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Probiotic Administration in Preterm Infants: Scientific Statement

/in ISAPP Science Blog /by KC

Board of Directors, International Scientific Association for Probiotics and Prebiotics

in collaboration with

Dr. Geoffrey Preidis MD PhD, Pediatric Gastroenterology, Hepatology & Nutrition

Prof. Andi L Shane MD MPH MSc, Pediatric Infectious Diseases

A recent report of a fatality in an extremely premature infant recipient of a probiotic product has resulted in a warning letter from the United States Food & Drug Administration (FDA) to healthcare practitioners about probiotic supplementation in preterm infants and a warning letter to the probiotic product manufacturer.

Publicly available information suggests that this fatality was the direct consequence of bacteremia resulting from ingestion of the probiotic organism Bifidobacterium longum subsp. infantis delivered in medium chain triglyceride oil. This situation differs from case reports of adverse events that resulted from extrinsic probiotic product contamination (1, 2). This is an important distinction, as the potential risks and mitigation strategies differ between etiologies. As complete details of this most recent fatality have not been released, specific factors that may have contributed to the adverse outcome are unknown. However, it is worth considering the context of this case report within the broader literature available on probiotic use in this population, including the wealth of data available on sepsis incidence.

Evidence from systematic reviews

Premature infants, especially those of <32 weeks gestation and with a birth weight <1500 g, are a vulnerable population at significant risk of morbidity and mortality.  Necrotizing enterocolitis (NEC) is highly prevalent (5-10% incidence) among very preterm infants, with mortality rates of 20-30% and high morbidity among survivors, including short gut syndrome, parenteral nutrition-associated liver disease, and neurocognitive delay.

A large body of literature exists on the use of probiotics in hospitalized preterm infants, with particular focus on the prevention of NEC. At least 85 randomised clinical trials (RCTs) (3) have been conducted to evaluate the use of probiotics in preterm infants for the prevention of diseases associated with prematurity, and a number of systematic reviews with meta-analyses have analysed these data in recent years. Most RCTs conducted in the neonatal intensive care unit (NICU) designate sepsis as one of the main outcome measures.

The most recent meta-analysis was published online October 2 in JAMA Pediatrics (3). This study included 106 trials on probiotic, prebiotic, synbiotic and lactoferrin interventions for either preterm infants <37 weeks and/or those with low birth weight (<2500 g). Administration of probiotics containing multiple strains were found to be most effective in the reduction of all-cause mortality (31% reduction), with a 62% decrease in incidence of severe NEC compared to placebo (moderate and high certainty evidence). Single strain probiotics combined with lactoferrin provided greatest efficacy in the reduction of late-onset sepsis incidence (67% risk reduction with moderate certainty evidence). It was noted that none of the included studies reported cases of probiotic-induced sepsis.

Other authors including groups from the Cochrane Collaboration, American Gastroenterological Association (AGA) and the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) have found similar results, and studies can be reviewed here:

Probiotics to prevent necrotising enterocolitis in very preterm or very low birth weight infants – Sharif, S – 2023 | Cochrane Library

Probiotics Reduce Mortality and Morbidity in Preterm, Low-Birth-Weight Infants: A Systematic Review and Network Meta-analysis of Randomized Trials – Gastroenterology (gastrojournal.org)

Probiotics for Preterm Infants: A Strain-Specific Systematic… : Journal of Pediatric Gastroenterology and Nutrition (lww.com)

No meta-analysis has attributed increased risk of sepsis to probiotic use in preterm infants – rather, in many cases a protective effect (or a trend toward protection) was reported. However, it is important to acknowledge the real but rare risk of probiotic-induced bacteremia in this population. In a recent review of case reports of probiotic-associated invasive infections in children, probiotic-induced bacteremia in premature infants were found to have resolved in most cases with use of effective antimicrobial therapy (4).

With data collected on over 10,000 preterm infants, substantial benefits demonstrated and a low level of risk identified, promise to improve outcomes in preterm infants who receive a probiotic product currently exists. Based on the evidence currently available, hospitals and NICUs across the globe have already adopted practices relating to probiotic use in preterm infants, some with significant health impacts (5, 6).

