The microbiome – will legal question marks stop progress? Part two – regulatory uncertainty

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Our understanding of the microbiome is developing rapidly. The systematic collection and analysis of human microbiome samples is generating an increasing – and fascinating - body of data. Based on this data, researchers and clinicians are now also recognising new potential for understanding human disease and developing treatments. What are the legal issues that could stand in the way of progress? In this article we consider regulatory uncertainty when developing microbiome-based therapeutic approaches.

Therapeutic approaches based on the microbiome

In part one of this series we considered the privacy issues that arise from the collection and analysis of microbiome samples. In this expanding field of research and associated data generation, we also see increasing interest in new therapeutic approaches.

Faecal microbiota transplants (or microbiotal transfer therapy), where gut bacteria from healthy donors are introduced to patients, is the most established of these. FMT is now widely recommended as a treatment for recurrent Clostridium difficile infection. The UK’s National Institute for Health and Care Excellence (NICE) has made available guidance supporting the use of FMT for this purpose since 2014. This calls for further research to investigate optimal dosage, mode of administration and choice of donor.

In addition to the treatment of infections from antibiotic resistant strains of bacteria, microbiome-based therapy is also under consideration for the treatment of a surprising range of other conditions.

The Bill & Melinda Gates Foundation has identified undernutrition in infants as a target for live microbial transfer. Clinical outcomes for undernourished infants are linked to altered gut microbiota. The Foundation’s Funding Challenge Round 22 called for proposals to identify new methods of manufacture for gut microbial biotherapeutics that will offer diversity and consistency needed for a useful treatment. The proposal highlights the need to address batch-to-batch production variability and risk of contamination in order to meet purity, potency and consistency standards required by regulators.

French company MaaT Pharma is developing a range of possible products deploying faecal microbiota. The EU Commission recently granted orphan designation for the company’s allogeneic faecal microbiota medicine in the treatment of graft-versus-host disease, a serious complication of some types of transplant. Orphan status has also been granted in the US and clinical trials are ongoing.

Ferring group company Rebiotix is investigation microbiota transfer for prevention of Clostridium difficile infection, plus a range of other conditions from ulcerative colitis to hepatic encephalopathy.

The gut-brain axis theory suggests that even those suffering from neurological conditions may receive benefit from faecal transplants. A recent US study involved treating 18 children with autism spectrum disorder for a period of eight weeks. Improvements in gastrointestinal problems were reported, and surprisingly also in Childhood Autism Rating Scale scores.

Using microbiota in treatment of disease

Clearly, the risks involved in transferring material containing live cells from one individual to another are substantial and need careful consideration and mitigating steps.  Microbiome-based therapy is difficult to categorise and does not fit neatly within one of the existing legal structures.

Although FMT is increasingly recognised as a valuable treatment for C. diff infection its regulatory status is uncertain. The grouping of European regulators tasked with supervising the use of substances of human origin (CASoHO) considered the issue in 2014, and asked the EU Commission to advise on the correct way to characterise FMT. The Commission's analysis made clear that EU law relating to transplanted tissues and cells do not apply to FMT. This is because although human cells are likely to be present in the transplanted material, they are not the main active component of the transplant. Regulation is therefore currently a matter for each country to determine.

The UK Human Tissue Authority’s advice recommends acting in accordance with its Guide to Quality and Safety Assurance for Tissues and Cells for Patient Treatment, particularly when seeking informed consent, performing donor serology testing and in relation to the traceability of samples from donor to recipient. When selecting donors suitable for participation in FMT programmes, a careful screening process is needed. Possible exposure to a range of viral, bacterial and other infections needs to be investigated in order to avoid inadvertently harming the recipient by the introduction of infectious agents with the transplanted material.

A microbial preparation that is developed for sale as a medicine will ordinarily fall within the scope of human medicines legislation. It then needs to be standardised sufficiently for clinical trials to be carried out and a marketing authorisation applied for. This is challenging given the complex and changing nature of the gut microbiome. MaaT Pharma is confident that it has achieved a stable, reproducible formulation “characterized by a high diversity and consistent richness of microbial species derived from pooled healthy donors and manufactured at the company’s centralized European cGMP production facility”. But maintaining consistent characteristics in a medicine of this kind will be much more difficult than with a small molecule active ingredient. There will also clearly be challenges in scaling up manufacture of a formulation, and ensuring consistency, once a marketing authorisation has been obtained and a product is being commercialised.

Engaging with regulators at an early stage can help to identify issues and find possible routes through them. Rebiotix is working with the US Food and Drug Administration to develop its microbiome restoration therapies, for example, with its lead product candidate benefiting from Fast Track, Orphan and Breakthrough Status designation. Rebiotix has been in close cooperation with the FDA for several years although it has yet to achieve a product launch.

Will regulatory uncertainty prevent progress?

This regulatory uncertainty should not stand in the way of the development of microbiome-based therapies. Regulatory authorities often have to deal with new product types and recognise the need to support their development when they offer a promising new avenue for treatment. It makes sense for developers to work with regulators from the early stages and plan a way through in order to avoid serious legal and reputational risks later on.

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