China Reform of the Regulatory Environment

Author Name Lei Zhu Author Title Global Regulatory Consulting Date Sep 2020

Contents Abbreviations ...... 12 Background ...... 13 Reform Impacts: 2016 ...... 15 Self-inspection of clinical data ...... 15 Priority review ...... 16 Additional capacity at CDE ...... 17 Marketing Authorisation Holder rationalisation / new classification /definition of new drugs ...... 18 Generic drug quality and efficacy consistency Evaluation (GQCE) ...... 18 Reform Impacts: 2017 ...... 19 Opening up of first-in-human (FIH) Phase I trials to global development ...... 20 Simplified process for gaining a marketing approval ...... 20 Clinical trial management 11...... 20 Acceleration of drug and medical device registration review process11 ...... 22 Drug and medical device lifecycle management11 ...... 23 Protecting innovator’s rights11 ...... 23 Reform Impacts: 2018 ...... 25 NHC release the Rare Disease List ...... 25 NMPA was elected as a member of the ICH Management Committee ...... 25 Announcement of NMPA on Technical Guideline for Acceptance of Overseas Drug Clinical Trial Data (2018, No.52) ...... 25 NMPA released the Circular on Adjusting the Approval Process for Drug Clinical Trial Evaluation (2018, Circular 50) ...... 26 NPC decided that the three-year period for the MAH pilot project is extended by one year ...... 26 Accelerate approval of urgently needed overseas new drugs ...... 27 Legislate independent Vaccine Administration Law17 ...... 27 CDE website add functions of IND permission ...... 28 Reform Impacts: 2019 ...... 29 Status of qualification notification of clinical site for medical device now available19 ...... 29 MAH ADR direct reporting system online ...... 29 High level decision on State Council executive meeting for oncology and rare disease drugs20 ...... 29 China to establish collaboration network for rare disease diagnosis, treatment21 ...... 30

2018 CDE Performance Review Meeting22 ...... 30 Drug volume purchasing pilot scheme in 4 (municipality cities)+7 (big cities)23 ...... 31 2019 Report on the work of the government24 ...... 31 eCTD implementation progress and plan in China ...... 33 Medical Device Animal Study Technical Review Guideline Part I: Decision Principles25 ...... 33 Medical device online registration system starts in Jun 201926 ...... 34 Approval procedure of medical device clinical trial permit application changed to implied approval27 ... 34 Second batch of clinical urgently needs oversea new drugs 28 ...... 35 NMPA advancing regulatory science initiatives in drug and medical device in China29 ...... 35 State Council releases legislative work plan for 201930 ...... 35 CDE solicit public comments on Key Considerations in Using Real World Evidence to Support Drug Development31 ...... 36 NHC solicited public comments on third batch of encouraging drug list for pediatric32 ...... 36 State Council issued the human genetic resources management regulations33 ...... 36 NMPA published the Medical Device registration 2018 annual review34 ...... 37 Jiao Hong attended the first BBS conference on global health in boao Asia35 ...... 37 CDE published the Drug registration 2018 annual review36 ...... 37 Vaccine Administration Law approved by the Standing Committee of the Chinese People's Congress37 ...... 38 NMPA Improvement Policy Concerning Bundling Review and Approval for Drugs and the Corresponding Supervision Plan38 ...... 38 State Council high level opinion on building a professional and specialized team of pharmaceutical products inspection39 ...... 38 Q&A on R&D of Biosimilars40 ...... 39 Revision of the Drug Administration Law of the People's Republic of China 41 ...... 40 NHSA Publishes Drug Catalogue of the National Basic Medical Insurance, Industry Injury Insurance and Maternity Insurance42 ...... 41 Implementation Plan to Support the Development of Boao International Medical Tourism Pilot Zone 4341 NMPA Releases Technical Guideline for Clinical Trial Endpoints for the Advanced NSCLC 44 ...... 42 NMPA officially joined national competent authority report (NCAR) exchange program of IMDRF45 ..... 42 Regulations of People's Republic of China on Management of Human Genetic Resources on June 10, 201946 ...... 43 CDE Announces Public Consultation on “Working Procedure for Breakthrough Therapy Designated Drugs”, “Working Procedure for Priority Review and Approval”, Technical Guidelines for Conditional

Marketing Approval Granted to Urgently Needed Drugs in Clinical Practice (Draft for Comments), as well as Explanatory Notes on Nov. 8, 201947 ...... 43 CDE Announces Public Consultation on Technical Guidelines for Clinical Changes to Already Marketed Drugs on Nov. 8, 201948 ...... 43 CDE Announces Public Consultation on Technical Guidelines for Researches Regarding Pharmaceutical Changes to Already Marketed Chinese Medicine, ...... 43 Technical Guidelines for Researches Regarding Pharmaceutical Changes to Already Marketed Chemical Drugs and Technical Guidelines for Researches Regarding Pharmaceutical Changes to Already Marketed Biologics (Draft for Comments) on Nov. 8, 201949 ...... 44 NMPA Circular on Adopting 15 ICH Guidelines Including E1: Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening on Nov. 12 201950 ...... 44 NMPA Circular on Adopting 13 ICH Guidelines Including SIA: Guideline on the Need for Carcinogenicity Studies of Pharmaceuticals on Nov.12, 201951 ...... 44 NMPA and NHC Releases “Administrative Measures for Drug Clinical Trial Organizations”on Nov. 29, 201952 ...... 44 NMPA Circular on Guarantee the Record Filing Procedure for Drug Clinical Trial Organizations Nov. 29, 201953 ...... 45 State Administration for Market Regulation (SAMR) SAMR Announces New Public Consultation on “Regulations on Drug Registration (Draft for Comments)” and Explanatory Note on the Issuance of Regulations on Drug Registration (Draft for Comments) on Dec. 10, 201954 ...... 45 NMPA Releases Guidance for Using Real-World Evidence to Support Drug R&D and Regulatory Review (Interim) and Explanatory Note to Guidance for Using Real-World Evidence to Support Drug R&D and Regulatory Review (Interim)55 ...... 45 CDR-ADR Circular on the Launch of E2B (R3) Electronic Transmission System56 ...... 46 NMPA Circular on Implementation of 11 ICH Guidelines Including Q2(R1) - Validation of Analytical Procedures: Text and Methodology57 ...... 46 NMPA Circular on Recommended Implementation of 4 ICH Guidelines Including “Q8 (R2) – Pharmaceutical Development”58 ...... 46 CDE Circular on Adjusting Administrative Procedures Regarding Drug Registration Application Acceptance, Dossier Submission, and Information Support Service During Novel Coronavirus Outbreak on Feb.2, 202059 ...... 46 SAMR Circular on Releasing “Forms and Templates Required During Examination and Approval of Advertisements for Drugs, Medical Devices, Health Food and Formula Food for Special Medical Use” on Feb 28, 201960 ...... 47 NMPA Announces Public Consultation on “Guidance for Quality Agreement of Contract Drug Manufacturing (Draft for Comments)” and “Reference Template for Quality Agreement of Contract Drug Manufacturing (Draft for Comments)” on March 2, 202061 ...... 47

NMPA Announces Public Consultation on “Working Procedures for Inspection of Drug Marketing Authorization Holders (Draft for Comments)” and “Key Points for Inspection of Drug Marketing Authorization Holders (Draft for Comments)” on March 2, 202062 ...... 47 SAMR Circular on 2020 Annual Legislation Program on March 17, 202064 ...... 48 NMPA Announcement on Administrative Regulations on Extended Clinical Trials for Medical Devices (Interim) and Explanatory Note to “Administrative Regulations on Extended Clinical Trials for Medical Devices (Interim)”65 ...... 48 State Administration for Market Regulation (SAMR) SAMR Announces Regulations on Drug Registration and NMPA Announcement on Implementing “Regulations on Drug Registration” 66 ...... 49 SAMR Announces Regulations on Supervision of Drug Manufacture on March 30, 202067 ...... 50 NMPA Announcement on Matters Concerning the Implementation of the Newly Revised “Regulations on Supervision of Drug Manufacture” on March 31, 202068 ...... 50 Explanatory Note to Policies in “Regulations on Supervision of Drug Registration”69 ...... 50 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials for R&D of Drugs Targeting Community Acquired Bacterial Pneumonia” and “Technical Guidance on Clinical Trials for R&D of Antimicrobial Agents Targeting Acute Bacterial Skin and Skin Structure Infection” on March 19, 2020 70 ...... 51 CDE Announces Public Consultation on “Guidance for Clinical Trials on Adalimumab Injection Biosimilars (Draft for Comments)” on Apr. 1, 202071 ...... 51 CDE Announces Public Consultation on “Guidance for Clinical Trials on Trastuzumab Injection Biosimilars (Draft for Comments)” on Apr. 7, 202072 ...... 51 CDE Announces Guidance for Clinical Trials on Pertuzumab Injection Biosimilars (Draft for Comments) on Apr.17, 202074 ...... 52 CDE Announces Public Consultation on “Technical Guidance on Clinical Trial Imaging Endpoint Process Standards for Anticancer Drugs (Draft for Comments)” on Apr.22, 202075...... 52 NHC Circular on Releasing “Administrative Regulation on National List of Drugs in Shortage (Interim)” on Apr. 20, 202076 ...... 53 NMPA and NHC Joint Announcement on Releasing “Good Clinical Practice for Drugs” on Apr.23, 202077 ...... 53 CDE Announces Public Consultation on ICH Guideline “Impurities: Guideline for Residual Solvents Q3C(R8) ”on Apr.29, 202078 ...... 53 NMPA Announces Public Consultation on Regulatory Documents Including “Basic Requirements and Review Key Points Regarding Application Procedure and Dossier for Re-registration of Domestically Manufactured Drugs (Draft for Comments)” on Apr.29, 202079 ...... 54 NMPA Announces Public Consultation on “M4 Module 1 Administrative Documents and Drug Information” (Draft for Comments) on Apr.29, 202080 ...... 54

NMPA Announces Public Consultation on “Basic Requirements for Drug Registration Application Dossier (Draft for Comments)”on Apr.29, 202081 ...... 54 NMPA Announces Public Consultation on “Technical Guidelines for Clinical Changes to Already Marketed Drugs (Draft for Comments)” on Apr.29, 202082 ...... 54 NMPA Releases “List of Reference Preparations for Generic Drugs (27th List) on Apr.29, 202083 ...... 54 NMPA Announces Public Consultation on 6 Regulatory Documents Including “Special Regulations on the Administration of Chinese Medicine Registration” on Apr. 29 202084 ...... 54 NMPA Announces Public Consultation on Regulatory Documents Including “Classification System for Registration of Chemical Drugs and Requirements for Application Dossier” on Apr. 29 202085 ...... 55 NMPA Announces Public Consultation on 7 Regulatory Documents Including “Classification System for Registration of Biologic Products and Requirements for Application Dossier (Draft for Comments)” .... 55 On Apr. 29 202086 ...... 56 CDE Announces Public Consultation on “Review Guidelines for the Acceptance of Active Pharmaceutical Ingredient (API) Registration” on Apr. 30 202087 ...... 56 CDE Announces Public Consultation on “Administrative Measures for the Communication on Drug R&D and Technical Review (Draft for Comments)” on Apr. 30 202088 ...... 56 CDE Announces Public Consultation on “Procedures for Review and Approval of Drug Conditional Marketing Authorization (Draft for Comments)” on Apr. 30 202089 ...... 56 CDE Announces Public Consultation on “Regulations on Associated Review and Approval of Pharmaceutical Active Ingredients, Pharmaceutical Excipients, Pharmaceutical Packaging Materials and Drug Preparations (Draft for Comments)” on Apr. 30 202090 ...... 56 CDE Announces Public Consultation on “Clinical Requirements for Drugs Listed Overseas but Not Yet Marketed Domestically” Apr. 30 202091 ...... 57 Apr. 22 202092 ...... 57 CDE Announces Public Consultation on “Guideline on the Submission of Clinical Trial Data (Draft for Public Review)” on May 6, 202093 ...... 57 CDE Releases “Technical Guideline for Studies of Nitrosamine Impurities in Chemical Drugs (Interim)” on May 8, 202094 ...... 57 CDE Announces Public Consultation on “Technical Guidelines on Preparing Safety Data Submission for Innovative Anti-Tumor Drug Marketing Application (Draft for Comments)” on May 9, 202095 ...... 57 NMPA Circular on Requiring Quality and Efficacy Consistency Evaluation of Generic Injectable Drugs on May 12, 202096 ...... 58 CDE Announces Public Consultation on “Guideline on Adaptive Designs for Clinical Trials (Draft for Public Review)” on May 13, 202097 ...... 58

CDE Announces Public Consultation on “Management System for Drug Clinical Trial Registration and Information Communication” and “Provisions on Requirements and Management of Development Safety Update Report” on Nov 8, 201998 ...... 58 NIFDC Announces Public Consultation on “Testing Procedures and Technical Requirements for Drug Registration (Draft for Comment)” on May 15, 202099 ...... 58 NMPA Releases “Technical Review Guideline for the Registration of Dengue Virus Nucleic Acid Detection Reagents” on May 14, 2020100 ...... 59 Technical Guidance for Using Real-World Evidence to Support R&D and Regulatory Review of Pediatric Drugs (Draft for Comments) on May 18, 2020101 ...... 59 NMPA Releases “Evaluation Guideline for Raw Material Changes to Passive Medical Devices” May 19, 2020102 ...... 59 CDE Announces Public Consultation on “Guidance for Clinical Trials on Tocilizumab Injection Biosimilars (Draft for Comments)” May 21, 2020103 ...... 59 CDE Announces Public Consultation on “Technical Guidance for Communications on Clinical Aspects Before the Initiation of Key Experiments During the Registration of Innovative Anticancer Drugs Supported by Single Arm Trials (Draft for Comments)” May 22, 2020104 ...... 60 CFDI Announces Public Consultation on Two Regulatory Documents Including “Regulations on Implementation Principles and Procedures of Drug Registration Inspections (Draft for Comments)” May 22, 2020105 ...... 60 CDE Notice on Gradually Restoring Office Administrative Services May 22, 2020106 ...... 60 CDE Releases “Guidance on Clinical Trial Design for Biosimilars of Liraglutide Injections”on May 28, 2020107 ...... 61 NMPA Releases “List of Reference Preparations for Generic Drugs (28th List)” on May 28, 2020108 ... 61 CDE Announces Public Consultation on “Technical Requirements Concerning Common Pharmaceutical Issues in Application for Phase I Clinical Trials of Innovative Chemical Drugs (Draft for Comments)” and “Summary Table for Information of Pharmaceutical Researches Related to Application for Phase I Clinical Trials of Innovative Chemical Drugs (Revised Version)” on June 1, 2020109 ...... 61 CMDE Circular on Further Regulating the Procedure of Acceptance and Filing Review for Medical Device Registration on June 5, 2020110 ...... 61 CMDE Circular Concerning Imported Medical Device Applying for Registration as Class II Device but Categorized Under Class III After Technical Review: Registration Application Withdrawal and Follow-up Procedures on June 5, 2020111 ...... 62 NMPA Announces Public Consultation on “The Measures for record filing regulation of Medical Representatives (Trial) (Draft for Comments)” on June 5, 2020112 ...... 62 CFDI Announces Public Consultation on “Drug Safety Credit Record Management System for Nonclinical Safety Evaluation Research Institutes and Clinical Trial Organizations (Draft for Comments)” on June 5, 2020113 ...... 62

CDE Announces Public Consultation on the “Guidance on Clinical Trial Design for Biosimilars of Denosumab Injections (Osteoporosis as Indications) (Draft for Comments)” June 5, 2020114 ...... 62 CDE Announces Public Consultation on “Technical Guidance for Communications Before Marketing Approval Application on Clinical Aspects Concerning Innovative Anticancer Drugs Supported by Single Arm Trials (Draft for Comments)” on June 5, 2020115 ...... 63 NMPA CDE Announces “The Administrative Measures for External Experts of CDE” and “The List of The First Batch of CDE (No. 4 of 2020)” on June 5, 2020116 ...... 63 NMPA Releases “Guideline on Management and Archiving of Required Documentation for Drug Clinical Trials” June 5, 2020117 ...... 64 CDE Announces Public Consultation on “Guideline on Pharmaceutical Development of Medicines (Chemical Drugs) for Paediatric Use (Draft for Comments)” on June 12, 2020118 ...... 64 NMPA Releases “List of Reference Preparations for Generic Drugs (29th List)” ...... 64 June 16, 2020119 ...... 64 Circular on the Release of “General Requirements for Biosafety of Vaccine Manufacturing Sites” on June 18, 2020120 ...... 64 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials for Modified New Chemical Drugs (Draft for Comments)” on June 24, 2020121 ...... 64 CDE Announces Public Consultation on “Technical Guidance on Endpoints of Clinical Trials for Advanced Hepatocellular Carcinoma (Draft for Comments)” on June 24, 2020122 ...... 65 NMPA Announces Launch of “Drug Registration application software (2020 version)” on June 24, 2020123 ...... 65 CMDE Notice on Information Support Service During July and August 2020: Technical Consultation Before Medical Device Registration Application on June 22, 2020124 ...... 65 CDE Announces Public Consultation on “Guidance on Designing Clinical Trials for GnRH Agonists in the Treatment of Advanced Prostate Cancer” on June 28, 2020125 ...... 65 CHP Circular on Implementing "Chinese Pharmacopoeia Pharmaceutical Excipient Monograph Guardianship Mechanism” on June 17, 2020126 ...... 65 NMPA Releases “Classification System for Registration of Biologic Products and Requirements for Application Dossier” on June 29, 2020127 ...... 66 NMPA Releases “Classification System for Registration of Chemical Drugs and Requirements or Application Dossier” on June 29, 2020128 ...... 66 NMPA Circular on Updating Drug Registration Fee Charging Standards on June30, 2020129 ...... 66 NIFDC Circular on Releasing “Testing Procedures and Technical Requirements for Drug Registration (Interim) (Version 2020)” and Related Matters on July 1, 2020130 ...... 66 NMPA Releases “Revised Appendix to Good Manufacturing Practice for Drugs (2010 Revision) – Blood Products” June30, 2020131 ...... 67

