Browsed by
Tag: good manufacturing practices

Is cord blood/umbilical cord stem cell treatment legal?

Is cord blood/umbilical cord stem cell treatment legal?

Virtually all the attention I’ve given to stem cells in my prior posts has been on autologous stem cell transplants. But the private stem cell clinic industry actually started with cord blood back in the early part of this century. I have written about the start of this field and the FDA’s first two cord blood clinic criminal investigations in Galileo’s Lawyer. The short of it is that even back then, the FDA didn’t think a private clinic’s use of cord blood was legal (though in my first case, the feds decided not to indict my client, out of the goodness of their hearts. I got involved in the second case after the clinic owners were indicted. One of them is living abroad as a fleeing felon, as the government has been unsuccessful in extraditing him).

And despite the misinformation spread by the most of the cord blood manufacturers selling cord blood or Umbilical Cord Stem Cells (“UCSCs”) to the private medical clinics, the FDA hasn’t changed its position:

Allogeneic cord blood use is still considered illegal by the FDA except for blood transfusions/FDA approved uses manufactured by companies which have NDA drug approval or an FDA biological license.

To restate the point in the affirmative, there are in fact a handful of cord blood-based products which are FDA legal, either by an NDA or a biological license.

Here is one such example approved via a biological license.

Of course, the company manufacturing this product has an FDA approved label, which is something that none of the products being sold to the private stem cell clinics have.

But beyond these handful of FDA approved or BLA licensed products, every other cord blood product on the market is considered illegal by the FDA, as they violate the FDA trifecta of misbranding, adulteration and introducing into interstate commerce an unapproved new drug.

So, what are the approved uses of cord blood?

Here is some language from the FDA’s web-site explaining the law from its page on cord blood.

“Approved Uses
Cord blood is approved only for use in “hematopoietic stem cell transplantation” procedures, which are done in patients with disorders affecting the hematopoietic (blood forming) system. Cord blood contains blood-forming stem cells that can be used in the treatment of patients with blood cancers such as leukemias and lymphomas, as well as certain disorders of the blood and immune systems, such as sickle cell disease and Wiskott-Aldrich syndrome.

* * * *
“Cord blood stored for use by a patient unrelated to the donor meets the legal definitions of both a “drug” and a “biological product.” Cord blood in this category must meet additional requirements and be licensed under a biologics license application, or be the subject of an investigational new drug application before use. The FDA requirements help to ensure that these products are safe and effective for their intended use.”

Here is the link to the FDA page:

How do the manufacturers of cord blood and UCSC’s try to get around the law? Or how do they try to convince their customers that what they’re selling is legal?

Sellers of cord blood and UCSC products argue the legality of their products by reference to the tissue regulations and specifically 21 CFR 1271.10 (a) (1)-(3). But that doesn’t work because they cannot meet the (4)(i) requirement of no systemic effect or metabolic activity. With a few notable exceptions, all stem cells work via a systemic effect or is dependent on metabolic activity (exceptions would include HCT/P’s for wound covering, fat transfer, or blood transplants for medical procedures, or to treat the above listed blood related diseases).

Here is a link to 21 CFE 1271.10

An FDA’s guidance document makes this clear, albeit indirectly. This is an excerpt from the FDA’s HCT/P guidance document for small firms:

“3. What are examples of some 361 HCT/Ps that meet the criteria in 21 CFR 1271.10(a)?
[meaning the facility only has to register and its products are not new drugs]
• Amniotic membrane when used alone or without added cells • Bone • Cartilage • Cornea • Fascia • Ligament • Pericardium • Peripheral or umbilical cord blood stem cells (for autologous use or use in a first or second degree blood relative) • Sclera • Skin • Tendon • Vascular graft • Heart valves • Dura mater • Reproductive cells and tissues (e.g., semen, oocytes, embryos)
All of the above are minimally manipulated, intended for homologous use only, and not combined with another article, with some exceptions.”

In other words, UCSC’s for autologous or first or second degree blood relatives are not considered drugs and are just regulated under tissue registry rules (part 361 referenced above). Otherwise, and that means all allogenic uses, are regulated as a drug and requires an IND, NDA or a biological license.

