This English translation of this Japanese review report is intended to serve as reference material made available for the convenience of users. In the event of any inconsistency between the Japanese original and this English translation, the Japanese original shall take precedence. PMDA will not be responsible for any consequence resulting from the use of this reference English translation. Stemirac for Injection_Nipro Corporation_review report  
Report on the Deliberation Results 
November 21, 2018 
Medical Device Evaluation Division, 
Pharmaceutical Safety and Environmental Health Bureau 
Ministry of Health, Labour and Welfare 
Classification   Human cell product 2. Human-derived somatic stem cell product 
Nonproprietary Name  Human (autologous) bone marrow-derived mesenchymal stem cells 
Brand Name    Stemirac for Injection 
Applicant    Nipro Corporation 
Date of Application  June 29, 2018 (Application for marketing approval) 
Results of Deliberation 
In its meeting held on November 21, 2018, the Committee on Regenerative Medicine Products and 
Biotechnology made the following decision and concluded that this result should be presented to the 
Pharmaceutical Affairs Department of the Pharmaceutical Affairs and Food Sanitation Council. 
The Committee’s decision: 
The product may be approved within the framework of conditional and time-limited approval. The following 
conditions and time-limit should apply. 
Conditions of Approval 
1. The product should be used only for patients considered eligible for the treatment and only under the 
supervision of a specialist with sufficient knowledge and experience in diagnosis and treatment of spinal 
cord injury at medical institutions fully capable of emergency care where patients are 
appropriately monitored and managed by vital sign check and laboratory test, etc. 
2. The applicant is required to conduct an approval condition-based post-marketing evaluation in all 
patients treated with the product during the period after the conditional and time-limited approval until 
reapplication for marketing approval. 
Time Limit of the Approval 
7 years  
2 Stemirac for Injection_Nipro Corporation_review report  
Review Report 
November 12, 2018 
Pharmaceuticals and Medical Devices Agency 
The following are the results of the review of the following regenerative medicine product submitted 
for marketing approval conducted by the Pharmaceuticals and Medical Devices Agency (PMDA). 
Brand Name    Stemirac for Injection 
Classification   Human cell product 2. Human-derived somatic stem cell product 
Nonproprietary Name  Human (autologous) bone marrow-derived mesenchymal stem cells 
Applicant    Nipro Corporation 
Date of Application  June 29, 2018 
Shape, structure, ingredients, quantities, or definition 
The product is a regenerative medicine product. Its primary constituent part is mesenchymal stem cells 
(MSCs). MSCs are isolated from the patient’s bone marrow fluid, cultured in vitro, and cryopreserved in a 
bag. The secondary constituent part of the product comprises a blood collection kit and a bone marrow 
collection kit to be used at a medical institution for the collection and transportation of the patient’s 
peripheral blood and bone marrow fluid. 
Application classification (1-1) New regenerative medical product 
Items Warranting Special Mention 
SAKIGAKE designation regenerative medical product (SAKIGAKE Regenerative Medical Product 
Designation No. 1 of 2015 [27 sai]; PSEHB/PED Notification No. 0210-4 dated February 10, 2016, by the 
Pharmaceutical Evaluation Division, Pharmaceutical Safety and Environmental Health Bureau, Ministry of 
Health, Labour and Welfare); the product underwent SAKIGAKE comprehensive evaluation consultation for 
regenerative medical products. 
Reviewing Office  Office of Cellular and Tissue-based Products
3 Stemirac for Injection_Nipro Corporation_review report  
Results of Review 
On the basis of the data submitted, PMDA has concluded that the product is expected to have a certain level 
of efficacy in the treatment of neurological symptoms and functional disorders associated with spinal cord 
injury, and that the product has acceptable safety (see Attachment). Given the only limited data available at 
present, the efficacy of the product must be verified by further evaluation after the marketing approval. 
As a result of its review, PMDA has concluded that the product may be approved for the indication or 
performance and dosage and administration or method of use shown below, with the following conditions. 
The approval should be conditional and time-limited in accordance with Article 23-26 of “the Act on 
Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, Regenerative and Cellular 
Therapy Products, Gene Therapy Products, and Cosmetics.” 
Indication or Performance 
Improvement of neurological symptoms and functional disorders associated with spinal cord injury only in 
patients with traumatic spinal cord injury assessed as American Spinal Injury Association Impairment Scale 
(AIS) grade A, B, or C 
Dosage and Administration or Method of Use 
Bone marrow aspiration should be aimed to be performed within 31 days after spinal cord injury, according 
to the systemic condition, etc. of the patient. Once produced, the product should be administered at the 
earliest time possible. 
Procedures for the collection of source materials of Stemirac 
(1) Patient’s peripheral blood is collected. The collected peripheral blood is put into a container (Nipro 
Celltry for serum) enclosed in the blood collection kit. After being tightly sealed, the container 
holding peripheral blood is transported to a facility designated by the marketing authorization 
holder. 
(2) Patient’s bone marrow fluid is collected. The collected bone marrow fluid is put into a container 
(Nipro Celltry for bone marrow), and the bone marrow fluid diluent DMEM, enclosed in the 
bone marrow collection kit, is added to be mixed. After being tightly sealed, the container holding 
bone marrow fluid is transported to a facility designated by the marketing authorization holder. 
Procedures for the administration of Stemirac to the patient 
The product is administered by intravenous drip infusion at a rate of 0.7 to 1.0 mL/min, as 0.5 × 108 to 2.0 × 
108 autologous bone marrow-derived MSCs (maximum dose, 3.34 × 106 cells per kg body weight) while 
being diluted ≥3-fold with physiological saline.  
Conditions of Approval 
1. The product should be used only for patients considered eligible for the treatment and only under the 
4 Stemirac for Injection_Nipro Corporation_review report  
supervision of a specialist with sufficient knowledge and experience in diagnosis and treatment of spinal 
cord injury, at medical institutions fully capable of emergency care where patients are 
appropriately monitored and managed by vital sign check and laboratory test, etc. 
2. The applicant is required to conduct an approval condition-based post-marketing evaluation in all patients 
treated with the product during the period after the conditional and time-limited approval until 
reapplication for marketing approval. 
5 Stemirac for Injection_Nipro Corporation_review report  
Attachment 
Review Report (1) 
September 20, 2018  
The following is an outline of the data submitted by the applicant and content of the review conducted by the 
Pharmaceuticals and Medical Devices Agency. 
Product Submitted for Approval 
Brand Name    Stemirac for Injection 
Classification   Human cell product 2. Human-derived somatic stem cell product 
Nonproprietary Name  Human (autologous) bone marrow-derived mesenchymal stem cells 
Applicant    Nipro Corporation 
Date of Application  June 29, 2018 
Shape, Structure, Ingredients, Quantities, or Definition 
The product is a regeneration medical product. Its primary constituent part is mesenchymal stem cells 
(MSCs). MSCs are isolated from the patient’s bone marrow fluid, cultured in vitro, and cryopreserved in a 
bag. The secondary constituent part of the product comprises a blood collection kit and a bone marrow 
collection kit to be used at a medical institution for the collection and transportation of the patient’s 
peripheral blood and bone marrow fluid. 
Proposed Indication or Performance 
Improvement of neurological symptoms and functional disorders associated with spinal cord dysfunction 
Proposed Dosage and Administration or Method of Use 
Bone marrow aspiration should be aimed to be performed within 31 days after spinal cord injury, according 
to the systemic condition, etc. of the patient. Once produced, the product should be administered at the 
earliest time possible. 
Procedures prior to the production of Stemirac 
(1) Patient’s bone marrow fluid is collected. The collected bone marrow fluid is put into a container (Nipro 
Celltry for bone marrow), and the bone marrow fluid diluent DMEM, enclosed in the bone marrow 
collection kit, is added to be mixed. After being tightly sealed, the container holding bone marrow fluid 
is transported to a facility designated by the marketing authorization holder. 
(2) Patient’s peripheral blood is collected. The collected peripheral blood is put into a container (Nipro 
Celltry for serum) enclosed in the blood collection kit. After being sealed, the container holding 
peripheral blood is transported to a facility designated by the marketing authorization holder. 
6 Stemirac for Injection_Nipro Corporation_review report  
Procedures for the administration of Stemirac to the patient 
The product is administered by intravenous drip infusion as 0.5 × 108 to 2.0 × 108 autologous 
bone marrow-derived MSCs (maximum dose, 3.34 × 106 cells per kg body weight) while being diluted 
≥3-fold with physiological saline. 
Table of Contents 
1 Origin or History of Discovery, Use in Foreign Countries, and Other Information ........................................ 7 
2 Manufacturing Method and Specifications and Outline of the Review Conducted by PMDA ....................... 8 
3 Stability and Outline of the Review Conducted by PMDA ........................................................................... 14 
4 Indication or Performance and Outline of the Review Conducted by PMDA………………………………15 
5 Pharmacokinetics of the Product and Outline of the Review Conducted by PMDA .................................... 19 
6 Nonclinical Safety and Outline of the Review Conducted by PMDA .......................................................... 20 
7 Clinical Study and Outline of the Review Conducted by PMDA ................................................................. 21 
8 Risk Analysis and Outline of the Review Conducted by PMDA .................................................................. 40 
9 Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion Reached 
by PMDA ....................................................................................................................................................... 43 
10 Overall Evaluation during Preparation of the Review Report (1) ............................................................... 43 
List of Abbreviations 
See appendix. 
7 Stemirac for Injection_Nipro Corporation_review report  
1 Origin or History of Discovery, Use in Foreign Countries, and Other Information 
1.1 Outline of the product submitted 
Stemirac is a human somatic stem cell product. Its (1) primary constituent part is cryopreserved cells 
developed from MSCs present in bone marrow fluid, which is collected from the patient. MSCs are cultured 
for growth in vitro, suspended in cryopreservation fluid containing patient’s own serum, and cryopreserved. 
The (2) secondary constituent part of the product comprises (i) a blood collection kit for the collection of 
patient’s peripheral blood and (ii) a bone marrow collection kit for the collection of patient’s bone marrow 
fluid, both of which are also used for the transportation of collected materials to a designated facility for the 
production of Stemirac. 
The product is indicated for spinal cord injury. In most cases, spinal cord injury is intractable and causes 
serious and persistent dysfunction, affecting regions controlled by the spinal cord below the level of injury 
site. Injury of the upper cervical spinal cord may lead to respiratory disorder or quadriplegia (Orthopedic 
knowledge update Spine. American Academy of orthopaedic surgeons; 2012.187-95). In Japan, there are 
≥100,000 patients with spinal cord injury, including approximately 5000 new patients per year. The major 
causes of the injury are traffic accident, fall from a height, and sports injury (Orthopedic knowledge update 
Spine. American Academy of orthopaedic surgeons; 2012.187-95, Nihon Sekizuishogai Igakkai Zasshi [The 
journal of the Japan Medical Society of Spinal Cord Lesion]. 2005;18:271-274). In Japan, age distribution of 
patients with spinal cord injury is characterized by bimodal peaks in young generation and in the elderly 
(Nihon Sekizuishogai Igakkai Zasshi [The journal of the Japan Medical Society of Spinal Cord Lesion]. 
2005;18:71-274). 
The constituent cells of the product have been confirmed to have the capacity for migration, neurotrophic 
factor secretion, immunomodulation, and differentiation. After being administered, the cells accumulate at 
the injury site, where they exhibit nerve-protecting effect mediated by neurotrophic factors, etc. and improve 
neurological symptoms associated with spinal cord injury by multiple mechanisms including 
immunomodulation, differentiation into nerve cells, etc. As with pharmaceutical products, Stemirac is 
expected to exhibit therapeutic effects by its pharmacological mechanism. The product is administered by 
intravenous drip infusion. 
Stemirac was designated as a breakthrough product under the SAKIGAKE Designation System for 
regenerative medicinal products on February 10, 2016, for the planned indication or performance of 
“improvement of neurological symptoms and functional disorders associated with spinal cord injury,” 
according to “Experimental implementation of the SAKIGAKE Designation System for medical devices, in 
vitro diagnostics, and regenerative medical products” (PFSB/ELD/OMDE Notification No. 0701-1 dated July 
1, 2015, issued by the Counsellor of the Minister's Secretariat, the Ministry of Health, Labour and Welfare 
(Evaluation and Licensing of Medical Device/Cellular and Tissue-based Products) (SAKIGAKE 
Regenerative Medical Product Designation No. 1 of 2015 [27, sai]). 
8 Stemirac for Injection_Nipro Corporation_review report  
1.2 History of development 
Spinal cord injury is classified into (i) primary injury directly caused by external force such as tissue crush 
injury, bleeding, or axonotmesis and (ii) secondary injury that progresses over several months after injury, 
such as ischemia, inflammation, and delayed neuronal cell death. In the treatment of spinal cord injury, the 
prevention of progression of these secondary injury and the preservation of remaining functions are critical. 
The current standard treatments for spinal cord injury are surgical treatments such as reduction, 
decompression, fixation, etc. of the spine during the acute phase and rehabilitation (Handb Clin Neurol. 
2012;109:105-130). As a drug therapy, sodium methylprednisolone succinate is administered intravenously 
in bulk. However, its clinical benefit has not been fully recognized (Orthopedic knowledge update Spine. 
American Academy of orthopaedic surgeons; 2012.187-95). These treatments lead to little progress in 
neurological function with poor outcomes, and the demand for a new treatment option is growing. 
In the past, injured central or cerebral nerves were thought to be unrestorable. However, since late 1970s, the 
transplantation of neural cells such as oligodendrocytes and Schwann cells induced the re-myelination in 
injured central nerves of demyelinated animals (e.g., Ann N Y Acad Sci. 1987;495:71-85, Nature. 1977;266: 
68-9). The transplantation of neuronal stem cells into animals with spinal cord injury induced re-myelination 
and differentiation into nerve cells, leading to the recovery of neurological functions (Exp Neurol. 
2001;167:27-39). These outcomes demonstrated the possibility that injured nerve tissues are regenerated by 
cell transplantation. Honmou et al. of Sapporo Medical University, the developers of Stemirac, reported that 
the transplantation of rat bone marrow-derived MSCs into the injury site of demyelinated rats induced the 
re-myelination of demyelinated nerve axons (Glia. 2001;35:26-34). The intravenous administration of MSCs 
to rats with spinal cord injury caused MSC accumulation to the injury site, suppression of spinal cord tissue 
necrosis, neurotrophic factor secretion, and differentiation to neural cells, resulting in significant recovery 
of motor function (Brain Res. 2010;1343:226-35). In 2006, Honmou et al. began a clinical research to 
investigate the effect of intravenous administration of autologous bone marrow-derived MSCs to patients 
with cerebral infarction during the subacute phase (Brain. 2011;134:1790-1807). Then, an 
investigator-initiated clinical study in patients with cerebral infarction and another investigator-initiated 
phase II study (Study STR01-03) in patients with spinal cord injury began at Sapporo Medical University. 
Study STR01-03 suggested the efficacy of the product with an acceptable safety profile. The applicant 
introduced the technology related to the product from Sapporo Medical University, and filed the current 
application for marketing approval of the regenerative medicine product based on the results of Study STR 
01-03. 
2 Manufacturing Method and Specifications and Outline of the Review Conducted by PMDA 
The primary constituent part is MSCs collected from the bone marrow fluid of the patient, grown in adhesive 
dishes, suspended in cryopreservation fluid, and filled in a cryopreservation bag to be stored frozen. The cell 
culture medium and the cryopreservation fluid used in these processes contain patient’s own serum. 
9 Stemirac for Injection_Nipro Corporation_review report  
The secondary constituent part comprises a blood collection kit and a bone marrow collection kit used for the 
collection of patient’s peripheral blood and bone marrow fluid from the patient, both of which are also used 
for transportation of collected materials to a designated facility for the production of Stemirac. Each of the 
blood collection kit and the bone marrow collection kit contains a sterilized container (medical device Nipro 
Celltry). In addition, the bone marrow collection kit includes DMEM for bone marrow dilution. 
2.1 Manufacturing procedures 
2.1.1 Manufacturing process 
The manufacturing process of Stemirac involves the production of (i) the suspension of autologous 
bone marrow MSCs, the primary constituent part, and (ii) the secondary constituent part of the product. 
2.1.1.1 Manufacturing method of the primary constituent part 
The manufacturing processes of the autologous bone marrow MSC suspension are acceptance of patient’s 
peripheral blood, serum separation, preparation of ******** ********, acceptance of patient’s bone marrow 
fluid, ************************************************ 1 )********* ****, filling, capping, 
freezing, testing, packaging/labeling, and storage. ************** 
*********************************************************************** were identified as 
the critical processes. 
2.1.1.2 Manufacturing process of secondary constituent part  
The manufacturing processes of the blood collection kit are acceptance of the components, 
packaging/labeling/storage, and testing. The bone marrow collection kit, the other secondary constituent 
part, manufactured through the production of DMEM for bone marrow dilution (reconstitution, sterile 
filtration, filling, test for foreign matters in the solution, labeling/packaging, inspection/storage), acceptance, 
packaging/labeling/storage, and testing. 
