Another letter to the NIH (and FDA). Cancer patients as FMT donors. If you care about the future of FMT please consider also writing to them. (Mar 2019)

[Michael Harrop]

Sent to NIH https://www.nih.gov/about-nih/contact-us

I received a reply saying

Please send your question about the oversight and enforcement of adverse event reporting to the US Food and Drug Administration. You can find their contact information here: http://www.fda.gov/AboutFDA/ContactFDA/.

That seemed odd, but I guess the FDA is responsible for this. So sent it to [email protected] (EDIT: posted comment with their response).

Subject: FMT donor quality, cancer patients as FMT donors, clinical trial oversight and enforcement of adverse event reporting

As far as I could tell my last letter to the NIH about FMT donor quality went unheeded. So I resorted to individually emailing all 180 or so authors of every active FMT clinical trial. There were at least 2 trials that are using previous cancer patients as donors.

The fact that there are FMT trials using other cancer patients as donors shows there are 0 standards and this is the wild wild west of unregulated human experimentation.

Anyone who is up to date with the literature on all the different ways the gut microbiome impacts the entire body and is involved in virtually every disease state https://humanmicrobiome.info/intro/, and who is knowledgeable on everything we know to be transferable with FMT https://archive.fo/3V8El, should conclude that using an FMT donor who is not in perfect health and has a perfect health history is dangerous. Using former cancer patients as donors stoops far below the already egregiously deficient FMT donor standards.

What I want to know is how strict the oversight and enforcement of adverse event reporting is. How likely is it that the trials using other cancer patients as FMT donors will adequately track and report all adverse events? I think it's bad enough that this experiment is happening, but it would be an even worse tragedy if the results turn out how I expect, and it doesn't serve as a future warning due to poor tracking & reporting of adverse events.

When I analyzed the stool bank OpenBiome I found there isn't a requirement to report anything other than a severe adverse event. Which means they could be transferring all kinds of new problems to the recipients and it would never be reported unless it was immediately life-threatening.

And this study that put cancer patient's own stool back in them https://archive.fo/Q6qN6#selection-795.0-795.1 has no section in the study covering adverse events, and a "ctrl+f" for "adverse" has 1 result that is unrelated to adverse events.

I didn't see much useful info on this on the clinicaltrials.gov or NIH websites so I did a web search for "nih clinical trial oversight and enforcement of adverse event reporting" and found this excellent 2017 article which seems to confirm my fears: https://blog.primr.org/enforcing-reporting-to-clinicaltrials-gov/

There is also a 0% chance the test subjects have been allowed informed consent. How could they when the people running the trial aren't informed? If they were they would never be using cancer patients as FMT donors. It reminds me of this extremely unethical human experiment with antibiotics that I cannot believe passed the ethics board: https://archive.fo/WFg2A

That antibiotic study is also missing vital information about changes to stool, such as bristol stool type and other physical/visible characteristics which are important for deducing changes in the gut microbiome, and are all very simple to observe, track, and report on. And their brief statement of "No episodes of Clostridium difficile infection were recorded, nor any other disorders that are associated with dysbiosis" makes me very suspicious about their adverse event tracking & reporting, and what they think are "disorders associated with dysbiosis". For example, the average GI doctor doesn't seem to think "IBS = dysbiosis". Very very few doctors and even researchers seem to be up to date on the microbiome literature (they often cite lack of time), thus resulting in very problematic and questionable research & conclusions.

So not only was their experiment highly unethical, but the lack of information in their report significantly diminished the usefulness of it.

This 2018 review provides more evidence/support: Harms Reporting in Probiotics, Prebiotics, and Synbiotics Trials http://annals.org/aim/article-abstract/2687953/harms-reporting-randomized-controlled-trials-interventions-aimed-modifying-microbiota-systematic "Harms reporting is often lacking or inadequate. We cannot broadly conclude that these interventions are safe without reporting safety data."

So it seems the answer to my question of "how strict is the oversight and enforcement of adverse event tracking & reporting?" is that there is little to none. This is egregiously unethical and negligent.

