3rd Invitrx warning highlights FDA oversight weakness

The FDA seems oddly slow in oversight of unproven stem cell clinic-related firms like one here in California called Invitrx Therapeutics. I’ve written before about Invitrx, but interactions between them and the FDA have continued including a new warning letter. It’s become a puzzling situation.

More broadly, the FDA has done relatively little in the past two years on unproven stem cell clinics and associated firms such as product suppliers. The clinics alone now number above two thousand. Even just the riskiest slice of the big stem cell clinic industry pie, say those almost certainly engaging in non-compliant activities, contains hundreds of firms. The FDA should be taking dozens and dozens of strong actions per year in this space, but it isn’t even close.

Why does this matter?

The continuing FDA ineffectiveness here puts at least tens of thousands of American consumers at risk each year.  It’s also bad for the stem cell and regenerative medicine research field.

Let’s take a closer look at Invitrx and how the FDA has interacted with them. I believe it is emblematic of the problematic FDA approach more generally.  As part of the discussion, we’ll talk about some possible solutions if the FDA can adapt.

What is Invitrx Therapeutics?

Invitrx is an adult stem cell manufacturer. Their products include both stem cells and exosomes.  The former are allogeneic umbilical cord stem cells. Such products are generally defined as drugs requiring pre-approval from the FDA before marketing or use. In other words, you must work with the FDA in advance of selling such drugs. Two exosome products are also listed, which appear to be drugs as well. Per the latest warning letter:

“Therefore, these products are drugs as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)].”

I first took a closer look at this firm when William Shatner said he was receiving their stem cells. Shatner tweeted in a promotional way about it in 2019. Such celebrity promotion could encourage many everyday people to follow suit. Getting unproven cell therapies is risky. Most firms have no published, solid data to back up their offerings as safe and effective.

#ad Today I received restorative stem cells from my good friend Greg DiRienzo @ProgenaCell. The stem cells were manufactured by Invitrx here in So Cal. My friend Dr Mathi Senapathi gave the cells to me intravenously. Is it possible to turn back the clock? I will let you know.

— William Shatner (@WilliamShatner) May 31, 2019

On PubMed, I only found one paper by the firm founder Habib Torfi or mentioning the firm itself. It’s a case report on a single patient.  There may not be much data to specifically back up Invitrx offerings.

Invitrx warnings echo questions back at FDA too

How the FDA has handled what it has said are issues with Intrix highlights some of the broader challenges and questions for the agency. Remarkably, the firm’s most recent letter was its 3rd FDA warning letter. Here are the other two warning letters from this 5-year period including 2017 and 2020.

The newest warning letter, which followed a spring 2022 inspection by the FDA, details many issues including with cell therapy manufacturing practices and the firm’s Invitra products. As noted earlier, it says the products are unapproved drugs. In my opinion, the issues with this new letter overall collectively are not so different than those in the 2020 warning letter.

A surprising element here within Invitrx’s latest warning letter is the FDA inviting the firm to attend an in-person meeting with the agency, which may have happened a couple weeks ago. It’s hard to imagine a firm turning down such a “request.”

Three warning letters in a relatively short period of years is also unusual. Offhand, I don’t recall another regenerative firm getting that many in such a period. This unusual situation raises many questions about the FDA itself.

• Why is the FDA just sending multiple warning letters to this firm? Is Invitrx making steady progress toward compliance despite the numerous issues mentioned in the newest warning letter?
• Why is the FDA devoting resources to an in-person meeting in this Invitrx case? The FDA surely can’t do these kinds of in-person meetings with the vast array of different unproven stem cell clinics and suppliers who might have compliance issues. Is Invitrx quite different than the others?
• What is the explanation for the FDA doing nothing at all about the many hundreds of other cell clinics and supplier firms or just sending them vaguely-defined letters during the last few years? As to the latter, these vague letters were not official warnings and not even untitled letters so their impact may have been minimal.

