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Schedule Y by akshdeep sharma

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Akshdeep Sharma
Akshdeep Sharma

This document provides a summary of Schedule Y, the regulatory framework for clinical trials in India. Key points include: - Schedule Y was established under the Drugs and Cosmetics Act of 1945 and outlines the regulations for conducting clinical trials in India, in line with ICH GCP guidelines. - It addresses approval for clinical trials, responsibilities of sponsors, investigators and ethics committees, informed consent, different phases of clinical trials, and special populations. - Appendices provide details on application process, data requirements, animal studies, informed consent format and investigator undertakings to ensure compliance. - Revisions to Schedule Y have aimed to strengthen clinical research governance in India and align it with global standards, while

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SCHEDULE Y PRESENTED BY- AKSHDEEP SHARMA CLINICAL RESEARCH (STUDENT)
Lets Revise the History • Drug and Cosmetic Act, 1940 was enacted(D/C Act) • Pharmacy Act , 1948 • Drug and Magic Remedies Act, 1954 • The Narcotic and Psychotropic Substance Act and Rules, 1985 • Ethical guidelines for Biomedical Research on Human Participants,2000 by ICMR
• Indian GCP Guidelines,2001 • Amendments to Drug and Cosmetic Act,2002 • Revised Schedule Y, 2005 • Guidelines for Pre Clinical Data for r-DNA Vaccines,2007 Lets Revise the History
Drug and Cosmetics Act,1940  In 1940 D/C Act Was enacted  In 1945 Drug Rules were Promulgated in December and enforcement Start in 1947 Now have been called as D/C Act Objective- To ensure that the drug is available to the People are safe and cosmetics marketed for safer use.
Schedules to Rules, 1945 Schedule A- Forms for marketing application for licenses, issue, and renewal 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 to import of other drug. E1- list of poisonous substance under Ayurveda,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 to manufacture of other drug
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 CT Schedules to Rules, 1945
Schedule Y The enforcement that came into existence in 1988 was an essential provision for providing support to the upscale of generic pharma scenario present in those days. With the entry of large pharmaceutical companies along with the multiple multinationals in field of clinical research the needs changed and a revised version of Schedule Y in line with ICH-GCP (International Council of Harmonization and Good Clinical Practice) standard was put forth in 1995. Since then multiple revisions to Schedule Y took place to provide a healthy environment for clinical research to be conducted in India.
What actually Schedule Y is?
Schedule Y It’s a Law not merely a Guideline यह एक कानून न के वल एक दिशाननिेश है
Schedule Y Schedule Y ,the current regulator (of CDSCO), enforced law in India has been established under Drug and Cosmetic Act,1945. The regulations to be followed when conducting Clinical Trial in India.
‘REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS IN INDIA’ Schedule Y
Amended Schedule Y ‘Regulations and Guidelines for permission for development (preclinical and/or clinical), import and manufacture of New Drugs for Marketing in India’ DATE- 20TH JAN,2005
Why Changes in Schedule Y To frame guidelines for the current scenario of Clinical research. CDSCO and DTAB(Drug Testing Advisory Board) 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.
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 FORM 12- To import Study drug for examination , test or analysis
Clinical Trial 1. Approval for clinical trials 2. Responsibilities of sponsor 3. Responsibilities of Investigator 4. Informed Consent 5. Responsibilities of Ethics Committee 6. Human Pharmacology (Phase l) 7. Therapeutic Exploratory Trials (Phase ll) 8. Therapeutic confirmatory Trials (Phase lll) 9. Post Marketing Trials (lV)
Clinical Trials : Special Studies  Clinical trials required if the indication is relevant to special population e.g. pediatrics, geriatrics,and pregnancy  Members knowledgeable about pediatric, ethical, clinical and psychosocial issues  Mature minors and adolescents to sign an assent form  Other – Post-marketing surveillance, BA/BE
Approval for Clinical Trials  Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective ethics committees.  The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics committees as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site.