The Chinese Pharmacopoeia Commission Releases “Working Procedures for Drug Generic Name Review and Approval” on July 1, 2020132 ...... 67 NMPA and NHC Circular on Publishing “Pharmacopoeia of the People’s Republic of China (Edition 2020)” on June 24, 2020133 ...... 67 M4 Module 1 Administrative Documents and Drug Information on July 1, 2020134 ...... 67 CDE Releases “Rules on Assessment and Management of Safety Information During Drug Clinical Trials (Interim)” on July 1, 2020135 ...... 67 CDE Releases “Administration Rules on Development Safety Update Reports (Interim)” on July 1, 2020136 ...... 67 CDE Releases “Administration Rules for Drug Clinical Trial Registration and Information Communication (Interim)” on July 1, 2020137 ...... 68 CDE Releases “Review Guidelines for the Acceptance of Chemical Drug Registration (Interim)” on July 2, 2020138 ...... 68 CDE Releases “Guidelines for the Acceptance of Biological Product Registration” on July 2, 2020139 . 68 CDE Announces Public Consultation on “General Format and Guidance for Preparing Drug Technical Documents: ‘Manufacturing Process’, ‘Quality Standards’ and ‘Package Insert’ (Drafts for Comments)” on July 6, 2020140 ...... 68 CDE Announces Public Consultation on “Technical Guideline on Clinical Trials for Immune Cell Therapy Products (Draft for Comments)” on July 6, 2020141 ...... 68 The NMPA Releases Three Regulatory Documents Including “Working Procedure for Review and Approval of Breakthrough Therapy Designated Drugs (Interim)” on July 7, 2020142 ...... 69 CDE Notice on New Version of Drug Clinical Trial Registration and Information Release Platform System on July 10, 2020143 ...... 69 CDE Releases “Drug Registration Application Dossier Format, Stylistic Rules and Layout Standards” on July 8, 2020144 ...... 69 CDE Releases “Guideline for Management of Drug Clinical Trials During the Covid-19 Outbreak (Interim)” on July 14, 2020145 ...... 69 CDE announces Public Consultation on “Technical Guideline for Pharmaceutical Changes to Innovative Drugs (Chemical Drugs) During Clinical Trials (Draft for Comments)” on July 14, 2020146 ...... 69 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials for Antineoplastic Drugs Used in Combination Therapy” on July 17, 2020147 ...... 69 CDE Announces Public Consultation on “Guidance on Statistical Design in Clinical Trials for Antineoplastic Drugs” on July 17, 2020148 ...... 70 CDE Releases “Guideline on the Submission of Clinical Trial Data (Interim)” on July 20, 2020149 ...... 70 The CDE Releases “Guidance for Clinical Trials on Rituximab Biosimilars” on July 20, 2020150 ...... 70

CDE Releases “Guidance for Clinical Trials on Trastuzumab Injection Biosimilars” on July 20, 2020151 ...... 70 NMPA Announcement on Adoption of “ICH E2C (R2) Guideline: Periodic Benefic-Risk Evaluation Report (PBRER)” on July 17, 2020152 ...... 70 The Center for ADR Announces Public Consultation on “Application Dossier and Requirements for Switching Drugs from Prescription to OTC Status (Revision Draft for Comments)” on July 24, 2020153 70 The CDE Releases “Guideline on Non-Inferiority Clinical Trials for Drugs” on July 24, 2020154 ...... 71 NMPA Opinions on Further Improving the Quality and Capacity of Adverse Event Monitoring System for Medical Products on July 28, 2020155 ...... 71 The CDE Announces Public Consultation on “Technical Guideline for Pharmaceutical Researches on Transdermal Patch Generics (Draft for Comments)” on July 24, 2020156 ...... 71 CDE Announces Public Consultation on 4 Technical Guidance Including “Technical Guidance on Clinical Trials of Antibacterial Drugs for the Treatment of Complicated Urinary Tract Infection” on July 31, 2020157 ...... 71 CDE Announces Public Consultation on “Guidance on Real World Data Used to Generate Real World Evidence (Draft for Comments)” on Aug. 3, 2020160 ...... 72 on Aug. 3, 2020161 ...... 72 CDE Announces Public Consultation on “Guidance on Research and Validation of Aseptic Processing and Sterilization of Injection Drugs” on Aug. 3, 2020166 ...... 73 The CDE Under NMPA Releases “Record Filing Procedures and Requirements for Separated Packaging of Drugs Manufactured Overseas” on Aug. 3, 2020167 ...... 73 NHSA Announces Public Consultation on “2020 Working Plan of Adjusting Drug Catalogue Covered by National Healthcare (Draft for Comments)” on Aug. 3, 2020168 ...... 73 CDE Announces Public Consultation on “Guidance on Clinical Trial Design for Oncolytic Virus- Based Drugs” (Draft for Comments)” on Aug. 7, 2020169 ...... 73 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials of Drugs for the Treatment of Lipid Metabolism Disorders (Draft for Comments)” on Aug. 10, 2020169 ...... 74 CDE Notice: Public Consultation on “ICH M7 Guideline: Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk. Questions and Answers” and “M7 Q&A Support Document” on Aug. 10, 2020170 ...... 74 CDE Announces Public Consultation on “Technical Guidance on Similarity Assessment and Indication Extrapolation of Biosimilars (Draft for Comments)” on Aug. 14, 2020171 ...... 74 CDE Releases 5 Technical Guidelines Including “Technical Guideline for Research and Development of Preventive Vaccines Against Covid-19 (Interim)” on Aug. 14, 2020172 ...... 74 CDE Announces Public Consultation on 11 Technical Guidance Including “Technical Guidance on Bioequivalence Study of Olanzapine Orally Disintegrating Tablets” on Aug. 19, 2020173 ...... 75

CDE Announces Public Consultation on “Technical Guideline for Researches on Generic Fulvestrant Injections (Draft for Comments)” on Aug. 19, 2020174 ...... 75 CDE Announces Public Consultation on “Guidance on Adjusting for Covariates Clinical Trials for Drugs” on Aug. 19, 2020175 ...... 75 CDE Notice on Issuing Electronic Administrative Documents for APIs on Aug. 20, 2020176 ...... 75 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials for Influenza Antivirus Drugs (Draft for Comments)” on Aug. 21, 2020177 ...... 75 CDE Announces Public Consultation on “Technical Guidance on Clinical Investigations Concerning Medicines for the Control of Myopia Progression” on Aug. 24, 2020178 ...... 75 CDE Announces Public Consultation on “Technical Guidance on Clinical Trials for Human Stem Cell Based Therapeutic Products and Their Derivatives (Draft for Comments)” on Aug. 24, 2020179 ...... 76 CDE Announces Public Consultation on “Technical Guidance on Drug Immunogenicity Studies (Draft for Comments)” on Aug. 24, 2020180 ...... 76 CDE Releases “List of Chemical Drugs of Specific Clinical for Which Reference Preparations Cannot Be Recommended (1st List)” for Public Review on Aug. 24, 2020181 ...... 76 CDE Announces Public Consultation on “Technical Guideline for Nonclinical Studies of Diagnostic Radiopharmaceuticals (Draft for Comments)” on Aug. 27, 2020182 ...... 76 CDE Announces Public Consultation on “Guidance for Clinical Trials on Omalizumab Injection Biosimilars (Draft for Comments)” on Aug. 27, 2020183 ...... 76 CDE Releases “Technical Guidance for Using Real-World Evidence to Support R&D and Regulatory Review of Pediatric Drugs (Interim)” on Aug. 27, 2020184 ...... 77 CDE Announces Public Consultation on “Guidance on Enrichment Strategies and Design for Drug Clinical Trials (Draft for Comments)” on Aug. 27, 2020185 ...... 77 CDE Releases “Technical Guideline for Testing Minimal Residual Disease During Clinical Trials of Drugs for Acute Lymphoblastic Leukemia” on Aug. 28, 2020186 ...... 77 CDE Announces Public Consultation on “Guideline for Subgroup Analyses in Clinical Trials for Drugs (Draft for Comments)” on Aug. 28, 2020187 ...... 77 CDE Announces Public Consultation on “Guidance on Clinical Pharmacology Studies for Pediatric Drug Development” (Draft for Comments)” on Sep. 1, 2020188 ...... 77 CDE Announces Public Consultation on “Guidance on Clinical Trial Design for Oncolytic Virus- Based Drugs” (Draft for Comments)” on Aug. 7, 2020189 ...... 77 CDE Announce Public Consultation on “Technical Guidance on Clinical Trials for Medicines Treating Age-Related Macular Degeneration” on Sep. 9, 2020190 ...... 78 CDE Announces Public Consultation on “Technical Guidance on Pharmaceutical Research and Changes for Biologics During Clinical Trial (Draft Published Online for Comments)” on Sep. 10, 2020191 ...... 78

NMPA and National Intellectual Property Administration Announce Public Consultation on “Implementation Measures Concerning Early Resolution Mechanism for Drug Patent Disputes (Interim) (Draft for Comments)” on Sep. 11, 2020192 ...... 78 CDE Announces Public Consultation on “Technical Guidance on Drug-Drug Interaction Studies (Draft for Comments)” on Sep. 11, 2020193 ...... 78 Conclusions ...... 79 References ...... 81

Abbreviations

BE Bioequivalence CDE Center for Drug Evaluation CFDA Chinese Food and Drug Administration (old name of NMPA) CMDE Center for Medical Device Evaluation, NMPA CPP Certificate of Pharmaceutical Product CROs Contract Research Organisations EC Ethics Committee EU European Union FDA Food and Drug Administration FIH First in Human GMP Good Manufacturing Practice GCP Good Clinical Practice GQCE Generic drug quality and efficacy consistency Evaluation HGRAC Human Genetic Resource Administration of China ICH International Council for Harmonisation IND Investigational New Drug MA Marketing Authorisation MAA Marketing Authorization Application MAH Marketing Authorization Holder NDA(s) New Drug Application(s) NHC National Health Committee NMPA National Medical Products Administration (formerly CFDA) NPC National People’s Congress US United States VAT Value added tax

Background

China is currently the second largest pharmaceutical market in the world and was estimated in 2017 to be worth $122.6 billion. It was also the biggest emerging market for pharmaceuticals with growth tipped to reach between $145 billion and $175 billion by 20221.

Due to its high potential for growth, China has also become one of the most important regions for global drug development, but historically the regulatory environment in China was considered highly challenging for the following reasons:

 The Chinese drug registration process differs from that seen in many other countries, in that new drug applications (NDAs) for all imported drugs, whether marketed overseas or not, are required to include data from local clinical trials);  Major differences exist between international standards and some local products and manufacturers as far as quality is concerned;  The timeframe for review and approval of new drugs is longer than for most major countries;  A lack of capacity in the regulatory body has resulted in a backlog of applications.

In August 2015, the China State Council released “Opinions on Reforming the Review and Approval System for Drugs and Medical Devices.” The intention of this reform was to promote a structural change and upgrade of the pharmaceutical industry and bring products already marketed in China up to international standards in terms of efficacy, safety and quality. These reforms aim to:

 Eliminate the existing backlog of registration applications;  Establish an environment for maximizing the quality of generic drugs;  Create a framework in China that encourages research and development of new drugs in line with global development;  Improve the quality and increase the transparency of the review and approval process.

China has a large pharmaceutical industry; it is estimated that there are between 4,500 and 6,000 manufacturers 2, with businesses based on generics, active pharmaceutical ingredients or traditional Chinese medicine. Most of the manufacturers are small or medium-sized enterprises. There are however many manufacturing sites in China that meet global Good Manufacturing Practice (GMP) standards. Previous regulations meant that the Marketing Authorisation Holder (MAH) also had to be the owner of the manufacturing site. The reform has seen the separation of the activities of MAH and manufacturer and so the environment is now more flexible allowing research companies to hold the MA whilst contracting out the product manufacture to a third party.

Generic drugs available in China tend to have several approved manufacturers and there is a sparsity of official guidance for the generics industry. The China Food and Drug Administration* (CFDA) has published “restricted” and “promoted” categories of generic drugs suggesting that a more sound control and guidance of the generics industry is expected.

There has traditionally been stiff competition in the generics arena, which has meant that local Chinese companies have not been interested in developing innovative new drugs, thus their current capacity for such development is low. In the recent past, these companies have relied on bioequivalence (BE) trials for generic drug registration but with CFDA’s* new requirements they will need to start focusing on generic quality and efficacy; as such, any data considered inaccurate or incomplete will not be accepted and therefore there is potential for existing licenses to be withdrawn.

*Note: CFDA became NMPA (National Medical Products Administration) in 2018. CFDA has been used in this document to relate to any Guidance or procedure that pre-dates the 2018 reforms.

Reform Impacts: 2016 Table A: Reforms 2016

Reform Detail / Opportunity

Self-inspection of clinical data CFDA announced a self-inspection programme for clinical data, this required MA applicants, contract research organisations (CROs) and clinical sites to self-inspect. More than 1600 applications pending approval1 This initiative began in July 2015 and uncovered fake and incomplete data which resulted in non-approvals and in some cases investigations by CFDA.

CFDA used its experts to inspect selected studies that were suspicious in terms of data authenticity. For future new drug applications, CFDA requires applicants to include a clinical trial self-inspection report, which CFDA will review.

After 12 months, CFDA reported that around 90% of the backlogged applications had been withdrawn by applicants or rejected by CFDA4.

Reform Detail / Opportunity

Priority review In February 2016, CFDA announced a new ‘priority review’ process to encourage new drug innovation to meet unmet medical needs and to encourage overseas sponsors to plan and perform clinical development in China in parallel with the US, EU, Japan and other countriesError! Reference source not found.. An updated version was published in 2 017.

 ‘Priority review’ status can be requested based on the following criteria:  Innovative drug which is not approved anywhere worldwide  Innovative drug where the manufacturing is to be transferred to a site in China  Global clinical trial application to China in parallel with the US or EU  The innovative drug is for HIV/AIDS, viral hepatitis, a rare disease(s), for malignant tumours and for paediatric indications  The product is a newly launched generic drug.

Positive priority review status provides applicants with ‘priority reviewer resources’ allocated by the Center for Drug Evaluation (CDE) and priority communication pathways to obtain advice and expedited feedback from the CDE/CFDA.

CFDA considers that the target approval time for a priority review, from submission, is six months or less however this is not yet being seen consistently. The scheme seems to have worked well for applications submitted after February 2016.

 On Dec 28, 2017, NMPA updated opinions on priority review with two modifications in the scope, which are in line with State Council Opinions of Deepening the Reform of the Review and Approval System and Encouraging the Innovation of Drugs and Medical Devices (6).New drug application with clinical trial performed by National Clinical Medical Research Center and confirmed by CDE management department shall be given priority review and approval.

Reform Detail / Opportunity

 Under the circumstances in which there is a major threat to the public health, registration applications for drugs that have been granted compulsory licensing shall be given priority review and approval. The specific circumstances under which there is a major threat to the public health and the specific procedures for initiating compulsory licensing shall be promulgated separately by National Health and Family Planning Commission together with relevant authorities.

Additional capacity at CDE In 2015 there were only around 70 reviewers to handle an annual load of more than 7,000 drug applications in the CDE. Following a new hiring exercise, 600 new drug reviewers were in place by the end of 20164. Additional hiring of reviewers has continued in 2017–2018.

Reform Detail / Opportunity

Marketing Authorisation Holder MAH system reform ensures that drug research and development institutions can obtain and hold MAs without rationalisation / new needing to own the manufacturing site7. classification /definition of new  Encourages drug research and development institutions to transfer manufacturing to an established drug drugs manufacturer with an associated site inspection in order to validate the manufacturing process.  Major incentive for local new drug innovators in China, who can now hold marketing authorisations independently.  Reform implemented in a phased manner starting with a trial in ten selected provinces, mostly on China’s east coast, over three years  Encourages drug researchers/institutions to focus on Research and Development and alleviates the need to invest in their own manufacturing plants.

Creation of a new classification of drug, “new to the world”, to replace the previous “new to China” category8.  Based on the global marketing authorisation approval status and the location of the manufacturing site(s) (inside or outside China).  Removes the previous definitions that were based on the specific status in China, and aligns classification more closely to other regulatory agencies. Generic drug quality and Generic drug manufacturers are required to start drug consistency research on quality and efficacy; target efficacy consistency Evaluation completion date by the end of 20189. (GQCE) Product list has been developed by CFDA that lists which generic drugs need this consistency evaluation. For evaluation purposes, the comparator product is the “innovator drug,” or a globally recognised similar drug. Innovator drug means the first marketed drug globally with the full data package to support its safety and efficacy.

Reform Impacts: 2017

On March 17 2017, CFDA announced its decision to change the requirement on imported drug registration. The changes are to encourage foreign-developed new drugs to undergo clinical investigation within China and outside China in parallel, intended to shorten the time period between approval outside China and approval inside China to meet the need for new drugs for Chinese patients.

These changes bring China more into line with global standards, processes and timelines. It is expected that the new policy will have a positive impact on Ex-China sponsors who can develop a full clinical development program inside China, with significantly shortened regulatory review processes. The CFDA marketing authorization approval can be in parallel with the US, EU or any other country’s approval.

It is envisaged that more foreign (ex-China) sponsors will want to conduct research in China and more foreign new drugs are likely to be approved. There is hope that the changes will encourage foreign sponsors to invest in China and set up new drug research centers, with an associated increase in activity for Chinese clinical trial sites and investigators and potentially CROs in China. Key changes in 2017 are shown in Table B: Reforms 2017.

Table B: Reforms 2017

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Opening up of first-in-human (FIH) This means that for new chemical drugs and new therapeutic biological products foreign Phase I trials to global development applicants can have a full clinical development plan executed inside China in parallel with the global development programmeError! Reference source not found..

This change effectively opens an FIH Phase I market in China . Note: preventative vaccines still may not undergo a global trial inside China.

Simplified process for gaining a Previously, foreign-developed new drugs needed three submissions: marketing approval  Multinational clinical trial submission to request global Phase II or III trial in China;  After the drug had been approved in US or EU and a certificate of pharmaceutical product (CPP) was available, submission to CFDA to request clinical trial waiver (requesting exemption from need to do any additional local trials);  NDA submission to CFDA for market approval.

