Schedule y

this slide tells about schedule Y, Good Clinical Practice, CDSCO, Ethics committee, consent form, Serious Adverse Events and compensation rules

1. SCHEDULE Y BY DR KUMAR GOURAV PG resident, pharmacology 1

2. CONTENTS Definition Introduction Regulatory framework of India Rules in schedule Y Good clinical practice rules Informed consent Amendments Organisation Institutional ethical committee Compensation rules SAE reporting 2

3. What is schedule y ? Schedule Y refers to the requirements and guidelines for permission: To import Manufacture of new drugs for sale or To undertake clinical trials in India. 3

4. introduction At present the following acts and rules regulate the manufacture, export and clinical research of drugs and cosmetics in India : Drugs and Cosmetics Act, 1940 Drugs and Cosmetics rules, 1945 Pharmacy Act, 1948 Drugs and Magic Remedies (Objectionable Advertisements) Act, 1954 4

5. introduction 5 . Narcotic Drugs and Psychotropic Substances Act,1985 6 . Medicinal and Toilet preparation (Excise Duties) Act, 1955 7 . Drugs (Price Control ) Order, 1955 under Essential Commodities Act, 1955 5

6. REGULATORY FRAMEWORK OF INDIA The Main regulatory laws operating in India are the Drug and Cosmetics Act (1940) and the Drugs and Cosmetics Rules (1945). The Act and Rules are binding on allopathic and other systems of medicine and regulate imports, manufacture, distribution, and sale of drugs in India 6

7. REGULATORY FRAMEWORK OF INDIA The enforcement came into existence in 1988 . Revised version of Schedule Y in line with ICH-GCP (International Council of Harmonization and Good Clinical Practice) standard was put forth in 1995. 7

8. Schedule y Rules 122 A, 122 B, 122 D, 122 DA, 122 DAA, 122 DAB, 122 E, 122 DD of the Drugs and Cosmetics Rules (1945) deals with schedule Y 8

9. RULES PERMISSION FOR 122 A To import New drugs 122 B To manufacture New drugs 122 D To Import or Manufacture fixed dose combinations 122 DA To conduct clinical trials for New Drug/Investigational New drug 122 DAA Definition of Clinical Trial 122 DAB Reports of Serious Adverse Events (SAEs) including deaths. 122 E New Drug 122 DD Registration of Ethics Committee (EC). 9

10. 122 DAA - Definition of Clinical Trial A systematic study of new drug(s) in human subject(s) to generate data for discovering and/or verifying the clinical, pharmacological (including pharmaco –dynamic and pharmaco -kinetic) and/or adverse effects with the objective of determining safety and/ or efficacy of the new drug. 10

11. 122E– Definition of New Drug A drug which has not been used in the country , new claim for a drug already approved, FDC (combined for the first time or change in ratio) and all vaccines. 11

12. APPENDIX Some highlights of Schedule Y in terms of its appendices; which provide the guidelines to conduct clinical trials are: Appendix V – Informed consent Appendix VII – Undertaking by the Investigator Appendix VIII – Ethics Committee Appendix X – Contents of Protocol Appendix XI – Data elements for reporting SAE 12

13. Application for permission It shall made in Form 44 accompanied with the following data in accordance with appendices, namely Clinical and pharmaceutical information Animal pharmacology data Animal Toxicology data Human Clinical pharmacology data Regulatory status in other countries Prescribing information 13

14. Clinical trials 1. Approval for Clinical trials Clinical trials on a New drug shall be initiated only after permission by licensing authority and approval from EC . All trial Investigator(s) should possess appropriate qualifications, Protocol amendments if become necessary before initiation or during the course of a clinical trial, all such amendments should be notified to the Licensing Authority in writing 14

15. CLINICAL TRIALS 2. Responsibilities of Sponsor Implementing and maintaining quality assurance Submit status report to the licensing authority periodically Serious adverse event (SAE) should be reported to the licensing authority within 14 calendar days. In case of studies prematurely discontinued for any reason including lack of commercial interest in pursuing the new drug application, a summary report should be submitted within 3 months. 15

16. Clinical trials 3. Responsibilities of Investigator The Investigator(s) shall be responsible for the conduct of the trial according to the protocol Ensure adequate medical care is provided to the subject SAE and unexpected AE should be reported to the sponsor within 24 hrs and to the EC within 7 working days 16

17. Clinical trials 4.Informed consent Freely given informed written consent Provide information about the study verbally and in written Non-Technically and understandable language. Legally acceptable representative 17

18. Clinical trials 5.Responsibilities of ethics committee Approval trial protocol to safe guard right, safety and well being of all trial subject Particular care to protect right, safety and well being of all vulnerable subjects 18

19. 6. Human pharmacology (phase i) Participant Number : 10-100 Type of Participant : Healthy volunteers Study Design : Open label 1 o Objective : Estimate Safety , Efficacy & Tolerability with single & multiple doses Other Objectives : Assessment of pharmacokinetics and pharamacodynamics Study Duration : Months to 1 year 19