Responsibility of Sponsor  Quality assurance to ensure compliance to GCP guidelines of CDSCO(Central Drug Standard Control Organization) Submission of status report at prescribed periodicity; reasons for premature termination to be communicated Serious adverse event to be communicated promptly (within 14 calendar days) to DCGI(Drug Controller General Of India) and other investigators
Responsibilities of Investigator Responsible for conduct of trial according to protocol and GCP  Compliance as per undertaking format Medical care for AEs SAE reporting to Sponsor within 24 hrs EC within 7 days Informed consent
Responsibilities of EC Safeguard rights, safety, wellbeing of subjects Special care for vulnerable subjects Reason’s for revoking approval and information to investigator / regulatory authority Ongoing review
1.Human Pharmacology (Phase l) Safety and tolerability – Objective 2.Therapeutic Exploratory Trials (Phase ll) To evaluate the effectiveness of a drug for particular indication. To determine the short term side effects and risk associated with the drug To determine the dose and regimen for phase lll trials. Clinical Trial
Clinical Trial 6.Therapeutic confirmatory Trials (Phase lll) Demonstration of therapeutic benefit Drug is safe and effective for use and Provide and adequate basis for marketing approval 7.Post Marketing Trials (lV) Performed after drug approval and related to the approved indication Includes drug-drug interaction, dose-response or safety studies, mortality/morbidity studies
Studies in Special Population Information supporting the use of the drug in children, pregnant women, nursing women, elderly patients, patients with renal or other organ systems failure, and those on specific concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern (Appendix I, item 8.3). Types 1. Geriatrics 2. Pediatrics 3. Pregnant or Nursing Women
Geriatrics Geriatric patients should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if- the disease intended to be treated is characteristically a disease of aging; or the population to be treated is known to include substantial numbers of geriatric patients
Pediatrics The timing of pediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments.
The pediatric studies should include – clinical trials, relative bioequivalence comparisons of the pediatric formulation with the adult formulation performed in adults definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used. These studies should be conducted in the pediatric patient population with the disease under study.
Pregnant or Nursing Women Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or fetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable. For new drugs intended for use during pregnancy, follow-up data (pertaining to a period appropriate for that drug) on the pregnancy, fetus and child will be required
Post Marketing Surveillance PSUR : Periodic Safety Update Reports New drugs should be closely monitored for their clinical safety; submission of in order to- report all the relevant new information (patient exposure) summarize the market authorization status in different countries and any significant variations related to safety; and indicate whether changes should be made to product information PSURs shall be submitted every 6 months for the first two years after approval
For subsequent two years – the PSURs need to be submitted annually PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period. PSUR : Periodic Safety Update Reports
Rules under Schedule Y Rule 122 A 122 B 122 D 122 DA 122DAA 122 E Permission To Import New Drugs To manufacture New Drugs To import or manufacture fixed dose Combinations To conduct Clinical Trials for New Drug/Investigational New Drug Definition of Clinical Trial Definition of New Drug
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.
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 changed
APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY AUTHORITIES, FEES AND TEST LICENCE
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 CDRL/CDTL Gov. Drug Testing Laboratories
DRUG REGULATION IN INDIA • Directorate General of Health Services Ministry of Health and Family Welfare • Drugs Controller General of India. CDSCO-Central Drugs Standard Control Organization Retail and Distribution Manufacturing Practice Clinical Trials and new drug development
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
Appendix I-A Data required to be submitted by an applicant for grant of permission to import &/or manufacture a new drug already approved in the country. a) Introduction b) Chemical and pharmaceutical information c) Marketing information d) Special studies
Appendix III Animal toxicology (Non-clinical toxicity studies) 1) SDTS(Single Dose Toxicity Study)- Minimum 5 animal, 24hr observation 2) DRS(Dose Ranging Study)- On one Rodent Species 3) RDTS(Repeated Dose Systemic Toxicity Study)- a) 14 to 28 days- on 1 Rodent and 1 Non Rodent b)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)
Appendix IV-Animal Pharmacology Animal pharmacology studies are done to see the effect if IP on different systems like  CVS-(Cardiovascular System)  CNS-(Central Nervous System)  ANS-(Autonomic Nervous System)  RS-(Respiratory System)  US-(Urinary System)  GIT-(Gastrointestinal System)
Appendix V- INFORM CONSENT  Trial involves research  Purpose  Trial treatments and randomization  Trial procedures  Risk  Benefit  Alternative treatments  Compensation / treatment for injury  Subject’s responsibilities  Experimental aspects  Any payment
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 information
Format of Informed Consent Form  Study Title  Subject’s Initials e.g. Subject’s Name/ Date of Birth / Age  Consent Statements with initials in a) Signature (or Thumb impression) of the Subject b) Legally Acceptable Representative  Signature of the Investigator  Study Investigator’s Name  Signature of the Witness  Name of the Witness
Appendix VI- FDC’s 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 .  The third group of FDC includes those which are already marketed The fourth group of FDC includes those whose individual active ingredients have been widely used.
