#c diff

One thing that’s increasingly undeniable is that the composition of your microbial nation is related in significant ways to both your physical and mental health. What’s more, as antibiotic resistant “super bugs” proliferate, FMTs are becoming increasingly central to treating dangerous gut infections that otherwise stand a high chance of killing you.

“Eat Shit and Prosper” is Stephen Skolnick’s delightfully named newsletter about poop and health science. Skolnick is a physicist by training, but has a long history of collaboration with Openbiome, a nonprofit that coordinates between doctors, patients and donors to provide safe FMTs:

https://stephenskolnick.substack.com/

In an edition of Eat Shit from last December, Skolnick recounts the amazing history and dismaying future of FMTs. In 2013, the FDA announced it would regulate FMTs as “Investigational New Drugs,” which could only be administered as part of a registered clinical trial:

https://stephenskolnick.substack.com/p/a-monopoly-on-poop

At that point, FMTs were already in widespread use by docs to treat otherwise untreatable cases of Clostridioides difficile (C. diff), an antibiotic resistant bacterial infection that literally makes you shit yourself to death. These doctors were in no position to run registered clinical trials, which meant that they would have to stop using the most effective therapy they had for a potentially lethal infection.

Doctors and patients kicked up a fuss, and the FDA walked back its guidance, announcing that it would exercise “discretion” in enforcing its Investigational New Drug rule, giving a pass to docs who were treating C. diff with FMTs:

https://www.federalregister.gov/documents/2013/07/18/2013-17223/guidance-for-industry-enforcement-policy-regarding-investigational-new-drug-requirements-for-use-of

That’s where things have stood for the past decade or so. The “discretion” rule means that patients could still get FMTs, but their insurance wouldn’t cover it. But even if you had cash to pay for an FMT, your doc probably wouldn’t administer it for anything except a C. diff infection, despite the promising signs that FMT can help treat other conditions, and despite the generally safe nature of FMTs.

If your doc did give you an FMT, chances are good that they sourced their poop from Openbiome. Openbiome recruits very healthy people, gets them to poop in a bag, then processes the poop — removing nonbacterial solids, testing it for pathogens, freezing it, portioning it, and sending it to docs. All this is done at cost, and it’s not cheap: $1–2k/treatment, mostly due to cold-chain logistics (the poop is shipped at -80C).

Despite the cost, and despite the limitations on treatment, the Openbiome method has proved very reliable. Indeed, FMTs as a whole are pretty darned safe, with the most common side-effects being transient gas and bloating. In the past decade, there’ve been a total of six “adverse effects” associated with Openbiome’s 5,000+ procedures, all in severely immunocompromised people, and none conclusively linked to the treatment:

https://www.sciencedirect.com/science/article/pii/S0016508522003511/pdf

A decade into this system, the FDA has taken the next step forward — only it’s actually a step backwards.

During this intervening decade, a pharma company called Ferring has conducted clinical trials on FMTs and received approval for an FMT product called Rebyota. The process for making Rebyota is effectively identical to the process used by Openbiome: collect poop, remove solids, test for pathogens, add glycerol, freeze and ship.

The main difference between Rebyota and Openbiome’s poop is price. While Openbiome charges $1–2k per treatment, Rebyota charges $10,800

That’s some expensive shit!

Fine. Getting Rebyota through clinical trials means that insurers might start covering it, and perhaps some patients will prefer brand-name poop to open-source poop. But as part of the FDA’s approval of Rebyota, the agency also rescinded its “discretionary enforcement” guidance, making it illegal for docs to source their poop from Openbiome:

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enforcement-policy-regarding-investigational-new-drug-requirements-use-fecal-microbiota

For Ferring, this is a monopoly on shit, one that lets them charge patients $10.8k for poop that costs $1–2k to process. The FDA does not claim that this is being done in the name of safety. Instead, an FDA official told Skonick that the goal was to “incentivize innovation without creating an access crisis.”

