Microbiome Therapeutics eBook - Advancing the Microbiome Therapeutics Industry
This eBook reviews the biggest challenges that the microbiome industry is yet to overcome, and the most urgent opportunities for innovation.
Advancing the Microbiome Therapeutics Industry
The microbiome therapeutics field still has a journey ahead before delivering a globally approved product. What more can be done to further prepare the biopharmaceutical industry and clinical understanding for production of microbiome-based therapies? This exclusive Microbiome Therapeutics eBook reviews the story so far, the biggest challenges that the industry is yet to overcome, and the most urgent opportunities for innovation.
The following pages deliver an overview of the existing regulatory landscape, lessons learned in standardising manufacturing, and the current demands for technologies in research and development.
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The Regulatory Environment of Microbiome-Based Therapies in the US and EU
The Regulatory Environment of Microbiome-Based Therapies in the US and EU
The information in this report does not constitute legal advice and should not be interpreted as such.
The advancement of live microbiome therapies into laterphase clinical trials such as 4D Pharma’s Blautix or Rebiotix/Ferring Pharmaceutical’s RBX2660 has raised hopes of a near-future where we will be able to prevent or treat diseases by modulating the microbiome. While new companies are joining the microbiome industry each year, there is one barrier of entry that makes life in the industry as difficult as one can expect in an emerging field: regulatory uncertainty. The following sections review the current situation in two parts of the world where the microbiome industry is advancing fast, namely the US and the EU.
At the present time, the FDA has not approved any live microbiome therapy other than a vaccine for the prevention or treatment of diseases. While the FDA is well aware of evidence supporting the use of probiotics as adjuvant, treatment or prevention interventions for several major health conditions, more research is needed in order to establish the safety and efficacy of such treatments before such products can be commercialized.1
In 2016, the FDA issued a guidance document that can help commercial and non-commercial entities who want to sponsor an Investigational New Drug Application (IND) understand
regulation on chemistry, manufacturing, and control (CMC). The guidance document also applies to products commercialized as foods and dietary supplements.2
When reviewing an IND application, the FDA focuses on issues concerning the safety and rights of subjects when evaluating Phase 1, 2, and 3 of a clinical trial and on issues concerning the quality of the scientific evaluation of the drugs in Phase 2 and 3. Key elements evaluated include the identification and control of raw materials, stability assurance, and non-clinical safety assessments. In generic terms, the CMC section of an IND should include the description and characterization of the drug substance, the name and the address of the
manufacturers, the method of manufacture, drug substance specifications, and product composition. IND must also submit non-clinical information about pharmacological and toxicological studies of the product in laboratory animals or in vitro and clinical information describing previous human experience and its relevance for the evaluation of the study.
Case Study: The Uncertain Status of Fecal Microbiota Transplantation (FMT)
FMT is currently regulated by the FDA as a live biotherapeutic product for the treatment of individuals with Clostridium difficile infection (CDI) not responding to standard therapies yet it does not require an Investigational New Drug Application (IND) for physicians performing the procedure or from the stool banks providing the material. The problem is, FDA has not clearly defined whether FMT can be regarded as a product, a procedure or both. Those interested in researching and eventually commercializing other types of microbiota transplants such as vaginal or oral might face a similar situation unless FDA’s stance on FMT evolves and similar standards will be applied for other microbiota transplants.3
The European medicine regulatory system consists of a network of around 50 regulatory authorities from the 28 EU members, Iceland, Liechtenstein, Norway, the European Commission and the European Medicine Agency (EMA). All member states must operate by the same requirements regarding the authorization and monitoring of medicine. When a company seeks to commercialize a product in the EU, it can send an authorization application to EMA. After passing through several stages, the European Commission can provide or deny a marketing authorization that is valid everywhere in the EU. This procedure is known as the centralized approach and is compulsory for innovative medicines. Those who do not fall within the scope of this procedure must seek authorization by national component authorities in the member states.4
Although the EU has been a leader in microbiome research, it lags behind the US in the development of a regulatory framework for microbiome therapies. For instance, the FDA has been working with companies and institutions involved in microbiome research for almost a decade while the European regulators have not. More so, the FDA has provided a draft guide for those involved in the development of microbiome therapy, something which the EU has yet to do.
Case Study: FMT under Gene, Cells, and Tissue Regulations
Several EU countries have introduced some national rules and other countries require products to be compliant with the European directive 2004/23 on quality and safety of tissues and cells. These rules mostly concern the appropriateness of the facility, processing and testing, the raw material, use of equipment, and preservation and storage for release. It is possible that FMT will eventually be included in the gene, cell, and tissue regulations, including the hospital exemption system in the European Advanced Therapy Medicinal Products.6 However, it appears to be less clear what will happen to other microbiome therapy currently under development.
