NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019

The New Drugs and Clinical Trials Rules, 2019 (NDCT Rules, 2019) apply to all new drugs, investigational new drugs for human use, clinical trials, bioequivalence studies, bioavailability studies, and ethics committees. The rules also apply to orphan drugs, phytopharmaceutical drugs, and biomedical and health research.

1. New Drugs and Clinical Trials (NDCT) rules, 2019 An Overview Akash Agnihotri T utor Department of Pharmacology Amrita School of Medicine, Faridabad NDCT 2019 by Akash Agnihotri 1

2. NDCT 2019 Draft copies of new clinical trials rules on public domain: 7th February, 2018 Objections and suggestions invited from all stakeholders Central Government notified “New Drugs and Clinical Trials Rules, 2019” on 19th Mar 2019 New Drug and Clinical Trial Rules, 2019 are applicable from 19th Mar 2019, except Chapter 4 [Ethics Committee for Biomedical and Health Research], which came into force after 180 days (i.e. 21st Sep 2019) 2 NDCT 2019 by Akash Agnihotri

3. The New Drugs & Clinical Trial Rules, 2019 New rules are structured around: 13 chapters, which includes 107 rules and 8 schedules Will apply to: All new drugs Investigational new drugs Clinical trials Biomedical and health research Ethics committees 3 NDCT 2019 by Akash Agnihotri

4. The New Drugs & Clinical Trial Rules, 2019 New rules override part XA and Schedule Y of medicine and cosmetics rules, 1945 Earlier regulations and schedule Y will still be applicable for veterinary use drugs 4 NDCT 2019 by Akash Agnihotri Schedule Y was a law that outlined the requirements and guidelines for conducting clinical trials and importing or manufacturing new drugs in India Part XA As per Drugs and cosmetic Rules 1945, part X-A, import or manufacture of new drug for clinical trials or marketing

5. NDCT 2019, Aimed P romoting clinical research within the country by implementing: Time-bound review of applications Allowing increased predictability and transparency of regulatory pathway Providing clarity on many complex subjects, including post-trial access After a series of media allegations of unethical practices, in 2013 the CDSCO office made stricter regulations for conducting clinical trials NDCT 2019 by Akash Agnihotri 5

6. Highlights in the 2019 NDCT Amendments of drugs and cosmetics rules, 1945: R ule 97 includes 122DAA in the drugs and cosmetic rules 1945, which consists: N on-application of certain rules for new drugs and investigational new drugs for human use Part XA and schedule Y shall not be applicable with regard to new drugs and investigational new drugs for human use NDCT 2019 by Akash Agnihotri 6

7. New Definitions in NDCT Rule 2019 NDCT 2019 by Akash Agnihotri 7

8. New Definitions: Clinical Trial “Clinical trial” in relation to a new drug or investigational new drug means, any systematic study of such new drug or investigational new drug in human subjects to generate data for discovering or verifying its: Clinical or Pharmacological, including pharmacodynamics, pharmacokinetics or Adverse effects With the objective of determining the safety, efficacy or tolerance of such new drug or investigational new drug NDCT 2019 by Akash Agnihotri 8

9. New Definitions: Academic Clinical Trial R ule 2(a) C linical trial of a drug already approved for a certain claim I nitiated by any investigator, academic or research institution F or a new indication or new route of administration or new dose or new dosage form R esults of such a trial are intended to be used only for academic or research purposes and not for seeking approval of the central licensing authority or regulatory authority of any country for marketing or commercial purpose NDCT 2019 by Akash Agnihotri 9

10. New Definitions: Biomedical & Health Research R ule 2(h) Research including studies on: Basic, applied and operational research Clinical research Designed primarily to increase scientific knowledge about diseases and conditions (physical or socio- behavioural ) their detection and cause Evolving strategies for health promotion, prevention or amelioration of disease Rehabilitation but does not include clinical trial NDCT 2019 by Akash Agnihotri 10