Under the new policy, there is no need for the second submission (clinical trial waiver) and the sponsor can move directly to the NDA submissionError! Reference source not found..

This simplified process could shorten the whole approval process by about one year.

Clinical trial management 11 CFDA will no longer accredit clinical sites with Good Clinical Practice (GCP).  Opens up potential for clinical sites in all qualified hospitals,  Likely increase in the number of sites able to manage clinical trials  CFDA retains responsibility for site inspections

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Opens clinical trial market to all qualified hospitals and to social funds, creating increased capacity for clinical trials in China

Sponsor can sub-contract inspection or audit for sites to check if they are qualified.  Opportunities for CRO QA departments to expand to take on extra work

Improvement in Ethics Committee (EC) process and review  Each region or province may set up a regional EC to guide EC activities and monitor trials and investigators in the region.  Includes proposal for EC submission and approval prior to investigational new drug (IND) submission to CFDA/CDE.  For a multi-centre trial, after EC approval by the lead site, other sites can accept lead site’s approval without repeating review.  With EC review before IND submission, CFDA/CDE reviewers will be able to review comments from sites, including trial design comments, encouraging a more active review of protocol by ECs.

Improvement in the clinical trial/IND review process means a pre-submission consultation meeting between CFDA and the sponsor will be required for all Phase I or Phase III trial applications. If after 60 working days following submission, there are no comments from CFDA/CDE, the submission can be considered approved. Any substantial amendment for an ongoing trial must be submitted to CFDA in timely manner.  Potential for CRO regulatory affairs functions to expand to co-ordinate/lead meetings.

Clinical trial data from studies outside China can be used in China for registration, including any BE studies for generic drugs approved in the US, or EU or Japan. These studies will be subject to an on-site inspection by CFDA.

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Acceleration of drug and medical device For drugs and medical devices which are indicated for serious life-threatening conditions or for registration review process11 significant unmet medical needs, where early- or mid-stage clinical data predicts outstanding clinical benefit, CFDA can grant a conditional approval to allow early marketing in China. The conditional approval requires an approved risk management plan and a commitment to complete required clinical trial(s) based on CFDA’s review and conclusion, much the same as is currently the norm in the EU.

China’s Ministry of Health issued a rare disease list for China (See 2018 section) and set up a rare disease patient registration process.  The orphan drug and medical device manufacturer/applicant can apply for a clinical trial waiver or an agreed decrease in trial subject numbers.  For orphan drugs or medical devices that are already approved outside China, CFDA can issue a conditional approval to allow marketing in China, while the sponsor completes commitment for clinical trial based on CFDA’s review and conclusion.

Stricter controls on injectable formulations mean that they will not be approved if an oral formulation of same product already meets clinical needs.

Active pharmaceutical ingredient, excipient and package material management moves from a specific approval process to a drug master file process.  Brings this in line with the majority of the rest of the world

Support for new drugs to enter the market by encouraging hospitals to give priority to the purchase of new drugs that have established safety and efficacy data at a reasonable price.

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 The Chinese Government are looking for a process for maintaining an insurance drug list following price negotiation with the sponsor but in the meantime they have committed to have new drugs included on the insurance drug list. Drug and medical device lifecycle The new MAH policy has been on trial in ten provinces since November 2015. management11  The MAH holds all responsibilities for the drug development, regulatory and supply process, including nonclinical, clinical, manufacture, drug quality, marketing and delivery, clinical use and safety reporting.  The MAH is responsible for safety reporting and should propose the actions to improve quality control, timely labelling change or other change initiated from safety analysis.  Re-evaluation of marketed injectable drugs for safety, efficacy and quality control is consistent with the re-evaluation of generic drug quality and efficacy re-evaluation started in 2016. The purpose is to upgrade drug quality and remove low-quality products from the market. The same exercise is ongoing for medical devices.  Inspection system for whole regulatory, development and supply process will be put in place. Nonclinical and clinical process will be inspected by CFDA; manufacturing process and quality control will be inspected by provincial-level FDA; sales and marketing processes will be inspected by city-level FDA.

Protecting innovator’s rights11 Establishment of an effective drug-patent system  Every application for drug approval will include a statement on drug patent non- infringement.  If an applicant is challenging another party’s patent, the applicant should inform the patent-holder within 20 days after formal submission; the patent-holder should initiate any necessary legal action against the applicant within 20 days after being informed by the applicant and, in parallel, inform CFDA.  CFDA can implement a waiting period of up to 24 months while any decision from a legal process is pending.

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 If no legal decision has been given within 24 months, CFDA has the right to issue the new MA.

Clinical trial data protection  An applicant can apply for a clinical trial data protection request, along with their NDA application.  Six-year protection for new drug, ten-year protection for new orphan drug or new pediatric drug, three-year protection for modified orphan drug or pediatric drug and ten- year protection for new biological products.  The protection starts from the date of drug approval. Within this protection period, CFDA will not approve the same drug from different applicants.

Reform Impacts: 2018

Note: CFDA became National Medical Products Administration (NMPA) in 2018

Table C: Reforms 2018

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NHC release the Rare Disease List The National Health Committee issued the 1st batch list of Rare Diseases on May 11, 2018.  The list is attached as a PDF below: note this is in Chinese, with bilingual disease list.

41) 关于公布第一批罕见病目录的通知.pdf

NMPA was elected as a member of the On June 7, NMPA issued a notice saying that at the first meeting of the International ICH Management Committee Conference on Technical Registration of Human Drugs in Kobe, Japan, NMPA was elected as a member of the International Council for Harmonisation (ICH) Management Committee12.

Announcement of NMPA on Technical On July 10, 2018, NMPA released the final version of “Technical Guideline for Acceptance of Guideline for Acceptance of Overseas Overseas Drug Clinical Trial Data”13. Drug Clinical Trial Data (2018, No.52)  As per the Basic Principles for Acceptance of Overseas Clinical Trial Data, applicants should ensure the authenticity, integrity, accuracy and traceability of overseas clinical trial data.  The generation process of overseas clinical trial data should comply with relevant requirement of ICH Good Clinical Practice (GCP).  Applicants should ensure the design of clinical trials are scientific, the quality management systems of clinical trials comply with the requirements, as well as clinical data statistical analysis is accurate and integrated.

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 For drugs which undertake research and development synchronously in China and abroad (ex-China), for which the clinical trials are to be conducted in China, in order to ensure the scientific nature and validity of clinical trial designs and data statistical analysis, applicants/sponsors may communicate with CDE before conducting the pivotal clinical trials so as to ensure that the designs of pivotal clinical trials are consistent with the basic technical requirements for drug registration in China.

NMPA released the Circular on Circular 50 was released by NMPA on July 27, 201814. Adjusting the Approval Process for Drug In order to encourage innovation, speed up the creation of new drugs, meet the needs of public Clinical Trial Evaluation (2018, Circular drug use, and implement the responsibility of the applicant's research and development, 50) according to the General Office of the CPC Central Committee and the General Office of the State Council "Opinions on Deepening the Reform of the Examination and Approval System and Encouraging the Innovation of Pharmaceutical Medical Devices", related to the review and approval of drug clinical trials:  For drug clinical trial applications in China, if within 60 days from the date of application acceptance and payment, the applicant has not received a refusal or questions from CDE, the drug clinical trial may be carried out in accordance with the submitted clinical trial protocol.

NPC decided that the three-year period On Oct. 26, 2018, in order to better summarize the pilot experience of the MAH pilot project, for the MAH pilot project is extended by and to lay down a good foundation for reform and improvement of the drug management one year system, and pave the way for the revision of the Drug Administration Law of the People's Republic of China, The Sixth Session of the Standing Committee of the 13th National People's Congress (NPC) decided that the three-year period for the MAH pilot project should be extended by one yearError! Reference source not found..

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 This pilot project authorized the State Council to launch MAH system in some places at the 17th meeting of the Standing Committee of the 12th National People's Congress on November 4, 2015.  This decision came into force on November 5, 2018.

Accelerate approval of urgently needed On October 30, 2018, the NMPA official website issued the "Notice on the Release of the First overseas new drugs Batch of Clinically Urgently Needed New Drugs List"16.

In order to implement the spirit of the meeting of the State Council and speed up the urgent need for new overseas drugs to enter China, the NMPA and the NHC have formulated the “Clinical Urgent Need for Overseas Drug Evaluation and Approval Work Procedures”:  There are 8 new overseas drugs which have been approved recently, and the list of the other 40 new overseas drugs has now been announced in accordance with the procedures.

临床急需境外新药审评审批工作程序（2018年第79号）_CN_EN.doc Drugs in the urgently needed new overseas drug list may be submitted in accordance with the "Clinical Urgent Need for Overseas New Drug Evaluation and Approval Work Procedures", and the NDA application shall be directly submitted.  The CDE shall establish a special channel to expedite review.  If NDA application has not yet been submitted, the applicant can contact the CDE at any time for consultation meeting and submit NDA application as soon as possible.

Legislate independent Vaccine http://www.nmpa.gov.cn/WS04/CL2101/331940.html Administration Law17 Nov 11 2018 NMPA published draft version of Vaccine Administration Law for public comments18.

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Shaken by Changsheng Bio-technology Co in Changchun vaccine scandal (Changsheng Bio- technology Co, the vaccine manufacturer, which is based in Jilin province, was found to have committed serious law violations by China's drug authorities in July and August in connection with the production of a rabies vaccine. The violations included fabricating production records and using expired ingredients) the Chinese authority will legislate via an independent Vaccine Administration Law in parallel with pharmaceutical products. The new Vaccine Administration Law aims to impose "the strictest" regulations on vaccines to ensure the safety and quality of these products. The new law intends to improve China's vaccine management system and eliminate regulatory loopholes exposed by the scandal.

Under the released draft, health and drug authorities will supervise the entire production chain of vaccines. Drug authorities should also be more thorough in inspecting vaccine production sites. Manufacturers must digitally record data related to production and inspection of vaccines, and must also certify the authenticity, integrity and traceability of the data, according to the draft document. Approval procedures and inspections must cover every batch of vaccines before they enter the market. Authorized institutes must inspect and approve vaccines, and report to China's top drug authority and provincial-level drug authorities if there are any major safety or quality risks found, so that they can be dealt with immediately.

Serious violations of the law, such as producing fake or substandard vaccines, will receive harsh penalties.

CDE website add functions of IND In Dec 2018, CDE website added new functions on IND to allow the public access to the IND permission application (including progress, supplement notice, and download of IND permission) This was previously accessible by applicant only. So far, 8 IND permissions were public in CDE website signifying the formal establishment of the system in China.

Reform Impacts: 2019

Table D: Reforms 2019

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Status of qualification notification of From January 1, 2019, all sites participating in a Medical Device Clinical Trial shall complete clinical site for medical device now their medical device site qualification notification, which was according to “Medical Device available19 Clinical Study Institution Notification Regulation, [CFDA Notice 2017 No.145], effective from January 1, 2018, transition period until December 31, 2018.

The status of medical device sites qualification notification is now available in the old website of NMPA with link as below (data migration ongoing). http://218.240.145.213:9000/CTMDS/apps/pub/public.jsp#

MAH ADR direct reporting system online This system is associated with the NMPA reform of ADR reporting which emphasises that MAH is the main responsible body of pharmaceuticals is now online.

High level decision on State Council China will further shorten the time required for the registration and approval of new oncology executive meeting for oncology and rare drugs and cut prices, a State Council executive meeting chaired by Premier Li Keqiang disease drugs20 decided on February 11, 2019.

Experts will select overseas new drugs to meet urgent clinical needs, while import policies will be improved for faster launch of the drugs in China.

China will step up efforts to ensure more early diagnosis and treatment of cancer, and offer preferential value added tax (VAT) policies for drugs for treatment of rare diseases. Starting

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on March 1, 2019 for the first group of drugs, which includes 21 drugs for treatment of rare disease, VAT will be 3% to align with oncology drugs.

China to establish collaboration network China will establish a national collaborative network of hospitals for rare disease diagnosis for rare disease diagnosis, treatment21 and treatment to promote the early detection and effective treatment of such diseases, according to a decision by the National Health Commission (NHC).

Comprised of 324 hospitals selected for their capacity and experience in treating patients with rare diseases, the network will facilitate the timely transfer of difficult and complicated cases between hospitals and the allocation of quality medical resources for them.

Meanwhile, hospitals in the network are urged to further train medical workers on rare disease knowledge and clinical skills, focusing on improving their abilities to identify, diagnose and treat such cases.

China will establish a system for rare disease patients to be registered.

2018 CDE Performance Review Meeting22 In their performance review meeting CDE looked at key achievements in 2018:

 enforcement of process reform,  implementation and acceleration of the approval of urgently needed overseas new drugs16;  reducing approval process time for drug clinical trial evaluation14,  excipient/active ingredient/package material bundling review  China marketed drug catalogue (Orange Book)  GQCE9 and ICH.

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 In 2018, total 7336 applications submitted to CDE, 9796 applications completed evaluation, backlog application reduced to 3440 applications, which was a reduction of 14% compared to 2017.

In 2018, a batch of new and effective drugs for public health prevention and control, oncology, rare diseases and other urgently needed drugs completed the technical review and approval, which provided motivation for innovation in research in China.

Drug volume purchasing pilot scheme in 4 The purpose of the 4+7 volume purchasing is to cut the drug price, increase market access, (municipality cities)+7 (big cities)23 support to reform of healthcare system.

Although the National Health Insurance Bureau has successively published explanations for the policy, this policy still shook the pharmaceutical industry. For mature products entering into the policy scope, the price pressure is very high and industry is concerned about whether the purchase price reduction and quantity are complementary.

Innovation is undoubtedly the direction that is very key in the future.

2019 Report on the work of the 2018 Key achievements in healthcare: government24  Coordinated medical service, medical insurance, and pharmaceutical reforms continued.  Made steady progress in developing the tiered diagnosis and treatment model.  Raised the level of government subsidies for rural and non-working urban residents' basic medical insurance and the reimbursement rate of their serious illness insurance.

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 The reform for evaluation and approval of new medicines was stepped up; the prices of 17 oncology drugs were slashed and these drugs were included in the national medical insurance catalogue.  Strengthened oversight over food and drug safety and investigated and took stern action in defective vaccines cases.

Tasks in 2019:  Strengthen R&D and the application of big data and artificial intelligence technologies, foster clusters of emerging industries like bio-medicine.  Ensure access to basic medical and health services. Continue to increase basic medical insurance and serious disease insurance protection for rural and non- working urban residents. Lower and unify the deductible line for serious disease insurance, raise the reimbursement rate, and further reduce the burden of medical care for people with serious diseases and people living in poverty.  Strengthen the prevention and treatment of serious diseases. Take action in cancer prevention and treatment, and promote preventive screening, early diagnosis and treatment, and promote breakthroughs in cancer research.  Improve prevention and treatment of common chronic illnesses. Outpatient medicines for treating high blood pressure, diabetes, etc., will be made reimbursable under the medical insurance scheme.  Implement and improve the policy on interprovincial on-the-spot settlement of medical bills through basic medical insurance accounts; enable patients to use their medical insurance cards for medical treatment in any designated hospital and settle their bills straight away regardless of the locality.  Continue the reform of public hospitals and encourage the development of privately run hospitals.

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 Establish a system for remote medical care services, enhance the training of community medical workers, and improve services provided both under the tiered diagnosis and treatment model and by contracted family doctors.  Prevention will continue to be a priority.  Maternal and child healthcare services will be improved.  Support the preservation, innovation, and development of traditional Chinese medicine.  Drugs and vaccines - strengthen the entire process of their regulation from production to use. eCTD implementation progress and plan in On Mar 8, CDE presented the eCTD progress and plan in 2019 annual meeting of China China Association of Pharma Equipment.  The China specification and technical requirement are published for public comments in March 2019.  China eCTD pilot implementation date will be May 2019, no formal implementation timeline available yet.  In the early phase, submission of dossier will use CD plus hardcopy, then transfer to gateway submission gradually.  CDE suggested that industry should be well prepared for eCTD.  For cost efficiency, small and medium companies may consider outsourcing (to CRO). Medical Device Animal Study Technical NMPA issued “Medical Device Animal Study Technical Review Guideline Part I: Decision Review Guideline Part I: Decision Principles” on April 19. The guideline provided the principles considerations on using live Principles25 animal for medical devices development, decision tree and listed 12 devices as examples to discuss if study in live animals is needed: 1. Porous coated bioprosthetic hip prosthesis 2. Electrocardiography machine

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3. Cross-linked sodium hyaluronate gel for injection 4. Absorbable hernia patch 5. External defibrillation products 6. Ultrasound soft tissue cutting hemostasis system 7. Implantable pacemaker 8. Drug eluting stent 9. Degradable metal screws for internal fixation 10. Stapler 11. Anastomat 12. Absorbable surgical anti-adhesion products

Medical device online registration system CMDE (Center for Medical Device Evaluation, NMPA) announced that medical device online starts in Jun 201926 registration system (eRPS) is implemented in Jun 2019. This system allows local Category 3, import Category 2 & 3 medical device registration and Category 3 high risk medical device clinical trial applications. E-submission is optional and paper dossier under current requirement are still allowed before Oct 31. From Nov 1, submission dossier including paper and e-dossier should follow the Table of Contents by International Medical Device Regulators Forum (IMDRF). This is the gateway for the online submission. http://erps.cmde.org.cn/ Approval procedure of medical device On April 1 2019, NMPA issued the Adjustment of Medical Device Clinical Trial Approval clinical trial permit application changed to Procedure. Since the date, for clinical trial permit application, if no feedback from NMPA implied approval27 within 60 working days, sponsor can directly start the clinical trial. NMPA will no longer issue the trial approval letter. Similar to drug, applicant can download and print the trial approval letter from NMPA website. If necessary, pre-IND meeting can be required by sponsor. Other requirements of medical device clinical trial, continuous follow the Registration Regulation of Medical Device.

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Second batch of clinical urgently needs Following the 1st batch released in October 2018, CDE released the 2nd batch of drug oversea new drugs 28 products of urgently medical needs in China on May 29, in which 26 products are included. If there is no ethnic difference, local clinical trial data can be waived for NDA/BLA. The new drugs added include orphan drugs, paediatric drugs, also include treatments for life-threatening diseases for which there is either currently no approved product, or for which the new drug offers a substantial clinical advantage over existing approved therapies. The draft list was published for public comments in Mar.

