The document outlines the regulatory requirements and guidelines in India for permission to import, manufacture, and conduct clinical trials of new drugs. It discusses the relevant sections of Schedule Y and the Drugs and Cosmetics Rules, 1945. Key points include the application process for import/manufacture using Form 44, responsibilities of sponsors and investigators, ethics committee oversight, and guidelines for the different phases of clinical trials from Phase I to Phase IV. It also addresses requirements for special populations like pediatrics, geriatrics, and pregnant/nursing women. Post-marketing surveillance and periodic safety update reporting are mandated.

1. Presented by
Mpharm (ceutics)
Mahaboobjani
Guieded by: RAJA REDDY
SIR
R.NO:256212886021

2. • SCHEDULE Y:
REQUIREMENTS AND GUIDELINES FOR
PERMISSION TO IMPORT AND OR MANUFACTURE OF
NEW DRUGS FOR SALE OR TO UNDERTAKE
CLINICALTRIALS.
See Schedule Y rules: l22A, l22B, 122D, 122DA,
122DAA and 122E. includes
Responsibilities
Applications
Appendices
Refinements

3. • PART XA OF D&C RULES 1945:
122A: Application for permission to import new drug.
122B: Application for approval to manufacture new drug.
122D: Permission to import or manufacture FDC.
122DA: Permission to conduct clinical trials for new drug /
investigational new drug.
122DAA: Clinical Trial Definitions
122E: New Drug Definitions

4. Drug Regulatory Laws
1940: Drug and Cosmetic Act.
1985: Narcotic drugs and psychotropic substances act.
2000: Ethical guidelines for biomedical research on human
subjects ,ICMR.
2001: Indian GCP guidelines.
2002: Amendment to D & C act.
2005: Revised
Future: 1) Guidelines for pre-clinical data for r- DNA
vaccines, diagnostics & biologicals , DBT.
2) Draft guidelines for stem cell research/
regulation, ICMR.

5. Why there was need for amendment
REVISED OLD
1.Application for permission 1.Clinical Trials
2.Clinical Trials 1.1:Nature of Clinical Trials
1.Approal for Clinical Trials 1.2:Permission for Trials
2.Responsibility of sponser 1.3:Responsibility of sponser/ investigator
3.Responsibility of investigator
4.Informed consent-new
5.Responsibility of ethics committee-new
6.Human pharmacology(ph I) 5.Human clinical pharmacology(ph I)
7.Therapeutic exploratory trials(ph II) 6.Exploratory trials(ph II)
8.Therapeutic exploratory trials(ph III) 7.Confirmatory trials(ph III)
9.Post marketing trials(ph IV)-NEW
3.Studies in special population 8.Special studies
1.geriatric,pediatric
2.Pregnant or nursing women,
3.post marketing surveillance , BA/BE 12.Post marketing surveillance

6. Application for permission:
 Application for permission to import or manufacture new
drugs for sale or to undertake clinical trials shall be made in
Form 44.
• chemical and pharmaceutical information as prescribed in
Appendix I;
• animal pharmacology data as prescribed in item 3 of
Appendix I and Appendix IV
• animal toxicology data as prescribed in Appendix I and
Appendix III;
• human Clinical Pharmacology Data as prescribed in
Appendix I
• regulatory status in other countries as prescribed in
Appendix I.
 the application for import of small quantities of drugs for
such purpose should also be made in Form 12.

7. 122 – DAA:
Clinical Trial Definition
Systematic study of new drugs in human subjects;
to generate data for discovering/verifying clinical,
pharmacological (PK & PD) or adverse effects;
to determine safety and efficacy of the new drug;

8. CLINICAL TRIAL:
(1) Approval for clinical trial
 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 committee(s). The Licensing Authority as
defined shall be informed of the approval of the respective
institutional ethics committee(s) as prescribed in Appendix
VIII, and the trial initiated at each respective site only after
obtaining such an approval for that site.
 All trial Investigator(s) should possess appropriate
qualifications, training and experience and should have access
to such investigational and treatment facilities as are relevant
to the proposed trial protocol. A qualified physician (or dentist,
when appropriate) who is an investigator or a sub-investigator
for the trial, should be responsible for all trial-related medical
(or dental) decisions.

