Regulatory Action

The myriad options available to companies looking to develop microbiome-focused therapies is exciting, but it is also a double-edged sword. The development of bacterial-based therapies comes with significant manufacturing challenges. Can sufficient quantities truly be produced to influence a community of trillions of microbes? With FMT requiring donor screening to ensure quality and consistency and further implications for companies working with genetically modified bacteria, the budding regulatory landscape for these types of products is already proving to be difficult to navigate. 

Kaleido Biosciences is pursuing small-molecule drugs through novel chemistry to modulate the metabolic output and profile of the microbiome. Their lead candidate, KB195, is currently in phase II development and has the potential to be used for urea cycle disorders. Because KB195 is a small molecule drug, manufacturing is a relatively straightforward, transferable and scalable process. A live bacterial product (LBP) is a product (other than a vaccine) that contains living organisms intended to treat human disease. Probiotics are similar in that they contain living organisms. Although probiotics are legal, in most countries they cannot be marketed to cure or prevent disease. While, Kaleido’s candidates are not LBPs, Susan Stewart, SVP, Regulatory Affairs & Quality at the company, understands the challenges that companies pursuing LBPs may face in seeking a solid regulatory framework. 

“Our microbiome metabolic therapies are regulated by CDER at the FDA, and so our early development can follow regulations covering Generally Recognized as Safe (GRAS) compounds under Food Law, and drug products under Drug Law when pursuing therapeutic indications,” Stewart says.

But the FDA isn’t ignoring LBPs. The Agency has hosted public workshops to address the rapid advancement of LBPs into late-stage clinical trials and to allow the industry to voice its concerns pertaining to manufacturing and regulatory affairs for microbiome-derived therapies. “The FDA has shown a willingness to advance this new medical target as is shown by its position on the development of LBPs as biologics under INDs and its specific exemption for fecal microbiota transplant for treatment of recurrent C. difficile infections by clinicians.” explains Stewart.

The FDA released its first guidelines on the regulation of live biotherapeutics for clinical trials in 2012, which included definitions and examples of accepted assays for purity, potency and stability; the guideline was updated in 2016 (1). Some industry experts have argued that that LBPs should be regulated under the same guidelines that govern the approval and manufacturing of tissue transplants, but because LBPs do not meet the FDA’s definition of regenerative medicine therapies, they cannot be assessed under the same regulatory framework. 

In Europe, the European Pharmacopoeia Commission has set the quality requirements for LBPs with a monograph on “Live biotherapeutic products for human use (3053)” and two general chapters, “Microbial examination of live biotherapeutic products (LBP): test for enumeration of microbial contaminants (2.6.36)” and “Microbiological examination of live biotherapeutic products: test for specified microorganism (2.6.38).” The texts became effective in April 2019 (2). These specifically exclude FMT and products intended as gene therapy agents.

A significant number of clinical trials for microbiome products are now well underway and Stewart is confident, particularly in the US, that regulatory support for all aspects of microbiome drug development exists. She says, “positive late-stage clinical data for microbiome therapies in development will be critical for the advancement of the entire field.”