NMPA advancing regulatory science In Apr 2019, NMPA initiated the strategic plan of China Regulatory Science project and initiatives in drug and medical device in identified nine priority areas in first batch. The areas include cell and gene therapy products, China29 nanomedicine, drug-device combination products, post-market drug safety vigilance and evaluation, AI devices, new material in medical devices, real world data for medical device, and safety assessment of Chinese traditional medicine and cosmetics. Three key objectives for the project are specified: establish 3-5 bases for regulatory science; initiate key regulatory science projects; introduce series drug evaluation and supervision policies/tools/standards/methods. State Council releases legislative work State Council announced the China 2019 legislative work plan in May 2019. Four healthcare plan for 201930 related legislation are involved: 1. Regulation of safety in Biotech development (lead by Ministry of Science and Technology) 2. Regulation of clinical practice management on new technology of biomedical (lead By NHC) 3. Human Genetic Resource Administration of China (lead by Ministry of Science and Technology) 4. Revision of Regulation of medical device management (by NMPA)

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CDE solicit public comments on Key Real-world data (RWD) and real-world evidence (RWE) are playing an increasing role in Considerations in Using Real World health care decisions. In China, CDE has already begun to utilize RWE in the review Evidence to Support Drug Development31 practices. This guideline will facilitate industry and CDE to clarify the scope of RWE, explore the principle of the RWE evaluation, and provide a feasible guidance to use of the RWE.

Key Considerations in Using Real-World Evidence to Support Drug Development(Draft for Public Review).docx

NHC solicited public comments on third The third batch of encouraging drug list for pediatric selection is led by NHC and national batch of encouraging drug list for pediatric expert committees. The screening principles are: not registered in China, urgently pediatric32 unmet medical needs, evidence-based, expert opinion.

State Council issued the human genetic National regulations on the management of human genetic resources recently released by resources management regulations33 the State Council, which will go into effect on July 1. The regulations apply to the collection, preservation and using of a range of genetic materials containing human genomes and genes (organs, tissues and cells) and impose requirements on human genetic resource information (data derived from the genetic resource materials). It is issued to regulate and encourage reasonable employing of human genetic resources in scientific researches, developing biological medicine (drugs or medical devices) and improving diagnosis and treatments. According to the regulations, foreign organizations and individuals, as well as organizations directly controlled by them, are not allowed to collect or preserve China’s human genetic resources, nor is providing such resources abroad. Collecting, preserving, utilizing, and providing human genetic resources abroad should be in accordance with ethics principles, submit to corresponding ethics investigations, and meet the technical standards formulated by scientific administrative departments of the State Council, with no violations on the country’s public health, national security, and public interests. Sales of human genetic resources are prohibited, said the regulations.

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It is mentioned in the regulation that “In order to obtain the market approval of relevant drugs and medical devices in China, international cooperative clinical trials conducted in clinical institutions using human genetic resources of China, which do not involve the exit of human genetic resources materials, do not need approval”. During the period before effective date, applications accepted before 5 pm June 28 2019 will follow the “old” procedure. Applications accepted after this time point will follow the procedure in the new regulation.

NMPA published the Medical Device This report summarized the 2018 data of key regulations update, registration project registration 2018 annual review34 submission & approval, and key innovative medical devices approval information.

Jiao Hong attended the first BBS In June, 2019, Jiao Hong, Director of the NMPA, attended the first BBS conference on conference on global health in boao global health in Boao Asia BBS. Jiao Hong said that China, as an important part of the Asia35 global pharmaceutical supply chain, is providing a large number of high-quality pharmaceutical products to the world. NMPA always gives top priority to public health protection, adheres to the bottom line of drug safety, promotes innovative development, improves regulatory capacity, and deepens international cooperation, so as to make every effort for drug safety and effectiveness and contribute to global health. During the meeting, Jiao Hong met with who Deputy Director-general Dr. Suzanne Jacobs and GAVI CEO Dr. Seth Berkley respectively, and had in-depth discussions on topics such as vaccine regulatory system, drug and vaccine pre-certification, and innovative vaccine development.

CDE published the Drug registration 2018 This report summarized the 2018 data of key technical guidelines, registration project annual review36 submission & approval, and key innovative drug approval information. In 2019, CDE objectives include: (I) Actively promoting the implementation of various reform tasks

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(II) Performing law-based duties for better drug review & approval (III) Continue to promote the evaluation system to keep abreast of the international standards (IV) Continue to promote the modernization of review system and construction of the CDE talent team Vaccine Administration Law approved by The Vaccine Administrative Law approved in end of June, and effective from December 1, the Standing Committee of the Chinese 2019. This is the first law focus on vaccine management that features penalties on the People's Congress37 production and sale of substandard or fake vaccines. The new law, which is the strictest and most comprehensive on vaccines in China, will cover the research and development, production, distribution, use, supervision and management of vaccines in the country.

Background story: Legislate independent Vaccine Administration Law17 NMPA Improvement Policy Concerning NMPA announce a new policy to optimize and replace all former regulations about active Bundling Review and Approval for Drugs ingredient, excipient and packaging material. The regulation effective on Aug 15, 2019. Any and the Corresponding Supervision Plan38 inconsistency between this policy and the former relevant documents of the Bundling Review, this policy shall prevail. Dossier requirement of excipient (trial), packaging material (trial), Product list which exempted from registration, and basic requirement of annual report are attached. State Council high level opinion on The State Council recently issued a high level opinion on building a team of professional building a professional and specialized and specialized team of pharmaceutical drug inspectors. team of pharmaceutical products The document advances improving the pharmaceutical drug inspection system by inspection39 establishing national and provincial teams of specialized inspectors. According to the document, the inspectors will be an important force for strengthening drug supervision and ensuring drug safety.

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A professional, specialized drug inspection system with full-time inspectors as the main body and part-time inspectors as the supplement will be established within the next three years. Q&A on R&D of Biosimilars40 CDE summarized their considerations on the most frequently asked questions during biosimilar drug review, and released the Q&A on Jul 31, 2019. Registration strategy: Recommend of stepwise development of CMC, pre-clinical and clinical. After completion of CMC and pre-clinical similarity comparison, suggest to have pre-IND meeting with CDE to clarify the follow-up studies and study design. Suggest to perform a comparative PK study first in the stage of clinical research, which is followed up by a process o communication with CDE before following head to head safety and efficacy studies. Reference Drug selection: Highly recommend to select China approved originator as the reference drug. If the reference drug manufactured by different site (same license holder with originator), the evidence of comparability with the originator should be approved by CDE before starting the trial. Immunogenicity comparative study: Suggest to collect immunogenicity data in all clinical studies, including PK and PD studies. Equivalence margin of clinical similarity comparative study: The equivalence margin is generally estimated based on the Confidence Interval of the efficacy of the originator, and is determined with consideration of clinical significance. Indication extrapolation: Applicants must provide sufficient scientific evidence to support the application for indication extrapolation. For the reference drug has been approved for multiple indication, if the candidate drug is clinically similar to the reference drug through the comparison study, an extrapolation to

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other indications of the reference drug can be considered if the comparative study shows that the candidate drug is clinical similar to the reference drug. Extrapolation of indications must be considered case by case according to variety features and sufficiency of data on similarity. Indications for extrapolation should be those with clinically related pathological mechanism and/or identical relevant receptor, together with the same working mechanism and target. In a clinical comparative test, appropriate indication is selected and the safety and immunogenicity of indication for extrapolation are fully evaluated.

Prescription Information: Prescription Information of biosimilar drugs should be drafted generally based on the consideration not to affect their clinical use and to be conducive to post-marketing safety monitoring. Data on the clinical trial in the instructions of biosimilar drugs should reflect effectiveness and safety rather than similarity. Attention should be paid to the difference of the trade names of the reference drugs and the biosimilar drugs from the generic names. It is advised that the generic name instead of its trade name of the reference drugs be used in the reference to data on clinical studies of reference drugs.

Revision of the Drug Administration Law of The Standing Committee of the National People's Congress on Aug 26 2019 approved the the People's Republic of China 41 2nd revision to the Drug Administration Law, the core piece of legislation governing the pharmaceutical industry in China. The revision, effective as of Dec 1 2019, introduce several welcome changes to the original Drug Administration Law:  Most of the current regulatory reforms are legally banded in the Law: encourage clinical value-oriented drug innovation, drug for urgent needs (e.g. rare disease and severe disease), traditional medicine development, pediatric drug; IND approval within 60 working days; clinical trial in process control; bundling review; conditional

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approval; priority review; MAH; online drug sell; post market management; risk management; drug reserve & supply system; build professional and specialized inspector team, etc.

 Update the scope of fake drugs. In general, importing drugs without approval will still result in serious legal consequences, including the revocation of business permits. However, importing "a small amount" of drugs that do not cause health damage or interfere with existing treatment can be exempt from legal consequences,  Increase penalties for legal violations. Producing and selling fake drugs, for example, results in suspension of the business and revocation of certificates. A fine of up to 30 times the value of the products produced or sold will be levied, compared to the penalty of five times the value that is stipulated in the existing law.  Intelligence property reform is not included in this revision. As all these updates need details instruction to landing, more regulatory updates is expected in the future. NHSA Publishes Drug Catalogue of the New version of the National Medical Insurance drug catalogue is released with National Basic Medical Insurance, Industry comprehensive adjustment made aiming at optimizing the structure, reducing the drug cost Injury Insurance and Maternity Insurance42 burden of the public and improving the efficiency in the use of medical insurance funds. The catalogue establishes standard for drug payment by the insurance funds. The circular also announces a series of decisions regarding the implementation policies, covering the following aspects: reimbursing standard; implementation on local levels; centralized procurement and national drug database; price negotiation of drugs entering the catalogue. The new version will be effective on Jan 1 2020. Implementation Plan to Support the This is the level plan announced on Sep 17, 2019, which is an optimize version of previous Development of Boao International Medical plan in 2013. Tourism Pilot Zone 43

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The plan outlined major tasks of the pilot zone, located in Hainan, including developing top level medical service providers and research institutes and developing quality medical tourism services. By 2025, the zone will boast world class medical technologies, equipment and drugs, according to the plan. With the new policy, import approval of drug and medical device to the pilot zone will be faster. Data gathered on clinical use in the zone can be used for future registration in China. The measure may help to reduce the time for innovative overseas drugs to enter the domestic market. The administration is working with the Hainan provincial government to formulate detailed regulations to promote domestic access of overseas drugs, she said. NMPA Releases Technical Guideline for Lung cancer is the number one cause of death among people with malignant tumors in Clinical Trial Endpoints for the Advanced China. In lung cancer, 85% is non-small cell lung cancer (NSCLC). This guideline provides NSCLC 44 the general consideration on different clinical trial endpoints, and expect to give reference to NSCLC clinical trial design. NMPA officially joined On September 19 2019, IMDRF-16 meeting in Yekaterinburg, Russian, NMPA officially national competent authority report (NCAR) joined national competent authority report (NCAR) exchange program of IMDRF. exchange program of IMDRF45 The NCAR Exchange Program facilitates the exchange of relevant post market safety information on medical devices with global distribution. The aim is to trigger rapid adoption of field safety corrective actions in all concerned geographies to avoid death or serious deterioration of health. Up to date, there are more than 20 countries/regions joined this program. NMPA next step is share and exchange the information with member countries, timely obtain serious adverse events of medical device globally, which to secure the safety use of medical device in China.

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Regulations of People's Republic of China The newly issued national regulations aim at effectively protecting and reasonably utilizing on Management of Human Genetic human genetic resources. The regulations apply to the collection, preservation and using of Resources on June 10, 201946 a range of genetic materials containing human genomes and genes (organs, tissues and cells) and impose requirements on human genetic resource information (data derived from the genetic resource materials). It is issued to regulate and encourage reasonable employing of human genetic resources in scientific researches, developing biological medicine (drugs or medical devices) and improving diagnosis and treatments. According to the regulations, foreign organizations and individuals, as well as organizations directly controlled by them, are not allowed to collect or preserve China’s human genetic resources, nor is providing such resources abroad. CDE Announces Public Consultation on These three guidance documents are issued according to new requirements established in “Working Procedure for Breakthrough the updated Regulations on Drug Registration. The drafts are released for public Therapy Designated Drugs”, “Working consultation until November 13 2019. Any suggestions and feedback can be submitted Procedure for Priority Review and through the feedback form attached as second reference file and sent to CDE´s contact Approval”, Technical Guidelines for email boxes. Conditional Marketing Approval Granted to These notes gives supplementary information on the issuing of this draft guidance, Urgently Needed Drugs in Clinical Practice explaining the background, drafting process, key considerations and major content, and (Draft for Comments), as well as special issues that need to be highlighted. Explanatory Notes on Nov. 8, 201947

CDE Announces Public Consultation on This document is intended to give instructions as well as to further regulate studies and Technical Guidelines for Clinical Changes administration on post-approval clinical changes to drugs that are already in the market, to Already Marketed Drugs on Nov. 8, following the newly revised Drug Administration Law. The draft is now released to invite 201948 public review. Any suggestions and feedback should be submitted to CDE´s contact email box before November 13 2019. CDE Announces Public Consultation on Technical Guidelines for Researches

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Regarding Pharmaceutical Changes to Already Marketed Chinese Medicine, These documents are intended to give instructions as well as to further regulate studies on Technical Guidelines for Researches post-approval pharmaceutical changes to chemical drugs and biologics that are already in Regarding Pharmaceutical Changes to the market, following the newly revised Drug Administration Law. The drafts are now Already Marketed Chemical Drugs and released to invite public review. Any suggestions and feedback should be submitted through Technical Guidelines for Researches the feedback form attached as second reference file to CDE´s contact email box before Regarding Pharmaceutical Changes to November 13 2019. Already Marketed Biologics (Draft for Comments) on Nov. 8, 201949

NMPA Circular on Adopting 15 ICH NMPA announces the decision to adopt 15 ICH guidelines of “E Series” in China. The Guidelines Including E1: Extent of circular explains specific requirements and effective date of each of these guidelines. Population Exposure to Assess Clinical Relevant guidance documents are available on the website of Center for Drug Evaluation Safety for Drugs Intended for Long-Term (CDE). These 15 ICH guidelines are listed in the annex. Treatment of Non-Life-Threatening on Nov. 12 201950

NMPA Circular on Adopting 13 ICH NMPA announces the decision to adopt 13 ICH guidelines in China. Applicants are required Guidelines Including SIA: Guideline on the to conduct researches following ICH guidelines as soon as possible, but always based on Need for Carcinogenicity Studies of the current technical requirements. Non clinical studies that start from May 1 2020 should Pharmaceuticals on Nov.12, 201951 adopt these 13 ICH non clinical guidelines. Relevant guidance documents are available on the website of Center for Drug Evaluation (CDE). These 13 ICH guidelines are listed in the annex. NMPA and NHC Releases “Administrative NMPA and National Health Commission jointly releases these administrative measures Measures for Drug Clinical Trial following the newly established Drug Administration Law. These measures are effective Organizations”on Nov. 29, 201952 from December 1 2019.

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NMPA Circular on Guarantee the Record This circular is issued following the newly released “Administrative Measures for Drug Filing Procedure for Drug Clinical Trial Clinical Trial Organizations”, which gives further instructions on the implementation of Organizations Nov. 29, 201953 these measures. The administration of clinical trial organizations has changed from qualification accreditation to record filing. State Administration for Market Regulation This draft regulation is issued to meet the requirements established by the newly released (SAMR) SAMR Announces New Public Drug Administration Law and Law on Vaccine Administration. Any suggestions and Consultation on “Regulations on Drug feedback should be submitted through SAMR’s web portal, the authority’s contact email or Registration (Draft for Comments)” and by email before December 17 2019. The draft regulation as well as an explanatory note on Explanatory Note on the Issuance of its issuance are attached as annexes. Regulations on Drug Registration (Draft for These regulations apply to activities of drug R&D, registration and supervision for the Comments) on Dec. 10, 201954 purpose of marketing authorization. The content contains the following chapters: General Provisions; Basic Systems and Requirements; Registration for Drug Marketing Authorization; Accelerating Drug Marketing Authorization; Changes and Re-registration after Market Approval; Application Acceptance, Supplementary Dossier and Procedure Withdrawal; Dispute Resolution; Procedure Timing; Administration and Supervision; Legal Liabilities; Supplementary Provisions. This note gives further explanations on the issuance of this draft regulation, providing supplementary information on the following aspects: background and necessity of its issuance; drafting process; key considerations and major content of the new draft.

NMPA Releases Guidance for Using Real- NMPA announces the issuance and release of this guidance document, which is intended to World Evidence to Support Drug R&D and give further instructions and set requirements regarding the application of real-world Regulatory Review (Interim) and evidence in drug R&D as well as regulatory review/approval. The guidance and an Explanatory Note to Guidance for Using explanatory note to its issuance are provided as annexes. Real-World Evidence to Support Drug R&D This document gives supplementary information on the issuance of this guidance regarding and Regulatory Review (Interim)55 the background and process of its drafting, as well as further explanation on its major content.

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CDR-ADR Circular on the Launch of E2B The Center for Drug Reevaluation and National Center for ADR Monitoring announces the (R3) Electronic Transmission System56 launch of E2B (R3) electronic transmission system intended for the submission of individual case safety reports, starting from January 1 2020. Detailed instructions on the submission process are provided in the “Working Procedure of Individual Case Safety Report Submission Through E2B (R3) Electronic Transmission System”, which is attached as annex. There will be trial period for the system operation, during which the previous channel and requirements for submission remain valid.

NMPA Circular on Implementation of 11 NMPA issues this circular to inform the implementation of 11 ICH guidelines. ICH Guidelines Including Q2(R1) - Pharmaceutical researches starting 6 months after the publication date of this circular are Validation of Analytical Procedures: Text required to follow these ICH guidelines, otherwise applicants should follow them as soon as and Methodology57 possible. List of these 11 ICH guidelines and the corresponding Chinese titles is provided as Annex.