Risk benefit analysis and considerations for healthcare implementation

Further work needs to be done to support probiotic administration in the NICU. Collaborative efforts include recommendations for practical steps to improve probiotic product quality assurance specifically for NICU use, published in July 2023 in JAMA Pediatrics (7).

It is important to note that few (or possibly no) effective interventions are without an adverse event profile, and probiotics are no exception. Even food has a safety standard of reasonable certainty and on a regular basis, individuals suffer fatal foodborne infections. When considering the clinical indications for any intervention for an individual patient or a population of individuals, a thorough comparison of all available data on both the potential risks and the potential benefits is warranted.

The American Gastroenterological Association (8) and other major societies (including ESPGHAN and the World Gastroenterology Organisation) (9, 10) endorse probiotic products for the prevention of NEC among preterm low birth weight infants. The societies’ guidelines agree that the recommendation to use probiotics is conditional. Conditional recommendations are sensitive to patients’ values and preferences, and to the guideline panel’s perception of risk-benefit balance.  However, the recent FDA letter does not acknowledge these recommendations and further, recommends against probiotic use in preterm infants despite the robust efficacy data. With interventions such as probiotic administration, ideally shared clinical decision-making with patient and clinician would ensue. Regulatory warnings inform the risk-benefit calculation but typically do not invalidate a clinical recommendation.

Summary

  • Probiotic administration to preterm infants has been demonstrated to significantly reduce the risk of NEC, sepsis and death in large systematic reviews with meta-analyses.
  • Meta-analyses have not identified significant adverse events or safety concerns, although rare case reports have documented sepsis attributed to probiotics.
  • Stringent manufacturing standards are recommended for probiotics in vulnerable populations such as preterm infants.
  • Standardized comprehensive safety reporting across probiotic intervention studies is needed, along with funding for the conduct of long term studies.
  • The risks and benefits of probiotic administration should be considered in both the specific population and individual patients, with regulatory frameworks to enable implementation.
  • More information about this fatality should be immediately released so healthcare professionals and researchers can learn from this experience and continue to provide optimal evidence-based patient care.

To inquire about expert academic physicians available for media comment, please contact ISAPP’s Executive Director, Marla Cunningham, at marla@nullisappscience.org

See also:

NEC Society: Statement on FDA Warning of Probiotics in Preterm Infants

References

(1) Vallabhaneni S, Walker TA, Lockhart SR, et al. Notes from the field: Fatal gastrointestinal mucormycosis in a premature infant associated with a contaminated dietary supplement–Connecticut, 2014. MMWR Morb Mortal Wkly Rep. 2015;64(6):155-156.

(2) Bizzarro MJ, Peaper DR, Morotti RA, Paci G, Rychalsky M, Boyce JM. Gastrointestinal Zygomycosis in a Preterm Neonate Associated With Contaminated Probiotics. Pediatr Infect Dis J. 2021;40(4):365-367.

(3) Wang Y, Florez ID, Morgan RL, et al. Probiotics, Prebiotics, Lactoferrin, and Combination Products for Prevention of Mortality and Morbidity in Preterm Infants: A Systematic Review and Network Meta-Analysis. JAMA Pediatr. 2023 Oct 2:e233849.

(4) D’Agostin M, Squillaci D, Lazzerini M, et al. Invasive Infections Associated with the Use of Probiotics in Children: A Systematic Review. Children (Basel). 2021 Oct 16;8(10):924.

(5)  Rath CP, Athalye-Jape G, Nathan E, et al. Benefits of routine probiotic supplementation in preterm infants. Acta Paediatr. 2023 Jul 28.

(6) Bui A, Johnson E, Epshteyn M, Schumann C, Schwendeman C. Utilization of a High Potency Probiotic Product for Prevention of Necrotizing Enterocolitis in Preterm Infants at a Level IV NICU. The Journal of Pediatric Pharmacology and Therapeutics 2023;28(5):473–475.

(7)  Shane AL, Preidis GA. Probiotics in the Neonatal Intensive Care Unit-A Framework for Optimizing Product Standards. JAMA Pediatr. 2023 Sep 1;177(9):879-880.

(8) Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020 Aug;159(2):697-705.