9. (2) Responsibilities of Sponsor:
 The clinical trial Sponsor is responsible for implementing
and maintaining quality assurance systems to ensure that the
clinical trial is conducted and data generated , documented and
reported in compliance with the protocol and Good Clinical
Practice(GCP) Guidelines issued by the Central _Drugs
Standard Control Organization , Directorate General of Health
Services, Government of India as well as with all applicable
statutory provisions.
 Sponsors are required to submit a status report on the
clinical trial to the Licensing Authority at the prescribed
periodicity.
 Trial Status Report to Licensing Authority : Annually
 Premature Termination : Summary report within
3m ( Study, , Dose, Duration, ADR &reasons for discontinuati
on ).
 Serious Adverse Event : Report to LA & other investigators
within 14 days.

10. (3) Responsibilities of the Investigator( s):
(i)The Investigator(s) shall be responsible for the conduct of
the trial according to the protocol and the GCP Guidelines and
also for compliance as per the undertaking given in Appendix
VII.
(ii) Document SOPs. Management of all ADR / AE
Reporting unexpected AE to :- Sponsor within 24 hours.
- EC within 7 day.
(4) EC RESPONSIBILITIES:
(i) Safeguard rights, safety & well being
(ii) Protect vulnerable subjects
(iii) Obtain and maintain record of SOPs
(iv) Ongoing review based on Periodic progress report
(v) If EC revokes its approval-
1.Record reasons for it 2.Inform the Investigator & LA
immediately .

11. (5) Informed Consent:
 In all trials, a freely given, informed, written consent is
required to be obtained from each study subject. The
Investigator must provide information about the study verbally
as well as using a patient information sheet, in a language that
is non-technical and understandable by the study subject. The
Subject's consent must be obtained in writing using an
'Informed Consent Form'. Both the patient information sheet as
well as the Informed Consent Form should have been approved
by the ethics committee and furnished to the Licensing
Authority.
 Where a subject is not able to give informed consent. The
same may be obtained from a legally acceptable representative.

12. ESSENTIAL STEPS OF CLINICAL PHARMACOLOGY:
 Phase I: (Human Pharmacology)Safety & Tolerability ( PK,
PD & MTD.
 Phase II: (Therapeutic Exploratory Trial)Therapeutic benefits
in few patients.
 Phase III: (Therapeutic Confirmatory Trial)Therapeutic
benefit in more patients .
 Phase IV: (Post Marketing Trials)Related to Approved
indication.

15. (6)Human Pharmacology(Phase I):
 The objective of studies in this Phase is the estimation of
safety and tolerability with the initial administration of an
investigational new drug into human(s). Studies in this Phase
of development usually have non-therapeutic objectives and
may be conducted in healthy volunteers subjects or certain
types of patients.
 Studies conducted in Phase I:
(a) Maximum tolerated dose: To determine the tolerability of
the dose range expected to be needed for later clinical studies
and to determine the nature of adverse reactions.
(b) Pharmacokinetics: characterization of a drug's absorption,
distribution, metabolism and excretion.
(c) Pharmacodynamic data, It may guide the dosage and dose
regimen to be applied in later studies.

16. (7) Therapeutic exploratory trials (Phase II):
 The primary objective of Phase II trials is to evaluate the
effectiveness of a drug for a particular indication or indications
in patients with the condition under study and to determine the
common short-term side-effects and risks associated with the
drug.
 An important goal for this Phase is to determine the dose((s)
and regimen for Phase III trials. Doses used in Phase II are
usually (but not always) less than the highest doses used in
Phase 1.
 Additional objectives of Phase II studies can include
evaluation of potential study endpoints, therapeutic regimens
(including concomitant medications) and target populations
(e.g. mild versus severe disease) for further studies in Phase II
or III.

17. (8) Therapeutic confirmatory trials (Phase III):
 Phase III studies have primary objective of demonstration or
confirmation of therapeutic benefit(s). Studies in Phase III are
designed to confirm the preliminary evidence accumulated in
Phase II that a drug is safe and effective for use in the intended
indication and recipient population. These studies should be
intended to provide an adequate basis for marketing approval.
 For drugs intended to be administered for long periods, trials
involving extended exposure to the drug are ordinarily
conducted in Phase III.
 For new drugs approved outside India, Phase III studies need to
be carried out primarily to generate evidence of efficacy and
safety of the drug in Indian patients when used as
recommended in the prescribing information. Prior to conduct
of Phase III studies in Indian subjects, Licensing Authority
may require pharmacokinetic studies to be undertaken to verify
that the data generated in Indian population is in conformity
with the data already generated abroad.

