The authenticity of probiotic foods and dietary supplements: facts and reflections from a court case

ABSTRACT There are numerous excellent papers on probiotics and food supplements’ authenticity and safety, but this article is unique compared to the others. It summarizes judicial events regarding the authenticity of a probiotic formulation (the De Simone Formulation (DSF)) commercially available under the trademark VSL#3® until 2016. In 2019, the U.S. District Court found the distributors of the “new” VSL#3® liable for having sold an untested “copy product” different from the DSF. The jury required one of the distributors to pay the owner of the DSF $15 million dollars, and the District Court entered judgment in this amount. The District Court’s monetary judgment was affirmed by the U.S. Court of Appeals in 2021. This article arises from this judicial affair to examine the rules and regulations protecting patients and doctors from misrepresentations and the potential role of class actions brought by consumers to dissuade companies from taking advantage of regulatory deficiencies.


Introduction
Definition of "Evidence": "data presented to a court or jury in proof of the facts in issue and which may include the testimony of witnesses, records, documents, or objects." Which rules and regulations are currently in place to protect consumers? Which data are available to prove the risks or safety of probiotics? How reliable are these indicators?
From the testimony of Prof. Claudio De Simone on 22 March 2016 before the United States District Court for the District of Maryland, in the case De Simone et al., v. VSL Pharmaceuticals, Inc. et al., Civil Action No. TDC-15-1356. « In January 2016, I was contacted by a patient from England who has been diagnosed with ulcerative colitis and who has been managing his conditions with use of VSL#3-branded probiotic along with other treatments prescribed by his doctor. The UK patient mentioned that his condition had been managed very well with the use of the original De Simone Formulation sold as "VSL#3" in past years (using 4 sachets/days) but recently he began to feel sick after he consumed a recently purchased box of "VSL#3" (lot number 507,132 expiry date 07/2017) newly purchased from the pharmacy. He went to the pharmacist where he made the purchase and learned that other consumers were bringing up similar complaints to the pharmacist and that the name of the strains listed on the box of the product were changed in the newlypurchased VSL#3. The UK patient went on a search to purchase boxes of "VSL#3" reporting the original names of the strains (original De Simone Formulation) from a different source. He was successful in finding the original version and decided to resume taking of the product. After he started to take the original De Simone Formulation (lot LM537 expiry date 10/ 2017), his symptoms began to resolve. Being puzzled, the UK patient questioned by e-mail the UK distributor of VSL#3 (Ferring UK) about the quality of the product, and after a few days received a written reply from Ferring UK. In the reply, Ferring UK sought to reassure him that nothing had changed with the product labeled "VSL#3", with the exception of the strains designation, which, according to Ferring UK, had been updated and "modernized". The UK patient was not satisfied by Ferring UK's reply, supported by the fact that to him also the taste and color of the new version of VSL#3 was different from the original version that he had come to rely upon. The patient wrote again to Ferring UK inquiring if the manufacturer of the product had changed. Ferring UK replied that it passed the question on to the manufacturer. Suspicious, the UK patient contacted me to learn why this "new VSL#3" made him very sick. This inquiry prompted me to investigate the existence of a "new VSL#3" product launched in the UK, and to determine if this "new" formulation has the same properties as the original De Simone Formulation, which is product manufactured by Danisco and studied and commercialized for more than 10 years". This is the "odyssey" of a UK patient suffering from an inflammatory bowel disease using the probiotic VSL#3 prescribed by his doctor. This real-life story is used here to examine how and whether the average consumer can assess whether a probiotic product is safe and effective for his health. First, we need to frame the normative and some definitions that are commonly applicable to probiotic products

Rules and regulations
The Food and Agriculture Organization of the United Nations and World Health Organization define probiotics as "live microorganisms that when administered in adequate amounts confer a health benefit on the host" (Hill et al., 2014). In Europe, probiotics are regulated by the "European Food Health Declaration Regulation" [Directive 2000/13/EU;Regulation 178/2002/EC;Regulation 1924/ 2006. The purpose of the regulations is to provide safeguards. All health claims related to probiotics must be approved by the European Food Safety Authority (EFSA). EFSA publishes a list of bacterial cultures with a qualified presumption of safety (QPS), which means that they are not subject to a safety assessment. EFSA is also responsible for assessing health claims for probiotic products (Efsa, 2021). In the United States, most probiotic products are classified as food or dietary supplements. Dietary supplements must comply with Good Manufacturing Practice (GMP) guidelines, which do not include quality or efficacy testing. As in Europe, nutritional supplements cannot make disease-specific claims, but in the United States, they can make structural or functional claims, such as "promotes healthy digestion". Besides, a class of probiotics are intended to be administered under medical supervision to manage the symptoms of a specific disease or condition and whose unique nutritional needs are determined by medical evaluation based on accepted scientific principles. In the United States, these products fall under the category of medical foods. Medical foods are not drugs, and therefore are not subject to the regulatory requirements applicable to drugs. However, medical foods that make false or misleading claims are considered misbranded under section 403(a)(1) of the Federal Food, Drug, and Cosmetic Act (FDCA) (Frequently Asked Questions About Medical Foods; Second Edition Guidance for Industry, 2016).