20. 6. Human pharmacology(phase i) Objectives of phase I maximum tolerated dose Pharmacokinetics Pharmacodyanamics Early measurement of drug activity 20

21. 7. Therapeutic exploratory trials (phase II) Participant Number : 50-500 Type of Participant : patients who have the disease that the drug is expected to treat Study Design : Randomized controlled 1 o Objective : To study –● Efficacy & Safety ● Dose response relationship ● Dose & regimen for next phase Other Objectives : Safety and tolerability in patients Study Duration : 3-5 years 21

22. PHASE III(MULTI-CENTRE TRIAL) Study Type : Therapeutic confirmatory studies. Participant Number : 1000-3000. Type of Participant : Patients. Study Design : Randomized controlled. 1 o Objective : Confirm efficacy in large population. Other Objectives : safety and tolerability. Study Duration : 3-5 years 22

23. Phase IV(Post-marketing surveillance) Study type : Therapeutic use. Participant Number : Large population Type of Participant : Patients prescribed approved drug. Study Design : Open label 23

24. Phase IV(Post-marketing surveillance) 1 o Objective : ● Early detection ADR, compliance ●Drug- drug interaction ●Comparison with other drug ● Pharmacosurveillance & pharmacoeconomic s Other Objectives : Therapeutic application during wider use in community Study Duration : No fixed duration 24

25. 3. studies in special population 1. Geriatrics They should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if The disease is characteristically a disease of aging Substantial numbers of geriatric patients 25

26. 1. GERIATRICS 3.Common in the elderly are likely to be encountered 4.When the new drug is likely to alter the geriatric patient's response 26

27. 2. paediatrics Begin with older children before extending the trial to younger children and then infants. If the new drug is for diseases predominantly or exclusively affecting paediatric patients, clinical trial data should be generated in the paediatric population except for initial safety and tolerability data 27

28. 2. paediatrics Diseases occurring in both adults and pediatric patients, for which there are currently no or limited therapeutic options, pediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit. Written informed consent should be obtained from the parent/legal guardian. 28

29. 3. Pregnant or nursing women. They should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or fetus / nursing infants Where the data generated from women who are not pregnant or nursing, is not suitable. 29

30. 3. Pregnant or nursing women follow-up data on the pregnancy, fetus and child will be required. Where applicable, excretion of the drug or its metabolites into human milk should be examined 30

31. 4. Post marketing Surveillance closely monitored new drugs clinical safety Periodic Safety Update Reports (PSUR)- to report all relevant new information PSUR shall be submitted every 6months for the first 2 years New studies specifically planned or conducted to examine a safety issue should be described in the PSURs. 31

32. 5. Special Studies- Bioavailability / Bioequivalence Studies conducted according to the guidance for BA and BE studies Evaluation of the effect of food on absorption following oral administration All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed. 32

33. Good Clinical Practices Good Clinical Practices (GCP) is an international ethical & scientific quality standard for designing, conducting, recording & reporting trials that involve the participation of human subjects. It ensures the : RIGHTS SAFETY WELL BEING 33

34. ICH The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a joint initiative of the experts in pharmaceutical industry of Europe, Japan and the United States to discuss scientific and technical aspects of pharmaceutical product registration. 34

35. Indian GCP guidelines Released in Dec 2001(Developed by CDCSO and endorsed by DCGI) In general, in line with ICH GCP Has Revised Schedule Y (Jan 2005) 35

36. Principles of ICH GCP 2.1 Clinical trials should be conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with GCP and the applicable regulatory requirement(s). 36

37. Principles of ICH GCP 2.2 Before a trial is initiated, risks and inconveniences should be weighed against the anticipated benefit for the individual , trial subject and society. A trial should be initiated and continued only if the anticipated benefits justify the risks. 37

38. Principles of ICH GCP 2.3 The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society. 2.4 The available nonclinical and clinical information on an investigational product should be adequate to support the proposed clinical trial. 38

39. Principles of ICH GCP 2.5 Clinical trials should be scientifically sound, and described in a clear, detailed protocol. 2.6 A trial should be conducted in compliance with the protocol that has received prior institutional review board (IRB)/independent ethics committee (IEC) approval/favorable opinion. 39

40. Principles of ICH GCP 2.7 The medical care given to, and medical decisions made on behalf of, subjects should always be the responsibility of a qualified physician or, when appropriate, of a qualified dentist. 2.8 Each individual involved in conducting a trial should be qualified by education, training, and experience to perform his or her respective task(s). 40

41. Principles of ICH GCP 2.9 Freely given informed consent should be obtained from every subject prior to clinical trial participation. 2.10 All clinical trial information should be recorded, handled, and stored in a way that allows its accurate reporting, interpretation and verification. 41

42. Principles of ICH GCP 2.11 The confidentiality of records that could identify subjects should be protected, respecting the privacy. 2.12 Investigational products should be manufactured, handled, and stored in accordance with applicable good manufacturing practice (GMP). 2.13 Systems with procedures that assure the quality of every aspect of the trial should be implemented. 42

