Yoko Ishiguro, Healthcare Economics and Government Affairs Manager, Medtronic North Asia (Korea and Japan), Tokyo, Japan, yoko.ishiguro@medtronic.com)

Under the Japan HTA known as “cost effectiveness evaluation (CEE),” which was introduced in 2019, there have already been more than 37 ongoing cases or accomplished projects in this scheme. In January of 2022, Ministry of Health, labor and welfare (MHLW) announced that it made the first decision for Zolgensma from Novartis (Generic name: Onasemnogene abeparvovec).

1. Reimbursement of Zolgensma

   This product has been reimbursed in Japan on May 20^th, 2020.

   1. Indication: spinal muscular atrophy (SMA) type I

      SMA is a genetic disease which causes muscle wasting and weakness due to malfunction Survival of Motor Neuron (SMN 1) that is intended to make motor neurons with collaboration with SMN 2. SMA type I is the most severe one among 4 types. Patients usually experience a sudden hypanakinesis when they are 1 week old. Dysphagia and Percutaneous Endoscopic Gastrostomy (PEG) to be followed.

      2). Price per patient: JPY 167,077,222 (USD 1,135,882)

      This is the first drug which has a price more than JPY 1 billion in Japan reimbursement history. The conventional drug is Spinraza from Biogen (Generic name: nusinersen). Spiranza works towards SMN 2 to produce enough protein for motor neurons independently. As a synthetic anti-sense oligonucleotide, Spiranza demonstrated a significant outcome, which resulted in receiving high reimbursement price in 2017. Zolgensma approaches to SMN 1 by passing into the nerve to restore the function with functional copy of SMN 1.

2. CEE selection of Zolgensma

   Japan CEE is an unique system showing different process after reimbursement for price adjustment. Until price adjustment, there are several steps that usually take about 20 months for accomplishment.

   • Product selection
   • Preliminary discussion (main objective is to determine cohort and comparator)
   • Manufacturer reports submission
   • Academia review (at the end of the academic review, academia to submit the report by themselves)
   • Appraisal
   • Price adjustment

     Japan CEE targets only exclusive products which have bigger market size than threshold (JPY 5 billion annually) or relatively expensive products (No clear criteria). Zolgensma was designated to the CEE scheme due to high price. The determination of product selection was open on May 13^th, 2020

3. Suspension of CEE process

On January 28^th,2022, MHLW opened their decision to temporarily pause the process to collect enough data for analysis. From the report, we could read points below ^[1].

• It seems that both reports from manufacturer and academia have been considered, but the expert panel decided not to evaluate based on them. They concluded that both reports have a kind of scientific robustness, but there were limitations. The evidence used for the simulation was not robust enough for the long-term conclusion.
• Ideally, expert committee wants to evaluate the product based on real-world data generated in Japan. However, the data used for Regulatory Affairs process and CEE was not acceptable from their perspective.
• Expert committee decided to ask for manufacturer’s additional data collection. The CEE process to be postponed until the data collection. To generate the more robust data than existing foreign data, they need to have more participants. The expected CEE resumption timing would be after May 2026. It is based on assumption that manufacturer could collect Japanese data 10 or 20 cases annually.
• Until the data collection, manufacturers have to report status annually. If they accomplished the data collection before the expected timeline, they could resume the CEE scheme at that time.

Reference

[1] https://www.mhlw.go.jp/content/12404000/000888633.pdf