11. New Definitions: Biomedical & Health Research (BHR) BHR to be conducted in accordance with “ National Ethical Guidelines for Biomedical and Health Research involving Human Participants” by ICMR EC for BHR is required to be registered with DHR, MoH&FW Observational & non interventional study of a drug which is not a new drug, however it is advisable to submit such protocols to CDSCO for confirmation NDCT 2019 by Akash Agnihotri 11

12. New Definitions: Orphan Drugs R ule X Means a drug intended to treat a condition which affects not more than five lakh persons in India, without any financial gain foreseen by pharma company but for benefit of humanity NDCT 2019 by Akash Agnihotri 12

13. New Definitions: Orphan Drugs Newly Approved Orphan Drugs Approved in 2024: Fidanacogene elaparvovec-dzkt (Treatment of adults with moderate to severe hemophilia B (congenital factor IX deficiency) Atidarsagene autotemcel (Treatment of children with pre-symptomatic late infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early juvenile (ESEJ) metachromatic leukodystrophy (MLD) Approved in 2023: Donislecel-jujn (Treatment of adults with Type 1 diabetes who are unable to approach target HbA1c because of current repeated episodes of severe hypoglycemia despite intensive diabetes management and education NDCT 2019 by Akash Agnihotri 13

14. New Definitions: Orphan Drugs Top 5 Selling Orphan Drugs in the World (Feb, 2022) NDCT 2019 by Akash Agnihotri 14 (Ibrutinib) (Daratumumab) ( Elexacaftor / tezacaftor /ivacaftor) ( Emicizumab ) ( Olaprib ) (Drug Name)

15. New Definitions: Post-Trial Access R ule CC Making a new drug or investigational new drug available to a trial subject after completion of clinical trial through which the said drug has been found beneficial to a trial subject during clinical trial NDCT 2019 by Akash Agnihotri 15

16. New Definitions: New Drug Rule W NDCT 2019 by Akash Agnihotri 16

17. Ethics Committee for Clinical Trials NDCT 2019 by Akash Agnihotri 17

18. 4 pillars of principle of medical ethics NDCT 2019 by Akash Agnihotri 18

19. Ethics Committee Constitution 7 Members Minimum 50% of members must be from outside NDCT 2019 by Akash Agnihotri 19

20. Ethics Committee for Clinical Trials Deals with Regulatory CT as well as Academic CT & BA/BE Constitution: M inimum 50% of members must be from outside Compensation: Regulatory trial  DCGI, Academic trial  guidelines by ICMR Registration with CDSCO: 5 years validity Independent ethics committee: According with rule 7,same site/radius of 50 kms EC approving BHR,BA/BE, CT  register with CDSCO & DHR NDCT 2019 by Akash Agnihotri 20

21. Ethics Committee for Clinical Trials (continued) Time line 60 Days Timeline: Clinical trial as part of discovery, research, manufacture and marketing 90 Days Timeline: For other applications of CT and new drug Permission from Central Licensing Authority ( CLA) needed CLA permission not needed in : Trials solely for academic research NDCT 2019 by Akash Agnihotri 21

22. Ethics Committee approval for Clinical Trials Multicentric CT: EC approval from each site EC not present at site: Other site can give approval & bear all responsibilities Independent EC approval After approval: Inform Central Licensing Authority (CLA) within 15 days If rejected and applying to another EC: details of rejection to be submitted to CLA NDCT 2019 by Akash Agnihotri 22

23. Accelerated approval to new drug Approval after phase 2 if it shows remarkable efficacy For life threatening disease, unmet medical needs Surrogate endpoints considered Phase 4 CT needed for validation of clinical benefit NDCT 2019 by Akash Agnihotri 23

24. Serious Adverse Event (SAE) reporting and assessment A Serious Adverse Event (SAE) is defined as any adverse drug event that is life threatening or associated with:  Death Inpatient hospitalization Prolonged hospitalization Persistent or significant disability or incapacity A congenital anomaly or birth defect Causality assessment : Scales- WHO, Naranjo’s NDCT 2019 by Akash Agnihotri 24

