Schedule Y amendments

Amendments in Schedule Y in 2013,2014 inserted three new rules, new appendix XII: compensation in case of injury or death during clinical trial, amendments in ICD and appendix V inform consent form format.

1. Schedule Y Drug and cosmetics rule 1945, Amendments Prashant Ramanand

2. Schedule Y: Schedule Y, the current drug regulator (CDSCO – Central Drugs Standard Control Organization) enforced law in India has been established under Drugs and Cosmetic Act 1945. REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS…

3. Rules of Schedule Y 122 A Permission to Import of new drug 122 B Permission to manufacture new drug 122 C Application for approval to manufacture new drug classifiable under Schedule C and C1 122 D Permission to import or manufacturer fixed dose 122 DA Application to conduct CT on new drug or IND/INP 122 DAA Definition of Clinical trial 122 DB Suspension or cancellation of permission/approval 122 DC Appeal: Can be done within 60 days to Central Govt. from an order passed by LA 122 E Definition of new Drug

4. Schedule Y application: Application for permission: For the Import or manufacture of new drug for sale To take permission for clinical trial, should be made in form 44 All new drug substances discovered in India clinical trial required to carried out from Phase I to Phase IV.

5. All new drug substances discovered out side India, phase I data from that country need to be submitted to regulatory authorities (CDSCO) in India, after submission permission may be granted to repeat phase I or subsequent phase II or III. Phase III trials are required to be conducted in India before permission to market the drug in India is granted Schedule Y application Cont …

6. Amendments of Schedule Y: SN Notification no. date Rule Details 1. G.S.R. 53 (E) dated January 30, 2013 Inserted 122 DAB- Compensation for injury or death during CT Expansion of responsibility of sponsor, Investigator & EC Amendment in Appendix V (Inform Consent) Insertion of New Appendix XII Compensation for injury or death during CT & Procedures to analyze the SAEs reports & its timelines 2. G.S.R. 63(E) dated February 01, 2013 122 DAC Specifies conditions under which application for conduct of clinical trials Authority of CT inspection sponsor including their all parties members, employees and their premises as well. 3. G.S.R. 72(E) dated February 08, 2013 122 DD. Mandatory registration of the Ethics Committees (EC) Inspection of EC, Members should not less than SEVEN & chairman should be outside from the institute. Opinion for the compensation as case of injury or death as according to Appendix XII

7. SN Notification no. date Rule Details 4. G.S.R. 611(E) dated 31 st July,2015 Inform Consent: AV recording for the vulnerable subject in CT of new chemical Entity or new molecule & only audio in case of anti HIV/anti leprosy trial of individual subjects Appendix V(Inform consent) : “Possibility to failure of IP to provide therapeutic effect”. In the case of placebo control trial, “the placebo administered to the subjects shall not have therapeutic effect”. 5. G.S.R. 889(E) Dated 12 th Dec, 2014 122 DAB Sponsor , Investigator and EC responsibility has been amended Appendix V Appendix XII, mainly changes in time lines of SAE reporting and process Quantum of compensation in case of not permanent injury Amendment of Schedule Y:

8. G.S.R. 53 (E) dated January 30, 2013 122 DAB-Compensation for injury or death during CT In the case of injury free medical management shall be given to subject as long as required In the case subject death subject’s nominee would be entitle for the financial compensation All compensation or expenses in medical management shall be borne by sponsor. The sponsor shall give undertaking along with application regarding medical management and financial compensation

9. G.S.R. 889(E) dt. 12 th Dec.,2014 “Free medical management shall be given as long as required or till such time it is established that the injury is not related to the clinical trial, whichever is earlier”. Quantum of compensation shall be given in case of no permanent injury (inserted)

10. Responsibility: Sponsor G.S.R . 53 (E) dated January 30, 2013 Any report of SAE of death after due analysis shall be forwarded to chairman of EC and chairman of Expert committee of LA and copy of LA and head of Institute where CT has been conducted within 10 calendar days of the occurrence of SAE. Any report other than death shall be forwarded to LA, chairman of EC and Head of institute where trial has been conducted within 10 calendar days of the occurrence of SAE . Details of compensation shall be submitted to LA within 30 days of order of LA for compensation also paid compensation to subject.

11. G.S.R. 889(E) dt. 12 th Dec., 2014 Responsibility of sponsor: Any report of SAE after due analysis shall be forwarded to chairman of EC and LA and head of Institute where CT has been conducted within 14 calendar days (earlier was 10 days) of the occurrence of SAE .

12. Responsibility of Investigator: G.S.R. 53 (E) dated January 30, 2013 Report of SAE shall be forwarded to Sponsor and EC within 24 hrs. of their occurrence Any report of SAE of death after due analysis shall be forwarded to chairman of EC and chairman of Expert committee of LA and copy of LA and head of Institute where CT has been conducted within 10 calendar days of the occurrence of SAE . Any report other than death shall be forwarded to LA, chairman of EC and Head of institute where trial has been conducted within 10 calendar days of the occurrence of SAE Shall inform to subject’s or their nominee to claim compensation in case of trial related injury or death.

13. Responsibility of EC : G.S.R . 53 (E) dated January 30, 2013 Any report of SAE of death after due analysis with opinion of compensation shall be forwarded to chairman of Expert committee of LA and sponsor copy of LA within 21 calendar days of the occurrence of SAE . Any report of SAE other than death after due analysis with opinion of compensation shall be forwarded to chairman of Expert committee of LA and sponsor copy of LA within 21 calendar days of the occurrence of SAE .

