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.
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.
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.
1. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm617168.htm 2. https://www.fda.gov/downloads/BiologicsBloodVaccines/ GuidanceComplianceRegulatoryInformation/Guidances/ General/UCM292704.pdf
3. Hoffmann, D. E., et al. (2017). "A proposed definition of microbiota transplantation for regulatory purposes." Gut microbes 8(3): 208-213.
4. https://www.ema.europa.eu/en/documents/leaflet/european-regulatory-system-medicines-europeanmedicines-agency-consistent-approach-medicines_en.pdf
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.
