In the past two posts (Part One and Part Two) I have covered details about a serious lapse in quality control on the part of Genetech, the source of contaminated cord blood-derived products, which was injected into 15 patients who have developed serious infections, as tracked by the CDC. Genetech sold the donor-derived cord blood product to Liveyon, LLC (Yorba Linda, CA), which sold the vials of contaminated product to clinics in multiple states. The FDA had conducted an on-site audit of Genetech last June, and issued a Warning Letter to Genetech in November. However, as reported in a Washington Post article published on February 28th, Liveyon had received reports of patients suffering adverse events as early as June 5,, 2018, with E. coli and other bacteria being cultured from tissue samples obtained by physicians treating the affected patients. A full recall of the implicated lots of product was initiated by Liveyon on September 28, 2018.
As reported in the Washington Post story, some of the patients suffered such serious infections that they were hospitalized; in one case for 58 days. So, I was somewhat taken aback when the reporters quoted the founder and CEO of Liveyon, John Kosolcharoen, as stating “We’re a victim as much as the patients who were infected…” The article indicated that the company’s executives believed the series of infections were the result of careless handling of the company’s product vials by clinicians. Even after the CDC concluded that the vials already were contaminated before being opened by physicians, the article states that Mr. Kosolcharoen “…continues to believe that doctor error contributed to the rash of infections.”
The statements and opinions of Mr. Kosolcharoen would seem to imply that Liveyon didn’t have much of a role to play in this tragic sequence of events. In fact, Mr. Kosolcharoen was quoted in the Washington Post article as saying:
“I gotta be a little mad at FDA,” he said. “Had we been notified that they had done an inspection of Genetech and found these deviations, we would have stopped buying from them immediately.”
From Mr. Kosolcharoen’s comments, I guess we should be blaming the FDA for not doing Liveyon’s job, because it is Liveyon’s job to ensure that the vials of product they were selling met all of the regulations outlined in 21 CFR 1271.
Let’s start with the most basic requirement for a company that is distributing HCT/Ps. Liveyon is required to have in place a fully compliant Quality System, as stated in (with edits):
§ 1271.160 Establishment and maintenance of a quality program.
(a) General. If you are an establishment that performs any step in the manufacture of HCT/Ps, you must establish and maintain a quality program intended to prevent the introduction, transmission, or spread of communicable diseases through the manufacture and use of HCT/Ps.
Sharp eyed readers of that statement might hasten to point out that the language in 1271.160 refers to “…an establishment that performs any step in the manufacture of HCT/Ps…”, while Liveyon is a distributor of HCT/Ps. But sometimes you need to know something to know something, and this is one of those times. Contemplate the following (with edits):
§ 1271.3 How does FDA define important terms in this part?
…(e) Manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor.
Clearly, the FDA requires all entities involved in any phase of a business involving HCT/Ps to implement a robust Quality System. But what does that mean in terms of concrete actions Liveyon should have been taking?
An important section in 1271 is the following (with edits):
§ 1271.55 What records must accompany an HCT/P after the donor-eligibility determination is complete; and what records must I retain?
(a) Accompanying records. Once a donor-eligibility determination has been made, the following must accompany the HCT/P at all times:
(2) A statement whether, based on the results of screening and testing, the donor has been determined to be eligible or ineligible; and
(3) A summary of the records used to make the donor-eligibility determination. …
(b) Summary of records. The summary of records required by paragraph
(a)(3) of this section must contain the following information:
(1) A statement that the communicable disease testing was performed by a laboratory:
(i) Certified to perform such testing on human specimens under the Clinical Laboratory Improvement Amendments of 1988 (42 U.S.C. 263a) and 42 CFR part 493; …
(2) A listing and interpretation of the results of all communicable disease tests performed;
In this case, Liveyon should have been reviewing a set of documents accompanying each lot of product shipped from Genetech, including the donor eligibility forms that are supposed to be filled out prior to acquiring or processing the donated tissue. If you recall in Part Two, one of the sins Genetech committed was that it didn’t have the donor eligibility forms to pass on, or the forms were incomplete. If I am the Liveyon inspector of newly arrived product, and I don’t see the donor eligibility forms for the lots, those lots should have been placed in quarantine until the proper paperwork had been provided.
Then there is the matter of the testing of the donated tissue to ensure that it is free of contamination. A review by the Liveyon inspector of the paperwork on the infectious agent testing of the donated tissue might have revealed that the assays used weren’t intended for screening HCT/Ps for diseases like HIV or Hepatitis. Furthermore, the Liveyon inspector might have realized something was amiss when the paperwork on infectious agent screening indicated that Genetech was performing the assays in-house. As indicated in the 1271.55 excerpt above, only analysis performed in a CLIA-certified laboratory is acceptable for declaring the product to be free of infectious contamination. Genetech clearly didn’t have a CLIA-certification, so the Liveyon inspector seems to have been accepting product that had not been evaluated properly. Otherwise, how did Liveyon end up with distributing contaminated product? So, it is quite puzzling that the owner of Liveyon would blame the FDA for failure to notify them of issues with the product they were selling, since if they had a compliant quality program the red flags would be evident.
Liveyon also failed to notify the FDA of complaints from physicians about possible contamination. Mr. Kosolchareon indicated in the Washington Post story that their internal opinion was that the contamination was a result of clinician mis-handling. But this is beside the point, and since a credible complaint had been received, either Liveyon was obligated to alert the FDA to the adverse events or they should have been in contact with Genetech, and Genetech would have alerted the FDA. In any event, the FDA should have been informed of these early cases of adverse patient outcomes involving potentially contaminated product.
There were other ways for Liveyon to realize that Genetech didn’t know what they were doing. For example, in the Quality System operated by Liveyon, vendor audits should have played an important role in ensuring compliance with all cGMP requirements. Given how out of control Genetech appears to have been and for a considerable length of time (the Warning Letter mentions “mid-2017” as a documented starting point), it is hard for me to understand how even a “desk audit” by Liveyon of their supplier would have failed to turn up their gross deficiencies. Of course, one possible explanation is that vendor audits weren’t performed, while another is that the results of any such audits weren’t fully appreciated.
The behavior of Liveyon in this situation is puzzling at best, since there were huge gaps in the process required for providing a safe, contamination-free product for use by the regenerative medical community. However, there are a couple of other issues with the Genetech product that the FDA mentioned in the Warning Letter that I will consider in the next post, along with some of the lessons the Liveyon debacle has highlighted, including the inherent risks associated with donor-derived materials.