2.1.2 In-process control test 
Table 1 shows the in-process control tests during the production of the autologous bone marrow MSC 
suspension, the primary constituent part. The patient’s peripheral blood is the source material of serum, 
which is to be contained in the cell culture medium for the production of the primary constituent part and in 
the cryopreservation fluid. Peripheral blood is collected from the patient for multiple times, and 
the maximum volume for each collection is 400 mL. A total of approximately 1000 mL of the peripheral 
blood is collected. A total of 20 to 50 mL of the patient’s bone marrow fluid, the source material of the 
product, is collected from the iliac bone of the patient. The collected peripheral blood and bone marrow fluid 
are put in the respective kits for transportation to the designated production site. 
                                                        1) To be conducted if the total cell count in the first passage is below the control limit. 
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Table 1. In-process control tests of autologous bone marrow mesenchymal stem cell suspension 
Process Test items 
Acceptance of peripheral blood   
******************** Virus testb ************** 
Serum separation  ***************************** ***** endotoxin, mycoplasma tests) 
****************** preparation  Filter integrity 
Acceptance of bone marrow fluid  
******************** Mycoplasma test ************** ******** 
**** ********** Filter integrity 
**** ******** 
**************  ******** 
******** ************************ ********
**** ******** 
******** ************************ 
**** ******** 
********* ************************ 
**** ******** 
*********** filling, capping 
Filter integrity ********** Sterility ************************** ******************** 
**** ****** 
**** **** 
a:***************************************************************************** b:******************** 
Table 2 shows the in-process control tests in the manufacturing process of bone marrow diluent DMEM 
enclosed in the bone marrow collection kit, a secondary constituent part. 
Table 2 In-process control tests of bone marrow collection kit (bone marrow diluent DMEM) 
Process Test item 
Sterile filtration Filter integrity 
Filling ****** 
2.2 Safety evaluation of adventitious infectious agents 
2.2.1 Peripheral blood and bone marrow fluid 
The acceptance of patient’s peripheral blood and the bone marrow fluid depends on the record of 
history-taking at the medical institution and serological test or nucleic acid-amplification test for viruses, etc. 
(HBV, HCV, HIV-1, HIV-2, HTLV-1, parvovirus B19, and Treponema pallidum). Mycoplasma testing is 
performed at the production site. All source substances conform to the Standard for Biological-Materials 
(Notification No. 210 issued by the Ministry of Health, Labour and Welfare, dated May 20, 2003). 
2.2.2 Biological materials other than peripheral blood and bone marrow fluid 
Table 3 shows biological materials other than peripheral blood and bone marrow fluid of patients used in the 
production of the primary constituent part. 
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Table 3. Biological materials other than peripheral blood and bone marrow fluid of patients used in the manufacture of the 
primary constituent part 
Source material Animal Site Processes in which the material is used 
Heparin sodium Pig Intestinal mucosa************** 
Trypsin-EDTA solution 
Trypsin Pig Pancreas *********************** filling, 
capping ** ************** Lactose Cow Milk 
Trypsin Activator Pig Pancreas 
Heparin sodium used is a pharmaceutical product approved for marketing in Japan. 
Trypsin powder is the source material of trypsin-EDTA solution and is derived from the spleen of healthy 
pigs. All biological materials conform to the Standard for Biological-Materials (Notification No. 210 issued 
in 2005 by the Ministry of Health, Labour and Welfare). 
2.3 History of the manufacturing process development 
Main changes made in the manufacturing methods during the development of the main construct are as 
follows. 
 Method A to B: *********************** 
 Method B to C: ************** 
 Method C to the proposed manufacturing method: ***************, **************************, 
*************************************************************, ********************* 
******************** 
Equivalency in quality attributes was evaluated before and after each change in the manufacturing method, 
which confirmed the quality equivalency and homogeneity of the primary constituent part throughout 
the manufacturing process development. The primary constituent part produced by Method B was used in the 
clinical study 2 ) in 8 patients (STR0103-03, STR0103-04, STR0103-05, STR0103-06, STR0103-07, 
STR0103-09, STR0103-10, and STR0103-11) and the primary constituent part produced by Method C was 
used in the same clinical study in 5 patients (STR0103-12, STR0103-14, STR0103-15, STR0103-16, and 
STR0103-17) [see Section 7.1]. 
2.4 Characterization 
Table 4 shows the characterization conducted on the primary constituent part [see Sections 4.1-4.4].   
                                                        2) Study STR01-03 
12 Stemirac for Injection_Nipro Corporation_review report  
Table 4 Specification for characterization 
Surface antigen FCM (cell surface antigen phenotype) 
Migration FCM (expression of migration-related receptors and adhesion factors), migration assay, quantitative RT-PCR (gene expression of adhesion/ invasion-associated factors) 
Secretion of neurotrophic factors, etc. ELISA (expression of humoral factors), quantitative RT-PCR (gene expression of humoral factor) 
Immunomodulation ELISA and quantitative RT-PCR (expression of immunomodulatory factors), FCM (cell surface antigen phenotype) 
Differentiation Differentiation potencies of osteoblasts, adipocytes, chondrocytes, and neural cells 
2.5 Evaluation of the manufacturing process 
2.5.1 Removal of process-related impurities 
The residual amount of process-related impurities was evaluated based on ************** in **** process. 
Table 5 shows the estimated residual amounts in the final product of *********** 
************************** **************, and ******, components contained in the cell 
culture medium used in the manufacturing process. The residual amount of antibiotics (penicillin- 
streptomycin) in the final product for the clinical study was measured, and the following results were 
obtained: penicillin, ********* units3) (mean **** units) and streptomycin ************ μg (mean **** 
μg). In the proposed manufacturing method, antibiotics are added to the cell culture medium only 
*********** [see Section 2.3], the residual amount of the each component in the commercial product is 
therefore expected to be lower than that in the product for the clinical study. Because of the extremely low 
safety concerns of the residual amount of each impurity, no control parameters are set for process-related 
impurities. 
Table 5. Estimated residual amount of process-related impurities 
Process-related impurities, their types and components Estimated residual amount (mg) in 40 mL study product 
******** 
******** *********** 
********** ************* 
****** ************* 
***************** **** 
**************************** ***** 
********************* ***** 
************************** ************* 
******************************* *********** 
************** ************ 
2.5.2 Verification 
Variation factors in the manufacturing process of the primary constituent part have not been clearly identified 
at present. In order to ensure the intended quality of every product, a verification-based quality control 
strategy was established. The strategy comprises process parameters and the in-process control tests for the 
potential risks due to varying quality attributes of the peripheral blood and the bone marrow fluid, and the 
specifications and tests for the primary constituent part shown in Table 6. The characteristics required for the 
                                                        3) Value calculated as ***μg/unit 
13 Stemirac for Injection_Nipro Corporation_review report  
product include ************************************************************************** 
*****************************************************. 
2.6 Control of the product 
Tables 6 and 7 show the specification for the primary and secondary constituent parts, respectively. 
No reference material is set for either constituent part. 
Table 6. Specification for the primary constituent part 
Test item Testing method 
Appearance, description Visual inspection 
******** ************ 
********** ************ 
Cell surface antigen analysis 
*****-positive 
*****-positive *****-positive *****-negative *****-negative *****-positive *****-positive 
Sterility Rapid test for microorganisms
Endotoxin test Japanese Pharmacopoeia 
Mycoplasma test Japanese Pharmacopoeia 
Table 7. Specification for the secondary constituent part 
Second construct Test item 
Blood collecting kit Appearance 
Bone marrow collecting kit 
 Appearance 
Bone marrow diluent DMEM 
Description 
****** 
Endotoxin Sterility 
********************* 
Volume collected 
Foreign insoluble matter 
Insoluble particulate matter
************** 
2.R Outline of the review conducted by PMDA 
Stemirac is produced from the patient’s autologous peripheral blood and bone marrow fluid. Considering 
extremely limited production experience during the development phase and little knowledge about 
the manufacturing process in the present situation, the reduction of quality variation among products is a 
critical task in quality control. The applicant’s verification plan includes quality risk assessment-based items 
which are necessary for controlling potential critical quality attributes related to clinical efficacy, i.e., cell 
surface antigen phenotype showing the characteristic feature of MSCs, the secretion of neurotrophic factors 
and immunomodulatory factors in response to inflammatory cytokines, and adhesion factors related 
to migratory capacity. This verification-based production control will help manage quality variation among 
products, and thus the proposed quality control strategy is acceptable. Data on the various quality attributes 
14 Stemirac for Injection_Nipro Corporation_review report  
of the product in post-marketing production should be collected, and critical quality attributes should be 
identified based on data on clinical benefit and safety. 
3 Stability and Outline of the Review Conducted by PMDA 
3.1 Stability of the primary constituent part 
Table 8 shows the outline of the stability tests of the primary constituent part. 
Table 8. Outline of the stability tests of the primary constituent part 
 Number of batches Storage condition Testing period Storage form 
Long-term testing 3 -80 ± 5°C 3 months Cell cryopreservation bag with polyethylene tubing Stress test 1 ********* ****** 
In the long-term testing and the stress test, no clear changes were observed in the quality attributes 
throughout the test period. 
Accordingly, the shelf-life of the primary constituent part was determined as 3 months when stored in a 
cryopreservation bag with a polyethylene tube attached at ≤-80°C. 
3.2 Stability of dosing suspension 
The primary constituent part of Stemirac is thawed before dosing. The stability of the thawed dosing 
suspension was evaluated using ********** as the index. Table 9 shows the outline of the test. 
Table 9. Outline of the stability test of the dosing suspension Number of batches Storage condition Thawing conditionEvaluation time points Storage form 
3 30 ± 2°C Rapid thawing in water bath at 37°C
0, 0.25, 0.5, 0.75, 1.0, and 2.0 hours Cell cryopreservation bag with a polyethylene tube
********** at 30 ± 2°C was ≥****% at 2 hours after thawing. 
Accordingly, it was determined that the administration of the primary constituent part should be started 
immediately after thawing at 37°C and completed within 1 hour after thawing. 
3.3 Stability of the secondary constituent part 
Table 10 shows the outline of the stability tests of the bone marrow diluent DMEM contained in the 
bone marrow collection kit, a secondary constituent. 
Table 10. Outline of the stability tests of secondary constituent part 
 Number of batches Storage conditionTest periodStorage condition 
Long-term testing 3 5 ± 3°C 12 months Syringe (polypropylene syringe barrel + butyl rubber gasket) Accelerated testing 3 25°C/60% RH 6 months 
15 Stemirac for Injection_Nipro Corporation_review report  
The long-term testing and the accelerated testing showed no clear changes in the quality attributes throughout 
the test period. 
Accordingly, the shelf-life of a bone marrow collection kit was determined as 1 year when stored at 5 ± 3°C. 
The shelf-life of a blood collection kit was determined as 3 years when stored in a cool and dry place out of 
direct sunlight, in accordance with the shelf life of the sterilized container (medical device Nipro Celltry). 
3.R Outline of the review conducted by PMDA 
Based on the data submitted, PMDA accepted the storage method and the shelf-lives of the primary and 
secondary constituent parts, and the results of the stability evaluation of the dosing suspension. 
4 Indication or Performance and Outline of the Review Conducted by PMDA 
Studies on the indication or performance were conducted using the test samples (referred to as “MSCs 
derived from patients” in this section) obtained, according to the manufacturing method, by cultivating 
surplus cells from those produced for the clinical study, unless specified otherwise. 
4.1 Migratory capacity of cells (attached data 4-1) 
4.1.1 Expression of chemokine receptors and growth factor receptors 
The expression of chemokine receptors (** types) and growth factor receptors (** types) was investigated by 
flow cytometry (FCM). There were no chemokine receptors commonly expressed in MSCs derived from 3 
patients. In contrast, growth factor receptors, i.e., EGFR, HGFR, NGFR, and Tie2 were expressed in MSCs 
derived from all 3 patients. 
4.1.2 Migratory capacity toward chemokines and growth factors 
Migratory capacity toward chemokines and growth factors was investigated by transwell migration assy. 
Using the culture medium with or without adding each chemokine (** types) or growth factor (** types), the 
relative migratory ratio was calculated from the number of cells that migrated through the membrane. The 
MSCs derived from 3 patients showed that the relative migratory ratio tended to increase in the presence of 
each of these chemokines and growth factors. Chemokine MCP-1 (***-*** fold) and growth factor EGF 
(***-*** fold) showed a particularly high migratory ratio. 
4.1.3 Expression of adhesion factors and invasion-associated factors 
Changes in the expressions of adhesion factor (ITGA4 and ITGB1) genes and invasion-associated factor 
(MMP1, MMP2, TIMP1 and TIMP2) genes in MSCs in response to inflammatory cytokines 
(******************************************** **************************************) 
were investigated by real-time reverse transcription polymerase chain reaction (RT-PCR). In the MSCs 
derived from 3 patients, all of these factors were expressed without inflammatory cytokine stimulation. In 
contrast, ******************************** only MMP1 (****-***** fold, ****-***** fold, 
respectively) was expressed in response to inflammatory cytokine stimulation. 
16 Stemirac for Injection_Nipro Corporation_review report  
The expression of adhesion factors (*** types) was investigated by FCM. A total of 7 types of adhesion 
factors (NCAD, CD44, NCAM, ALCAM, ITGAV, ITGA4, and ITGB1) were identified in MSCs derived 
from 3 patients. 
4.2 Expression and secretion of humoral factors such as neurotrophic factors (attached data 4-2) 
Gene expression and secretion of neurotrophic factors and other humoral factors 
(***********************************************************) and their changes induced by 
inflammatory cytokine stimulation (**********************************************************) 
were investigated using MSCs derived from 3 patients. 
The investigation of gene expression by real-time RT-PCR showed the expression of all factors without 
stimulation, and inflammatory cytokine stimulation increased NGF expression (***-*** fold and ***-*** 
fold, respectively) by *************************. 
The investigation by enzyme linked immunosorbent assay (ELISA) showed the secretion of 
proBDNF, matureBDNF, VEGF, PlGF, and HGF without stimulation, and inflammatory cytokine 
stimulation increased the secretion of *****************, VEGF, and HGF. 
4.3 Immunomodulatory activity (attached data 4-3) 
4.3.1 Expression and secretion of immunomodulatory factors 
Gene expression and secretion of immunomodulatory factors (TSG-6, CX3CL1, and TGF-β1) and their 
changes by inflammatory cytokine stimulation (************************************** 
****************** **) were investigated using MSCs derived from 3 patients. 
Immunomodulatory factor expression was investigated by real-time RT-PCR identified all genes expressed 
without stimulation, and inflammatory cytokine stimulation increased the expression of 
**************************** TSG-6 and increased the expression of *************************** 
************* CX3CL1. TGF-β level did not change in the presence of any stimulation. 
Immunomodulatory factor secretion was investigated by ELISA. No TSG-6 secretion was observed in any 
conditions tested, including no stimulation. CX3CL1 secretion was not observed without stimulation, 
but markedly increased by***************. TGF-β1 secretion was observed without stimulation and the 
secretion level did not change by inflammatory cytokine stimulation. 
4.3.2 Suppressive macrophage induction 
TSG-6, CX3CL1, and TGF-β1 secreted from MSCs are believed to induce the differentiation of phagocytes 
such as macrophages and microglia from activated form (M1) to suppressed form (M2), leading to the 
suppression of cell death (Stem Cells. 2012;30:044-53, Neurobiol Dis. 2013;58:249-57, etc.). The activity to 
17 Stemirac for Injection_Nipro Corporation_review report  
induce the differentiation of **************-stimulated ******* cells from M1 (CD86-positive, 
CD163-negative) to M2 (CD86-negative, CD163-positive) was investigated by FCM. Co-culturing of MSCs 
derived from 3 patients and ****** cells resulted in decreased M1-form ******* cell count and increased 
M2-form ****** cell count. 
4.4 Differentiation into nerve cells (attached data 4-4) 
The capacity of MSCs to differentiate into nerve cells was investigated by real-time RT-PCR, 
immunostaining, and Nissl staining 
MSCs derived from 3 patients were cultivated for 24 hours in a neurodifferentiation-inducing medium, and 
the expression of a nerve cell marker MAP2 was investigated by real-time RT-PCR. The expression 
increased in all samples tested. The expression of markers of neural stem cells (SOX2 and nestin) and nerve 
cells (neurofilament) was investigated by immunostaining. SOX2 and nestin were expressed before the 
induction of neurodifferentiation, and neurofilament was expressed at 24 hours after the induction. MSCs 
were investigated for the presence of Nissl bodies, organelles specifically found in nerve cells, by Nissl 
staining. Nissl bodies were identified at 24 hours after the induction of neurodifferentiation. 
MSCs obtained from 1 patient formed spheres. After 7-day cultivation in the neurodifferentiation 
induction medium, neurite-like processes were developing on the spheres. The expression of the markers of 
neuronal stem cells (nestin) and nerve cells (neurofilament) was investigated by immunostaining. 