Joining the market of microbiome-based therapies requires companies to have a clear understanding of the distinction between dietary supplements and drugs from a regulatory point of view. When a microbiome-based product is advertised for scopes that do not include prevention or treatment, they are typically understood as dietary supplements by regulatory bodies.
If a company’s intention is to commercialize a product as a drug, it must previously establish ways in which specific products will be evaluated for safety and efficacy in a defined population. From the perspective of a regulatory body, an accurate evaluation of a product will include a clear definition of the product’s purpose in terms of clinical outcomes for a clearly-defined population.
While no live microbiome therapy has yet been approved by regulatory bodies in the US or the EU, the American market appears to be less uncertain from a regulatory perspective, as the FDA has been working with companies and institutions involved in microbiome research and provided a draft guide for commercial and non-commercial researchers. Regulatory bodies in the EU must act fast if their intention is to provide similar conditions for the European microbiome market.
3. Hoffmann, D. E., et al. (2017). "A proposed definition of microbiota transplantation for regulatory purposes." Gut microbes 8(3): 208-213.
5. Union, E. (2004). "Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells." Official Journal of the European Union 102: 48-58.
6. Verbeke, F., et al. (2017). "Faecal microbiota transplantation: a regulatory hurdle?" BMC gastroenterology 17(1): 128.
Where are the biggest gaps in current technologies to understand complex interactions?
Where are the biggest gaps in current technologies to understand complex interactions?
As with any new field of research, there is a lot of excitement around the potential of human microbiome therapeutics, but also a lot of uncertainty. As the complexity of live microorganisms continues to baffle and inspire simultaneously, what roles could technology play to support our understanding?
In June 2019, we asked microbiome therapeutics professionals around the world where the biggest gaps are in technology to aid research and development within the field. The following is a selection of the varied responses to this question.
“A comprehensive enterprise solution to combine all researches and results together.”
“A lack of sampling capability in the site of interest - we analyse stool and consider it a useful indicator of everything from the stomach to the descending colon.”
“Addressing functionality of microbiome.”
“Identifying host-microbe mechanisms.”
“Improvement in machine learning algorithms that can be applied to the large data, to be able to find correlations in the complex interactive network between the host and their microbiome.”
“Better models of in vivo interactions that correlate to humans.”
“Biomarkers for disease susceptibility and treatment effect.”
“Compelling data on the efficacy or treatments.”
“Defined, standardized animal models.”
“Endogenous retroviral DNA influence, anthropological data exploration of adolescent immune exposure that determines microbiome landscape.”
“Getting results that are repeatable and specific down to species and bacterial metabolite.”
“How to employ extant knowledge to make patient clinical decisions regarding probiotics. The rheumatologist’s use of data to effect autoimmune/CTD patients.”
“PK of LBPs and how they can be manipulated despite inter-patient variability.”
“Standardization and communication.”
“Identification/precise microbiome mapping and connection with disease.”
“Interplay between microbial sub strains, bacteriophages and other microbiome with diet and its effect on metabolism. The technology more often gives a snapshot and it is difficult to assess how bacterial turnover really affects physiology. We need elegant high throughput compact data sets to work with. This is the biggest hurdle, it is unclear what tiny amounts of rare bacteria might do.”
“Lack of understanding of molecular pathways and sequencing expertise within R&D.”
“Complex data analysis for pleiotropic mechanisms, manufacturing capacity of anaerobes, restrictive regulatory design which doesn't correspond to systems approaches necessary for microbiome-based applications.”
“Connecting microbial strains and species to functional activity.”
“Defined communities to pinpoint the effects of specific microbe-associated metabolic pathways to host phenotypes.”
“Modulation of different microbiome populations and communities to systematically define their interactions with the host and computer simulations/modelling of these effects.”
“Strain level ID and phenotyping.”
Standardization and Opportunities in Manufacturing Microbiome Therapeutics
Explore the challenges and latest developments in standardising manufacturing of microbiome-based drugs
Background on manufacturing microbiome therapeutics
Currently, fermentation is a commonly used method to manufacture commercial probiotic strains such as Lactobacillus spp. or Bifidobacterium spp. The advantage is that it can be easily scaled-up at relatively low cost, but the challenge is do it while respecting good manufacturing practices (GMP). When working to obtain cGMP certification, costs increase rapidly: in the case of manufacturing microbiome therapeutics, increased cost resolve around large batch fermenting vessels and anaerobic chambers for manipulation. This means that new strategies will have to be developed to enable large scale probiotic manufacturing.
