Friday and Saturday showed a burst in FDA activity related to unproven stem cells and regenerative products including a warning letter to the unproven perinatal “stem cell” provider Liveyon.
This was an unusual 48-hour period and a very good one for those who believe in science-based regenerative medicine but in my view a bad day for perinatal stem cell clinic and exosome suppliers. For general background on exosomes see these past The Niche posts.
I’m sure there are a lot of hardworking folks at the FDA who deserve hat tips for this effort and also former Commissioner Scott Gottlieb, but I give a particularly big hat tip to Dr. Peter Marks, head of the FDA’s CBER branch (pictured at left).
Here’s a summary of the actions on Friday and Saturday:
- Warning Letter to Liveyon Labs/Liveyon LLC (and accompanying press release: FDA sends warning to companies for offering unapproved umbilical cord blood products that may put patients at risk.) The PR also mentions two recent untitled letters, “In addition to the warning letter issued to Liveyon Labs and Liveyon LLC earlier this month, the FDA sent untitled letters to RichSource Stem Cells, Inc., and Chara Biologics, Inc., for offering unapproved stem cell products to patients.”
- So-called 483 inspection reports now publicly available on Liveyon LLC and Liveyon Labs. These were sent to Erin M. Sairafe, Chief Compliance Officer for both firms.
- On Saturday, the FDA CBER branch issued a safety communication on exosomes that includes reports of adverse events in Nebraska due to an unproven exosome drug product.
Starting with Liveyon, it has been back in the news the last month or so because of the compelling podcast Bad Batch. The warning letter to the firm was addressed to Liveyon CEO/President Roya Panah and founder John Kosolcharoen. Who is Roya Panah? It turns out that Panah (pictured at right from LinkedIn) also goes or went by the name Roya Kosolcharoen and may be John’s ex-wife.
The letter lists many problematic issues for the company based on an inspection in May of the company’s own production facilities. Note that this is an important point on the location because since the product from independent supplier Genetech led to a dozen or more people going to the hospital, Liveyon has been making its own biologics.
The new warning letter focuses in part on insufficient testing of the umbilical cord product and concerns about sterility. Notably, the letter also indicates that Liveyon’s products are unapproved drugs. It also recommends testing this kind of product for Zika virus.
From the accompanying PR from the FDA:
“The FDA’s mission includes protecting public health by helping to ensure the safety and efficacy of medical products that patients rely on. The agency is aware that there are establishments who prey upon vulnerable populations by commercially marketing stem cell products with false and misleading claims about their effectiveness for treating serious diseases,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research. “The FDA is taking this action today because Liveyon Labs and Liveyon LLC failed to take appropriate measures to protect patient safety. As evidenced by the number of actions that the agency has taken this month alone, there are still many companies that have failed to come into compliance with the Federal Food, Drug, and Cosmetic Act and FDA’s regulations during the period in which the agency intends to exercise enforcement discretion for certain products with respect to FDA’s investigational new drug and premarket approval requirements, when the use of the product does not raise reported safety concerns or potential significant safety concerns. This period, which ends in November 2020, has allowed product manufacturers time to engage with the FDA to determine if they need to submit a marketing authorization application and, if so, seek guidance on how to submit their application to the FDA for approval. The agency continues to urge these manufacturers to engage with the agency about their regulatory requirements in the coming months.”
Shifting gears, what about the exosome notice by the FDA? Overpriced and “underscienced” exosomes are gaining more traction in the unproven stem cell clinic sphere, perhaps in part because of the actions against adipose stem cell clinics. Here’s a key part of the FDA communication on exosomes, noting adverse events:
“The Food and Drug Administration (FDA) is informing the public, especially patients, health care practitioners, and clinics, of multiple recent reports of serious adverse events experienced by patients in Nebraska who were treated with unapproved products marketed as containing exosomes. These reports were brought to the agency’s attention by the Centers for Disease Control and Prevention, among others, and the agencies worked with the Nebraska Department of Health and Human Services. FDA is carefully assessing this situation along with our federal and state partners.