Nestin-positive cells were identified in the spheres. The neurite-like cells on the spheres were nestin-negative 
and neurofilament-positive. 
4.5 In vivo evaluation of the action mechanism of MScs 
No in vivo studies were conducted on the action mechanism of the product. The applicant discussed 
the mechanism of action based on published literature on MSCs, and provided the following explanation. 
4.5.1 Effect on motor function (reference data 4-A-1) 
A single dose of rat MSCs was intravenously administered to a rat model of spinal cord injury (at 6 hours, 1, 
3, 7, 10, 14, 21, or 28 days after spinal cord injury), and time-course change in the hind-limb motor function 
was evaluated up to 42 days after injury using Basso-Beattie-Bresnahan (BBB) score. Improved motor 
function was observed at all observation time points in the group receiving rat MSCs as compared with the 
vehicle group. The sooner the treatment was given after injury, the greater the motor function improved 
(Brain Res. 2010;1343:226-35). 
4.5.2 Effect on nerve functions (reference data 4-A-10) 
Mouse MSCs were transplanted into the spinal cord of a rat model of demyelination (induced by X ray 
irradiation followed by the administration of ethidium bromide 3 days later). The spinal cord was isolated 
18 Stemirac for Injection_Nipro Corporation_review report  
after 21 days for electrophysiological evaluation. Results showed recovery of nerve conduction velocity (J 
Neurosci. 2002;22:6623-30). 
4.5.3 Accumulation at the injured site (reference data 4-A-1) 
A single dose of LacZ-labeled rat MSCs (LacZ-rMSC) was administered intravenously to a rat model of 
spinal cord injury (6 hours, 1, 3, 7, 10, 14, 21, or 28 days after spinal cord injury). The spinal cord was 
isolated at 1 week after administration. Immunostaining of the frozen sections of the spinal cord 
identified LacZ-rMSCs accumulated at and around the injury site (Brain Res. 2010;1343: 226-35) [see 
Section 5.2]. 
4.5.4 Secretion of neurotrophic factors (reference data 4-A-1) 
A single dose of MSCs was administered intravenously to a rat model of spinal cord injury (6 hours, 1, 3, 7, 
10, 14, 21, or 28 days after spinal cord injury), and BDNF secretion in the spinal cord was evaluated at 3 
days after administration. BDNF concentration was higher in rats receiving MSCs than in the vehicle group, 
at all measuring time points (Brain Res. 2010;1343:226-35). 
4.5.5 Immunomodulatory effect (reference data 4-A-1 and 4-A-2) 
A single dose of MSCs was administered intravenously to a rat model of spinal cord injury (6 hours, 1, 3, 7, 
10, 14, 21, or 28 days after spinal cord injury). Necropsy of rats at 42 days after injury showed suppression of 
the formation of necrotic cavities at the site of the lesion (Brain Res. 2010; 343:226-35). Rat MSCs or the 
vehicle was administered to a rat model of spinal cord injury at 7 days after the injury. A week later, 
immediately after the administration of a single intravenous dose of Evans blue to the rats, leakage of Evans 
blue from the blood-spinal cord barrier around the injury site was evaluated. The leakage was lower in 
the group receiving rat MSCs than in the vehicle group (Exp Neurol. 2015;267:152-64). 
4.5.6 Differentiation into nerve cells (reference data 4-A-1) 
A single dose of rat MSCs was administered to a rat model of spinal cord injury, and frozen sections of the 
spinal cord were prepared a week later. Immunostaining of the sections showed part of MSCs accumulated at 
the injury site were positive for NeuN, a marker of nerve cells, or for GFAP, a marker of glia cells (Brain Res. 
2010;1343:226-35). 
4.R Outline of the review conducted by PMDA 
The applicant’s explanation about the action mechanism of an intravenous dose of the product on the 
recovery of neural function after spinal injury: 
Intravenously injected MSCs are expected to migrate around the injury site in response to growth factors and 
chemokines, thereby secreting invasion factors such as MMP and TIMP to infiltrate into the injury site [see 
Sections 4.1 and 4.5.3]. MSCs are also expected to exhibit a nerve-protective effect by secreting neurotrophic 
factors and immunomodulatory factors at the injury site [see Sections 4.2, 4.3, 4.5.4, and 4.5.5]. Furthermore, 
MSCs have capacity to differentiate into nerve cells, the occurrence of which was observed at the injury site 
19 Stemirac for Injection_Nipro Corporation_review report  
[see Sections 4.4 and 4.5.6]. These biological and pharmacological characteristics of MSCs is expected to 
help recover motor activity and neural function affected by spinal cord injury [see Sections 4.5.1 and 4.5.2]. 
PMDA’s view: 
The data submitted suggest the promising effects of MSCs with their variety of biological and 
pharmacological characteristics that help recover motor and neural functions after spinal cord injury. The 
applicant should continue to source knowledge from research papers, etc. about new biological and 
pharmacological characteristics of MSCs, and new findings should be communicated to healthcare 
professionals appropriately. 
5 Pharmacokinetics of the Product and Outline of the Review Conducted by PMDA 
The pharmacokinetic data of Stemirac submitted were the results of a pharmacokinetic study on GFP-labeled 
rat MSCs in rats and the study on the accumulation of LacZ-labeled rat MSCs at the site of spinal cord injury 
in rats. 
5.1 Pharmacokinetics in normal rats (attached data 5-a) 
MSCs isolated from the bone marrow of GFP-transgenic rats (GFP-rMSCs) were cultivated and administered 
as a single intravenous dose to the femur of female rats. The distribution of GFP-rMSCs was monitored in 
blood immediately after administration, and in the liver, kidney, heart, lung, spleen, pancreas, salivary gland, 
stomach, brain, spinal cord, thyroid, ovary, muscle, bone marrow fluid, blood, and urine at 2 and 24 hours 
and 1, 2, 3, and 4 weeks after administration, using a confocal laser microscope. GFP-rMSC was distributed 
in the spleen and lung at 2 hours after administration. GFP-rMSCs in the lung became undetectable at 1 week 
after administration. In the spleen, GFP-rMSCs was detectable up to 4 weeks after administration only 
sporadically. No GFP-rMSC was detected in other organs, blood, and urine. 
5.2 Accumulation at the site of injury in a rat model of spinal cord injury (reference data 4-A-1) 
A single intravenous dose of LacZ-labeled rat MSCs (LacZ-rMSCs, 1.0 × 106 cells) was administered to the 
femur of a rat model of spinal cord injury. A week later, the cross section of the immunostained spinal cord 
including the injury site was monitored with a confocal microscope. The accumulation of LacZ-rMSCs was 
detected at and around the injury site of the spinal cord (Brain Res. 2010;1343:226-35). 
5.R Outline of the review conducted by PMDA 
The applicant’s explanation about the pharmacokinetics of the product: 
Following an intravenous dose of MSCs to normal rats, MSCs were distributed in the lung and spleen, but 
not in other tissues, bone marrow fluid, or urine. The result suggests that MSCs are degraded mainly in the 
spleen. Intravenous MSCs administered to a rat model of spinal cord injury are mostly eliminated as in 
normal animals. The results however suggested that some MSCs accumulate at the site of spinal cord injury. 
MSCs may have migrated due to the attraction effect of inflammation at the injury site, but a 
precise mechanism of the accumulation remains unclear. 
20 Stemirac for Injection_Nipro Corporation_review report  
Approximately 5.5% of rat MSCs administered to a rat model of spinal cord injury were found to accumulate 
at the injury site (Neuroscience. 2016;335:221-231). This suggests that the product administered to patients 
with spinal cord injury partly accumulates at the injury site and otherwise are distributed as described in 
Section 5.1. 
PMDA accepted the explanation of the applicant about the pharmacokinetics of the product. 
6 Nonclinical Safety and Outline of the Review Conducted by PMDA 
The nonclinical safety data of Stemirac submitted included the results of a general toxicity study in dogs 
(including the evaluation of the effect on the central nervous system, respiratory system, and cardiovascular 
system), a karyotyping study, and a soft agar colony formation assay. 
6.1 General toxicity (including the effect on the central nervous system, respiratory system, and 
cardiovascular system) (attached data 6-a) 
A single-dose toxicity study was conducted in dogs as shown in Table 11. The product caused no 
toxicological change or had no effect on the central nervous system, respiratory system, or cardiovascular 
system. 
Table 11. Single dose toxicity study (including the evaluation of the effect on the central nervous, respiratory, and cardiovascular systems) 
Study system Route of administra-tion Dose (cells/kg) Main findings Attached data 
Male and female dogs (beagle) 
intravenous 0, 3.34 × 106 
Adhesion of the lung and thoracic cavity wall and localized inflammation of the lung were observed in males of 3.34 × 106 cells/kg group. These change were considered spontaneous, based on intensity and frequency. FOB was measured within 6 hours post-dose, and respiratory rate, ECG, heart rate, blood pressure, and body weight were measured up to 6 hours post-dose and on the day before necropsy performed at 2 weeks post-dose. No product-induced abnormalities were observed at any time point. 
6.2 Other safety (tumorigenicity) 
6.2.1 Soft agar colony formation assay (attached data 6-a-4, 6-a-5, 6-a-6) 
Cells were obtained from the product cultured for ** passages, inoculated on soft agar plates, and cultivated 
for 2 weeks. No colonies with anchorage-independent growth were observed. 
6.2.2 Karyotyping (attached data 6-a-1, 6-a-2, 6-a-3) 
P1-cultured cells or cells obtained from the product cultured for ** passages were subjected to counting of 
chromosomes and karyotyping by G-band staining. The cells comprising the product maintain the normal 
karyotype without transformation. 
21 Stemirac for Injection_Nipro Corporation_review report  
6.R Outline of the review conducted by PMDA 
Based on the data submitted, PMDA concluded that there are no particular concerns about the nonclinical 
toxicity of the product. 
7 Clinical Study and Outline of the Review Conducted by PMDA 
The applicant submitted efficacy and safety evaluation data, in the form of results data from 1 Japanese phase 
II study shown in Table 12. 
Table 12. Clinical study on the efficacy and safety 
Data cate -gory Region Study Phase Study patients Number enrolledOutline of dosage and administration Main endpoints
Evalu-ation Japan STR01-03 II 
Patients with cervical cord injury diagnosed as ASIA Impairment Scale of A, B, orC 
17 A single dose of MSCs (0.5 × 108 - 2.0 × 108 cells/body [≤3.34 × 106 cells/kg]) Efficacy Safety 
The outline of the clinical study was as follows. 
7.1 Japanese clinical study 
7.1.1 Japanese phase II study (attached data 7-1: Study STR01-03 [**, ****-**, ****]) 
An open-label, uncontrolled study was conducted in 1 study site involving patients with cervical cord 
injury graded as A, B, or C of American Spinal Injury Association Impairment Scale (AIS)4) at the primary 
enrollment (before the collection of peripheral blood and bone marrow fluid, the source materials of 
Stemirac) and at the secondary enrollment (before the administration of Stemirac) to investigate the efficacy 
and safety of the product. The target sample size was 10 (≥5, ≤20) patients for each AIS grade of A, B, and 
The main inclusion criteria at the primary enrollment were 1) within 14 days after suffering spinal cord injury, 
2) main injury at the cervical cord, 3) partial injury identified by diagnostic imaging, 4) AIS grade of A, B, or 
C, and 5) 20 through 70 years of age. The main inclusion criteria at the secondary enrollment were 1) being 
able to undergo Stemirac treatment within 54 days after spinal cord injury, 2) readiness of Stemirac for 
clinical study that meets shipping standards, and 3) AIS grade of A,B, or C. Patients were required to meet all 
these criteria. 
The methods for collecting peripheral blood and bone marrow fluid from patients, dosage, and method use of 
the product were as follows.                                                         4) A 5-grade evaluation of the level of severity rated on a scale of A to E  A, Complete paralysis (complete loss of motor and sensory functions at segments S4-5);  B, Paresis (complete loss of motor function below the neurological level, sensory function including that at segments S4-5 is preserved); C, Paresis (motor function is preserved below the neurological level, and less than half of key muscles in the paralyzed region have functional strength of MMT (manual muscle test) grade ≥3 (able to move against gravity). D, Paresis (motor function is preserved below the neurological level, and more than half of key muscles in the paralyzed region have functional strength of MMT grade ≥3 (able to move against gravity). E, Normal (both motor and sensory functions are normal) 
22 Stemirac for Injection_Nipro Corporation_review report  
Collection of patient’s peripheral blood and bone marrow fluid 
Bone marrow fluid (≤60 mL) was collected from the iliac bone, etc. Peripheral blood was collected 
in multiple times to prepare autologous serum to be used for cell culture. Autologous serum was prepared for 
the primary culture of Stemirac, then, the inoculation of bone marrow fluid was started. Approximately 
1000 mL of peripheral blood was required.  
Dosage and administration or method of use 
Immediately after thawing, the product (containing 0.5 × 108 - 2.0 × 108 MSCs/body [maximum dose, 3.34 × 
106 cells/kg]) was administered intravenously as a single dose over 30 minutes. 
Peripheral blood was collected from all 17 patients eligible for the primary enrollment, and bone marrow 
fluid was collected from 15 patients.5) A total of 13 patients6) met the inclusion criteria and did not meet the 
exclusion criteria for the secondary enrollment. These 13 patients received treatment with Stemirac and were 
included in the efficacy analysis population. The safety analysis population included the 17 patients eligible 
for the primary enrollment and the 13 eligible for the secondary enrollment. 
Table 13 shows the characteristics of 13 patients included in the efficacy analysis population. All had 
traumatic spinal cord injury and were eligible for the final evaluation on Day 220. There were only 2 patients 
with AIS B. According to the applicant, the target sample size of 5 subjects seemed difficult to achieve for 
patients with AIS B due to a limited number of patients. Based on the treatment results in patients with AIS 
A or C, Stemirac treatment was expected to have efficacy in patients with AIS B as well. The applicant 
therefore terminated the study before the number of patients with AIS B reached the target sample size. 
                                                        5) A total of 2 patients discontinued the study due to suspected hematologic disease (myelodysplastic syndrome) (Patient ID STR0103-01) and a high level of anti-hepatitis B virus antibody (Patient ID STR0103-02). 6) A total of 2 patients discontinued due to chromosomal abnormality of peripheral blood (Patient ID STR0103-08) and pyrexia, precluding the administration of the clinical study product within 54 days (Patient ID STR0103-13). 
23 Stemirac for Injection_Nipro Corporation_review report  
Table 13. Patient characteristics (efficacy analysis population) 
Patient ID 
Age Sex Injury siteType of injury History of surgery 
Days from injury 
Before primary enrollmenta 
Immediate-ly before treatmentbTo surgeryTo treatment
STR0103-03 A A 34 MaleC5 Fracture dislocationNil - 47 
STR0103-04 A A 56 FemaleC5 No bone injury Posterior decompression 1 49 
STR0103-05 C C 47 MaleC5 No bone injury Nil - 47 
STR0103-06 C C 58 MaleC4 No bone injury Nil - 49 
STR0103-07 B B 23 MaleC5 Fracture Posterior fixation 2 54 
STR0103-09 C C 36 MaleC4 No bone injury Posterior decompression 13 53 
STR0103-10 C C 52 MaleC5 No bone injury Posterior decompression 2 46 
STR0103-11 C C 55 MaleC4 No bone injury Nil - 52 
STR0103-12 B B 43 MaleC5 No bone injury Posterior decompression 1 51 
STR0103-14 A A 65 MaleC4 No bone injury Posterior decompression 0 43 
STR0103-15 A A 66 MaleC4 No bone injury Nil - 54 
STR0103-16 A A 55 MaleC3 Fracture Posterior decompression + posterior fixation 16 51 
STR0103-17 A A 21 MaleC4 Fracture dislocationPosterior fixation) 2 43 
a Evaluated within 14 days after spinal cord injury b Evaluated before the secondary enrollment and within 7 days before treatment with the study product  
The primary efficacy endpoint was the percentage of patients who achieved ≥1 grade improvement in AIS at 
220 (± 14) days after spinal cord injury from immediately before (≤7 days before) the day of treatment (40 ± 
14 days after injury). No hypothesis on efficacy was set in advance. 
The secondary efficacy endpoints were (i) the percentage of patients who achieved ≥2 grade improvement in 
AIS at 220 (± 14) days after spinal cord injury from immediately before (≤7 days before) the day of treatment 
(40 ± 14 days after injury); (ii) changes in the score of each item (motor function/sensory function [light 
touch, pin-prick test]) and total score of ISCSCI-92 7 ) (Paraplegia. 1994;32:70-80, Spinal Cord. 
1997;35:266-74) at 220 (± 14) days after spinal cord injury from immediately before (≤7 days before) the day 
of treatment (40 ± 14 days after injury); and (iii) change in the total score of SCIM-III8) (Disabil Rehabil. 
2007;29:1926-33) at 220 days (± 14) after spinal cord injury from immediately before (≤7 days before) the 
day of treatment (40 ± 14 days after injury). 
