Here, Chrysi Sergaki from the Medicines and Healthcare products Regulatory Agency (MHRA), UK, explores how innovators and regulators can navigate the challenges affecting the development and regulation of microbiome therapeutics to bring safe and efficacious therapies to patients as soon as possible.
The human microbiome is a key player in our understanding of health and disease. This network of trillions of microorganisms residing in our gut and across our body has opened new avenues in medicine, offering the promise of innovative, minimally invasive therapies. As late-stage clinical development, manufacturing, quality control processes and regulation for microbiome-based treatments evolve, standardisation becomes a critical and complex challenge. This article discusses the complexity of microbiome-based medicinal products and the novel challenges being encountered to characterise and measure this complexity in a robust manner as they progress through the different stages of clinical development that can delay the progress of products to the market.
This report addresses the key factors shaping pharmaceutical formulation, including regulation, QC and analysis.
Access the full report now to discover the techniques, tools and innovations that are transforming pharmaceutical formulation, and learn how to position your organisation for long-term success.
What you’ll discover:
Key trends shaping the pharmaceutical formulation sector
Innovations leading progress in pharmaceutical formulation and how senior professionals can harness their benefits
Considerations and best practices when utilising QbD during formulation of oral solid dosage forms
Can’t attend live? No worries – register to receive the recording post-event.
The gut microbiome: a therapeutic goldmine
The potential of manipulating and harnessing the gut microbiome to treat and prevent disease, has seen a wave of clinical trials emerge”
The human gut is a dynamic ecosystem saturated with a diverse array of bacteria, viruses, fungi and other microorganisms. This intricate network is vital for maintaining gut health, our immune system, and even mental wellbeing. Its disruption has been linked to a wide range of diseases, including inflammatory bowel diseases, cancer, metabolic disorders and neurodegenerative conditions. Recognition of the potential of manipulating and harnessing the gut microbiome to treat and prevent disease, has seen a wave of clinical trials emerge. However, as this field expands, it faces an equally growing array of conceptual and technical challenges.
Conceptual challenges: basic ecosystem biology and microbiology
The basis of many challenges is the dynamic nature of the microbiome, which is vastly underexplored and not well understood. The microbiome is an ever-changing ecosystem, influenced by changes in our diet, exercise, environment and health status, to name a few. It is essential to recognise that changes in the microbiome’s composition and function are not exclusive to individuals with diseases. This ecosystem sensitivity, along with the complexity of the human body and lifestyle, makes it difficult to understand how the microbiome is affected by its environment and how these changes impact us.
All microbiomes, even healthy ones, can contain pathogenic microbes”
To add to the complexity, the dynamic nature of microbes means that beneficial microbes can become pathogenic and vice versa depending upon the environment in which they exist.1 All microbiomes, even healthy ones, can contain pathogenic microbes, without causing inflammation or infection, such as Clostridium difficile.C. difficile can cause serious infections for some but has also been found in the microbiomes of healthy individuals with no problems. The potential of each microbe to become pathogenic can also be dictated by the environment, even leading to dormancy, frequently overlooked by strictly DNA-based investigation. This lack of comprehensive understanding of microbiome ecology and dynamics affects all stages of innovation; from describing the mechanism of action, to dosing, toxicity, efficacy and ultimately the success of clinical trials.
Disturbing an ecosystem can lead to loss of biodiversity, population imbalances, habitat destruction, changes in function (eg, metabolism and nutrient cycling), loss of resilience and increased vulnerability to disease.2 Manipulating the microbiome requires a level of ecosystem disturbance and predicting and controlling the effect of these interventions – both on the microbiome and the human body – requires better understanding of the microbial ecology of the human body, which is not a simple task.
Beyond bacteria, the microbiome is home to a less-explored realm of fungi, archaea, viruses and parasites that have a role to play within the ecosystem, which is not well studied or understood. This dynamic microbial interaction includes competition for nutrients, cross-feeding and genetic exchange, among other interactions, contributing to the fluctuation in microbiome composition and functionality. It is crucial to emphasise that the dynamics of these events are highly complex, interconnected and, notably, vary significantly from person to person.
Quality control: can we trust our data?
