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SCHEDULE Y :

SCHEDULE Y RAVI KESHARI(ravikesharimpharm@gmail.com) Suneel Pandey( suneel2312@rediffmail.com ) PSIT Kanpur (Pharmaceutics) (Amended Version -2005)

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Purpose : To frame guidelines for conduct of Clinical research. Creating opportunities for Foreigners in India. Control and regulation for new drugs. CDSCO and DTAB formulated GCP under Schedule Y in 2005.

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Why India : India offers unique opportunities for conducting clinical trials in view of : the large patient pool, well- trained and enthusiastic investigators and premiere medical institutes available in the country considerable low per patient trial cost, as compared to developed countries.

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S ystematic study of pharmaceutical products On human subjects To discover or verify the clinical, pharmacological effects. adverse effects. safety and efficacy. Phases : Human/Clinical Pharmacology trials (Phase I) Exploratory trials (Phase II) Confirmatory trials ( Phase III) Phase IV ( Post Marketing Surveillance )

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The purpose of clinical trial is to find out whether a medication or treatment regimen is safe and effective for the treatment of a specific condition or disease.

Requirements and guidelines on clinical trials for import and manufacture of new drug :

Requirements and guidelines on clinical trials for import and manufacture of new drug Clinical Trials Nature of trials Permission for trials Responsibilities of Sponsor/Investigator 2. Chemical and Pharmaceutical Information 3. Animal Toxicology Acute toxicity Long-term toxicity

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Reproduction studies Local toxicity Mutagenicity and Carcinogenicity 4. Animal Pharmacology 5. Human/Clinical Pharmacology trials (Phase I) 6. Exploratory trials (Phase II) 7. Confirmatory trials (Phase III) 8. Special Studies 9. Submission of Reports (Appendix II to Sch Y) 10. Regulatory status in other countries 11. Marketing Information

Nature of trials:

Nature of trials Already approved/marketed drugs, phase III trials as required under item 7 of Appendix I (to Sch. Y) usually are required. If not than is initiated from one phase earlier to the phase of trials in other countries. For new drug substances discovered in other countries phase I trials are not usually allowed to be initiated in India unless phase I data as required under Item 5 of the said Appendix from other countries are available. For new drug substances discovered in India, clinical trials are required to be carried out in India right from phase I as required from Item 5 of the said Appendix.

Permission for trials:

Permission for trials May be obtained by applying in Form 12 for a test license (TL) to import or manufacture the drug under the Rules. Data appropriate for the various phases of clinical trials to be carried out should accompany the application as per format given in Appendix I (Items I-4). The names of investigators and institutions should also be submitted for approval. The investigators selected should possess appropriate qualifications and experience . Permission to carry out clinical trials with a new drug is issued along with a test license in Form 11. It is desirable that protocols for clinical trials be reviewed and approved by the institution’s ethical committee . For new drugs having potential for use in children, permission for clinical trials in the paediatric age group is normally given after phase III trials as required under item 7 of the said Appendix, in adults are completed. However, if the drug is of value primarily in a disease of children, early trials in the paediatric age group may be allowed.

Responsibilities of Sponsor/ Investigator:

Responsibilities of Sponsor/ Investigator Sponsors are required to submit to the Licensing Authority as given under Rule 21 an annual status report on each clinical trial, namely, ongoing, completed, or terminated. In case a trial is terminated, reason for this should be stated. Any unusual, unexpected, or serious adverse drug reaction (ADR) detected during a trial should be promptly communicated by the sponsor to the Licensing Authority under Rule 21 and the other investigators. In all trials an informed, written consent is required to be obtained from each volunteer/patient in the prescribed form (See Appendix V), which must be signed, by the patient/volunteer and the chief investigator.

Chemical and Pharmaceutical Information (See Appendix I to Sch. Y, Item 2):

Chemical and Pharmaceutical Information (See Appendix I to Sch. Y, Item 2) Most of the data under this heading are required with the application for marketing permission. When the application is for clinical trials only, information covered in item 2.1 to 2.3 of Appendix I will usually suffice.

