Live biotherapeutic products: PRI calls for clear regulation as microbiome research booms

18 Sep 2020 --- As industry strides toward a better understanding of the gut microbiome, clear scientific and pharmaceutical standards are needed for live biotherapeutic products (LBPs). This is according to the Pharmabiotic Research Institute (PRI), a Europe-based regulatory expertise center for the development of LBPs.

“Researchers and developers of microbiome drug products face a wide range of challenges. They are not all that different from those faced by people working to develop advanced therapies (gene and cell-based) in the last several years,” Dr. Magali Cordaillat-Simmons, executive director of the PRI, tells NutritionInsight.

She continues that the regulatory challenges are as complex as drug development itself. Regulators must consider how the quality, safety and efficacy of LBPs can be ensured and demonstrated.

“Since all of these questions in part depend on the clinical indication and the target population, developers are engaging more and more with regulatory bodies to secure their development in the absence of specific guidelines in the EU,” Dr. Cordaillat-Simmons adds. 

In its new review, published in Experimental & Molecular Medicine, PRI aims to help stakeholders in microbiome-based products understand that the active substance or the ingredient of a product does not define its regulatory status. Clarification of the terminology and corresponding regulatory status of probiotics and LBPs (Source: Nature).

LBPs versus probiotics
The World Health Organization (WHO) defines probiotics as “live microorganisms that when administered in adequate amounts confer a health benefit on the host.” 

However, the authors of this review focus on live microorganisms as active pharmaceutical substances intended to be used in the treatment or prevention of disease in humans.

When a product containing probiotic strains aims to prevent or treat disease, it is an LBP. There are several LBPs in pre-clinical and clinical developments currently, according to PRI

“By nature, both LBPs and probiotics contain living microorganisms as an active substance. The difference is how the product is placed on the market. The WHO’s probiotic definition applies to the microorganisms and, therefore, the substance, but does not presume how products containing those substances will be placed on the market,” explains Dr. Cordaillat-Simmons. 

“Thus, ‘probiotic’ substances can be developed as dietary supplements, food ingredients or drugs, depending on what these substances are intended to do and to whom,” adds co-author Dr. Alice Rouanet. 

Legislative framework
Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach the market in the US and in Europe. Under the current EU framework, LBPs legally have no “separate status.” 

The EU considers them to be “biological medicinal products as the active substances are live microorganisms, which are biological substances...LBPs have to comply with the biological medicinal product legislative and regulatory framework.”

“There is a real lack of specific guidelines for LBPs and other microbiome-based drug products. At the moment, developers have to try to adapt the existing guidelines on biological medicines to the particular nature of their products,” says Dr. Cordaillat-Simmons.

Her ideal scenario would be national and European health authorities “dedicating energy” to understanding the particular nature of LBPs. 

“They should also understand the fundamental paradigm shift that the microbiome represents for several fields. Then they can begin the arduous and necessary work needed to develop microbiome-specific guidelines for drug developers. This will ultimately benefit European patients, many of whom suffer from high unmet medical needs,” she adds. 

Gut health under the microscope
Investigations of the inner-workings of the gut microbiome have been proliferating in recent years. Recent discoveries include that consuming foods rich in lactic acid bacteria may enrich the intestines and that Westernized diets may reduce gut diversity. 

Bruno Pot, science director for Yakult Europe and PRI president, notes that today there are often questions about the cause and effect relation, such as asking whether observed microbiota differences the cause or the consequence of the disease. 

“However, ongoing research is yielding larger and more reliable databases. It is now widening the scope from ‘who is there’ to ‘what are they doing there.’ These results will lead very soon to a much better understanding of the gut microbiota’s complex functions and therefore define what gut health is, thus also answering the cause or consequence question,” he explains. The gut relies on the right combination and diversity of various microorganisms to result in a stable ecosystem.

Shaping research for the decades to come
The gut is notoriously complex. It depends on the right combination and diversity of various microorganisms to result in a stable ecosystem, states Pot. This ecosystem then needs to have the right metabolic and physiological activities, immune and endocrinological stability, as well as the correct interaction with the brain. 

“Understanding this complexity, as well as the individual variation, the impacts of diet, environment, stress or medication, are the major research objectives for the next decades. However, it allows for the development of generalized or personalized therapies that will be key in preventing or treating diseases that have a link with the microbiota,” Pot details. 

He adds that the “nicest” part of this perspective is that for many of these diseases, there are currently no “traditional” treatment options that have no heavy side effects or are toxic on the longer term.

“The expectations for better gut health management, therefore, are very high. The presence of a clear regulatory framework for developers to reach that point will also be crucial to the speed of these developments,” Pot concludes. 

By Katherine Durrell