Some of the systems being explored currently include disposable or low capital cost bioreactor designs, dynamically changing growth conditions and inoculation strategies reducing batch-to-batch variability as well as novel, low-cost media components. But companies in this space are realistic, and a number of challenges will need to be addressed. In July 2019, Informa polled 89 executives operating in the microbiome space. When asked what the biggest challenge they are facing specifically around manufacturing and scaling up, three issues dominated: the importance of viability, potency and purity was the biggest challenge for 30% of respondents, followed by creating new standards (25%) and limited choice of CDMOs for certain types of bacteria (20%).iii
Current challenges within data collection and sequencing
While interest in microbiome therapeutics is growing rapidly, it is still a relatively new space of research and study, and there are multiple issues that need to be addressed in this space including data collection and sequencing. Data collection issues include variability as well as complexity of the data. Indeed, one of the biggest challenges when dealing with the microbiome is that it is not easy to extract significant data samples. Often, we are not dealing with a singular fungible unit, but rather a collection of organisms, or sometimes even a whole ecosystem.
This poses quite a challenge when using traditional sampling processes, as extracting large representative samples is often unfeasible, if not impossible. Furthermore, when the microbiome is studied in a specific point in time, it reduces our understanding of its variability. As such, scientists are often limited to studying individual microbiotic species, in a single point and time, rather than studying the interaction between multiple species and the human system over a prolonged period.
This also means that some data sets that we collect in one area of the body is not necessarily significant for other parts of the body. For example, some microbes might have a specific role in one part of our body, and a different one in another part.
Furthermore, while the technologies we have are able to detect and identify specific species, they often have issues when trying to identify different strains of the same species. This is especially troublesome, as some of these strains might have a different impact on our health.
In an effort to avoid limited data sets, some might be tempted to collect large, all-encompassing data sets. This leads to another relevant issue, the one relative to data analysis and quality of data. Overall, this means that, using our current existing technologies, it is quite challenging to monitor, catalog and identify individual members of a specific microbiome, as well as understanding how microbiota communities interact and influence their host-pathogen over prolonged period of times. Limited data sets create a very narrow window of understanding while larger data sets are often impossible to analyze. As such, some companies are hoping that artificial intelligence might be able to assist in data analytics of the more complex data sets. Eagle Genomics is one such company. They are developing IT platform solutions for the microbiomics space. They have even partnered with Microsoft Genomics in the hope of being able to scale they current products and solutions.
Roles and relationships between pharmaceutical companies and regulatory bodies
Microbiome therapeutics has long been the playground of small biotech companies. But as recent investments have shown, big pharma has been quite interested in entering the game. For example, AstraZeneca invested $20 million in Seres Therapeutics to work on microbiome medicines in immuno-oncology while AbbVie has elected to collaborate with Synlogic to target the inflammatory bowel disease market. As pharma get more implicated in the microbiome space, their involvement becomes key to the development of a regulatory framework.
In the US, the current regulatory pathway for microbiome therapeutics is still being defined. While three drugs are going through phase III trials: two have done so by using an orphan drug status (SER-109 by Seres Therapeutics and RBX-2660 by Rebiotix which are specifically indicated for the treatment of C. difficile infection) while the third, RP-G28 (Ritter Pharmaceuticals) is in trials for the treatment of lactose intolerance. The orphan drug regulatory strategy, while enabling product approval, has a significant downside for even when these microbiome therapeutics are approved, they will achieve an orphan drug status. This means they will be available uniquely for a specific indication, and end up being priced accordingly. Developing more encompassing regulatory pathways for microbiome therapeutics is necessary going forward, but our understanding of the microbiome is limited, which has complicated the development of a distinct regulatory framework. Relying on innovative data points (such as real-world data) to demonstrate value might be a valuable strategy to reduce regulatory agency anxiety.iv
Its important to note that regulatory bodies are usually quite willing to work early with innovators to develop standardized regulatory frameworks, and usually look to industry to assist in the preparation of practical real-world frameworks. For big pharma, this will mean developing frameworks for two key requirements. First, a framework to work on the characterisation of microbiome products and second, frameworks for well-designed clinical studies with defined endpoints.
Strategies for defining manufacturing protocols
Manufacturing is one of the biggest bottlenecks faced by microbiome companies. Despite decades of experience growing bacteria to produce biologics, there is actual very limited experience in manufacturing live bacterial therapies within GMP environments, which is essential for pharmaceutical products.