Animal Toxicology (Appendix I – Sch. Y - Item 4.2) :

Animal Toxicology (Appendix I – Sch. Y - Item 4.2) Acute toxicity Acute toxicity studies should be carried out in at least two species, usually mice and rats using the same route as intended for humans. In addition, at least two more route should be used to ensure systemic absorption of the drug. Mortality should be looked for up to 72 hrs after parentral administration and up to 7 days after oral administration . Symptoms, signs and mode of death should be reported, with appropriate macroscopic and microscopic findings where necessary

Reproduction studies (Appendix I – Sch. Y, item 4.4):

Reproduction studies (Appendix I – Sch. Y, item 4.4) Reproduction studies need to be carried out only if the new drug is proposed to be studied or used in women of childbearing age. Two species should generally be used, one of them being non-rodent if possible. It mainly includes three types of studies …. Fertility studies Teratogenicity studies Perinatal studies

Local toxicity (See Appendix I, Sch. Y, Item 4.5) :

Local toxicity (See Appendix I, Sch. Y, Item 4.5) These studies are required when the new drug Is proposed to be used typically in humans. The drug should be applied to an appropriate site to determine local effects in a suitable species such as guinea pigs or rabbits, if the drug is absorbed from the site of applications, appropriate systemic toxicity studies will be required.

Long-term toxicity (See Appendix I – Sch. Y, Item 1.3) :

Long-term toxicity (See Appendix I – Sch. Y, Item 1.3) Studies should be carried out in at least 2 mammalian species, of which one should be a non-rodent. Duration of study will depend on whether the application is for marketing permission or for clinical trial. In these studies the drug should be administered 7 days a week by the route intended for clinical use in humans. The number of animals required for these studies, i.e. the minimum number on which data should be available. Control group of animals should also be included for the comparison of the TD and ED.

Mutagenicity and Carcinogenicity (See Appendix I, Sch. Y Item 4,6) :

Mutagenicity and Carcinogenicity (See Appendix I, Sch. Y Item 4,6) Studies are required to be carried out if the drug or its metabolite is related to a known carcinogen or when the nature and action of the drug is such as to suggest a carcinogenic/mutagenic potential. For carcinogenicity studies, at least two species should be used. Species should not have high incidence of spontaneous tumors and should preferably be known to metabolize the drug in the same manner as humans. At least three does levels should be used; the highest does should be sub-lethal but cause observable toxicity; the lowest does should be comparable to the intended human therapeutic does or a multiple of it. A control group should always be included.

Animal Pharmacology (See Appendix I to Sch. Y, Item 3.2) :

Animal Pharmacology (See Appendix I to Sch. Y, Item 3.2) Specific pharmacological actions are those with therapeutic-potential for humans. These should be described according to the animal models and species used. Wherever possible, dose response relationships and ED 50s should be given. Special studies to elucidate mode of action may also be described. General pharmacological action (see Appendix I to Sch. Y, Item 3.3) are effects on other organs and systems, especially cardiovascular, respiratory and central nervous systems. Pharmacokinetic data help to relate the drug effect with plasma concentration and should be given to the extent available.

Special Studies:

Special Studies Include studies on solid oral dosage forms, such as BA and dissolution studies. These are required to be submitted on the formulations manufactured in the country. (See Appendix I, Items 8.1 and 8.2) These include studies to explore additional aspects of the drug, e.g. use in elderly patients or patients with renal failure, secondary or ancillary effects, interactions, etc. (See Appendix I to Sch. Y, Item 8.1 and 8.2).

Submission of Reports (Appendix II to Schedule Y) :

Submission of Reports (Appendix II to Schedule Y) The reports of completed clinical trials shall be submitted by the applicant duly signed by the investigator within a stipulated period of time. The applicant should do so even if he is no longer interested to market the drug in the country unless there are sufficient reasons for not doing so.

Regulatory status in other counties:

Regulatory status in other counties It is important to state if any restrictions have been placed on the use of the drug in any other country, e.g. dosage limits, exclusion of certain age groups, warnings about adverse drug reaction, etc. (See Appendix I, Sch. Y, Item 9.2) Likewise, if the drug has been withdrawn from any country especially by a regulatory directive such information should e furnished along with reasons and their relevance, if any, to India (See Appendix I, Item 9.1(d)).

Marketing Information:

Marketing Information The product monograph should comprise the full prescribing information necessary to enable a physician to use the drug properly. It should include description, actions, indications, dosage precautions, drug interactions, warnings and adverse reactions. The drafts of label and carton texts should comply with provisions of Rules 96 and 97 of the said rules.

