academic researcher or physician wishes to perform an unapproved drug treatment. Sponsor initiated IND’s are used by pharmaceutical companies while studying new drugs or new applications for existing drugs [20]. Both of these types of studies require approval from institutional review board (IRB), which is an independent body constituted of medical, scientific and non-scientific members, whose responsibility is to ensure the protection of rights, safety and wellness of human subjects involved in the clinical trial. The IRB must review, approve and provide continuing review of the trials, protocols and of the methods and materials used in obtaining informed consent of the subjects. However there are certain issues regarding the research of probiotics. As we know the statutory definition of a drug in the FDCA is an article intended to diagnose, cure, mitigate, treat or prevent disease (21 U.S.C 321 (g)). This definition is used among other things to define how and when a research study can be used to make claims about a product. If a clinical research trial measures an outcome that indicates a substance ability to diagnose, cure, mitigate, treat or prevent a disease and the study is used to make claims about the substance, the FDA will consider the substance as a drug. The measured outcomes are considered as endpoints, and if the endpoints measures the way a substance diagnose, cure, mitigate, treat or prevent a disease, it is described as a drug or disease endpoint. Use of disease endpoint has two important consequences: 1) the research becomes drug research, and is therefore subject to higher levels of scrutiny and human subject protection than research on non-drug substances. 2) The research cannot be used to support product claims for foods and dietary supplements. Because probiotics generally promote wellness and balance, many of the studies that have been undertaken on probiotics have been conducted using endpoints that would be viewed by the FDA as disease endpoints. For example, a test conducted on fermented milk, on its ability to reduce the incidence of common infectious diseases in healthy children. Even though the study documented a decreased incidence rate in common infectious disease, the use of the product is regarded as a drug. Under the current FDA regulatory framework for claims, this study could only be used to substantiate a drug claim, therefore making fermented milk a drug according to FDA. This had complicated the process where the researchers and manufacturers are concerned that the studies with disease endpoints will take their products out of the food and dietary supplements market where they believe most of these products belong. Compounding this problem is the paucity of the endpoints that are not disease endpoints. It is challenging to measure health improvement in healthy person. Some researchers have suggested that the focus of probiotic studies could be the measurement of homeostasis. It provides a rationale based in solid statistical theory as a way to measure wellness or health maintenance [21]. One challenge to demonstrate the value of this kind of approach is to identify the appropriate biomarkers that can be used to study. The following properties would be important in a biomarker:

1) maintaining moderate levels of the biomarker would be associated with good health

2) High or low values would be associated with ill health

3) biomarker levels in the same person would fluctuate over time

Such biomarker could be individual endpoint or be formed as a ratio of two other biomarkers, when maintaining the same relative amounts of the two component biomarkers would be desirable [21]. If a biomarker which is available and which could be used as the outcome measure in a randomized control trial to provide evidence that the experimental food is able to improve the maintenance of human health. However the FDA often require IND for studies related to probiotics even in cases where IND is not appropriate. This would create significant problems in some cases, for investor initiated IND’s which causes the academic researcher should depend upon the manufacturers. In addition to this the cost and time required to complete an IND may have some effect on probiotic research.

In relative to this, the key concern is that in the draft FDA guidance, it has been stated that all probiotics are live bio therapeutic products (even the ones being marketed as foods or dietary supplements) and therefore require going through IND process. This would have been the case even if the product manufacturer intended the research to test claims that are legal for foods. The IND subcommittee viewed this articulation of the law as inaccurate because under the current law, assignment of a particular use of a substance or microorganism to a product category is properly based on the claims made, rather than on the nature of research of supporting those claims.