The clearest and most recent statement from the FDA (or maybe I’ve just buried the lead)

The most definitive FDA statement showing the illegality of allogeneic, non-FDA approved cord blood or UCSCs comes from its November 28, 2018 warning letter to Genetech concerning the cord blood product it manufactured for Liveyon, which product caused infections in at least 12 people. Here is an article about the recall of the product:

Here is the heart of the FDA’s warning letter:

“Specifically, the umbilical cord blood products fail to meet the criterion established by 21 CFR 1271.10(a)(2), that “The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.” As noted above, the umbilical cord blood products are intended to treat a variety of orthopedic conditions. Because the umbilical cord blood products are not intended to perform the same basic function or functions of umbilical cord blood in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system, using the umbilical cord blood products to treat orthopedic conditions is not homologous use as defined in 21 CFR 1271.3(c).

In addition, the umbilical cord blood products fail to meet the criterion set forth in 21 CFR 1271.10(a)(4). Specifically, the products, manufactured from donated umbilical cord blood, are dependent on the metabolic activity of living cells for their primary function and are not for autologous use, allogeneic use in a first-degree or second-decree blood relative, or reproductive use. (emphasis added)

As stated above, because your products do not meet all the criteria in 21 CFR 1271.10(a), and Genetech does not qualify for any exception in 21 CFR 1271.15, the products are regulated as drugs under section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. Please be advised that to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. The umbilical cord blood products are not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.”

It’s a mouthful, but in short, Genetech’s cord blood product is an unapproved new drug and there was no biological license for it, making it illegal under federal law. There’s more in the warning letter about why the product is illegal, like the fact that the products are being produced in a facility which is NOT complaint with current good manufacturing or tissue practices (CGMP and CGTP), which makes the products adulterated, but that’s just shooting a dead horse.

Here is a pdf of the FDA’s warning letter to Genetech:


So, what does this all mean practically for the patients receiving these treatments?

FYI: I’ve worked on the defense side of FDA criminal investigations of unapproved new drugs for upwards of thirty years.

I have never heard an OCI investigator (FDA office of criminal investigations) even suggest that a patient could be a target. The patients are the victims of the crime, duped by the scum-sucking purveyors of false hope, such is the mindset of the FDA OCI. So, there is zero chance you will get into trouble with the feds if you fall prey to these possible future federal prisoners.

Of course, you’ll be using a treatment which is not FDA approved or biologically licensed. More importantly, the product you’re taking has been produced in a facility which has not met the rigorous requirements of a drug approved or biological licensed manufacturing facility. Don’t be fooled by claims that the facility has an FDA tissue or bank facility registration (the above described part 361). That’s different and a lesser standard.

So, if you’re someone who would only take legal FDA products, then taking cord blood or UCSCs for the treatment of a disease where the product does not have FDA approval and was not produced in an FDA biologically licensed facility is not for you.

If, on the other hand, you don’t mind taking a treatment which the FDA hasn’t blessed, then you need to do a risk/benefit analysis after being properly informed. The point of this post is to advise you that despite what the clinic owner is telling you, or what the manufacturer is telling the clinic owner, the product you’re receiving is not FDA approved or biologically licensed and has not been manufactured in a facility which has met the FDA drug approval or biological license standards. With this information, you are better able to make an informed decision.

What does this mean for the UCSC clinics and the cord blood product manufacturers of non-FDA approved non-biologically licensed products?

The above is how the FDA views what you’re doing. Most of the time, the FDA gets it way when it decides to take on people who sell drugs which violate the FDA’s trifecta, but not always. (See e.g. chapters 2, 4 and 9 of the aforementioned Galileo’s Lawyer.)

Still, to relate one of my favorite quotes from Damon Runyon: “The race isn’t always to the swift, or the fight to the strong, but that’s the way to bet.” So, be careful (and lucky).

Rick Jaffe, Esq.

FDA sends a Happy New Year greeting to another stem cell operation!

FDA sends a Happy New Year greeting to another stem cell operation!

