Dr.s.s amended schedule y

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  • 122-E. Definition of new drug   For the purpose of this Part, ‘new drug’ shall mean and include-   (a)    a new substance of chemical, biological or biotechnological origin; in bulk or prepared dosage form; used for prevention, diagnosis, or treatment of disease in man or animal; which, except during local clinical trials, has not been used in the country to any significant extent; and which, except during local clinical trials, has not been recognized in the country as effective and safe for the proposed claim; (b)    a drug already approved by the licensing authority mentioned in Rule 21 for certain claims, which is now proposed to be marketed with modified or new claims, namely, indications, dosage forms (including sustained release dosage form) and route of administration; (c)    a fixed dose combination of two or more drugs, individually approved earlier for certain claims, which are now proposed to be combined for the first time in a fixed ratio, or if the ratio of ingredients in an already marketed combination is proposed to be changed, with certain claims, viz. indications, dosage form (including sustained release dosage form) and route of administration. [See items (b) and (c) of Appendix VI to Schedule Y.] Explanation: For the purpose of this rule- (i)                  all vaccines shall be new drugs unless certified otherwise by the licensing authority under Rule 21; (ii)                a new drug shall continue to be considered as new drug for a period of four years from the date of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier.  
  • DCGI IS THE LICENCING AUTHORITY IN INDIA
  • Rm – raw material FF – finished formulation 122-A. Application for permission to import New Drug   (1) (a) No new drug shall be imported, except under, and in accordance with, the permission granted by the Licensing Authority as defined in clause (b) of rule 21; (b) An application for grant of permission to import a new drug shall be made in Form 44 to the Licensing Authority, accompanied by a fee of fifty thousand rupees:   Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such application shall be fifteen thousand rupees:   Provided further that any application received after one year of the grant of approval for the import and sale of new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix 1 or Appendix 1 A of Schedule Y, as the case may be.” ;   (2) The importer of a new drug when applying for permission under sub-rule (1), shall submit data as given in Appendix 1 to Schedule Y including the results of local clinical trials carried out in accordance with the guidelines specified in that Schedule and submit the report of such clinical trials in the format given in Appendix II to the said Schedule:   Provided that the requirement of submitting the results of local clinical trials may not be necessary if the drug is of such a nature that the licensing authority may, in public interest decide to grant such permission on the basis of data available from other countries:   Provided further that the submission of requirements relating to Animal toxicology, Reproduction studies, Teratogenic studies, Perinatal studies, Mutagenicity and Carcinogenicity may be modified or relaxed in case of new drugs approved and marketed for several years in other countries if he is satisfied that there is adequate published evidence regarding the safety of the drug, subject to the other provisions of these rules.   (3) The Licensing Authority, after being satisfied that the drug if permitted to be imported as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, may issue an import permission in Form 45 and/or Form 45 A, subject to the conditions stated therein:   Provided that the Licensing Authority shall, where the data provided or generated on the drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied before permission, could be considered.”   122-B. Application for approval to manufacture New Drug other than the drugs classifiable under Schedules C and C(1)   (1) (a) No new drug shall be manufactured for sale unless it is approved by the Licensing Authority as defined in clause (b) of rule 21. (b) An application for grant of approval to manufacture the new drug and its formulations shall be made in Form 44 to the Licensing Authority as defined in clause (b) of rule 21 and shall be accompanied by a fee of fifty thousand rupees:   Provided that where the application is for permission to import a new drug (bulk drug substance) and grant of approval to manufacture its formulation/s, the fee to accompany such application shall be fifty thousand rupees only.   Provided further that where a subsequent application by the same applicant for that drug, whether in modified dosage form or with new claims, is made, the fee to accompany such subsequent application shall be fifteen thousand rupees:   Provided further also that any application received after one year of the grant of approval for the manufacture for sale of the new drug, shall be accompanied by a fee of fifteen thousand rupees and such information and data as required by Appendix I or Appendix I A of Schedule Y, as the case may be.”;   (2) The manufacturer of a new drug under sub-rule (1) when applying for approval to the licensing authority mentioned in the said sub-rule, shall submit data as given in Appendix I to Schedule Y including the results of clinical trials carried out in the country in accordance with the guidelines specified in Schedule Y and submit the report of such clinical trials in the format given in Appendix II to the said Schedule.   (2A) The Licensing Authority as defined in clause (b) of rule 21 after being satisfied that the drug if approved to be manufactured as raw material (bulk drug substance) or as finished formulation shall be effective and safe for use in the country, shall issue approval in Form 46 and/or Form 46 A, as the case may be, subject to the conditions stated therein:   Provided that the Licensing Authority shall, where the data provided or generated on the drug is inadequate, intimate the applicant in writing, and the conditions, which shall be satisfied before permission could be considered.   (3) When applying for approval to manufacture of a new drug under sub-rule (1) or its preparations to the State licensing authority, an applicant shall produce along with his application, evidence that the drug for the manufacture of which application is made has already been approved by the licensing authority mentioned in Rule 21:   Provided that the requirement of submitting the result of local clinical trials may not be necessary if the drug is of such a nature that the licensing authority may, in public interest decide to grant such permission on the basis of data available from other countries:   Provided further that the submission of requirements relating to Animal toxicology, Reproduction studies, Teratogenic studies, Perinatal studies, Mutagenicity and Carcinogenicity may be modified or relaxed in case of new drugs approved and marketed for several years in other countries if he is satisfied that there is adequate published evidence regarding the safety of the drug, subject to the other provisions of these rules.   Rule 122C has been omitted.   122D. Permission to import or manufacture fixed dose combination   (1) An application for permission to import or manufacture fixed dose combination of two or more drugs as defined in clause (c) of rule 122 E shall be made to the Licensing Authority as defined in clause (b) of rule 21 in Form 44, accompanied by a fee of fifteen thousand rupees and shall be accompanied by such information and data as is required in Appendix VI of Schedule Y.   (2) The Licensing Authority after being satisfied that the fixed dose combination, if approved to be imported or manufactured as finished formulation shall be effective and safe for use in the country, shall issue permission in Form 45 or Form 46, as the case may be, subject to the conditions stated therein: Provided that the Licensing Authority shall where the data provided or generated on the fixed dose combination is inadequate, intimate the applicant in writing, and the conditions which shall be satisfied before grant of approval/permission could be considered: 122DA. – Application for permission to conduct clinical trials for New Drug/Investigational New Drug.-   (1) No clinical trial for a new drug, whether for clinical investigation or any clinical experiment by any Institution, shall be conducted except under, and in accordance with, the permission, in writing, of the Licensing Authority defined in clause (b) of rule 21.   (2) An application for grant of permission to conduct,- (a) human clinical trials (Phase-I) on a new drug shall be made to the Licensing Authority in Form 44 accompanied by a fee of fifty thousand rupees and such information and data as required under Schedule Y; (b) exploratory clinical trials (Phase-II) on a new drug shall be made on the basis of data emerging from Phase-I trial, accompanied by a fee of twenty-five thousand rupees; (c) confirmatory clinical trials (Phase-III) on a new drug shall be made on the basis of the data emerging from Phase-II and where necessary, data emerging from Phase-I also, and shall be accompanied by a fee of twenty-five thousand rupees:   Provided that no separate fee shall be required to be paid along with application for import/manufacture of a new drug based on successful completion of phases of clinical trials by the applicant.   Provided further that no fee shall be required to be paid alongwith the application by Central Government or State Government Institutes involved in clinical research for conducting trials for academic or research purposes.   (3) The Licensing Authority after being satisfied with the clinical trials, shall grant permission in Form 45 or Form 45A or Form 46 or Form 46-A, as the case may be, subject to the conditions stated therein:   Provided that the Licensing Authority shall, where the data provided on the clinical trials is inadequate, intimate the applicant in writing, within six months, from the date of such intimation or such extended period, not exceeding a further period of six months, as the Licensing Authority may, for reasons to be recorded, in writing, permit, intimating the conditions which shall be satisfied before permission could be considered:   Explanation – For the purpose of these rules Investigational New Drug means a new chemical entity or a product having therapeutic indication but which have never been earlier tested on human being.   122DB, Suspension or cancellation of Permission / Approval.   If the importer or manufacturer under this Part fails to comply with any of the conditions of the permission or approval, the Licensing Authority may, after giving an opportunity to show cause why such an order should not be passed, by an order in writing stating the reasons therefor, suspend or cancel it.   122DC. Appeal.   Any person aggrieved by an order passed by the Licensing Authority under this Part, may within sixty days from the date of such order, appeal to the Central Government, and the Central Government may after such enquiry into the matter as is considered necessary, may pass such order in relation thereto as it thinks fit.”