The trademark
According to the European Union Intellectual Property Office (EUIPO), the trademark makes it possible to identify the product as originating from a particular company and, therefore, to distinguish that product from those of other companies. According to Article 51(1)(c) of Regulation, No. 207/ 2009, the proprietor of the European Union trademark shall be liable to a revocation of the trademark either on application to the EUIPO or on the basis of a counterclaim in an action brought before it by a third party if the proprietor is liable to mislead the public particularly as to the nature, quality or geographical origin of the goods identified by the trademark. In the case of probiotic products, as long as they contain probiotic lactic acid bacteria, which are of the same species, although of different origin, the trademark remains valid. The owner of a trademark used to identify a probiotic formulation can change the strains, geographical origin, production methods, concentration of the strains without incurring any risk of trademark revocation.
The United States Patent and Trademark Office (USPTO) considers the principle that when a trademark over time becomes so identified with a particular product, its continued use constitutes an affirmation of fact of continuity. The brand in some cases is not only a symbol of "origin," but also a symbol of a "certain type of goods or services and their level of quality". A sudden or substantial change in the nature or quality of the goods sold under a trademark may so change the nature of the thing symbolized that the mark becomes fraudulent. Since a brand name can come to function as a representation of continuity of product contents and quality, any change of the product sold under that trademark would deceive consumers familiar with the old brand and ignorant of any change.

Taxonomy
In the description of probiotic strains, it is recommended to utilize a nomenclature following the International Code of Nomenclature. The microorganism's name must be the name of the genus and the name of the species (and subspecies name, where appropriate), followed by the strain name and/or the collection number (i.e. Lactobacillus acidophilus ATCC 4356) (Binda et al., 2020). Nevertheless, this procedure does not guarantee that the deposited strain information is correct. It depends on the kind of deposit activated by the strains' depositor. For example, the Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ) offers a "safe deposit" service for the preservation of microorganisms which does not require a complete, accurate identification procedure for the strains to be deposited. Accordingly, strains deposited in a "safe deposit" are not suited for identification purposes or patent deposits (i.e. Lactobacillus acidophilus DSM24735).

Strain identification and characterization
The continuous change in the taxonomic assignment of probiotic strains has two causes: a) the relocation of organisms previously included in older taxonomic into new taxonomic groups; b) the increased knowledge of discrimination markers by which microorganisms previously catalogued in specific taxa are reclassified in other taxa already known. The omics disciplines are assuming more importance in defining microbial taxonomy and determining similarity and divergence among probiotic strains. Genomics permits the knowledge about the whole repertoire of genetic features codified by the microbial genome allowing identification of probiotics down to the strain level and reconstruction of phylogenetic relationships (Binda et al., 2020;Kapli et al., 2020).
The whole-genome analysis of probiotics permits to determine the presence of genetic determinants associated with the production of beneficial metabolites, the degradation of harmful compounds, and the competition with pathogens. Genomics also allows identifying genetic markers responsible for antibiotic resistance or transmissible mobile elements (Hendriksen et al., 2019).
The other side of the coin is that, unfortunately, there are no standardized and universally adopted analysis conduits to date (Endrullat et al., 2016). Presently, genomic's results depend on the method used and the "bona fides" of who materially performs the analysis.
The genome analysis alone is not sufficient in characterizing the complexity of probiotics whose global characteristics depend on a plethora of factors, including the interaction with other microorganisms and the host. Genetically identical strains cultivated in a different setting or varying growth methods may present different phenotypic characteristics. This phenomenon attains to epigenetic traits representing stably heritable phenotypes resulting from changes in a chromosome without alterations in the DNA sequence (Berger et al., 2009). By considering that different phenotypes can be showed by genetically identical organisms, the phenotypic characterizations of probiotics must accompany genetic analysis. Such characterization concerns the morphological and metabolic characteristics of microbial strains which not only provide information useful for discriminatory purposes but even physiological and biochemical feature as growth temperature, pH value, enzymatic activity and compound metabolism permitting to evaluate their suitability as probiotics (Nomura et al., 1999;Yang et al., 2010). Since the phenotypes presented by microbial strains results to be essential for their beneficial effects on host health, the phenotypic characterization should prevail on the genomic one in case of discrepancy. Presently, proteomics and lipidomics are the most promising tools to investigate probiotics phenotypically. Proteomics is the analysis of the entire protein complement of a cell, tissue, or organism under a specific, defined set of conditions (Graves & Haystead, 2002). Lipidomics research studies the structure and function of the complete set of lipids (the lipidome) in a given cell or organism as well as their interactions with other cellular components (Yang & Han, 2016). Each probiotics' manufacturer has its own "secret recipe" to multiply bacterial strains at a high concentration, high viability with the lowest price. Substrates and cryoprotectants differ from manufacturer to manufacturer. The outcome is that the finished product will have genotypic and phenotypic characteristics depending on the manufacturer.

