1. Schedule Y Presented By-MANISH KUMAR SHARMA Presented ToCENTER FOR CLINICAL RESEARCH SHARDA UNIVERSITY, GREATER NOIDA,UP6/1/2012

2. Outline of Presentation1. History2. Drug and cosmetic Act,1940 and Schedules3. What actually Schedule Y is ?4. Old/New(amended) Schedule Y5. Why Changes in Schedule Y ?6. Rules under it7. Divisions of Schedule Y8. New Amendments9. Conclusion6/1/2012 3. Lets revise the History Drug and Cosmetic Act, 1940 was enacted(D/CAct) Pharmacy Act , 1948 Drug and Magic Remedies Act, 1954 The Narcotic and Psychotropic Substance Act andRules, 1985 Ethical guidelines for Biomedical Research onHuman Participants,2000 by ICMR6/1/2012 4. Indian GCP Guidelines,2001 Amendments to Drug and Cosmetic Act,2002 Revised Schedule Y, 2005 Guidelines for Pre Clinical Data for r-DNA Vaccines,20076/1/2012 5. Drug and Cosmetics Act,1940 In 1940 D/C Act Was enactedin 1945 Drug Rules were Promulgated in December and enforcement Start in 1947 Now have been called as D/C ActObjective- To ensure that the drug is available to the People are safe and cosmetics marketed for safer use.6/1/2012 6. Schedules to Rules, 1945 Schedule A- Forms for marketing application for licenses, issue, andrenewal B- Fee for test/analysis by CDL or SDL C/C1- talk about I/M/S/D of sera, vaccines D-List of drugs exempted from the provisions that are applicable toimport of other drug E- Omitted , E1- list of poisonous substance underAyurveda,Unani,Sidha system F- Production/testing/storage/packaging/labeling F1-biological preparations F2- SD F3- umbilical tapes G- List of drug used under medical supervision H- List of drug sold under Prescription I-Omitted J-Diseases may not cure/prevent by drugs K-List of drugs exempted from the provisions that are applicable to6/1/2012manufacture of other drug 7. M-GMP N-List of minimum equipment in Pharmacy O-Standards for disinfections P- Life period of drug Q-List of dyes/coloring agents in soap/cosmetics R-Standards for Mechanical contraceptives S-Standards for cosmetics T-GMP for A/U/S system of medicines U- Records for manufacturing/raw materials in drugs V- Standards for potent medicines X- List of drugs whose I/M/S are governed by special provision W- Omitted Y- About CT6/1/2012 8. Schedule Y The enforcement that came into existence in 1988was an essential provision for providing support tothe upscale of generic pharma scenario present inthose days. With the entry of large pharmaceutical companiesalong with the multiple multinationals in field ofclinical research the needs changed and a revisedversion of Schedule Y in line with ICH-GCP(International Council of Harmonization and GoodClinical Practice) standard was put forth in 1995. Since then multiple revisions to Schedule Y tookplace to provide a healthy environment for clinicalresearch to be conducted in India.6/1/2012 9. 6/1/2012 10. Schedule YIts a Law not merely a Guideline6/1/2012 11. Schedule Y Schedule Y ,the current regulator (ofCDSCO), enforced law in India hasbeen established under Drug andCosmetic Act,1945. The regulations to be followed whenconducting Clinical Trial in India.6/1/2012 12. contt..REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS IN INDIA6/1/2012 13. Amended Schedule Y Regulations andGuidelines for permissionfor development (preclinicaland/or clinical), import andmanufacture of New Drugsfor Marketing in India DATE- 20TH JAN,20056/1/2012 14. Why Changes in Schedule Y To frame guidelines for the current scenario of Clinical research. CDSCO and DTAB formulated GCP under Schedule Y in 2005. Schedule Y 1988 relevant to predominantly generic industry. GCP trials since 1995, and arrival of IPR regime in 2005. Integration of India in global clinical development and legal support to GCP guidelines. Improvements in quality of clinical trials. It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines.6/1/2012 15. Rules under Schedule Y RulePermission 122 ATo Import New Drugs 122 BTo manufacture New DrugsTo import or manufacture fixed dose 122 DCombinations 122 DA To conduct Clinical Trialsfor New Drug/Investigational NewDrug 122DAADefinition of Clinical Trial 122 EDefinition of New Drug6/1/2012 16. Rule 122DA To conduct Clinical Trials for New Drug/Investigational New Drug New chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings.6/1/2012 17. 