It seems like much of the research is done at universities and thus the researchers would have a very easy time simply contacting their athletics departments in order to recruit top college athletes to be FMT donors. Is this not the case?




Original 04 Mar 2019 (8 comments).

 

[Michael Harrop]

Given the article yesterday https://www.nytimes.com/2019/03/03/health/fecal-transplants-fda-microbiome.html that mentioned the FDA, I also wrote to them (and would encourage others to do so as well): https://archive.fo/Kiakw#selection-1997.0-2001.0

The Fecal Transplant Foundation founder advised me that:

they don’t consider email as a comment they officially count either, only the official Public Comments section and you have to put the official FDA identification number (from the Federal Register) or it won’t be counted either.

So I found a "Guide to Submitting Comments to the FDA" page on the FDA's website. It directs me to regulations.gov. There I typed in "fecal transplant" into the search and got 197 results.

She then advised me to:

Do your search on the Federal Register website. All of this pertains to the Draft Guidances published by FDA in 2013 and 2016. You’ll want to do two comments, each to refer to one of the Draft Guidance publications.

I did a search there and found these two guidances:

1. https://www.federalregister.gov/documents/2013/07/18/2013-17223/guidance-for-industry-enforcement-policy-regarding-investigational-new-drug-requirements-for-use-of
2. https://www.federalregister.gov/documents/2016/03/01/2016-04372/enforcement-policy-regarding-investigational-new-drug-requirements-for-use-of-fecal-microbiota-for

If you visit one of those links, scroll down a bit, on the right there's a link that brings you to the correct comment page:

Docket Number: FDA-2013-D-0811

She also said:

The 2nd draft guidance (2016) was to take the public’s pulse on nor allowing donor stool banks, at all. It would have effectively ended widespread FMT, and could/will probably be what they enact to give the drug companies what they want, to end FMT so they will (1) be able to enroll enough subjects for their trials and (2) effectively end any competition for their products.

So here's what I'm submitting as a comment for the 2016 guidance:

I'm told that "This draft guidance (2016) is to take the public’s pulse on not allowing donor stool banks, at all. It will effectively end widespread FMT, the purpose of which is to: (1) be able to enroll enough subjects for trials and (2) effectively end any competition for synthetic FMT products".

I am someone with chronic illness who's been following the microbiome literature daily for years. I strongly believe FMT to be a potential cure/treatment for most illnesses currently beyond medical capabilities. This link, and the references it contains, have a plethora of related and supporting information for my position, statements, and claims: https://forum.humanmicrobiome.info/threads/another-letter-to-the-nih-and-fda-cancer-patients-as-fmt-donors-if-you.59/

Even though I recently did an analysis of the main US stool bank's (OpenBiome) safety and efficacy and found it to be severely lacking, I still believe that stool banks are vital to safe and effective FMTs, and should play a major role in the future of FMT. Virtually all official sources of FMT have these same major donor quality issues. Including clinical trials, synthetic FMT products, clinics/doctors/hospitals, etc.. This is the most major problem with FMT currently. FMT donor criteria is woefully inadequate, and current testing capabilities cannot determine safety nor efficacy. It's currently looking like fewer than 0.5% of the population qualifies to be a high-quality donor. Random patients certainly cannot be expected to find these people on their own. We likely need the expansion of stool banks to multiple locations around the US in order to be local to high-quality donors across the country.

The FDA's focus needs to be on enforcing higher donor quality standards, regardless of who is procuring the donors. As well as drastic improvements to clinical trial oversight and enforcement of all adverse event tracking and reporting. Current standards are resulting in a massive waste of time and money, putting patients' health at risk, and significantly delaying the time till patients have access to high-quality FMT donors.