NMPA Circular on Recommended NMPA issues this circular to inform the recommended implementation of 4 ICH guidelines: Implementation of 4 ICH Guidelines Q8(R2) - Pharmaceutical Development; Q9 - Quality Risk Management; Q10 - Including “Q8 (R2) – Pharmaceutical Pharmaceutical Quality System; Q11- Development and Manufacture of Drug Substances Development”58 (Chemical Entities and Biotechnological/Biological Entities). Since the date of publication, drug applicants are suggested to follow the requirements established in these guidelines in the product R&D. List of these four ICH guidelines and the corresponding Chinese titles is provided as Annex. CDE Circular on Adjusting Administrative CDE has decided to temporarily adjust its administrative services related to drug registration Procedures Regarding Drug Registration application, dossier submission and consultation. From February 3 2020: 1). Online Application Acceptance, Dossier submission platform “Applicant’s Window” will be the channel for submission of electronic Submission, and Information Support dossier; 2). On-site channels for accepting documents of registration application, corrective and supplementary submission will be shut down and be replaced by postal service

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Service During Novel Coronavirus channel; 3). On-site consultation and information support will be closed and replaced by Outbreak on Feb.2, 202059 telephone communication.

SAMR Circular on Releasing “Forms and SAMR announces to release a compilation of reference forms and templates that are to be Templates Required During Examination used during the examination and approval of advertisements of drugs, medical devices, and Approval of Advertisements for Drugs, health food and formula food for special medical use. These document models are issued Medical Devices, Health Food and Formula under the framework of “Interim Administrative Measures for the Examination and Approval Food for Special Medical Use” on Feb 28, of Advertisements for Drugs, Medical Devices, Health Food and Formula Food for Special 201960 Medical Use”, which are intended to establish unified document format and standards for administrative procedures. The compilation of documents is provided as Annex. NMPA Announces Public Consultation on NMPA issues these two draft documents following requirements of the newly released “Guidance for Quality Agreement of national Drug Administration law. They are intended to give guidance to drug Marketing Contract Drug Manufacturing (Draft for Authorization Holders (MAHs) and contracted drug manufacturers in assuming Comments)” and “Reference Template for responsibilities and guarantee product quality. These two draft documents are now released Quality Agreement of Contract Drug for public consultation and they are provided as Annexes. Any suggestions and comment Manufacturing (Draft for Comments)” on should be submitted to NMPA’s contact email before March 18 2020. March 2, 202061

NMPA Announces Public Consultation on NMPA issues these two draft documents to give specific guidance on the implementation of “Working Procedures for Inspection of the newly released national Drug Administration Law and Vaccine Administration Law. They Drug Marketing Authorization Holders are intended to further regulate the inspection procedure on drug Marketing Authorization (Draft for Comments)” and “Key Points for Holders (MAHs), requiring MAHs to assume responsibilities for drug safety, efficacy and Inspection of Drug Marketing Authorization quality control during manufacturing, distribution and drug use. These two draft documents Holders (Draft for Comments)” on March 2, are now released for public consultation and are provided as Annexes. Any suggestions and 202062 comment should be submitted to NMPA’s contact email before March 18 2020.

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CDE issued Guidance for Clinical Trials on The patent on rituximab in China expired on 2013, following which many manufacturers of Rituximab Biosimilars (Draft for China and overseas have initiated R&D on its biosimilars. This draft guidance is issued Comments) on March 17, 202063 based on “Technical Guideline for Development and Evaluation of Biosimilars (Interim)” as well as characteristics of rituximab, which is intended to provide technical reference for its clinical research and development. It covers content of the following aspects: general introduction; major considerations in clinical research design for rituximab (pharmacokinetics comparison study; effectiveness comparison study; safety and immunogenicity studies); and summary.

SAMR Circular on 2020 Annual Legislation The SAMR announces the approval of 2020 annual legislation program and work plan, Program on March 17, 202064 which covers 7 final drafts of administrative laws and regulation, revision of 48 ministerial regulations, and a series of legislative proposals regarding market supervision and administration. Regulations on drug registration, manufacturing, distribution; release of biologics; online drug selling; medical device registration, manufacturing, distribution, adverse event monitoring; IVD registration, etc. are within this annual plan. The circular establishes procedure and principles for legislation drafting and revision, as well as gives detailed information on the implementation of the plan. A list of regulations included in the plan is provided within the circular. NMPA Announcement on Administrative These regulations apply to all extended clinical trials for medical devices that are conducted Regulations on Extended Clinical Trials for within China. “Extended clinical Trials” refer to the following practice: For a medical device Medical Devices (Interim) and Explanatory that has not been approved for marketing, it is allowed to be used by institutions that are Note to “Administrative Regulations on conducting its clinical trials on patients diagnosed with life-threatening diseases for which Extended Clinical Trials for Medical effective treatment is not available yet. The use of medical devices for extended clinical Devices (Interim)”65 trials should be based on the observation that existing clinical trials may benefit the subject,

and the patient cannot be admitted to the clinical trials that are already in process because the selection of participants has been completed. The regulations include the following

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This document was not published and chapters: General Principles; Rights and Responsibilities; Conditions for Starting; Procedure available on the website of NMPA until March Management; Data Collection; Supplementary Provisions. 20, 2020. This note provides further explanations and guidance concerning some major aspects established by the newly released regulations: 1). Application scope of extended clinical trials; 2). Proposal for starting extended clinical trials; 3). Agreement with trial participants; 4). Recording filing; 5). Data submission.

State Administration for Market Regulation These regulations are released under the State Administration for Market Regulation Decree (SAMR) SAMR Announces Regulations on No. 27 after the approval. They apply to activities of drug R&D, registration and supervision Drug Registration and NMPA for the purpose of marketing authorization within China, covering drugs, biologics and Announcement on Implementing traditional Chinese medicines. The content contains the following chapters: General 66 “Regulations on Drug Registration” Provisions; Basic Systems and Requirements; Registration for Drug Marketing

Authorization; Expedite Approval for Drug Marketing Authorization; Changes and Re- This document was not published and registration after Market Approval; Application Acceptance, Withdrawal and Dispute available on the website of NMPA until March Resolution; Procedure Timing; Administration and Supervision; Legal Liabilities; 30, 2020. Supplementary Provisions. Effective Date Jul 1, 2020

The NMPA announcement is issued following the newly released “Regulations on Drug Registration” as supplementary decision on its implementation, aiming to facilitate a smooth transition from the old regulation to the new one. The document clarifies regulatory requirements and gives specific explanations on administrative procedures regarding drug registration before and after the new regulation take effect.

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SAMR Announces Regulations on These regulations are released under the State Administration for Market Regulation Decree Supervision of Drug Manufacture on March No. 28 after the approval. They apply to administrative activities of supervision and 67 30, 2020 inspection on manufacturing of drugs marketed in China. The content is organized in the following chapters: General Provisions; Drug Production Permission; Administration of Drug This document was not published and Manufacture; Supervision and Inspection; Legal Liabilities; and Supplementary available on the website of NMPA until March Supervisions. 30, 2020. Effective Date Jul. 12020 NMPA Announcement on Matters This announcement is issued following the newly released “Regulations on Supervision of Concerning the Implementation of the Drug Manufacture” as supplementary decision on its implementation. The document clarifies Newly Revised “Regulations on regulatory requirements and gives specific explanations on administrative procedures Supervision of Drug Manufacture” on regarding drug manufacturing, license application, approval and renewal etc. before and 68 March 31, 2020 after the new regulation takes effect. The announcement includes the following checklists and forms that are required in the procedures mentioned: 1). Checklist for Drug Manufacture License Application Dossier; 2). Checklist for GMP Compliance Inspection Application Dossier; 3). Drug Manufacture License Application Form; 4). GMP Compliance Inspection Application Form. These checklists and forms are provided as Annexes.

Explanatory Note to Policies in This note gives further explanations to the issuance of the newly released “Regulations of “Regulations on Supervision of Drug Drug Registration” as well as new policies and measures established through a series of 69 Registration” Q&As. It covers key topics including regulation issuing background; issuing purpose and principles; strengthened supervision on drug life circle; reform on administrative procedures regarding drug review and approval; new concepts and mechanism introduced; measures to encourage drug innovation and research, etc.

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CDE Announces Public Consultation on CDE has issued these two draft guidance documents to give technical reference to the R&D “Technical Guidance on Clinical Trials for and clinical trials of medicines targeting bacterial infection. Now the administrative authority R&D of Drugs Targeting Community is inviting public opinions on these two drafts, which are provided as Annexes. Any Acquired Bacterial Pneumonia” and suggestions and feedback should be submitted to CDE’s contact email boxes. “Technical Guidance on Clinical Trials for R&D of Antimicrobial Agents Targeting Acute Bacterial Skin and Skin Structure Infection” on March 19, 2020 70

CDE Announces Public Consultation on Currently many companies of China and overseas are in the process of developing “Guidance for Clinical Trials on biosimilars of Adalimumab, which was originally developed and marketed by Abbot Adalimumab Injection Biosimilars (Draft for Laboratories. This draft guidance is intended to provide technical reference for conducting 71 Comments)” on Apr. 1, 2020 clinical researches on Adalimumab biosimilars. The draft guidance is now released online to invite public opinion. Any feedback and suggestions should be submitted to CDE’s contact email boxes. The draft guidance is provided as Annex. CDE Announces Public Consultation on Trastuzumab, sold under the brand name Herceptin; and originally developed by Roche, is a “Guidance for Clinical Trials on monoclonal antibody specially used for cancer that is HER2 receptor positive. Currently Trastuzumab Injection Biosimilars (Draft many companies of China and overseas are in the process of developing trastuzumab 72 for Comments)” on Apr. 7, 2020 Injection biosimilars. This draft guidance is intended to provide technical reference for conducting clinical researches for developing trastuzumab biosimilars and is now released online to invite public opinion. Any feedback and suggestions should be submitted to CDE’s contact email boxes. The draft guidance is provided as Annex.

CDE Announces Guidance for Clinical Denosumab entered Chinese market under the brand name Xgeva® in 2019 and its patent Trials on Denosumab Injection Biosimilars in China will be expired on 2022. Currently many manufacturers in China have initiated R&D on denosumab injection biosimilars. This draft guidance is issued based on “Technical

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(Malignant Tumors as the Indications) Guideline for Development and Evaluation of Biosimilars (Interim)” as well as characteristics (Draft for Comments) on Apr. 10, 202073 of denosumab, which is intended to provide technical reference for its clinical research and development. This guidance only discusses denosumab biosimilars targeting cancer patients. It covers content of the following aspects: general introduction; clinical research strategies for denosumab biosimilars; major considerations in clinical study design (pharmacokinetics comparison study; effectiveness comparison study; other aspects such as safety and immunogenicity studies and extrapolation of indications); and summary. This note gives further information regarding the issuance of this draft guidance on the following aspects: 1). Background and purpose; 2). Process of issuance; 3). Major content and key consideration in the guidance. CDE Announces Guidance for Clinical Pertuzumab entered Chinese market under the brand name Perjeta® in 2018. It is a Trials on Pertuzumab Injection Biosimilars monoclonal antibody used in treatment of metastatic HER2-positive breast cancer. The 74 (Draft for Comments) on Apr.17, 2020 patent of Pertuzumab will be soon be expired in EU (2023) and US (2024), and currently many manufacturers in China have initiated R&D on Pertuzumab biosimilars.This draft

guidance is issued based on “Technical Guideline for Development and Evaluation of Biosimilars (Interim)” as well as characteristics of Pertuzumab, which is intended to provide technical reference for its clinical research and development. It covers content of the following aspects: general introduction; clinical research strategies for Pertuzumab biosimilars; major considerations in clinical study design (pharmacokinetics comparison study; effectiveness comparison study; other aspects such as safety and immunogenicity studies); and summary. CDE Announces Public Consultation on This draft guidance is issued to set up a standard process regarding the clinical trial imaging “Technical Guidance on Clinical Trial endpoint for the R&D of anticancer drugs, aiming at further regulating industrial standard Imaging Endpoint Process Standards for and establishing technical requirements. Any suggestions and feedback should be Anticancer Drugs (Draft for Comments)” on Apr.22, 202075

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submitted through the Feedback Form and sent to CDE´s contact email boxes. The form, the draft guidance and an explanatory note are provided as Annexes. NHC Circular on Releasing “Administrative Following “State Council Circular on Guarantee Supplies and Maintaining Prices of Drugs in Regulation on National List of Drugs in Shortage”, NHC has established these administrative measures to further strengthen the 76 Shortage (Interim)” on Apr. 20, 2020 supply and supervision of drugs in shortage. The interim regulation is provided as Annex 1. Drug shortage that cannot be solved on local level should be reported through the form provided as Annex 2 to the administration of central government. NMPA and NHC Joint Announcement on NMPA and NHC have jointly established the new Good Clinical Practice (GCP) for drugs Releasing “Good Clinical Practice for and now announce its release. This guidance is intended to further regulate research and 77 Drugs” on Apr.23, 2020 clinical trials on drugs as well guarantee the quality of these practices. The guidance document is provided as Annex. This guidance applies to clinical trials conducted for the application of drug registration and regulates activities that are relevant to drug clinical trials. The Good Clinical Practice (GCP) established here are quality standards for the whole process of clinical trials, covering trial design, organization and implementation, supervision, inspection, record registration, analysis, making conclusion and report submission. Content of the document are organized in the following chapters: General Principles; Terminologies and Definitions; Ethics Committee; Investigators; Clinical Trial Organizers and Sponsors; Trial Program Design; Investigator’s Brochure; Management of Required Dossier; Supplementary Provisions. Effective Date Jul 1 2020 CDE Announces Public Consultation on This ICH guideline is now in the third stage of regional regulatory consultation and ICH Guideline “Impurities: Guideline for discussion. The CDE announces to collect opinion on the step 2b draft guideline on regional Residual Solvents Q3C(R8) ”on Apr.29, level. Any suggestions and feedback should be submitted to CDE´s contact email boxes 78 2020 before the deadline for comments.

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NMPA Announces Public Consultation on Following the NMPA announcement on the implementation of the newly released Regulatory Documents Including “Basic “Regulations on Drug Registration”, the administrative authority has drafted these two Requirements and Review Key Points regulatory documents concerning re-registration application for domestically manufactured Regarding Application Procedure and drugs and drugs manufactured overseas. These two drafts are provided as Annex 1 and Dossier for Re-registration of Domestically Annex 2. Any suggestions and feedback should be submitted through the feedback form Manufactured Drugs (Draft for Comments)” provided as Annex 3 and sent to NMPA’s contact emails. on Apr.29, 202079 NMPA Announces Public Consultation on The NMPA has decided to revise Module 1 of M4 CTD guidance document following “M4 Module 1 Administrative Documents requirements established in the newly released “Regulations on Drug Registration”. The and Drug Information” (Draft for draft of the revision is now released to invite public opinion. Any suggestions and feedback 80 Comments) on Apr.29, 2020 should be submitted to the authority’s contact email box. The draft is provided as Annex. NMPA Announces Public Consultation on This draft guidance document is issued as a follow up of NMPA announcement on the “Basic Requirements for Drug Registration implementation of the newly released “Regulations on Drug Registration” to further improve Application Dossier (Draft for the administrative procedure. Any suggestions and feedback on the draft should be 81 Comments)”on Apr.29, 2020 submitted through the feedback form provided as Annex 2 and sent to the authority´s contact email box. The draft guidance is provided as Annex 1. NMPA Announces Public Consultation on NMPA revised this draft guidance according to requirements established in the newly issued “Technical Guidelines for Clinical Changes “Regulations on Drug Registration”. The draft is now released to invite public review. All to Already Marketed Drugs (Draft for suggestions and feedback should be submitted to the authority’s contact email before the 82 Comments)” on Apr.29, 2020 deadline. The draft guidance is provided as Annex. NMPA Releases “List of Reference The 27th list of reference preparations for generic drugs has been given approval by the Preparations for Generic Drugs (27th List) Generic Drug Advisory Committee and now is announced to be released by NMPA. The list 83 on Apr.29, 2020 is provided as Annex. NMPA Announces Public Consultation on 6 The NMPA has issued the following six draft regulatory documents regarding the Regulatory Documents Including “Special administration and supervision of Chinese medicine registration and marketing: “Special Regulations on the Administration of Regulations on the Administration of Chinese Medicine Registration”, “Classification System

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Chinese Medicine Registration” on Apr. 29 for Chinese Medicine Registration and Requirements for Application Dossier”, “Post- 202084 approval Changes to Marketed Chinese Medicines and Requirements for Application Dossier”, “Technical Guidelines for Researches Regarding Pharmaceutical Changes to Already Marketed Chinese Medicines”, “Review Guidelines for the Acceptance of Chinese Medicine Registration”, and “Review Guidelines for the Acceptance of Chinese Medicine Post-approval Changes”. All these drafts are now released for public review. Any suggestions and feedback can be submitted through the online portal, or through feedback forms provided as Annex 12 then sent to corresponding contact person according to the information sheet provided as Annex 13. An explanatory note is released for each draft for further reference. All drafts and notes are provided as Annexes. NMPA Announces Public Consultation on Following the newly issued Regulations on Drug Registration, the NMPA has issued the Regulatory Documents Including following five draft regulatory documents regarding the administration and supervision of “Classification System for Registration of chemical drug registration and marketing approval: Classification System for Registration of Chemical Drugs and Requirements for Chemical Drugs and Requirements for Application Dossier; Post-approval Changes to 85 Application Dossier” on Apr. 29 2020 Marketed Chemical Drugs and Requirements for Application Dossier; Technical Guidelines for Researches Regarding Pharmaceutical Changes to Already Marketed Chemical Drugs; Review Guidelines for the Acceptance of Chemical Drug Registration; Review Guidelines for the Acceptance of Chemical Drugs Post-approval Changes. These drafts together with an explanatory note for each are provided as Annexes. Any suggestions and feedback can be submitted through feedback form provided as Annex 6 then sent to NMPA’s contact email boxes. NMPA Announces Public Consultation on 7 Following the newly issued “Regulations on Drug Registration”, the NMPA has issued the Regulatory Documents Including seven draft regulatory documents regarding the administration and supervision of biological “Classification System for Registration of product registration and marketing approval. They cover aspects of registration classification Biologic Products and Requirements for system, post-approval changes, post-marketing researches on pharmaceutical changes, Application Dossier (Draft for Comments)”