18. (9) Post Marketing Trials (Phase IV):
 Post Marketing trials are studies (other than routine
surveillance) performed after drug approval arid related to the
approved indication(s).
 These trials go beyond the prior demonstration of the drug's
safety, efficacy and dose definition.
 These trials may not be considered necessary at the time of
new drug approval but may be required by the
 Licensing Authority for optimizing the drug's use.
 They may be of any type but should have valid, scientific
objectives.
 Phase IV trials include additional drug-drug interaction(s),
dose-response or safety studies and trials designed to support
use under the approved indication(s), e.g. mortality/morbidity
studies, epidermiological studies etc.

20. REGULATORY REQUIREMENTS FORCLINICAL
PHARMACOLOGY:
 Drug discovered in India : Phase I data
 Drug discovered outside India : Foreign Phase I data
required for Phase II/III permission
 Accompanying documents : Protocol, CRF,IB, IC, EC
Clearance , Investigator’s undertaking.
Sample size : Depending upon type of study
 EC application can parallel DCGI application
 Toxicological / clinical data abbreviate, deferred or
omitted for life threatening diseases (or diseases of special
relevance to Indian health Scenario)
 Amendments notified to DCGI & EC within 30 days&
approval obtained.

22. 3. Studies in special populations:
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.
(1)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;
 the population to be treated is known to include substantial
numbers of geriatric patients;
 when the new drug is likely to alter the geriatric patient's
response (with regard to safety or efficacy)compared with that
of the non-geriatric patient.

23. (2) Paediatrics:
 The timing of paediatric 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.
 If the new drug is for diseases predominantly or exclusively
affecting paediatric patients, clinical trial data should be
generated in the paediatric population except for initial safety
and tolerability data, which will usually be .obtained in adults.
 If the new drug is intended to treat serious or life-threatening
diseases, occurring in both adults and paediatric patients, for
which there are currently no or limited therapeutic options,
paediatric population should be included in the clinical trials
early, following assessment of initial safety data and
reasonable evidence of potential benefit.

24.  If the new drug has a potential for use in paediatric patients –
Paediatric studies should be conducted.
 The paediatric studies should include -
 (a) clinical trials,
 (b) relative bioequivalence comparisons of the paediatric
formulation with the adult formulation performed in adults,
 (c) definitive pharmacokinetic studies for dose selection
across the age ranges of paediatric patients in whom the drug is
likely to be used.
 If the new drug is a major therapeutic advance for the paediatric
population – the studies should begin early in the drug development ,
and this data should be submitted with the new drug application.
 For clinical trials conducted in the paediatric population, the
reviewing ethics committee should include members who are
knowledgeable about pediatric , ethical, clinical and psychosocial
issues.

25. (3) 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 foetuses/nursing infants.
 For new drugs intended for use during pregnancy, follow-up data
on the pregnancy, foetus and child will be required. Where
applicable, excretion of the drug or its metabolites into human milk
should be examined and the infant should be monitored for predicted
pharmacological effects the drug.
(4) Post Marketing Surveillance.-
 (i) Subsequent to approval of the product, new drugs should be
closely monitored for their clinical safety once they are
marketed. The applicants shall furnish Periodic Safety Update
Reports (PSURs) in order to-
 (a) report all the relevant new information from appropriate
sources;
 (b) relate these data to patient exposure;

26.  Ordinarily all dosage forms and formulations as well as indications for new
drugs should be covered in one PSUR.
 All relevant clinical and non-clinical safety data should cover only the
period of the report (interval data).
 The PSUR submitted -6 months for first 2 years after approval of the drug
is granted to the applicant.
 For subsequent two years - the PSURs need to be submitted annually.
 PSURs due for a period must be submitted within30 days of the last day of
the reporting period.
 In all cases involving serious unexpected adverse reactions must be
reported to the licensing authority within 15 days of initial receipt of the
information by the applicant.
 If marketing of the new drug is delayed by the applicant after obtaining
approval to market, such data will have to be provided on the deferred basis
beginning from the time the new drug is marketed.
 New studies specifically planned or conducted to examine a safety issue
should be described in the PSURs.

27. (v) A PSUR should be structure
(a) A title page stating:
(b) Introduction,
(c) Current worldwide market authorization status,
(d) Update of actions taken for safety reasons,
(e) Changes to reference safety information,
(1) Estimated patient exposure,
(g) Presentation of individual case histories,
(h) Studies,
(I) Other information,
(j) Overall safety evaluation,
(k) Conclusion,
(I) Appendix providing material relating to indications,
dosing, pharmacology and other related information.