Strain deposit
The strains with probiotic properties may be deposited in an International Depository Authority (IDA) (e.g. American Type Culture Collection (ATCC), BIOTEC Culture Collection (BCC), Deutsche Sammlung von Mikroorganismen und Zellkulturen (DSMZ), National Collection of Industrial, Food and Marine Bacteria (NCIMB), Pasteur Institute). Unless the deposit is made according to the Budapest treaty on the International Recognition of the Deposit of Microorganisms for the Purposes of Patent Procedure, the strains are deposited as "safe deposit", which is the most frequent case since naturally occurring strains of bacteria are not patentable being the bacteria "manifestations of laws of nature". When a bacterial strain is selected for industrial production, the manufacturers (e.g. DuPont, Lallemand, Chr Hansen) develop and install a cell bank system that consists of a master cell bank (MCB) and a working cell bank (WCB). Only the bacterial cells from the WCB tested for viability and contaminants are used in the daily manufacturing processes. For a valid and correct identification of the strains isolated from the finished product in commerce, it is necessary to access the strains in use at the WBC.

Colony forming units
Probiotics are enumerated as colony-forming units (CFU). CFU is a measure of how many bacteria are present and able to divide and form colonies. If the probiotic bacteria can divide and form colonies, which indicates they are alive. Manufacturers report the total microbial content on the supplement's information label. CFUs are generally in the order of millions or billions per serving and should reflect the number of bacteria expected to be present at the end of the product's shelf-life (de Simone, 2019).

Storage of probiotics
Since probiotics must be ingested alive to ensure their health benefits and may die during storage, storage is critical. The stability of a probiotic product depends on a combination of several factors, e.g. packaging, temperature, and humidity. The optimum storage temperature depends highly on the excipients and the probiotic strain. Low storage temperatures result in lower viability losses. The storage temperature listed on the probiotic packaging is recommended by the manufacturer.

Manufacturer, distributor
Manufacturers may produce the probiotic strain or buy it from third parties and sell the finished probiotic product directly to retailers or distributors. The distributor's name is disclosed on the probiotic product's label, as well as the name of the packager, while that of the strains' manufacturer might be absent.

The scientific studies
Probiotics provide general health benefits in various conditions, including digestive disorders, antibiotic-related diarrhea, allergies, liver disease, autism, to mention a few topics (Ahmed et al., 2019;Blaabjerg et al., 2017;Chidambaram et al., 2020;Furrie, 2005;Pace et al., 2015). Most of probiotics' effects results to be strain -specific (e.g. vitamin synthesis and gut barrier reinforcement) and/or diseases-specific meaning the they are exerted by only specific strains within the microbial population or carried out only in presence of specific physiological conditions associated to diseases. In addition, some medical conditions, e.g. inflammatory bowel diseases, the probiotics' benefits are dosespecific (de Simone, 2019;McFarland et al., 2018;Palumbo et al., 2019;Trinchieri et al., 2017;Wilkins & Sequoia, 2017). In this context, several evidences support the idea that not all probiotics are equally effective, although there is no unanimous consent about how to classify microorganism as probiotics or which probiotic should be used for specific diseases since their properties are deeply influenced by their origin, manufacturing processes, and product quality control (Cruchet et al., 2015;de Simone, 2019;McFarland, 2015;Szajewska et al., 2016) By surveying more than 127 bacterial strains belonging to the genus Lactobacillus, Domig and colleagues determined that only 3% were found to have probiotic potential using as a criteria their survival in target organs, as well as, their ability to resist bile and gastric juices. (Domig et al., 2014) A meta-analysis evaluating data from 228 trials found significant efficacy evidence for 7 (70%) of probiotic strain(s) among four preventive indications and 11 (65%) probiotic strain(s) among five treatment indications. Furthermore, in the context of adult antibiotic-associated diarrhea, efficacy has been demonstrated only for some strains (e.g. Lactobacillus reuteri 55730), while probiotic activities have not been determined for other Lactobacillus strains (McFarland et al., 2015).