Synthetic FMT products hold little promise currently. A restriction to focus on them would be extremely misguided and would severely hinder the future and potential of FMT. Due to current technological limitations, we are at least a decade away from being able to identify, extract, and synthetically reproduce the vital microbes in a healthy human stool donor. For example, the current synthetic products have only isolated bacteria, despite other studies showing phages may be more important. And while we know very very little about human gut bacteria, we know even less about phages.

As is, I tell people to avoid clinical trials due to low donor quality. If they want patients for their trials they need to prove to us that their donor quality is very high. We need the donor info I listed in my OpenBiome analysis. We need to see "we're using these top athletes as donors for our clinical trial". THAT will draw us.

I also don't see how a stool bank hinders FMT clinical trials since the stool bank can and does provide FMT for clinical trials.

Rather, having a stool bank raises the standards since other options now have to offer patients something better than what the stool bank is offering. This is one of the primary benefits of competition/capitalism. To hinder this with unnecessary termination of stool bank use seems like an abuse of power/corruption/regulatory capture.

There are so many of us extremely desperate for high-quality FMT donors that we've resorted to DIYing. The problem is that few of us are lucky enough to have access to one of the top 0.5%. Thus our DIY donors are often dangerously low quality. But this is to say that the idea of there being no demand due to a stool bank existing is ridiculous. Many/most of us need FMT for things other than c.diff.

Due to current donor quality deficiencies, I think it's largely a waste of time and money to use OpenBiome for anything other than "well it's a life or death situation and we have no other options" (IE: c.diff). For "discovery" purposes it seems completely useless, and thus there is plenty of room for other entities to acquire higher-quality donors and use them to experiment with conditions other than c.diff.

 

[Michael Harrop]

FDA's response (didn't seem to address any of my concerns):

Thank you for writing to the Center for Biologics Evaluation and Research (CBER) regarding fecal microbiota transplantation (FMT). CBER, one of seven centers within the U.S. Food and Drug Administration (FDA), is responsible for the regulation of many biologically-derived products, including blood intended for transfusion, blood components and derivatives, vaccines and allergenic extracts, and cell, tissue and gene therapy products.

FDA has oversight of products that are used to prevent, treat, or cure a disease or condition in humans. For example, fecal microbiota intended for such use(s) meet the definition of an unapproved new drug. As you are aware, fecal microbiota for transplantation (FMT) has not been approved for any use. Accordingly, FDA would consider it to be an Investigational New Drug (IND).

In 2013, the FDA held a public workshop to discuss the regulatory and scientific issues associated with fecal microbiota for transplantation (FMT). During this workshop many physicians and scientists expressed concerns that FMT is not appropriate for study under the agency’s IND regulations and that applying IND requirements to FMT would make this treatment unavailable to those individuals with C. difficile infections not responsive to standard therapies. A link to the workshop can be found here: https://wayback.archive-it.org/7993/20170112100407/http://www.fda.gov/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/ucm341643.htm.

FDA recognizes the high degree of scientific interest in manipulating a patient’s microbiome as a treatment for a variety of serious diseases and conditions. In July, 2013, FDA issued a guidance document (https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM361393.pdf) describing the Agency’s intention to exercise enforcement discretion for FMT used to treat recurrent C. difficile that has not responded to standard therapies. FDA’s intention was to accommodate the immediate needs of very sick patients with C. difficile infection that is not responsive to standard therapies. There are often few or no other treatment options for these patients and the illness can be disabling and life-threatening. By asserting jurisdiction, FDA can help assure that data relating to the safety and effectiveness of FMT are developed under appropriate standards, and help assure that the rights, safety, and welfare of human subjects receiving this investigational new drug are adequately protected.

In addition to the current guidance, FDA has also issued draft guidance (https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Vaccines/UCM488223.pdf) for public comment. The guidance is not for implementation at this time. However, after FDA evaluates all of the comments received, the agency may issue a final guidance for implementation that contains some or all of the additional criteria.

The draft guidance introduced two additional criteria for the use of FMT to treat patients with C. difficile infections not responsive to standard therapies.