122-E. 122-E. -Not been used in the country under labeling conditions- Approved but now proposed to be marketed with modified or new claims indications, dosage, dosage form , route of administration-FDC, individually approved, to be combined for the first time in a fixed ratio or if ratio is changed6/1/2012 18. 6/1/2012 19. Old schedule Yin the older version there are only 5 appendicesAppendix I: Declaration of HelsinkiAppendix II: Schedule YAppendix III: Format for submission of Pre-clinical and clinical data for r-DNA based vaccines, diagnostics and other biologicals.Appendix IV: Investigators BrochureAppendix V: Essential Documents6/1/2012 20. 6/1/2012 21. Significant changesNew conceptOlder concept1)Clinical trials 1.1 Nature of CTa) Definition of CT 1.2 Permission of CTb) ICD New1.3 ICD but no detailsc) responsibilities of ethical1.4 Responsibilities ofcommittee- Newsponsor/investigatord) PMS- New2) Studies in special populations No PMSa) Geriatric2) Special Studiesb) PediatricsNo Separationc) Pregnantd) PMS - Newe) BA/BE - New3)Formats for critical documents6/1/2012 22. Appendix I Data to be submitted along with the application to conduct clinical trials / import / manufacture of new drugs for marketing in the country.a. Introduction about the drugb. Chemical and pharmaceutical information (e.g. Enatiometry)c. Animal pharmacologyd. Animal toxicologye. Human /clinical pharmacology(Phase-I)f. Therapeutics exploratory(Phase-II)g. Therapeutics confirmatory(Phase-III)h. Special studies( paediatrics, pregnant)i. Regulatory status in other countries if availablej. Prescribing information(drug labeling and prescribing inf.) 6/1/2012 23. APPLICATION FOR PERMISSIONUNDER FORM 44, REGULATORYAUTHORITIES, FEES AND TESTLICENCE6/1/2012 24. Regulatory authoritiesMinistry of Chem & Ministry of HealthMinistry of Sci & Ministry ofFertilizersTechEnviro Health SecretaryDBTNPPA DGHS Department ofAdditionalNational Director General ofBiotechnologySecretaryPharmaceutical Health ServicesPricing AuthorityGEACDCGI GeneticDrug ControllerEngineering PricingGeneral of India Approval Regulations Committee CDRL/CDTL Gov. Drug Testing Laboratories State Drug Regulatory Authority :FDA 25. PROCESS Approval Form 45APPLICATION (IMP FF)FORM 44-Imp FFApproval Form 45-Imp RmA (IMP RM)-Mfg FF-Mfg RmApproval Form 46-CT(MFG FF) Application FormNOC FOR CT + Test46 A (MFG RM)Licence for Import 26. Fee according to Schedule Y Import ff/ Mfg ff/ Import bulk + Mfg ff= Rs 50,000/-of new drug Application by same applicant,= Rs 15,000/-for modified dosage form or with new claim Secondary applicants after 1 = Rs 15,000/-year of approval Import / Mfg FDC= Rs 15,000/- Conduct Clinical trial with ND/IND Phase I= Rs 50,000/- Phase II = Rs 25,000/- Phase III= Rs 25,000/- No separate fee to be paid along with application for import / mfg based on successful completion 27. Appendix I-AData required to be submitted by an applicant for grant ofpermission to import &/or manufacture a new drug already approvedin the country.a) Introductionb) Chemical and pharmaceutical informationc) Marketing informationd) Special studies 6/1/2012 28. Appendix IIIAnimal toxicology (Non-clinical toxicity studies) 1) SDTS- Minimum 5 animal, 24hr observation 2) DRS- On one Rodent Species 3) RDTS- a) 14 to 28 days- on 1 Rodent and 1 Non Rodentb)90 days- same as above but introduction of HIGH DOSE REVERSAL . 4) MFS- Rodent Species, Dose selection should be done on basis of 14 to 28 days studies. 