For example, when Lonza formed a Joint Venture with Chr Hansen to accelerate development in the microbiome space, they quickly acquired microbiome expertise and capacity that might have taken them a lot of time to build organically; unfortunately, Chr Hansen’s experience is not in GMP environments but rather in manufacturing agricultural products, where being cGMP compliant was not necessary. This means Lonza and Chr Hansen will have to invest considerable sums to upgrade cGMP-compliant pharma production capabilities.v
This shortage of manufacturing capacity is especially important for companies working on intestinal microbiome strains, which represent the majority of companies in space. As gut microbes require low-oxygen culture conditions and produce spores that can contaminate other cultures, high standards must be applicated during production.
Developing manufacturing standards will be key in this space, as they will be highly scrutinised by regulatory authorities, especially when one considers the batch-to-batch variations that are implicit with living organisms. Live culture compositions will need to be standardised to demonstrate to regulatory bodies that reproducibility is possible. Other key concerns will likely include potency (the quantity of product require to obtain desired efficacy); purity (no detectable pathogens); and identity (the presence of certain organisms, especially when those being responsible for therapeutic effect are not identified).
Further requirements will most likely include additional containment areas to ensure “clean” areas remain sterile: as M. John Aunins, from Seres Therapeutics mentioned his presentation on manufacturing considerations for microbiome -based productsvi: “you really have to make sure that you've got unique facility designs that have appropriate classifications, that have appropriate pressure gradients, so that you can both keep bugs you don't want out, keep your bugs in.” Final considerations will have to be made to demonstrate that beneficial effects are still present when the product gets to the consumer and through to the expiration date of the product.
Going forward, some other ideas manufacturers can explore include minimising the use of reusable equipment (to limit the chance of cross contamination), use extensive decontamination procedures to make sure that they address concerns of cross-contamination and making sure the environmental testing will actually address the microbes being produced.
Australia Therapeutic Goods Administration (TGA) has proposed a framework for regulating faecal microbiota transplant (FMT) products by suggesting a risk-based approach to regulating FMT products. Under the proposal, the TGA will treat minimally manipulated FMT products as Class 1 or Class 2 biologicals, depending on whether they are manufactured in the treating hospital or remotely for shipping to a healthcare facility.
These regulations will form the basis of key, general requirements, such as the standards the TGA will require of hospital-based manufacturing facilities. As producers of Class 1 biologicals, hospitals will be exempt from good manufacturing practices, since it is believed that proximity and immediacy of the biological production unit to where it is used addresses key concerns around long-term stability of microbiotic therapeutics.vii
iNewman, Tim. “How 'good' viruses may influence health”, January 6th, 2020, https://www.medicalnewstoday.com/articles/327167 (Last Visited 18th of February 2020).
iiForbes and al. A Fungal World: Could the Gut Mycobiome Be Involved in Neurological Disease? Frontiers in Microbiology, January 9th, 2019. https://www.frontiersin.org/articles/10.3389/fmicb.2018.03249/full (Last Visited 18th of February 2020).
iiiBurrows, Andrew. The state of manufacturing and commercialization of microbiome therapeutics - Data report analysis, November 2019. https://informaconnect.com/manufacturing-commercialization-microbiome-therapeutics/ (Last Visited 18th of February 2020)
ivMoodley, Thunicia and Mistry, Erin. Could the Gut Microbiome Revolutionize Medical Care? Current Status and Initial Considerations for Successful Development and Commercialization of Microbiome Therapies. Syneos Health, April 2019. https://www.syneoshealth.com/sites/default/files/documents/Syneos_Health_Consulting_Microbiome_1_April_2019.pdf (Last Visited 18th of February 2020).
vPress Release, Bloomberg. “Lonza and Chr. Hansen in Joint Venture to Accelerate Momentum in Microbiome”, Bloomberg, Aril 2nd 2019. (Last Visited 10th of February 2020).
viUnited States Food and Drug Administration / National Institute of Allergy and Infectious Diseases. “Science and regulation of Live Microbiome-Based Products used to Prevent, Treat and Cure diseases in humans”, Rockville, Maryland, Friday, April 19, 2019 Website: https://www.fda.gov/media/128302/download (Last Visited 10th of February 2020).
viiTaylor, Nick. “Australia proposes manufacturing standards for faecal transplant products” 28th of November, 2019. Website: https://www.biopharma-reporter.com/Article/2019/11/28/Australia-proposes-manufacturing-standards-for-faecal-transplants (Last Visited 10th of February 2020).
Are Standards for Manufacturing Microbiome Therapeutics Really Far Off?