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On Apr. 29 202086 review guidelines for acceptance of application. These drafts together with an explanatory note for issuance are provided as Annexes. Any suggestions and feedback can be submitted through feedback form provided as Annex 9 then sent to NMPA’s contact email boxes. CDE Announces Public Consultation on These guidelines are drafted following requirements established in the newly issued “Review Guidelines for the Acceptance of “Regulations on Drug Registration”. The draft is now released online to invite public opinion. Active Pharmaceutical Ingredient (API) Any suggestions and feedback should be submitted through the feedback provided as 87 Registration” on Apr. 30 2020 Annex 3 and sent to CDE’s contact email boxes. The draft together with an explanatory note on its issuance are provided as Annex 1 and Annex 2. CDE Announces Public Consultation on CDE has drafted an updated version of these guidelines to meet new needs from the “Administrative Measures for the industry for a more efficient and faster channel of communication with the administrative Communication on Drug R&D and authority during drug registration and review. This draft (provided as Annex) is now released Technical Review (Draft for Comments)” on to invite public consultation. Any suggestions and feedback should be submitted through the 88 Apr. 30 2020 feedback form provided as Annex and sent to CDE´s contact email box. CDE Announces Public Consultation on These procedures are established to follow up the newly issued “Regulation of Drug “Procedures for Review and Approval of Registration” and as a revision of previous draft version. This draft is now released online to Drug Conditional Marketing Authorization invite public review. Any suggestion and feedbacks can be submitted through the feedback 89 (Draft for Comments)” on Apr. 30 2020 from provided as Annex and sent to CDE´s email box. The draft together with an explanatory note to its issuance are also provided as Annexes. CDE Announces Public Consultation on These draft regulations are made according to requirements established in the newly issued “Regulations on Associated Review and “Regulations on Drug Registration” and now are released online to invite public review. Any Approval of Pharmaceutical Active suggestions and feedback should be submitted through the feedback form provided as Ingredients, Pharmaceutical Excipients, Annex and sent to CDE’s email box. The draft together with an explanatory note are also Pharmaceutical Packaging Materials and provided as Annexes. Drug Preparations (Draft for Comments)” on Apr. 30 202090

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CDE Announces Public Consultation on The administrative authority in China is in the process of accelerating the marketing of brand “Clinical Requirements for Drugs Listed name drugs and generic drugs that are already listed overseas in China. This guidance is Overseas but Not Yet Marketed drafted to provide technical standard for the industry and regulators. It is now released 91 Domestically” Apr. 30 2020 online to invite public opinion. Any suggestions and feedback should be submitted through the annexed feedback form and sent to CDE’s contact email box. The draft guidance is also provided as Annex. CDE Announces Public Consultation on This draft guidance is issued to set up a standard process regarding the clinical trial imaging “Technical Guidance on Clinical Trial endpoint for the R&D of anticancer drugs, aiming at further regulating industrial standard Imaging Endpoint Process Standards for and establishing technical requirements. Any suggestions and feedback should be Anticancer Drugs (Draft for Comments)” submitted through the Feedback Form and sent to CDE´s contact email boxes. The form, Apr. 22 202092 the draft guidance and an explanatory note are provided as Annexes.

CDE Announces Public Consultation on This guideline is drafted to further standardize the procedure of drug clinical trial data “Guideline on the Submission of Clinical submission. Now the draft is released online to invite public opinions. Any suggestions and Trial Data (Draft for Public Review)” on May feedback should be submitted to CDE’s contact email boxes. The draft guideline together 93 6, 2020 with an explanatory note to its issuance are provided as Annexes. CDE Releases “Technical Guideline for CDE Releases “Technical Guideline for Studies of Nitrosamine Impurities in Chemical Drugs Studies of Nitrosamine Impurities in (Interim)” 94 Chemical Drugs (Interim)” on May 8, 2020 CDE Announces Public Consultation on These guidelines are intended to provide instructions on the organization, analysis and “Technical Guidelines on Preparing Safety summarizing of safety data for innovative anti-tumor drugs that are under applications to be Data Submission for Innovative Anti-Tumor marketed for the first time. The document gives specific guidance and explanations on data Drug Marketing Application (Draft for source; standardization of data presentation and suggestions for adverse reaction 95 Comments)” on May 9, 2020 determination; and suggestions for preparing the safety data dossier.

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NMPA Circular on Requiring Quality and This circular is issued to inform drug marketing authorization holders (MAHs) of NMPA’s Efficacy Consistency Evaluation of Generic requirements for quality and efficacy consistency evaluations of generic injectable drugs. 96 Injectable Drugs on May 12, 2020 For products that are already marketed but have not been reviewed according to principles of consistency evaluation, the MAH is required to carry out this activity and submit the application for authority’s review following administrative procedure of “supplementary application”. CDE Announces Public Consultation on This guideline focuses on the important concepts and principles for adaptive designs in “Guideline on Adaptive Designs for Clinical clinical trials, primarily on the use of adaptive designs in confirmatory clinical trials of Trials (Draft for Public Review)” on May 13, chemical drugs, biological products and traditional Chinese medicines, although the 97 2020 concepts are also relevant for exploratory studies. It provides guidance to sponsors and applicants submitting investigational new drug applications, new drug applications, biologics licensing applications, or supplemental applications on whether and/or how to appropriately use adaptive designs for clinical trials. Some commonly used adaptive designs will be discussed from a regulatory perspective, including recommendations for the sponsor to consider and some specific requirements. CDE Announces Public Consultation on These two regulatory documents are issued to meet new requirements established in “Management System for Drug Clinical relevant regulations: After the application of conducting clinical trials is approved for a drug, Trial Registration and Information applicants are required to register and update information of the trials as well as submit the Communication” and “Provisions on development safety update reports. These two drafts are released for public consultation Requirements and Management of until November 15 2019. Any suggestions and feedback should be sent to CDE’s contact Development Safety Update Report” on emails through the feedback from attached as second reference document before the Nov 8, 201998 deadline for comments. NIFDC Announces Public Consultation on This regulatory decision is drafted as supportive document to the newly issued “Regulation “Testing Procedures and Technical on Drug Registration” to reflect updated requirements concerning testing and inspection Requirements for Drug Registration (Draft required in drug registrations. The draft decision together with its annexes are now released for Comment)” on May 15, 202099

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to invite public review and are provided as Annex 1. Any suggestions and feedback should be submitted through the feedback form provided as Annex 3 and sent to NIFDC´s contact email box. An explanatory note to the issuance is provided as Annex 2. NMPA Releases “Technical Review The administrative authority announces to release this technical review guideline expecting Guideline for the Registration of Dengue to further improve the efficiency and quality of device registration. The guideline is provided Virus Nucleic Acid Detection Reagents” on as Annex. May 14, 2020100 Technical Guidance for Using Real-World This guidance is drafted based on the practical needs of pediatric drug R&D and regulatory Evidence to Support R&D and Regulatory review of China as well as the implementation of ICH E11 (R1). It focuses on major Review of Pediatric Drugs (Draft for considerations in using real-word evidence (RWE) to support pediatric drug R&D procedure, 101 Comments) on May 18, 2020 which are applicable to pediatric drugs including chemical drugs, Chinese medicines and biological products. The document includes content in the following sessions: Introduction; basic considerations (applicable scope of RWE, application time of RWE; relations between RWE and common clinical trials; cases of RWEs in supporting the R&D pediatric drugs; and key aspects worth special attention. NMPA Releases “Evaluation Guideline for The NMPA announces the issuance and publication of this guideline to further improve the Raw Material Changes to Passive Medical quality in device registration review and supervision. The guideline is provided as Annex. Devices” May 19, 2020102 CDE Announces Public Consultation on Tocilizumab, sold under the brand name Actemra® and originally developed by Roche, is a “Guidance for Clinical Trials on humanized igG1 monoclonal antibody against the human interleukin-6 (IL-6) receptor Tocilizumab Injection Biosimilars (Draft for produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. Currently 103 Comments)” May 21, 2020 many companies of China and overseas have initiated the development of tocilizumab Injection biosimilars, and this draft guidance is issued expecting to provide technical reference for clinical researches of this aspect. Now the draft is released online to invite public opinion. Any feedback and suggestions should be submitted through the attached

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feedback form and sent to CDE’s contact email boxes. The draft guidance, feedback form and an explanatory note are provided as Annexes. CDE Announces Public Consultation on This draft guidance is issued to encourage drug innovation facilitate the communication of “Technical Guidance for Communications technical issues between applicants and regulatory authority during the R&D of innovative on Clinical Aspects Before the Initiation of anticancer drugs supported by single arm trials. This guidance does not apply to cell therapy Key Experiments During the Registration and gene therapy products. Now it is released online to invite public review. Any of Innovative Anticancer Drugs Supported suggestions and feedback should be submitted through the attached feedback form and by Single Arm Trials (Draft for Comments)” sent to CDE´s contact email boxes. The draft together with an explanatory note to its May 22, 2020104 issuance are provided as Annexes. CFDI Announces Public Consultation on CFDI has drafted these two regulatory documents as supportive documents to the newly Two Regulatory Documents Including issued Regulation on Drug Registration, specifying general principles, administrative “Regulations on Implementation Principles procedures, timing and requirements for drug inspections during registration; Regulations on and Procedures of Drug Registration Implementation Principles and Procedures of Drug Registration Inspections; Key Points and Inspections (Draft for Comments)” May 22, Determination Principles for Drug Registration Inspections. These drafts are now released to 2020105 invite public review. Any suggestions and feedback should be submitted through the attached feedback form and sent to CFDI contact email box. Draft documents, together with an explanatory note to the issuance and the feedback form are provided as Annexes. CDE Notice on Gradually Restoring Office This notice is issued to inform the public that CDE’s administrative services provided in Administrative Services May 22, 2020106 office that were suspended during the Covid-19 pandemic are partially restored from May 25 2020. The office for dossier submission and pick-up is opened, while on-site consultation and information service are still suspended. Meanwhile, document submission and administrative procedures are still encouraged to be carried out through postal service channel. Visitors to CDE office are required to make appointment in advance by registering their health information in the form provided as Annex and sending it to CDE’s email box.

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CDE Releases “Guidance on Clinical Trial CDE Releases “Guidance on Clinical Trial Design for Biosimilars of Liraglutide Injections” Design for Biosimilars of Liraglutide CDE releases this guidance after the official approval, expecting to give technical guidance 107 Injections”on May 28, 2020 for the R&D of liraglutide injection biosimilars. The guidance together with an explanatory note to its issuance are provided as Annexes. NMPA Releases “List of Reference The 28th list of reference preparations for generic drugs has been given approval by the Preparations for Generic Drugs (28th List)” Generic Drug Advisory Committee and now is announced to be released by NMPA. The list 108 on May 28, 2020 is provided as Annex. CDE Announces Public Consultation on Aiming at encouraging the R&D of new drugs and providing technical reference for common “Technical Requirements Concerning pharmaceutical issues concerning drug safety that constantly occur during the application Common Pharmaceutical Issues in for phase I clinical trials of innovative drugs, the CDE has drafted the Technical Application for Phase I Clinical Trials of Requirement document and proposed a revision on the “Summary Table for Information of Innovative Chemical Drugs (Draft for Pharmaceutical Researches Related to Application for Phase I Clinical Trials of Innovative Comments)” and “Summary Table for Chemical Drugs”, which is the annex part of “Technical Guidance on Phase I New Drugs Information of Pharmaceutical Researches Registration” released by the former CFDA in 2018. These two drafts together with an Related to Application for Phase I Clinical explanatory note to the issuance and the feedback form are provided as Annexes. Any Trials of Innovative Chemical Drugs suggestions and feedback should be submitted through the feedback form to CDE´s email (Revised Version)” on June 1, 2020109 addresses. CMDE Circular on Further Regulating the The CMDE has this issued this circular to inform device registration applicants of Procedure of Acceptance and Filing supplementary requirements related to filing review procedures: In case of lack of Review for Medical Device Registration on documents in the application dossier, the CMDE will issue a letter with comprehensive 110 June 5, 2020 information and applicants should make one single supplementary/corrective submission; supplementary/correction submission should be made as associated submission to the initial submission; the regulatory authority will include advices on technical review in the feedback given for filing review.

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CMDE Circular Concerning Imported The CMDE has noted numerous cases in regulatory review of imported device registration Medical Device Applying for Registration applications that many devices categorized as class II by applicants in submission are as Class II Device but Categorized Under designated as class III device after the technical review by the authority. These applications Class III After Technical Review: with error in classification are required to be withdrawn and re-submitted after correction. Registration Application Withdrawal and This circular gives specific explanations on how to withdraw submitted application in this Follow-up Procedures on June 5, 2020111 case and how to make new submission after having received feedback from the administrative authority. NMPA Announces Public Consultation on To implement the General office of the central committee of the communist party of China “The Measures for record filing regulation and the General Office of the State Council about "The opinion on deepening the reform of of Medical Representatives (Trial) (Draft for the review and approval system and encouraging the innovation of drugs and medical 112 Comments)” on June 5, 2020 devices ([2017] no. 42)”, to standardize the working behaviour of medical representatives, NMPA organized to draft “The Measures for record filing regulation of Medical Representatives (trial) (draft)". Now it is released online to invite public review. Please send comments via email to [email protected] before June 19, 2020, with the subject line "Feedback on Measures for record filing regulation of Medical Representatives". CFDI Announces Public Consultation on This regulatory document is drafted according to the Regulations for Drug Registration to “Drug Safety Credit Record Management establish specific administrative measures for managing drug safety credit record in System for Nonclinical Safety Evaluation nonclinical safety evaluation research institutes and clinical trial organizations. Any Research Institutes and Clinical Trial suggestions and feedback should be submitted through the attached feedback form and Organizations (Draft for Comments)” on sent to CFDI’s contact email box. The draft, together with an explanatory note and the June 5, 2020113 feedback form are provided as Annexes. CDE Announces Public Consultation on Denosumab, sold under brand name Prolia® for the treatment of osteoporosis and originally the “Guidance on Clinical Trial Design for developed by Amgen, is a is a fully human monoclonal antibody directed against receptor Biosimilars of Denosumab Injections activator of nuclear factor-κB ligand (RANKL), which interferes with the formation, activation, (Osteoporosis as Indications) (Draft for and survival of osteoclasts. Currently many companies of China and overseas have initiated Comments)” June 5, 2020114

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the development of denosumab Injection biosimilars, and this draft guidance is issued expecting to provide technical reference for clinical researches of this aspect. Any suggestions and feedback should be submitted through the attached feedback form and sent to CDE´s contact email boxes. The draft guidance, together with an explanatory note and the feedback form are provided as Annexes. CDE Announces Public Consultation on This draft guidance is issued based on the “Technical Guidance for Communications on “Technical Guidance for Communications Clinical Aspects Before the Initiation of Key Experiments During the Registration of Before Marketing Approval Application on Innovative Anticancer Drugs Supported by Single Arm Trials (Draft for Comments)”, which is Clinical Aspects Concerning Innovative intended to facilitate the communication of technical issues between applicants and Anticancer Drugs Supported by Single Arm regulatory authority before the submission of marketing approval application. Any Trials (Draft for Comments)” on June 5, suggestions and feedback should be submitted through the attached feedback form and 2020115 sent to CDE´s contact email boxes. The draft together with an explanatory note to its issuance are provided as Annexes. NMPA CDE Announces “The To protect drug approval science fair, give full play to the important role of experts in drug Administrative Measures for External registration evaluation decision, according to the State Council about “The opinion on the Experts of CDE” and “The List of The First reform of review and approval system of drugs and medical devices"(guo fa [2015] 44), the Batch of CDE (No. 4 of 2020)” on June 5, General office of the central committee of the communist party of China and General Office 2020116 of the State Council about "The opinion on deepening the reform of the review and approval system and encouraging the innovation of drugs and medical devices([2017] no. 42)”, and drug administration relevant regulations of China, CDE has formulate “The Administrative Measures for External Experts of CDE” (see appendix 1), and approved by NMPA, It is hereby issued. In accordance with the prescribed procedures, CDE has organized the selection of external experts, and with the approval of the NMPA, hereby publish the list of the first batch of external experts of CDE (see Annex 2). If there is any change in the expert information,

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please inform CDE to update. CDE will continue to carry out external expert selection work, specific issues will be announced later. NMPA Releases “Guideline on Following requirements established in updated major regulations on drug administration, the Management and Archiving of Required NMPA announces the issuance and release of this guideline expecting to provide technical Documentation for Drug Clinical Trials” instructions on the management of drug clinical trial files. The guideline is provided as 117 June 5, 2020 Annex. CDE Announces Public Consultation on The CDE has drafted this guideline expecting to promote and give instructions to the “Guideline on Pharmaceutical development of paediatric medicines. Any suggestions and feedback should be submitted Development of Medicines (Chemical through the feedback form attached and sent to CDE’s contact email box. The draft Drugs) for Paediatric Use (Draft for guideline together with a note to its issuance and the feedback form are provided as Annex. Comments)” on June 12, 2020118 NMPA Releases “List of Reference The 29th list of reference preparations for generic drugs has been given approval by the Preparations for Generic Drugs (29th List)” Generic Drug Advisory Committee and now is announced to be released by NMPA. The list 119 June 16, 2020 is provided as Annex. Circular on the Release of “General The circular jointly issued by 5 administrative authorities announces the establishment and Requirements for Biosafety of Vaccine publication of the requirements for vaccine manufacturing biosafety, which are temporary 120 Manufacturing Sites” on June 18, 2020 emergency requirements during the Covid-19 prevention and control. The requirement document is provided as Annex CDE Announces Public Consultation on The CDE has drafted this guidance that particularly applies to the category of “modified new “Technical Guidance on Clinical Trials for drugs” specified in article 4 on the classification for drug registration in the newly issued Modified New Chemical Drugs (Draft for “Regulations for Drug Registration”. It is intended to explain the expected clinical 121 Comments)” on June 24, 2020 advantages of drugs under this category and how these advantages can be proved by clinical trials. The draft guidance together with an explanatory note and a feedback form are provided as Annexes. Any suggestions and feedback on the draft should be submitted through the form and sent to CDE’s contact email addresses.

