#1Regulatory requirements to prevent viral shedding during gene therapy in Japan Teruyo ARATO, Daisuke MAEDA (PMDA) Teruhide YAMAGUCHI (NIHS)#2Shedding of Virus Shedding of Virus <In Hospital> ??? Viral Product into Patients' Patient Blood, Urine, Feces, Sputum... ??? ויוי ??? EL <Out of Hospital>#3Current regulatory requirements for viral shedding in Japan > We have no written document which shows regulatory requirements for viral shedding studies for gene therapy vectors in Japan. "Law Concerning the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms " (Law No. 97 of 2003 ) Sponsor is required to prevent the transmission of vectors from patients to 3rd parties in clinical use of gene therapy products, according to the Cartagena Protocol on Biosafety (Type 1Use).#4Regulation of Gene Therapy Products and its Approval Research and Development Non-(pre-) clinical Study Pre-IND to MHLW IND to PMDA Clinical Trial New drug application Approval as a New Drug Assessment of Adverse Effect on Biological Diversity (viral vectors) Guidelines for assuring the Quality and Safety of gene therapy products#5Evaluation of Clinical Study of Gene Therapy in Japan Clinical Research Head of the Organization Clinical Trial under the Regulations of Pharmaceutical Law Sponsor I Submission of Protocol Submission of Protocol ¦ Report Report Minister of MHLW Minister of MHLW Judgment of newness Report Consultation Report YES Consultation No Report within one month Health Science Council Guidelines for Gene Therapy Clinical Research Food and Pharmaceutical Affairs Council Guidelines for Assuring the Quality and Safety of Gene Therapy Products Type 1 Use Regulations in Japan ✦#6Flowchart of Approval of Type 1 Use Regulations in JAPAN (Clinical Trial) Sponsor intending to use Gene therapy product (genetically-modified virus) in Clinical trial Draft of Application for Approval "Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" Approval User The Use Complying with the Published Use Regulations The Minister of MHLW The Minister of the Environment Consultation with Experts Food and Pharmaceuticals Affairs Council Public Consultation Approved if No Adverse Effect on Biological Diversity Could Arise Formulation of Information on Correct Use (as needed) Publication of the Approved Use Regulations and Information on Correct Use#7Flowchart of Approval of Type 1 Use Regulations in JAPAN (Clinical Research) Head of the Medical Institute intending to use Gene therapy product (genetically-modified virus) in Clinical Research Draft of "Type 1 Use Regulations" Application for Approval and "Biological Diversity Risk Assessment Report" Approval User The Use Complying with the Published Use Regulations The Minister of MHLW The Minister of the Environment Consultation with Experts Health Science Council Public Consultation Approved if No Adverse Effect on Biological Diversity Could Arise Formulation of Information on Correct Use (as needed) Publication of the Approved Use Regulations and Information on Correct Use#8"Type 1 Use Regulations" and Information Necessary for Assessment "Biological Diversity Risk of Adverse Effect on Biological Diversity Assessment Report" I. Information concerning recipient organism or the taxonomical species to which the recipient organism belongs II. Information concerning preparation of living modified organisms III. Information concerning the Use of living modified organisms IV. Assessment of Adverse Effect on Biological Diversity V. Comprehensive assessment#9"Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" I. Information concerning a recipient organism or the taxonomical species to which the recipient organism belongs 1. Taxonomical position and State of distribution in natural environment 2. History and present state of Use (including history of use for human or animal drugs, or history and present state of industrial use) 3. Physiological and ecological properties (1) Basic properties (2) Environmental conditions allowing colonization or growth (3) Predacity or parasitism (4) Mode of propagation or reproduction (5) Pathogenicity (6) Productivity of harmful substances (7) Other information (including conditions of inactivation)#10"Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" II. Information concerning preparation of living modified organisms 1. Information concerning donor nucleic acid (1) Composition and origins of component elements (2) Functions of component elements 2. Information concerning vector (1) Name and origin (2) Properties 3. Method of preparing living modified organisms (1) Structure of the entire nucleic acid transferred to recipient organism (2) Method of transferring nucleic acid transferred to recipient organism (3) Processes of rearing living modified organisms#11"Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" II. Information concerning preparation of living modified organisms 4. State of existence of nucleic acid transferred to cells and stability of expression of traits caused by the nucleic acid 5. Methods of detection and identification of living modified organisms and their sensitivity and reliability 6. Difference from the recipient organism or the taxonomical species to which the recipient organism belongs#12"Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" 1. Content of the Use 2. Method of the Use III. Information concerning the Use of living modified organisms 3. Method of collecting information by person who wishes to obtain approval after the start of Type 1 Use 4. Emergency Measures which should be taken to prevent Adverse Effects on Biological Diversity in case Adverse Effects on Biological Diversity could arise 5. The result of Use in laboratory or Use in an environment similar to that in which Type 1 Use is intended 6. Information obtained from use abroad#13"Type 1 Use Regulations" and IV. Assessment of Adverse Effect on "Biological Diversity Risk Biological Diversity Assessment Report" 1. Property of reducing other microorganisms (1) Identification of microorganisms likely to be affected (2) Evaluation of concrete details of adverse effect (3) Evaluation of likelihood of adverse effect (4) Judgment of existence of Adverse Effect on Biological Diversity 2. Pathogenicity (1) Identification of wildlife likely to be affected (2) Evaluation of concrete details of adverse effect (3) Evaluation of likelihood of adverse effect (4) Judgment of existence of Adverse Effect on Biological Diversity#14"Type 1 Use Regulations" and IV. Assessment of Adverse Effect on "Biological Diversity Risk Biological Diversity Assessment Report" 3. Productivity of harmful substances (1) Identification of wildlife likely to be affected (2) Evaluation of concrete details of adverse effect (3) Evaluation of likelihood of adverse effect (4) Judgment of existence of Adverse Effect on Biological Diversity 4. Property of transmitting nucleic acid horizontally (1) Identification of wildlife or other microorganisms likely to be affected (2) Evaluation of concrete details of adverse effect (3) Evaluation of likelihood of adverse effect (4) Judgment of existence of Adverse Effect on Biological Diversity 5. Other Properties#15"Type 1 Use Regulations" and "Biological Diversity Risk Assessment Report" V. Comprehensive Assessment of Adverse Effect on Biological Diversity Comprehensive judgment should be performed based on each item listed in section IV. Measures to minimize the potential risk due to viral shedding appropriate methods for disposal of instruments handling of excrement from the patients control for patient isolation rooms#16Research paper (properties of virus) Non-clinical study (eg.Biodistribution) Information obtained administration route, doses,·· from use abroad Risk Assessment Study design Containment Measures "Type 1 Use Regulations" "Biological Diversity Risk Assessment Report"#17Publication of Domestic Law and Regulations The following website provides information on domestic law, related domestic regulations, list of the approved LMO under the law. Japan Biosafety Clearing House: • Domestic Law and Regulations for LMOS http://www.bch.biodic.go.jp/english/law.html ⚫ List of Approved LMOS (GT products ) : http://www.bch.biodic.go.jp/iyaku_kaigi 1.html#18Isolation Period after Administration of GT products for Viral Shedding/Cartagena (1) Vector Gene Targeted disease Medical Institution/ Administration Isolation Cartagena Method Period Approval Sponsor adenosine ADA- Hokkaido Univ. Bone marrow 3 days 2005 deaminase deficiency Hospital cells, ex vivo (ADA) HSV-TK and recurrent Tsukuba Univ. Lymphocytes, 3 days 2005 ALNGFR leukemia Hospital ex vivo Retro (acute /TAKARA BIO 3 days 2007 GVHD) Inc. MDR1 (multi-drug resistance 1) Breast Cancer Institute cancer Hospital of CD34 cells, ex vivo 10 days 2005 JFCR#19Targeted disease Medical Institution/ Isolation Period after Administration of GT products for Viral Shedding/Cartagena (2) Vector Gene Administration Isolation Cartagena Period Approval Method Sponsor HSV-TK Prostate cancer Kobe Univ. Hospital Bone 3 days 2005 metastases or Intra-prostatic Adeno HSV-TK Prostate Okayama Intra-prostatic 24 hours 2005 cancer Univ.Hospital Kitasato Univ. 2007 Hospital Sendai FGF-2 ASO / Berger's Kyushu Univ. Hospital disease Hindlimb. skeletal muscles 1 week 2006 AAV aromatic L- Late-stage Jichi Medical Intracerebral 72 hours 2006 amino acid Parkinson School decarboxylase disease Hospital#20Action after the Isolation Period is Over (1) Vector Gene Targeted Medical Action after the Isolation Period disease Institution/ Sponsor ADA ADA- Hokkaido deficiency Univ. RCV ( - ) in blood Hospital →Discharge HSV-TK recurrent Tsukuba and leukemia Univ. Retro ALNGFR (acute GVHD) Hospital /TAKARA RCV ( + ) in blood >>Continued isolation BIO Inc. MDR1 Breast Cancer cancer Institute Hospital of JFCR RCV ( Discharge - ) →RCV ( + ) after Re-isolation ( until patient tested negative for RCV)#21Action after the Isolation Period is Over (2) Vector Gene Targeted HSV-TK disease Prostate cancer Medical Institution/ Sponsor Action after the Isolation Period Kobe Univ. Hospital Adeno HSV-TK Prostate Okayama cancer Univ.Hospital Kitasato Univ.Hospital Vector ( - => ) in blood and urine Discharge Vector ( + ) in blood and urine Continued isolation Sendai FGF-2 ASO / Berger's disease Kyushu Univ. Hospital Vector ( - ) →Vector ( + ) after Discharge AAV aromatic L-amino Late-stage Jichi Medical Parkinson' School acid decarbox ylase s disease Hospital Re-isolation (until patients tested negative for Vector )#22Containment Measures during gene therapy Blood, body fluid and excrement from a patient during the isolation period → Disposal after sterilization -> • Instruments used in drug administration (e.g., needle, syringe and tube) → Disposal after sterilization -> Instruments in contact with blood, body fluid and excrement from a patient → Disposal after sterilization, or sufficient cleaning Each medical institute's rules for infectious waste disposal should be followed.#23Suitability of monitoring (1) Patients will be isolated until testing negative for v irus, but⚫ ➤ detection method have not been standardized. ➤ it is difficult to choose the detection method. Sensitivity depends on detection methods Infectivity shows real Existence of virus Sensitive method=PCR? Detection sequence#24Suitability of monitoring (2) Patients will be isolated until tested negative for Virus, but. Monitoring should be carried out how frequent? until when? ➤ When virus is detected for long period, such as in case of oncolytic virus therapies, patients must continue to be isolated? These issues of monitoring of viral shedding should be continuously discussed.#25BACK UP#26Law Concerning the Conservation and Sustainable Use of Biological Diversity through Regulations on the Use of Living Modified Organisms" (Law No. 97 of 2003) "Type 1 Use" means The Use of living modified organisms without preventive measures against their dispersal into environment. e.g. Performance of gene therapy in medical Institutes "Type 2 Use" means The Use of living modified organisms while taking preventive measures against their dispersal into environment. e.g. Manufacture of gene therapy vectors in plants