14. G.S.R. 889(E) dt. 12 th Dec.,2014 Responsibility of Investigator : Any report of SAE of death after due analysis shall be forwarded to chairman of EC and LA and head of Institute where CT has been conducted within 14 calendar days (Earlier 10 days calendar days) of the occurrence of SAE . Investigator report all SAE within 24 hrs.to sponsor and EC. Responsibility of EC: In case of SAE report after due analysis shall be forwarded to LA with the opinion of compensation paid by the sponsor within 30 days (Earlier 21 calendar days) of SAE occurrence.

15. Inform Consent : Appendix V A freely given, informed, written consent is required to be obtained from each study subject patient information sheet as well as the Informed Consent Form should have been approved by the ethics committee and furnished to the Licensing Authority Where a subject is not able to give informed consent (e.g. an unconscious person or a minor or those suffering from severe mental illness or disability), the same may be obtained from a legally acceptable representative (a legally acceptable representative is a person who is able to give consent If subject and LAR are not able to give consent then an impartial witness should be present during the entire in formed consent process who must append his/her signatures to the consent form

16. Amendment in ICD: G.S.R. 53 (E) dated January 30, 2013 Essential elements of ICD have been amended by addition of “In the event of injury, free medical management will be given to subject as long as required” “In the trial related injury or death, the sponsor shall provide financial compensation for the injury or death”.

17. Format of ICD amended T o include subjects Address, qualification, occupation, Annual income Name and address of nominee Mandatory to hand over a copy od duly filled ICD to the subject or his/her attendant

18. G.S.R . 611(E) dated 31 st July,2015 Inform Consent: AV recording for the vulnerable subject in CT of new chemical Entity or new molecule & only audio in case of anti HIV/anti leprosy trial of individual subjects Appendix V(Inform consent) : “Possibility to failure of IP to provide therapeutic effect”. In the case of placebo control trial, “the placebo administered to the subjects shall not have therapeutic effect ”.

19. New Appendix XII: G.S.R. 53 (E) dated January 30, 2013 Compensation in case of injury or death during clinical trial In this Appendix complete process are given about that how will be reporting of SAEs or death/injury to the Licensing Authority and what is the process of analyzing SAEs or cause of death and the timeline for reporting SAEs, The reports of SAEs should be prepared and submitted in Death- Red Cover injury - Blue Cover Other than injury/death-White Cover

20. Reasons consider as injury or death due to CT G.S.R. 53 (E) dated January 30, 2013 Adverse effect of IP Protocol violation, scientific misconduct, negligence by sponsor or his representative or Investigator Failure of IP to provide intended therapeutic effect Use of placebo in placebo control trial For injury to child in utero due to participation of subject in trial Any clinical trial procedures involve in the study Adverse effect due to concomitant medication

21. G.S.R. 889(E) dt. 12 th Dec.,2014 Appendix XII “Failure of IP to provide intended the standard care though available, was not provided to the subject as per the clinical trial protocol. “Use of placebo in placebo control trial standard care though available, was not provided to the subject as per the clinical trial protocol”. addition of “In the case of no permanent injury, the quantum of compensation shall be commensurate with the nature of the non-permanent injury and loss of wages”. The investigator shall report all serious AE to LA & EC with in 24 hrs. of the their occurrence. If investigator fails to report in stipulated period, he have to furnish the reason for the delay to the satisfaction of LA.

22. The sponsor and investigator in case of death after due analysis shall forward their report on Death to chairman of EC and LA within 14 calendar days. The EC shall forward report on SAE of death after due analysis with opinion of compensation to LA with in 30 calendar days of their occurrence. LA shall forward report of PI, Sponsor and EC to expert committee (inserted) Expert committee examine the report and give its recommendations to LA for the purpose of arriving the cause of death within 105 days of their occurrence. G.S.R. 889(E) dt. 12 th Dec.,2014 Appendix XII

23. In the case of death the expert committee recommend quantum of compensation paid by sponsor to subject’s nominee within 150 days of receiving the report of SAE of death. SAE other than Death: Sponsor and investigator shall forward their report of SAE after due analysis to LA within 14 calendar days of their occurrence. EC shall forward their report of SAE after due analysis with their opinion regarding the compensation to LA within 30 calendar days. LA examine the report and order to pay quantum of compensation paid by sponsor to subject within 150days Sponsor shall have to pay compensation within 30 days of receipt of such order from LA. G.S.R. 889(E) dt. 12 th Dec.,2014 Appendix XII

24. Compensation = BxFxR / 99.37 B = Base Amount (8 lakhs ) F= Factor depending on age (Workmen Compensation Act) R= Risk Factor (severity & seriousness, co-morbidities etc. 0.5- 4.0) Formula on Quantum of Compensation :

25. Appendix- Schedule Y Data required to be submitted for grand permission to import and or manufacture a New drug alreay approved in the country Structure content and format for CT report Animal Toxicology Animal pharmacology Inform Consent FDC Undertaking by the investigator Ethics Committee Stability Testing Content of protocol for CT Data Elements for reporting SAE Compensation in case of injury or death during clinical trial ( G.S.R. 53 (E) dated January 30, 2013)

26. Thank You…!!!