intellim Corporation, founded in 2005, is a relatively new CRO in Japan.
Since its establishment, with particular strengths in the field of oncology. thanks to our clients, we have received many projects from various other therapeutic fields. Furthermore, we have been focusing on the field of Regenerative Medicine since 2015.
Here at intellim, we can contribute to your success at every stage of your product development. As a CRO leading in regenerative medicine, we strive to promote and share information in this therapeutic field.
Special Measures for the Purpose of Development
In Japan, regenerative medicine is managed by various regulations, approval processes, and special measures. This section summarizes the special regulatory measures between PMDA (Pharmaceutical and Medical Devices Agency), USFDA (US Food and Drug Administration), and EMA (European Medicines Agency). ※1,2,3,4,5
Table.1 Special measures by PMDA, FDA, EMA
|PMDA||・Conditional and Time-Limited Approval
・Orphan Drug Designation
|EMA||・Conditional Marketing Authorization
“Conditional and Time-Limited Approval”, is a special measure in Japan, which can be described as an approval system which helps reflect the difficult characteristics of regenerative medicine, such as quality and effectiveness, due to the use of human cells.
＜Conditional and Time-Limited Approval＞
If the conditions 1to3 are met, the Minister of Health, Labor and Welfare may give conditional approval with a time limit not exceeding seven years.
Approval must be reapplied within the approval time limit.
- 1. The product is not homogeneous.
- 2. The product should have the potential efficacy, effect or capability.
- 3. The product should not cause a significant harmful effect in comparison to its efficacy, presuming it to have no value as a regenerative medicine product.
Strategy In Japan
If foreign sponsors without a legal entity in Japan would like to conduct a clinical trial, an In-Country Clinical Caretaker conducts tasks related clinical trials in Japan instead of sponsors. In addition, by selecting the appropriate doctor, clinical trial can be conducted as an Investigator-initiated Study.
Some regenerative medicine products approved in Japan have not conducted randomized or control studies. This is different from the conventional approval process, which is based on randomized controlled trials. We have made a list of such regenerative medicine products approved in Japan.※6
Table.2 Regenerative medicine products approved in Japan and trial designs of them
|Brand name・Generic name||Indication||Approval
|Trial designs for evaluating efficacy and safety|
（Autologous Cultured Epidermis）
|Severe burns||2007||open-label, single arm|
|Severe birthmarks (giant congenital melanocytic nevus)||2016/9||open-label, single arm (Investigator-initiated, Japan)|
|Epidermolysis bullosa (epidermolysis bullosa dystrophica and junctional epidermolysis bullosa)||2018/11||①open-label, single arm (PhaseⅡ, Japan)
②open-label, single arm (Investigator-initiated, PhaseⅢ, Japan)
（Autologous Cultured Cartilage）
|Traumatic articular cartilage defects or osteochondritis dissecans of the knee (excluding knee osteoarthritis)||2012/6||open-label, single arm (Japan)|
（Autologous skeletal myoblast sheet）
|Severe Heart Failure due to Chronic ischemic Heart Disease||2015/9||open-label, single arm (PhaseⅡ, Japan)|
（Allogenic mesenchymal stem cells from bone marrow）
|Acute graft-versus-host disease||2015/9||①open-label, single arm (PhaseⅠ/Ⅱ, Japan)
②open-label, single arm (PhaseⅡ/Ⅲ, Japan)
|Relapsed/refractory CD19 positive B-ALL
Relapsed/refractory CD19 positive DLBCL
|2019/2||①open-label, single arm (PhaseⅡ, 11 countries including Japan)
②open-label, single arm (PhaseⅡ, 10 countries including Japan)
③open-label, single arm (PhaseⅡ, USA)
|Collategene intramuscular injection 4mg
|Critical limb ischemia||2019/2||①randomized, double-blind, placebo-controlled （PhaseⅢ, Japan）
②open-label, single arm（Japan）
③open-label, single arm（Clinical research, Japan）
④randomized, double-blind, placebo-controlled（PhaseⅡ, USA）
⑤randomized, double-blind, placebo-controlled（Additional PhaseⅡ, USA）
