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.

Invitrx
Invitrx Therapeutics marketing image from their website. Screenshot.

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.

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.

6 thoughts on “3rd Invitrx warning highlights FDA oversight weakness”

  1. PS: One other key thing regarding “Civil” vs “Criminal” actions. A “criminal” conviction leaves one with a “criminal record”. A single low level misdemeanor can often be eventually “expunged” from one’s record, but it takes petitioning the court and/or a certain passage of time. A felony, is most often a permanent criminal record and the consequences to one’s life are heavy. It can effect employment, ability to travel, right to vote, right to own a firearm and many, many other things.
    Try travelling even to Canada (which one would “think” is sort of a EU like thing w/ the USA, almost a no-border free n easy travel back-n-forth but NO!!). Try entering Canada from the USA with certain “criminal” charges on one’s record – and they just turn a person right around facing south and say, “Sorry, can’t enter as we ran your background and you have a XYZ conviction in the state of NC or wherever-ville USA, and Canada does not allow any priors of that type entry w/o a special petition and approval of a Magistrate” blah blah.
    Most companies today, to so much as flip burgers, run a background check on every prospective employee using 3rd party firms with deep deep databases and who do nothing but background checks. Almost ANY prior felony background and prison or jail time and one can forget getting employment as there’s just too many “other” people w/o criminal records to choose from.
    Certain jobs, and even a relatively low level non violent misdemeanor conviction is a huge red flag – such as being a police officer, the military, any position working for a private and/or govt agency(s) requiring a security clearance etc. “Some” jobs – they even check for civil actions such as a prior bankruptcy even or “credit problems” – police officers/law enforcement being one of them.

    I believe though that the idea of Dr Paul to have the FDA levy more fines has strong merit. The use of monetary fines – is one of the oldest law enforcement and govt “regulatory compliance” tools we have, and goes way, way back to even old English law, etc. And Dr Paul is correct IMO that the fine needs to be made high enough, but within limits, to “get the attention” of the violators and hopefully get some of them to comply vs paying escalating fines as repeat offenders.
    It can’t be a $million dollar fine obviously, but start at say $5K or $10K per failure to comply with 1st formal warning ltr and up-it $5K per each failure to comply after that per ea additional new warning ltr seems reasonable to me.
    It’s done ALL THE TIME in too many regulatory areas to even count – the EPA uses this method/model as an example. Get caught illegal dumping and fine #1 might be a $1,000 bucks say. Get caught again and it might be $3,000 bucks. Get caught illegal dumping too many times – and it might lead to a misdemeanor criminal charge being filed, including being arrested and spending a day in the local jail and a court date before a judge, etc.
    Escalating fines and consequences is used as I stated, ALL the time in both civil regulatory and criminal law. Get charged with a 1st criminal misdemeanor and the judge would likely give a person a $500 buck fine or whatever and promise to show-up for 10 days of “community service”. Skip all your court dates and get arrested over and over for similar misdemeanors (say illegal narcotic use as a common example) and at some point the judge during arraignment might say, “No quick release and promise to appear this time ! You do 5 days in county jail and we call it square on all 6 of your priors. And, if I see you again after that you’ll get one yr of informal probation added on + fines and a day or two in jail again”. Like that.
    No consequences and no “teeth” to the enforcement actions as Dr Paul described in his, “Hi, this is the FDA and this is your 10th super-duper strict warning letter, and we really, really mean it this time !!” and why would anyone or any firm/business comply ? It becomes a joke and a farce – people wad up the “warning letter”, laugh and toss it in the trash.
    Monetary fines w/ a escalating scale = the next logical step by the FDA as described IMO too.

  2. “Most firms have no published, solid data to back up their offerings as safe and effective.” – Perhaps they can experiment on a handful of mice in a lab and get an FDA green light like Pfizer recently did?

    Also, doesn’t the DOJ need to get a misdemeanor or felony conviction before the FDA can levy a fine?

        1. Thanks, Bill.
          I thought there were some civil rather than criminal fines possible. The FDA has broad authority in that regard and from that doc it seems it can be fairly independent, such as per this, “If FDA finds that a monetary civil penalty is warranted, it may assess the penalty absent DOJ’s or the courts’ involvement.” That’s key I think for FDA officials. Connecting with and getting action from DOJ can be a headache. Of course, those penalized can appeal in the end, but I doubt they would have much success. FDA appears to have wide latitude on the scale of the penalty too. For some clinics, it seems like marketing issues and other violations would be easy for the FDA to identify as a strong foundation for penalties. This could be done on a large scale too, perhaps against the 100 or 200 riskiest firms and/or repeat offenders ID’d by the agency.

    1. No. There is no requirement for a misdemeanor and/or felony “criminal” conviction to take place for a govt agency to levy a “monetary fine” against a person or entity ? I can list 100’s of examples. A few simple ones: Local code enforcement in every city across the USA. IF a person adds a room addition w/o the proper permits – it’s not a “criminal” matter referred to the city DA and/or County DA ? It’s a civil regulatory matter – and the code enforcement folks levy monetary fines against homeowners all the time. Fail to timely pay one’s utility bills on a home – and the city utility department can and will levy “Late penalty(s)” which involves no “criminal” proceedings whatsoever. They can also, w/o any “criminal” filings or proceedings – eventually cut the power and all utilities to one’s home or office for fail to pay bills due. Street sweeper fines in my screwed up city – a private contract firm follows the street sweeper around on “sweeper days” and levies fines, aka “writes tickets” to those who forgot to wake up and move their car. No sworn, gun carrying “law enforcement officer” has anything to do with it – let alone a city criminal prosecutor office, etc. Civil enforcement – no “law enforcement” aka “police” involved in any way, shape or form. A neighbor sues a neighbor over a property line dispute. “The court” (civil division) can determine one neighbor “won” and the other “lost” and the solution does not involve any “criminal” process such as a misdemeanor or felony or a DA/DOJ or prosecutor or jail time – it involves a monetary settlement, aka a “civil court process”. Medical malpractice is a “civil court process” as in ladies blinded by stem cells injected in their eyes causing blindness – and no “criminal” charges were ever filed, nor any DOJ or other prosecutors involved. A civil attorney sued the medical stem cell clinic (several actually) – and won settlements in the 7 figure range, aka $millions of dollars. No felony or misdemeanor or “police” or any “criminal prosecuting offices” (DOJ, DA, State’s attorney, etc) charges of any kind were ever filed in those civil lawsuit cases. CIVIL law vs CRIMINAL law – two sides of the USA justice system and regulatory structure and bureaucracies. The FDA does have a “criminal” arm – their office of “OCI” aka “criminal investigations office” and its totally separate from their “civil enforcement” side. The agents of the FDA OCI office carry badges, firearms, handcuffs and have the same arrest powers as any other “sworn law enforcement officer” in the land. The FDA has made arrests in the past – usually involving extreme egregious acts such as environmental dumping of toxins and/or death of patient/victims, trafficking in stolen or adulterated drugs or regulated medical products, egregious cases involving food products leading to severe outcomes, medical tampering by nurses in a hospital, VA hospital criminal violations, moving-selling certain types of highly regulated medical equipment such as X-ray machines w/o the proper permits, trafficking in things like illegal steroids and performance enhancing drugs using doctor’s offices, etc Google “FDA OCI Most wanted fugitive list” to see what types of folks they are hunting for criminal violations, and why.

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