Presentation of how to write DSUR

1. Developmental Safety Update Report (DSUR) Dr.S.Gunasakaran, MD Dr.S.Gunasakaran,MBBS,MD 1

2. OBJECTIVE Dr.S.Gunasakaran,MBBS,MD 2

3. Objective of DSUR Ongoing assessment of risk to trial subjects Notification of Ethics Committees and Regulators at regular intervals Actions proposed to address safety concerns Dr.S.Gunasakaran,MBBS,MD 3

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6. SCOPE of DSUR Dr.S.Gunasakaran,MBBS,MD 6

7. Scope of DSUR Data from Interventional Clinical Trials Commercial and Non-Commercial Sponsors Safety findings from non-clinical studies Safety findings from clinical trials conducted by co-development partner Non-interventional / Compassionate use Dr.S.Gunasakaran,MBBS,MD 7

8. When should a DSUR be prepared? Dr.S.Gunasakaran,MBBS,MD 8

9. Sponsor overseeing more than one clinical trial of a single investigational product should prepare one DSUR With single Data Lock Point (DLP) Dr.S.Gunasakaran,MBBS,MD 9

10. Periodicity and DSUR Data Lock Point Dr.S.Gunasakaran,MBBS,MD 10

11. Periodicity and DSUR Data Lock Point Intended to be annual report As long as sponsor conducts clinical trials with ID As long as appropriate to satisfy local regulatory requirements DSUR Executive Summary supplemented with line listings of SAE for Ethics committee IRBs Investigators Dr.S.Gunasakaran,MBBS,MD 11

12. Periodicity and DSUR Data Lock Point DSUR should be submitted no later than 60 calendar days from DSUR data lock point Development International Birth Date (DIBD): Date of the sponsor’s first authorization to conduct a clinical trial in any country For administrative convenience, DIBD is the last day of MOA Clinical trials going in one country and are later initiated in any other countries, one DSUR on same DIBD Dr.S.Gunasakaran,MBBS,MD 12

13. Change of DSUR Data Lock Point Dr.S.Gunasakaran,MBBS,MD 13

14. Change of DSUR Data Lock Point Once the drug has received a marketing approval in any country Change the DSUR data lock point to Coincide with IBD DSUR and PSUR should be synchronized During synchronization, the period covered by next DSUR should not be longer than 1 year Dr.S.Gunasakaran,MBBS,MD 14

15. Interruption or Discontinuation Of Clinical Trials Dr.S.Gunasakaran,MBBS,MD 15

16. Interruption or Discontinuation of Clinical Trials DSUR should be prepared and submitted Sponsor not collected any further data pertinent to the clinical development programme in the period of DSUR, a covering letter Dr.S.Gunasakaran,MBBS,MD 16

17. FINAL dSUR Dr.S.Gunasakaran,MBBS,MD 17

18. Final DSUR When annual reports of clinical trials no longer required in a country, DSUR should be accompanied by a Cover letter Whether or not clinical trials are continuing elsewhere Dr.S.Gunasakaran,MBBS,MD 18

19. Responsibilities for Preparing & Submitting DSUR Sponsor’s Responsibilities Shared Responsibilities Non-Commercial Sponsor Responsibilities Multiple sponsors in formal agreements Dr.S.Gunasakaran,MBBS,MD 19

20. Reference Safety Info Dr.S.Gunasakaran,MBBS,MD 20

21. Reference Safety Information Used to assess whether the safety information received during the reporting period remains consistent with previous knowledge of safety profile of ID. IB is the RSI SmPC is the RSI for non-commercial sponsors conducting clinical trial with marketed products Dr.S.Gunasakaran,MBBS,MD 21

22. Format and presentation Of DSUR Dr.S.Gunasakaran,MBBS,MD 22

23. Table of contents Title page Executive summary Introduction Worldwide Marketing Authorization Status Update on actions taken in the Reporting Period for Safety Reasons Changes to Reference Safety Information Estimated Exposure Cumulative subject exposure in Clinical Trials Patient Exposure from Marketed setting Dr.S.Gunasakaran,MBBS,MD 23

