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The Microbiome Represents a Paradigm Shift for European Pharmaceutical Regulators

Ammonia Oxidising Bacteria: A Live Topical Therapeutic

Recent microbiome research has demonstrated the important role that 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,’ such as 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 can also affect the efficacy of other drugs, such as new chemical entities and biotechnological products. An example of this inter-play is the way a microbiome’s composition can affect cancer therapy and on the responder/non-responder status to treatment.

As such, two important questions for European pharmaceutical regulators have now become evident:

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?

Live Biotherapeutic Products (LBPs, such as 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, the safety of these products involves concerns that are 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.

The harmonisation of European guidelines is sorely needed today, as more and more products are in development and science has demonstrated the central role that the microbiome plays in human health. Patients deserve assessment of the utmost quality and this will require harmonisation 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, which has been engineered for the specific nature of the products, and by harmonisation of such assessments at the EU level through specific guidelines.

Can we continue to ignore the importance of the microbiome in designing and developing drugs?

We know that drugs can influence the microbiome, the most 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 antibiotic treatments given to infants can alter the microbiome, which can lead to the development of chronic pathologies in adults. Therefore, it could be argued that Microbiome alteration results in 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 the patient’s microbiome has an influence on the efficacy of their treatment and characterising the patient’s microbiome seems to be a necessary factor in the optimization of drug efficacy. Administering drugs to ‘non-responder’ patients brings up the 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.

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 when we work on designing and assessing drugs: either drugs exerting their effect on the microbiome itself, such as LBPs, or drugs exerting their effect on the human side, but which may have a detrimental influence on its microbial counterpart.

It is time for the authorities to tackle this issue head-on. Industry is generally ahead of regulation, but it is unfortunate to hear such a deafening silence from European regulators on this issue, which could potentially affect a large swath of new drug products coming to market in the 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. However, once again, biotechnology companies are being created in staggering numbers in the US, while in Europe, the lack of regulatory framework impedes their financing and growth.

I 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 harmonise in order to enable the emergence of this new industry; but above all, to ensure the safety and benefit of future patients.

 

Dr. Magali Cordaillat-Simmons works as the Scientific and Regulatory Affairs Director at the Pharmabiotic Research Institute(PRI), located in Aurillac, France. She also manages the progression of the association’s European regulatory strategy.

 

Dr. Magali Cordaillat-Simmons will be taking part in the roundtable discussion about regulatory aspects for LBPs at the Microbiome R&D and Business Collaboration Forum: Europe. Download the full agenda here

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