                                                         7) Consists of motor function score and sensory function (light-touch and pin-prick sensations) score. Motor function score is a total of the MMT of the representative key muscle groups at 10 segments from C5 to T1 and from L2 to S1. The normal score is 100, which is the sum of the scores of the right and left half of the body (50 each). For sensory function, light-touch sensation and pin-prick sensation at the representative key sensory sites in 28 segments from C2 to S4-5 are counted as 0 (compete loss), 1 (partial loss), or 2 (normal), and the sum of the counts is calculated (normal total score = 112). 8) Spinal Cord Independence Measure evaluating disability in (i) self-care (subtotal, 0–20), (ii) respiration and sphincter management (subtotal, 0–40), and (iii) mobility (subtotal, 0–40) in the 100-point scale 
24 Stemirac for Injection_Nipro Corporation_review report  
Table 14 shows efficacy data of each patient. 
Table 14. Efficacy data of each patient 
Patient ID 
AIS immediately before treatmenta 
AIS at 220 days after injury 
Change in AIS 
ISCSCI-92 SCIM-III 
Change at 220 days after injury from immediately before treatment 
Total score at 220 days after injury 
Total change at 220 days after injury from immediately before treatment 
At 220 days after injury 
No change 
1-grade improvement 
2-grade improvement 
Motor function 
Light touch sensation 
Pin-prick sensation 
Total 
Total score 
Self-care (subtotal) 
Respiration and sphincter management (subtotal) 
Movement (subtotal) 
STR0103-03 
C - - ● 18 232667 1204 14 1 10 3 
STR0103-04 C - - ● 13 44471041499 11 0 10 1 
STR0103-14 B - ● - 0 161026 54 2 4 0 4 0 
STR0103-15 B - ● - 3 191133 61 2 4 0 4 0 
STR0103-16 B - ● - 5 201338 66 3 5 0 4 1 
STR0103-17 A ● - - 0 8 6 14 24 0 0 0 0 0 
STR0103-07 B C - ● - 7 1 4 12 18317 21 2 10 9 
STR0103-12 D - - ● 57 48471522772 12 0 10 2 
STR0103-05 
D - ● - 56 211087 25276 86 15 34 37 
STR0103-06 D - ● - 51 6 4 61 22024 34 2 21 11 
STR0103-09 D - ● - 47 0 0 47 21965 77 17 33 27 
STR0103-10 D - ● - 36 383611028667 77 14 36 27 
STR0103-11 D - ● - 39 6 6 51 22482 92 18 36 38 
a Evaluated before the secondary enrollment and within 7 days before treatment with the clinical study product.  Table 15 shows the percentage of patients achieving ≥1 grade improvement in AIS. Of 13 patients in the 
efficacy analysis population, 12 showed ≥1 grade improvement, except 1 patient with AIS A (Patient ID 
STR0103-17). 
Table 15. Percentage of patients achieving ≥1 grade improvement in AIS 220 days after spinal cord injury from immediately 
before treatment 
AIS immediately before treatment 
Number of patients (Number of patients with ≥1 grade improvement/number of patients analyzed) 
Percentage of patients with ≥1 grade improvement [95% CI] (%) 
A 5/6 83.3 [43.7, 97.0] 
B 2/2 100 [34.2, 100.0] 
C 5/5 100 [56.6, 100.0] 
Total 12/13 92.3 [66.7, 98.6] 
Table 16 shows the percentage of patients achieving ≥2 grade improvement in AIS. A total of 3 patients, 
namely STR0103-03 and STR0103-04 (both from AIS Grade A to C) and STR0103-12 (from AIS Grade B 
to D), achieved ≥2 grade improvement. 
25 Stemirac for Injection_Nipro Corporation_review report  
Table 16. Percentage of patients achieving ≥2 grade improvement in AIS 220 days after spinal cord injury from 
immediately before treatment 
AIS immediately before treatment 
Number of patients (Number of patients with ≥2 grade improvement/number of patients analyzed) 
Percentage of patients with ≥2 grade improvement [95% CI] (%) 
A 2/6 33.3 [9.7, 70.0] 
B 1/2 50.0 [9.5, 90.6] 
C 0/5 0.0 [0, 43.5] 
Total 3/13 23.1 [8.2, 50.3] 
Table 17 shows changes in the score of each item (motor function/sensory function [light-touch sensation, 
pin-prick sensation]) and the total score of ISCSCI-92. The mean score of each item (motor function/sensory 
function [light-touch sensation, pin-prick sensation]) and the mean total score increased at 220 (± 14) days 
after spinal cord injury, regardless of AIS A, B, or C. 
Table 17. Change in the score of ISCSCI-92 at 220 days after spinal cord injury from immediately before treatment 
AIS immediately before treatment Item Change (mean ± SD) 95% CI 
A (N = 6) 
Motor function 6.5 ± 7.4 -1.3, 14.3 
Light-touch sensation 21.7 ± 12.1   9.0, 34.3 
Pin-prick sensation 18.8 ± 15.4   2.7, 35.0 
Total score 47.0 ± 33.0  12.3, 81.7 
B (N = 2) 
Motor function 32.0 ± 35.4 -285.7, 349.7 
Light-touch sensation 24.5 ± 33.2 -274.1, 323.1 
Pin-prick sensation 25.5 ± 30.4 -247.7, 298.7 
Total Score 82.0 ± 99.0 -807.4, 971.4 
C (N = 5) 
Motor function 45.8 ± 8.3  35.5, 56.1 
Light-touch sensation 14.2 ± 15.4 -4.9, 33.3 
Pin-prick sensation 11.2 ± 14.3 -6.6, 29.0 
Total 71.2 ± 26.7 38.0, 104.4 
All patients (A + B + C) (N = 13) 
Motor function 25.5 ± 22.6 11.9, 39.2 
Light-touch sensation 19.2 ± 15.8  9.7, 28.8 
Pin-prick sensation 16.9 ± 16.5  7.0, 26.9 
Total 61.7 ± 41.5 36.6, 86.8 
N: Number of patients analyzed  
Table 18 shows the change in total SCIM-III scores. The mean total score increased at 220 (± 14) days after 
spinal cord injury, regardless of AIS A, B, or C. 
Table 18. Change in total SCIM-III score at 220 days after spinal cord injury from immediately before treatment 
AIS immediately before treatment Change (mean ± SD) 95% CI 
A (N = 6) 3.3 ± 3.1  0.1, 6.6 
B (N = 2)  9.5 ± 10.6 -85.8, 104.8 
C (N = 5) 62.8 ± 22.8  34.5, 91.1 
All patients (A + B + C) (N = 13) 27.2 ± 32.4   7.6, 46.7 
The safety endpoint was the collection of all adverse events that occurred after the primary enrollment and 
before the end of the final evaluation (at 220 [± 14] days after spinal cord injury). 
26 Stemirac for Injection_Nipro Corporation_review report  
Adverse events occurred in 100% (17 of 17) of patients before Stemirac treatment and in 100% (13 of 13) of 
patients after treatment. A total of 362 adverse events were observed (200 events before treatment, 162 
events after treatment). Table 19 shows adverse events occurring in ≥20% of patients. No deaths or serious 
adverse events occurred. 
Table 19. Adverse events observed in ≥20% of patients 
Adverse events observed after treatment (N = 17) Adverse events observed after treatment (N = 13) 
Event Number of patients  PercentageEvent Number of patients  Percentage
Urinary tract infection 12 70.6 Erythema 5 38.5 
Dermatitis contact 11 64.7 Dermatitis contact 5 38.5 
Weight decreased 10 58.8 Drug-induced liver injury 5 38.5 
Dry skin 8 47.1 Seborrhoeic dermatitis 4 30.8 
Drug-induced liver injury 7 41.2 Haemorrhage subcutaneous 4 30.8 
Pneumonia 5 29.4 Fall 4 30.8 
Rhinitis allergic 4 23.5 Skin exfoliation 3 23.1 
Depression 4 23.5 Excessive granulation tissue 3 23.1 
Catheter site injury 4 23.5 Erythema 3 23.1 
Hepatic function abnormal 4 23.5 Catheter site injury 3 23.1 
Pleural effusion 4 23.5 
 Muscle spasms 4 23.5 
Erythema 4 23.5 
Pain 4 23.5 
MedDRA/J ver. 20.0 
Anaemia (Grade 2; 2 events in 2 patients) following peripheral blood collection and puncture site pain 
(Grade 1; 1 event in 1 patient) following bone marrow fluid collection were causally related to the collection 
of peripheral blood or bone marrow fluid, or to the administration of the product. 
7.R Outline of the review conducted by PMDA 
7.R.1 Clinical positioning 
The applicant’s explanation about the clinical positioning of the product: 
The product, while accumulating at the site of spinal cord injury, exhibits its neurotrophic and protective 
actions mediated by the secretion of neurotrophic factors and anti-inflammatory action. These actions are 
expected to suppress the progression of the secondary injury of the spinal cord after acute phase treatment 
and promote the recovery of neural function. The product is thus expected to be recognized as a new 
treatment option for patients with neurological symptoms and functional disorders associated with spinal 
cord injury. 
PMDA’s view: 
Given the characteristics of MSCs described in the data on indication or performance [see Section “4. 
Indication or Performance and Outline of the Review Conducted by PMDA”] and the results of the clinical 
study, the product can be a new treatment option for patients with spinal cord injury with persisting 
neurological symptoms and functional disorders aiming to suppress the progression of the secondary injury 
and promote the recovery of neural function. 
27 Stemirac for Injection_Nipro Corporation_review report  
7.R.2 Efficacy 
7.R.2.1 Appropriateness of the design of the clinical study 
PMDA’s view: 
Study STR01-03 was an uncontrolled study. The possibility cannot be excluded that there were factors other 
than the effect of Stemirac (spontaneous recovery, effect of rehabilitation, etc.) affecting the results, and the 
available data are limited. For the evaluation of the efficacy of the product, control data should have been 
obtained for comparison against the clinical course with the standard therapy. 
7.R.2.2 Efficacy endpoints 
The applicant’s explanation about the justification for the efficacy endpoints of Study STR01-03: 
The product is expected to improve the neurological symptoms and functional disorders associated with 
spinal cord injury. AIS and ISCSCI-92 are major indices for comprehensive evaluation of functional 
disorders presenting as neurological symptoms after spinal cord injury. AIS is often used in published articles 
and for the evaluation of a long-term natural course of symptoms. Therefore, AIS was used as the primary 
endpoint. ISCSCI-92 helps evaluate precisely neurological symptoms related to motor function and sensory 
function (light-touch sensation and pin-prick sensation). SCIM-III is a practical index of functional disorders 
that helps evaluate important issues for patients with spinal cord injury such as respiratory control, bedsore 
prevention, outdoor mobility, and riding in a car. Accordingly, ISCSCI-92 and SCIM-III were used as the 
secondary endpoints. 
The time point of efficacy evaluation was 220 days after spinal cord injury. This was decided by referring to 
published literature, according to which the outcome of patients with spinal cord injury on the standard 
therapy almost stabilizes 6 months after injury (J Neurosurg. 1993;79:500-507), which is around Day 180 
post-dose of Stemirac. 
PMDA’s view: 
The efficacy endpoints and the evaluation timing in Study STR01-03 are acceptable for the exploratory 
evaluation of the efficacy of the product for patients with spinal cord injury. 
7.R.2.3 Results of efficacy evaluation 
The applicant’s explanation about the efficacy of the product: 
Prior to a discussion on the efficacy results of Study STR01-03, a research was conducted as per Table 20 on 
the prognosis of neurological function in patients with spinal cord injury who received the standard treatment. 
The research focused on changes in AIS from 1 month after spinal cord injury, because the time from injury 
to treatment was close to that in Study STR01-03. 
Table 20 Outline of the method used for data search 
Database Pubmed 
Search period **, **** 
Keywords spinal cord injury AND ASIA AND prognosis 
Narrowing condition Articles on the AIS-based evaluation of spinal cord injury at 30 days and 1 year after injury  
28 Stemirac for Injection_Nipro Corporation_review report  
As a result, reports from Scivoletto, et al (Arch Phys Med Rehabil. 2004;85:485-9, Front Hum Neurosci. 
2014;8:1-11) were only available and relevant. Table 21 shows the characteristics, etc. of patients with spinal 
cord injury evaluated in this reference article and in Study STR01-03. The degree of improvement in AIS in 
Study STR01-03 was greater than that in patients receiving the standard treatment reported in the article 
(Table 22). This indicates that the severity of symptoms decreased following the treatment with Stemirac. 
Table 21 Comparison of results between the report of Scivoletto et al. and Study STR01-03 
 Report of Scivoletto et al. Study STR01-03 
Evaluation index AIS AIS 
Evaluation timing 
Early phase 30 days after injury 40 ± 14 days after injury 
Late phase 1 year after injury 220 ± 14 days after injury 
Age (mean ± SD) 50.4 ± 19.3 47.0. ± 14.7 
AIS at early phase evaluation AIS A, 84 patients AIS B, 19 patients AIS C, 129 patients AIS D, 52 patients AIS A, 6 patients AIS B, 2 patients AIS C, 5 patients AIS D, no patient 
Injury site Cervical cord injury, 81 patients Thoracic cord injury, 147 patients Lumbar cord injury, 54 patients Cervical cord injury, 13 patients 
Table 22 Change in AIS grade after 1 year from 30 days after injury (report of Scivoletto et al.) 
AIS at 30 days after injury Percentage 1 year after injury 
AIS A AIS B AIS C AIS D AIS E 
A 95.2 0  2.4  2.4 0 
B 0 52.6 21.1 26.3 0 
C  0.8 0 44.2 53.5 1.6 
D  1.9 0 0 96.2 1.9 
The results of Study STR01-03 also showed a tendency toward improvement in ISCSCI-92 (motor function 
and sensory function) and SCIM-III in patients with AIS A, B, or C, demonstrating improved functional 
disorders and neurological symptoms in these patients. 
A patient (STR0103-17) with AIS A was not able to experience improvement in AIS and SCIM-III. The 
patient had cervical cord injury secondary to fracture dislocation at C4. The spinal cord continued to be 
compressed without being reduced over 2 days after injury, resulting in the spread of edema from the brain 
stem throughout the entire spinal cord. In contrast, another patient (STR0103-16) had only fracture, and the 
other (STR0103-03) had fracture and dislocation which was promptly reduced. They showed favorable 
recovery despite AIS A immediately before treatment. 
PMDA’s view on the efficacy of the product: 
Study STR01-03 was an exploratory study conducted at a single study site and yielded limited data due to no 
control group and the limited number of subjects, etc. Given a limited number of patients with AIS B in the 
clinical setting, it would be difficult to have patients sufficient for the target sample size. Even so, the early 
termination of the study was rather inappropriate. The report of Scivoletto et al. presented by the applicant 
shows different patient characteristics in their study from those in Study STR01-03; more than half of 
participated patients had non-traumatic spinal cord injury, and some had injury of spinal cord other than 
29 Stemirac for Injection_Nipro Corporation_review report  
cervical cord. In addition, there are limitations to the efficacy evaluation of the product because of limited 
comparability of the external comparison with the study data from Scivoletto, et al. 
However, 12 of 13 patients experienced ≥1 grade improvement in AIS in Study STR01-03, including 2 grade 
improvement achieved by 2 of 6 patients with AIS A spinal cord injury that is unlikely to cure spontaneously. 
These results suggest the efficacy of Stemirac. Also, ISCSCI-92 and SCIM-III scores increased in 13 and 12 
patients, respectively, out of 13 patients after treatment with the product, although the extent of improvement 
differed among patients, showing improved activities of daily lives in many patients. Thus, the results of 
Study STR01-03 indicate that the product is effective to a certain extent for neurological symptoms and 
functional disorders associated with spinal cord injury. However, the fact should be noted that neither AIS 
nor SCIM-III improved in 1 patient (STR0103-17) with AIS A spinal cord injury due to fracture dislocation, 
and the possibility cannot be ruled out that the severity of injury affects the efficacy of the product. A 
relationship between the efficacy of the product and patient characteristics, such as AIS in the early 
post-injury phase, site or type of injury, a history of surgery, etc. should be further evaluated based on 
post-marketing data collected. 
Thus, Stemirac is expected to have a certain level of efficacy. Still, the investigation should be continued 
because of the limited data currently available. 
The above conclusion by PMDA will be discussed at the Expert Discussion. 
7.R.3 Safety 
The applicant’s explanation about the safety of the product: 
In Study STR01-03, there were no deaths or other serious adverse events. Adverse events causally related to 
the collection of peripheral blood or bone marrow fluid or the administration of the product were anaemia 
(Grade 2, 2 events in 2 patients) due to peripheral blood collection and puncture site pain (Grade 1, 1 event in 
1 patient) due to bone marrow fluid collection. 
Adverse events newly occurring after the use of Stemirac in ≥20% of patients were subcutaneous 
haemorrhage in 30.8% (4 of 13) of patient, seborrhoeic dermatitis in 30.8% (4 of 13) of patient, and fall in 
23.1% (3 of 13) of patients, all of which were characteristic to patients with spinal cord injury. The following 
are the reasons for the occurrence of these events and the judgment on a causal relationship to the product: 
 Haemorrhage subcutaneous (4 events in 4 patients) was considered due to bruise, and its causal relation 
to the product was ruled out for all patients.  
