Over the past three posts (Part One, Part Two and Part Three) I have cited sections of 21 CFR 1271 as they relate to the manufacturing of HCT/Ps, such as cord blood-derived products produced by Genetech and sold by Liveyon that resulted in 15 patients (so far) suffering often severe adverse events due to having been injected with microbially-contaminated product.
It should go without saying that a member of the regenerative medical community should have an absolute expectation that any company engaged in selling HCT/Ps would know of the appropriate rules and follow them, in order to minimize the distribution of contaminated products. As I explored in some detail in the last post, clearly there seemed to have been gaps in the Quality System in place at Liveyon, which resulted in their accepting into inventory product that didn’t come close to meeting a number of the requirements in 1271.
In order to protect yourself and your patients, you need to hold accountable anyone selling HCT/P-derived products and ask some hard questions about the process to produce the vials of magic goop. Consider the following, in order to minimize the risk of injecting contaminated, donor-derived products into your patients:
- Ask to see the lot certification that the product is free of contamination. Retain the document in your files.
- Ask the sales rep about the most recent on-site audit the distribution company conducted of the facility procuring the raw material. For umbilical cord blood products, this would require an audit of the medical facility obtaining the umbilical cords, including donor-eligibility documentation. If they haven’t conducted an on-site audit of the facility collecting the material, then this could lead to a repeat of the Liveyon debacle.
- Ask for donor-eligibility documentation for the product lot you are being asked to inject.
- Ask the sales rep when the company conducted an on-site audit of the facility processing the raw material to produce the vials that are being offered for sale if the material isn’t processed internally. The same issue applies here as indicated in Item 2; no on-site audit means no definitive knowledge about the production facility’s adherence to cGMP regulations as applied to the product on offer.
I am not sure Liveyon could have provided the appropriate documentation if physicians injecting Liveyon product had asked these questions, but maybe. Unfortunately, the Washington Post article I quoted in the last post, also mentions that there were two other patients who tested positive for bacterial agents after receiving injections of a donor-derived material, but which wasn’t sold by Liveyon, meaning there is another vendor of magic goop that is putting your patients at risk. It would appear that the track record of companies producing sterile, peri-natal derived products isn’t the greatest.
In view of the apparent risks associated with donor-derived products, you could save yourself the hassle and uncertainty by not using these types of HCT/Ps, since the FDA considers them to be drugs. In the Warning Letter the FDA issued to Genetech, the following statement appears (with edits):
Information and records gathered during the inspection and information available on the Liveyon website, www.liveyon.com, reflect that your products are intended to treat a variety of orthopedic conditions. Therefore, your 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)].
The FDA goes on in the Warning Letter to indicate that the umbilical cord blood (with edits):
…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).
The FDA also cites another regulation, 1271.10(a)(4), to further rain on Genetech’s parade (with edits):
…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.
The implications for clinicians using cord blood-derived anything are not subtle. The Agency has declared cord blood-derived products to be drugs, and since no one I know of has done the heavy lifting to perform the pre-market approval studies required of cord blood-derived drugs for orthopedic indications, anyone injecting these materials is using an unapproved drug.
Now we get to an interesting development in the Liveyon debacle. A press release was issued on March 1, 2019, with the title “Liveyon Pure® Debuts Clinical Trial Grade Stem Cell Concentrate Derived from Umbilical Cord Blood”. Really.
The press release extols the efforts by Liveyon Labs, which appears to be a separate entity from Liveyon, LLC, to improve the characterization of the contents of the vials of cord blood product that Liveyon Labs intends to sell to physicians wanting to treat “…patients suffering from orthopedic pain and injuries…[since] the stem cells found in the Liveyon PURE Product® may help regenerate bone, muscle, and cartilage…”. According to Liveyon’s CEO, John Kosolcharoen, “I’m proud that Liveyon provides a detailed description of cell viability, identity, growth factor expression and safety testing.”
Obviously, users of the new Liveyon non-compliant cord blood products might appreciate the reassurance, but unless the viability of the nucleated cells in their vials is zero, the spiffy new products from Liveyon Labs will be unapproved drugs in the view of the FDA. The press release goes on to assure everyone that Liveyon knows what it is doing, proclaiming, “Liveyon Labs also has an experienced team of compliance and regulatory personnel…”, but have any of them read 1271.10(a)(4)? Because if they have, then Liveyon Labs would be shipping vials filled with dead cells to avoid having the FDA give them a Warning Letter about selling an unapproved drug. Time will tell.
While I had hoped to address a research paper on autologous therapy in the next post, I will turn my attention to another purveyor of magical goop, Chara Biologics.