Lack of confidence in data has increased concerns about the field over the years”
Technical challenges make understanding the microbiome as an ecosystem even more difficult. While the evolution of omics technologies has revolutionised microbiome research, the data generated is compromised by the inherent bias of these methodologies and the lack of effective standardisation. From sampling and storage to extraction and analysis, methods can vary and give different results, leading to contradictory findings.3 This lack of confidence in data has increased concerns about the field over the years, a problem which becomes even greater for understudied microbes like fungi and viruses.
As technology progresses, we have started questioning the taxonomy and the definition of strain, as well as the functional capabilities of microbes, considering genome structure, phenotypic plasticity, functional redundancy and the regulation of gene expression at a fundamental level.4 This not only poses issues for intellectual property (IP) but also regulatory challenges as the product progresses to clinical trials.
The imperative for standardisation
The complexity and potential variability in microbiome therapies necessitates robust standardisation across all stages of research and development. Efforts to standardise microbiome therapies are already underway, with several reference reagents available and international studies revealing the variability in methodologies across the world.5,6 These standards should be robust and applicable for the evolving field, accommodating advances in microbiome science and technology. Standardised methods offer several benefits:
Confidence in data allowing for more robust evidence of therapeutic efficacy from clinical trials
Robust evidence that can reduce uncertainties for regulators and facilitate faster approvals, ultimately accelerating the availability of these treatments for patients
Assurance that therapies consistently meet quality and safety standards, protecting recipients from potential harm and/or unreliable treatments
Fostering of trust in the industry, attracting investment and promoting innovation.
Clinical trials: ensuring safe and effective therapies
The diversity of the human microbiome between individuals, health state and even time, complicates trial design and data interpretation”
Late-stage clinical development for microbiome therapies involves designing and conducting robust clinical trials. However, the diversity of the human microbiome between individuals, health state and even time, complicates trial design and data interpretation. Furthermore, there is growing scrutiny surrounding preclinical-trial data due to the over-reporting of transferable disease phenotypes between species and relevance of the data produced to human health.
It is critical that innovators address how the quality and consistency of the product should be thoroughly evaluated, and it is their responsibility to justify and establish reporting procedures to achieve this. It has been shown that the microbiome, and even microbiome-associated particles, may cause a varied immune response and toxicity from person to person. Dosing must therefore be tightly controlled, using a risk-based approach and considering the target population. Ultimately, clinical trials are expected to have variable results due to the nature of the microbiome, yet it is imperative to have confidence that the data is true, accurate and reliable, while working towards understanding the sources of variability in order to progress the product to the market.
Open and honest discussion with regulators is of utmost importance…”
To address these challenges, the research community must work collaboratively to develop agreed upon criteria, eg, for inclusion and exclusion, as well as controlling and/or accounting for cofounding factors and utilising standardised reporting. Open and honest discussion with regulators is of utmost importance and will help ensure that clinical trial results are interpretable and trustworthy.
Navigating the regulatory landscape for microbiome therapeutics
The regulatory landscape for microbiome therapies is evolving rapidly, with multiple initiatives across the world. Recognising the challenges of the field, regulators often welcome open dialogue with innovators from the earliest stages of product development. Openly discussing the conceptual and technical challenges of the field, describing the evidence-based decision-making processes, providing robust rationale, reliable data, comprehensive risk management and analysis can streamline the approval process for both regulators and innovators.
Innovators are the experts of their field, whereas the expertise of regulators lies in reviewing the evidence”
Innovators have a responsibility to provide evidence that helps regulators make informed decisions, as well as to improve the evidence as technology progresses, and to challenge unsuitable methodologies. Innovators are the experts of their field, whereas the expertise of regulators lies in reviewing the evidence, not on deciding how the science should be done.
Concerted effort needed to accelerate microbiome therapies
The microbiome has huge therapeutic potential, offering new hope for the treatment and prevention of a wide range of diseases. However, the challenges of late-stage clinical development, manufacturing, regulation and quality control, demand a concerted effort to accelerate innovation in the field.
Standardisation is not an option; it is an imperative. Only through the establishment of clear, internationally recognised standards can we ensure the safe, effective and consistent development of microbiome therapies.
