Accelerating microbiota product development:The Societal Impact Value Cycle as a conceptual model to shape and improve public-private valorization processes

Despite their potential for preventing and reducing diseases, the availability of marketed probiotics with a relevant health or risk reduction claim is lagging behind. Food and pharmaceutical companies, as well as universities, are challenged to collaborate across the innovation value chain to deliver on the promises of microbiota research and development. A shared understanding of the knowledge valorization process is essential for the success of such public-private partnerships. Conceptual models enable stakeholders to discuss and understand complex processes and their corresponding activities but current models are lacking granularity in terms of activities taking place. Building upon the microbiota valorization and technology transfer cycle, this review synthesizes 32 conceptual models on knowledge valorization into a Societal Impact Value Cycle that describes relevant activities. The cycle is contextualized to the microbiota industry and 8 key points for successful innovation are highlighted. The model elucidates the importance of including unmet needs in wider society for generating socioeconomic benefits. While market and society domains contained the highest number of barriers in the probiotics industry, they were scarcely covered by the reviewed literature, highlighting their underexposure. The resulting generally applicable model aids stakeholders in outlining a thorough strategy to deliver really new and radical innovations

Innovations for microbiome targeting interventions - a patent landscape analysis indicating overall patenting activity decline and promising target disease areas

The human microbiota have been implicated in the aetiology and remedy of a host of disorders. However, due to the pervasive uncertainty inherent in the field of microbiota-targeting interventions and associated issues with establishing rigorous safety and efficacy profiles, regulatory oversight is suboptimal. This can dissuade innovators from further exploring novel and much needed health interventions. Modification of regulatory protocols and practices requires focussed efforts and funding to build the evidence base around future regulatory needs. Such modification can be critically informed by identification of changes and trends in technology fields to facilitate identification of regulatory gaps. To this purpose, this study rigorously collected and analysed patent data from Espacenet - covering the years 2013-2018 - and created a patent landscape analysis of microbiome targeting interventions with a focus on medicinal products. Pertinent patenting activity has declined overall. While, in absolute terms, patents most frequently claimed inventions targeting disorders of the gut and alimentary tract, relative year-on-year interest increases have been substantial for cancer, and disorders of the (neuro-)muscular and respiratory systems - driven by the private sector. Academic stakeholders showed top interest in disorders of the metabolism, anti-infectives, and skeletal and dermatological diseases. Although medicinal preparation claims dominated our dataset, a third of patents claimed food preparations, while only 1% claimed application as a diagnostic. Finally, China is, by an inordinate margin, a market of particular interest for both domestic and foreign innovators, indicating that microbiome targeting intervention innovation for EU and US markets might be frustrated. This study is the first to empirically demonstrate that live biotherapeutic product innovation is decelerating and potentially frustrated, supporting the urgent need for improved regulatory standards. Our results indicate which disease areas deserve particular attention for research funding to facilitate proper regulatory appraisal in the near- to mid-term future

Comparing probiotic and drug interventions in irritable bowel syndrome: a meta-analysis of randomised controlled trials

Clinical decisions made by health professionals to recommend either drug or probiotic interventions for irritable bowel syndrome (IBS) should be supported by proper knowledge of the efficacy rates of both types of interventions. In this article, we performed a systematic review and meta-analysis to examine the efficacy of both probiotic- and drug interventions in IBS. Medline was searched between January 2015 - January 2021. Randomised controlled trials (RCT) recruiting participants > 18 years old with IBS and examining the effect of probiotics or drugs were eligible for inclusion. The data of the primary outcome, i.e. the persistence of IBS symptoms (dichotomous symptom data), were pooled to obtain a relative risk (RR), with a 95% confidence interval (CI). Secondary outcomes, abdominal pain- and bloating scores (continuous data), were pooled using a standardised mean difference with a 95% CI. The search identified 269 citations of which 32 RCTs were eligible. Our meta-analysis indicated that both probiotic and drug interventions are able to improve the persistence of IBS symptoms (RR 0.60 [0.51; 0.92] versus 0.87 [0.81; 0.92], respectively) and abdominal pain scores (standardised mean difference (SMD) -0.35 [-0.56; -0.14] versus -0.10 [-0.20; 0.00], respectively). However, determining the overall efficacy of both intervention types is inherently complex and such results should be interpreted with care, due to the large diversity of probiotic- and drug types and doses, which is also complicated by variety in IBS subtypes. Hence, as a first step, more large scale randomised double blind placebo-controlled trials focussing on a specific IBS subtype targeted with specific probiotic strains or specific pharmaceutical modalities should be executed, enabling a more proper comparison between trials

Challenges and best practices for big data-driven healthcare innovations conducted by profit–non-profit partnerships – a quantitative prioritization