  • for new drug substances discovered in countries other than India, Phase I data as required under items 1,2, 3, 4, 5 (data from other countries) and 9 of Appendix I should be submitted along with the application. After submission of Phase I data generated outside India to the Licensing Authority, permission may be granted to repeat Phase I trials and/or to conduct Phase II trials and subsequently Phase III trials concurrently with other global trials for that drug. Phase III trails are required to be conducted in India before permission to market the drug in India is granted;
  • Special studies: Bioavailability/Bioequivalence Studies.- (i) For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out wherever applicable. These studies should be conducted under the labeled conditions of administration. Data on the extent of systemic absorption may be required for formulations other than those designed for systemic absorption. (ii) Evaluation of the effect of food on absorption following oral administration should be carried out. Data from dissolution studies should also be submitted for all solid oral dosage forms. (iii) Dissolution and bioaviliability data submitted with the new drug application must provide information that assures bioequivalence or establishes bioavailability and dosage correlations between the formulation(s) sought to be marketed and those used for clinical trials during clinical development of the product. (See items 8.1, 8.2 and 8.3 of Appendix I,). (iv) All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalance studies as prescribed.
  • Dr.s.s amended schedule y

    1. 1. Amended Schedule “Y” Dr. Surinder Singh (Drugs Controller General of India) Directorate General Health Services (Ministry of Health & Family Welfare) Govt. of India
    2. 2. Overview <ul><li>Schedule Y – what it covers and associated rules </li></ul><ul><li>Application for permission under form 44, regulatory authorities and fees </li></ul><ul><li>Important consideration </li></ul><ul><li>Appendices of Schedule Y </li></ul><ul><li>Loopholes & further refinement </li></ul>
    3. 3. <ul><li>SCHEDULE “Y” </li></ul><ul><li>WHAT IT COVERS & ASSOCIATED RULES </li></ul>
    4. 4. What is Schedule Y <ul><li>Regulation and guidelines for permission to import and / or manufacture of new drugs for sale or to undertake clinical trials </li></ul><ul><li>It has outlined extensive study criteria in line with the globally accepted formats such as ICH and US FDA guidelines </li></ul><ul><li>REFER TO RULES 122A, 122B, 122D, 122DA, 122DAA and 122E </li></ul>
    5. 5. Part X-A of D & C Rules, 1945 <ul><li>122-A Application for permission to import new drug </li></ul><ul><li>122-B Application for approval to manufacture new drug </li></ul><ul><li>122-D Permission to import or manufacture FDC/NDC </li></ul><ul><li>122-DA Permission to conduct clinical trials for New Drug / Investigational New Drug </li></ul>
    6. 6. Clinical trial <ul><li>122-DAA </li></ul><ul><ul><li>“Clinical trial” means a systematic study of new drug(s) in human subject(s) to generate data for discovering and / or verifying the clinical, pharmacological (including pharmacodynamic and pharmacokinetic) and /or adverse effects with the objective of determining safety and / or efficacy of the new drug. </li></ul></ul>
    7. 7. New drug <ul><li>122-E </li></ul><ul><li>Not been used in the country under labeling conditions </li></ul><ul><li>Approved but now proposed to be marketed with modified or new claims – indications, dosage, dosage form , route of administration </li></ul><ul><li>FDC, individually approved, to be combined for the first time in a fixed ratio or if ratio is changed </li></ul><ul><li>Vaccines are new drugs unless otherwise certified </li></ul><ul><li>Considered new drug for 4 years from date of first approval or inclusion in IP </li></ul>
    8. 8. Investigational new drug <ul><li>New chemical entity or a product having therapeutic indication but which has never been earlier tested on human beings </li></ul>
    9. 9. APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY AUTHORITIES, & FEES
