Overview of biological product evaluation in CDE, CFDA

Transcription

1 Overview of biological product evaluation in CDE, CFDA WCBP, Washington, DC. Date: Jan. 24, 2017 Jianhui LUO Office of Pharmaceutical Science of Biological Products 1

2 Outline Introduction of CDE and biological product review Changing undergoing in CDE Guidelines and hot topics concerning biologics New concept, practice & challenge Review of import biological product applications by CDE from 2014 to

3 Part 1: Introduction of CDE and biological product review 3

4 Organization Frame Diagram of CDE Director Chief Scientist Administrative Office Office of Management and Communication Office of Human Resource Office of Finance Office of Quality Management Office of clinical Evaluation of TCMs and Ethno- Medicine Office of Pharmaceutical Science of TCMs and Ethno- Medicine Office of Pharmaceutical Science of New Drug Office of Pharmaceutical Science of Generic Drug Office of Pharmaceutical Science of Biological Products Office of Pharmacology and Toxicology Office of Clinical Evaluation Ⅰ Office of Clinical Evaluation II Office of Clinical Evaluation of Biological Products Office of Biostatistics and Clinical Pharmacology 4

5 Functions of CDE Technical review of drug registration applications (IND/NDA/supplemental ) 01 Involved in developing regulations, rules and policy Other tasks assigned by CFDA 06 Duties and Guiding drug review activities of local authority 05 Responsibilities Following up application trend and legal issues related to drug evaluation International collaboration and cooperation 5

6 Divisions involved in biologics evaluation CMC division Pharmacology and toxicology division Clinical division Biostatistics division 6

7 Review Process Domestic Sponsors Import Application Local Authority Application Provincial Institute for drug control On-site inspection Center for Food and Drug Inspection of CFDA Domestic application CoA of generic data drug On-site inspection report CoA of new drug On-site inspection before approval Data Receiving Task Assignment Professional Team Review Comprehensive Evaluation Technical Review CFDA Approved new Validation of OTC Certificate of drug generic drug instructions Complaint and Service Center Analysis National Institutes for Food and Drug Control name Chinese Pharmacopoeia Commission Center for Drug Reevaluation of CFDA Advisory Panel 7

8 Part 2: Changing undergoing in CDE 8

9 The Opinions of the State Council on Reforming the Evaluation and Approval System of Drugs and Medical Devices (No. 44[2015] of the State Council), issued by the State Council On Aug. 18, 2015, the milestone of China s reform on Drug Evaluation and Approval system. 9

10 What s said in the State Council s document? To resolve the backlog of drug review and approval, to exercise strict control over the approval of oversupplied drugs. To optimize the review and approval procedures of innovative drugs. To adjust drug registration classification, defining the new drugs more stringently. To strengthen the clinical test verification. To carry out the pilot work of Drug Marketing Authorization Holder (MAH) System Others: Service based on the mode of government purchase; Quality consistency evaluation for generic drugs; Simplified drug approval process ; Strengthened communication and information disclosure in review and approval. 10

11 Changing undergoing in CDE, CFDA Applicable guidelines issued by CFDA or other international agency Guidelines on phase I clinical trial (for comments and suggestion), with simplified data requirements for application dossier Application and designation for priority review, pre-ind meeting, and accelerated approval CMC Changes during development and / or post marketing, developing guidelines 11

12 Part 3:Guidelines and hot topics concerning biologics Biosimilars Recombinant Mab application and approval Innovative biologics Cellular therapy 12

13 I. Biosimilars Similar not identical, biomedicinal similar Comparability study Original as comparator Critical process control, Critical quality attributes similar Well designed and controlled Clinical trial, PD marker may be used as clinical surrogate endpoint Post market surveillance, immunogenicity 13

14 Diagram for Decision-making of Biosimilar Development CMC and quality Similar Difference Not similar comparing study PD,PK, immunogenicity uncertainty PD,PK, toxicity Non-clinical Similar Difference Not similar Clinical PD,PK, immunogenicity Similar uncertainty Clinicalpharmacology, safety and efficacy Not similar Biosimilar Carefully going on Better to quit 14

15 II. Recombinant Mab application and approval Antigen target or clinical indication Clinical trial approved Marketing application approved Application under review 15

16 List of Mab ( hot target and indication) Antigen target EGFR, IgE, TNF-α,IL-12,IL-6R,IL-8 DR5, RANKL, BLyS, CD20,VEGF, CD38, HER2, CD52, CTLA-4, LFA-3, CD-22, CD-11a, CD25, PD-1, PD-1L, IL-17A, IGF- 1R and so on Disease or indication Tumor, autoimmune disease, infectious disease, respiratory disease, cardiovascular disease, neuron disease, and so on 16

17 III. Innovative biologics Unmet medical needs Accelerated approval procedure, top priority review Pre-IND meeting and pivotal clinical trial meeting Guidance on phase I clinical trial application (for comments and suggestion) Conditional approval on market Committed study 17

18 IV. Cellular therapy Guideline on Pre-clinical Trial and Quality Control of Stem Cell Products Intended as Medicinal Technology, issued jointly by CFDA and NHFPC in Measures for the Administration of Clinical Trials for Stem Cell Products, issued by NHFPC in Specifying the institute s qualification, the clinical trial procedure, reporting system, experts committee, supervision, etc. Drafting guidelines on cellular products intended for biologics registration, by CDE in 2016 (for public consideration). Note: NHFPC, National Health and Family Planning Commission of the PRC 18