 Seborrhoeic dermatitis (4 events in 4 patients) was attributable to inability to remove lipids adhering to 
the face, etc. due to paralysis, and its causal relationship to the product was ruled out for all patients. 
 Fall (7 events in 3 patients) occurred in their daily activity lives or during rehabilitation and was not 
accompanied by dizziness, etc. A causal relationship of the events to the product was ruled out for all of 
the patients. 
30 Stemirac for Injection_Nipro Corporation_review report  
Adverse events which occurred in <20% of patients before Stemirac treatment and ≥20% of patients after 
treatment were skin exfoliation (23.1%, 3 of 13) and excessive granulation tissue (23.1%, 3 of 13). The 
following are the reasons for the occurrence of these events and their causal relationship to the product. 
 Skin exfoliation (5 events in 3 patients) was accompanied by the use of tapes and diapers, and a causal 
relationship to the collection of peripheral blood or bone marrow fluid or Stemirac treatment was ruled 
 Excessive granulation tissue (3 events in 3 patients) was caused by the insertion of a cannula for a 
purpose other than Stemirac treatment. A causal relationship to the collection of peripheral blood or 
bone marrow fluid or Stemirac treatment. 
These results demonstrated the safety of the product in patients with spinal cord injury. However, because of 
the current limited data, safety data of the product should be further collected in the post-marketing setting. 
As of August 2018, all 13 patients who had been treated with Stemirac in Study STR01-03 were in good 
condition (2.0 to 4.3 years after injury), without any noteworthy diseases. 
PMDA asked the applicant to explain risks associated with peripheral blood collection, bone marrow fluid, or 
intravenous infusion of the product, with a concern for the systemic condition of patients with spinal cord 
injury. 
The applicant explained as follows, noting that these risks would be highlighted in the package insert. 
(a) Risks associated with the collection of peripheral blood and bone marrow fluid 
In addition to anemia following peripheral blood collection and puncture site pain observed following 
bone marrow fluid collection in Study STR01-03, the collection of peripheral blood or bone marrow 
fluid may involve the following risks. 
In patients with spinal cord injury, the impaired autonomic nervous system causes the instability of 
hemodynamics and may pose a risk of hypotension. There is no use experience of Stemirac in the following 
patient groups, and the collection of peripheral blood or bone marrow fluid may aggravate their symptoms: 
patients with serious systemic condition due to endocrine metabolic disease, cardiovascular disease, 
respiratory disease, gastrointestinal disease, severe multiple injuries, multiple organ failure, etc; patients with 
serious intracranial lesions, severe constriction of major vessels, dissecting aortic aneurysm, severe 
arteriosclerotic changes, severe calcification, etc; and patients with severe spinal and spinal cord diseases 
(osteoporosis, spinal cord tumor, spinal vascular malformation, syringomyelia, etc.). In addition, there may 
be a risk of bleeding from the punctuation site in patients with poorly controlled blood pressure. 
(b) Risks associated with the intravenous administration of the product 
31 Stemirac for Injection_Nipro Corporation_review report  
Pulmonary embolism, thrombus formation, etc. have been reported as risks associated with the intravenous 
administration of cells. These are the likely risks in patients with spinal cord injury because they often have 
enhanced blood coagulability. Also, the possibility cannot be completely ruled out that cancer may relapse 
due to the immunomodulatory effect of the product and the effect of factors secreted by the product, and that 
infection may occur or become aggravated due to the immunomodulatory effect of the product. In addition, 
the following risks cannot be totally excluded: hypersensitivity (including anaphylaxis) caused by the use of 
antibiotics, animal-derived materials, etc; infection due to the use of human- or animal-derived materials or 
source materials; and ectopic tissue formation due to MSCs’ potential to differentiate into various types of 
cells. 
PMDA’s view on the safety of the product: 
In Study STR01-03, adverse events causally related to the collection of peripheral blood or bone marrow 
fluid or the administration of Stemirac were anaemia (grade 2, 2 events in 2 patients) due to peripheral blood 
collection and puncture site pain (grade 1, 1 event in 1 patient) due to bone marrow fluid collection. All these 
events were non-serious. There were no other adverse events for which causal relatioship to the collection of 
peripheral blood or bone marrow fluid or the administration of Stemirac could not be ruled out. These results 
suggest that the product is well tolerated in patients with spinal cord injury. However, because the product’s 
safety data are limited, relevant data should be further collected in the post-marketing setting. New findings 
should be communicated to healthcare professionals in an appropriate manner. The applicant’s explanation 
about the risks associated with the collection of peripheral blood or bone marrow fluid, or the intravenous 
administration of Stemirac, with a concern for the systemic condition of patients with spinal cord injury, and 
their risk reduction effort through highlighting these risks in the package insert are appropriate. In order to 
prevent the risk of pulmonary embolism, thrombus formation, etc., in particular, healthcare professionals 
should be informed of the importance of the infusion rate, and the product should be used at medical 
institutions fully capable of emergency care whereat the patient condition is managed and monitored 
appropriately by vital sign check and laboratory test, etc. To prevent the risk of anemia associated with 
peripheral blood collection, the procedure to obtain a source material for the production of Stemirac, 
information on blood collection interval and the required total volume should be provided in the package 
insert, etc. A blood collection plan should be designed in light of the patent’s age, body weight, systemic 
condition, etc. Blood should be collected where the patient condition is managed and monitored 
appropriately by vital sign check and laboratory test, etc. 
The above conclusion by PMDA will be discussed at the Expert Discussion. 
7.R.4 Indication or performance 
The applicant’s justification for the indication or performance: 
Study STR01-03 showed improvement in indicators such as AIS and ISCSCI-92 for neurological symptoms 
and SCIM-III for functional disorders following Stemirac treatment. Therefore, the indication or performance 
32 Stemirac for Injection_Nipro Corporation_review report  
of the product of “improvement of neurological symptoms and functional disorders associated with spinal 
cord injury” is appropriate. 
The applicant’s view, in relation to indication or performance, on the use of Stemirac in (a) pediatric patients, 
(b) patients with AIS D, and (c) patients with spinal cord injury other than cervical cord injury: 
(a) Use of the product in pediatric patients 
Table 23 outlines a literature search conducted to investigate the safety of the product in pediatric patients, 
which was not investigated in Study STR01-03. 
Table 23. Outline of the method used for data search 
Database Pubmed 
Search period **, **** 
Keywords (clinical trial OR clinical test)AND(cell therapy OR cell transplantation) AND (safety OR risk) AND (child OR children) 
Narrowing condition Articles on the use of MSCs in children 
Table 24 shows the age of children, dosage regimen of MSCs, and adverse events reported in each article 
extracted. All articles reported about patients treated with autologous bone marrow-derived MSCs. 
Table 24. Clinical results following MSC treatment in children 
Article 
Method of administration 
Disease Age (Years) 
Body weight(kg) 
Number of treatment 
Number of cells(cells/kg) 
Treatment -related adverse events Remark 
Proc Natl Acad Sci U S A. 2002;99: 8932-37 
i.v. drip infusion 
Osteogenesis imperfecta 3 N/A 2 1 × 106 Not occurred - 
5 × 106 Not occurred - 
Osteogenesis imperfecta 4 N/A 2 1 × 106 Not occurred - 
4.37 × 106 Not occurred - 
Osteogenesis imperfecta 2 N/A 2 1 × 106 Not occurred - 
1 × 106 Not occurred - 
Osteogenesis imperfecta 3 N/A 2 1 × 106 Not occurred - 
2.85 × 106 Not occurred - 
Osteogenesis imperfecta 3 N/A 2 1 × 106 Not occurred - 
5 × 106 Not occurred - 
Osteogenesis imperfecta 3 N/A 2 
1 × 106 Not occurred - 
5 × 106 Not occurred 
Urticaria caused by anti-fetal calf serum antibody 
Bone Marrow 
drip in
Metachromatic leukodystrophy 5 13 1 2 × 106 Occurred Mild pyrexia not requiring treatment 
33 Stemirac for Injection_Nipro Corporation_review report  
Article 
Method of administration 
Disease Age (Years) 
Body weight(kg) 
Number of treatment 
Number of cells(cells/kg) 
Treatment -related adverse events Remark 
Transplant. 2002;30:215-22 
Hurler's syndrome 5 23 1 4 × 106 Not occurred - 
Hurler's syndrome 6 20 1 10 × 106 Not occurred - 
Metachromatic leukodystrophy 7 21 1 10 × 106 Not occurred - 
Hurler's syndrome 5 18 1 10 × 106 Not occurred - 
Transplantation. 2006;81: 1390-7 
i.v. drip infusion 
GVHD 8 N/A 2 2 × 106 Not occurred - 
1 × 106 
GVHD 12 N/A 2 0.7 × 106 Not occurred - 
1.3 × 106 
Blood Cells Mol Dis. 2008;40: 25-32 
i.v. drip infusion 
Haemophago -cytic syndrome 14 72.5 3 Total, 0.4 × 106Not occurred - 
GVHD 9 39 1 2 × 106 Not occurred - 
GVHD 14 37.5 1 0.4 × 106 Not occurred - 
GVHD 4 15 1 3.0 × 106 Not occurred - 
Lancet. 2008;71: 1579-86 
i.v. drip infusion 
GVHD Mean, 22 (0.5-64) N/A 1-5 0.4-9.0 × 106 Not occurred 25 children out of total 55 patients 
Biol Blood Marrow Transplant. 2014;20: 229-35 
i.v. drip infusion 
GVHD Mean, 8.6 (0.2-17.5)Mean, 32.1 
Twice weekly for 4 weeks 
2 × 106 Not occurred 75 patients 
N/A, No information available  The above literature search did not identify any adverse event specific to children, suggesting that the safety 
risk is low when the product is administerd according to the dosage and administration or method of use 
proposed for the product, i.e., “a single dose intravenous administration at the dose of 0.5 × 108 to 2.0 × 108 
cells/body (maximum dose, 3.34 × 106 cells/kg body weight).” 
At the same time, the collection of peripheral blood, while necessary for the production of Stemirac, may 
pose a potential risk of anemia due to children’s smaller circulating blood volume. The volume and the 
intervals of peripheral blood collection should be controlled according to the patient’s condition, body weight, 
laboratory value (hemoglobin level), etc. The package insert and other written materials will hightlight the 
importance of paying attention to the onset or aggravation of anemia at blood colletion for the use of the 
product in patients with low body weight, such as children. The risks associated with peripheral blood 
collection in children is reduced to an acceptable level by these precautions. According to the Guidelines of 
the Japan Society for Hematopoietic Cell Transplantation, up to 12% of the circulating blood 
34 Stemirac for Injection_Nipro Corporation_review report  
(10 mL/kg) may be collected at a time from the peripheral blood of a child for autologous blood donation. 
There are no further restrictions on the volume of blood, body weight, age, etc. for autologous blood donation 
(Guidelines of the Japan Society for Hematopoietic Cell Transplantation. vol. 2, Iyaku Journal 
Co., Ltd.;2015. p.115). 
According to the Guidelines of the Japan Society for Hematopoietic Cell Transplantation, children aged ≥1 
and ≤15 years are eligible for bone marrow donation. In clinical practice, the volume of bone marrow fluid to 
be collected for hematopoietic cell transplantation is 10 to 15 mL/kg (Guidelines of the Japan Society for 
Hematopoietic Cell Transplantation. vol. 2, Iyaku Journal Co., Ltd.;2015. p.114 and 117). Therefore, the 
volume of bone marrow fluid (up to 50 mL) required for the production of Stemirac is within the acceptable 
range from the aspect of the associated risk. However, bone marrow fluid is collected from the children’s 
iliac bone as in adults, and risks of iliac osteomyelitis, septic shock, or sacroiliac joint injury (due to the 
penetration of the needle through the iliac bone) following bone marrow fluid collection remain. These risks 
will be highlighted in the package insert for risk reduction. 
The product is intended for the improvement of neurological symptoms and functional disorders associated 
with spinal cord injury through nerve protection by neutrotrophic factor secretion, cavitation suppression by 
immuomodulation, stabilization of the blood-spinal cord barrier, etc. Given this action mechanism, the 
efficacy of Stemirac is unlikely to be affected by the age of patients. 
After spinal cord injury, patients are forced to live with residual disability for years. The use of the product in 
children thus is of high social significance and is accepable from the risk-and-benefit point of view. 
(b) Use of the product in patients with AIS D 
In Study STR01-03, Stemirac improved neurological symptoms in all patient groups with AIS A, B, and C 
consistently. SCIM-III showed marked improvement particularly in patients with AIS C, demonstrating a 
high clinical significance. The product is therefore expected to have efficacy in patients with AIS D as well, a 
patient population excluded from Study STR01-03. 
(c) Use of the product in patients with spinal cord injury other than cervical cord injury 
Spinal cord injury accompanies disorders of nerve function directly caused by the primary injury such as 
tissue crushing, bleeding, axonotmesis, etc., and the secondary injury including ischemia, inflammation, 
delayed-onset neuronal cell death, etc. (Front Cell Neurosci. 2016;10:98). Regardless of the site affected, 
disorder develops through the same mechanism. The product administered intravenously accumulates at the 
injury site, improves neurological symptoms and functional disorders by protectiing nerves through the 
secretion of neurotrophic factor, etc., suppressing cavitation through its immunomoduratory effect, and 
stabilizing the blood spinal cord barrier. Given this action mechanism, the efficacy of the product is unlikely 
to be injurysite-specific. Similarly, possible adverse events following Stemirac treatment are unlikely to be 
injury site-specific, and the safety risks posed by Stemirac for the treatment of cervical cord injury and those 
35 Stemirac for Injection_Nipro Corporation_review report  
for spinal cord injury affecting non-cervical regions are expected to be the same. Accordingly, defining the 
indication of the product, regardles of the injury site, as spinal cord injury is appropriate. 
PMDA’s view on indication or performance: 
As discussed in Section 7.R.2, the product is expected to have a certain level of efficacy in treating 
neurological symptoms and functional disorders associated with spinal cord injury, based on the results of 
Study STR01-03, despite limited data. 
PMDA’s view on the use of product in the context of indication or performance in (a) in pediatric patients, 
(b) patients with AIS D, (c) patients with spinal cord injury other than cervical cord injury, and (d) patients 
with non-traumatic spinal cord injury: 
(a) Use in pediatric patients 
Pediatric use of Stemirac was not investigated in Study STR01-03. Despite that, the applicant’s literature 
search identified no concerns specific to the use of bone marrow-derived MSCs in children, and the pediatric 
use of the product according to the proposed dosage and administration or usage method is thus acceptable. 
However, patients are required to undergo the collection of peripheral blood and bone marrow fluid, a 
substantial volume of which must be obtained within a given time frame to produce Stemirac. The 
procedures will expose pediatric patients to a high risk, due to their smaller volume of circulating blood than 
adults. In order to minimize such risk, general guidelines for the total volume of peripheral blood and 
bone marrow fluid and a standard collection schedule should be clearly presented in the “Precautions for 
Indication or Administration Method” section of the package insert. The section should also advise that the 
use of the product in children must be determined carefully in light of the patient’s age, body weight, 
systemic condition, etc. Then, blood collection and bone marrow fluid collection must be performed while 
patient condition is monitored and managed appropriately through vital sign check, laboratory tests, etc. 
In the post-marketing setting, safety and efficacy data of the product in children should be collected for 
evaluation. 
(b) Use in patients with AIS D 
AIS D is defined as “paresis (motor function is preserved below the neurological level, and no less than half 
of key muscles in the paralyzed region have functional strength of the manual muscle test (MMT) Grade ≥3.” 
This patient population have a relatively good condition than other patients with spinal cord injury, albeit a 
variety of symptoms. 
However, the clinical benefit of Stemirac in patients with AIS D is unknown because of no use experience in 
Study STR01-03. Therefore, the product should be indicated for patients with AIS A, B, or C. The efficacy 
and safety of the product in patients with AIS D should be investigated in another clinical study. 
(c) Use in spinal cord injury other than cervical cord injury 
36 Stemirac for Injection_Nipro Corporation_review report  
Although there are no use experiences of Stemirac for spinal cord injury affecting non-cervical regions, the 
expected action mechanism of the product is not dependent on the injury site in the spinal cord. Study 
STR01-03 demonstrated a certain level of efficacy of the product on neurological symptoms and functional 
disorders associated with spinal cord injury. The use of product for spinal cord injury affecting non-cervical 
regions is unlikely to pose additional safety concerns. Therefore, the indication of the product does not need 
to be limited to cervical cord injury. In the post-marketing setting, the efficacy and safety data should be 
collected by injury site for evaluation. 
