Regulation of Regenerative Medicine in Japan - Pmda

1 Regulation of Regenerative Medicine in Japan Yoshiaki Maruyama Review Director, Office of Cellular and Tissue-based Products PMDA, Japan Outline The Act on the Safety of Regenerative Medicine (Safety Act). The Act on Pharmaceuticals and Medical Devices (PMD Act). Evolving Early Access Schemes Develop Guidelines Regulatory Framework for Regenerative Medicine in Japan Regenerative Medicine All medical technologies using Production and marketing of processed cells which safety and Regenerative and cellular efficacy have not yet been therapeutic products by firms established The Act on the Safety of The Act on Pharmaceuticals and Regenerative Medicine (Safety Act) Medical Devices (PMD Act). Medical Care or Clinical Research Commercial Product Marketing Authorization Purpose Organizations and Authorities in Japan MHLW Safety Act Health Policy Bureau Health and Welfare Branches Certified committees Pharmaceutical and PMD Act Environmental Health Bureau Hospitals Approval Decision, License Execution Manufactu PMDA MAHs ring Sites CPFs Office of Cellular and Tissue based Products Product Review Office of Manufacturing Quality and Compliance Office of Safety I Site Inspections Outline The Act on the Safety of Regenerative Medicine (Safety Act).

2 The Act on Pharmaceuticals and Medical Devices (PMD Act). Evolving Early Access Schemes Develop Guidelines Regulatory Framework for Regenerative Medicine in Japan Regenerative Medicine All medical technologies using Production and marketing of processed cells which safety and Regenerative and cellular efficacy have not yet been therapeutic products by firms established The Act on the Safety of The Act on Pharmaceuticals and Regenerative Medicine (Safety Act) Medical Devices (PMD Act). Medical Care or Clinical Research Commercial Product Marketing Authorization Purpose These measures may help limit the unregulated marketing of unproven stem cell-based interventions as medical practice, which the JSRM previously worried would make Japan a therapeutic haven'' for predatory foreign firms. Rules for Hospitals and Clinics Plans (3,593).

3 High Risk (class I). Medical Clinical Certified special committee care research Hospitals / Clinics MHLW Health Science Council Provision (Within for Regenerative Medicine 90 days). opinion evaluation 0 17. submission Plan Change order submission (Within 90 days). Special committee = 48. Middle Risk (class II). Certified special committee for Regenerative Medicine MHLW. Hospitals / Clinics evaluation 88 45. submission Plan Provision submission Low Risk (class III) Committee = 102. Certified committee Hospitals / Clinics for Regenerative Medicine MHLW. evaluation 3,389 54. submission Plan Provision submission (As of 31 March 2017). Technology excluded by Cabinet Order Out of the scope of application of the Act Yes No Human embryotic stem cells, iPS cells, cells similar to iPS cells Class I. Yes No Risk Classification Cells to which gene was introduced Class I.

4 Yes No Regenerative Medical Xenogeneic cells No Yes Class I. Technology Allogeneic cells No Yes Class I. Stem cells are used Cell culture Class II. Yes Yes No No Homologous use Class II. No Yes Class III. Purpose is reconstruction, repair or formation of human body structure of function Cell culture Class II. Yes Yes No No Homologous use Class II. Homologous use Class II No No Yes Yes Class III Class III. Example of Risk Classification Class Example Transplantation of retinal pigment epithelium sheets Class I. derived from autologous iPS cells in patients with age- (High risk). related macular degeneration Class II Autologous bone marrow cell infusion therapy for liver (Meddle risk) cirrhosis Class III. Activated lymphocyte therapy for malignancies (Low risk). Cell Processing Facility Outside hospital Within hospital Corporate factory.

5 Etc Medical institution Notified Licensed (Local) = 2,427 sites = 52 sites Collection Processing, storage Processing, storage Accreditation (Overseas). = 4 sites (Taiwan). = 1 site (Korea) Transplant (As of 31 March 2017). Outline The Act on the Safety of Regenerative Medicine (Safety Act). The Act on Pharmaceuticals and Medical Devices (PMD Act). Evolving Early Access Schemes Develop Guidelines Regulatory Framework for Regenerative Medicine in Japan Regenerative Medicine All medical technologies using Production and marketing of processed cells which safety and Regenerative and cellular efficacy have not yet been therapeutic products by firms established The Act on the Safety of The Act on Pharmaceuticals and Regenerative Medicine (Safety Act) Medical Devices (PMD Act). Medical Care or Clinical Research Commercial Product Marketing Authorization Purpose Regenerative Medical Products in the PMD Act PMD Act Regenerative Drug Medical Device (Revised PAL) Products Regenerative medical products are defined as processed (more than minimal manipulation) live human/animal cells that are intended to be used 1) for either (1) the reconstruction, repair, or formation of structures or functions of the human body or (2) the treatment or prevention of human diseases, or 2) for gene therapy.