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CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical instructions and “Technical Guidance on Endpoints of suggestions in clinical research pathways and design for the R&D of drugs targeting Clinical Trials for Advanced Hepatocellular advanced hepatocellular carcinoma. The draft guidance, together with an explanatory note Carcinoma (Draft for Comments)” on June and a feedback form are provided as Annexes. Any suggestions and feedback should be 122 24, 2020 submitted through the form and sent to the CDE’s contact email addresses. NMPA Announces Launch of “Drug According to the relevant requirements of the newly released Drug Registration Regulation, Registration application software (2020 drug registration applicants are required to download the drug registration application 123 version)” on June 24, 2020 software (Version 2020) in a timely manner from July 1, 2020. Effective Date Jul 1, 2020 CMDE Notice on Information Support CMDE releases this notice to inform the public regarding its consultation service available Service During July and August 2020: during July and August of 2020 on medical device registration procedure before submitting Technical Consultation Before Medical the application. Detailed information on related department and service available timetable Device Registration Application on June are provided in the notice. The arrangement of consultation service during Covid-19 124 22, 2020 outbreak will temporarily follow the circular No. CMDE2020/3, which is provided as “Related Document”. CDE Announces Public Consultation on The CDE has drafted this guidance to establish the technical standards, expecting to “Guidance on Designing Clinical Trials for provide instructions on the drug R&D process. The draft guidance together with an GnRH Agonists in the Treatment of explanatory note and a feedback form are provided as Annexes. Any suggestions and Advanced Prostate Cancer” on June 28, feedback should be submitted through the form and sent to CDE’s contact email boxes. 2020125 CHP Circular on Implementing "Chinese As follow-up measures to the newly issued Chinese Pharmacopeia Version 2020, this Pharmacopoeia Pharmaceutical Excipient “guardianship mechanism” is to be implemented on the administration of pharmaceutical Monograph Guardianship Mechanism” on excipient standard monograph. The monograph of each pharmaceutical excipient included 126 June 17, 2020 in the Chinese Pharmacopeia will be assigned to a responsible “guardian” institute for drug testing and control to guarantee its implementation. The “guardian” institute has the

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following responsibilities: Providing technical consultation service regarding the application of pharmacopeia standards; collecting feedback and opinions from the public on the current pharmacopeia and staying updated with industrial development to coordinate in the assessment and revision of pharmacopeia standards. The contact information of all “guardian institutes” and their assigned responsible pharmaceutical excipients are provided in the Annex. NMPA Releases “Classification System for The guidance on classification of biologics and submission dossier for product registration is Registration of Biologic Products and issued following the new requirements established in the Regulations on Drug Registration. Requirements for Application Dossier” on Apart from announcing the release of this guidance, the circular also specifies the effective June 29, 2020127 date and requirements for transitional period. The guidance is provided as Annex. NMPA Releases “Classification System for The guidance on classification of chemical drugs and submission dossier for product Registration of Chemical Drugs and registration is issued following the new requirements established in the Regulations on Drug Requirements or Application Dossier” on Registration. Apart from announcing the release of this guidance document, the circular also June 29, 2020128 specifies the effective date and requirements for transitional period. The guidance is provided as Annex. NMPA Circular on Updating Drug The NMPA has issued two regulatory documents to reflect the decision of adjusting Registration Fee Charging Standards on administrative fees for drug registration: “Charging Standards for Drug Registration Fees” June30, 2020129 and “Implementing Rules for Drug Registration Fees”. For drug registration application accepted before July 1, 2020, applicants are required to make the payment within 15 working days from July 1 2020. Drug registration fee will be exempt for medicines targeting the treatment and prevention of Covid19 during the pandemic. NIFDC Circular on Releasing “Testing These requirements are established in line with the newly issued Regulations on Drug Procedures and Technical Requirements Registration. The NIFDC circular stipulates measures on the implementation of these for Drug Registration (Interim) (Version requirements, covering aspects of applications submitted before the document issuance; 2020)” and Related Matters on July 1, administrative timeline; registration standard reevaluation; testing reports for drugs and 2020130 biologics manufactured overseas; and communication channel with the authorities. The

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“Testing Procedures and Technical Requirements for Drug Registration (Interim) (Version 2020)” is provided as Annex. NMPA Releases “Revised Appendix to The NMPA has revised the Good Manufacturing Practice of Blood Products according to Good Manufacturing Practice for Drugs article 310 of GMP (2010 Revision). Now the new version of GMP- Blood Products is (2010 Revision) – Blood Products” June30, released as supportive document to the GMP (2010 Revision). The new guidance is 2020131 provided as Annex. The Chinese Pharmacopoeia Commission Following the newly issued “Regulations for Drug Registration”, the Chinese Pharmacopoeia Releases “Working Procedures for Drug Commission has issued a set of regulatory decision and guidance on the determination, Generic Name Review and Approval” on review and approval of generic names for innovative Chinese proprietary medicines, July 1, 2020132 chemical drugs and biological products. These documents apply to the review and approval of drug generic names as part of certain marketing authorization applications. The decision and guidance are provided as Annexes 1- 4. NMPA and NHC Circular on Publishing The Pharmacopoeia of China 2020 Edition has been reviewed and approved during the “Pharmacopoeia of the People’s Republic plenary meeting of the 11th executive committee. The new pharmacopoeia will be effective of China (Edition 2020)” on June 24, 2020133 from December 30, 2020. Catalogue of 4 volumes that compose the pharmacopeia are provided as Annexes. M4 Module 1 Administrative Documents CDE has revised the M4 Module 1 document following requirements established by newly and Drug Information on July 1, 2020134 issued regulation on drug administration, drug registration and vaccine administration. CDE Releases “Rules on Assessment and The CDE has issued this regulatory document on administrative rules applying to safety Management of Safety Information During information management during drug clinical trials. These are supportive rules to the newly Drug Clinical Trials (Interim)” on July 1, released Regulations on Drug Registration. The document is provided as Annex. 2020135 CDE Releases “Administration Rules on The CDE has issued these administrative rules to regulate the creation and management of Development Safety Update Reports “development safety update reports (DSUR)” following the requirements established in the (Interim)” on July 1, 2020136 new Regulations on Drug Registration. The regulation is provided as Annex.

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CDE Releases “Administration Rules for The CDE has issued these administrative rules to regulate registration and information Drug Clinical Trial Registration and communication concerning drug clinical trials following the requirements established in the Information Communication (Interim)” on new Regulations on Drug Registration. The regulation is provided as Annex. July 1, 2020137 CDE Releases “Review Guidelines for the The CDE has issued these guidelines on authority’s acceptance of chemical drug Acceptance of Chemical Drug Registration registration applications. The guidelines include two parts: Part I applies to drugs under (Interim)” on July 2, 2020138 category 1,2 and 5,1 according to registration classification system; Part I applies to drugs under category 3, 4 and 5,2. Each part is a separate guideline, and they are provided as Annex 1 and Annex 2. CDE Releases “Guidelines for the The CDE has issued these interim guidelines on authority’s review and acceptance of Acceptance of Biological Product biological product registration applications. The guidelines include three parts: Part I applies Registration” on July 2, 2020139 preventive biological products; Part II applies to therapeutic biological products; and Part III applies to IVDs that are regulated as biologics. Each part is a separate guideline and is provided as Annex 1, Annex 2 and Annex3. CDE Announces Public Consultation on Following the new Regulations of Drug Registrations, the CDE has drafted a set of guidance “General Format and Guidance for documents on the preparation of drug registration application dossier concerning Preparing Drug Technical Documents: “manufacturing process”, “Quality Standards” and “Package Inserts” of Chinese medicines, ‘Manufacturing Process’, ‘Quality chemical drugs and biological products. All these draft guidance documents, together with Standards’ and ‘Package Insert’ (Drafts for corresponding explanatory notes and a feedback form are provided as Annexes. Any Comments)” on July 6, 2020140 suggestions and feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Announces Public Consultation on The CDE has drafted this guideline as part of technical review system for cellular and gene “Technical Guideline on Clinical Trials for therapy products, expecting to provide instructions and reference for drug registration Immune Cell Therapy Products (Draft for applicants in product R&D. The draft guideline, together with an explanatory and a feedback Comments)” on July 6, 2020141 form are provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE´s contact email boxes.

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The NMPA Releases Three Regulatory The NMPA has issued and released the following three interim regulatory decisions Documents Including “Working Procedure regarding drug prioritized and conditional review and approval as supportive measures to for Review and Approval of Breakthrough the implementation of the new Regulations of Drug Registration: “Working Procedure for the Therapy Designated Drugs (Interim)” on Review and Approval of Breakthrough Therapy Designated Drugs”, “Working Procedure for July 7, 2020142 Drug Conditional Marketing Authorization Application, Review and Approval” and “Working Procedure for Drug Prioritized Marketing Authorization Review and Approval”. All three decisions are provided as Annexes. CDE Notice on New Version of Drug The CDE informs that its “Drug Clinical Trial Registration and Information Release Platform Clinical Trial Registration and Information System” has completed the process of update and improvement. A new version is launched Release Platform System on July 10, and has started to operate. The new system can be accessed with the same user account 2020143 as the one used for “applicant’s window”, but a procedure of account connection is needed. The notice also provides contact information of CDE for technical support regarding the new system. CDE Releases “Drug Registration The CDE has issued and released these set of rules and standards as supportive document Application Dossier Format, Stylistic Rules to the new Regulations of Drug Registration. The regulatory document is provided as Annex. and Layout Standards” on July 8, 2020144 CDE Releases “Guideline for Management This interim guidance is issued to standardize drug clinical trials during the Covid-19 of Drug Clinical Trials During the Covid-19 pandemic, aiming to provide safety management measures. The guidance is provided as Outbreak (Interim)” on July 14, 2020145 Annex. CDE announces Public Consultation on The CDE has drafted this guideline as supportive document to the new Regulations on Drug “Technical Guideline for Pharmaceutical Registration. The draft guideline together with an explanatory note and the feedback form Changes to Innovative Drugs (Chemical are provided as Annexes. Any suggestions and feedback should be submitted through the Drugs) During Clinical Trials (Draft for form and sent to CDE’s contact email box. Comments)” on July 14, 2020146 CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical instructions for efficient “Technical Guidance on Clinical Trials for R&D of antineoplastic drugs applied in combination therapy. The draft guidance, together

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Antineoplastic Drugs Used in Combination with an explanatory note and feedback form, are provided as Annexes. Any suggestions and Therapy” on July 17, 2020147 feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Announces Public Consultation on This draft guidance is issued to facilitate the understanding and application of statistical “Guidance on Statistical Design in Clinical design in clinical trials concerning the R&D of antineoplastic drugs. The draft guidance and Trials for Antineoplastic Drugs” on July 17, an explanatory note to its issuance are provided as Annexes. Any suggestions and 2020148 feedback should be submitted to CDE’s contact email addresses. CDE Releases “Guideline on the This guideline is issued to further standardize the procedure of drug clinical trial data Submission of Clinical Trial Data (Interim)” submission following the new requirements on drug registration application dossier. The on July 20, 2020149 guideline is effective on October 1, 2020 for chemical drugs and biological products. Its effective date for Chinese medicines will be explained in “Classification System for Chinese Medicine Registration and Requirements for Application Dossier”. The CDE Releases “Guidance for Clinical The CDE has issued and released this guidance after public consultation, expecting to Trials on Rituximab Biosimilars” on July provide a technical reference for conducting clinical researches on Rituximab biosimilars as 20, 2020150 well as establish criteria regarding product technical review. The guidance is provided as Annex. CDE Releases “Guidance for Clinical Trials The CDE has issued and released this guidance after public consultation, expecting to on Trastuzumab Injection Biosimilars” on provide a technical reference for conducting clinical researches on developing trastuzumab July 20, 2020151 biosimilar. The guidance is provided as Annex NMPA Announcement on Adoption of “ICH The NMPA announces that marketing authorization holders (MAHs) can submit periodic E2C (R2) Guideline: Periodic Benefic-Risk safety update report following the ICH E2C (R2) guideline: Periodic Benefic-Risk Evaluation Evaluation Report (PBRER)” on July 17, Report (PBRER) since publication date of this announcement. Meanwhile, reports prepared 2020152 according to national regulations and guidelines are also accepted. The Center for ADR Announces Public The ADR has drafted this administrative regulation as a revised version on current Consultation on “Application Dossier and regulatory documents following new requirements established in the updated Drug Requirements for Switching Drugs from Administration Law and Regulations for Drug Registration. The draft together with an Prescription to OTC Status (Revision Draft explanatory note to its issuance and a feedback form are provided as Annexes. Any for Comments)” on July 24, 2020153

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suggestions and feedback should be submitted through the form and sent to the center’s contact email box. The CDE Releases “Guideline on Non- The CDE releases this guideline after public consultation to give instructions to sponsor in Inferiority Clinical Trials for Drugs” on July understanding, implementing and evaluation non-inferiority clinical for drugs. The guideline 24, 2020154 is provided as Annex. NMPA Opinions on Further Improving the This policy paper describes NMPA’s five-year plan on strengthening adverse event Quality and Capacity of Adverse Event monitoring system for drug and medical device through a series of measures concerning a Monitoring System for Medical Products on comprehensive and efficient administrative and regulatory framework; more professional July 28, 2020155 personnel; an updated monitoring system featuring multichannel for reporting, advanced function of data analysis and efficient tracking mechanism; and extended international collaboration. The paper further specifies authority’s action plan on each aspect. The CDE Announces Public Consultation The CDE has drafted this guideline to specify research considerations and technical on “Technical Guideline for requirements for generics of transdermal patches, which is intended to provide instructions Pharmaceutical Researches on for registration applicants in product R&D. The draft guideline, together with an explanatory Transdermal Patch Generics (Draft for note to its issuance and a feedback form are attached as Annexes. Any suggestions and Comments)” on July 24, 2020156 feedback should be submitted through the form to CDE´s contact email boxes. CDE Announces Public Consultation on 4 The CDE has drafted 4 technical guidance on clinical trials for antibacterial drugs for the Technical Guidance Including “Technical treatment of uncomplicate urinary tract infection, complicated intra-abdominal infection, Guidance on Clinical Trials of Antibacterial complicated urinary tract infection, and hospital-acquired bacterial pneumonia/ventilator- Drugs for the Treatment of Complicated associated bacterial pneumonia. All 4 draft guidance together with their corresponding Urinary Tract Infection” on July 31, 2020157 feedback forms are provided as Annexes. Any suggestions and feedback should be submitted through the forms and sent to CDE’s contact email boxes. NMPA Announces Public Consultation on The NMPA has drafted these regulations to further strengthen the administration of post- “Administrative Measures for Post- marketing changes made to drugs and highlight the responsibility of marketing authorization Marketing Changes to Drug (Interim) (Draft holders (MAHs). The draft together with a feedback form are provided as Annexes. Any for Comments)” on July 31, 2020158 suggestions and feedback should be submitted through the form and sent to NMPA’s contact email box.

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NMPA Announces Public Consultation on The NMPA has drafted these interim regulations to strengthen the administration on “Interim Regulations for Local Agents of activities related to local agents appointed by overseas marketing authorization holders Overseas Drug Marketing Authorization (MAHs). The draft regulations are provided as Annex. Any suggestions and feedback should Holders (Draft for Comments)” on Aug. 3, be submitted to the authority´s contact email box.

2020159 CDE Announces Public Consultation on The CDE has drafted this guidance to provide technical suggestions for clinical researches “Guidance on Real World Data Used to of therapeutic protein drugs. The draft guidance together with an explanatory note and Generate Real World Evidence (Draft for feedback form are provided as Annexes. Any suggestions and feedback should be Comments)” on Aug. 3, 2020160 submitted through the form and sent to CDE´s contact email boxes. CDE Releases “Guidance for Clinical Trials The CDE has issued and published this guidance after public consultation to provide on Bevacizumab Injection Biosimilars” technical reference for conducting clinical researches on developing bevacizumab on Aug. 3, 2020161 biosimilars. The guidance is provided as Annex CDE Releases “Guidance for Clinical Trials The CDE has issued and published this guidance after public consultation to provide on Adalimumab Injection Biosimilars” technical reference for conducting clinical researches on Adalimumab biosimilars. The on Aug. 3, 2020162 guidance is provided as Annex.

Technical Guidance on Pharmacokinetic This guidance applies to the clinical R&D of therapeutic protein drugs, particularly focusing Research of Therapeutic Protein Drugs on the differences in pharmacokinetics (PK) between therapeutic protein drugs and common (Draft for Comments) on Aug. 3, 2020163 small molecule drugs. It is intended to specify key considerations in PK studies and propose suggestions in research plan design. Content of the guidance is structured in general introductions, aspects of PK research and bioanalysis. CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical suggestions on “Technical Guidance on Bioequivalence bioequivalence studies of narrow therapeutic index drugs with pharmacokinetic parameters Studies of Drugs with Narrow Therapeutic as the primary. The draft guidance together with an explanatory note and feedback form are Index (Draft for Comments)” on Aug. 3, attached as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE´s contact email boxes. 2020164

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CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical suggestions on rational “Technical Guidance on Model-Informed application of model-informed drug development approach in R&D. The draft guidance Drug Development (Draft for Comments)” together with an explanatory note and feedback form are attached as Annexes. Any on Aug. 3, 2020165 suggestions and feedback should be submitted through the form and sent to CDE´s contact email boxes.

CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical suggestions on R&D and “Guidance on Research and Validation of regulatory review on injection drugs. The draft guidance together with an explanatory note Aseptic Processing and Sterilization of are provided as Annexes. Any feedback should be submitted to CDE´s contact email boxes. Injection Drugs” on Aug. 3, 2020166 The CDE Under NMPA Releases “Record The CDE has issued this regulatory document following new requirements established in Filing Procedures and Requirements for Regulations on Drug Registration. The circular specifies the implementation of new Separated Packaging of Drugs requirements of record filing for separated packaging of overseas produced drugs before Manufactured Overseas” on Aug. 3, 2020167 and after the Regulations on Drug Registration takes effective. The document is provided as Annex. NHSA Announces Public Consultation on The National Healthcare Security Administration has drafted the 2020 working plan “2020 Working Plan of Adjusting Drug regarding adjustments to drug reimbursement catalogue covered by the national healthcare Catalogue Covered by National Healthcare system and invites public review. According to the plan, western medicines, Chinese patent (Draft for Comments)” on Aug. 3, 2020168 drugs and herbal decoction pieces will be in the scope of adjustments. Drugs of urgent clinical needs, generics, pediatric drugs and medicines for the treatment of Covid19 will be included in the list. A detailed working procedure is also unveiled covering the whole process of preparation of the catalogue, review and approval, issuing the list of drugs for price negotiation, price negotiation and confirmation of the list. Any suggestions and feedback to the draft should be submitted to NHSA´s email box. CDE Announces Public Consultation on Oncolytic viruses are a form of immunotherapy that uses viruses to infect and destroy “Guidance on Clinical Trial Design for cancer cells, which has shown potentials to provide treatment for many types of malignant

Reform Detail / Opportunity

Oncolytic Virus- Based Drugs” (Draft for tumors. The CDE has drafted this guidance expecting to give technical suggestions on Comments)” on Aug. 7, 2020169 clinical design regarding oncolytic virus-based therapy and drugs. The guidance, an explanatory note and a feedback form are provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Announces Public Consultation on The CDE has drafted this guidance to provide technical suggestions to support the R&D of “Technical Guidance on Clinical Trials of drugs targeting lipid metabolism disorders. The draft guidance together with an explanatory Drugs for the Treatment of Lipid note and a feedback form are provided as Annexes. Any suggestions and feedback should Metabolism Disorders (Draft for be submitted through the form and sent to CDE´s contact email boxes. Comments)” on Aug. 10, 2020169 CDE Notice: Public Consultation on “ICH This ICH guideline is now in step 3 for regulatory consultation and discussion. According to M7 Guideline: Assessment and Control of the organization’s procedure requirement, CDE announces the launch of regional regulatory DNA Reactive (Mutagenic) Impurities in consultation on these draft documents (step 2b) in China. Any suggestions or feedback can Pharmaceuticals to Limit Potential be communicated in Chinese or English and submitted to CDE´s contact email boxes. Carcinogenic Risk. Questions and Answers” and “M7 Q&A Support Document” on Aug. 10, 2020170 CDE Announces Public Consultation on The CDE has drafted this guidance to provide technical suggestions on the R&D and “Technical Guidance on Similarity regulatory review of biosimilars. The draft together with the feedback form are provided as Assessment and Indication Extrapolation Annexes. Any suggestions and feedback should be submitted through the form and sent to of Biosimilars (Draft for Comments)” on CDE´s contact email boxes. Aug. 14, 2020171 CDE Releases 5 Technical Guidelines The CDE announces to release the following 5 technical guidelines to provide technical Including “Technical Guideline for standards concerning R&D of vaccines for the prevention and control of Covid-19 pandemic. Research and Development of Preventive These guidelines cover aspects of vaccine R&D, pharmaceutical research on mRNA Vaccines Against Covid-19 (Interim)” on vaccines, non-clinical effectiveness studies and evaluation and clinical evaluation. All 5 Aug. 14, 2020172 guidelines are provided as Annexes.

Reform Detail / Opportunity

CDE Announces Public Consultation on 11 The CDE has drafted 11 technical guidance on bioequivalence study of the following Technical Guidance Including “Technical generics: Olanzapine Orally Disintegrating tablets, Abiraterone Acetate Tablets, Calcium Guidance on Bioequivalence Study of Acetate Tablets, Entecavir Tablets, Imatinib Mesylate Tablets, Carbamazepine Tablets, Olanzapine Orally Disintegrating Tablets” Leflunomide Tablets, Rivaroxaban Tablets, Sacubitril Valsartan Sodium Tablets, Lanthanum on Aug. 19, 2020173 Carbonate Chewable Tablets, and Vildagliptin Tablets. All 11 draft guidance together with their corresponding explanatory note to issuance and a feedback form are provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE´s contact email box. CDE Announces Public Consultation on The CDE has drafted this guideline to specify research plan and technical requirements for “Technical Guideline for Researches on generic fulvestrant injections. The draft guideline together with an explanator note and a Generic Fulvestrant Injections (Draft for feedback for are provided as Annexes. Comments)” on Aug. 19, 2020174 CDE Announces Public Consultation on The CDE has drafted this guidance expecting to facilitate the understanding and technical “Guidance on Adjusting for Covariates requirements regarding the covariate adjustment during clinical trials for drugs. The draft Clinical Trials for Drugs” on Aug. 19, guidance together with a note to its issuance are provided as Annexes. Any suggestions 2020175 and feedback should be submitted to CDE’s contact email boxes. CDE Notice on Issuing Electronic The CDE informs applicants that the electronic API registration system has finished Administrative Documents for APIs on improvement and upgrading process. Administrative permits and other related documents Aug. 20, 2020176 for APIs are issued in electronic version from now on and are available through “Applicant’s Window”. CDE Announces Public Consultation on The CDE has drafted this guidance based on “Clinical Trials Guidance on Influenza “Technical Guidance on Clinical Trials for Treatments” issued in 2012 to provide further technical instructions on drug R&D and Influenza Antivirus Drugs (Draft for improve clinical accessibility for patients. The draft together with a feedback form are Comments)” on Aug. 21, 2020177 provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Announces Public Consultation on The CDE has drafted this guidance expecting to give technical suggestions on R&D and “Technical Guidance on Clinical evaluation of medicines for the treatment and control of myopia progression. The draft

Reform Detail / Opportunity

Investigations Concerning Medicines for guidance and a feedback form are provided as Annexes. Any suggestions and feedback the Control of Myopia Progression” on should be submitted through the form and sent to CDE´s contact email boxes. Aug. 24, 2020178 CDE Announces Public Consultation on The CDE has drafted this guidance as part of its plan for establishing the regulatory review “Technical Guidance on Clinical Trials for framework for cell and gene therapy products. The draft guideline, an explanatory note to its Human Stem Cell Based Therapeutic issuance and a feedback form are provided as Annexes. Any suggestions and feedback Products and Their Derivatives (Draft for should be submitted through the form and sent to CDE’s contact email boxes. Comments)” on Aug. 24, 2020179 CDE Announces Public Consultation on Facing the increasing development of therapeutic protein drugs, the CDE has drafted this “Technical Guidance on Drug guidance to provide technical suggestions to immunogenicity studies during drug R&D. Immunogenicity Studies (Draft for The draft guidance and an explanatory note to its issuance are provided as Annexes. Any Comments)” on Aug. 24, 2020180 suggestions and feedback should be submitted to CDE’s contact email boxes. CDE Releases “List of Chemical Drugs of The CDE has drafted this list following NMPA’s Circular on Requiring Quality and Efficacy Specific Clinical for Which Reference Consistency Evaluation of Generic Injectable Drugs and now publishes it online to invite Preparations Cannot Be Recommended public review. The list and a feedback form are provided as Annexes. Any suggestions and (1st List)” for Public Review on Aug. 24, feedback should be submitted through the form and sent to CDE’s contact email boxes. 2020181 CDE Announces Public Consultation on The CDE has drafted this guidance to support and regulate the R&D of diagnostic “Technical Guideline for Nonclinical radiopharmaceuticals in China. The draft guidance together with an explanatory note to its Studies of Diagnostic issuance and a feedback form are provided as Annexes. Any suggestions and feedback Radiopharmaceuticals (Draft for should be submitted through the form and sent to CDE’s contact email boxes. Comments)” on Aug. 27, 2020182 CDE Announces Public Consultation on Omalizumab is a recombinant, humanized, monoclonal antibody against human “Guidance for Clinical Trials on immunoglobulin E (IgE). Currently the R&D of omalizumab biosimilars has been initiated by Omalizumab Injection Biosimilars (Draft for several manufacturers. This draft guidance is intended to provide technical reference for Comments)” on Aug. 27, 2020183 conducting clinical researches on developing omalizumab biosimilars and is now released online to invite public opinion. The draft guidance together with an explanatory note to its

Reform Detail / Opportunity

issuance and a feedback form are provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Releases “Technical Guidance for The CDE has issued this guidance to assist researchers in understanding the application of Using Real-World Evidence to Support real-world evidence in the R&D and clinical trials concerning pediatric drugs after the public R&D and Regulatory Review of Pediatric consultation on the draft. The guidance is provided as Annex. Drugs (Interim)” on Aug. 27, 2020184 CDE Announces Public Consultation on The CDE has drafted this guidance expecting to facilitate more accurate definition of target “Guidance on Enrichment Strategies and population for drug clinical trials as well as to improve the efficiency. The draft guidance and Design for Drug Clinical Trials (Draft for an explanatory note to its issuance are provided as Annexes. Any suggestions and Comments)” on Aug. 27, 2020185 feedback should be submitted to CDE’s contact email boxes. CDE Releases “Technical Guideline for The CDE has issued this guideline after public consultation on the draft expecting to provide Testing Minimal Residual Disease During technical standard for industry regarding the application of minimal residual disease (MRD) Clinical Trials of Drugs for Acute as an important biomarker to measure effectiveness of treatment during the R&D of drugs Lymphoblastic Leukemia” on Aug. 28, for Acute lymphoblastic leukemia (ALL). The guideline is provided as Annex. 2020186 CDE Announces Public Consultation on The CDE has drafted this guideline expecting to provide technical advices on exploring “Guideline for Subgroup Analyses in efficacy and safety differences in patients of different characteristics during clinical trials and Clinical Trials for Drugs (Draft for evaluating the risk-benefit of subgroups. The draft guideline and an explanatory note are Comments)” on Aug. 28, 2020187 provided as Annexes. Any suggestions and feedback should be submitted to the CDE’s contact email boxes. CDE Announces Public Consultation on The CDE has drafted this guideline to clarify technical requirements for clinical “Guidance on Clinical Pharmacology pharmacology considerations during pediatric drug R&D. The draft together with an Studies for Pediatric Drug Development” explanatory note to its issuance and a feedback form are provided as Annexes. Any (Draft for Comments)” on Sep. 1, 2020188 suggestions and feedback should be submitted through the form to CDE’s contact email box. CDE Announces Public Consultation on Oncolytic viruses are a form of immunotherapy that uses viruses to infect and destroy “Guidance on Clinical Trial Design for cancer cells, which has shown potentials to provide treatment for many types of malignant

Reform Detail / Opportunity

Oncolytic Virus- Based Drugs” (Draft for tumors. The CDE has drafted this guidance expecting to give technical suggestions on Comments)” on Aug. 7, 2020189 clinical design regarding oncolytic virus-based therapy and drugs. The guidance, an explanatory note and a feedback form are provided as Annexes. Any suggestions and feedback should be submitted through the form and sent to CDE’s contact email boxes. CDE Announce Public Consultation on The CDE has issued this guidance to give technical advices for the R&D of medicines for “Technical Guidance on Clinical Trials for the treatment of age-related macular degeneration (AMD). The guidance is provided as Medicines Treating Age-Related Macular Annex. Degeneration” on Sep. 9, 2020190 CDE Announces Public Consultation on The CDE has draft this technical guidance expecting to specify requirements and provide “Technical Guidance on Pharmaceutical scientific advices for pharmaceutical researches and changes in this aspect concerning Research and Changes for Biologics biologic products during clinical trials. The draft guidance, an explanatory note to its During Clinical Trial (Draft Published issuance and a feedback form are provided as Annexes. Any suggestions and feedback Online for Comments)” on Sep. 10, 2020191 should be submitted through the form and sent to CDE’s contact email boxes. NMPA and National Intellectual Property This draft interim regulation is drafted jointly by two administrative authorities to set specific Administration Announce Public measures towards the establishing of patent linkage mechanism. The draft regulation, an Consultation on “Implementation Measures explanatory note to its issuance and a feedback form are provided as Annexes. Any Concerning Early Resolution Mechanism suggestions and feedback for Drug Patent Disputes (Interim) (Draft for Comments)” on Sep. 11, 2020192 CDE Announces Public Consultation on The CDE has drafted this guidance expecting to provide technical advices on designing “Technical Guidance on Drug-Drug drug R&D strategies. The draft guidance, an explanatory note to its issuance and a Interaction Studies (Draft for Comments)” feedback form are provided as Annexes. Any suggestions and feedback should be on Sep. 11, 2020193 submitted through the form and sent to CDE’s contact email boxes.

Conclusions

The 2016 - 2019 reforms represent major changes for China’s regulatory environment and are expected to better align the country with global regulatory norms by:

 Reducing the IND (clinical trial) and NDA review timeline.  Strengthening the standards for generic drugs,  Reforming clinical trial data quality requirements and  Introducing a priority review process for innovative drugs,  Accelerate the registration speed for unmet medical needs.

NMPA (formerly CFDA) is clearly encouraging foreign sponsors and applicants to undertake global studies in China and recommending that local clinical sites are part of global studies to help ensure clinical trial data meet the requirements needed for China and for global registration. The clinical trial reforms announced by NMPA will hopefully overcome some of the reluctance of foreign sponsors to include China in global programs as the IND review timeline of 60 days mirrors that seen outside of China.

It is anticipated that the new requirements for generic drug quality and efficacy evaluation and self- inspection of clinical data will upgrade generic drug standards, clinical trial quality and clinical site GCP compliance. It is acknowledged however that these new standards may also present some initial challenges for generic pharmaceutical companies; however CROs should be able to advise, fill any knowledge gaps and conduct required BE studies. This evolution is likely to provide a boost for China’s CRO industry but it is likely that local CROs will face major hurdles as they attempt to enhance their own quality processes in order to meet the NMPA’s stricter requirements. Sponsors will be motivated to use reliable CROs with established standards to manage their trials and generate reliable data to meet requirements and support approvals.

The reforms will undoubtedly benefit new drug innovators planning to conduct meaningful, scientific trials. This should ensure that trial site resources are used more effectively on good quality research which will have a long-term, positive impact for the Chinese pharmaceutical industry. The reforms will have a profound and lasting impact on China’s pharmaceutical industry. It is likely some of the manufacturers and their drugs will disappear over the next few years. However, there is a major incentive for innovative local companies to progress their efforts in new drug development.

More reforms can be anticipated and indeed the Government has already laid out some of the plans for 2019 therefore it is essential that local China regulatory expertise is available to closely monitor these changes and ensure accurate and timely communication to all relevant stakeholders. In addition, a robust China regulatory strategy consultation or assessment will need to be prepared and agreed on much earlier than before in order that Chinese activities can be effectively integrated into the global program from the start.

On March 30, 2020, State Administration for Market Regulation (SAMR) announces “Regulations on Drug Registration” and NMPA Announcement on Implementing “Regulations on Drug Registration”, to be effective on July 1, 2020. The key features are set as below:  The 2020 DRR summarized the experience and stabilize the achievements of the reform of review and approval system of drugs and medical devices, according to the State Council about “The opinion on the reform of review and approval system of drugs and medical devices"(guo fa [2015] 44), and the General office of the central committee of the communist party of China and General Office of the State Council about "The opinion on deepening the reform of the review and approval system and encouraging the innovation of drugs and medical devices([2017] no. 42)”.  The 2020 DRR optimize the management process to implement the reform requirements of "delegating control and service". In drug registration, through introduction of "60 working days IND review and approval, the drug evaluation, registration inspection, testing carried out by "parallel" instead of "sequential", and set start and finish time points and total timeline, further improve the efficiency of the review and the applicant within the timeline for drug approval is expected.  The 2020 DRR take risk management as the principle, play precision management. If safety problems or other risks are found during the drug clinical trial, the sponsor shall promptly adjust the clinical trial protocol, suspend or terminate the clinical trial, and report to CDE; Changes during clinical trials shall be evaluated for their impact on subject safety risks and shall be reported in the safety update report during development or supplementary application shall be submitted.  The 2020 DRR also consider how to maintain stable and highlight management attributes, at a time new technologies, new production organization methods, new therapeutic and research ideas are emerging. Therefore, the 2020 DRR is based on frame work and no appendix, while the flexibility will be reflected in the accompanying guidelines and working procedures. More than 50 accompanying guidelines and working procedures are planned, so far, there are 30 announced for public consultation. The plan is to be implemented in stages by the end of 2020.

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76 http://www.nhc.gov.cn/yaozs/s7655g/202004/f1cbe67ec7ef4c228ed2290946745d04.sht ml 77 http://www.nmpa.gov.cn/WS04/CL2138/376852.html 78 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315046 79 http://www.nmpa.gov.cn/WS04/CL2138/376948.html 80 http://www.nmpa.gov.cn/WS04/CL2138/376949.html 81 http://www.nmpa.gov.cn/WS04/CL2138/376950.html 82 http://www.nmpa.gov.cn/WS04/CL2138/376951.html 83 http://www.nmpa.gov.cn/WS04/CL2138/376952.html 84 http://www.nmpa.gov.cn/WS04/CL2138/376953.html 85 http://www.nmpa.gov.cn/WS04/CL2138/376954.html 86 http://www.nmpa.gov.cn/WS04/CL2138/376956.html 87 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315053 88 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315048 89 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315047 90 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315052 91 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315054 92 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315043 93 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315060 94 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315061 95 http://www.cde.org.cn/news.do?method=largeInfo&id=315065 96 http://www.nmpa.gov.cn/WS04/CL2138/377442.html 97 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315068 98 http://www.cde.org.cn/news.do?method=largeInfo&id=314969 99 https://www.nifdc.org.cn/nifdc/zxgx/20200515102723648.html 100 http://www.nmpa.gov.cn/WS04/CL2138/377444.html 101 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315079 102 http://www.nmpa.gov.cn/WS04/CL2138/377515.html 103 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315083 104 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315084 105 http://www.cfdi.org.cn/resource/news/12320.html 106 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315085 107 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315088 108 http://www.nmpa.gov.cn/WS04/CL2138/377890.html 109 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315138 110 https://www.cmde.org.cn/CL0004/21037.html 111 https://www.cmde.org.cn/CL0004/21038.html 112 http://www.nmpa.gov.cn/WS04/CL2101/378021.html 113 http://www.cfdi.org.cn/resource/news/12399.html 114 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315147 115 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315148 116 http://www.cde.org.cn/news.do?method=viewInfoCommon&id=315149 117 http://www.nmpa.gov.cn/WS04/CL2138/378032.html

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