Are Standards for Manufacturing Microbiome Therapeutics Really Far Off?
While the microbiome therapeutics industry is still in its infancy, the lack of defined standards remains a major challenge affecting projects, across R&D and manufacturing. Companies have yet to identify the best processes to produce a high-quality medicinal product under regulatory scrutiny. Demonstrating reproducibility in live culture compositions is one hurdle yet to be overcome by standardisation, among many more.
How long is the road to defining the standards required? What steps are yet to be made, and could some solutions be right under our noses? Five industry experts gave us their view.
The microbiome is a complex system consisting of multiple conditions and organism interactions, the most significant clinical outcomes are often related to multiple bacterial consortia and not to specific strain. Setting the standard for producing such complex communities will probably require much more scientific know-how combined with production and regulatory experience.
I believe that the clinical potential and clinical results will be the engine for setting up the margins and requirements as we see today in the case of FMT compared to new strain approval. The scientific community tends to underestimate the gaps in the end product formulation and focus on the culturing and pre clinical outcome, this will be the ground for innovation as we expect companies with unique capabilities to take the lead to market.
Delphine Lauté-Caly, PhD, Molecular Microbiology Team Lead, 4DPharma
Manufacturing represents a key hurdle for microbiome therapeutics, as with any new modality. 4D pharma recognised this and invested in our internal capabilities, with cGMP certification and capacity to supply all our ongoing clinical trials. Before considering how far off, it is worth asking whether Live Biotherapeutics necessitate new standards, or are sufficiently covered by existing legislation for medicines, particularly biologics? There are clearly additional considerations when working with live bacteria, but standards may be covered by existing legislation regarding consistency, purity, contamination and process, for example. The European Pharmacopoeia issued quality standards for LBPs which came into effect in 2019, however these do not explicitly cover manufacturing. In the US, the FDA has issued guidelines on clinical development of LBPs but not manufacturing. As the field matures, industry input into any discussion around standards for manufacturing, or any other aspect of microbiome therapeutics, will be vital.
I believe that there is still a hurdle to overcome when it comes to defining manufacturing standards, a hurdle imposed by the limitations of our scientific understanding of the microbiome. We have not fully determined how deeply we must examine a microbiome in order to be reasonably confident in our predictions of its functions and outcomes for a patient or product. Until we can confidently state the minimum level of detail that we need, we won't be able to set consistent manufacturing standards. Hopefully, identification of therapeutic uses will provide us with a benchmark that we can use to determine the minimum accuracy thresholds, and thus set standards for manufacturing and production.
Lita M Proctor, PhD [V], NHGRI/NIH, HMP, NIH
Over a decade ago, the human microbiome field was catalysed by the application of sequencing technologies. The microbiome field benefited greatly from our ability to directly sequence the microbes of the microbiomes from the human body. Sequence analysis formed the cornerstone for this field and sequence-based standards are currently under development by several government agencies and by commercial entities for the analysis and interpretation of sequence data. In that regard, I believe the microbiome therapeutics industry is very close indeed to having defined standards for manufacturing purposes.
However, I believe that inherent in this question is the assumption that only one class of standard – for sequence analysis and interpretation – will be needed for industry. In fact, it is becoming abundantly clear that sequence data will not be the only metric needed to evaluate the efficacy of any microbiome-based product or intervention. This is because simply ‘naming the microbe’ will not be sufficient to determine the efficacy of many future microbiome-based products. For example, some products will be focused on a specific microbe, where sequence standards may be sufficient, but other products will be focused on specific metabolic properties or on specific cellular properties of the microbe or microbes in the product. As such, we will need functional data, such as the analysis of specific microbial properties of the microbe or microbes in a product, to evaluate the efficacy of that product. This means that standards will need to be developed for other classes of technologies, such as metabolomics or other HTP technologies, for manufacturing purposes. Most of the current attention in this field has been on sequence data but if this field – and any applications or products which may emerge from this field – is to advance, we will need to develop standards which are tailored for each class of microbiome-based product.
Industrial microbiome therapeutics manufacturing strategies are a critical step and a key challenge towards the commercialization which need to be addressed in the most efficient way. Are these therapeutics likely to be regulated in the same way as other pharmaceuticals, food additives or nutritional/dietary supplements? This will be the basis to define specific manufacturing standards inclusive of safety, purity, consistency and reliability.
Before defining standardization however, live biotherapeutics manufacturing technology need to be developed at scale and which is currently lacking. Indeed, most of microbiota origin strains are strict anaerobes, highly sensitive to environmental stresses encountered during processes, with complex, often unknown nutrient requirements, and limited or variable growth.