In February 2012, this concern appeared to have been addressed to a certain degree by the FDA. In final guidance relating to clinical trial with live bio therapeutic products (LBP), the FDA stated that the guidance does not apply to products lawfully marketed as conventional foods or dietary supplements that are proposed for investigation solely to evaluate an LBP use in affecting the structure or function of the body [22]. As such it appears that an IND would not be required for studies of foods and dietary supplements that are conducted to make structure/function claims. However, other language in the February 2012 guidance stated that if a clinical investigation is intended to evaluate a product’s ability to diagnose, cure, mitigate, treat or prevent a disease, an IND is required under 21 C.F.R. Part 312. The IND subcommittee expressed concern that, even with the new guidance in place, the FDA will interpret any study with clinical endpoints as one in which the intent is to diagnose or cure the disease, even if the sponsor asserts that the intent of the study is to make reduction of risk of disease claim. In addition the new guidance is not broad enough, as it does not mention investigations related to medical foods or foods for special dietary use.

Recommendations:

As I had already mentioned earlier, that probiotics fall under multiple categories, expertise about them is spread unevenly across multiple centers at the FDA without a single authoritative agency leading to inconsistencies in the IND process and also where few manufacturers believe that probiotics should be regulated separately as their believe that the current regulatory framework is not flexible enough while others believe that the current regulatory framework provides a comprehensive and potentially flexible framework for regulating the probiotic products . In my opinion to address this issue I would recommend that the FDA could create more streamlined process, which includes creation of new regulatory pathway within the FDA where dedicated offices that would make initial decisions about the product and then depending upon the type of the probiotic product, assign the product either to the designated center or either to the new pathway. Probiotic products which would fall into the new pathway should be regulated differently when compared to other regulated products. For example, certain probiotics may be subjected to an abbreviated IND process; in addition, research on probiotics in this category could be conducted on a disease endpoint such that the probiotics which fall under this new pathway would have certain similarities that distinguish them from drugs. In addition to this, other recommendations would be that the FDA should establish collaborative pathways for products that may fit within the traditional categories. The public and the relevant stakeholders should have input into these establishing these pathways using educational outreach, public meetings etc, to gather information regarding the products. Also the FDA should consider the opinion of the scientific and technical advisory boards regarding the probiotics. More importantly, to work out all these recommendations, there is a need for adaptation of definitions and standards. As probiotics is relatively new subject for scientific research and product development, there is a need for internationally accepted definitions and precise language to describe the products and their impact on health and disease. According to Joint Food and Agriculture Organization, the definition of probiotics: “Live microorganisms which, when administered in adequate amounts, confer a health benefit on the host”. This definition may need to be revisited as knowledge expands regarding the mechanisms of action of probiotics and as novel formulations and genetically engineered microorganisms become available. In addition to this, certain products are claimed to be probiotics and are marketed with taxonomically incorrect or fictitious microbial names. In order to avoid this confusion, all the microorganisms which are used as probiotics be defined by genus, species and strains and also I would recommend the use of current nomenclature codes. And also reevaluation of the section 301 (11) of the FDCA should be done by congress as the provision prohibits the addition of food of an approved drug, a licensed biological product for which substantial clinical investigations have been instituted. This would result in the substances that are not going to be marketed as drugs or biologics to be marketed as food and thus widely available. Congress should add probiotic to the list of dietary supplements in DSHEA, so that it would listed with other articles noted in the statute as vitamins, minerals, herbs and other botanicals. The category of the products that are considered as foods should be clarified and expanded which would further direct us towards the concerns relating the research endpoints. Clearly the present scenario of probiotics states that there should be a need for preclinical studies to provide biological basis of and jurisdiction for design of later phase clinical trials. The probiotic markets of both Japan and the European Union are much larger and more mature than the US probiotic market, because of long histories of traditional use, consumer comfort with microbial ingredients in food, different regulatory frameworks, and perceived health benefits from probiotic products in those regions. Currently in the USA most probiotics are sold as food ingredients, particularly in fermented dairy products and in capsules, as dietary supplements. For specific well-characterized probiotics, a long history of use as food ingredients provides support for safe use in humans as well as some of the evidence needed to make general health claims. However, to establish preventive or therapeutic claims for patient populations, it is time to reconsider the biological basis of the effects of probiotics and whether there is a need to address new issues that may have a positive or negative effect on the safety and efficacy of these products in these populations. Advances in the understanding of the relationship between the microbiota and the development of the innate and adaptive immune system provide an important new opportunity to understand the mechanisms by which particular probiotic strains exert specific clinical effects and to revisit dose-response characteristics. Validated methods in preclinical studies, such as the use of in vitro and in vivo animal models of disease, may provide important new data and surrogate markers of both safety and efficacy of probiotics. These may translate into better-designed preclinical studies of healthy subjects and patients, as well as increasing the success rate of phase 2 and 3 clinical studies. However concerns relating to research endpoints lead to several conclusions. There are no validated biomarkers for disease prevention, without these acceptable endpoints companies may struggle to conduct useful clinical trials for non-drug claims. Researchers and manufacturers are concerned that studies with disease endpoints will take their products out of the food and dietary supplements due to the current FDA framework for claims. In this case I would recommend that the FDA should adopt clear guidelines for when an IND is required and an abbreviated IND process that would allow researchers, to bypass phase 1 clinical studies. If the proposed research is to support the development of a new drug, then an IND should be required or if the research is to investigate non drug claims for a food or dietary supplement, IND should not be required even if the researchers use a disease end point.