(d) Use of the product for non-traumatic spinal cord injury 
In Study STR01-03, all patients receiving Stemirac treatment had traumatic spinal cord injury. The efficacy 
and safety of the product in patients with non-traumatic spinal cord injury is unclear because the cause of 
non-traumatic spinal cord injury is different from that of traumatic spinal cord injury, and there is no use 
experience of the product for the treatment of non-traumatic spinal cord injury. Therefore, the use of the 
product should be limited for the treatment of traumatic spinal cord injury. This should be clearly stated in 
the “Indication or Performance” section to ensure the proper use of the product. 
Thus, the indication or performance of Stemirac should be defined as “Improvement of neurological 
symptoms and functional disorders associated with spinal cord injury in patients with traumatic spinal cord 
injury assessed as American Spinal Injury Association Impairment Scale (AIS) grade A, B, or C.” 
The above conclusion will be discussed at the Expert Discussion. 
7.R.5 Dosage and administration or method of use 
The proposed dosage and administration or method of use: 
Bone marrow aspiration should be aimed to be performed within 31 days after spinal cord injury, according 
to the systemic condition, etc. of the patient. Once produced, the product should be administered at the 
earliest time possible. 
Procedures prior to the production of Stemirac 
(1) Patient’s bone marrow fluid is collected. The collected bone marrow fluid is put into a container 
(Nipro Celltry for bone marrow), and the bone marrow fluid diluent DMEM, enclosed in the 
bone marrow collection kit, is added to be mixed. After being tightly sealed, the container holding 
bone marrow fluid is transported to a facility designated by the marketing authorization holder. 
(2) Patient’s peripheral blood is collected. The collected peripheral blood is put into a container (Nipro 
Celltry for serum) enclosed in the blood collection kit. After being tightly sealed, the container 
holding peripheral blood is transported to a facility designated by the marketing authorization 
holder. 
Procedures for the administration of Stemirac to the patient 
37 Stemirac for Injection_Nipro Corporation_review report  
The product is administered by intravenous drip infusion at a rate of 0.7 to 1.0 mL/min, as 0.5 × 108 to 2.0 × 
108 autologous bone marrow-derived MSCs (maximum dose, 3.34 × 106 cells per kg body weight) while 
being diluted ≥3 fold with physiological saline. 
The applicant’s justification for the dosage and administration or method of use of the product: 
The dosage regimen of the product in the clinical study (STR01-03) was “a single intravenous dose of 0.5 × 
108 to 2.0 × 108 cells/body (maximum dose, 3.34 × 106 cells/kg),” which was determined based on the results 
of studies on the number of effective cells among bone marrow-derived mesenchymal cells and the number 
of times of administration in model animals (Exp Neurol. 2006;199:56-66, Brain Res. 2008;1236:30-8, Brain 
Res. 2010;1343:226-35, etc.), and on the results of the single dose toxicity study in dogs [see Section 6.1]. 
Study STR01-03, in which the product was administered intravenously as a single dose within the specified 
range of the number of cells, revealed no relationship between the number of administered cells and efficacy 
or no serious adverse events. No adverse events such as vascular pain were observed when the product was 
administered while being diluted ≥3 fold with physiological saline. The proposed dosage regimen are 
therefore considered appropriate. 
In terms of the appropriateness of infusion rate based on the product’s cell density, the potential risks 
attributable to the infusion rate are local irritation due to change in osmotic pressure and embolism and 
thrombus formation. These risks are discussed below. 
(a) Local irritation due to change in osmotic pressure 
The cell density of the final product is ******* to ******* cells/mL, and 1 to 2 bags of the final product, 
each containing 20 mL of cell suspension, are supplied for each patient. The product is administered at a rate 
of up to 1.0 mL/min, while being diluted with physiological saline, which is added at the rate of 2.0 mL/min 
through a tube connected along the drip infusion line. The osmotic pressure of the product is approximately 
***** mOsm, and the osmotic pressure of the dosing solution diluted 3 fold with physiological saline, the 
worst diluting condition, is approximately *** mOsm. Since the limit of the osmotic pressure of a solution 
that can be administered through the peripheral vein is considered to be 800 to 1000 mOsm/kg H2O 
(Guidelines for Parenteral and Enteral Nutrition. 3rd Ed, Shorinsha;2013. p33-4), the above procedures for 
administration is appropriate. In Study STR01-03, the product was administered at a rate of 0.7 to 1 mL/min, 
and no adverse events such as vascular pain were observed. 
(b) Embolism and thrombus formation 
In a single dose toxicity study in dogs, the product was administered under the condition equivalent to 
the maximum cell administration rate in clinical use (cell suspension containing 5.0 × 106 cells /mL per bag 
was administered at the rate of 1.0 mL/min). Results showed no abnormalities such as embolism and 
thrombus formation. In Study STR01-03, no adverse events related to cell density of the dosing suspension 
were observed. A caution statement is to be presented in the “Precautions for Dosage and Administration or 
Method of Use” section to the effect that “out of concern for potential risks of embolism, thrombus formation, 
38 Stemirac for Injection_Nipro Corporation_review report  
and intravascular haemolysis posed by intravenous administration of cells, the infusion rate should not 
exceed 1.0 mL/min.” 
In Study STR01-03, the product was administered at a rate of 0.7 to 1.0 mL/min. It took an average of 
48 minutes to administer the content of 2 bags and an average 25 minutes per bag. The stability of the 
product has been demonstrated up to 2 hours after thawing. The “Precautions for Dosage and Administration 
or Method of Use” section notes that “the product should be thawed at 37°C as specified by the marketing 
authorization holder, and the thawed suspension should not be stored and should be administered 
immediately within 1 hour after thawing.” 
Based on the above, the applicant considers that the infusion rate is appropriate. 
The Study STR01-03 required the study product be administered within 54 days after spinal cord injury. The 
product administered within this time frame showed efficacy without any serious adverse event. In clinical 
practice, however, it often takes a long time before the actual procedure is started to treat spinal cord injury. 
For this reason, strictly restricting the dosing timing to within 54 days after injury, as per the Study 
STR01-03, is rather impractical. Therefore, the “Dosage and Administration or Method of Use” section will 
define the timing of bone marrow fluid collection, instead of the dosing timing, because these timings are 
closely linked. Based on the dosing timing (43-54 days after injury) and experience in production of Stemirac 
(median time for cell cultivation, approximately *** days; time for the quality test of the finished product, ** 
days), bone marrow fluid collection timing was defined as approximately 31 days after injury, and the dosing 
timing of suspension as the earliest time possible after production. 
PMDA’s view on Dosage and Administration or Method of Use: 
Given the results of the nonclinical studies and Study STR01-03, the dosage regimen or method of use of 
suspension should be described as “a single dose intravenous administration at 0.5 × 108 to 2.0 × 108 
cells/body (maximum dose, 3.34 × 106 cells/kg)” as proposed by the applicant. The proposed infusion rate is 
also acceptable. However, to ensure the safety of intravenous infusion and the stability of the thawed 
suspension, the guideline for the infusion rate should be presented in the “Dosage and Administration or 
Method of Use” section. 
As specified in the “Dosage and Administration or Method of Use” section, the maximum dose depends on 
body weight, and therefore Stemirac may not always be consumed completely. Cautionary advice should 
be given against inadvertent overdosing in the “Precautions for Dosage and Administration or Method of Use” 
section. Further, healthcare professionals should be informed of how to prepare dosing suspension for partial 
use appropriately through written materials.  
Stemirac is an autologous cell-based product that requires a certain time to be produced. As the applicant 
points, when the dosing timing in clinical practice is strictly defined as within 54 days in the “Dosage and 
39 Stemirac for Injection_Nipro Corporation_review report  
Administration or Method of Use” section following the Study STR01-03, a possible scenario is that the 
product is not ready to be administered to the patient within the specified time frame. In this point of view, 
and based on their production experience and treatment results during the clinical study, the applicant 
has made a proposal to give a guideline for the timing of bone marrow fluid collection, which is closely 
linked to the timing of the administration of Stemirac suspension, as within 31 days after injury and to advise 
that the dosing suspension should be administered the earliest time possible after production. This proposal is 
acceptable. 
Accordingly, the “Dosage and Administration or Method of Use” section may be described as proposed by 
the applicant, with the additional guideline for infusion rate. 
The above conclusion will be discussed at the Expert Discussion. 
7.R.6 Qualifications for medical institutions and doctors using Stemirac 
Qualifications for medical institutions and doctors handling the product listed by the applicant: 
 Specialists in spinal cord injury (specialists in neurosurgery, orthopedic surgery, neurology [cerebral 
neurology], or emergency medicine or anesthesiology) 
 Medical institutions capable of safe and hygienic bone marrow and peripheral blood collection 
 Doctors who have attended a training seminar organized by the marketing authorization holder 
 Medical institutions capable of malignant tumor testing or have test results available 
 General medical institutions accommodating emergency care, or medical institutions prepared for 
emergency care by allying with a hospital accommodating such service 
PMDA’s review: 
The qualifications for medical institutions and doctors proposed by the applicant are generally acceptable in 
the context of the proper use of the product in clinical practice. The final conclusion on the appropriateness 
of these requirements are to be made based on the actual practice in the treatment of spinal cord injury in 
Japan. Because the collection of autologous peripheral blood and bone marrow fluid is essential to produce 
Stemirac, the total volumes of peripheral blood and bone marrow fluid required and a standard time schedule 
for these procedures should be communicated to healthcare professionals through the package insert, a 
seminar, etc. so as to ensure the proper use of the product. 
The clinical study on Stemirac was conducted only in an exploratory manner involving a small number of 
patients and yielded limited efficacy data. Therefore, efficacy data should be collected in the post-marketing 
setting for further evaluation. The efficacy evaluation should be conducted based on baseline and post-dose 
AIS, etc. by an evaluator well-trained for evaluation based on these scales. A majority of patients are 
expected to be transferred from an acute phase hospital to a rehabilitation hospital during the course of 
treatment. Cooperation should be established between them to collect efficacy and safety data for a specific 
time period. Patient eligibility criteria for the treatment, product properties, administration method, 
40 Stemirac for Injection_Nipro Corporation_review report  
precautions for use, etc. should be communicated to doctors appropriately at a training seminar and via 
written materials. Stemirac must be handled by doctors who have acquired such knowledge. 
The above conclusion will be discussed at the Expert Discussion. 
8 Risk Analysis and Outline of the Review Conducted by PMDA 
8.1 Post-marketing investigations 
The applicant’s explanation about their post-marketing surveillance plan of the product: 
Because of the limited information available on the efficacy and safety of the product obtained from Study 
STR01-03, a comparative use results survey will be conducted to further evaluate the efficacy and safety of 
the product in the post-marketing setting. Data will be analyzed by comparison between patients who use the 
product and those who do not (Table 25). 
Table 25. Outline of the post-marketing comparative use results survey (draft) 
Objective Evaluation of the efficacy and safety of Stemirac
Survey method All-case surveillance 
Population Patients with spinal cord injury in acute to subacute phase
Observation period 12 months after injury 
Efficacy survey items 
Primary endpoint  Percentage of patients with AIS A achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury Secondary endpoints  Percentage of patients with AIS A achieving ≥2 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Percentage of patients with AIS B or C achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Percentage of the sum of patients with AIS A, B, and C achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ±7 days) after injury (based on Cochran-Mantel-Haenszel test stratified by “AIS A” and “sum of AIS B and C”)  Mean change in the sum of ISCSCI-92, SCIM-III, and SF36 scores at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Change in the level of injury site (ISCSCI-92) at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury 
Safety survey items Anemia, puncture site pain during bone marrow fluid collection, and other malfunctions and adverse events; causal relationship to Stemirac and incidence of each malfunction or adverse event 
Population 
Patients enrolled in the survey are defined as ITT population. All patients in ITT population except the following are defined as the full analysis set (FAS). FAS is the main population for the efficacy and safety analyses. Observation on patients excluded from FAS continues. Patients excluded from FAS: (Stemirac group) Patients withdrawn before function evaluation including AIS at week 6 to 8 (49 ± 7 days) after injury, patients undergone function evaluation including AIS at week 6 to 8 (49 ± 7 days) after injury but withdrawn before treatment with Stemirac (Control group) Patients withdrawn before function evaluation including AIS at week 6 to 8 (49 ± 7 days) after injury 
Target sample size 
Target number of analyzable patients 49 patients each in the Stemirac and control groups (17 patients with AIS A, 32 patients with AIS B or C; all suffering cervical cord injury, aged 20 to 70 years). The target sample size is to be re-defined based on the results of the interim analysis.  Justification for the target sample sizes  According to Scivoletto, et al., the standard treatment improved AIS by 1 grade in 4.8% of patients with AIS A at 30 days after injury. In Study STR01-03, Stemirac improved AIS by 1 grade in 83.3% of patients with AIS A. In light of these outcomes, when the percentage of patients achieving ≥1 grade improvement in AIS is obtained by ** test, conservatively assuming the estimated percentage of improvement by the standard treatment to be ***%, the estimated percentage of improvement by Stemirac ***%, 2-sided significance level of **%, and a power of test **%, 17 each of patients with AIS A are required for both the Stemirac and control groups.  
41 Stemirac for Injection_Nipro Corporation_review report  
 Similarly, when the percentage of patients achieving ≥1 grade improvement in AIS in patients with AIS 
B or C is obtained by** test, conservatively assuming the estimated percentage of improvement by the standard treatment to be ***%, the estimated percentage of improvement by Stemirac ***%, 2-sided significance level **%, and a power of test **%, 32 each of patients with AIS B or C are required for both the Stemirac and control groups.  
 In each stratum of “AIS A” and “sum of AIS B and C,” when a power of ***% is obtained as above and each stratum shows a tendency toward favorable efficacy of Stemirac, the power of Cochran-Mantel-Haenszel test, if used, will be sufficient because it exceeds the power of test in each stratum.  Based on the above reasons, the target sample size was set as 49 (17 patients with AIS A and 32 patients with AIS B or C) for both the Stemirac and control groups.Expected necessary number of patients to be enrolled 113 in the Stemirac group, 120 in the control group (even where patients of these necessary numbers are enrolled, if these numbers do not satisfy the target number of analyzable patients, i.e., 49 per group, the survey is to be continued until this is achieved.)   Justification for the expected necessary number of patients to be enrolled The expected necessary number of patients was determined so that the target numbers of analyzable patients is achieved. Assuming the rate of withdrawal to be **% in the Stemirac group and **% in the control group, and considering the possibility of enrollment of patients with AIS D, patients with spinal cord injury other than cervical cord injury, and patients aged <20 years or >70 years, the necessary number of patients was calculated based on the results of the epidemiological survey of spinal cord injury (Paraplegia. 1995;33:183-8). The calculation yielded the required number of patients of 113 for the Stemirac group and 120 for the control group 
Timing of analysis 
Interim analysis: When the number of analyzable patients reaches ** in both Stemirac and control groups 
(AIS Grade A ≥** patients, the sum of AIS Grade B and C ≥** patients) Final analysis: When data from the survey sheets of all enrolled patients are finalized. 
The efficacy survey items were selected aiming to evaluate the improvement of neurological symptoms and 
functional disorders associated with spinal cord injury. In addition to AIS, ISCSCI-92, and SCIM-III used in 
the clinical study, SF36 was selected as a comprehensive scale for health-related QOL to evaluate the 
efficacy of Stemirac in a multifaceted manner. As many functional tests as possible are planned to be 
performed immediately after injury (within 7days), including AIS, followed by functional tests at 6 to 8 
weeks (49 ± 7 days) after injury, by which AIS grading will be confirmed. The functional tests will be 
performed again at a 6-month (180 ± 30 days) interval after injury, which is considered long enough for 
Stemirac treatment to exert its effect, according to the results of Study STR01-03. AIS will be evaluated 
using video imaging. The Central Assessment Committee will finalize the AIS assessment by checking the 
results from each medical institution against video images taken at evaluation, so that the evaluation and 
assessment are objective. 
The safety survey items selected are a causal relationship and the incidences of malfunctions and adverse 
events including anemia and puncture site pain at bone marrow fluid collection, which are the risks of 
Stemirac identified in the clinical study. Hypersensitivity (including anaphylaxis) is caused by antibiotics and 
animal-derived materials used during the production of Stemirac, and it has been identified as an important 
potential risk, although did not occur in Study STR01-03. Accordingly, hypersensitivity-related data will be 
collected as well. Further, the safety of Stemirac in children is an important missing information, and is to be 
collected in the survey. The safety survey is scheduled to be conducted at 6 to 8 weeks (49 ± 7 days), 
6 months (180 ± 30 days), and 12 months (360 ± 30 days) after injury. Only life/death status will be checked 
at 12 months after injury. 
42 Stemirac for Injection_Nipro Corporation_review report  
8.R Outline of the review conducted by PMDA 
PMDA’s view: 
Because of the limited clinical use experience, continuous monitoring of the efficacy and safety of Stemirac 
is essential in the post-marketing setting. The applicant proposes a survey designed with a control group of 
patients who are eligible for Stemirac treatment but do not receive it, and efficacy and safety are evaluated by 
the comparison of functional outcomes between the Stemirac group and the control group. However, it is 
possible that the condition of spinal cord injury improves spontaneously. Comparison with a non-randomized 
control group has a risk of bias in selection. Some of the evaluation indices of the survey are subjective. 