(9) WGO Practice Guideline: Probiotics and Prebiotics. Available from: https://www.worldgastroenterology.org/guidelines/probiotics-and-prebiotics

(10) van den Akker CHP, van Goudoever JB, Shamir R, et al. Probiotics and Preterm Infants: A Position Paper by the European Society for Paediatric Gastroenterology Hepatology and Nutrition Committee on Nutrition and the European Society for Paediatric Gastroenterology Hepatology and Nutrition Working Group for Probiotics and Prebiotics. J Pediatr Gastroenterol Nutr. 2020 May;70(5):664-680.

EFSA’s QPS committee issues latest updates

/in ISAPP Science Blog /by KC

By Bruno Pot, PhD, Vrije Universiteit Brussel and Mary Ellen Sanders, PhD, Executive Science Officer, ISAPP

On July 2nd, the European Food Safety Authority (EFSA) published the 12th update of the qualified presumption of safety (QPS) list, a list of safe biological agents, recommended for intentional addition to food or feed, covering notifications from October 2019-March 2020. It was good news to all stakeholders to see that EFSA discussed the recent taxonomic changes within the genus Lactobacillus (see ISAPP blog here) as well as addressed some microbes being considered as potential, novel probiotics.

What is QPS?

In 2005 EFSA established a generic approach to the safety assessment of microorganisms used in food and feed, prepared by a working group of the former Scientific Committee on Animal Nutrition, the Scientific Committee on Food and the Scientific Committee on Plants of the European Commission. This group introduced the concept of “Qualified Presumption of Safety” (QPS), which described the general safety profile of selected microorganisms. The QPS process was mainly developed to provide a generic pre‐evaluation procedure harmonized across the EU to support safety risk assessments of biological agents performed by EFSA’s scientific panels and units. A QPS assessment is performed by EFSA following a market authorisation request of a regulated product requiring a safety assessment. Importantly, in the QPS concept, a safety assessment of a defined taxonomic unit is performed independently of the legal framework under which the application is made in the course of an authorisation process.

QPS status is granted to a taxonomic unit (most commonly a species), based on reasonable evidence. A microorganism must meet the following four criteria:

1.       Its taxonomic identity must be well defined.

2.       The available body of knowledge must be sufficient to establish its safety.

3.       The lack of pathogenic properties must be established and substantiated (safety).

4.       Its intended use must be clearly described.

Any safety issues, noted as ‘qualifications’, that are identified for a species assessed under QPS must be addressed at the strain or product level. Microorganisms that are not well defined, for which some safety concerns are identified or for which it is not possible to conclude whether they pose a safety concern to humans, animals or the environment, are not considered suitable for QPS status and must undergo a full safety assessment. One generic qualification for all QPS bacterial taxonomic units is the need to establish the absence of acquired genes conferring resistance to clinically relevant antimicrobials (EFSA, 2008).

If an assessment concludes that a species does not raise safety concerns, it is granted “QPS status”. Once EFSA grants a microorganism QPS status, it is included on the “QPS list” and no microorganism belonging to that group needs to undergo a full safety assessment in the European Union.

The QPS list is re‐evaluated every 6 months by the EFSA Panel on Biological Hazards based on three “Terms of Reference” (ToR)*. This evaluation is based on an extensive literature survey covering the four criteria mentioned above.

What happened to the genus Lactobacillus?

In April 2020, based on a polyphasic approach involving whole genome sequencing of more than 260 species of the former genus Lactobacillus, the genus was reclassified into 25 genera including the emended genus Lactobacillus, which includes host-adapted organisms that have been referred to as the L. delbrueckii group, the earlier described genus Paralactobacillus as well as 23 novel genera, named Acetilactobacillus, Agrilactobacillus, Amylolactobacillus, Apilactobacillus, Bombilactobacillus, Companilactobacillus, Dellaglioa, Fructilactobacillus, Furfurilactobacillus, Holzapfelia, Lacticaseibacillus, Lactiplantibacillus, Lapidilactobacillus, Latilactobacillus, Lentilactobacillus, Levilactobacillus, Ligilactobacillus, Limosilactobacillus, Liquorilactobacillus, Loigolactobacilus, Paucilactobacillus, Schleiferilactobacillus, and Secundilactobacillus. Read more in the original paper here or on the ISAPP blog here).