There are currently no FDA-approved exosome products. Certain clinics across the country, including some that manufacture or market violative “stem cell” products, are now also offering exosome products to patients. They deceive patients with unsubstantiated claims about the potential for these products to prevent, treat or cure various diseases or conditions. They may claim that they these products do not fall under the regulatory provisions for drugs and biological products – that is simply untrue. As a general matter, exosomes used to treat diseases and conditions in humans are regulated as drugs and biological products under the Public Health Service Act and the Federal Food Drug and Cosmetic Act and are subject to premarket review and approval requirements.”
I’m hoping to learn more about what happened with the exosomes in Nebraska such as who administered them and who was the supplier.
Overall, the FDA continues to generally increase its activity in the unproven stem cell and regenerative medicine arena. The last few days have been particularly encouraging.
It was the responsibility of LIVEYON to ensure that the products they purchase for use in processing to manufacture products intended to treat a variety of orthopedic conditions meet FDA standards for safety and efficacy.
Here are some of the FDA findings when they inspected LIVEYON:
At the close of the inspection, FDA investigators issued a Form FDA 483 to Erin M. Sairafe, Chief Compliance Officer for both Liveyon Labs and Liveyon LLC, listing inspectional observations, which described a number of significant deviations from CGMP and CGTP. FDA has found additional significant deviations upon further review of the information collected during the May 2019 inspection, as discussed below. The deficiencies include, but are not limited to, the following:
1. Failure to screen a donor of cells or tissues by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. Since operations began in January 2019, Liveyon Labs has processed cord blood units from (b)(4) donors supplied by (b)(4), located in (b)(4), and cord blood units from (b)(4) donors supplied by (b)(4), located in (b)(4). For example:
a. FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s), must indicate that a potential donor is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility. The “DT-001 Form 1 Recovery Site Assessment” received from cord blood supplier (b)(4) did not adequately assess a donor’s residence in, or travel to, areas identified by the Centers for Disease Control and Prevention with active ZIKV transmission. We recommend that you review FDA Guidance for Industry, Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products (updated May 2018), available at https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm488582.pdf.
b. The “DT-001 Form 4 Donor Risk Assessment Interview” received from cord blood supplier (b)(4) did not indicate if the donor has been diagnosed with Creutzfeldt-Jacob disease (CJD) or variant Creutzfeldt-Jacob disease (vCJD).
2. Failure to test donor specimens using appropriate FDA-licensed, approved or cleared donor screening tests, in accordance with the manufacturer’s instructions, to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents or diseases [21 CFR 1271.80(c)]. Specifically, Liveyon Labs tested (b)(4) umbilical cord blood donors for ZIKV with a test that was not FDA licensed, approved, or cleared for HCT/P donor screening. Liveyon Labs relied on such tests, which is not appropriate to prevent the introduction, transmission, or spread of ZIKV through HCT/Ps.
3. Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)]. For example:
a. Liveyon Labs failed to adequately validate the aseptic process used to manufacture your PURE® and PURE PRO® products since operations began in January 2019. By the nature of their routes of administration, your products purport to be sterile and are expected to be sterile. The media fill batch sizes used for your validation study LL-VAL-004, entitled “Validation of Aseptic Processing of the PURE® Product”, did not represent the maximum commercial batch size. The study utilized (b)(4) vials per batch, however batches were observed to be manufactured with up to (b)(4) vials.
b. Liveyon Labs processed cord blood units from two different donors (b)(4). This practice, which you refer to as (b)(4) processing”, is considered high risk and significantly increases the potential for cross-contamination and mislabeling. Since manufacturing operations began in (b)(4), you (b)(4) processed (b)(4)% of your (b)(4) batches. In addition, you failed to track which batches have been processed (b)(4) potentially failing to identify contaminated umbilical cord blood product if one of the batches failed sterility or was processed using cord blood from an ineligible donor.
c. The gowning procedure LL-QA-014, entitled “Gowning Qualification Program,” has not been implemented. Appropriate gowning reduces the potential for the manufacturing personnel to inadvertently contaminate the product during the aseptic manufacturing process.
d. Liveyon Labs used a non-sterile (b)(4) and the associated non-sterile (b)(4) to manufacture approximately (b)(4) batches of your products between January 16, 2019 and May 20, 2019, raising the potential for microbiological contamination. This (b)(4) and (b)(4) are labeled “For research use only.”