6 Before IND: Pharmaceutical Affairs Consultation on R&D Strategy 160 FY2012 FY2016. MEDICAL DEVICE. 140. 16 3. 4. 4. DRUG 9% 4%. 120 38. 0% 3. 13%. 100 Regenerative 13. 58. Medicine . 1 1. 80 35%. 36%. 48. 66. 60. 40 5 2. 2. 55%. 6 66 48%. 28. 20 46. 20 32. 7 13. 0. 1 2 3 4 5. PMD Act IND: Submission of the Clinical Trial Notification Attached documents Statement regarding the reason why the sponsoring of the proposed clinical trial is scientifically justified. A protocol of the proposed clinical trial Cell therapy Gene therapy An explanation document used for informed Total consent and 46consent form 15. Sample of Case Report Form . Sponsor 27 9. Current investigator's brochure Investigator 19 6. Timing (As of April 2017). The first notifications; 31 days before (others; 2 weeks before). Marketing Authorization Autologous skeletal myoblast HeartSheet Kit A Kit B.

7 Product Main Indication: Component Autologous Culture Epidermis JACE Serious heart failure due to Container for tissues harvested IHD Frozen myoblast cells Indication: Product Serious burns treatment Kits for Conditional &Subcomponent Wound after removal of Serum separation Time-limited giant congenital approval melanocytic nevus Kits for sheet preparation And Media Allogeneic MSC TEMCELL HS Inj. Autologous Cultured Cartilage JACC. Indication: Traumatic cartilage defects Indication: and osteochondritis Allogeneic Steroid refractory acute dissecans GVHD. 126_3991. Ref. Japan Tissue Engineering Co., Ltd. (J-TEC), HP. Reimbursement Prices Product Price Unit TEMCELL HS Inj. 868,680 JPN / bag 13,898,880 JPN 1 treatment course HeartSheet 6,360,000 JPN Kit A (Pre tissue collection). 1,680,000 JPN Kit B (Sheet culture). 14,760,000 JPN.

8 1 treatment course 120,000 USD. Outline The Act on the Safety of Regenerative Medicine (Safety Act). The Act on Pharmaceuticals and Medical Devices (PMD Act). Evolving Early Access Schemes Develop Guidelines Evolving Early Access Schemes Type US EU JP. Orphan Priority review Accelerated review Priority review Orphan designation Orphan designation Orphan designation Conditional Accelerated approval for Conditional MA Conditional & Time-limited serious or life- threatening MA under exceptional approval illnesses circumstances Approval for oncology drug, Orphan drug RMAT. Priority Break through therapy PRIME SAKIGAKE. & Fast track designation Pilot project on adaptive path Forerunner review assignment (Rolling submission) (Rolling submission) (Rolling submission). RMAT: Regenerative Medicine Advanced Therapy Designation Orphan Designation (1) Number of patients The number of patients who may use the drugs, medical device or Regenerative Medicine should be less than 50,000 in Japan ( million people in 2016).

9 (2) Medical needs The drugs, medical devices or Regenerative Medicine should be indicated for the treatment of serious diseases, including difficult-to-treat diseases. In addition, they must be drugs, medical devices or Regenerative Medicine for which there are high medical needs satisfying one of the following criteria. There is no appropriate alternative drug/medical device/ Regenerative Medicine or treatment High efficacy or safety is expected compared with existing products (3) Possibility of development There should be a theoretical rationale for the use of the product for the target disease, and the development plan should be appropriate. References: Criteria for Orphan Designation by the MHLW Minister (Pharmaceutical and Food Safety Bureau Notification No. 0401-11). Orphan Designation Product Name Anticipated intended use or Name of applicant receiving Date of indications on the designation designation designation NPR-01 External fistulas due to Crohn's Nihon Pharmaceutical Co.

10 , Ltd. 12/12/2013. disease (including anal fistulas). JR-031 Acute graft-versus-host disease TEMCELL HS Inj. Japan Chemical Research Co., Ltd. 12/12/2013. Cultured human Rapid epithelialization of lesions Japan Tissue Engineering Co., Ltd. 11/25/2014. autologous epidermal removed nevi in patients with giant cell sheet JACE congenital melanocytic nevi EYE-01M Corneal epithelial stem cell deficiency Japan Tissue Engineering Co., Ltd. 3/25/2015. CTL019 CD19-positive B-cell acute Novartis Pharma 5/25/2016. lymphoblastic leukemia CD19-positive diffuse large B-cell lymphoma CD19-positive follicular lymphoma Evolving Early Access Schemes Type US EU JP. Orphan Priority review Accelerated review Priority review Orphan designation Orphan designation Orphan designation Conditional Accelerated approval for Conditional MA Conditional & Time-limited serious or life- threatening MA under exceptional approval illnesses circumstances Approval for oncology drug, Orphan drug RMAT.