24. Table of Contents (Contd..) Presentation of Safety Data from Clinical Trials General considerations Interval line listing of SARs Cumulative summary tabulations Deaths in reporting period Subjects who dropped out Significant findings from Clinical trials Completed CTs and Interim Analysis Ongoing Clinical Trials Dr.S.Gunasakaran,MBBS,MD 24

25. Table of Contents (Contd..) Other therapeutic use of investigational drug New safety data related to combination therapies Relevant findings from non-interventional clinical studies Relevant findings from other studies Safety findings from marketing experience Other information Non-clinical data Long-term follow-up Dr.S.Gunasakaran,MBBS,MD 25

26. Table of Contents (Contd..) Literature Other DSURs Significant manufacturing changes Lack of efficacy Phase I protocol modifications Late Breaking information Overall safety assessment Dr.S.Gunasakaran,MBBS,MD 26

27. Table of Contents (Contd..) Evaluation of risks Benefit risks considerations Conclusions Summary of important risks Appendices to DSUR Dr.S.Gunasakaran,MBBS,MD 27

28. TITLE PAGE Dr.S.Gunasakaran,MBBS,MD 28

29. Title page DSUR number (reports should be numbered sequentially) Investigational drug(s) Reporting Period Date of Report Sponsor name and address Confidentiality statement Note regarding the inclusion of unblinded information in the DSUR Dr.S.Gunasakaran,MBBS,MD 29

30. EXECUTIVE SUMMARY Dr.S.Gunasakaran,MBBS,MD 30

31. Executive summary Concise summary of the important information contained in the report Together with title page, serves as Stand alone document for EC submission Dr.S.Gunasakaran,MBBS,MD 31

32. Information in Executive summary Introduction – Report version & Reporting period ID: MOA, class, indications, dose , RoA Estimated cumulative clinical trial exposure Marketing Authorization? Yes / No – If yes, no. of countries Summary of overall safety assessment Summary of important risks Actions taken for safety reasons including changes to IB Conclusion Dr.S.Gunasakaran,MBBS,MD 32

33. INTRODUCTION Dr.S.Gunasakaran,MBBS,MD 33

34. Introduction Reporting period and sequential number of report Brief description of the drug, eg., therapeutic class, mode of action, route of administration, formulation Dr.S.Gunasakaran,MBBS,MD 34

35. Worldwide Marketing Authorization status Marketing application submitted in one or more countries Table format Dr.S.Gunasakaran,MBBS,MD 35

36. Update on Actions Taken in the Reporting Period for Safety Reasons Refusal of authorization of clinical trial Partial or complete trial suspension for ethical or safety reasons Failure to obtain marketing approval for tested indication Protocol modifications due to safety reasons Formulation changes due to safety reasons Restrictions in study populations or indications Dr.S.Gunasakaran,MBBS,MD 36

37. Changes to Reference Safety Info Significant safety related changes to IB Changes to Contraindications Warnings Precautions Adverse reactions of special interest Interaction Carcinogenicity, mutagenicity from non-clinical studies Dr.S.Gunasakaran,MBBS,MD 37

38. Status of Clinical trials ongoing and completed during Re. Period Separate tables can be provided by Indication Formulation Study population Table should contain the following information Protocol no. Clinical trial phase (I-IV) Status Ongoing completed Dr.S.Gunasakaran,MBBS,MD 38

39. Table should include Abbreviated study title Study design Uncontrolled, controlled, open, single blind, double blind, parallel, cross over etc Dose and regimen of study drug and comparators Subject population Age, sex, indication, special population groups, impaired renal or hepatic function Date of first visit for first patient Planned enrollment of study as a whole Dr.S.Gunasakaran,MBBS,MD 39