Appendix VII Undertaking By The Investigator 1) Full name, address and title of the Principal Investigator 2) 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 qualification 3) 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. 6) Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator. 7) Signature with Date.
Appendix VII.2 Commitments by The Investigator a. Study not to begin until EC / DCGI approval b. Adherence to protocol c. Personal supervision d. Ensure requirements of IC and EC review e. Report of AE to sponsor f. Understanding of investigator’s brochure g. Ensure that all associates, colleagues and employees suitably qualified and experienced and aware of their obligations h. Report all unexpected serious adverse events to the Sponsor in 24 hrs and EC within 7 days. i. Maintenance of records and availability for audits / sponsor inspection / EC and DCGI. Cooperation in audits
Appendix VIII ETHICS COMMITTEE COMPOSITION ICH GCP Indian GCP Schedule-Y • At least 5 members. •At least 1 member - nonscientific area. •Quorum members number not detailed. •Maximum number is not detailed. •Not recommended. •Fairly small (5-7 members). • 1 member from non- scientific area •The quorum should have a minimum of 5 members. •12 to 15 is the maximum recommended number. •Member Secretary belongs to the same Institution. •At least 7 members. •Not Explained. •The quorum should have at least 5 members. •Maximum number is not detailed. •Not recommended.
Appendix IX- Stability testing of New Drugs 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.
STABILITY TESTING Stress testing of the drug substance should be conducted to identify- a. The degradation pathways b. Evaluate the intrinsic stability of the molecule and c. Validate the stability indicating power of the analytical procedures used. Stress testing may generality be carried out on a single batch of the drug substance. It should include the effect of-Temperature, humidity, oxidation, photolysis on the drug substance. TWO TYPES OF STUDY IS DONE 1)Long-term testing should cover a minimum of 12 months’duration on at least three primary batches of the drug substance or the formulation at the time of submission
STABILITY TESTING 2)Accelerated testing should cover a minimum of 6 months duration at the time of submission. Study conditions for drug substances and formulations intended to be stored under general conditions. Study conditions and Duration of study i)Long term 30°C± 2°C/65% RH ± 5%RH 12 months ii)Accelerated 40°C± 2°C/75% RH ± 5% RH 6 months If 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.
Appendix X – Contents of the Proposed Protocol  Title page  Table of content a) a) introduction b) Study rationale c) Study design d) Study population e) Subject eligibility f) Study treatment g) AE h) Data analysis i) Undertaking by investigator NOTE- Protocol is assigned by sponsor after getting CDA from investigator
Appendix XI- Data Elements For Reporting SAE in a Clinical Trial a) 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 investigator
New Amendments on 30.06.2009 CLINICAL RESEARCH ORGANISATION – REGISTRATION These guidelines have been approved by DTAB 1)Rule 122 DAB. – Registration of clinical research organization for conducting clinical trials. The clinical research organization, contracted in writing by the sponsor to carry out any or all obligations transferred to it by the sponsor, shall perform such functions only, if it is duly registered, under the rules, by the Licensing Authority defined in Clause (b) of Rule 21.
New Amendments on 18th Nov.2011 1)Rule 122-DAB- compensation during injury or death during clinical trial In case of injury in clinical trial the compensation is based as per the recommendation of EC/IRB , it may be financial or medical. 2) In case of death his/her legal heirs are entitled for the financial compensation, subject to the confirmation to EC
Schedule Y by akshdeep sharma

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Schedule Y by akshdeep sharma

  • 1. SCHEDULE Y PRESENTED BY- AKSHDEEP SHARMA CLINICAL RESEARCH (STUDENT)
  • 2. Lets Revise the History • Drug and Cosmetic Act, 1940 was enacted(D/C Act) • Pharmacy Act , 1948 • Drug and Magic Remedies Act, 1954 • The Narcotic and Psychotropic Substance Act and Rules, 1985 • Ethical guidelines for Biomedical Research on Human Participants,2000 by ICMR
  • 3. • Indian GCP Guidelines,2001 • Amendments to Drug and Cosmetic Act,2002 • Revised Schedule Y, 2005 • Guidelines for Pre Clinical Data for r-DNA Vaccines,2007 Lets Revise the History
  • 4. Drug and Cosmetics Act,1940  In 1940 D/C Act Was enacted  In 1945 Drug Rules were Promulgated in December and enforcement Start in 1947 Now have been called as D/C Act Objective- To ensure that the drug is available to the People are safe and cosmetics marketed for safer use.