Maybe this all makes perfect sense inside the FDA, but I don’t get it.

Do FDA warning letters work?

This risky recent period of general FDA inactivity even includes a long phase after the FDA discretionary period for clinics firms ended.

What was that discretionary period?

In a nutshell, the agency gave firms until May 2021 to become compliant. The date long passed and hundreds of firms remain non-compliant, but we’ve seen no clear spike in FDA activity. The disconnect here undermines the power of the FDA’s words. (Note that I don’t know if Invitrx is non-compliant right now and that’s something only the FDA defines for any particular firm or product, but the pattern of warning letters is very concerning.)

The FDA has continued to issue just a few of these warning letters for the whole unproven stem cell clinic industry annually for the past two years or so. Not only are these warning letters too few in number, but also it’s becoming increasingly unclear whether these letters do much good.

In a satirical spirit, imagine a future scenario with the FDA contacting some stem cell firm with a letter that begins, “This is your firm’s tenth warning letter from us as you’ve marketed your unapproved cell therapy drug products over the last eight years. Address these issues.”

Or else what? An eleventh letter will arrive?

Are stem cell clinics taking the FDA seriously? I don’t know anymore.  The agency needs to make some big changes in this space.

Ideas for better oversight of clinics

Here are just a few ideas to make unproven clinic and supplier oversight better.

First and most importantly, as I’ve said before the FDA should begin fining non-compliant cell therapy firms. Fines of $10,000 or $50,000 per violation to hundreds of non-compliant firms would send a powerful message.  It would be quick and powerful. Clinics would take it seriously.

In addition, the FDA should allow itself to issue warning letters to clinics without in-person inspections. While in-person visits are needed to assess GMP-type issues, the agency can tell if a product appears to be an unapproved drug without going to the manufacturer in person. In some ways, that’s the bigger issue to confront.

Also, those warning letters have to mean something to recipients. Firms should realize that an unheeded warning letter could lead to an injunction shortly thereafter. That means the FDA has to actually issue a logical number of injunctions annually. That’s not happening.

Problems with FDA priorities or resources?

Someone who had worked at the FDA once told me the main reason the agency doesn’t go for more injunctions is that it is worried it will lose an important court case. I don’t know if that’s true, but it’s a worrisome mindset.

There is a pending appeal of a federal district court decision last year that went against the FDA in its requested injunction on adipose cell clinics. The uncertainty of the appeal could make the FDA nervous, but the case doesn’t directly apply to many hundreds of clinics that sell unrelated products like perinatal cellular drugs. Maybe the FDA is worried that a loss on the adipose cell case appeal would undermine its broader efforts on unproven clinics.

One other possibility for little activity in this space is a lack of resources. Perhaps the FDA believes it can only handle one or two injunctions at a time over a period of a few years. Does the FDA need far more CBER employees? A better, more efficient relationship with the DOJ? This isn’t 2009-2010 when there were just a few unproven clinic firms. Again, there are thousands now.

Or could it be that the FDA leadership doesn’t feel this clinic problem is a priority? I hope that the relatively new FDA Commissioner Robert Califf is not going to back away from addressing the clinic problem more decisively. We’re not over the COVID pandemic yet, but it seems reasonable for CBER to be devoting more resources to this giant unproven cell therapy mess.

Looking ahead

The FDA does have a relatively new division of CBER that has been signing relevant warning letters for the last couple of years. It’s the “Office of Biological Products Operations – Division 2.” Could this Division 2 take big and more consistent measures in 2023 on the unproven clinic problem? Does Division 2 have enough staff?

Overall, another deja vu year of minimal FDA oversight of the vast unproven clinic space is a serious public health problem.

A final thought is that the FDA may be flirting with the idea of reclassifying some cellular products in this space to no longer be defined as drugs and in so doing it would no longer consider hundreds of firms to be non-compliant. In a sense, it would be shrinking the scope of its problems here just bureaucratically. That would be a high-risk experiment.