Collaborative efforts among researchers, manufacturers, regulators and clinicians will create the foundation for the future of microbiome therapeutics, unlocking the full potential of this exciting field for the benefit of patients worldwide.
In our aim to unlock its full potential, we need to go back to basics and think about the microbiome as the complex and dynamic ecosystem it is”
Finally, in our aim to unlock its full potential, we need to go back to basics and think about the microbiome as the complex and dynamic ecosystem it is. Microbiome innovators should pave the way by thinking outside the box and facing the challenges headfirst, acknowledging the innate limitations of current approaches. Regulators across the world realise these challenges and are increasingly encouraging active discourse at the earliest stages of the application process. The goal is – or should be – common after all: to bring novel, safe and efficacious therapeutics to patients as soon as possible.
About the author
Chrysi Sergaki is the Microbiome Group Leader at the Medicines and Healthcare products Regulatory Agency (MHRA), UK, leading the microbiome standardisation programme, as well as research projects on microbiome, AMR, microbial diagnostics and cancer immunotherapy irAEs. She has led the establishment of the first three WHO International Reference Reagents for the microbiome, by co-ordinating international collaborative studies and the development of a guidance document for microbe-based medicinal products, to facilitate the regulatory process and ensure patient safety. Before joining the MHRA, Chrysi completed her PhD at the University of Warwick, UK, researching microbial interactions and their impact on the host.
References
Kamada N, Kim YG , Sham HP, et al. Regulated Virulence Controls the Ability of a Pathogen to Compete with the Gut Microbiota. Science [Internet]. 2012. [cited 2023 Dec];336(6086):1325–9. Available from: https://science.sciencemag.org/content/336/6086/1325.long
Nearing JT, Comeau AM, Langille MGI. Identifying biases and their potential solutions in human microbiome studies. Microbiome. 2021 May 18;9(1).
Van Rossum T, Ferretti P, Maistrenko OM, Bork P. Diversity within species: interpreting strains in microbiomes. Nature Reviews Microbiology [Internet]. 2020 [cited 2023 Dec] 4;1–16. Available from: https://www.nature.com/articles/s41579-020-0368-1
WHO/BS/2022.2416: A WHO collaborative study to evaluate the candidate 1st WHO International Reference Reagents for Gut Microbiome analysis by Next-Generation Sequencing [Internet]. www.who.int. [cited 2023Dec]. Available from: https://www.who.int/publications/m/item/who-bs-2022.2416
WHO/BS/2023.2455 WHO 1st Reference Reagent for DNA extraction of gut microbiome [Internet]. www.who.int. [cited 2023Dec]. Available from: https://www.who.int/publications/m/item/who-bs-2023.2455
This website uses cookies to enable, optimise and analyse site operations, as well as to provide personalised content and allow you to connect to social media. By clicking "I agree" you consent to the use of cookies for non-essential functions and the related processing of personal data. You can adjust your cookie and associated data processing preferences at any time via our "Cookie Settings". Please view our Cookie Policy to learn more about the use of cookies on our website.
This website uses cookies to improve your experience while you navigate through the website. Out of these cookies, the cookies that are categorised as ”Necessary” are stored on your browser as they are as essential for the working of basic functionalities of the website. For our other types of cookies “Advertising & Targeting”, “Analytics” and “Performance”, these help us analyse and understand how you use this website. These cookies will be stored in your browser only with your consent. You also have the option to opt-out of these different types of cookies. But opting out of some of these cookies may have an effect on your browsing experience. You can adjust the available sliders to ‘Enabled’ or ‘Disabled’, then click ‘Save and Accept’. View our Cookie Policy page.
Necessary cookies are absolutely essential for the website to function properly. This category only includes cookies that ensures basic functionalities and security features of the website. These cookies do not store any personal information.
Cookie
Description
cookielawinfo-checkbox-advertising-targeting
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category "Advertising & Targeting".
cookielawinfo-checkbox-analytics
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Analytics".
cookielawinfo-checkbox-necessary
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category "Necessary".
cookielawinfo-checkbox-performance
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category "Performance".