19 Part 4: New concept, practice & challenge 19

20 New concept & challenge (Definition and understanding of biosimilar ) Physical-chemical structure vs. biological function, apparently characteristic vs. substantial effect ; Pharmaceutical attributes (product quality) vs. clinical therapeutic performance (clinical value); Local aspects of data vs. whole profile of product; Clinical evidence, totality. 20

21 New practice and challenge (Continuous manufacturing and QbD) Batch or lot definition, quality consistency; Variation control; space design, validation; Manufacturing cycle, holding, in process control, PAT; Homogeneous, pooling & combining; Manufacturing capacity and matching between steps, seamless connection between upstream and downstream, and among process facilities or steps; Model separation and combination in system. 21

22 Part 5: Review of import biological product applications (2014~2016) Application acceptances and review completions Comparison between import applications and domestic applications Priority review list 22

23 Acceptances and completions of biological product review from 2014 to 2016 (annual task ) Acceptance Completion Note: Review completions means the review tasks which have completed by the CDE and submitted to the CFDA. The total number of yearly accepted biological product applications is in the range of 400 to 600 over the past three years (by acceptance numbers). Due to the effort of resolving the backlog of drug review and approval, 2016 has seen a significantly progress in the number of applications completed. In 2016, the number of tasks completed is 1.5 times that of accepted tasks. 23

24 Acceptances and completions of biological product review from2014 to 2016 (vaccine vs. therapeutic product ) 450 Acceptance 600 Completion Vaccine tasks Therapeutic tasks Vaccine tasks Therapeutic tasks Note: Review completions means the review tasks which have completed by the CDE and submitted to the CFDA. Of the accepted tasks, vaccine tasks are less than therapeutic tasks. It is the same with the tasks completed. 24

25 Comparison between import applications and domestic applications from 2014 to 2016 (number) Acceptance Completion Total number 48.91% 51.09% Domestic applications Import applications 47.86% 52.14% Domestic applications Import applications Annual number Import applications Acceptance Completion The number of import applications is comparable with domestic applications over 2014~2016. The proportion of completed tasks to accepted tasks for import applications is comparable with that for domestic applications Domestic applications Acceptance Completion 25

26 Comparison between import applications and domestic applications (vaccine vs. therapeutic product) 120 Acceptance 120 Completion Vaccine Domestic applications Import applications Domestic applications Import applications Completion Therapeutic product Acceptance Domestic applications Import applications Domestic applications Import applications For vaccine review, domestic applications are more than import applications. Contrarily, the domestic applications are less than import applications for therapeutic product review

27 Acceptances and completions of import products from 2014 to 2016 (IND/BLA/Supplemental/re-registration) IND Acceptance 4.65% IND Completion Total 3.59% 29.84% BLA 34.47% BLA number 61.98% 4.59% Supplementar y application Import re-registration 57.74% 3.14% Supplementary application Import re-registration 200 Acceptance 200 Completion 150 IND 150 IND Annual number Among the import applications of biological products, the supplementary applications are the most, accounting for more than 50%, followed by the IND applications. The numbers of IND applications and BLA increased stably these years. BLA Supplementary application Import re-registration BLA Supplementary application Import re-registration 27

28 Biological products listed in priority review in 2016 Acceptance Type Name Indications Stage number 1 JXSS14xxxx BLA Adalimumab Solution for Injection Rheumatoid arthritis Import Being reviewed (RA) application 2 JYSB14xxxx Supplementary Insulin Glargine Injection Diabetes type 1 and Import Approved 3 JYSB14xxxx application type 2 application Note: the same product 4 JXSS16xxxx BLA Reassortant Rotavirus Vaccine, Live,Oral,Pentavalent(Vero Cell) Prophylactic vaccine Import application Being reviewed 5 JXSS16xxxx BLA Tocilizumab Injection Active systemic Import Approved 6 JXSS16xxxx juvenile idiopathic application arthritis(sjia) Note: the same product with different specifications 7 JXSS16xxxx 8 CXSL16xxxx IND Recombinant Human Coagulation Factor Ⅷ for Injection 9 CXSL16xxxx IND Therapeutic Hepatitis B Adenovirus Injection 10 JXSL16xxxx IND Recombinant Coagulation Factor VIII for 11 JXSL16xxxx Injection 12 JXSL16xxxx 13 JXSL16xxxx 14 JXSL16xxxx 15 JXSL16xxxx Note: the same product with different specifications or different target populations Hemophilia A Chronic hepatitis B Hemophilia A Domestic application Domestic application Import application Waiting for sponsor's reply Waiting for sponsor's reply Waiting for sponsor's reply Among 15 (by acceptance numbers) or 7 (by products) priority review tasks in 2016, only 2 are domestic applications. 28

29 Thank you 29

30 Back up slides 30

31 Acceptances and completions of biological product review from 2014 to 2016 (IND/BLA/Supplemental/re-registration) Annual number Acceptance Completion IND BLA Supplementary application Import re-registration IND BLA Supplementary application Import re-registration Acceptance Completion Total number 49.86% 1.76% 6.27% 42.11% IND BLA Supplementary application Import re-registration 48.13% 2.23% 6.99% 42.65% IND BLA Supplementary application Import re-registration The supplementary applications are the most, accounting for nearly 50% of all the applications, followed by the IND applications, then the BLA and the import re-registration applications. 31