5) FFS- should be carried out for all drugs( Appendix I- 4.4)6/1/2012 29. Animal toxicology (Non-clinical toxicity studies)Other Studiesa.Hypersensitivityb. Genotoxicityc. Carcinogenicity 6/1/2012 30. Appendix IV-Animal Pharmacology Animal pharmacology studies are done to see the effect ifIP on different systems like CVS CNS ANS RS US GIT6/1/2012 31. Appendix V- INFORM CONSENT Trial involves research Purpose Trial treatments and randomization Trial procedures Risk Benefit Alternative treatments Compensation / treatment for injury Subjects responsibilities Experimental aspects Any payment6/1/2012 32. Essential Elements of Informed Consent Confidentiality New information Voluntary participation Person/s to contact for study information Rights of subject, if study related injury Reasons for termination Duration of study Number of subjects Any other pertinent information6/1/2012 33. Format of Informed Consent Form Study Title Subjects Initials e.g. Subjects Name/ Date of Birth / Age Consent Statements with initials ina) Signature (or Thumb impression) of the Subjectb) Legally Acceptable Representative Signature of the Investigator Study Investigators Name Signature of the Witness Name of the Witness 6/1/2012 34. Appendix VI- FDCsCombination therapy with two or more agents having complementary mechanisms of action is an example of incremental innovation that may extend the range of therapeutic options in the treatment of almost every human diseaseData requirements of Fixed Dose CombinationsFixed Dose combinations (FDC) fall into four groups andtheir data requirements accordingly. The first group of FDC includes those in which one or moreof the active ingredients is a new drug. The second group of FDC includes those in which activeingredients already approved/marketed . The third group of FDC includes those which are alreadymarketed6/1/2012 35. Appendix VII Undertaking By The Investigator1) Full name, address and title of the Principal Investigator2) Name and address of the medical college, hospital or other facility where the clinical trial will be conducted: Education, training &experience that qualify the Investigator for the clinical trial (Attach details including Medical Council registration number, and / any other statement of qualification3) Name and address of all clinical laboratory facilities to be used in the study.4) Name and address of the Ethics Committee ,responsible for approval and continuing review of the study.5) Names of the other members of the research team (Co- or sub-Investigators) who will be assisting the Investigator in the conduct of the investigation. 36. VII.2 Commitments by The Investigatora. Study not to begin until EC / DCGI approvalb. Adherence to protocolc. Personal supervisiond. Ensure requirements of IC and EC reviewe. Report of AE to sponsorf. Understanding of investigators brochureg. Ensure that all associates, colleagues andemployees suitably qualified and experienced andaware of their obligationsh. Report all unexpected serious adverse events tothe Sponsor in 24 hrs and EC within 7 days.i. Maintenance of records and availability for audits /sponsor inspection / EC and DCGI. Cooperation in 6/1/2012audits 37. Appendix VIIIETHICS COMMITTEE COMPOSITIONICH GCP Indian GCP Schedule-Y At least 5 members. Fairly small (5-7 At least 7 members.At least 1 member -members).nonscientific area. 1 member from non-Not Explained.Quorum members scientific area The quorum shouldnumber not detailed.have at least 5The quorum should have a members.Maximum number isminimum of 5 members. Maximum number isnot detailed. not detailed.12 to 15 is the maximumNot recommended. recommended number. Not recommended.Member Secretarybelongs to the sameInstitution. 