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Challenges ahead in the probiotic field – insights from Probiota2019

By Dr. Mariya Petrova, Microbiome insights and Probiotics Consultancy (MiP Consultancy), Bulgaria.

Recently, I attended the Probiota Conference, which brings together representatives from industry and academia on the topic of probiotics and related fields. The goal of many of the speakers at the conference was to provide insight about how to translate scientific discoveries for, and share commercial insights with, end consumers. I would like to share a few points that caught my attention.

Do good science. End-consumers rely on news coverage of science, which unfortunately is too often more sensationalist than accurate. Prof. Gregor Reid’s talk, “Disentangling facts from fake news,” noted that news article titles such as “Probiotics labeled ‘quite useless’” and “Probiotics ‘not as beneficial for gut health as previously thought’” – after research was published last year in Cell (here and here) – were misleading to end-users and of great concern to people in the field of probiotics who are familiar with the totality of the data. Researchers have a responsibility to situate their results in the context of existing evidence. However, Prof. Reid also observed that “too many products are called probiotics with strains not tested in humans”; “too many products are making un-verified claims”; “too many journalist don’t have expertise in science”; “too many rodent studies making association with human health”; “researchers making up their own terms without defining them”. So how do we solve this? Do good science and communicate results clearly, accurately and without bias – to journalists, to peers and to end-users. (See related ISAPP blogs here and here).

Understand the probiotic mode of action. Understanding probiotic modes of action may be the most challenging issues ahead of us. Currently, we have too little understanding of mechanisms by which probiotics provide health benefits. Probiotic strains are living microorganisms, which most likely work through multiple mechanisms and molecules, but we indeed need more in-depth research. When I reflect on my own experience and the struggles to do molecular studies, I can appreciate how difficult this research is. Although others may be focused on screening the microbiome and developing bioinformatics tools, I applaud the researchers trying to develop deeper understandings of how probiotics function, which will enable more rational approaches to probiotic selection and use. (See related ISAPP blog here.)

New names, new glory. The forthcoming reclassification of the Lactobacillus genus was discussed. We are faced with the largest taxonomic upheaval of this genus in history, including many economically important species. The current Lactobacillus genus will be split into at least ten genera. The species and strain names will not change, but many species will have different genus names. Researchers are expected to propose that all new genera names will begin with the letter “L.” The reclassification can help us better understand the mode of action of industrially important probiotics and help tailor probiotic applications. The changes will be communicated with regulatory bodies such as EFSA and FDA. Name changes could also have consequences for medical stakeholders and may lead to potential issues with intellectual properties. Consumers of probiotic products will likely be less affected by this change, but an educational website targeted to consumers could be beneficial. (See related ISAPP blog here.)

EFSA claims as expected. EFSA claims and regulations were also discussed. To date, approximately 400 health claims applications have been submitted to EFSA without any approved. Experts advised to keep the claims simple and easy. EFSA’s strict approach to claims may have the advantage of compelling industry to conduct studies that better support health claims. Responsible companies are adapting to regulatory requirements and are developing good products, and they will probably succeed in meeting claim standards. Nevertheless, it seems that although health claims are deemed important to companies and medical representatives, end-users of probiotics obtain information from other sources. Obtaining health claims is only one piece of the puzzle. Also important is providing science-based information to end-users, especially those keen on keeping their good health through nutrition.

Be transparent. Don’t forget to disclose the strains you use on product labels. Strains designation is one key way to distinguish your product and it is an important way to communicate to your consumer exactly what is in your product. Surprisingly still, some scientific papers fail to report the strains they used to perform their clinical trials. The field is moving towards more transparency with high-quality clinical trials, the best-selected strains for certain condition and clear designation of the probiotic strain on the label. (See related ISAPP infographics here, here and here)

Educate, educate and again educate. Often discussed at the conference was the subject of educating the end consumers. Companies should take a proactive approach to engage consumers and promote understanding of the available evidence where probiotics can promote health. It is difficult for consumers to differentiate science-based evidence from journalistic sensationalism or researcher self-aggrandizement. A major obstacle is also the ready availability in the marketplace of unproven products containing strains that have been tested only in animal models or not proven experimentally at all. Taking the need for reliable communications on probiotics and probiotics to end-users very seriously, ISAPP has developed a range of science-based videos and infographics. The infographics include topics such as how to read the labels of the probiotics products (USA and EU versions) and a probiotic checklist. Thanks to the enthusiastic work of many volunteers, some ISAPP infographics can now be found in 10 different languages.

Despite having great discussions, one thing keeps troubling my mind: Where is the field of probiotics going and how will it look like in 10 or 20 years? The fight for probiotics is not over, despite the progress we have made so far.