Considerations based on the UK patient story
In the past, the UK patient had always benefited from the VSL#3 product's efficacy in controlling his condition. Even if the patient did not change how the product is stored and consumed, some product batches did not benefit him. He asked for information from the pharmacist. The pharmacist recalled similar cases and mentioned that the product, although still called VSL#3, had changed the strains' denomination. The patient went to the distributor of VSL#3, Ferring UK, and the distributor sent the matter back to the manufacturer. The UK patient only learned the truth about the true nature of the new VSL#3 after he met in person with Prof De Simone. There is no news about his health status and whether he continues to take VSL#3 or other probioticsend of the story. According to EUIPO, the owner of a trademark used to commercialize a probiotic formulation is allowed to change the strain types, and/or their production methods and concentration maintaining the trademark unaltered. There is no obligation on a trademark proprietor to guarantee a certain quality level or consistency of the probiotic product with that covered by the same trademark prior to modifications. If under the same brand is commercialized a different preparation, it is up to the consumer to read the other information reported on the product's packaging and verify whether it is safe or beneficial. The EUIPO assumes that the patient will be intelligent enough to understand that something is wrong and diligent to the point that and that each time he buys the product, he checks that its ingredients are the same, even if the brand is still the same. A deterioration of the product's quality leads to a "disqualification" in the commercial sense of the good, according to EUIPO, but not to the trademark's cancellation. To understand why his body reacted differently to the two products, the UK patient double-checked if the new VSL#3 and the original VSL#3, had the same number of billions of bacteria, i.e. 450 billion CFU/sachet. Current probiotic product labeling rules require disclosure to consumers of the number of live bacteria per serving expressed in colonyforming units (CFU) (i.e. the number of live bacteria that can form colonies when grown on an agar plate for counting). The CFUs do not appreciate the difference in the number of dead cells present in probiotic formulations. Dead bacterial cells result from stress from industrial processes, including biomass production and lyophilization. Dead bacteria organisms "follow" the live bacteria from the initial production stages and cannot be removed from the product. If the viability of bacteria produced under certain production conditions is impaired (low-quality product), larger overfills are required to reach the amount of CFUs indicated on the label. The consumer will ingest a daily total amount of bacteria (live + dead bacteria) much bigger than that indicated by the CFUs reported on the label (Fiore et al., 2020). In this context, doctors are unaware about the "hidden contents" which can affects the "real effects" of the product they prescribe to patients. Although an increasing body of evidence suggest that dead bacteria and/or the components released by the bacteria breakage may be characterized by immunomodulatory, and metabolic effects, different study evidenced no activities for such bacterial components within the probiotics (Sarkar, 2018). In both scenarios, potential risks can be associated with the presence of excessive quantities of non-vital bacteria. In fact, if no probiotic activity were associated with dead bacteria, their excessive presence may impair the effectiveness of the administered products. As the opposite, the presence of undisclosed excessive amounts of active bacteria may result harmful, especially in immunocompromised subjects, if their numbers are high enough to affect the balance between anti-inflammatory and pro-inflammatory cytokines and other cellular functions.
The presence of non-viable cells in the finished product impacts the subject's immune and biological responses by enhancing IgA production and by modulating host T-cell responses (Lahtinen, 2012). Products with equal numbers of CFUs but a different number of dead cells have a nonidentical profile of safety and efficacy due to a different impact on gene expression, suggesting that both cell surface and actively secreted molecules may affect the intestinal transcriptome (van Baarlen et al., 2009). The two products were identical in terms of CFUs, but the UK patient did not know that CFUs are a misleading unit of comparison.