  • 5. Schedules to Rules, 1945 Schedule A- Forms for marketing application for licenses, issue, and renewal 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 to import of other drug. E1- list of poisonous substance under Ayurveda,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 to manufacture of other drug
  • 6. 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 CT Schedules to Rules, 1945
  • 7. Schedule Y The enforcement that came into existence in 1988 was an essential provision for providing support to the upscale of generic pharma scenario present in those days. With the entry of large pharmaceutical companies along with the multiple multinationals in field of clinical research the needs changed and a revised version of Schedule Y in line with ICH-GCP (International Council of Harmonization and Good Clinical Practice) standard was put forth in 1995. Since then multiple revisions to Schedule Y took place to provide a healthy environment for clinical research to be conducted in India.
  • 9. Schedule Y It’s a Law not merely a Guideline यह एक कानून न के वल एक दिशाननिेश है
  • 10. Schedule Y Schedule Y ,the current regulator (of CDSCO), enforced law in India has been established under Drug and Cosmetic Act,1945. The regulations to be followed when conducting Clinical Trial in India.
  • 11. ‘REQUIREMENTS AND GUIDELINES FOR PERMISSION TO IMPORT AND / OR MANUFACTURE OF NEW DRUGS FOR SALE OR TO UNDERTAKE CLINICAL TRIALS IN INDIA’ Schedule Y
  • 12. Amended Schedule Y ‘Regulations and Guidelines for permission for development (preclinical and/or clinical), import and manufacture of New Drugs for Marketing in India’ DATE- 20TH JAN,2005
  • 13. Why Changes in Schedule Y To frame guidelines for the current scenario of Clinical research. CDSCO and DTAB(Drug Testing Advisory Board) 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.
  • 14. 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 FORM 12- To import Study drug for examination , test or analysis
  • 15. Clinical Trial 1. Approval for clinical trials 2. Responsibilities of sponsor 3. Responsibilities of Investigator 4. Informed Consent 5. Responsibilities of Ethics Committee 6. Human Pharmacology (Phase l) 7. Therapeutic Exploratory Trials (Phase ll) 8. Therapeutic confirmatory Trials (Phase lll) 9. Post Marketing Trials (lV)
  • 16. Clinical Trials : Special Studies  Clinical trials required if the indication is relevant to special population e.g. pediatrics, geriatrics,and pregnancy  Members knowledgeable about pediatric, ethical, clinical and psychosocial issues  Mature minors and adolescents to sign an assent form  Other – Post-marketing surveillance, BA/BE
  • 17. Approval for Clinical Trials  Clinical trial on a new drug shall be initiated only after the permission has been granted by the Licensing Authority under rule 21 (b), and the approval obtained from the respective ethics committees.  The Licensing Authority as defined shall be informed of the approval of the respective institutional ethics committees as prescribed in Appendix VIII, and the trial initiated at each respective site only after obtaining such an approval for that site.