FDA/NIH Public Workshop on Science and Regulation of Live Microbiome-based Products: No Headway on Regulatory Issues

September 20, 2018

By Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP

On September 16, 2018, the US Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) and National Institute of Allergy and Infectious Diseases (NIAID) collaborated on the organization of a public workshop on “Science and Regulation of Live Microbiome-based Products Used to Prevent, Treat, or Cure Diseases in Humans”.  I was present at this meeting along with ISAPP vice-president, Prof. Daniel Merenstein MD, who lectured on the topic of probiotics and antibiotic-associated diarrhea.

Prof. Dan Merenstein speaking at CBER/NIAID conference

While regulatory issues are often discussed at other microbiome conferences, the fact that this meeting was organized by the FDA suggested it was a unique opportunity for some robust discussions and possible progress on regulatory issues involved with researching and translating microbiome-targeted products. The regulatory pathways to drug development seem clear enough, but regulatory issues for development of functional foods or supplements are less clear. Jeff Gordon and colleagues have previously pointed out regulatory hurdles to innovation of microbiota-directed foods for improving health and preventing disease (Greene et al. 2017), and at the 2015 ISAPP meeting, similar problems were discussed (Sanders et al. 2016).

The meeting turned out to be mostly about science. Some excellent lectures were given by top scientists in the field (see agenda below), but discussion about regulatory concerns was a minimal component of the day. Questions seeding the panel discussions focused on research gaps, not regulatory concerns: an unfortunate missed opportunity.

Bob Durkin, deputy director of the Office of Dietary Supplements (CFSAN), left after his session ended, suggesting he did not see his role as an important one in this discussion. One earlier question about regulatory perspectives on prebiotics led him to comment that the terms ‘probiotic’ and ‘prebiotic’ are not defined. From U.S. legal perspective he is correct, as there are no laws or FDA regulations that define these terms. But from a scientific perspective, such a statement is disappointing, as it shows the lack of recognition by U.S. regulators of the widely cited definitions developed by top researchers in these fields and published in 2014 and 2017, respectively.

Two issues not addressed at this meeting will require clarification from the FDA:

The first is how to oversee human research on foods or dietary supplements. CBER’s oversight of this research has meant most studies are required to be conducted under an Investigational New Drug (IND) application. From CBER’s perspective, these studies are drug studies. However, when there is no intent for research to lead to a commercial drug, the IND process is not relevant. Even if endpoints in the study are viewed as drug endpoints by CBER, there should be some mechanism for CFSAN to make a determination if a study fits legal functions of foods, including impacting the structure/function of the human body, reducing the risk of disease, or providing dietary support for management of a disease. When asked about this, Durkin’s reply was that CFSAN has no mechanism to oversee INDs. But the point was that without compromising study quality or study subject safety, it seems that FDA should be able to oversee legitimate food research without forcing it into the drug rubric. CBER acknowledged that research on structure/function endpoints is exempt from an IND according to 2013 guidance. But FDA’s interpretation of what constitutes a drug is so far-reaching that it is difficult to design a meaningful study that does not trigger drug status to them. For example, CBER views substances that are given to manage side effects of a drug, or symptoms of an illness, as a drug. Even if the goal of the research is to evaluate a probiotic’s impact on the structure of an antibiotic-perturbed microbiota, and even if the subjects are healthy, they consider this a drug study. With this logic, a saltine cracker eaten to alleviate nausea after taking a medication is a drug. Chicken soup consumed to help with nasal congestion is a drug. In practice, many Americans would benefit from a safe and effective dietary supplement which they can use to help manage gut disruptions. But in the current regulatory climate, such research cannot be conducted on a food or dietary supplement in the United States. There are clearly avenues of probiotic research that should be conducted under the drug research oversight process. But for other human research on probiotics, the IND process imposes research delays, added cost, and unneeded phase 1 studies, which are not needed to assure subject safety or research quality. Further, funders may choose to conduct research outside the United States to avoid this situation, which might explain the low rate of probiotic clinical trials in the United States (see figure).

The second issue focuses on actions by CBER that have stalled evidence-based use of available probiotic products. This issue was discussed by Prof. Merenstein in his talk. He pointed out that after the tragic incident that led to an infant’s death from a contaminated probiotic product (see here; and for a blog post on the topic, see here), CBER issued a warning (here) that stated that any probiotic use by healthcare providers should entail an IND. This effectively halted availability of probiotics in some hospital systems. For example, at Johns Hopkins Health-system Hospitals, the use of probiotics is now prohibited (see below). Patients are not allowed to bring their own probiotics into the hospital out of concern for the danger this poses to other patients and staff. This means that a child taking probiotics to maintain remission of ulcerative colitis cannot continue in the hospital; an infant with colic won’t be administered a probiotic; or a patient susceptible to Clostridium difficile infection cannot be given a probiotic. Available evidence on specific probiotic preparations indicates benefit can be achieved with probiotic use in all of these cases, and denying probiotics can be expected to cause more harm than benefit.