Big data-driven innovations are key in improving healthcare system sustainability. Given the complexity, these are frequently conducted by public-private-partnerships (PPPs) between profit and non-profit parties. However, information on how to manage big data-driven healthcare innovations by PPPs is limited. This study elucidates challenges and best practices in managing big data-driven healthcare innovations by PPPs in the Netherlands. Fifteen technical, organizational, competence and ethical/legal challenges and best practices to overcome these challenges were identified in expert interviews with key opinion leaders (KOLs) and through literature review. They were prioritized by a second KOL-panel in an online questionnaire and results were interpreted by a focus-group. ‘Data variety’ was the main challenge, followed by ‘lack of data sharing’ and ‘insufficient data quality’. PPPrespondents ranked appropriate big data skills significantly lower (P = 0.049) and conservatism towards health care decisions significantly (P = 0.026) than non-PPP respondents. The profit sub-group ranked data access higher compared to the non-profit sub-group (P = 0.022). Continuous dialogue between stakeholders, cost-benefit analyses and pilot experiments might overcome conservatism. In conclusion, PPPs should blend skills and resources to maximize benefits of big data-driven healthcare innovations. Mitigating actions could overcome technical issues, whilst a better common support base might prevent conservatism and lack of data sharing

European General Practitioners perceptions on probiotics:Results of a multinational survey

Public opinion and consumer adoption of probiotics is influenced by the perception and recommendations of General Practitioners (GPs), but the perceptions and recommendations of European GPs currently appear to be underreported. This paper therefore relates the perceptions of European GPs towards probiotics with their recommendations. Standardized telephonic interviews were conducted with 1318 GPs to assess current perceptions. Fisher's exact tests were performed to quantify the relationship between perceptions and recommendation behavior. 80 % of GPs recommend probiotics in their practice at least sometimes, primarily for antibiotic associated diarrhoea, infectious diarrhea and abdominal pain. GPs that are familiar with the mode of action of probiotics, and/or who perceive them to be safe or efficacious, are more likely to recommend probiotics. The relation between non-recommending behavior and disagreeing on one of the statements seems to be weaker, suggesting that other factors such as culture/previous experiences could be responsible for their non-recommending behavior. Perceptions of European GPs towards probiotics are predominantly positive. Additional research is needed to identify whether and to what extent proximal factors, such as social norms and culture are of influence on the perceptions and recommendation behavior of currently non-recommending GPs to foster innovation in this domain

Inadequate safety reporting in the publications of randomised clinical trials in irritable bowel syndrome: drug versus probiotic interventions

Randomised controlled clinical trials (RCTs) offer a unique opportunity to obtain controlled efficacy and safety data to support clinical decisions. However, most RCT reporting has a stronger focus on efficacy rather than safety. This study aimed to identify the safety profile of both probiotic and drug interventions in irritable bowel syndrome (IBS). In connection to this paper, an accompanying paper was published in which a meta-analysis was conducted to evaluate the efficacy of probiotic interventions compared to that of drug interventions in IBS. Together, these two studies provide a first assessment regarding the feasibility to determine a burden to benefit ratio for both probiotic and drug interventions in IBS. RCTs including participants (>18 years old) with IBS and comparing probiotic or drugs interventions with control groups were identified by a systematic search of MEDLINE (January 2015 - Jan 2021). Reported safety profiles in drug studies were completer and more detailed as compared with studies on probiotics. Several inconsistencies in safety reporting were identified between and within drug and probiotic studies, such as: didn't report on safety; only reported adverse reactions (ARs) or adverse events (AEs) with a certain severity; didn't report the total number of AEs; didn't split in the control- or experimental arm; didn't specify AEs; and used different thresholds for 'common' AEs. Hence, it is difficult to compare safety data from drug and probiotic RCTs across and between different studies. On the current approaches to safety reporting, we could not establish an unambiguous safety profile for neither probiotic and drug interventions in IBS. These shortcomings hamper a critical comparison of the burden to benefit ratio for IBS intervention

Multispecies probiotics promote perceived human health and wellbeing: Insights into the value of retrospective studies on user experiences

When taking a broader perspective on the societal impact of probiotics, engagement of end-users is important to discover unmet needs, define relevant health benefits and identify key considerations for successful implementation in daily practice. This study therefore takes a retrospective approach and analyses a database of user experiences to review the effects of four multispecies probiotic formulations. The user experiences were analysed in a dependent sample manner (without control group) and complement previous randomised controlled trials that have been performed with the formulations. The database consisted of 584 evaluable user experiences regarding the impact of probiotic supplementation on perceived quality of life (QoL), gastrointestinal (GIT) symptoms and reported stool consistency after two weeks of consumption. Two different scales were used (n=344 in a 5-point scale; n=240 in a 10-point scale), which are presented as separate analyses. In the combined population of the 5-point-scale questionnaire, a significant increase in perceived QoL and a significant reduction in perceived GIT symptoms was observed. Descriptive summaries also indicate that diarrhoea- and constipation-like stool patterns are reduced following supplementation. Moreover, half of participants indicated that probiotic supplementation had a positive effect on their unmet medical need, and 64% of users were likely to continue using the product. Similar results were observed in the 10-point scale questionnaire. Considering the clinical relevance of probiotic supplementation in specific target groups, subgroup analyses were performed on participants who consumed the products for diarrhoea, constipation, Inflammatory Bowel Disease, Irritable Bowel Syndrome, and antibiotic usage. Overall, findings support the potential of probiotics to advance perceived human health and support the daily wellbeing of users. This systematic analysis of user experiences thereby contributes to the external validity of studies evaluating clinical effects of probiotics and increases knowledge on their societal impact