The current definition of probiotics does not consider patients with predisposing factors, i.e. immunosuppression, prior hospitalization, or surgical interventions. In these patients, also "probiotic bacteria" can cause serious infections or untoward reactions. However, even if he wanted to, the pharmacist would not know to whom to report the facts, and if once he had made the report, someone would ever consider it. The Health Authorities are focused on drugs, not on probiotics, which they generally consider safe. In the UK patient's mind, the next step to understanding why he did not feel good when he took those sachets of VSL#3 containing strains with different names from the original VSL#3 (the De Simone Formulation) was to call the distributor Ferring UK. The company sought to reassure him that "nothing had changed with the product labeled 'VSL#3', with the exception of the strains designation, which, according to Ferring UK, had been updated and 'modernized'".
Many probiotics producers prefer not to change the denomination of the product's strains to ensure the patient the qualitative continuity of the product, independently from any further modification or updating of the taxonomy. Moreover, the recent taxonomic names are not easy to read or remember (e.g. Lactobacillus paracasei becomes Lacticaseibacillus paracasei, Lactobacillus plantarum is now Lactiplantibacillus plantarum, and Lactobacillus brevis is currently reported as Levilactobacillus brevis) (Zheng et al., 2020). While from a taxonomic point of view, it might be appropriate to update the bacteria's denomination, de facto this process does not help the consumers. In fact, Ferring's explanation did not convince the patient. He wrote back to the company and asked if nothing had changed since the product had a different color and taste than the previous one. Ferring pulled out of this by saying that they would investigate the matter with the company that makes the product. Frustrated and depressed, the UK patient did not pose further questions to Ferring. No way to know who produced the bacteria sold under the brand VSL#3. On the VSL#3 package, Ferring was reported as the distributor and Actial as the owner of the trademark VSL#3. He turned directly to the one who, from what he was able to learn based on public documents, was the formulation's inventor, Prof. Claudio De Simone. Prof De Simone asserted his rights against the VSL#3 brand owners and its distributors. They tried to appropriate the studies conducted in patients with inflammatory bowel disease with the De Simone Formulation when commercialized under the brand VSL#3 containing a new untested formulation (Bibiloni et al., 2005;Gionchetti et al., 2000Gionchetti et al., , 2003Huynh et al., 2009;Karimi et al., 2005;Kuhbacher et al., 2006;Lee et al., 2012;Miele et al., 2009;Mimura et al., 2004;Ng et al., 2010;Pronio et al., 2008;Sood et al., 2009;Tursi et al., 2004Tursi et al., , 2010Ulisse et al., 2001). At that time, a good number of scientific articles were available on the safety and identification of probiotics (Koirala & Anal, 2021;Suez et al., 2019;Zuntar et al., 2020), but it was the first time that experts and evidence were tested in a legal battle. The genotypic and phenotypic analyses performed on the original De Simone Formulation and in the VSL#3 products sold after 2016 evidenced that the two microbial blends have different characteristics. Cinque and colleagues through the use of specific stain and microscopy imaging, determined that the VSL#3 formulation produced in Italy and sold in UK presented significantly higher proportions of dead bacteria than the original De Simone formulation (Cinque et al., 2016(Cinque et al., , 2017. A similar discrepancy between the VSL#3 products containing the original VSL#3 made in the U.S.A (the De Simone formulation) and the VSL#3 manufactured in Italy has been reported by Biagioli and colleagues in animal models of IBDs (Biagioli et al., 2017). Trinchieri and colleagues have provided further evidences about the difference between VSL#3 products manufactured at different sites by comparing, in vitro, the production of metabolites and their effects on a rat intestinal epithelial cell line. Obtained results evidenced significant differences in the production and metabolism of 1,3-dihydroxyacetone (DHA) (Trinchieri et al., 2017). In short, the VSL#3 produced by Actial in Italy did contain seven strains instead of eight as the previous US-made VSL#3  On 20 July 2020, Ferring, following an article on the "VSL#3 affair" published in the Geneva newspaper "Le Temps", stated that "the company is confident that its manufacturers meet the strict quality and good manufacturing practice requirements applicable to VSL#3" (Le temps, Face aux pharmas, un médecin en résistance) [48].
As of March 2021, Ferring no longer distributes VSL#3 in Europe. The distribution of VSL#3 by Ferring had already been suspended in 2018 in Canada when the Canadian authorities started to question Ferring about VSL#3. Ferring and Actial still oppose the public release of the correspondence exchanged with Health Canada regarding the product.