These name changes could have considerable economic, scientific and regulatory consequences, as discussed during an expert workshop organised by the Lactic Acid Bacteria Industrial Platform (LABIP). One of the points discussed during this workshop was the possible implication of the name change on the QPS list in Europe and the FDA’s GRAS list in the USA.

What did EFSA do?

In a 42-page document, which can be found here, amongst others, the species of the former genus Lactobacillus that were already listed on the QPS list, have been formally renamed at the genus level. The species names remained the same, as the taxonomic revision from April 2020 only affected the genus name. As a result, the genus names of 37 former Lactobacillus species on the QPS were updated, and now span 13 different genera. Table 1 delineates these nomenclature updates.

Table 1: Taxonomic revision of the 37 species formerly of the Lactobacillus genus present on the QPS list (published here).

Earlier denomination                                                      Updated denomination
Lactobacillus acidophilus                     Lactobacillus acidophilus
Lactobacillus alimentarius Companilactobacillus alimentarius
Lactobacillus amylolyticus Lactobacillus amylolyticus
Lactobacillus amylovorus Lactobacillus amylovorous
Lactobacillus animalis Ligilactobacillus animalis
Lactobacillus aviarius Ligilactobacillus aviarius
Lactobacillus brevis Levilactobacillus brevis
Lactobacillus buchneri Lentilactobacillus buchneri
Lactobacillus casei Lacticaseibacillus casei
Lactobacillus collinoides Secundilactobacillus collinoides
Lactobacillus coryniformis Loigolactobacillus coryniformis
Lactobacillus crispatus Lactobacillus crispatus
Lactobacillus curvatus Latilactobacillus curvatus
Lactobacillus delbrueckii Lactobacillus delbrueckii
Lactobacillus dextrinicus Lapidilactobacillus dextrinicus
Lactobacillus diolivorans Lentilactobacillus dioliovorans
Lactobacillus farciminis Companilactobacillus farciminis
Lactobacillus fermentum Limosilactobacillus fermentum
Lactobacillus gallinarum Lactobacillus gallinarum
Lactobacillus gasseri Lactobacillus gasseri
Lactobacillus helveticus Lactobacillus helveticus
Lactobacillus hilgardii Lentilactobacillus hilgardii
Lactobacillus johnsonii Lactobacillus johnsonii
Lactobacillus kefiranofaciens Lactobacillus kefiranofaciens
Lactobacillus kefiri Lentilactobacillus kefiri
Lactobacillus mucosae Limosilactobacillus mucosae
Lactobacillus panis Limosilactobacillus panis
Lactobacillus paracasei Lacticaseibacillus paracasei
Lactobacillus paraplantarum Lactiplantibacillus paraplantarum
Lactobacillus pentosus Lactiplantibacillus pentosus
Lactobacillus plantarum Lactiplantibacillus plantarum
Lactobacillus pontis Limosilactobacillus pontis
Lactobacillus reuteri Limosilactobacillus reuteri
Lactobacillus rhamnosus Lacticaseibacillus rhamnosus
Lactobacillus sakei Latilactobacillus sakei
Lactobacillus salivarius Ligilactobacillus salivarius
Lactobacillus sanfranciscensis Fructilactobacillus sanfranciscensis

EFSA further specifies that “To maintain continuity within the QPS list, all the strains belonging to a previous designed Lactobacillus species will be transferred to the new species. Both the previous and new names will be retained”. (Emphasis added.)

Impact of the QPS update on the probiotic field

The probiotic field can also take note of this current update for its review of two ‘next generation’ probiotic species evaluated for possible QPS status, Akkermansia muciniphila and Clostridium butyricum.  Akkermansia muciniphila has been actively researched as a probiotic to help manage metabolic syndrome (Depommier et al. 2019). A probiotic preparation containing both Akkermansia muciniphila and Clostridium butyricum has been studied in a randomized controlled trial for postprandial glucose control in subjects with type 2 diabetes (Perraudeau et al 2020). The committee’s decisions:

  • Akkermansia muciniphila is not recommended for QPS status due to safety concerns;
  • Clostridium butyricum is not recommended for QPS status because some strains contain pathogenicity factors; this species is excluded for further QPS evaluation.