25. Timeline for reporting SAE Investigator to Sponsor, EC, CDSCO: Initial report < 24 hrs   Full analyzed report, investigator must submit a report 14 days of event S ponsor must also provide free medical management for the appropriate time Recommendation for compensation: Chairperson of Ethics committee to DCGI : <30 calendar days Chairperson of Expert committee to DCGI: <60 days of receipt of report from ethics committee Order of compensation from DCGI to Sponsor :<90 days of receipt of report Final compensation paid by sponsor to patient/relative:< 30 days of receipt of order NDCT 2019 by Akash Agnihotri 25

26. Compensation and Formulas NDCT 2019 by Akash Agnihotri 26

27. Quantum of compensation and formulas Formula in Case of clinical trial related death: NDCT 2019 by Akash Agnihotri 27

28. Quantum of compensation and formulas For permanent disability: Compensation = (DX90XC)/(100X100) C= Quantum of compensation in case of death D= Percentage of disability SAE causing life‑threatening disease : Compensation = N x W N=Number of days for life‑threatening situation requiring medical care, irrespective of days of hospitalization W=Minimum wage per day of the unskilled worker (in Delhi) R eversible SAE in case it is resolved: Compensation = 2 x W x N W = Minimum wage per day of the unskilled worker (in Delhi) N = Number of days of hospitalization NDCT 2019 by Akash Agnihotri 28

29. Some Important Changes and Alterations of New Rule NDCT 2019 by Akash Agnihotri 29

30. Important Points of NDCT 2019 1. New and Old License Application Fee Structure Application fees for Phass-1-4 clinical trials now increased up to 6-8 folds NDCT 2019 by Akash Agnihotri 30

31. Important Points of NDCT 2019 After approval of a Clinical Trial, it is now valid for 2 years from the date of its approval There are two typed of Ethics Committees (EC): One for Clinical Trials & BA/BE studies (Under CDSCO) One for Biomedical & Health Research (Under ICMR) The Validity of EC registration is now 5 years DCGI should be informed about the approval granted by the EC within 15 working days of the grant of such approval NDCT 2019 by Akash Agnihotri 31

32. Important Points of NDCT 2019 In case of rejection of trial application, the applicant may request to reconsider the application within a period of 60 days from the date of rejection of the application. A 6 monthly report of clinical trial should be submitted to DCGI through SUGAM portal. But enrollment status should be submitted to DCGI every 3 months. The termination of the clinical trial and BA/BE study should be notified to CLA within 30 days with detail of its cause for termination. NDCT 2019 by Akash Agnihotri 32

33. Important Points of NDCT 2019 Post-trial access of drug to the patients (should be provided by the sponsor at free-of-cost to the trial subject after the trial is over), which completely depends on recommendation of the investigator and its approval by EC. For conducting an academic clinical trial (intended solely for academic research purposes) only Ethics Committee approval is mandatory (no permission is required from DCGI) and such clinical trial should not used for promotional or approval purposes. NDCT 2019 by Akash Agnihotri 33

34. Important Points of NDCT 2019 The Sponsor should provide free medical management to the “ subject as long as required as per the opinion of investigator, or till such time it is established that the injury is not related to ” the clinical trial or BA/BE study. “ The sponsor or its representative and the investigator shall forward their reports on Serous Adverse Events (SAE) of death after due analysis” to DCGI, HOI, Chairperson of EC within 14 days of the “Knowledge of occurrence of SAE of death” NDCT 2019 by Akash Agnihotri 34

35. Important Points of NDCT 2019 Periodic Safety Update Report (PSUR): Timeline is reserved as per old regulation but content & structure is now should be arranged with very detailed and exhaustive EU PBRER (ICH) format. EU PBRER: European Union Periodic Benefit Risk Evaluation Report NDCT 2019 by Akash Agnihotri 35 As per the Drugs and Cosmetics Act, 1940 & Rules, 1945 including NDCT Rules, 2019 PSURs are required to be submitted every six months for first two years from the date of approval and for subsequent two years annually

36. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 36

37. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 37

38. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 38

39. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 39

40. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 40

41. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 41

42. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 42

43. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 43

44. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 44

45. Overall comparison of new rules with former rules NDCT 2019 by Akash Agnihotri 45

46. Flow chart on the compensation procedures in case of serious adverse events and death during the clinical trials NDCT 2019 by Akash Agnihotri 46

47. Flow chart on the compensation procedures in case of serious adverse events and death during the clinical trials NDCT 2019 by Akash Agnihotri 47

48. Flow chart on general procedure of grant of approval to conduct clinical trials in India NDCT 2019 by Akash Agnihotri 48

49. References Dubey A, Kotian B, Ravi GS. New Drugs and Clinical Trials Rules, 2019: Towards Fast-track Accessibility of New Drugs to the Indian Population. Indian J of Pharmaceutical Education and Research. 2019;53(4s):s451-s459. NDCT Rule 2019. Accessed by: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-documents/NewDrugs_CTRules_2019.pdf Singh N, Madkaikar NJ, Gokhale PM, Parmar DV. New drugs and clinical trials rules 2019: Changes in responsibilities of the ethics committee. Perspect Clin Res. 2020 Jan-Mar;11(1):37-43. doi : 10.4103/picr.PICR_208_19. Epub 2020 Jan 31. PMID: 32154148; PMCID: PMC7034142. Annapurna SA, Rao SY. New drug and clinical trial rules, 2019: an overview. Int J Clin Trials 2020;7(4):278-84. Urooj M, Husain GM, Khan MA, Kazmi MH. Compensation to clinical trial participants in India: A gap analysis. Int J Pharm Investig . 2017 Apr-Jun;7(2):41-46. doi : 10.4103/jphi.JPHI_31_17. PMID: 28929045; PMCID: PMC5553263. Postgraduate Pharmacology by Sougata Sarkar, Paras Medical Publisher, 2020. Orphan Drug Report 2022, by By Melanie Senior and Andreas Hadjivasiliou , April 2022 NDCT 2019 by Akash Agnihotri 49

50. MCQs on NDCT 2019 NDCT 2019 by Akash Agnihotri 50

51. MCQ No. 01 The renewal of the ethics committee must be completed ____________ NDCT 2019 by Akash Agnihotri 51 60 days before the expiry of the license 90 days prior to the expiry of the license 30 days before the expiry of the license 120 days prior to the expiry of the license

52. MCQ No. 02 The validity period of Ethics Committee registration is ____________ NDCT 2019 by Akash Agnihotri 52 1 Year 3 Years 5 Years 10 Years

53. MCQ No. 03 In cases where patients have an expected mortality of 90% or more within 30 days, the quantum of compensation should be: NDCT 2019 by Akash Agnihotri 53 ₹ 1 Lakh ₹ 2 Lakh ₹ 5 Lakh ₹ 10 Lakh

54. MCQ No. 04 Before initiating a study involving primary data collection, the Principal Investigator must ensure that various approvals are obtained. Which of the following approvals is absolutely mandatory? NDCT 2019 by Akash Agnihotri 54 Scientific committee approval Ethics committee approval Technical committee approval Regulatory authority approval

55. MCQ No. 05 According to the timeline for reporting Serious Adverse Events (SAEs) and the order of compensation from DCGI to the Sponsor, the compensation order should be issued: NDCT 2019 by Akash Agnihotri 55 Within 30 days of receipt of the SAE report Within 60 days of receipt of the SAE report Within 90 days of receipt of the SAE report Within 120 days of receipt of the SAE report

56. MCQ’s Answer Key NDCT 2019 by Akash Agnihotri 56 b) 90 days prior to the expiry of the license c) 5 Years b) 2 Lakh b) Ethics Committee Approval c) Within 90 days of receipt of the SAE report

57. Thank you NDCT 2019 by Akash Agnihotri 57