40. Estimated Exposure Dr.S.Gunasakaran,MBBS,MD 40

41. Cumulative subject exposre Data on subject exposure to the Investigational product Active comparators Placebo No of trial subjects by age group, gender and ethnic origin Dr.S.Gunasakaran,MBBS,MD 41

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43. Estimated Exposure Dr.S.Gunasakaran,MBBS,MD 43

44. Presentation of Safety data from Clinical trials Should contain both cumulative and interval safety information related to IP Interval line listings of SAR Cumulative tabulations of SARs since DBID If MedDRA used, PT should be used Tabulations of only Serious Non-Serious and Incidental findings should not be included Dr.S.Gunasakaran,MBBS,MD 44

45. General Considerations Dr.S.Gunasakaran,MBBS,MD 45

46. General Considerations Version of Coding dictionary used Version of document Version used as Reference Safety Information Dr.S.Gunasakaran,MBBS,MD 46

47. Interval line listings of SARs Key information on all blinded and unblinded SARs reported during reporting period SARs should be listed by protocol, indication or other variables Dr.S.Gunasakaran,MBBS,MD 47

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49. Cumulative Summary tabulations Content of tabulations Criteria for inclusions Summary tabulations should present cumulative safety data from the DBID to the data lock point Summary tabulations include no. of SARs organised by SOC for Investigational product Placebo comparator Dr.S.Gunasakaran,MBBS,MD 49

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51. Deaths in the Reporting Period Dr.S.Gunasakaran,MBBS,MD 51

52. Deaths in the Reporting Period A list of subjects who died during participation in the investigation Should be provided as appendix Following information at a minimum Case number Assigned treatment Cause of death Dr.S.Gunasakaran,MBBS,MD 52

53. Subjects who dropped out Tabulations and listing on drop outs should be provided Should be provided as an appendix Safety issued identified from a review of these withdrawals should be described Dr.S.Gunasakaran,MBBS,MD 53

54. Significant findings from clinical trials during reporting period Completed clinical trials and interim analysis Ongoing clinical trials Concise summary of any preliminary safety findings Other therapeutic use of investigational drug New safety data related to combination therapies Dr.S.Gunasakaran,MBBS,MD 54

55. Relevant Findings Dr.S.Gunasakaran,MBBS,MD 55

56. Relevant findings from non-interventional studies Relevant findings from meta-analysed or pooled data of RCT Safety findings from marketing experience Dr.S.Gunasakaran,MBBS,MD 56

57. Other Information Dr.S.Gunasakaran,MBBS,MD 57

58. Other information Non clinical data Invivo or invitro studies Carcinogenicity, reproduction, immunotoxicity studies Long term follow up Gene herapy, cell therapy products, tissue engineered products Literature Other DSURs Significant manufacturing changes Lack of efficacy Dr.S.Gunasakaran,MBBS,MD 58

59. Overall Safety Assessment Dr.S.Gunasakaran,MBBS,MD 59

60. Overall Safety Assessment Concise, integrated assessment of all new Clinical information Non-clinical information Epidemiological information Dr.S.Gunasakaran,MBBS,MD 60

61. Evaluation of Risks Benefit Risk Considerations Conclusion Summary of important risks Dr.S.Gunasakaran,MBBS,MD 61

62. Appendices Dr.S.Gunasakaran,MBBS,MD 62

63. Appendices to the DSUR Investigator’s Brochure Cumulative table of important regulatory advice Status of ongoing and completed clinical trials Cumulative summary tabulations of Demographic Data Line listings of SARs Cumulative summary tabulation of SAEs Scientific abstracts (if relevant) Dr.S.Gunasakaran,MBBS,MD 63

64. Regional Appendices Dr.S.Gunasakaran,MBBS,MD 64

65. Regional Appendices Drop outs in association with Adverse events Deaths Summary Tabulations of SARs Dr.S.Gunasakaran,MBBS,MD 65

66. Questions….? Dr.S.Gunasakaran,MBBS,MD 66

67. Thank You Dr.S.Gunasakaran,MBBS,MD 67