For the probiotics products to be developed and manufactured with full confidence, safety of the products plays a vital role. Safety is clearly an overarching concern among all the probiotics stake holders from government regulatory agencies to manufacturers. The safety standards for probiotic dietary supplements are not sufficient. This is particularly an issue for dietary supplements sold prior to 1994 for which manufacturers need not submit any safety data to the FDA (section 413 © FDCA codified at 21 U.S.C Part 350(b)). The particular area of concern here is the GRAS substances and NDI, both of which require manufacturers to conduct their own safety assessments. In regards to NDI process, the concern is how manufacturers should determine if a probiotic was present in the food supply prior to 1994 or how can be it be determined as NDI. Clearly it is easier for the manufacturer if an ingredient is grandfathered in and not subject to FDA notification requirements. Another issue at stake in regards to NDI regulation is that in the recently released guidance by the FDA which states that not all microorganisms are dietary ingredients. As noted earlier manufacturers doesn’t want their probiotic products to be placed in drug category. Therefore manufacturers who are contemplating adding new or different probiotics to a dietary supplement want the new addition to consider as a dietary ingredient. Since there is no proper guidance and regulation for this, a whole lot of confusion is created. This process has raised issues concerning the safety use of the probiotics products in order to address this; I would recommend that the FDA should clarify guidance relating to NDI to allow newly discovered probiotics to be used as dietary supplements but only with safety assessment. Prior to this the FDA should use same approach for safety of NDI’s as is used for GRAS substances, which primarily focuses on the safety of the ingredient on its intended use as this approach doesn’t separately require safety assessment for every product. The FDA should establish procedures for the safety of the probiotic products which would require the companies to report serious adverse events to the FDA. More-over, categorization of the safety risks will be more appropriate which could be achieved by creating classes of the probiotic products based on the risks associated.

Other issue relating to probiotics is the characterization of the products. As characterization is used to identify the products and to ensure that a product is what it claims to be reliable identification by adequate methods confirms the identity of the strain in commercial use and is also necessary in labeling the product. The issue of characterization is particularly important in probiotics because unlike most regulated products, these are live microorganisms which change over time, making it more challenging to be certain of the characteristics of the product post manufacturing. However the FDA has not set characterization requirements specifically for probiotics either at the research or manufacturing stage. Although, the agency published guidance, that set forth the requirements for early clinical trials using LBP without the using the term probiotic which would clearly indicate that the FDA believes that the probiotics fits in LBP category. This would further explain that the LBP guidance is inappropriate for probiotic foods and dietary supplements not making the drug claims as the LBP characterization standards are mainly focused on products which may not fit for probiotics because safety and effectiveness may be dependent on both the characteristics of the product and microbiome of the consumer. Therefore, in terms of characterization requirements for probiotics I would recommend that the characterization standards should be developed by the FDA separately for drugs, foods and dietary supplements. The FDA should specifically address the seminal bacterial features whether the resulting product is the same or different from the previous products. And also more importantly characterization standards should be flexible enough to encompass new technology and must be specific enough for proper identification of strains. Lastly, regulators should clarify the degree to which probiotics must be characterized in terms of labeling and GMP.

