The Microbiome Represents a Paradigm Shift for European Pharmaceutical Regulators

Recent research on microbiomes has demonstrated the important role these communities of microorganisms play on human homeostasis. The gut microbiome is being thoroughly studied, and other microbiomes are now becoming the focus of greater attention as well as other organs of the host, due to the concept of ‘axes’, i.e. the gut-brain axis, gut-lung axis, gut-liver axis.

Furthermore, as the impairment of microbial functions has been associated with numerous pathologies in humans, we now know that the composition of the microbiome could also affect the efficacy of other “regular drugs” (i.e. New Chemical Entities, Biotechnological products, etc…). One example of this inter-play is the influence of a microbiome’s composition on cancer therapy and on the responder/non-responder status.

As such, two important questions for European pharmaceutical regulators have now become evident, and if we as scientists and researchers are being honest with ourselves, unavoidable:

1. How do we clarify the regulatory framework so that the specific nature of Live Biotherapeutic Products is taken into account in the assessment, and the resulting adaptations are made to the regulatory framework?

Indeed, Live Biotherapeutic Products (LBPs, i.e. medicinal products containing live micro-organisms) are the only type of medicinal product which exert their action locally and through a modification of the local ecosystem and local microbial functions, which in turn exert an effect on the host homeostasis. The assessment of Pharmacokinetics, or dosage, works on a different paradigm. Moreover, safety of these products involves concerns not usually assessed for other types of drugs (i.e. antibiotic resistance, virulence). Consequently, as of today, assessment is done on a case-by-case basis and may vary on the reference member state’s own knowledge of this type of product.

Harmonization and European guidelines are thus sorely needed today as more and more products are in development (reaching clinical phases) and science has demonstrated the central role that the microbiome plays in human health. Future patients deserve assessment of the utmost quality; this will necessarily require harmonization at the EU level, as well as the drafting of relevant guidelines dedicated to this type of product, and not the usual application of the “spirit” of other existing guidelines, as is often recommended. Patients’ safety will be ensured by an assessment engineered for the specific nature of the products, and by harmonization of such assessments at the EU level through specific guidelines.

2. Can we continue to ignore the importance of the microbiome in designing and developing regular drugs (i.e. new Chemical entities, Biotech products, etc…)?

We know that drugs can have an influence on the microbiome, the obvious example being antimicrobials; but more importantly, the microbiome of patients may also have a strong influence on the efficacy and perhaps even safety of other types of drugs.

There are alterations of microbiomes that may look benign due to their resilience, but we now know that an alteration of the microbiome caused by antibiotic treatments during infancy is associated with a higher prevalence of chronic pathologies in adults. Microbiome alteration could therefore be a ticking time bomb with severe consequences later on in life, and this should no longer be ignored when designing new drugs.

On the other hand, it has been shown in cancer therapy that the composition of patients’ microbiome had an influence on the efficacy of their treatment (responders/non-responders). Characterizing the patient’s microbiome therefore seems to become a necessary factor in comprehending how to optimize drug efficacy. Administering drugs to non-responder patients is obviously a question of safety, and the understanding of the influence of the microbiome may indeed be critical in the development of safer and more efficacious drugs.

In conclusion, advancements in understanding the true nature of human microbiomes represent a paradigm shift for the pharmaceutical industry and regulators, and will require them to approach the human body in an entirely different way. We are not just human, we are a symbiosis, within which bacterial cells outnumber their host’s counterparts. Therefore each of us should be considered a symbiont going forward when we work on designing and assessing drugs: either drugs exerting their effect on the microbiome itself, i.e. LBPs, or drugs exerting their effect on the human side, but which may have a detrimental influence on its microbial counterpart.

We believe it is time the authorities tackle this issue head-on. Industry is generally ahead of regulator due to constant innovation, but it is unfortunate to hear such a deafening silence from European regulators on this issue, an issue which could all the same affect a large swath of new drug products coming to market in the near future. While the FDA has been working on this since 2010, Europe seems to be lagging behind; and as such, this revolution in medicine will come that much later to the care of European patients.

This is particularly difficult to grasp, as Europe has been a leader in microbiome research, and is in point of fact well-positioned worldwide when it comes to understanding the mechanism of actions by which microbiomes influence human health. Once again, biotechnology companies are being created in staggering numbers in the US, while in Europe the lack of a regulatory framework impede their financing and growth.

We urge European member states to comprehend the significance of this transformative shift in the field of medicine, and address this need so that Europe may start to regulate and harmonize in order to enable the emergence of this new industry; but above all, to ensure the safety and benefit of future patients.