That is, the FDA changed its guidance and put nonprofit stool banks out of business because it wants to incentivize pharma companies to perform expensive clinical trials, and it believes that these companies won’t pay for trials if they have to compete with the likes of Openbiome, which would make it impossible to charge 900% markups on poop.

Trials are important! Evidence-based medicine is important! But Ferring’s clinical trials didn’t tell us anything we didn’t already know. FMTs were already the best therapy we had for C. diff. Testing Rebyota against a placebo didn’t tell us anything new — unlike testing Rebyota against the existing therapies, e.g. product from open stool banks.

Such a trial might have given rise to a very different regulatory outcome, because the cure rate reported by Rebyota is much lower than the cure rate from Openbiome’s own interventions:

https://link.springer.com/article/10.1007/s40265-022-01797-x

That is, using the $1k poop from Openbiome seems to be much more effective than using the $10.8k poop from Ferring. But Openbiome, a nonprofit, hasn’t been able to perform the kind of rigorous — and expensive — clinical trial that Ferring funded.

This points to a significant problem with the FDA’s model. The agency wants good clinical data for the medicines it regulates, as it should, It presumes that the only way to get that data is through granting commercial exclusivity to a for-profit, which ends up costing patients vast sums, and locking many patients out altogether.

This creates all kinds of new dangers. 150,000 people/year in the US contract Recurrent Clostridium difficile Infection (RCdI). FMT increases the cure rate by 20% relative to antibiotics alone. That means that if everyone with RCdI gets a poop transplant, 30,000 extra people will get better. That’s a big number!

For well insured people, Rebyota probably represents a cash-savings — if your insurance covers the $10,800 procedure, you might pay $500 out of pocket, which is far less than the $1–2K you’d pay to get an Openbiome poop transplant. But if you’re uninsured or underinsured, the FDA’s new enforcement rules mean that you’re now on the hook for $10,800.

The FDA did carve out a loophole: if your doc or their hospital are willing to prepare the poop transplant themselves, they can administer that. On the one hand, preparing a poop transplant isn’t that hard — some people do them at home, on their own:

https://web.archive.org/web/20211015060558/https://thepowerofpoop.com/epatients/fecal-transplant-instructions/

But on the other hand, there’s been exactly one death conclusively linked to FMT, and it was from one of these hospital-prepared transplants (the patient had just had a marrow transplant for cancer that wiped out their immune system, and the donor had a novel pathogen that the hospital failed to test for).

So the FDA has created a situation where, if you can’t afford a $10,800 proprietary formulation, your only option is to convince your doc or hospital to prepare their own poop transplant, which will cost less than the $10.8k for Rebyota, but more than the $1–2k from Openbiome, which has all kinds of economies of scale. And if you do manage it, you’ll be getting a procedure that has a much worse safety track-record than the Openbiome process that the FDA just killed.

The FDA has an important role to play here, but as with so many policy questions, how the FDA plays that role depends on things that are far upstream from the agency and its decisions. The choice to fund medical trials through the promise of exclusivity — and with it, extremely high margins — puts the FDA in the position of choosing winners in the marketplace: Ferring wins, Openbiome loses.

Ironically, this is the thing that exclusivity is supposed to prevent. By using profit to incentivize medical research, the FDA is supposed to be recruiting the Invisible Hand as its partner in regulation. But exclusivity is incompatible with the idea of medicine as a public good. The tens (hundreds) of millions that Americans will pay for $10.8k poop transplants from Ferring will add up to far more than it would cost to underwrite clinical trials for an open process like Openbiome’s.

The result: both Americans’ wallets and Americans’ guts suffer.

Catch me on tour with Red Team Blues in Hay-on-Wye, Oxford, Manchester, Nottingham, London, and Berlin!

If you’d like an essay-formatted version of this post to read or share, here’s a link to it on pluralistic.net, my surveillance-free, ad-free, tracker-free blog:

https://pluralistic.net/2023/05/29/oh-shit/#rebyota