Under current law, FDA regulation of the claims differs based on which category the product falls. There are number of claims that the FDA allows manufacturers to make about food and dietary supplements and each type of claim has its own substantiation requirements. For health related claims FTC requires adequate substantiation to establish a reasonable basis for a manufacturer claim. However, manufacturers find it difficult to know what constitutes adequate substantiation and particularly in the case of probiotics, whether FTC’s substantiation rules will apply is still confusing. It would be useful for the FDA to codify for the discretion based enforcement of qualified health claims and in process provide a mechanism for qualified health claims to be based not only upon FDA review but also from the authoritative public health bodies. By doing so it would help encourage research in the field of probiotics.

Conclusion

On an end note I want to mention that in establishing a regulatory framework for probiotics in the USA and other countries, certain foundational principles should be taken into consideration in terms of proportionality of risk, universal quality guidelines and flexibility. Regulatory burden should be proportional to risk. This very principle is already reflected in Canada and United States in distinction between food and drugs. In the context of probiotic products, the fact that the products identified as probiotic can have very different risk profiles that are affected not just by the intrinsic risk of the strain, but also by the intended application, needs to be recognized and communicated to regulators, researchers, industry and most importantly, consumers. Minimally, there should be a meaningful distinction in the language and regulatory requirements for the products which are intended to treat, cure or diagnose a disease from other products for which long term health benefits are less certain. The intended applications needs of the probiotic products should be considered and risk classification should be in place where there should be a mechanism for a strain to be regulated simultaneously at different risk levels for indeed different applications. In fact there should be a mechanism in place where consumers can obtain information on the evidence supporting the particular product without any regulatory intervention. One significant determinant associated with risk of probiotic products which is not always easily assessable by researchers, regulators or consumers is the risk of failed efficacy which includes the main factor “quality”. It is often challenging to manufacture probiotic products which are pure and stable for retail distribution. Both Canada and United States have pre-market approval that are appropriate for assessing the quality standards of the products however, this level of rigorous premarket review is not appropriate for lower risk products. In order to make this work, universally acceptable quality standards should be published where adequate level of control and enforcement can be achieved for lower risk products. Most importantly, as the science and technology surrounding these products are improving rapidly, flexibility plays a crucial role in regulation pathway. The regulation of the probiotic products should be flexible enough. In addition to being able to simultaneously accommodate products of different risk profiles, the regulatory framework for these products should also consider the scientific uncertainty associated with these products which will indeed help in assessing the lower risk products and also helps in identifying new hazards. Probiotics face challenges where there is dearth of conclusive findings as the safety and product development is evolving. The FDA should establish collaborative pathways for probiotics which does not fit into the traditional categories which would help the stakeholders most importantly consumers.

Works cited
[1] Saxelin, M. (2008). Probiotic formulations and applications, the current probiotics market, and changes in the marketplace: a European perspective. Clinical infectious diseases, 46(Supplement 2), S76-S79.Ben-Maimon, C. S., & Garnick, R. (2006). Biogenerics at the Crossroads. Nature Biotechnology , 268-269.

[2] See US Gov’t Accountibility Office GAO-11-102, Food labelling; FDA needs to reassess its approach to protecting consumers from false or misleading claims (2011), available at http://www.gao.gov/new.items/d11102.pdf.

[3] Kneifel W, Mattila-Sandholm T, von Wright A. Probiotic bacteria detection and estimation in fermented and non-fermented dairy products. In: Batt CA, Patel PD, editors. Encyclopedia of food microbiology. San Diego: Academic Press; 1999. p. 1783–9.

[4] Mainville I, Robert N, Lee B, Farnworth ER. Polyphasic characterization of the lactic acid bacteria in kefir. Syst Appl Microbiol. 2006;29:59–68.

[5] Anonymous. Guidelines for the evaluation of probiotics in food, Joint FAO/WHO Working Group report on drafting guidelines for the evaluation of probiotics in food. London, Ontario: FAO; 2002, p. 1

[6] Jacobsen CN, Nielsen VR, Hayford AE, Moller PL, Michaelsen KF, Paerregaard A, Sandstrom B, Tvede M, Jakobsen M. Screening of probiotic activities of forty-seven strains of Lactobacillus spp. by in vitro techniques and evaluation of the colonization ability of five selected stains in humans. Appl Environ Microbiol. 1999;65:4949–56.