RESPONSIBILITIES :

RESPONSIBILITIES Sponsor Investigator and Institution Selection SOP Allocation of duties and responsibilities Study management, data handling and record keeping. Information on Investigational Products Adverse Drug Reaction Reporting.Monitoring & Audit

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2. Monitor Qualifications The monitor should have adequate medical, pharmaceutical and / or scientific qualifications and clinical trial experience. Monitor should be fully aware of all the aspects of the product under investigation and the protocol (including its annexes and amendments).

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Responsibility To oversee the progress of the study and to ensure that the study conduct and data handling comply with the protocol, GCPs and applicable ethical and regulatory requirements. Ascertain that the institutional facilities like laboratories, equipment, staff, storage space etc. are adequate for safe and proper conduct of the study. Should verify that the investigational product(s) are supplied only to subjects who are eligible to receive it and at the specified dose(s) and time(s) Subjects are provided with the necessary instructions on proper handling of the product(s) Should promptly inform the sponsor and the ethics committee in case any unwarranted deviation from the protocol or GCP guidelines.

Investigator :

Investigator Qualifications Medical care of the study subjects Monitoring and Auditing of Records Communication with Ethics Committee Compliance with the protocol Records/Reports Progress Reports Termination and final report

Appendix I to Schedule Y :

Appendix I to Schedule Y Introduction Chemical and pharmaceutical information Animal pharmacology Animal toxicology Human/clinical pharmacology (Phase I) Exploratory clinical trials (Phase II) Confirmatory clinical trials (Phase III) Special studies Regulatory status in other countries Marketing information

APPENDIX I to Schedule YI :

APPENDIX I to Schedule YI Format for submission of Clinical Trial Reports Title of the trial : Name of the investigator and institution : Objectives of the trial: Design of study: Number of patients: Treatments given: drugs and dosage forms: Regimens: Observations made: Results: Discussions of results: Summary and conclusion:

APPENDIX V to Schedule Y :

APPENDIX V to Schedule Y It includes following forms……. Patient consent form for participation in a Phase I Clinical Trial Patient consent form for participation in Phase II and Phase III Clinical Trial

APPENDIX VI to Schedule Y :

APPENDIX VI to Schedule Y Data requirements of Fixed Dose Combinations Fixed Dose combinations (FDC) fall into four groups and their data requirements accordingly. The first group of FDC includes those in which one or more of the active ingredients is a new drug. The second group of FDC includes those in which active ingredients already approved/marketed . third group of FDC includes those which are already marketed, but in which it is proposed either to change the ratio of active ingredients or to make a new therapeutic claim. The fourth group of FDC includes those whose individual active ingredients have been widely used.

APPENDIX III :

APPENDIX III FORMAT FOR SUBMISSION OF PRECLINICAL AND CLINICAL DATA FOR r-DNA BASED VACCINES, DIAGNOSTICS AND OTHER BIOLOGICALS SPECIFICATION AND CHARACTERIZATION INFORMATION ON r-DNA VACCINES AND BIOLOGICAL PRODUCTS. Description in details of the method of r-DNA products Description on Identity-Physical, Chemical, Immunological and Biological wherever applicable. Potency General Safety Test. Data on sterility tests as per Indian Pharmacopia guidelines. Data on purity of recombinant product. DATA ON PRECLINICAL TESTING RECOMBINANT IMMUNODIAGNOSTIC REAGENTS. CLINICAL TRIALS Phase I : Human/Clinical Pharmacology Immunogenic Potency Phase II: Exploratory Clinical Trials- Preventive/Therapeutic Efficacy Phase III: Confirmatory Trials

APPENDIX IV :

APPENDIX IV INVESTIGATOR’S BROCHURE (IB) Introduction Contents of the IB: Table of contents Introduction Physical, chemical, and pharmaceutical properties and formulation parameters Non-clinical Studies The following section should discuss the following… Non-clinical Pharmacological ( Pharmacodymanics ) Pharmacokinetics and Product Metabolism in Animals Toxicology Effects in Humans Pharmacokinetics and Product Metabolism in Humans Safety and Efficacy Regulatory & Post-marketing Experiences

APPENDIX V :

APPENDIX V ESSENTIAL DOCUMENTS FOR THE CONDUCT OF A CLINICAL TRIAL The various Essential Documents needed for different stages of the study are classified under three groups… before the clinical phase of the study commences, during the clinical conduct of the study, and after completion or termination of the study.

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