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News - Atlantia Clinical Trials

Developing New Products in the Biotics Industry

Consumers are increasingly focused on health and nutrition in their decision-making. Alongside this, interest and understanding of the importance of the gut microbiota in health and disease continues to grow. The global market for functional foods and beverages is worth $216.4 billion today and is expected to grow to $324.4 billion by 20271. The biotics industry provides an expansive pool of new product opportunities. However, it faces several continuing and developing challenges. Not least of all the difficulties encountered in European Food Safety Authority (EFSA) health claim applications. Despite numerous applications, there are no EFSA authorised health claims for probiotics or prebiotics to-date. The development of postbiotics may be the most likely route for successful EFSA claim approval as their mechanistic pathways are often better defined. Their potential is also driven partially by their stability - simplifying characterisation and production. To make progress in this area, agreement on a clear definition of postbiotics is required. The International Scientific Association of Probiotics and Prebiotics (ISAPP) addressed this need last year2. However, further discussion and review may still be needed to improve clarity and consensus. To progress product development and improve chances for EFSA claim approval across all biotic groups, industry stakeholders must continue to improve product characterisation and study design used for substantiating evidence of health benefits, through acceptable marker identification, defined associated physiological health benefits and clearly characterised mechanistic pathways.

Definitions for future products

The definitions that ISAPP have proposed thus far for probiotics, prebiotics and synbiotics are simple, easy to understand and sufficiently comprehensive to capture wholly the broad scope of these functional foods. Focusing on postbiotics, the field requires well-defined terms to coalesce and promote emerging functional food groups. In ISAPP’s consensus paper for postbiotics it outlines several past proposed definitions for this group and proposes the definition “a preparation of inanimate microorganisms and/or their components that confers a health benefit on the host”. Similarly, to Aguilar-Toalá and colleagues3, I would question the appropriateness of grouping microorganism metabolites with non-viable cells as one product type. Contrarily, I believe the term postbiotics, as explained by ISAPP, nicely fits the requirements of non-viable microbial cells and cell structures. Whereas, I would champion metabiotics as the preferred terms for microorganism metabolites, which alone will cover a diverse range of substrates that require independent recognition.  Separating these biotics into two functional food groups will benefit the market and their potential for future claims.

Following this line of separation, I propose two slightly altered definitions that are simple, easy to understand, yet comprehensive, and, align with ISAPP’s previous definitions. Metabiotics could be defined as “non-viable products or metabolic by-products from microorganisms that, when administered in adequate amounts, confer a health benefit on the consumer”, and postbiotics as “non-viable microbial cells or cell structures, when administered in adequate amounts, confer a health benefit on the consumer”.  

While there is a clear need for new definitions, the elements of these need further careful consideration. For instance, substituting “host” for “consumer” is but one worthy aspect for future debate for these particular groups. Once these new definitions are clearly defined and accepted by the industry, a framework to expand on the good practices around a category, such as manufacturing, quality and enumeration, will be beneficial. However, such guidance will likely need to be product specific considering the diversity already defined within these two groups. Indeed, if future EFSA claims are to be considered, product characterization, including composition, manufacturing process and known mechanism of action will be required4.

Designing for scientific substantiation

For biotic products to be fully developed and successfully marketed, their safety, identity, purity and potency need to be clearly defined. Alongside this, quality pre-clinical and clinical studies are required for proof of benefits. Synbiotics; mixtures comprising live microorganism(s) and substrate(s) selectively utilized by host microorganisms that confer a benefit on the host, provide challenges for stable production and design of robust clinical studies. In particular for synergistic synbiotics, where the substrate is designed to be selectively utilized by the co-administered microorganism(s), the trial must be able to show that the combined effect is better than the effects of each component separately5. Such a requirement leads to studies with three to five treatment arms (control(s), single treatments and combination treatment). These studies are resource intensive, but these products hold great potential to enhance colonization of the probiotic and hence the number of responders within a population. Researchers have begun to use in vitro enrichment methods to formulate successful synergistic synbiotics and prove selective utilization6. However, ultimately, randomised blinded clinical studies are still essential to demonstrate positive outcomes equating to physiological health benefits in human populations.

To maximise chances of success when conducting such studies, there are several elements of the study design that need careful consideration. Firstly, one should consider the expected level of non-responders within the target population and integrate this into the power calculations. Inclusion and exclusion criteria should be defined to capture the specific population of interest and eliminate any confounding factors, while remaining true to reality. Biological sample collection methodology and analysis that allow appropriate microbial profiling of the study population should also be carefully planned and may include multiple sample times. Furthermore, study product should be administered at a quantity that is robust enough to cut through the established challenges of diet adherence and reporting while meeting market objectives, e.g. commercially available doses. For synbiotics, a health outcome and a microbiota outcome must be achieved in the same study. There should be one primary endpoint and, if this is to meet EFSA requirements, it must be a beneficial physiological effect. Including specific biomarker endpoints will also help in pertaining mechanisms. Finally, closely following ICH-GCP and EQUATOR guidelines (in particular CONSORT 2010 and SPIRIT 2013) provide the best opportunity for conducting a high-quality clinical study.

In summary, the field of biotics is vast and continues to grow. It is comprehensible that there is confusion among clinicians and consumers in understanding and differentiating the diverse products on the market. Unambiguous approved health claims will be a key aid in reducing this confusion. EFSA has improved guidance for the industry of the requirements for successful claims7 and continues to work with stakeholders to further develop these4. Within the current limitations, postbiotics, especially non-viable microbial products, have several advantages including known molecular structure, use in purified forms, increased stability and often known specific mechanisms of action. These diverse products pertain an array of highly desired beneficial properties. To realise their potential there is a significant need for definition consensus and the delivery of high-quality clinical trials to validate health claims.

References

1. BCC Publishing (2022). Functional Foods and Beverages: Global Markets (FOD100B). BCC Publishing, Wellesley, USA. pp. 304.

2. Salminen S, Collado MC, Endo A, Hill C, Lebeer S, Quigley EM, Sanders ME, Shamir R, Swann JR, Szajewska H, Vinderola G. (2021). The International Scientific Association of Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of postbiotics. Nature Reviews Gastroenterology & Hepatology 18(9): 649-67.

3. Aguilar-Toalá JE, Arioli S, Behare P, Belzer C, Berni Canani R, Chatel JM, D’Auria E, de Freitas MQ, Elinav E, Esmerino EA, García HS (2021). Postbiotics—When simplification fails to clarify. Nature Reviews Gastroenterology & Hepatology 18(11): 825-6.

4. EFSA (2019). EFSA remit & role: with focus on scientific substantiation of Health Claims made on foods. EFSA meeting with IPA Europe, Parma.

5. Swanson KS, Gibson GR, Hutkins R, Reimer RA, Reid G, Verbeke K, Scott KP, Holscher HD, Azad MB, Delzenne NM, Sanders ME (2020). The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on the definition and scope of synbiotics. Nature Reviews Gastroenterology & Hepatology 17(11): 687-701.

6. Kok CR, Gomez Quintero DF, Niyirora C, Rose D, Li A, Hutkins R. (2019). An in vitro enrichment strategy for formulating synergistic synbiotics. Applied and Environmental Microbiology 85(16): e01073-19.

7. EFSA NDA Panel (2016).  Guidance on the scientific  requirements  for  health  claims  related  to  the  immune  system,  the gastrointestinal tract and defence against pathogenic microorganisms. EFSA Journal 14(1): 4369, doi:10.2903/j.efsa.2016.4369.

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