FMT Standards for fecal microbiota transplant: Tools and therapeutic advances (Mar 2024, meeting report)

[Michael Harrop]

https://www.sciencedirect.com/science/article/abs/pii/S1045105624000150

This looks to have some important and interesting discussion. Unfortunately, it's paywalled. I'd like to read and respond to some of it. Someone from the FDA was there. I emailed one of the authors to request a copy.

Apparently, the webinar occurred in May 2022, then they submitted this for publishing a year later, and then another year later it was published. So it's 2 years old.

Abstract​

Fecal microbiota transplantation (FMT) has been demonstrated to be efficacious in preventing recurrent Clostridioides difficile (C. difficile) infections, and is being investigated for treatment of several other diseases including inflammatory bowel disease, cancer, obesity, liver disease, and diabetes.

To speed up the translation of FMT into clinical practice as a safe and standardized therapeutic intervention, additional evidence-based technical and regulatory guidance is needed. To this end in May of 2022, the International Alliance for Biological Standardization (IABS) and the BIOASTER Microbiology Technology Institute hosted a second webinar to discuss key issues still impeding the advancement and standardization of FMT.

The goal of this two-day webinar was to provide a forum for scientific experts to share and discuss data and key challenges with one another. Discussion included a focus on the evaluation of safety, efficacy, clinical trial design, reproducibility and accuracy in obtained microbiome measurements and data reporting, and the potential for standardization across these areas. It also focused on increasing the application potential and visibility of FMT beyond treating C. difficile infections.

Highlights​

• Fecal microbiota transplantation (FMT) has been demonstrated to be efficacious in preventing recurrent Clostridioides difficile infections, and is being investigated for treatment of several other diseases.
• Additional evidence-based technical and regulatory guidance is needed to speed up the translation of FMT into clinical practice.
• Standardization is required for definitions of FMT characterization, stability, safety and efficacy.
• DNA extraction/bioinformatic analysis must be standardized to provide reproducible measurements within microbiome studies.

 

[AmberAustin]

https://www.sciencedirect.com/science/article/abs/pii/S1045105624000150

This looks to have some important and interesting discussion. Unfortunately, it's paywalled. I'd like to read and respond to some of it. Someone from the FDA was there. I emailed one of the authors to request a copy.

Apparently, the webinar occurred in May 2022, then they submitted this for publishing a year later, and then another year later it was published. So it's 2 years old.

I'm a researcher so can access the full article through my job's library. Let me know if you'd like me to send it.

 

[high functioning autism]

I'm a researcher so can access the full article through my job's library. Let me know if you'd like me to send it.

Please share.

 

[Michael Harrop]

The author responded:

Apologies but there is no video available. However, the proceedings are well summarized here.
Here is a link that will work for about 45 days during which you can download the paper for free.

https://authors.elsevier.com/a/1ioHo3jeITUAQM

I'll read and comment later.

 

[Michael Harrop]

Both organizations work to improve and ensure the quality, safety, and regulation of biological drugs, speeding up their development by facilitating communication and providing forums for scientists to discuss data and key challenges. To further continue this conversation, they co-sponsored another webinar in May of 2022, which brought together stakeholders from academia, industry, government, and other scientific institutions to review recent scientific advances in the technical, regulatory, and standardization efforts surrounding FMT. These stakeholders also worked to identify, discuss, and reach consensus on key challenges hindering further progress. This webinar was organized around two themes, including (i) re-visiting the conversation on regulation and standardization of FMT, particularly focusing on evaluation of safety, efficacy, clinical trial design, reproducibility and accuracy of microbiome measurements, and the potential for standardization across these areas and (ii) increasing the application potential and visibility of FMT beyond preventing recurrent C. diff infections.

Dr. Paul E. Carlson Jr., a principal investigator in the Laboratory of Mucosal Pathogens and Cellular Immunology in the Center for Biologics Evaluation and Research at the FDA and an active member of the FDA microbiome working group, described the information required to be included in an Investigational New Drug application (IND) to FDA.

He has a 2020 paper here:
Regulatory Considerations for Fecal Microbiota Transplantation Products https://www.sciencedirect.com/science/article/pii/S1931312820300573

He lists some "generally performed" tests, but states that the FDA has no requirements other than the screening of donors for multi-drug-resistant organisms (MDRO), which seems ridiculous to me. That is one of the last things on my mind when screening a donor for safety and efficacy.

He comments on some of the requirements for an IND application. As I mentioned in a recent blog, IND seems inappropriate for FMT. For companies trying to make a drug from stool, it seems ok.

The primary objectives of the FDA during all phases of clinical investigations is to assure the safety and rights of subjects.

I noted in a past latter to the FDA that they are failing at this task https://forum.humanmicrobiome.info/threads/another-letter-to-the-nih-and-fda-cancer-patients-as-fmt-donors-if-you.59/.

Currently there are more than 600 actively recruiting clinical trials that are testing the efficacy of FMTs for a variety of indications.

While sometimes referred to as “the most complex biological material on Earth”, human feces contain hundreds of species of microbes (including viruses), thousands of small molecule metabolites (metabolome), a metaproteome, and a metatranscriptome. This is further complicated by the considerable differences observed in the gut microbiomes across different individuals (donors) which can explain why all fecal material is not equally efficacious.

Prof. Callahan added that there is no sufficient scientific evidence that pooling fecal samples contributes to increased diversity of the recipient's microbiome, increased transferability to recipients, or a positive clinical outcome as compared to single donors.

The wiki has a 2017 study on this https://humanmicrobiome.info/fmt/#impact-factors, but I would agree that a single study is "not sufficient".

Concerning demonstration of product purity (lack of impurities), no impurity testing (as it is required for drugs) is currently defined. This is a particularly challenging task as fungi, dead microorganisms, and their components and metabolites may all be active constituents of the fecal donor material, which contribute to efficacy and thus should not necessarily be considered impurities.

potency is likely not measurable by CFU as this assay is culture-dependent and not all bacteria can grow with selective media and conditions.

Dr. Goudarzi highlighted the difficulty of identifying the active metabolites in FMT due to a limited number of known microbial compounds (∼170) that comprises about 5% of the total detectable metabolites in fecal material.

FMT implementation remains challenging due to difficulties in identifying optimal donors and associated risk of pathogen transfer.

FMT must be standardized and industrialized, which is not yet possible as the fecal sample cannot be fully characterized due to inability to map up to 50% of the metagenomics reads, identify the function of up to 50% of the genes and identify up to 90% of the fecal metabolites [43].

Professor Wargo mentioned that in her experience, cancer patients that used “over the counter” probiotics were actually less responsive to immunotherapy, which was supported by in vivo experiments with mice [56].

Prof. Sokol who also added that, while the first probiotics were selected without any consideration of their role within the human microbiota

Prof. Rao added that also from a purely practical point of view, it is much simpler to prescribe a commercially available approved medicament that the patient can use by himself than undergo the complex procedure of obtaining patient consent under IND regulations and then finding the appropriate donor for FMT.

Good thing https://www.humanmicrobes.org/ exists to help you with that.


Overall, the discussion is about studying the components of stool. I/Human Microbes are not studying the components of stool; we're studying donors, stool characteristics, and FMT outcomes. The severe knowledge and technical limitations that are discussed highlight the need for other methods (such as the ones I/HM uses) to judge donor quality.