PHPSESSID
This cookie is native to PHP applications. The cookie is used to store and identify a users' unique session ID for the purpose of managing user session on the website. The cookie is a session cookies and is deleted when all the browser windows are closed.
viewed_cookie_policy
The cookie is set by the GDPR Cookie Consent plugin and is used to store whether or not user has consented to the use of cookies. It does not store any personal data.
zmember_logged
This session cookie is served by our membership/subscription system and controls whether you are able to see content which is only available to logged in users.
Performance cookies are includes cookies that deliver enhanced functionalities of the website, such as caching. These cookies do not store any personal information.
Cookie
Description
cf_ob_info
This cookie is set by Cloudflare content delivery network and, in conjunction with the cookie 'cf_use_ob', is used to determine whether it should continue serving “Always Online” until the cookie expires.
cf_use_ob
This cookie is set by Cloudflare content delivery network and is used to determine whether it should continue serving “Always Online” until the cookie expires.
free_subscription_only
This session cookie is served by our membership/subscription system and controls which types of content you are able to access.
ls_smartpush
This cookie is set by Litespeed Server and allows the server to store settings to help improve performance of the site.
one_signal_sdk_db
This cookie is set by OneSignal push notifications and is used for storing user preferences in connection with their notification permission status.
YSC
This cookie is set by Youtube and is used to track the views of embedded videos.
Analytics cookies collect information about your use of the content, and in combination with previously collected information, are used to measure, understand, and report on your usage of this website.
Cookie
Description
bcookie
This cookie is set by LinkedIn. The purpose of the cookie is to enable LinkedIn functionalities on the page.
GPS
This cookie is set by YouTube and registers a unique ID for tracking users based on their geographical location
lang
This cookie is set by LinkedIn and is used to store the language preferences of a user to serve up content in that stored language the next time user visit the website.
lidc
This cookie is set by LinkedIn and used for routing.
lissc
This cookie is set by LinkedIn share Buttons and ad tags.
vuid
We embed videos from our official Vimeo channel. When you press play, Vimeo will drop third party cookies to enable the video to play and to see how long a viewer has watched the video. This cookie does not track individuals.
wow.anonymousId
This cookie is set by Spotler and tracks an anonymous visitor ID.
wow.schedule
This cookie is set by Spotler and enables it to track the Load Balance Session Queue.
wow.session
This cookie is set by Spotler to track the Internet Information Services (IIS) session state.
wow.utmvalues
This cookie is set by Spotler and stores the UTM values for the session. UTM values are specific text strings that are appended to URLs that allow Communigator to track the URLs and the UTM values when they get clicked on.
_ga
This cookie is set by Google Analytics and is used to calculate visitor, session, campaign data and keep track of site usage for the site's analytics report. It stores information anonymously and assign a randomly generated number to identify unique visitors.
_gat
This cookies is set by Google Universal Analytics to throttle the request rate to limit the collection of data on high traffic sites.
_gid
This cookie is set by Google Analytics and is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visited in an anonymous form.
Advertising and targeting cookies help us provide our visitors with relevant ads and marketing campaigns.
Cookie
Description
advanced_ads_browser_width
This cookie is set by Advanced Ads and measures the browser width.
advanced_ads_page_impressions
This cookie is set by Advanced Ads and measures the number of previous page impressions.
advanced_ads_pro_server_info
This cookie is set by Advanced Ads and sets geo-location, user role and user capabilities. It is used by cache busting in Advanced Ads Pro when the appropriate visitor conditions are used.
advanced_ads_pro_visitor_referrer
This cookie is set by Advanced Ads and sets the referrer URL.
bscookie
This cookie is a browser ID cookie set by LinkedIn share Buttons and ad tags.
IDE
This cookie is set by Google DoubleClick and stores information about how the user uses the website and any other advertisement before visiting the website. This is used to present users with ads that are relevant to them according to the user profile.
li_sugr
This cookie is set by LinkedIn and is used for tracking.
UserMatchHistory
This cookie is set by Linkedin and is used to track visitors on multiple websites, in order to present relevant advertisement based on the visitor's preferences.
VISITOR_INFO1_LIVE
This cookie is set by YouTube. Used to track the information of the embedded YouTube videos on a website.