⑥open-label, single arm（PhaseⅡb, USA）
⑦randomized, double-blind, placebo-controlled（PhaseⅢ, some countries including Japan）
（Autologous mesenchymal stem cells from bone marrow）
|Improvement of neurological symptoms and dysfunctions in spinal cord injury||2018/11||open-label, single arm（PhaseⅡ, Japan）|
（Autologous cultured corneal epithelium）
|Limbal stem-cell deficiency||2020/2||open-label, single arm（PhaseⅢ, Japan）|
|Spinal muscular atrophy (SMA)（including patients with bi-allelic mutations in the SMN1) gene）||2020/2||open-label, single arm（PhaseⅠ, USA）|
※（Axicabtagene ciloleucel ）
|Relapsed/refractory large B-cell lymphoma||2020/12||①open-label, single arm（PhaseⅠ/Ⅱ, 6 countries）
②open-label, uncontrolled（PhaseⅡ, Japan）
|Relapsed/refractory large B-cell lymphoma||2021/2||①open-label, single arm(PhaseⅠ, USA)
②open-label, uncontrolled (PhaseⅡ, 10 countries including Japan)
（Autologous Cultured Oral Mucosal Epithelium）
|Limbal stem-cell deficiency||2021/5||open-label, single arm（PhaseⅢ, Japan）|
|Malignant glioma||2021/5||open-label, single arm（PhaseⅡ, Japan）|
＊：Approved in Japan and foreign country
Clinical Trial Subject Costs
Generally, in the United States or in Europe, the sponsor should bear the full cost of the medical treatment for the subject. However, in Japan, the universal health insurance system partially applies to clinical trials, thus some of the subject costs borne by the sponsor can be reduced.
This system is limited to medical services that are approved to be covered by insurance. Patients should pay the full amount for medical treatment that are not covered by insurance. In addition, in the case of mixed medical treatment, which is a combination of insured and uninsured medical treatment, patients are responsible for paying for medical treatment that is allowed by insurance as well. However, when a patient enters a clinical trial, insurance coverage is still permitted for some medical treatments. In such cases, the sponsor (pharmaceutical company, etc.) only covers the expenses for examinations exclusive to the clinical trial.
※not evaluated in the medical service fee system
|Expenses related to processed cells, etc. for investigational products||Medications||injections|
Figure.1 Subject’s burden of Sponsor initiated clinical trials
intellim’s Regenerative Medicine Services
intellim can offer wide range of services such as formulation of development strategies, non-clinical studies, clinical trials, application approval, and post-marketing studies.
In addition to the regulations and the environment of regenerative medicine development described in this column, there are other various issues and challenges in the development of regenerative medicine products, for example, validation of manufacturing and quality, PMDA consultation, site management, recruitment of patients with rare diseases, etc. we will propose the most optimum solution for you at every stage of development
【Citations and References】
※1：Comparison of new drug approval status and review period in Japan, the US and Europe – Focusing on 2019 approval-”, news of pharmaceutical industry research No.61, masao yoshida et al., November 2020.
※2：”Consideration of clinical trial design and statistical evaluation method in the development regenerative medicine product”, JPMA, ver.1.0, May 2021
※3：“Appendix Summary of clinical development history of individual products in Japan and the US, JPMA
※4：“Expedited Programs for Regenerative Medicine Therapies for Serious Conditions“ Guidance for Industry, FDA
※5：EUROPEAN MEDICINES AGENCY, https://www.ema.europa.eu/en (See Sep. 30, 2021)
※6：Review report issued by PMDA https://www.pmda.go.jp/PmdaSearch/saiseiSearch/ (See Sep. 30, 2021)
※7：Partial amendment of "Notes on the implementation of 'posted matters, etc., specified by the Minister of Health, Labour and Welfare based on the Rules for Medical Treatment, the Rules for Pharmaceutical Treatment, and the Standards for Medical Treatment' and 'drugs, etc., specified by the Minister of Health, Labour and Welfare relating to the specified medical care coverage system'", November 25, 2014