43. Informed consent Participation Title Research team Research funding Study location A brief introduction about the study Need for the study 43

44. Informed consent 8. No of participants 9. Reason for inclusion of that participant. 10. Duration of participation 11. Methodology in detail 12. Responsibility of the participant. 13. Benefit of the study 14. Risk of the study 44

45. Informed consent 15. Protection from harm 16. Privacy 17. Protection of privacy 18. Confidentiality 19. Compensation 20. Use of data 21. Voluntariness, no force 45

46. Informed consent 22. Right to refuse, right to withdraw, patient care right not affected 23. Time to decide 24. Clarify doubts: contact information 25. Retain a copy 46

47. Informed consent Same thing should be written by the participant with : Name Date Address Phone no 47

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49. Amendments in 2013 & 2014 Rule 122DAB –Compensation in case of injury or death during clinical trial(CT). Rule 122DAC- Permission to conduct Clinical Trial subject to certain Conditions, Authority for CT inspections, Actions in case of non-compliance Rule 122DD -Registration of Ethics Committee -Requirements and guidelines for registration of Ethics Committee 49

50. Amendments in 2015 Informed Consent A-V recording of informed consent process is required for vulnerable subjects in NCE/ NME trials. For anti-HIV & anti-leprosy drug trials, only audio recording. Essential elements in ICF –Possibility of failure of investigational product . –Placebo will not any therapeutic effect . 50

51. Amendments in 2018 The CT in relation to a new drug or investigational new drug in humans has to generate data for discovering or verifying its pharmacological interactions including pharmacodynamics, pharmacokinetic and adverse effects in order to determine the safety, efficacy or tolerance of new drugs. 51

52. organisation The New Drug Regulatory Process come under the purview of the Drugs Controller General of India (DCGI), who is the head of the Central Drugs Standard Control Organization (CDSCO), located in New Delhi . 52

53. organisation 53

54. organisation The DCGI is supported by various bodies, such as the Indian Council of Medical Research (ICMR) and Department of Biotechnology (DBT) in the evaluation of specific therapies or clinical trials. The ICMR, for example, provides expert advice in evaluation of Phase I trials or clinical trials relevant to national priorities, eg , malaria, AIDS etc.  54

55. Institutional ethics committee ( iec ) Consist of 8-12 members: Chairperson 1-2 from basic medical science area 1-2 clinicians 1 legal expert 1 representative of NGO 1 philosopher 1 lay person from the society Member secretary 55

56. FUNCTIONS OF IEC To provide competent review of all ethical aspects of the project Undertake review free from bias and influence Provide advice to the researchers on all aspects of welfare and safety of research participants To protect dignity, rights and well-being of the potential research participants. 56

57. FUNCTIONS OF IEC To ensure universal ethical values and international scientific standards in terms of local community values and customs. To assist in the development and the education of research community responsive to local health care requirements 57

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59. Compensation for clinical trials Rule of compensation applies to only those adverse events (AEs) that are required to be reported. As per the rules, all serious AEs (SAEs) are to be reported within a stipulated time frame. AE that do not fall into the SAE category are not required to be expeditiously reported and, therefore, do not fall under the clause of compensation. 59

60. Compensation rules The final formula for calculating compensation is: ( 8,00,000 x age factor x risk factor) 99.37 -where 800,000 rupees is the base amount; -age factor varies from 228.54 (≤ 16 years) to 99.37 (≥ 65 years); -the risk factor (ranging from 0.5 to 4.0) is decided on the basis of trial participants 60

61. Compensation rules ( i ) SAE causing permanent disability to the subject. Compensation = (D x 80 x C) 100 x 100 where, D = percentage disability the subject has suffered, C = quantum of compensation which would have been due for payment to the subject’s nominee(s) in case of death of the subject 61

62. Compensation rules (ii) SAE causing congenital anomaly or birth defect. The following four situations may arise due to congenital anomaly or birth defect: Still birth. Early death due to anomaly. No death but deformity which can be fully corrected through appropriate intervention. Permanent disability (mental or physical) 62

63. Compensation rules For all the above-mentioned situations, compensation of a fixed amount of 400,000 rupees is applicable. However, for situations (c) and (d), medical management, as long as required, has to be provided by the sponsor, in addition to the above-mentioned fixed amount of 400,000 rupees. 63

64. Compensation rules (iii) SAE causing life-threatening disease. Compensation = N x W where N = number of days for which the trial subject remained in a life-threatening situation requiring medical care, irrespective of number of days of hospitalization; W = minimum wage per day of an unskilled worker. 64

65. Compensation rules (iv) Reversible SAE in case it is resolved. In this situation, the compensation amount will be double the amount applicable for situation (iii), explained above. 65

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67. SAE REPORTING An event is serious when the patient outcome is: death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant Disability/incapacity Is a congenital anomaly/birth defect Require intervention to prevent permanent damage 67