As a prelude to more of what may be coming this year, the FDA has issued its first warning letter to a for-profit stem cell entity, on the third working day of the New Year. As per previous posts, expect more to follow in the coming weeks and months, targeting the most visible stem cell only entities.

Here is the warning letter:

Same ol, same ol, but with a twist

The letter is largely the FDA’s standard form warning letters to stem cell operations, but not quite. This entity, based in New Jersey, produces SVF (stromal vascular fractions) from adipose tissue, which is what most of these places do. That product is considered “more than minimally manipulated” under the FDA’s final guidance document. The business also apparently claims that its product may treat a wide variety of diseases, which makes the use “non-homologous,” under the aforesaid guidance document.

The letter also makes noises about a “biologics license.” Places like this New Jersey entity have more of a chance of seeing a unicorn than they do in obtaining a biological license.

And like two prior warning letters, this warning letter finds cGMP noncompliance, including not having a (very expensive) clean room, and well as numerous other facility, hardware, systems and documentation deficiencies involved in commercially producing drugs.

The rub/twist in this case

Based on the warning letter, it appears that this entity doesn’t actually treat patients, but rather just manufactures the product for resale/injection by health care providers.

The other rubs is that there is an IRB (Institutional Review Board) involved and, according to the warning letter, the product is listed “for research use only.” The FDA didn’t think either of these things helped the company’s case and made the product legal.

Just to recap the regulatory process

First, the FDA shows up for an inspections, usually unannounced and with at least three FDA inspectors. They stay for at least a week demanding to see documents. The last day of the inspection, the company is handed a 483 inspection report, which is the agency’s preliminary and non-binding and non-exhaustive findings/”observations.” (In these FDA stem cell inspections, I have to believe the agents have a standard form or template, since all of these entities have the same basic operation and operational deficiencies).

The company is given a short time to respond in writing to the noted 483 deficiencies. The FDA then reviews the response. The FDA is never satisfied with the response (at least in for- profit stem cell entities), so 3-6 months later, a warning letter arrives in the mail, usually after it is posted on the FDA warning letter web page
The company has another short period (15 working days) to respond to the warning letter. Most of the time, and especially if the entities respond without counsel, they just repeat their response to the 483 observations. The FDA then considers the response, and then . . . .?

What’s next?

This is the third warning letter issued against stem cell entities since late summer. (See my earlier post on the prior two warning letters:

So far, the FDA hasn’t taken the next step which would be a civil injunction action to stop the stem cell providers for administering and manufacturing their products. But dollars to donuts, the civil actions are coming. I suspect they will be (or the two summer warning letter at least) will be filed about the same time, so as to maximize the PR/threat impact.

The FDA’s choice of the three initial targets is interesting and possibly informative

The Florida stem cell clinic involves the most egregious facts. A nurse practitioner injected stem cell products into patients’ eyeballs and caused permanent vision damage, and the operation is run by someone without any actual health care background or training. This should be an easy case for the FDA, on the merits and more importantly, it and won’t cause public outrage even from the pro stem cell clinic field because of the bad facts. As I’ve said before, this is the best initial target, from the FDA and stem cell Mafioso’s point to view.

The California clinic supposedly uses some illegal or non FDA approved toxin either in or in the processing of its HCT/P’s. That’s about as good as you can get from the FDA’s point of view in terms of trying to solidify the FDA’s position on “more than minimal manipulation.” It’s going to be very hard for a federal judge to go for the stem cell advocate’s view if a clinic is using dangerous toxins in its product.

The New Jersey case is interesting and useful to the FDA because it targets an HCT/P manufacturer. This an important part of the FDA strategy because there are many, many docs out there using HCT/P’s who are buying the product from manufacturers like this New Jersey company. With this warning letter, the FDA is telling all these manufacturers that it hasn’t forgotten about them.

We’ll have to see how it all shakes out, but I’m still predicting that multiple injunction actions will be filed by the FDA in 2018, and I’ll bet sooner rather than later.

I still feel that the defense is going to be part legal and part public/legislative, and there’s probably still some arguments to be made which might be more receptive to the courts than to the FDA, but we’ll see.

Rick Jaffe, Esq.