Let’s face it, when a doctor uses live umbilical cord or amniotic products, he or she adds risk to the treatment equation compared to using the patient’s own tissues. Just how much risk is illustrated by a recently released FDA 483 inspection report on Invitrx Therapeutics. This report will give pause to any patient considering these therapies or to physicians who might use them.
My First Exposure to Infected Birth Tissues
While we were testing birth tissues for live cells, one of our research scientists pointed out a certificate that came with one of the products that said that the donor had tested positive for Cytomegalovirus (CMV). I was blown away by this in that the vast majority of the medical providers using this stuff would likely never see this piece of paper. My thoughts quickly focused on the informed consent issues this created. While the CMV virus is not a problem for patients with a healthy immune system, it can be fatal in patients with a compromised immune system. If you think about this further, you realize that we now have very sick patients (many on immune suppressant drugs) lining up in chiro offices to be treated with IV “stem cell” injections who may be impacted by being infected with this virus.
The Liveyon Debacle
Then came the dozen or more cases of severe and almost deadly bacterial contamination that happened with the umbilical cord product Liveyon. Here we had medical providers using this stuff for all sorts of applications like back pain and injecting it into discs and epidural without a shred of evidence it would help these patients. These patients then ended up in the ICU and many will never be the same.
I have called out this company a few times for producing white papers that purported to show that the product had mesenchymal stem cells, but on closer inspection couldn’t support that conclusion (see Invitrx blog 1, Invitrix blog 2). This was consistent with multiple authors who have tested birth tissue products and found no living stem cells (1-3). Recently the FDA issued a pretty scary inspection report on the company.
Before I get into the report, it’s important to note that none of these companies selling amniotic or umbilical cord products have any type of FDA review or approval. In fact, they all fill out a quickie 361 registration form that has no FDA oversight. The only thing FDA can do is to show up and inspect the lab, which is what happened here. After the agency is done with their inspection, they release a form 483 inspection report, which is what I’m quoting from below.
The FDA 483 Report
There were four main issues the FDA found (and then some smaller issues I won’t discuss):
- Infected donors
- Inadequate screening of donors
- Patient reactions to the product
- Sterility failures
The FDA found records of:
- Bacterial growth in one umbilical cord blood sample
- One donor that tested positive for Chagas disease and Hepatitis B
- Another batch of product was positive for gram-positive bacteria
It seems from the report that all of these products were shipped to doctor’s offices and hospitals.
Inadequate Screening of Donors
From the report: ” Relevant medical records, including the medical/social history interview and physical exams are not used to determine if a donor is eligible to donate human umbilical cord blood and umbilical cord tissue. Your firm received [redacted] donations of human umbilical cord and umbilical cord blood since March 2018, that were used in manufacturing of biological products. None of these donors were established as eligible and no written procedure describing how to make a donor eligibility determination is established. Each donation can be used to manufacture between 2 and 100 finished product vials.”
Invitrx also received umbilical cord units from known Zika infected areas and produced hundreds of doses without ever screening for the Zika virus. They also didn’t screen for the devastating and deadly brain disease known as Creutzfeldt–Jakob disease (CJD).
The FDA found records of the following patient reactions:
- An e-coli infection after a knee intra-articular injection
- Severe pain after bilateral hip injections
- “Wheezing”, skin reactions, “short(ness) of breath” after umbilical cord blood injection
- A patient who was “extremely ill”, “decreased appetite”, “slurred speech”
- Hives on the same day of the injection
- 13 other complaints
What’s interesting is that some of these reactions could be indications of Graft vs. Host disease which I have blogged on in the past.
87 manufacturing sterility breaches were detected. In addition, the report states that the FDA observed:
“…a technician in Clean Room processing open containers of in-process cord blood batch (Donor # INV while wearing only a single layer of non-sterile gloves for up to ten minutes at a time. At other times, this technician placed his hands into the ISO 5 bio-safety-cabinet(BSC) with non-sterile gloves and then donned sterile gloves inside the BSC.”
The FDA also observed debris (likely with contaminants from other patients although not specified) building up in the ISO 5 hoods used to process samples. There were also incorrectly labeled samples (labeled as from patient X when they were from patient Y) and unlabelled samples from different patient sources in the same clean area. Finally, there was inadequate monitoring of the sterility of the cleanroom and hoods.
