[비즈한국] The domestic product approval for 'JointStem', a stem cell therapy for degenerative osteoarthritis developed by R-Bio, an affiliate of Nature Cell007390, has been thwarted. Starting with the failed application for conditional approval to the Ministry of Food and Drug Safety (MFDS) based on Phase 2 clinical trial results conducted in Korea and the US in 2018, the company tasted defeat again on the 6th, following a previous rejection in April 2023, after attempting to obtain approval once more upon completing Phase 3 clinical trials in Korea.
Why is JointStem receiving the cold shoulder from the MFDS, unlike in the US where expectations are rising after securing the US Food and Drug Administration's (FDA) three major accelerated approval programs: RMAT (Regenerative Medicine Advanced Therapy), BT (Breakthrough Therapy), and EAP (Expanded Access Program)? We met with Lee Jang-ik, a professor at Seoul National University's College of Pharmacy who served as a clinical pharmacology reviewer and team leader at the FDA for 11 years, to hear the reasons.
Professor Lee first pointed out that the FDA and the MFDS have different perceptions of medicinal products. He explained, "The basic policy of the FDA is to evaluate the benefits and risks provided by a drug, and if the benefits are greater, it determines that the drug has value and grants approval," adding that the reason for this is "to provide patients with various choices." In contrast, Professor Lee pointed out that the MFDS is obsessed with safety and efficacy without such evaluations, ignoring the fundamental value of the drugs.
He also raised issues regarding the lack of 'clinical significance', which the MFDS has repeatedly cited as the reason for rejecting JointStem's product approval. Professor Lee stated, "Significance is verified through statistical methods, and efficacy can be judged through clinical trials," adding, "Especially for osteoarthritis treatments that use subjective patient judgments (PRO) such as WOMAC (joint function improvement) or VAS (pain improvement) as primary endpoints, clinical significance (which doctors judge objectively) cannot be applied. Therefore, the FDA judges approval solely based on statistical significance." He strongly criticized the MFDS, saying, "The MFDS is like saying 'a snake isn't a snake because it doesn't have legs.' They haven't even established a standard for judgment, yet they ask for an explanation of how much improvement is considered significant. The MFDS is not even prepared to review and approve innovative new drugs."
On the 8th, Nature Cell released opinions from global experts regarding the MFDS's judgment of clinical significance for JointStem on its website. John Devin Peipert, Deputy Director of the Birmingham Health Partners Centre for Regulatory Science and Innovation at the University of Birmingham, UK, and Professor Xiaodan Tan of Northwestern University Feinberg School of Medicine in the US, explained, "There is currently no common and universal approach worldwide regarding the 'Minimal Clinically Important Difference (MCID)' for evaluating therapeutic effects," adding, "As a standard reflecting meaningful changes from a patient's perspective, MCID is a fluid concept that changes depending on the situation rather than a fixed figure. Even if the same clinical indicators are used, evaluation results can vary depending on the research methodology."
Professor Lee also questioned the contradictory attitude of the MFDS. He pointed out, "When the MFDS approved the Phase 3 clinical trial plan for JointStem in Korea, it did not use clinical significance as a criterion for judgment, but then clinical significance suddenly emerged during the approval review stage," and remarked, "If we compare this to soccer, how is it different from a referee starting a match without applying the offside rule and counting a goal, only to suddenly impose the offside rule later?"
He added, "The MFDS shows a passive attitude toward cell and gene therapies developed by domestic companies while easily granting approval for cell and gene therapies from global pharmaceutical companies that have already received FDA approval. I don't understand why they ignore the clinical trial results of JointStem that the FDA has acknowledged." The FDA typically requires two or more pivotal clinical trials for new drug approval, and it is known that the results of the Phase 3 clinical trials conducted in Korea will be accepted for JointStem's US approval.
Except for 'CartiLife', an osteoarthritis treatment by BioSolution086820 which received conditional approval in April 2019 and formal approval on April 29th of this year, there have been zero cell and gene therapies approved for domestic companies since the implementation of the Advanced Regenerative Medicine and Advanced Biopharmaceuticals Act (Advanced Regenerative Medicine Act) in August 2020. Conversely, during the same period, four types of cell and gene therapies from global pharmaceutical companies that received FDA approval, such as Kymriah and Zolgensma, were approved by the MFDS and launched in Korea.
Professor Lee emphasized, "In a situation where patients are bearing high costs and going to Japan, which is called an advanced country in regenerative medicine, to receive JointStem injections, it makes no sense for the MFDS to deprive patients of the opportunity to choose their own treatment."