  • 18. Responsibility of Sponsor  Quality assurance to ensure compliance to GCP guidelines of CDSCO(Central Drug Standard Control Organization) Submission of status report at prescribed periodicity; reasons for premature termination to be communicated Serious adverse event to be communicated promptly (within 14 calendar days) to DCGI(Drug Controller General Of India) and other investigators
  • 19. Responsibilities of Investigator Responsible for conduct of trial according to protocol and GCP  Compliance as per undertaking format Medical care for AEs SAE reporting to Sponsor within 24 hrs EC within 7 days Informed consent
  • 20. Responsibilities of EC Safeguard rights, safety, wellbeing of subjects Special care for vulnerable subjects Reason’s for revoking approval and information to investigator / regulatory authority Ongoing review
  • 21. 1.Human Pharmacology (Phase l) Safety and tolerability – Objective 2.Therapeutic Exploratory Trials (Phase ll) To evaluate the effectiveness of a drug for particular indication. To determine the short term side effects and risk associated with the drug To determine the dose and regimen for phase lll trials. Clinical Trial
  • 22. Clinical Trial 6.Therapeutic confirmatory Trials (Phase lll) Demonstration of therapeutic benefit Drug is safe and effective for use and Provide and adequate basis for marketing approval 7.Post Marketing Trials (lV) Performed after drug approval and related to the approved indication Includes drug-drug interaction, dose-response or safety studies, mortality/morbidity studies
  • 23. Studies in Special Population Information supporting the use of the drug in children, pregnant women, nursing women, elderly patients, patients with renal or other organ systems failure, and those on specific concomitant medication is required to be submitted if relevant to the clinical profile of the drug and its anticipated usage pattern (Appendix I, item 8.3). Types 1. Geriatrics 2. Pediatrics 3. Pregnant or Nursing Women
  • 24. Geriatrics Geriatric patients should be included in Phase III clinical trials (and in Phase II trials, at the Sponsor's option) in meaningful numbers, if- the disease intended to be treated is characteristically a disease of aging; or the population to be treated is known to include substantial numbers of geriatric patients
  • 25. Pediatrics The timing of pediatric studies in the new drug development program will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments.
  • 26. The pediatric studies should include – clinical trials, relative bioequivalence comparisons of the pediatric formulation with the adult formulation performed in adults definitive pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used. These studies should be conducted in the pediatric patient population with the disease under study.
  • 27. Pregnant or Nursing Women Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant/nursing women or fetuses/nursing infants and where the data generated from women who are not pregnant or nursing, is not suitable. For new drugs intended for use during pregnancy, follow-up data (pertaining to a period appropriate for that drug) on the pregnancy, fetus and child will be required
  • 28. Post Marketing Surveillance PSUR : Periodic Safety Update Reports New drugs should be closely monitored for their clinical safety; submission of in order to- report all the relevant new information (patient exposure) summarize the market authorization status in different countries and any significant variations related to safety; and indicate whether changes should be made to product information PSURs shall be submitted every 6 months for the first two years after approval
  • 29. For subsequent two years – the PSURs need to be submitted annually PSURs due for a period must be submitted within 30 calendar days of the last day of the reporting period. PSUR : Periodic Safety Update Reports
  • 30. Rules under Schedule Y Rule 122 A 122 B 122 D 122 DA 122DAA 122 E Permission To Import New Drugs To manufacture New Drugs To import or manufacture fixed dose Combinations To conduct Clinical Trials for New Drug/Investigational New Drug Definition of Clinical Trial Definition of New Drug
  • 31. 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.
  • 32. 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 changed
  • 33. APPLICATION FOR PERMISSION UNDER FORM 44, REGULATORY AUTHORITIES, FEES AND TEST LICENCE
  • 34. 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 CDRL/CDTL Gov. Drug Testing Laboratories
  • 35. DRUG REGULATION IN INDIA • Directorate General of Health Services Ministry of Health and Family Welfare • Drugs Controller General of India. CDSCO-Central Drugs Standard Control Organization Retail and Distribution Manufacturing Practice Clinical Trials and new drug development
  • 36. 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
  • 37. Appendix I-A Data required to be submitted by an applicant for grant of permission to import &/or manufacture a new drug already approved in the country. a) Introduction b) Chemical and pharmaceutical information c) Marketing information d) Special studies
  • 38. Appendix III Animal toxicology (Non-clinical toxicity studies) 1) SDTS(Single Dose Toxicity Study)- Minimum 5 animal, 24hr observation 2) DRS(Dose Ranging Study)- On one Rodent Species 3) RDTS(Repeated Dose Systemic Toxicity Study)- a) 14 to 28 days- on 1 Rodent and 1 Non Rodent b)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)
  • 39. Appendix IV-Animal Pharmacology Animal pharmacology studies are done to see the effect if IP on different systems like  CVS-(Cardiovascular System)  CNS-(Central Nervous System)  ANS-(Autonomic Nervous System)  RS-(Respiratory System)  US-(Urinary System)  GIT-(Gastrointestinal System)
  • 40. Appendix V- INFORM CONSENT  Trial involves research  Purpose  Trial treatments and randomization  Trial procedures  Risk  Benefit  Alternative treatments  Compensation / treatment for injury  Subject’s responsibilities  Experimental aspects  Any payment
  • 41. 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 information
  • 42. Format of Informed Consent Form  Study Title  Subject’s Initials e.g. Subject’s Name/ Date of Birth / Age  Consent Statements with initials in a) Signature (or Thumb impression) of the Subject b) Legally Acceptable Representative  Signature of the Investigator  Study Investigator’s Name  Signature of the Witness  Name of the Witness
  • 43. Appendix VI- FDC’s 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 .  The third group of FDC includes those which are already marketed The fourth group of FDC includes those whose individual active ingredients have been widely used.