Considering these points, efficacy and safety should ideally be evaluated by randomized, double-blind, 
parallel group comparison. Even so, in practice, randomized comparison-based evaluation will be difficult to 
conduct once Stemirac becomes available for clinical use. After all, the applicant proposal, prospective 
comparison with the control group of patients who are eligible for Stemirac treatment but do not receive it, is 
the only possible alternative way to evaluate Stemirac’s efficacy and safety, on the premise that objectivity of 
evaluation or assessment is assured by increasing comparability between the groups. 
The efficacy objective of the treatment of patients with spinal cord injury, the target patients of Stemirac, is 
to improve various neurological symptoms associated with spinal cord injury and improve the activity of 
daily living. Because the survey is not designed for randomized, double-blind comparison, it requires higher 
objectivity of evaluation or assessment as mentioned earlier. In this respect, the primary endpoint should be 
“the percentage of patients with AIS A achieving ≥2 grade improvement in AIS,” which refers to motor 
function improvement for treatment outcome, instead of “the percentage of patients with AIS A achieving 
≥1 grade improvement in AIS,” which refers to partial improvement in sensory function. Because AIS is 
not meant for the evaluation of the activity of daily living, the results of SCIM-III, the functional disorder 
index, should also be referred to assess the clinical significance of Stemirac. 
Besides the proposed identified safety risks (anemia and puncture site pain at bone marrow fluid collection), 
important potential risk (hypersensitivity including anaphylaxis), and important missing information (safety 
in children), the following potential risks, although which did not occur in Study STR01-03, should be added 
in the safety survey items to collect data in the planned use results comparative survey. 
 Occurrence of hypersensitivity to antibiotics and animal-derived source materials used for the 
production of Stemirac, and the risk of infection caused by human- or animal-derived source materials 
 Risk of ectopic tissue formation due to the pluripotency of MSCs that constitute Stemirac 
 Risks of pulmonary embolism, thrombus formation, etc. caused by cells administered intravenously 
 Effect of Stemirac’s immunomodulatory activity and secretion factors on concurrent or past diseases 
(onset or aggravation of infection, relapse of cancer, etc.) 
In addition, reasons for not being able to produce Stemirac despite success in obtaining peripheral blood 
and/or bone marrow fluid should be gathered, if any of such cases. 
43 Stemirac for Injection_Nipro Corporation_review report  
The applicant’s proposal on the timing of the survey on efficacy and safety items is appropriate, judging from 
the time period required for the stabilization of outcome of spinal cord injury and the feasibility of follow-up 
for patients enrolled in the comparative use results survey. 
The results of the clinical study are currently available from only a single site. Therefore, it is critical to 
further evaluate the efficacy and safety of Stemirac at multiple centers, and the implementation of such study 
needs to be organized immediately.  
The details of the post-marketing use results survey will be finalized, taking account of the comments raised 
in the Expert Discussion. 
9 Results of Compliance Assessment Concerning the New Drug Application Data and Conclusion 
Reached by PMDA 
9.1 PMDA’s conclusion concerning the results of document-based GLP/GCP inspections and data 
integrity assessment 
The new drug application data were subjected to a document-based compliance inspection and a data 
integrity assessment in accordance with the provisions of the Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, 
and Cosmetics. On the basis of the inspection and assessment, PMDA concluded that there were no obstacles 
to conducting its review based on the application documents submitted. 
9.2 PMDA’s conclusion concerning the results of the on-site GCP inspection 
The new drug application data (7-1) were subjected to an on-site GCP9) inspection, in accordance with the 
provisions of the Act on Securing Quality, Efficacy and Safety of Pharmaceuticals, Medical Devices, 
Regenerative and Cellular Therapy Products, Gene Therapy Products, and Cosmetics. PMDA concluded that 
there were no obstacles to conducting its review based on the application documents submitted. 
10 Overall Evaluation during Preparation of the Review Report (1) 
On the basis of the data submitted, PMDA has concluded that the product is expected to have a certain level 
of efficacy in the treatment of neurological symptoms and functional disorders associated with spinal cord 
injury, and that the product has acceptable safety in view of its benefits. Despite limited information on the 
efficacy and safety, it is of significance to introduce the product to the clinical setting as a treatment option 
for patients with spinal cord injury. 
PMDA has concluded that the product may be approved if the product is not considered to have any 
particular problems based on comments from the Expert Discussion, with the conditions that require further 
efficacy confirmation and safety data collection for a certain time period in the post-marketing setting and a 
                                                        9) At the time of the submission of Stemirac for approval as a regenerative medicine, the Ministerial Ordinance on GCP for Regenerative Medical Products had not been enforced, and the Ministerial Ordinance on GCP for Drugs e was applied to the clinical study. 
44 Stemirac for Injection_Nipro Corporation_review report  
time limit in accordance with Article 23-26 of the Act on Securing Quality, Efficacy and Safety of 
Pharmaceuticals, Medical Devices, Regenerative and Cellular Therapy Products, Gene Therapy Products, 
and Cosmetics. The time limit according to the Article will be determined based on the post-marketing 
surveillance plan (time for pre-launch preparation, patient enrollment, observation of each patient, 
application preparation, etc.), and comments raised in the Expert Discussion. 
45 Stemirac for Injection_Nipro Corporation_review report  
Review Report (2) 
November 9, 2018 
Product Submitted for Approval 
Brand Name Stemirac for Injection 
Nonproprietary Name Human (autologous) bone marrow-derived mesenchymal stem cells 
Applicant Nipro Corporation 
Date of Application June 29, 2018 
List of Abbreviations 
See Appendix. 
1. Content of the Review 
Comments made during the Expert Discussion and the subsequent review conducted by the Pharmaceuticals 
and Medical Devices Agency (PMDA) are summarized below. The expert advisors present during the Expert 
Discussion were nominated based on their declarations etc. concerning the product submitted for marketing 
approval, in accordance with the provisions of the Rules for Convening Expert Discussions etc. by 
Pharmaceuticals and Medical Devices Agency (PMDA Administrative Rule No. 8/2008 dated December 25, 
2008). 
1.1 Efficacy 
PMDA concluded that the product is expected to have a certain level of efficacy in patients with spinal cord 
injury with persisting neurological symptoms and functional disorders, based on the results of a Japanese 
phase II study (STR01-03) conducted in patients with cervical cord injury assessed as Grade A, B, or C of 
American Spinal Injury Association Impairment Scale (AIS) to investigate the efficacy and safety of the 
product. 
Because of the limited efficacy information available at present, the efficacy of the product should be further 
evaluated in the post-marketing setting [Section “7.R.2.3 Results of efficacy evaluation” in Review Report 
(1)].  
The above conclusions of PMDA were supported by the expert advisors at the Expert Discussion. 
1.2 Safety 
After reviewing adverse events observed in Study STR01-03, PMDA concluded that the product is tolerated 
in patients with spinal cord injury. Because of the limited safety information available at present, safety data 
should be continuously collected in the post-marketing setting, and new findings should be provided 
appropriately to healthcare professionals. The risks associated with the collection of peripheral blood or 
bone marrow fluid and the risks of pulmonary embolism, thrombus formation, etc. associated with the 
46 Stemirac for Injection_Nipro Corporation_review report  
intravenous administration of the product should be highlighted in the package insert. The product should be 
used at medical institutions fully capable of emergency care whereat the collection of blood or bone marrow 
fluid and the administration of the product are performed while the patient condition is managed 
and monitored appropriately by vital sign check and laboratory test, etc. In order to minimize the risks of 
anemia, hypotension, etc. associated with peripheral blood collection, general guidelines for the total volume 
of peripheral blood required and a standard collection schedule should be presented in the package insert. 
Blood collection should be scheduled appropriately in light of the patient’s age, body weight, systemic 
conditions, etc [Section “7.R.3 Safety” of Review Report (1)]. 
The above conclusions of PMDA were supported by the expert advisors at the Expert Discussion. 
1.3 Indication or performance 
As a result of its review in Section “7.R.4 Indication or performance” in Review Report (1), PMDA 
concluded that the indication, or performance of the product should be set be as follows. 
Indication or Performance 
Improvement of neurological symptoms and functional disorders associated with spinal cord injury in 
patients with traumatic spinal cord injury assessed as American Spinal Injury Association Impairment Scale 
(AIS) Grade A, B, or C 
For the production of Stemirac, substantial volumes of peripheral blood and bone marrow fluid need to be 
collected within a given time frame, and this will pose a greater risk to pediatric patients due to smaller 
volume of circulating blood than in adults. The “Precautions for Dosage and Administration or Method of 
Use” section of the package insert should highlight that whether to use the product for children be decided 
carefully in light of the patient’s age, body weight, systemic condition, etc. 
The above conclusions of PMDA were supported by the expert advisors at the Expert Discussion. 
PMDA instructed the applicant to set indication or performance as above, along with the advice on the use of 
the product in children, i.e., whether to use should be carefully decided in light of the patient’s age, body 
weight, systemic condition, etc. 
The applicant responded appropriately to the above instructions, and PMDA accepted the actions taken. 
1.4 Dosage and administration or method of use 
As a result of its review in Section “7.R.5 Dosage and administration or method of use” in Review Report (1), 
PMDA concluded that a guideline for the infusion rate should be added to the proposed description of the 
“Dosage and Administration or Method of Use” section of the package insert, in the viewpoint of the safety 
of intravenous administration and the stability of thawed product. The maximum dose of the product is 
47 Stemirac for Injection_Nipro Corporation_review report  
determined based on per kg body weight, and using up of dosing suspension in a bag may lead to overdosing 
depending on patients’ body weight. This risk should be highlighted in the “Precautions for Dosage and 
Administration or Method of Use” section of the package insert, and how to prepare the dosing suspension 
for partial use should be communicated to health professionals appropriately, using written materials, etc. 
The above conclusions of PMDA were supported by the expert advisors at the Expert Discussion. 
PMDA instructed the applicant to give the above cautionary advice in the package insert and to communicate 
the details of how to prepare dosing suspension for partial use to healthcare professionals in an 
appropriate manner using written materials. 
The applicant responded appropriately and explained that the “Dosage and Administration or Method of Use” 
section would be revised as follows. 
Dosage and Administration or Method of Use 
Bone marrow aspiration should be aimed to be performed within 31 days after spinal cord injury, according 
to the systemic condition, etc. of the patient. Once produced, the product should be administered at the 
earliest time possible. 
Procedures for the collection of source materials of Stemirac 
(1) Patient’s peripheral blood is collected. The collected peripheral blood is put into a container (Nipro 
Celltry for serum) enclosed in the blood collection kit. After being tightly sealed, the container 
holding peripheral blood is transported to a facility designated by the marketing authorization holder. 
(2) Patient’s bone marrow fluid is collected. The collected bone marrow fluid is put into a container 
(Nipro Celltry for bone marrow), and the bone marrow fluid diluent DMEM, enclosed in the 
bone marrow collection kit, is added to be mixed. After being tightly sealed, the container holding 
bone marrow fluid is transported to a facility designated by the marketing authorization holder 
Procedures for the administration of Stemirac to the patient 
The product is administered by intravenous drip infusion at a rate of 0.7 to 1.0 mL/min, as 0.5 × 108 to 2.0 × 
108 autologous bone marrow-derived MSCs (maximum dose, 3.34 × 106 cells per kg body weight) while 
being diluted ≥3-fold with physiological saline. 
PMDA accepted the revised “dosage and administration or method use.” 
1.5 Qualifications for medical institutions and doctors using use Stemirac 
As a result of its review in Section “7.R.6 Qualifications for medical institutions and doctors using Stemirac” 
in Review Report (1) in relation to the proper use of the product in clinical practice, PMDA generally accepts 
the qualifications proposed by the applicant. Also, PMDA concluded that the total volumes of the peripheral 
blood and the bone marrow fluid necessary for the production of Stemirac and a standard collection schedule, 
48 Stemirac for Injection_Nipro Corporation_review report  
eligibility criteria for the treatment, properties of the product, administration method, precautions for use, etc. 
should be communicated appropriately via the package insert, written materials, and training seminar, and 
that Stemirac must be handled by doctors who have acquired such knowledge. 
Approval condition-based post-marketing evaluation is to be conducted before the expiry of the approval of 
Stemirac, and it requires AIS evaluation, etc. The evaluation must be conducted appropriately by well-trained 
evaluators at baseline and post dose. A majority of patients are expected to be transferred from an acute 
phase hospital to a rehabilitation hospital during the course of treatment. Both parties should establish 
Cooperation should be established between them to collect efficacy and safety data for a specific time period, 
not only at the time of treatment but also during the subsequent follow up period. 
Regarding the qualifications for medical institutions and doctors for the use of Stemirac, the following 
comments were raised by expert advisors at the Expert Discussion. 
 Given the real clinical practice in Japan, the involvement of an orthopedist or a neurosurgeon who has 
sufficient knowledge and experience in the treatment of spinal cord injury in the field of spinal surgery, 
is essential. 
 For the collection of peripheral blood and the bone marrow fluid required for the production of Stemirac, 
coordination with a hematologist with sufficient knowledge and experience in bone marrow collection 
and transplantation, peripheral blood stem cell transplantation, etc. is important. 
Other conclusions of PMDA were supported by the expert advisors. 
Based on the comments raised in the Expert Discussion, PMDA concluded that the qualifications for medical 
institutions and doctors for the use of Stemirac proposed by the applicant need the following addition: (i) 
involvement of an orthopedist or a neurosurgeon with sufficient knowledge and experience in the treatment 
of spinal cord injury (mandatory), and (ii) coordination with a hematologist with sufficient knowledge and 
experience in bone marrow collection and transplantation, peripheral blood stem cell transplantation, etc. 
Based on the above, PMDA instructed the applicant to set qualifications for medical institutions and doctors 
for the use of Stemirac according to its conclusions. In response, the applicant modified the qualifications by 
reflecting PMDA’s instruction. 
 Surgeons familiarized with the diagnosis and treatment of spinal cord injury, namely, specialists in 
neurosurgery or orthopedic surgery 
 Doctors who have attended a training seminar organized by the marketing authorization holder 
 Medical institutions well-prepared for prompt and appropriate actions against adverse events in 
coordination with hematologists with expert knowledge and skills in bone marrow fluid and peripheral 
blood collection (to be guided or assisted when tackling adverse events associated with these 
procedures) 
 Medical institutions capable of safe and hygienic bone marrow and peripheral blood collection 
49 Stemirac for Injection_Nipro Corporation_review report  
 Medical institutions capable of malignant tumor testing or have test results available 
 General medical institutions accommodating emergency care, or medical institutions prepared for 
emergency care by allying with a hospital accommodating such service 
PMDA accepted the above proposal. 
The applicant’s further explanation: 
In the approval condition-based post-marketing evaluation, efficacy will be evaluated by the central 
assessment committee, using video images. The applicant will confirm the feasibility of AIS evaluation, etc. 
including video imaging at each facility using Stemirac. Two or more doctors who have attended a training 
seminar organized by the marketing authorization holder will be responsible for the evaluation at baseline 
and post dose of Stemirac. PMDA accepted the explanation of the applicant. 
1.6 Approval condition-based post-marketing evaluation plan (draft) 
PMDA’s conclusion on the post-marketing investigations as a result of the review in Section “8.1 
Post-marketing investigations” of Review Report (1):  
 Because of the limited information available on the efficacy and safety of the product, an approval 
condition-based post-marketing evaluation should be conducted to evaluate the efficacy and safety of 
the product continuously in the post-marketing setting. 
 Efficacy evaluation should preferably be conducted in a form of a randomized, comparative study 
between a group treated with Stemirac and another group untreated. However, such study will be 
practically infeasible once the product is approved for marketing and made available in the clinical 
setting. Given this situation, there will be no alternative way to evaluate the efficacy and safety of 
Stemirac in an approval condition-based post-marketing evaluation, on the premise that the objectivity 
of evaluation and assessment is maintained by increasing comparability between the groups, but in a 
form of a comparative use results survey with a control group of patients not receiving Stemirac despite 
their eligibility, to collect data prospectively for comparison against patients treated with Stemirac, as 
proposed by the applicant.  
 In the approval condition-based post-marketing evaluation, the primary endpoint should be “the 
percentage of patients with AIS A showing ≥2 grade improvement in AIS,” which evaluates motor 
function improvement. 
 In addition to the proposed identified risks (anemia and puncture site pain at bone marrow fluid 
collection), important potential risk (hypersensitivity including anaphylaxis), and important missing 
information (safety in children), the following potential risks should be subjected to data collection as 
safety survey items. 
 Occurrences of hypersensitivity to antibiotics and animal-derived source materials used for the 
production of Stemirac, and the risk of infection caused by human- or animal-derived 
source materials 
 Risk of ectopic tissue formation due to the pluripotency of MSCs that constitute Stemirac 
50 Stemirac for Injection_Nipro Corporation_review report  
 Risk of pulmonary embolism, thrombus formation, etc. caused by cells administered intravenously 
 Effect of Stemirac’s immunomodulatory activity and secretion factors on concurrent or past 
diseases (occurrence or aggravation of infection, relapse of cancer, etc.) 