The publication of the next scientific opinion updating the QPS list is planned for December 2020, based on the 6-month assessments carried out by the BIOHAZ Panel.

Conclusion

Due to its scientific rigor and continuous updates, the EFSA QPS efforts provide useful perspective for the global scientific community on safety of candidate microbes for use in foods. Their embrace of the new taxonomic status of lactobacilli signals to other stakeholders that it is time to start the process of doing the same. Further, their assessment of species being proposed and studies as ‘next generation’ probiotics is an important reminder that a microbe’s status as a human commensal is not a guarantee of its safety for use in foods.

 

*QPS Terms of Reference (ToR) (quoted from here):

ToR 1: Keep updated the list of biological agents being notified in the context of a technical dossier to EFSA Units such as Feed, Pesticides, Food Ingredients and Packaging (FIP) and Nutrition, for intentional use directly or as sources of food and feed additives, food enzymes and plant protection products for safety assessment.

ToR 2: Review taxonomic units previously recommended for the QPS list and their qualifications when new information has become available. The latter is based on a review of the updated literature aiming at verifying if any new safety concern has arisen that could require the removal of the taxonomic unit from the list, and to verify if the qualifications still efficiently exclude safety concerns.

ToR 3: (Re)assess the suitability of new taxonomic units notified to EFSA for their inclusion in the QPS list. These microbiological agents are notified to EFSA and requested by the Feed Unit, the FIP Unit, the Nutrition Unit or by the Pesticides Unit.

 

Probiotics in fridge

The FDA’s view on the term probiotics, part 2: Further down the rabbit hole

/in ISAPP Science Blog, News /by KC

By James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA

A number of weeks ago I wrote on the ISAPP blog about US Food and Drug Administration (FDA) declining to file Generally Regarded As Safe (GRAS) notices that described the subject microorganism as a “probiotic” or “probiotic bacterium” (see The FDA’s view on the term “probiotics”). Now the FDA’s response to such GRAS notices has developed additional ramifications. Let me put them into two categories: Class 1 misdemeanors that will cause FDA to reject the notice, and Class 2 misdemeanors that will probably not prevent filing, but will cause FDA to raise questions. I should note that these thoughts are based on both my own direct experiences and my repeated telephone conference calls with FDA.

Class 1 Misdemeanors

  1. Using the term probiotic in any way in describing or characterizing the subject microorganism or its past, present, or intended use.
  2. Extended discussion of benefits derived from ingestion of the microorganism in animal or human research.
  3. Any mention, however brief, of the potential for the microorganism to be used in dietary supplements.

Class 2 Misdemeanors

  1. Including brief mentions of the microorganism serving as a probiotic. E.g., if you cite a study of the microorganism that you might previously have reported as “a study of the probiotic benefits” of the microorganism, change it to simply “a study of the benefits” of the microorganism. This same caution is advised when reporting opinions from the European Food Safety Authority (EFSA) or other authoritative bodies.
  2. Using the word “dose” in describing intended use. Also see #4 below.
  3. Virtually any use of the term “dietary supplement,” including in reporting past, current, or intended uses of the strain or the species in Europe or elsewhere, by anyone.
  4. Even relatively brief mentions of benefits. The recommended way of handling reporting of human studies of the species or strain is to avoid any narrative at all. Simply summarize the studies in tabular form, listing the citation, study design (RCT, open-label, etc.) and objective, study population (number, sex, age, characterization such as IBS patients, malnourished children, preterm infants), test article (microorganism binomial and strain), dose (but call it “administration level”—“dose” can be seen as indicating a drug or dietary supplement), duration, and safety-related results. Include methods used to ensure that any adverse events or severe adverse events would have been reported—medical examinations, self-report questionnaires, parental questionnaires, biochemical measures, etc.—and at what time points during or after the in-life portion of the research. Avoid ANY discussion of improvements seen in the test group.

Good luck!

The FDA’s view on the term probiotics, part 1

/in ISAPP Science Blog, News /by KC

By James Heimbach, Ph.D., F.A.C.N., JHEIMBACH LLC, Port Royal, VA

James Heimbach, food and nutrition regulatory consultant

Over the past 20 years as a food and nutrition regulatory consultant, I have filed about 40 GRAS notices with the United States Food and Drug Administration (FDA), including 15 strains of probiotic bacteria and 5 prebiotics. This fall I submitted notices dealing with 4 strains of bacteria and on January 16 received a telephone call from FDA that surprised me and initially infuriated me, but which I have come to understand.