    10. 10. Regulatory authorities Ministry of Chem & Fertilizers (NPPA) National Pharmaceutical Pricing Authority Pricing Regulations Ministry of Sci & Tech (DBT) Department of Biotechnology Ministry of Enviro Additional Secretary State Drug Regulatory Authority :FDA (GEAC) Genetic Engineering Approval Committee (DCGI) Drug Controller General of India (DGHS) Director General of Health Services Health Secretary Ministry of Health (CDL/CDTL) Gov. Drug Testing Laboratories
    11. 11. PROCESS <ul><li>APPLICATION FORM 44 </li></ul><ul><li>Imp ff </li></ul><ul><li>Imp rm </li></ul><ul><li>Mfg ff </li></ul><ul><li>Mfg rm </li></ul><ul><li>CT </li></ul>NOC FOR CT + Test Licence for Import Application Form 46 A (MFG RM) Approval Form 46 (MFG FF) Approval Form 45 A (IMP RM) Approval Form 45 (IMP FF)
    12. 12. FEES <ul><li>Import ff/ Mfg ff/ Import bulk + Mfg ff = Rs 50,000/- </li></ul><ul><li>of new drug </li></ul><ul><li>Application by same applicant, = Rs 15,000/- </li></ul><ul><li>for modified dosage form or with new claim </li></ul><ul><li>Secondary applicants after 1 = Rs 15,000/- </li></ul><ul><li>year of approval </li></ul><ul><li>Import / Mfg FDC = Rs 15,000/- </li></ul><ul><li>Conduct Clinical trial with ND/IND </li></ul><ul><ul><li>Phase I = Rs 50,000/- </li></ul></ul><ul><ul><li>Phase II = Rs 25,000/- </li></ul></ul><ul><ul><li>Phase III = Rs 25,000/- </li></ul></ul><ul><ul><li>No separate fee to be paid along with application for import / mfg based on successful completion </li></ul></ul>
    13. 13. Application Form 44 <ul><li>FORM 44 </li></ul><ul><li>(See Rules 122A, 122B, 122D and 122DA) </li></ul><ul><li>Application for grant of permission to import or manufacture a New Drug or to undertake clinical trial </li></ul><ul><li>I/We..……….. of ……….., hereby apply for grant of permission for import and / or clinical trial or for approval to manufacture of a new drug or fixed dose combination or subsequent permission of already approved new drug. The necessary information / data is given below : </li></ul><ul><li>1. Particulars of New Drug : </li></ul><ul><ul><li>Name of the drug : </li></ul></ul><ul><ul><li>Dosage Form : </li></ul></ul><ul><ul><li>Composition of the formulation : </li></ul></ul><ul><ul><li>Test specifications : </li></ul></ul><ul><ul><ul><li>Active ingredients : </li></ul></ul></ul><ul><ul><ul><li>Inactive ingredients : </li></ul></ul></ul><ul><ul><li>Pharmacological classification of the drug : </li></ul></ul><ul><ul><li>Indications for which proposed to be used : </li></ul></ul><ul><ul><li>Manufacturer of the raw material : </li></ul></ul><ul><ul><li>Patent status : </li></ul></ul>
    14. 14. FORM 44 Contd <ul><li>Data submitted along with the application </li></ul><ul><li>Permission to market new drug </li></ul><ul><li>Chemical and Pharmaceutical information </li></ul><ul><li>Animal Pharmacology </li></ul><ul><li>Animal Toxicology </li></ul><ul><li>Human / Clinical Pharmacology </li></ul><ul><li>Exploratory Clinical Trials </li></ul><ul><li>Confirmatory Clinical Trials </li></ul><ul><li>Bioavailability / dissolution and stability data </li></ul><ul><li>Regulatory status in other countries </li></ul><ul><li>Marketing information : </li></ul><ul><ul><li>(a) Proposed product monograph </li></ul></ul><ul><ul><li>(b) Drafts of labels and cartons </li></ul></ul><ul><li>Application for test license : </li></ul>
    15. 15. FORM 44 Contd <ul><li>Subsequent approval / permission for manufacture of already approved new drug </li></ul><ul><li>Formulation : </li></ul><ul><ul><li>Bioavailability / bioequivalence </li></ul></ul><ul><ul><li>Name of the investigator / centre </li></ul></ul><ul><ul><li>Source of raw mat and stability </li></ul></ul><ul><li>Raw Material </li></ul><ul><ul><li>Manufacturing Method </li></ul></ul><ul><ul><li>QC parameters, specs, stability </li></ul></ul><ul><ul><li>Animal toxicity </li></ul></ul>