1) The FMT product is not obtained from a stool bank.
2) The stool donor and stool are qualified by screening and testing performed under the direction of the licensed healthcare provider for the purpose of proving the FMT product to treat his or her patient.

The current draft guidance is an update to an earlier version of the draft guidance issued in 2014. The provision in the 2014 version that the donor be known either to the patient or to the treating licensed health care provider was subject to difficulties in interpretation, and the revised approach (i.e. that FDA does not intend to extend enforcement discretion for the investigational new drug (IND) requirements applicable to stool banks distributing FMT products) more accurately reflects our intent to mitigate risk, based on the number of patients exposed to a particular donor or manufacturing practice rather than the risk inherent from any one donor.

The 2016 draft guidance explains that a stool bank sponsor may request a waiver of certain IND regulations related to investigators and sub‐investigators. The Notice of Availability (https://www.federalregister.gov/documents/2016/03/01/2016-04372/enforcement-policy-regarding-investigational-new-drug-requirements-for-use-of-fecal-microbiota-for), published in the federal register, requests comments on which regulations are appropriate to waive.

Please note that the draft guidance has not yet been finalized, and the July 2013 guidance expresses the FDA’s current policy.

I hope this information is helpful. If you have additional questions or concerns, please feel free to contact me at 1-800-835-4709, or [email protected].

Sincerely,

 

[Michael Harrop]

One of the trials using cancer patients as donors: https://clinicaltrials.gov/ct2/show/NCT03341143 - University of Pittsburgh

Other one: https://clinicaltrials.gov/ct2/show/NCT03353402 - Sheba Medical Center in Israel

April 2019 article discussing a few of these trials and mentions Jennifer Wargo of MD Anderson Cancer Center in Houston, Texas, who is leading a similar clinical trial just getting underway https://www.sciencemag.org/news/2019/04/fecal-transplants-could-help-patients-cancer-immunotherapy-drugs

Article says:

preliminary results suggest some patients who initially did not benefit from immunotherapy drugs saw their tumors stop growing or even shrink after receiving a stool sample from patients for whom the drugs worked

---

Jan 2018 study (and article covering related studies) with mostly French researchers:

Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. https://archive.fo/vUAMp

The article in that link also covers both clinical trials.

---

1. Based on my own and others' DIY reports, plus all the current literature showing poor results for the current level of donor quality, I don't expect low-quality (IE: people who have had cancer) donors to be effective.
2. Even if they are effective it's likely not safe.
3. There is no reason not to use a high-quality (see: perfectly healthy, one of the fewer than 0.4% that pass this questionnaire: https://humanmicrobiome.info/fmt-questionnaire/) donor.

Oct 2019 study precisely supporting my position:
Transmission and clearance of potential procarcinogenic bacteria during fecal microbiota transplantation for recurrent Clostridioides difficile https://insight.jci.org/articles/view/130848 "Both durable transmission and clearance of procarcinogenic bacteria occurred following FMT, suggesting that additional studies on appropriate screening measures for FMT donors and the long-term consequences and/or benefits of FMT are warranted"

---

Yet another clinical trial using cancer patients as donors:
Fecal Microbiota Transplant and Pembrolizumab for Men With Metastatic Castration Resistant Prostate Cancer (Oct 2019, Portland VA Medical Center) https://clinicaltrials.gov/ct2/show/NCT04116775 "Patients whose disease responds to treatment will become stool donors to non-responders"

Another in South Korea (Feb 2020): https://clinicaltrials.gov/ct2/show/NCT04264975

<Inclusion Criteria for donors>
Patients who have partial or complete response to immunotherapy at the time of stool donation

Another in Austria (Oct 2020): https://clinicaltrials.gov/ct2/show/NCT04577729

using donor stool of former malignant melanoma patients, who have been in remission due to CI treatment for at least 1 year

---

Study using donors who were so unhealthy that they needed a gastric bypass:
Infusion of donor feces affects the gut-brain axis in humans with metabolic syndrome (Sep 2020, n=24) https://www.sciencedirect.com/science/article/pii/S2212877820301502