The essence of the call was that FDA was declining to file my probiotic notices because the notices had identified the subject bacteria as “probiotics” or “probiotic bacteria.” FDA suggested that I resubmit without calling the subject microorganisms “probiotics.”

 

 

As I said, I was surprised and frustrated, and I still would prefer that when FDA makes a policy swerve they would do it in a way that does not make extra work for me and delay my clients’ ability to get to market in a timely manner.

What I have had to do here is remove my advocate’s hat and put on my regulator’s hat. (I worked for FDA for a decade . . . long ago [1978 to 1988], but I still remember how to think like a regulator.) And here is the issue. Recall that GRAS is concerned with safety, not efficacy (generally recognized as safe, or GRAS), and the information provided in a GRAS notice is focused on safety (although benefits may be more-or-less incidentally covered). The reviewers at FDA are charged with assessing whether the notice provides an adequate basis to conclude that there is a reasonable certainty that no harm will result from the intended use. They are not charged, and they are not equipped, to evaluate what benefits ingestion of the substance or microorganism might provide. So they are not in a position to say whether the subject microorganism will “confer a health benefit on the host,” which is to say, they are not in a position to say whether or not it may be regarded as a probiotic. Remember, probiotics are defined as live microorganisms that, when administered in adequate amounts, confer a health benefit on the host (Hill et al. 2014).

Given that the FDA reviewers cannot say whether the notified microorganism is rightly called a probiotic, they are reluctant to sign off that they have no questions about a notice that calls it one. Regulatory agencies have to be careful; things sometimes come back to haunt them. Those who have been following FDA’s GRAS-notice response letters for a couple of decades will be aware that the agency is putting more and more disclaimers into the letters—about standards of identity, about potential labeling issues, about benefits shown in clinical trials, and about Section 201(II) of the FD&C Act.

One concern that FDA likely has is that if some issue comes up in the future regarding a claim made for benefits from use of a product containing the subject bacterium, someone may make the argument that FDA had accepted that the strain is indeed a probiotic and so it presumably confers probiotic benefits. In the case of probiotics, there are also some internal FDA politics. As ISAPP meeting attendees may already be aware, FDA’s Center for Biologics Evaluation and Research (CBER) would like to claim jurisdiction over all administration of live microorganisms, and the Center for Food Safety and Applied Nutrition (CFSAN) does not seem willing to have a confrontation.

I suspect that a similar situation obtains with the term “prebiotic.” Although I have filed a number of GRAS notices for prebiotics, they haven’t been called that; they have been called fructooligosaccharides, or tamarind seed polysaccharide, or polydextrose, or 2’-O-fucosyllactose. I don’t know how FDA would respond if a GRAS determination were filed with the substance labeled as a prebiotic.

So, I’ve decided that my sympathies lie with FDA. Until and unless a microorganism has been confirmed by competent authority to have probiotic properties when used as intended in a GRAS notice, FDA is probably correct in rejecting its right to be labeled a probiotic. If it’s any consolation, this new position by the FDA has its origin in their acknowledgment of the official scientific definition of the word “probiotic”.

When Mary Ellen Sanders (ISAPP’s Executive Science Officer) reviewed my first draft of this note, she asked what I had in mind by “competent authority,” to which I don’t have a good answer at the present time except to insist that it is not FDA’s Division of GRAS Notice Review. Thirty years ago, when I was at FDA, I was in the Office of Food Science and Nutrition, and that office was charged with making determinations of that type (although I don’t recall anything about probiotics coming before us). But FDA no longer has such an office. Until it does, or until it agrees on another source of authority on designation of microorganisms as non-CBER-domain probiotics, I suspect that CFSAN will continue to be very cautious in this area.

Read part 2 of this blog series here.

Challenges ahead in the probiotic field – insights from Probiota2019

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

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

/in featured, ISAPP Science Blog /by Mary Ellen Sanders

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

/in featured, News /by Mary Ellen Sanders

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.