It might be an unfortunate accident of history that probiotics have been delivered in foods and supplements more than drugs. The concept initially evolved in food in the early 1900’s, with Metchnikoff’s observation that the consumption of live bacilli in fermented milk had value for health. Probiotics have persisted as foods through to the modern day, likely because of their safety. The hundreds of studies conducted globally, including in the U.S. until 10-15 years ago, were not conducted as drug studies, even though most would be perceived today as drug studies by CBER. This has not led to an epidemic of adverse effects among study subjects. True, serious adverse events have been reported, but the overall number needed to harm due to a properly administered probiotic is negligible.

According to its mission, the FDA is “…responsible for advancing the public health by helping to speed innovations that make medical products more effective, safer, and more affordable and by helping the public get the accurate, science-based information they need to use medical products and foods to maintain and improve their health.” Forcing human research on products such as yogurts containing probiotics to be conducted as drug research, when there is no intent to market a drug and when the substances are widely distributed commercially as GRAS substances, does not advance this mission. Further, CBER actions that discourage evidence-based use of available probiotics keeps effective and safe products out of the hands of those who can benefit.

A robust discussion on these issues was not part of the meeting earlier this week.  Researchers in the United States interested in developing probiotic drugs will find CBER’s approaches quite helpful. Yet researchers interested in the physiological effects of, or clinical use of, probiotic foods and supplements will continue to be caught in the drug mindset of CBER. CFSAN does not seem interested. But without CFSAN, human research on, and evidence-based usage of, probiotic foods and supplements will continue to decline (see figure), to the detriment of Americans.

Human clinical trials on “probiotic”
1992-September 20, 2018

 

 

 

cber

CBER to hold public workshop on regulation of biologics

FDA’s Center for Biologics Evaluation and Research (CBER) is convening a public workshop Sept 17 in Rockville MD on the Science & Regulation of Live Microbiome-Based Products Used to Prevent, Treat, or Cure Diseases in Humans. It is now open for registration (free). See here for the program and here for additional info.

The evidence for efficacy, the safety and the regulatory framework for probiotics other live microbiome based products will be discussed. Prof. Dan Merenstein MD, ISAPP’s current Vice President, will speak on evidence, research and clinical use of probiotics for antibiotic associated diarrhea. Although the title suggests the meeting will focus on drugs, Dr. Bob Durkin from the Center for Food Safety and Applied Nutrition (CFSAN) of the FDA will speak on probiotic foods and dietary supplements.

This workshop is an opportunity for stakeholders to share with FDA and NIH concerns regarding the regulatory approach to probiotics adopted by the FDA. The path for development of probiotic drugs is reasonably clear. But the road to develop probiotic foods, supplements or microbiome-based dietary strategies to compensate for deficient microbiota is less so. These products are intended to improve gut function, nutritional status, immune status, metabolic properties and more. These are legal functions for foods and supplements, but the FDA doesn’t seem to see it that way.

The FDA has for the most part has approached probiotics as drugs (Sanders et al. 2016). Since probiotics are live microbes, and since CBER deals with drugs that are derived from living sources, CBER often oversees human research on probiotics. But there is no mechanism within CBER to oversee foods and supplements, and hence, human research on probiotics tends to be shunted into the investigational new drug (IND) process. But, the legal definitions of drugs and foods overlap – both can impact the structure/function of the human body and both can reduce the risk of disease. So conducting such research on probiotic foods – and not as part of the IND rubric – should be possible. Perhaps progress on this front can be achieved in the CBER workshop in September.

In a press announcement, FDA Commissioner Scott Gottlieb MD shared FDA perspective on probiotics and promoted this CBER conference. A couple of issues are noteworthy in this announcement by Gottlieb. First, the term ‘probiotic’ is used. Over the years, the FDA largely avoided use of this term, instead favoring the term live biotherapeutic product (LBP). But these terms are not synonymous. Probiotic is defined as a live microorganisms that, when administered in adequate amounts, confers a health benefit on the host (Hill et al. 2014). It spans multiple regulatory categories. A LBP is by definition a drug. The fact that Gottlieb used the term ‘probiotic’ may signal that he recognizes that not all probiotics are drugs. Second, Gottlieb’s announcement shows awareness that probiotics are legitimate components in foods and dietary supplements and states that the FDA is “committed to working with industry on efforts to provide information that can help consumers make more informed choices about these products.” This is a welcome statement to many researchers involved in probiotic foods and supplements in the United States. It suggests that the FDA is willing to look beyond probiotics as LBPs and develop regulatory approaches for research and claims appropriate to foods and supplements.

Innovation in this field, which has the potential to benefit many people globally, requires regulatory approaches that do not obstruct. Participation in this workshop may lead to improvements that both protect public safety and facilitate academic and industry researchers in the United States on the path to discovery.

 

Additional information:

Sanders ME, Shane AL, Merenstein DJ. Advancing Probiotic Research in Humans the United States: Challenges and strategies. Gut Microbes 7(2):97-100.

Warning letter from CBER: Dietary Supplements Containing Live Bacteria or Yeast in Immunocompromised Persons: Warning – Risk of Invasive Fungal Disease. Posted 12/09/2014.