6/1/2012 38. Appendix IX- Stability testing of NewDrugs Stability testing is to be performed to provide evidence on how the quality of a drug substance or formulation varies with time under the influence of various environmental factors such as- a. Temperature b. Humidity and c. Light Objective. - To establish shelf life for the formulation and recommended storage conditions.6/1/2012 39. STABILITY TESTINGStress testing of the drug substance should be conducted toidentify-a. The degradation pathwaysb. Evaluate the intrinsic stability of the molecule andc. Validate the stability indicating power of the analytical procedures used.Stress testing may generality be carried out on a single batchof the drug substance. It should include the effect of-Temperature, humidity, oxidation, photolysis on the drugsubstance.TWO TYPES OF STUDY IS DONE1)Long-term testing should cover a minimum of 12months duration on at least three primary batches of 6/1/2012 40. STABILITY TESTING2)Accelerated testing should cover a minimum of 6months duration at the time of submission.Study conditions for drug substances and formulationsintended to be stored under general conditions.Study conditions and Duration of studyi)Long term 30 C 2 C/65% RH 5%RH 12 monthsii)Accelerated 40 C 2 C/75% RH 5% RH 6 monthsIf at any time during 6 months testing under the accelerated storage condition, such changes occur then further studies are done.NOTE- The nature of the stress testing will depend on the individual drug substance and the type of formulation involved. 6/1/2012 41. Appendix X Contents of the ProposedProtocol Title page Table of contenta) a) introductionb) Study rationalec) Study designd) Study populatione) Subject eligibilityf) Study treatmentg) AEh) Data analysisi) Undertaking by investigatorNOTE- Protocol is assigned by sponsor after getting CDA frominvestigator6/1/2012 42. Appendix XI- Data Elements For Reporting SAE in aClinical Triala) Patient details(Age, sex, weight, height)b) Suspected drug( Generic name, DFD, ROA)c) Detail of SUSPECTED ADR( severity, start date, stop date, hospitalization or not)d) Details about investigator6/1/2012 43. New Amendments on 30.06.2009CLINICAL RESEARCH ORGANISATION REGISTRATIONThese guidelines have been approved by DTAB 1)Rule 122 DAB. Registration of clinical researchorganization for conducting clinical trials. The clinical research organisation, contracted inwriting by the sponsor to carry out any or allobligations transferred to it by the sponsor, shallperform such functions only, if it is duly registered,under the rules, by the Licensing Authority defined in6/1/2012 44. Schedule Y-1-Requirements and Guidelinesfor registration of clinical research2. Criteria fororganisations Registration(I) The Clinical Research Organisation shall be under the charge of a person who is responsible for the overall activities of the organisation. He shall be thoroughly familiar with the investigational product(s), the protocol, written informed consent forms or other information provided to the subjects, the standard operative procedures by the sponsors, GCP guidelines and other rules applicable to the conduct of clinical trials. 6/1/2012 The organisation shall have adequate(ii) 45. (iii) The organisation shall ensure that the trials are adequately monitored and the trial related responsibilities transferred to it, partially or fully, by the sponsor are discharged effectively and efficiently.(iv) The organisation shall implement quality assurance and quality control as per standard operative procedures designed for the purpose. Such SOPs shall be well documented.6/1/2012 46. New Amendments on 18th Nov.20111)Rule 122-DAB- compensation during injury or death duringclinical trialIn case of injury in clinical trial the compensation is based asper the recommendation of EC/IRB , it may be financial ormedical.2) In case of death his/her legal heirs are entitled for thefinancial compensation, subject to the confirmation to EC6/1/2012 47. ConclusionWith the Schedule Y, efforts are aligned in a single direction to ensure that irrespective of the country, the data generated is of good quality and standard which can be accepted worldwide6/1/2012 48. ReferencesGupta S.K, Basic principles of Clinical research and Methodology, 2007.6/1/2012 49. QUERIES????6/1/2012