The Ministry of Food and Drug Safety has revoked the license of Kolon Life Sciences' osteoarthritis gene therapy "Invossa" as it contained an ingredient that derived from a kidney instead of from cartilage.
The ministry said on May 27, "One of the main ingredients of Invossa was identified as kidney cells (293 cells), not cartilage cells, and the data submitted by Kolon Life Sciences were found to be false."
In addition, the ministry will file criminal charges against Kolon Life Sciences. The ministry’s action sent a shockwave through the Korean pharmaceutical industry.
Invossa is an injection of osteoarthritis gene therapy, consisting of a fluid containing human cartilage cells and another fluid containing cells transfected with transforming growth factor β1 (TGF-β1) of cartilage cells. It was licensed on July 12, 2017, as the country's first gene therapy drug. Recently, the transfected cells were found to be kidney cells, not cartilage cells, as stated in the document submitted by the company for approval.
Until now, the Drug Ministry has been looking into the data provided by Kolon Life Sciences that could prove why and how the substance of the drug had been changed. It also conducted additional verification, including its own test inspection of Invossa, on-site investigation of Kolon Life Sciences and due diligence on its U.S. subsidiary Kolon TissueGene.
Through this intensive investigation, the ministry confirmed that Kolon Life Sciences submitted false data at the time of the approval and did not submit major facts it discovered before the approval.
The ministry conducted short tandem repeats (STR) testing, a genetic system test, on the two fluids of Invossa, and found that the second fluid contained kidney cells, not cartilage cells. In the second fluid, gag and pole genes found only in kidney cells were found. Kidney cells are known to have the possibility of developing into cancer cells.
In particular, Kolon Life Sciences fabricated the data it submitted at the time of the approval to prove that the second fluid contained cartilage cells.
In order to prove that the second fluid contained cartilage cells, the fluid had to be compared with the first fluid. But Kolon Life Sciences compared it with a mixture of the two fluids.
Based on the findings, the ministry concluded that the data submitted by Kolon Life Sciences at the time of the approval was false.
The ministry found that Kolon TissueGene as well as Kolon Life Sciences had recognized in 2017, not recently, that Invossa's drug ingredients had changed.
While the ministry's investigation was underway, Kolon Life Sciences also failed to provide scientific evidence on how and why the ingredients of Invossa changed from cartilage to kidney cells. The company also failed to explain why it judged that the second fluid contained cartilage cells when it applied for a license.
The ministry said it is not much concerned about the safety of Invossa, noting that cells no longer survive 44 days after administration. It also said that no drug-related side effects were identified from those subject to clinical trials.
However, in order to prepare for possible side effects, the ministry said it will seek special management of all patients with the medication and undertake a long-term follow-up investigation for 15 years. In Korea, 3,707 cases of Invossa were administered in 438 hospitals and clinics.
Regarding the validity of Invossa, the results of the clinical trial itself were considered respectable. “I believe the drug can alleviate pain and improve functions as have been verified through the clinical tests,” said Kang Seok-yeon, director of bio-pharmaceuticals at the ministry.
Meanwhile, the ministry plans to further strengthen the quality and safety management of bio-medicine in the wake of the Invossa case.
In order to strengthen the origin and development status of cells in the R&D stage, safety and quality control standards will be prepared in stages from collection of cells to processing, storage and supply of cells.
In addition, for new drugs that took a long time to research and development, test data that was collected in the early stages of development will be re-tested with the latest test method. The ministry is planning to check important verification elements.
In addition, if there is a possibility of cell mixing, companies will be required to submit the results of genetic systematic tests on the cells used for research and development and manufacturing. The ministry will require long-term follow-up investigations, including sales and administration details of advanced biologic drugs and registration of abnormal cases, during the use phase after approval.
"We will take the case seriously and strengthen the patient-centered safety management system so that safer and better medicines can be developed and supplied in the future," Kang said.