Is the FDA Umbilical Cord Game Plan Clear? An Invitrx Update

Many watchers of the illegal selling of fake umbilical cord “MSC” products have been asking what’s up? We’re long past the FDA discretionary period and not much seems to have happened except for a bunch of letters that were sent in 2020 and 2021. However, if you look at the FDA correspondence on these issues, you can see that there could be a plan. Let’s dig in.

Selling Umbilical Cord Products for the Treatment of Human Disease without an FDA Drug Approval is Illegal

It doesn’t take a rocket scientist to read the huge number of FDA letters sent to umbilical cord manufacturers that any marketing for any umbilical cord product that mentions clinical use for that product or claims that it has live stem cells is not legal without full FDA clinical trials and approval. This was true before the FDA discretionary period ended. Despite that, while some smart umbilical product manufacturers folded their tents, some have held on and continued to sell products in this way. Many watchers have asked themselves how these companies are still in business.

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The Aircraft Carrier

A regulatory attorney once told me that the FDA and many government agencies work at the speed of a large aircraft carrier and not a small gunboat. That means that they take a long time to go through their process, but once they turn in your direction, you don’t want to be around. So how does that fit in with what’s happening now to these umbilical cord manufacturers?

The Process

The FDA follows a specific process with violative drug manufacturers, which is the category that these umbilical cord companies fall into:

  1. Warning Letter
  2. On-site Visit to Look for violations-Form 482 issued on entrance into the facility
  3. Form 483 which lists the violations found
  4. Correspondance back and forth about how the violations are being handled
  5. Injunction if the violative behavior continues

However, from the Warning Letter to the on-site visit can take 3-12 months. The visit can take weeks and then more months while all inspection observations are put together into a second letter. The companies are given chances to fix these issues, but since the main issue is an FDA approval that takes many years of clinical trials to get and these companies have never started that process, they can never satisfy the most basic requirements.

The InVitrx Example

In 2017, InVitx was sent an FDA Warning Letter about its cosmetic products. The letter is hard to follow, but basically, the company was using certain cell lines to produce these products which made them unapproved drugs. One of these products (Reluma) is still for sale today and still claims to be made using stem cells:

Back then it appears Reluma was being advertised for hair regrowth and today it’s advertised as a cosmetic.

On March 16th of 2020, the FDA sent a Warning Letter to InVitrx. Basically, the letter stated that the company’s umbilical cord tissue, amniotic tissue, and exosome products were drugs because they were being promoted to treat a variety of incurable diseases in violation of the homologous use rule in 21 CFR 1271.1. In addition, the company’s claim to be selling live stem cell products also pushed them into the drug category. Because InVitrx didn’t have FDA approval through clinical trials to sell these products, these were unapproved drug products.

The FDA also inspected InVitrx’s facility and reported those findings. There were a number of cGMP violations, which is common because most tissue manufacturers use a less stringent cGLP or cGTP manufacturing standard as those are commonly used to manufacture tissue products. cGMP is MUCH more stringent because it’s used to manufacture drugs at a larger scale.

In looking at the InVitrx website today, gone are the prior claims of selling umbilical cord stem cell products and exosomes (but they still sell Reluma as a stem cell based cosmetic product). The focus now seems to be on a company that InVitrx acquired which had an IND (Pharmicell) for the use of bone marrow MSCs to treat alcoholic Liver cirrhosis. There is also a partially completed IND application for an exosome product to treat eye diseases.

The FDA sent a second Warning Letter this week. This noted that the company responded to the FDA’s first letter in April of 2022 and that the agency felt the response was inadequate. The letter stated:

“You state that you have, “suspended all manufacture of all clinical drug substance and drug product batches at the 20503 Crescent Bay Drive, Lake Forest California facility intended for use in domestic clinical trials.” It is unclear from this statement whether you have suspended manufacture of all products identified in the FDA-483. Further, it is unclear, based on your response, whether you will manufacture your products at any of your other locations for distribution. Your response also describes “interim control[s]” you plan to implement prior to completing certain corrective actions, which suggests that Invitrx will resume manufacturing prior to adequately addressing the existing deficiencies.”

IMO from reading this letter, the FDA doesn’t believe that InVitrx has stopped manufacturing and selling these products.

The FDA also brings up the 800-pound Gorilla in the room:

“Your response also does not adequately address the failure to have an IND in effect for clinical investigations of your products and your lack of an approved BLA to lawfully market your products.”

Meaning that anything the company does to correct the cGMP manufacturing violations is moot because it doesn’t have FDA approval in place to sell these products.

Finally, the agency takes the IMHO unprecedented step of forcing the company into a face-to-face meeting so that it can ask questions and get answers:

“We also request your attendance at a Regulatory Meeting to discuss the status of the specific steps you have taken since the inspection to address any violations.”

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The InVitx Analysis

What’s going on here? Basically, IMHO the FDA has a company that has received multiple Warning Letters, with some of that activity happening during the COVID-19 period when CBER was heavily involved in vaccine-related matters. The new letter is signed by the new “Division 2” within CBER, which seems to be taking on the role of enforcer for birth tissue companies. It is slowly but surely tightening the noose and is likely close to issuing an injunction because there is a belief on the agency’s part that the company is playing games. That’s a pretty reasonable belief given that this company is now 3 Warning letters deep in 5 years.

The Bigger Picture

Many regulatory watchers are concerned that the agency has sent many Warning Letters but is not following up on companies that continue to sell umbilical and other birth tissue unapproved drug products. However, the agency is following its process, which is slow but does carry a big punch in the end. The FDA has opened a new division within CBER (Division 2) to continue the prosecution of these cases, so I would expect more regulatory actions this next year against companies that continue to sell unapproved birth tissue products.

The upshot? The FDA is like a big Aircraft Carrier. It moves slowly, but once it turns its guns, missiles, and jets in your direction, the only sensible move is to stop what you’re doing. I expect now that Division 2 is active that we’ll see more follow-up Warning Letters and injunctions coming down the pike that will remove the few remaining birth tissue companies still selling products.

Chris Centeno, MD is a specialist in regenerative medicine and the new field of Interventional Orthopedics. Centeno pioneered orthopedic stem cell procedures in 2005 and is responsible for a large amount of the published research on stem cell use for orthopedic applications. View Profile

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NOTE: This blog post provides general information to help the reader better understand regenerative medicine, musculoskeletal health, and related subjects. All content provided in this blog, website, or any linked materials, including text, graphics, images, patient profiles, outcomes, and information, are not intended and should not be considered or used as a substitute for medical advice, diagnosis, or treatment. Please always consult with a professional and certified healthcare provider to discuss if a treatment is right for you.

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