    16. 16. FORM 44 Contd <ul><li>Subsequent approval or approval for new indication – new dosage form : </li></ul><ul><ul><ul><li>Number and date of Approval already granted </li></ul></ul></ul><ul><ul><ul><li>Justification </li></ul></ul></ul><ul><ul><ul><li>Data on safety, efficacy and quality </li></ul></ul></ul><ul><ul><ul><li>A total fee of Rs………………… has been credited to the Government under the Head of Account …… (receipt enclosed) </li></ul></ul></ul><ul><ul><ul><li>Signature </li></ul></ul></ul><ul><ul><ul><li>Designation </li></ul></ul></ul><ul><ul><ul><li>Date </li></ul></ul></ul>
    17. 17. FORM 44 Contd <ul><li>Approval / permission for FDC </li></ul><ul><li>Justification </li></ul><ul><li>P’cokinetic / P’codynamic data </li></ul><ul><li>Any other data </li></ul>
    18. 18. Important Considerations - 1 <ul><li>HUMAN CLINICAL PHARMACOLOGY :- </li></ul><ul><li>Phase I (Human Pharmacology) – Safety and Tolerability with the initial administration of IND – MTD, Kinetics and Dynamics </li></ul><ul><li>Phase II (Therapeutic Exploratory Trials) – Effectiveness for a particular indication, small group </li></ul><ul><li>Phase III (Therapeutic Confirmatory Trials) – Therapeutic benefit in large number of patients </li></ul><ul><li>Phase IV (Post Marketing Trials) – Related to approved indication </li></ul>
    19. 19. IMPORTANT CONSIDERATIONS <ul><li>HUMAN CLINICAL PHARMACOLOGY :- </li></ul><ul><li>for new drug substances discovered in India : Trials are required to be carried out in India right from phase 1 and required data needs to be submitted. </li></ul><ul><li>for new drug substances discovered in countries other than India : Phase I data generated outside India, permission may be granted to repeat phase 1. Application for permission to initiate specific phase of clinical trial should also accompany Investigator’s brochure, proposed protocol, case record form, study subject’s informed consent document's) investigator’s undertaking and ethics committee clearance , if available </li></ul><ul><li>Sample size depends on type of study </li></ul><ul><li>EC application can be in parallel to DCGI application </li></ul><ul><li>Drugs indicated in life-threatening, serious disease or diseases of special relevance to Indian health scenario, toxicological / clinical data abbreviated, deferred or omitted </li></ul><ul><li>Administrative/Logistic Amendments notified to DCGI and EC within 30 days and approval obtained </li></ul>
    20. 20. Important Considerations - 2 <ul><li>PSUR :- </li></ul><ul><li>New drugs should be closely monitored for their clinical safety; submission of Periodic Safety Update Reports (PSUR’s) in order to- </li></ul><ul><li>report all the relevant new information (patient exposure) </li></ul><ul><li>summarize the market authorization status in different countries and any significant variations related to safety; and </li></ul><ul><li>indicate whether changes should be made to product information </li></ul><ul><li>  </li></ul><ul><li>PSURs shall be submitted every 6 months for the first two years after </li></ul><ul><li>approval </li></ul><ul><li>For subsequent two years – the PSURs need to be submitted </li></ul><ul><li>annually </li></ul><ul><li>PSURs due for a period must be submitted within 30 calendar days of </li></ul><ul><li>the last day of the reporting period. </li></ul>
    21. 21. IMPORTANT CONSIDERATIONS - 3 <ul><li>BA/BE </li></ul><ul><li>For drugs approved elsewhere in the world and absorbed systemically, bioequivalence with the reference formulation should be carried out. </li></ul><ul><li>Evaluation of the effect of food </li></ul><ul><li>Dissolution and bioavailability data to be submitted </li></ul><ul><li>All bioavailability and bioequivalence studies should be conducted according to the Guidelines for Bioavailability and Bioequivalence studies as prescribed (ICMR guidelines) </li></ul>
    22. 22. TEST LICENCE <ul><li>Application : </li></ul><ul><li>Form 12 application </li></ul><ul><li>Material Justification Plan </li></ul><ul><li>Treasury Challan of Rs 100 for first drug, followed by Rs 50 for additional drug </li></ul><ul><li>Test License obtained in FORM 11 </li></ul>
    23. 23. THANK YOU

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