4. Failure to thoroughly investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications, [21 CFR 211.192]. For example:
a. From January 16, 2019 to May 20, 2019, Liveyon Labs failed to thoroughly investigate 15 sterility failures and batches processed with cord blood units from ineligible donors:
i. You identified the contaminating organism(s) for your sterility failures but destroyed these batches without initiating/conducting an investigation using FORM-LL-037, entitled “Positive Sterility or EM Failure-Root Cause Analysis”.
ii. You processed cord blood units from ineligible donors and destroyed the final product batches from donors who tested positive for relevant communicable diseases without conducting an investigation. During this time period, donors tested positive for ZIKV, Hepatitis B, and syphilis.
iii. Despite (b)(4) processing (b)(4)% of your cord blood units, your investigations failed to extend to the (b)(4) processed batches. During this time period, your firm did not fail or destroy two batches manufactured on the same day due to positive sterility or infectious disease testing results.
iv. Your firm did not implement corrective or preventive actions.
b. Liveyon Labs failed to thoroughly investigate five in-process BSC settling plates failures. Three of the five settling plates were positive for P. glucanolyticus. The root cause and source of the contaminating organisms was not identified. No corrective actions were implemented, and four impacted in-process batches were subsequently distributed. In addition, you failed to use FORM-LL-037 to formally initiate and document your investigation.
Source: FDA Letter to Liveyon: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/liveyon-labs-inc-588399-12052019
issues listed in the letter are not easy to overcome, and one could argue, are indicative of a culture lacking in appropriate scientific oversight. More-so one https://www.6dollaressay.com/ could argue it speaks of a culture where profit
LOL – How about this one? “Approximate 50% profit margin! Become our partner!” https://firstcytebio.com
The issues listed in the letter are not easy to overcome, and one could argue, are indicative of a culture lacking in appropriate scientific oversight. More-so one could argue it speaks of a culture where profit is the key driver and not medicine.
Liveyon had made and submitted appropriate corrections by June 2019. A full description will soon be posted on the FDA Website.
The important question for consumers and providers to note is that a company that has been inspected by FDA and made the appropriate corrections is a much safer bet, than one that has NEVER undergone FDA scrutiny. There are dozens if not hundreds of those!
@Lexi,
That’s a very unusual perspective I’d say. I’ll be interested to see if FDA says all issues have been fully resolved.
The “selling an unapproved drug” issue seems insurmountable to me.
Not insurmountable. They’ll just need to develop compliant Quality Systems and clinical evidence that their ‘therapies’ deliver the efficacy that they promise.
There is the rub: they are selling prior to any robust scientific evidence that it has a robust and wide-scale beneficial effect. As this ‘product’ makes millions of dollars a year, how do you prevent the lure of profit not to skew actual scientific data in this case?
Insurmountable in the sense that they “made and submitted appropriate corrections” to the FDA that will somehow allow them to keep marketing their product. Of course, no matter what the FDA says, they will keep selling as long as their legal expenses don’t exceed their profit. They will also insist their product is 361 no matter what the FDA says. Only an injunction will make them stop. If almost killing people including children didn’t make them stop, I doubt this will either.
@Bill,
Interestingly, news just broke that Liveyon has voluntarily suspended sales of its product in response to the warning letter. Surprised?
https://www.washingtonpost.com/health/2019/12/13/california-stem-cell-company-halts-sales-after-fda-warning/
I kind of was.
Paul
A bit. Since the 2020 deadline is approaching, I won’t be surprised to see other manufacturers that have built up sufficient capital deciding to suspend sales and work within the FDA framework. I think the FDA will allow some of them to start safety trials without the usual pre-clinical requirements. I think some will sell until they are forced to stop because they are only in it for the money. They’ll just move on to the next money-making scheme, stem cell or otherwise.
Re: John K
https://www.justice.gov/opa/file/869161/download