Two tracks of stem cell medicine in Japan — how the spinal cord injury 'approved product' differs from knee 'provision plans'

Summary — In Japan, medical care using mesenchymal stem cells reaches patients by two broad routes. In one, a company-manufactured product is reviewed and approved on the basis of clinical trial data; in the other, a medical institution submits a provision plan under the regenerative medicine act and carries it out. The autologous bone marrow-derived mesenchymal stem cell product for spinal cord injury (conditional, time-limited approval in 2018) and mesenchymal stem cell treatment of the knee (Class II regenerative medicine) represent the two routes. This article compares them and what each means for the level of evidence.

Route 1: approved products under the Pharmaceuticals and Medical Devices Act

A company wishing to sell a regenerative medical product must submit clinical trial data for review by the Pharmaceuticals and Medical Devices Agency (PMDA) and approval by the Ministry of Health, Labour and Welfare. Japan adds a distinctive 'conditional, time-limited approval' pathway. Because the properties of source cells vary between people and proving efficacy in large trials can take a long time, marketing is allowed with conditions and a time limit (up to seven years) once safety is confirmed and efficacy is 'presumed', and data confirming efficacy must be submitted within that period.

Case 1: the spinal cord injury product

Based on Sapporo Medical University research, the spinal cord injury product expands mesenchymal stem cells from the patient's own bone marrow in the patient's serum and gives them intravenously. It received conditional, time-limited approval in December 2018 and is used at institutions meeting set conditions for patients who meet eligibility criteria. In 2021 the team reported improvements on the ASIA Impairment Scale and in motor and sensory scores in a case series of 13 patients. A 2019 news article in Nature reported scientists' concerns about approval based on small, uncontrolled data; the key point was that spontaneous recovery can occur early after injury, making effects hard to separate without a control group. Data accumulated during the conditional approval period will form the basis of the final judgement.

Route 2: provision plans under the regenerative medicine act

When a medical institution, under a physician's responsibility, collects and processes cells itself and provides them to patients, the regenerative medicine act in force since 2014 applies. It sorts care by risk into Class I (e.g. iPS or ES cell-derived), Class II (somatic stem cells such as mesenchymal stem cells) and Class III (e.g. processed somatic cells that are not stem cells), and the institution must submit a 'plan for the provision of regenerative medicine', reviewed by the relevant committee, to the Ministry. Cell-processing facilities need licensing or notification, and there are obligations to report adverse events and to report regularly.

Case 2: knee treatment

Injecting mesenchymal stem cells into the knee is Class II regenerative medicine and is provided, mostly as self-pay care, by institutions that have completed this procedure. A representative study is a Korean phase I/II study (2014, 18 patients), which reported improved pain and function scores and reduced cartilage defects on MRI in the high-dose group, though it was small and had no control group. Submitting a provision plan means the safety management procedure was followed; it does not mean the treatment's efficacy was confirmed by national review.

The two routes at a glance

• What is reviewed — approved products are reviewed on efficacy and safety data; provision plans on safety measures and delivery arrangements.
• Insurance — approved products can be covered by public health insurance; treatment under provision plans is mostly self-pay.
• Public information — approved products have PMDA review reports; for provision plans, some information is available from the Ministry and jRCT.

In short

The same mesenchymal stem cells carry different levels of evidence depending on the system they are provided under. Distinguishing first whether something is an approved product or treatment under a provision plan helps in understanding where it stands. See the 'Spinal Cord Injury', 'Knee Joint' and 'Japan's Regulatory System' pages for details.

Frequently asked questions

Q. Has treatment at an institution that submitted a provision plan been proven effective?
No. A provision plan is a procedure showing that safety measures and delivery arrangements have passed committee review; the state has not reviewed and recognised the treatment's efficacy. Information on efficacy must be checked separately in the papers and clinical trial results behind the treatment.

Q. How do Class II and Class III differ?
Class II covers care using somatic stem cells such as mesenchymal stem cells; Class III covers lower-risk care such as processed somatic cells that are not stem cells. The type of reviewing committee also differs.

Q. Where can the review of the spinal cord injury product be found?
Review reports and package inserts published by the Pharmaceuticals and Medical Devices Agency (PMDA) show the data behind the approval, patient eligibility and approval conditions.

How to look up clinical trial information

Ongoing and completed clinical trials can be checked on public registries. ClinicalTrials.gov, run by the U.S. National Library of Medicine, and jRCT, run by Japan's Ministry of Health, Labour and Welfare, publish each study's purpose, eligibility criteria, intervention, outcomes, institutions and status. Results are later published as journal papers, and the reference links below this article lead to the original information. It is also worth knowing that interventions not publicly registered are difficult to verify from outside, in both design and results.

The above summarises published papers and public-agency materials. University and institute names are given to identify research sources, not to introduce or recommend any medical institution. The suitability of any treatment is decided by the medical team.

Spinal Cord Injury & Knee Joints →