[7] Shah NP. Probiotic bacteria: selective enumeration and survival in dairy foods. J Dairy Sci. 2000;83:894–907.

[8] Guslandi M, Mezzi G, Sorghi M, Testoni PA. Saccharomyces boulardii in maintenance treatment of Crohn's disease. Dig Dis Sci. 2000;45:1462–4.

[9] Niedzielin K, Kordecki H, Birkenfeld B. A controlled, double-blind, randomized study on the efficacy of Lactobacillus plantarum 299V in patients with irritable bowel syndrome. Eur J Gastroenterol Hepatol. 2001;13:1143–7.

[10] Simons LA, Amansec SG, Conway P. Effect of Lactobacillus fermentum on serum lipids in subjects with elevated serum cholesterol. Nutr Metab Cardiovasc Dis. 2006;16:531–5.

[11] Commane D, Hughes R, Shortt C, Rowland I. The potential mechanisms involved in the anti-carcinogenic action of probiotics. Mutat Res. 2005;591:276–89.

[12] White JA. Probiotics and their use in diverticulitis. J Clin Gastroenterol. 2006; 40(7, Suppl 3)S160–2.

[13] Gorbach SL. Probiotics and gastrointestinal health. Am J Gastroenterol. 2000;95: Suppl 1:S2–4.

[14] Reid G, Hammond J-A. Probiotics some evidence of their effectiveness. Can Fam Physician. 2005;51:1487–93.

[15] Walker WA, Duffy LC. Diet and bacterial colonization: role of probiotics and prebiotics. J Nutr Biochem. 1998;9:668–75.

[16] Saavedra JM, Tschernia A. Human studies with probiotics and prebiotics: clinical implications. Br J Nutr. 2002; 87 Suppl 2:S241–6.

[17] See OECD, Safety Assessment of Transgenic organisms, Volume 4: OECD Consensus Documents 171-74 (2010).

[18] See partial list of microorganisms microbial derived ingredients that are used in foods, U.S. Food & Drug Administration (July 2001).

[19] See Riëtte van Laack, Senators Hatch and Harkin Request that FDA Withdraw Draft NDI Guidance, HYMAN PHELPS FDA LAW BLOG (Jan 10, 2012, 5:21 PM), http://www.fdalawblog.net/fda_law_blog_hyman_phelps/2012/01/senators-hatch-and-harkin-request-that-fda-withdraw-draft-ndi-guidance.html; Steven Daniells, Trade Associations Urge FDA to Issue Revised Draft Guidance on NDI Identity Issue, NUTRA INGREDIENTS USA (May 6, 2013), http://www.nutraingredients-usa.com/content/view/print/770878.

[20] See Information for Sponsor-Investigators Submitting Investigational New Drug Applications, U.S. FOOD & DRUG ADMINISTRATION, http://www.fda.gov/Drugs/DevelopmentApprovalProcess.

[21] Mary Ellen Sanders et al. Health Claims Substantiation for Probiotic and Prebiotic Products, 2 GUT MICROBES 127 (2011).

[22] Guidance for Industry: Early Clinical Trials With Live Biotherapeutic Products: Chemistry, Manufacturing, and Control Information, 77 Fed. Reg. 7794 (Feb. 21, 2012).

References

Fraser, C. M. (2013). Federal Regulation of Probiotics: An Analysis of the Existing Regulatory Framework and Recommendations for Alternative Frameworks1 (Doctoral dissertation, University of Maryland).

Farnworth, E. R. (2008). The evidence to support health claims for probiotics. The Journal of nutrition, 138(6), 1250S-1254S.

Hoffman, F. A., Heimbach, J. T., Sanders, M. E., & Hibberd, P. L. (2008). Executive summary: scientific and regulatory challenges of development of probiotics as foods and drugs. Clinical infectious diseases, 46(Supplement 2), S53-S57.

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