The Catastrophe of Conditional Approval Systems
Accessible Rail Medical Services Tetsuikai, Navitas Clinic Kawasaki
Tetsuya Tanimoto, MD
Terumo’s regenerative medicine product for heart failure treatment, "HeartSheet," achieved the world’s first practical application and received manufacturing and marketing approval in Japan in September 2015.
However, on July 19th, it was confirmed at the Ministry of Health, Labour and Welfare’s Pharmaceutical Affairs Council Subcommittee on Regenerative Medicine Products and Biological Technologies that the achievement criteria set at the time of conditional and time-limited approval were not met, and it was deemed inappropriate to grant regular approval for HeartSheet. Following this decision, Terumo announced the discontinuation of its sales the very next day. A similar conclusion was reached at the higher-level Pharmaceutical Affairs Council meeting held on July 24th.
While detailed clinical performance data for HeartSheet is not yet clear, let us revisit its efficacy within the limits of publicly available information.
HeartSheet involves harvesting the patient's own skeletal muscle progenitor cells, culturing and proliferating them ex vivo, forming them into a cellular sheet, and transplanting five sheets onto the surface of the heart. It is used for the treatment of severe heart failure due to ischemic heart disease, where standard treatments including pharmacotherapy and invasive treatments are insufficient, categorized as NYHA functional class III or IV and with a resting left ventricular ejection fraction of 35% or less.
At the time of conditional and time-limited approval, the evaluation material consisted only of one uncontrolled domestic clinical trial incorporating seven cases. No evaluation of life expectancy was possible, and the main evaluation criterion was the postoperative left ventricular ejection fraction. Remarkably, there were no cases of improvement; five cases remained stable, and two cases worsened. The criteria for efficacy evaluation were not pre-set in the clinical trial, making it a challenging dataset to assess.
Therefore, the post-approval condition evaluation plan included proactive collection of external control data related to life expectancy and analysis of survival time, as well as evaluation of the proportion of cases where the left ventricular ejection fraction improved by 5% or more.
As a result, in the discussions for regular approval, the trial performance survey and clinical research submitted included registrations of 67 cases (of which 49 were for efficacy analysis), and a control group of 104 cases (102 of which were analyzed). The lack of demonstrated efficacy was as expected, and I was not particularly surprised. There are limitations to comparisons with external controls, but no superiority was shown in the primary evaluation criterion, which is the duration until cardiac-related death, and improvements in secondary criteria such as left ventricular ejection fraction were also not observed.
The question is whether there was ever a need to apply a conditional and time-limited approval system to such a product. While I do not deny the industrial policy motives of wanting to promote domestic regenerative medicine products or accumulate technical know-how in Japan, what about the cost aspect?
Naturally, there is no adjusted foreign price for HeartSheet, and the reimbursement price was set based on the cost calculation method, with the cost of the A kit for culturing cells being 6.36 million yen and the B kit for transplantation being 1.68 million yen per five sheets, totaling 14.76 million yen. This price was reduced from Terumo’s initial desired price of 18.89 million yen. The estimated number of applicable patients was 123 over five years, but the number of cases in the current usage performance survey was significantly lower. A simple calculation of the cost for 67 cases is approximately 988.92 million yen. While the cost per patient is high, when considered as a development expense, it was not a significant amount.
Even if various related costs in addition to the product cost are added, if the order was around 1 billion yen, couldn't the companies have borne the cost, or obtained research funding to conduct clinical research? What was the significance of moving the approval system and disbursing public insurance for a product of uncertain efficacy? Further discussion on this matter is necessary.
This article was originally published in Japanese in Iyakukeizai (Pharmaceuticals and Economics) on Aug 1, 2024.