  • 44. Appendix VII Undertaking By The Investigator 1) Full name, address and title of the Principal Investigator 2) 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 qualification 3) 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. 6) Protocol Title and Study number (if any) of the clinical trial to be conducted by the Investigator. 7) Signature with Date.
  • 45. Appendix VII.2 Commitments by The Investigator a. Study not to begin until EC / DCGI approval b. Adherence to protocol c. Personal supervision d. Ensure requirements of IC and EC review e. Report of AE to sponsor f. Understanding of investigator’s brochure g. Ensure that all associates, colleagues and employees suitably qualified and experienced and aware of their obligations h. Report all unexpected serious adverse events to the Sponsor in 24 hrs and EC within 7 days. i. Maintenance of records and availability for audits / sponsor inspection / EC and DCGI. Cooperation in audits
  • 46. Appendix VIII ETHICS COMMITTEE COMPOSITION ICH GCP Indian GCP Schedule-Y • At least 5 members. •At least 1 member - nonscientific area. •Quorum members number not detailed. •Maximum number is not detailed. •Not recommended. •Fairly small (5-7 members). • 1 member from non- scientific area •The quorum should have a minimum of 5 members. •12 to 15 is the maximum recommended number. •Member Secretary belongs to the same Institution. •At least 7 members. •Not Explained. •The quorum should have at least 5 members. •Maximum number is not detailed. •Not recommended.
  • 47. Appendix IX- Stability testing of New Drugs 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.
  • 48. STABILITY TESTING Stress testing of the drug substance should be conducted to identify- a. The degradation pathways b. Evaluate the intrinsic stability of the molecule and c. Validate the stability indicating power of the analytical procedures used. Stress testing may generality be carried out on a single batch of the drug substance. It should include the effect of-Temperature, humidity, oxidation, photolysis on the drug substance. TWO TYPES OF STUDY IS DONE 1)Long-term testing should cover a minimum of 12 months’duration on at least three primary batches of the drug substance or the formulation at the time of submission
  • 49. STABILITY TESTING 2)Accelerated testing should cover a minimum of 6 months duration at the time of submission. Study conditions for drug substances and formulations intended to be stored under general conditions. Study conditions and Duration of study i)Long term 30°C± 2°C/65% RH ± 5%RH 12 months ii)Accelerated 40°C± 2°C/75% RH ± 5% RH 6 months If 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.
  • 50. Appendix X – Contents of the Proposed Protocol  Title page  Table of content a) a) introduction b) Study rationale c) Study design d) Study population e) Subject eligibility f) Study treatment g) AE h) Data analysis i) Undertaking by investigator NOTE- Protocol is assigned by sponsor after getting CDA from investigator
  • 51. Appendix XI- Data Elements For Reporting SAE in a Clinical Trial a) 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 investigator
  • 52. New Amendments on 30.06.2009 CLINICAL RESEARCH ORGANISATION – REGISTRATION These guidelines have been approved by DTAB 1)Rule 122 DAB. – Registration of clinical research organization for conducting clinical trials. The clinical research organization, contracted in writing by the sponsor to carry out any or all obligations transferred to it by the sponsor, shall perform such functions only, if it is duly registered, under the rules, by the Licensing Authority defined in Clause (b) of Rule 21.
  • 53. New Amendments on 18th Nov.2011 1)Rule 122-DAB- compensation during injury or death during clinical trial In case of injury in clinical trial the compensation is based as per the recommendation of EC/IRB , it may be financial or medical. 2) In case of death his/her legal heirs are entitled for the financial compensation, subject to the confirmation to EC