 Reasons for not being able to produce Stemirac despite success in obtaining peripheral blood and/or 
bone marrow fluid should be gathered, if any of such cases. 
 The proposed timing of the survey of efficacy and safety evaluation is appropriate, judging from the 
time period required for the stabilization of outcome of spinal cord injury and the feasibility of 
follow-up for patients enrolled in the comparative use results survey. 
The above opinions of PMDA were supported by the expert advisors at the Expert Discussion. The following 
comments were raised from the expert advisors: 
 The assessment of neurological symptoms at the respective medical institutions should be performed by 
≥2 doctors. 
 Collected data must be valid for the analysis of a relationship between the dosing timing and efficacy of 
Stemirac. 
 It is important to ensure the comparability between both groups remains acceptable. If the sample size is 
planned to be adjusted as a result of the interim analysis, a procedure for the adjustment should be 
strictly determined in advance. 
 Data on allodynia in the course of motor function recovery should be collected. 
Based on the comments raised in the Expert Discussion, PMDA instructed the applicant to review the 
approval condition-based post-marketing evaluation plan. 
The applicant submitted the outline of the approval condition-based post-marketing evaluation plan shown in 
Table 26, and provided the following explanation. 
Table 26. Outline of the approval condition-based post-marketing evaluation (draft) 
Objective Evaluation of the efficacy and safety of Stemirac
Survey method All-case surveillance 
Population Patients with traumatic spinal cord injury with AIS Grade A, B, or C at enrollment in acute to subacute phase 
Observation period 12 months after injury 
Survey period Until the re-submission of an approval application after conditional and term-limited approval 
Efficacy survey items 
Cohort 1, Patients with AIS Grade A at 6 to 8 weeks (49 ± 7 days) after injury Primary endpoint  Percentage of patients achieving ≥2 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days ) after injury Main secondary endpoints  Percentage of patients achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Mean change in the total scores of ISCSCI-92, SCIM-III, and SF36, and change in the level of injury (ISCSCI-92) at 180±30 days from 6 to 8 weeks (49±7 days) after injury  Cohort 2, Patients with AIS Grade B or C at 6 to 8 weeks (49 ± 7 days) after injury Primary endpoint Percentage of patients with AIS Grade B or C achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury Main secondary endpoints  Mean change in the sum of ISCSCI-92, SCIM-III, and SF36 scores and change in the level of injury 
51 Stemirac for Injection_Nipro Corporation_review report  
(ISCSCI-92) in patients with AIS Grade B or C at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Percentage of patients with AIS Grade B achieving ≥1 grade improvement in AIS, and percentage of patients with AIS Grade B achieving ≥2 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Percentage of patients with AIS Grade C achieving ≥1 grade improvement in AIS at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Mean change in the sum of ISCSCI-92, SCIM-III, and SF36 scores and change in the level of injury (ISCSCI-92) in patients with AIS Grade B at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury  Mean change in the sum of ISCSCI-92, SCIM-III, and SF36 scores and change in the level of injury (ISCSCI-92) in patients with AIS C at 180 ± 30 days from 6 to 8 weeks (49 ± 7 days) after injury 
Safety survey items Anemia, puncture site pain during bone marrow fluid collection, and other malfunctions and adverse events; causal relationship to Stemirac and incidence of each malfunction or adverse event 
Population 
Patients enrolled in the surveillance are included in ITT population. FAS is used as the main population for efficacy analyses. Secondary analyses are performed in ITT population. The safety analysis population is the ITT population excluding those without any safety data.  FAS is defined as the population of patients in whom all of the following criteria are met. Stemirac group:  Patients who are enrolled in the surveillance, have peripheral blood and bone marrow fluid collected, and are treated with Stemirac  Patients who have the result of AIS evaluation at 6 to 8 weeks (49 ± 7 day) after injury Control group  Patients enrolled in the surveillance  Patients who have the result of AIS evaluation at 6 to 8 weeks (49 ± 7 day) after injury  The primary endpoint is analyzed in 2 separate cohorts; cohort 1 consisting of patients with cervical cord injury aged 20 to 70 years with AIS Grade A in FAS and cohort 2 consisting of patients with cervical cord injury aged 20 to 70 years with AIS Grade B or C in FAS. 
Target sample size 
Target number of analyzable patients (FAS)Cohort 1 Patients with cervical cord injury aged 20 to 70 years with AIS Grade A at week 6 to 8 after injury: 27 in the Stemirac group, 54 in the control group. If the number of patients enrolled in the control group reaches the target sample size before that in the Stemirac group does, further enrollment of up to 81 patients was accepted in the control group, aiming at the ratio of the Stemirac group to the control group of 1 to 3.  Justification for the target sample size According to Scivoletto, et al., the standard treatment improved AIS by 2 grades in 4.8% of patients with AIS Grade A at 30 days after injury. In Study STR01-03, Stemirac improved AIS by ≥2 grades in 33.3% of patients with AIS Grade A. In light of these outcomes, when the percentage of patients achieving ≥2 grade improvement in AIS is obtained by ** test, conservatively assuming the estimated percentage of improvement to be ***% in the control group and ***% in the Stemirac group, 2-sided significance level **%, the power of test **%, and the assignment ratio *******************, 27 and 54 patients with AIS Grade A, respectively, are required for the Stemirac group and the control group.  Cohort 2 Patients with cervical cord injury aged 20 to 70 years with AIS Grade B or C at week 6 to 8 after cervical cord injury: 63 in the Stemirac group, 125 in control group. If the number of patients enrolled in the control group reaches the target sample size before that in the Stemirac group does, further enrollment of up to 189 patients was accepted in the control group, aiming at the ratio of the Stemirac group to the control group of to 3.  Justification for the target sample size Similarly to Cohort 1, when the percentage of patients achieving ≥1 grade improvement in AIS in patients with AIS B or C is obtained by ** test conservatively assuming the estimated percentage of improvement by the standard treatment to be ***% and the estimated percentage of improvement by Stemirac ***%, 2-sided significance level **%, and the power of test **%, 63 and 125 patients with AIS Grade B or C are required for the Stemirac group and the control group, respectively.Expected necessary numbers of patients to be enrolled198 in the Stemirac group, 414 in the control group  Justification for the expected necessary number of patients to be enrolled The expected necessary number of patients was determined so that the target number of analyzable patients is achieved. Assuming the rate of withdrawal to be **% in the Stemirac group and **% in the control group, considering the possibility of enrollment of patients ineligible for the analysis of the primary endpoint, the necessary number of patients was calculated based on the results of the epidemiological survey of spinal cord injury (Paraplegia. 1995;33:183-8). The calculation yielded the required number of patients of 108 for the Stemirac group and 227 for the control group in Cohort 1, and 198 for the 
52 Stemirac for Injection_Nipro Corporation_review report  
Stemirac group and 414 for the control group in Cohort 2. Accordingly, the expected necessary number of patients to be enrolled was set at 198 in the Stemirac group and 414 in the control group. 
Timing of analysis 
Interim analysis Cohort 1 When the number of patients enrolled (FAS) reaches ** in the Stemirac group and ** in the control group.Cohort 2 When the number of patients enrolled (FAS) reaches ** in the Stemirac group and ** in the control group. Final analysis: At the completion of surveys on all efficacy-related items until 6 months after injury are completed with the target number of analyzable patients (FAS) of each cohort. Check for life/death status at 12 months after injury is to be continued after the final analysis. 
 According to Scivoletto et al (Arch Phys Med Rehabil. 2004;85:485-9, Front Hum Neurosci. 
2014;8:1-11), patients with AIS A will have different prognosis from that of patients with AIS B or C at 
week 6 to 8 (49 ± 7 days) after injury. Therefore, patients with AIS A will be separated from the cohort 
of patients with AIS B or C, and efficacy will be evaluated in the hypothesis test-based number of 
patients. 
 The primary endpoint in Cohort 1 (AIS A) will be the percentage of patients showing ≥2 grade 
improvement in AIS, and that in Cohort 2 (AIS B or C) the percentage of patients showing ≥1 grade 
improvement in AIS. According to Scivoletto et al (Arch Phys Med Rehabil 2004; 85: 485-9, Front 
Hum Neurosci 2014; 8: 1-11), the percentage of patients showing ≥1 grade improvement in AIS after 
receiving the standard treatment is expected to be similar between those with AIS B and those with AIS 
C. Therefore, the primary endpoint in Cohort 2 (AIS B or C) will be calculated as the percentage of the 
sum of patients with AIS B and C achieving the target improvement. In patients with AIS B or C, 
≥1 grade improvement in AIS indicates improved motor function. Thus, the objectivity of the evaluation 
is ensured by the visual assessment of the patient’s motor function based on video imaging. 
 The interim analysis will be conducted to investigate the comparability between the Stemirac group and 
the control group. There will be no revision of the number of patients. Instead, the following plans will 
be added. 
 In the interim analysis, the independent monitoring committee will evaluate bias in patient 
characteristics between the groups and possible factors affecting the improvement in AIS. 
 The independent monitoring committee will review the record of efficacy endpoints and possible 
confounding factors. When non-uniformity is observed in the distribution of possible confounding 
factors, the independent monitoring committee will investigate the necessity of performing the final 
analysis with such confounding factors taken into account. The independent monitoring committee 
will make recommendation to the department of the sponsor responsible for the management of the 
post-marketing surveillance based on the above investigation. 
 The department responsible for the management of the surveillance will instruct the department 
responsible for the conduct of the surveillance to take necessary measures. The department 
responsible for management of the surveillance will not disclose the results of the interim analysis 
and the details of the recommendation to the department responsible for conduct of the surveillance 
or the medical institutions. 
 The analyses in both Cohorts 1 and 2 will require patients to be enrolled for approximately 5 years. 
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 The following potential risks will be included in the safety specifications, and relevant information will 
be collected in the comparative use results survey to be conducted. 
 Occurrences of hypersensitivity to antibiotics and animal-derived source materials used in 
the manufacture process of the product, and the risk of infection caused by human- or 
animal-derived source materials 
 Risk of ectopic tissue formation due to the pluripotency of MSCs that constitute Stemirac 
 Risk of pulmonary embolism, thrombus formation, etc. caused by cells administered intravenously 
 Effect of Stemirac’s immunomodulatory activity and secretion factors on concurrent or past 
diseases (occurrence or aggravation of infection, relapse of cancer, etc.) 
 Reasons for not being able to produce Stemirac despite success in obtaining peripheral blood and/or 
bone marrow fluid should be gathered, if any of such cases. 
 Neurological symptoms are to be assessed by ≥2 doctors at each medical institution. 
 Collected data must be valid for the analysis of a relationship between the dosing timing and efficacy of 
Stemirac. 
 Information on allodynia during recovery of motor function will be collected. 
PMDA’s view on the outline of the approval condition-based post-marketing evaluation (draft): 
Due to the expected different clinical courses of spinal cord injury, the applicant plans to conduct the efficacy 
evaluation assigning patients with AIS B or C to a separate cohort from that of patients with AIS A and 
determining the number of patients for each cohort by hypothesis testing. These plans of the applicant are 
acceptable. The primary endpoint for Cohort 2 (AIS B or C), the percentage of patients achieving ≥1 grade 
improvement in AIS in combined patients with AIS B or C to evaluate motor function improvement, is also 
acceptable. Yet, the efficacy of Stemirac for each AIS B and C should also be explained based on the 
secondary endpoints, the results of separate analyses in patients with AIS B and C and based on SCIM-III, 
etc., the indices for functional disorders. 
PMDA accepted the draft of approval condition-based post-marketing evaluation and response by the 
applicant. 
2. Overall Evaluation 
As a result of the above review, PMDA concluded that the product may be approved with the modified 
descriptions of Indication or Performance and Dosage and Administration or Method of Use shown below 
and the following conditions of approval, provided that necessary cautionary advice is given in the package 
insert and information concerning the proper use of the product is disseminated appropriately in the 
post-marketing setting. This is conditional and time-limited approval in accordance with Article 23-26 of the 
Act on Securing Quality, Efficacy and Safety of Pharmaceuticals and Medical Devices, Regenerative and 
Cellular Therapy Products, Gene Therapy Products, and Cosmetics. The time limit according to said Article 
is 7 years, and the product need not be classified as a specified regenerative medical product. 
54 Stemirac for Injection_Nipro Corporation_review report  
Indication or Performance 
Improvement of neurological symptoms and functional disorders associated with spinal cord injury in 
patients with traumatic spinal cord injury assessed as American Spinal Injury Association Impairment Scale 
(AIS) grade A, B, or C 
Dosage and Administration or Method of Use 
Bone marrow aspiration should be aimed to be performed within 31 days after spinal cord injury, according 
to the systemic condition, etc. of the patient. Once produced, the product should be administered at the 
earliest time possible. 
Procedures for the collection of source materials of Stemirac 
(1) Patient’s peripheral blood is collected. The collected peripheral blood is put into a container (Nipro 
Celltry for serum) enclosed in the blood collection kit. After being tightly sealed, the container holding 
peripheral blood is transported to a facility designated by the marketing authorization holder. 
(2) Patient’s bone marrow fluid is collected. The collected bone marrow fluid is put into a container 
(Nipro Celltry for bone marrow), and the bone marrow fluid diluent DMEM, enclosed in the 
bone marrow collection kit, is added to be mixed. After being tightly sealed, the container holding 
bone marrow fluid is transported to a facility designated by the marketing authorization holder. 
Procedures for the administration of Stemirac to the patient 
The product is administered by intravenous drip infusion at a rate of 0.7 to 1.0 mL/min, as a dose of 0.5 × 108 
to 2.0 × 108 autologous bone marrow-derived MSCs (maximum dose, 3.34 × 106 cells per kg body weight) 
while being diluted ≥3-fold with physiological saline. 
Conditions of Approval 
1. The product should be used only for patients considered eligible for the treatment and only under the 
supervision of a specialist with sufficient knowledge and experience in diagnosis and treatment of spinal 
cord injury, at medical institutions fully capable of emergency care where patients are 
appropriately monitored and managed vital sign check and laboratory test, etc. 
2. The applicant is required to conduct an approval condition-based post-marketing evaluation in all 
patients treated with the product during the period after the conditional and time-limited approval until 
reapplication for marketing approval.  
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Appendix 
List of Abbreviations **** ********************************* 
**** *********** 
***** ********** 
****** ******************** 
******* ******************************** 
******* ******************************** 
********** ** 
AIS American Spinal Injury Association Impairment Scale 
ALCAM Activated leukocyte cell adhesion molecule 
ASIA American Spinal Injury Association 
BDNF Brain-derived neurotrophic factor 
CI Confidence interval 
CX3CL1 Fractalkine 
DMEM Dulbecco’s Modified Eagle’s Medium 
EDTA Ethylenediaminetetraacetic acid 
EGF Epidermal growth factor 
EGFR Epidermal growth factor receptor 
ELISA Enzyme linked immunosorbent assay 
FAS Full analysis set 
FCM Flow cytometry 
FOB Functional observational battery 
GFP-rMSC MSC cultivated from the bone marrow of GFP gene-transgenic mice 
HBV Hepatitis B virus 
HCV Hepatitis C virus 
HGF Hepatocyte growth factor 
HGFR Hepatocyte growth factor receptor 
HIV Human immunodeficiency virus 
HTLV Human T-cell leukemia virus 
ISCSCI-92 International Standards for Neurological and Functional Classification of Spinal Cord Injury 1992 version 
ITGA4 Integrin 4 
ITGAV Integrin V 
ITGB1 Integrin β1 
ITT Intent-to-treat 
LacZ-rMSC LacZ-labeled rat MSC 
MAP2 Microtubule-associated protein 2 
MCP-1 Monocyte chemoattractant protein-1 
MMP1 Matrix metalloproteinase1 
MMP2 Matrix metalloproteinase2 
MMT Manual muscle test 
MSC Mesenchymal stem cell 
MedDRA Medical Dictionary for Regulatory Activities 
MedDRA/J Medical Dictionary for Regulatory Activities Japanese version 
NCAD Neural cadherin 
NCAM Neural cell adhesion molecule 
NGF Nerve growth factor 
NGFR Nerve growth factor receptor 
PMDA Pharmaceuticals and Medical Devices Agency 
ii Stemirac for Injection_Nipro Corporation_review report  
PlGF Placental growth factor 
RT-PCR Reverse transcription polymerase chain reaction 
SCIM Spinal cord independence measure 
Sapporo Medical University 
Sapporo Medical University, the public university of Hokkaido 
TGF-1 Transforming growth factor-1
TIMP1 Metallopeptidase inhibitor 1 
TIMP2 Metallopeptidase inhibitor 1 
TSG-6 TNF-stimulated gene-6 
Tie2 Receptor-type tyrosine kinase Tie2 
VEGF Vascular endothelial growth factor 