Concluding remarks
The UK patient has experienced first-hand that probiotic products are not interchangeable. Different strains produced using different methods and reagents will have different effects. Any reformulation will require a thorough reassessment to ensure that the documented properties of the original formulation are retained.
The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) recently published a position statement calling for better quality control of probiotics. They note that "procedures such as fermentation, matrix composition, cell harvesting, spray-drying, freezedrying and storage conditions like temperature, humidity and pH, are just several out of a wider array of manufacturing determinants that can affect microbial survival, growth, viability and ultimately the study results and/or clinical outcomes" (Kolacek et al., 2017).
Also, the FDA states in numerous guidance documents: "In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products are generally derived from living material human, animal, or microorganism -are complex in structure, and thus are usually not fully characterized" (FDA.Gov, 2021). The FDA further notes: "Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes". Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product's safety, identity, purity and potency (FDA.gov, Frequently Asked Questions About Therapeutic Biological Products). In Europe, there are rules, but they are easily circumvented. The EUIPO provisions regarding probiotics are incomprehensible, considering that we are dealing with peoples' health. The consumer cannot understand whether the probiotic he is taking is identical to what was purchased previously if the manufacturer is permitted to maintain the same brand when the product's qualitative and quantitative characteristics had changed. Continuous taxonomic reclassifications with subsequent substitution of strain names do not help the consumer. Authorities do not pay much attention to the probiotics' quality because they are not generally registered as a drug. The definition of probiotic gives an illusion of safety.
Moreover, in Europe, the judicial system is such that those who cheat have a good chance of getting away with it, or if convicted, it will be after dozens of years from the facts and the punishment laughable. Just consider the recent case of the drug Mediator, which in the 1990s was used to treat overweight diabetics, until it was withdrawn in 2009 due to possible heart damage. The Mediator has caused the deaths of at least 500 individuals. The trial ended in early 2021. The manufacturer, Servier, was ordered to pay a fine of EUR 2.7 million, and the company's former vice-president was sentenced to four years in prison with a suspended sentence. The French medical regulator was also fined more than €300,000 for its lack of vigilance in the scandal (France24.com, 2021). Consumers in the U.S.A are significantly better protected not only by USPTO and by a judicial system that is efficient and quite rightly remedial for the guilty. On 23 July 2019, some patients on behalf of all individuals who purchased the probiotic "VSL#3 ® " brought a Class Action against Alfasigma U.S.A Inc., VSL Pharmaceuticals Inc. and Leadiant Biosciences Inc. The Class Action ". . . alleges that the defendants nevertheless engineered a new formulation for VSL#3 and continued selling it as the original product" and "Defendants omitted in their marketing the fact that the post-May 2016 formulation of VSL#3 was materially different from the De Simone Formulation, and the clinical evidence concerning the De Simone Formulation simply does not apply to the Fraudulent Formulation currently sold under the VSL#3 brand name," The lawsuit argues that the new formulation was "fundamentally different" from the previous version, and that "not even a single clinical study" had been performed to support the company's claims of the new product's efficacy and safety. The consumers seek hundreds of millions of dollars in damages. The Class Action was filed with the aggravating circumstance of the civil "RICO Act" (Racketeer Influenced and Corrupt Organizations Act), a federal law of the United States, originally designed to combat organized crime. On 20 December 2020, the Maryland District Court rejected an attempt to dismiss the case filed by Alfasigma U.S.A Inc., VSL Pharmaceuticals Inc. and Leadiant Biosciences Inc. The case could go to trial in 2022 (Classaction.org, 2021). A few years ago, one would not have expected to develop survey methods to investigate probiotic products' authenticity. As physicians, we knew that there was illegal trafficking of drugs and that there had been scandals regarding how generic drugs were manufactured and placed on the market. Thanks to a rather unregulated market, probiotic products now represent one of the more accessible and profitable ways to make money (de Simone, 2019). When a company decides to mislead consumers regarding the probiotic identity and quality knowingly, the matter becomes very serious. The judicial authority must intervene promptly and impose punitive penalties of hundreds of millions.

Disclosure statement
Claudio De Simone is a retired Professor from The University of L'Aquila, Italy. He is the inventor of the De Simone Formulation (commercialized as VSL#3 until early 2016 and nowadays as Visbiome in the U.S.A and Vivomixx in EU). He served as CEO in some of the companies of the Actial Group until 2014/2015. He owns one share of VSL Pharmaceuticals and is the majority shareholder of EXEGI Pharma US.

Funding
No funds were employed.

Author's contribution
CDS conceptualized and wrote the manuscript.