Fist, any physician that injects this stuff should be VERY concerned. This is not the first inspection report from one of these birth tissues companies to come back with multiple problems. How can you as a doctor be sure that the stuff you’re injecting into patients isn’t contaminated? I’m not sure there is a way to know for sure.
Why is this happening? A decade ago we had a handful of tissue processors nationwide that sold birth tissues for niche use in surgeries. At that point, the 361 registration system was likely enough to keep track of these few major players. However, because of the stem cell wild west bonanza, many more small players have popped up and decided to process their own tissues. This has created a secondary market of companies that are likely too small to have all of the safeguards in place.
While autologous products can get contaminated or injection can drag skin bacteria into a deep part of the body, this is a one on one risk like surgery. However, these tissue processors all represent a one on many risk, meaning that all it takes is one bad batch to infect dozens or hundreds of patients nationwide. Hence, it’s time for the FDA to begin greater oversight of the birth tissues industry and require pre-certification of labs and processes.
The Liveyon and Invitrx cases also bring up legal issues. Meaning that they may break new ground in malpractice law. Let’s review.
What happens when there is a serious complication created by the use of these contaminated products? Especially when the doctor has no published data that they will help the condition being treated? Liveyon is an apt example.
In fact, all of the doctors and medical records I have reviewed in the Liveyon cases (I am the medical expert on most of them) had one common thread. The physicians believed that they were injecting mesenchymal stem cells (MSCs) and since papers had been published on MSCs showing some efficacy in some of these conditions, they believed the injections were justified. However, it turns out the product they were injecting had no MSCs. Hence, in fact, there was no evidence that this product would help these patients.
The attorneys on these cases are taking the position that using these products without any clinical data showing efficacy was in and of itself a breach of the standard of care. In addition, it’s the doctor who would act as the last safeguard here. Meaning he or she had an ethical duty to know enough about the science to understand that the sales reps never provided enough information to prove that they were selling an MSC product.
Mitigating Your Risk
Is there a simple way to mitigate these risks? Maybe. Only use or purchase birth tissues that have been terminally sterilized with technologies like gamma irritation. Meaning these products should be much less risky in that the bacteria and viruses have been killed off. Even then, you need to make sure the company uses the higher 35-40 kGY gamma irradiation standard (4). This is critical as while 25 kGy will kill bacteria, it takes a higher dose to kill viruses. This could be a problem, as the average doses used for gamma sterilization by tissue banks varies from 15 to 35 kGY (5).
The upshot? This stuff is really scary. No doctor wants to inject something into a patient that is infected with hepatitis or e coli. However, how can you be sure? With the present state of regulation of the birth tissues industry, there is no way to be sure.
(1) Berger D, Lyons N, Steinmetz, N. In Vitro Evaluation of Injectable, Placental Tissue-Derived Products for Interventional Orthopedics. Interventional Orthopedics Foundation Annual Meeting. Denver, 2015. https://interventionalorthopedics.org/wp-content/uploads/2017/08/AmnioProducts-Poster.pdf
(2) Becktell L, Matuska A, Hon S, Delco M, Cole B, Fortier L. Proteomic analysis and cell viability of nine amnion-derived biologics. Orthopedic Research Society Annual Meeting, New Orleans, 2018. https://app.box.com/s/vcx7uw17gupg9ki06i57lno1tbjmzwaf
(3) Panero, A, Hirahara, A., Andersen, W, Rothenberg J, Fierro, F. Are Amniotic Fluid Products Stem Cell Therapies? A Study of Amniotic Fluid Preparations for Mesenchymal Stem Cells With Bone Marrow Comparison. The American Journal of Sports Medicine, 2019 47(5), 1230–1235. https://doi.org/10.1177/0363546519829034
(4) Pruss A, Kao M, Gohs U, Koscielny J, von Versen R, Pauli G. Effect of gamma irradiation on human cortical bone transplants contaminated with enveloped and non-enveloped viruses. Biologicals. 2002 Jun;30(2):125-33. https://www.ncbi.nlm.nih.gov/pubmed/12127314
(5) Singh R, Singh D, Singh A. Radiation sterilization of tissue allografts: A review. World J Radiol. 2016;8(4):355–369. doi: 10.4329/wjr.v8.i4.355