28.  (5) Special studies: Bioavailability/Bioequivalence
 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 labelled conditions of
administration.
 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.
 Dissolution and bioavailability 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.
 Compliance with ICMR guidelines BA/ BE studies.

29. APPLICATION
FORM44
-Imp ff
-Imp rm
-Mfg ff
-Mfg rm
-C T
APPROVAL FORM
45(IMP FF)
APPROVAL FORM
45A(IMP RM)
APPROVAL FORM
46(MFG FF)
APPROVAL FORM
46A(MFG RM)
NOC FOR C T AND
TEST LICENSE FOR
IMPORT

30. Application Fees:
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.

31. TEST LICENCE
Application form No. 12
Material Justification Plan
Treasury Challan ( Rs. 100 )
Test License obtained in form 11

32. 122 – E:
New drug definition
Investigational New Drug (IND): New chemical entity or
product having therapeutic indication but never tested on
human beings.
Not used in the country
Approved drug : 1. New claims(Indications, dosage , dosage
form, route)
2. FDCs(New / Modified)
Note:
Vaccines are new drugs unless
1. Certified
2. Till 4 year or
3. Included in IP

33. Appendices:
I : Data required for import/manufacture/conduct CT of new
drugs.
I A : ….Drugs approved in other country
II : Format for clinical study reports(ICH E6)
III : Animal toxicology
IV : Animal pharmacology
V :Informed consent.
VI: FDC
VII: Undertaking by the investigator.
VIII : Ethics committee
IX : Stability testing
X : Proposed protocol
XI : SAE Reporting

34. APPENDIX I:
DATA TO BE SUBMITTED ALONG WITH THE
APPLICATION TO CONDUCT CLINICAL
TRIALS/IMPORTIMANUFACTURE OF NEW DRUGS
FOR MARKETING IN THE COUNTRY
1. Introduction
2. Chemical and pharmaceutical information
2.1. Information on active ingrédients
2.2. Physicochemical Data
2.3. Analytical Data
2.4. Complete monograph specification
2.5. Validations
2.6. Stability Studies
2.7. Data on Formulation

35. 3. Animal Pharmacology
4. Animal Toxicology
5. Human / Clinical pharmacology
6. Therapeutic exploratory trials (Phase II)
7. Therapeutic confirmatory trials (Phase III)
8. Special studies
9. Regulatory status in other countries
10. Prescribing information
11. Samples and Testing Protocol/s
APPENDIX -IA:
DATA REQUIRED TO BE SUBMITTED BY AN APPLICANT FOR
GRANT OF PERMISSION TO IMPORT AND / OR MANUFACTURE A
NEW DRUG ALREADY APPROVED IN THE COUNTRY.
1.Introduction

36. REVISED OLD
Data should be submitted along with
application to conduct clinical
trials/import/manufacture of new drug.
Data required to submitted with application
for permission to market a new drug.
2.1 Information of active ingredients 2.1Specifications of API/In active
ingredients
2.2 Physicochemical data 2.2 Physicochemical proportion
2.3 Analytical data-NEW
2.4 Monograph Specifications 2.4 Tests for identifications of API.
2.5 Validations-NEW
2.7 Data on formulation 2.2 and 2.5
3.4 Safety pharmacology-NEW
4.3 Male Fertility Studies-NEW
4.6 Allergenicity / Hypersensitivity-NEW
11.Samples and testing protocol 10.3 Sample… with testing protocol

37. 2.Chemical and Pharmaceutical information.
3. Marketing information
4. Special studies conducted with approval of Licensing
Authority .
APPENDIX II:
STRUCTURE, CONTENTS AND FORMAT FOR
CLINICAL STUDY REPORTS
1. Title Page:
2.Study Synopsis
3. Statement of compliance with the 'Guidelines for Clinical
Trials.
4. List of Abbreviations and Definitions
5. Table of contents
6. Ethics Committee:

38. 7. Study Team
8. Introduction
9. Study Objective
10. Investigational Plan
11. Trial Subjects
12. Efficacy evaluation
13. Safety Evaluation
14. Discussion and overall Conclusion
15. List of References
16. Appendices
APPENDIX III:
ANIMAL TOXICOLOGY (NON-CLINICAL TOXICITY
STUDIES)
1. General Principles:

39. 1.1 Systemic Toxicity Studies
Single-dose Toxicity Studies(2 rodents)
Repeated-dose Systemic Toxicity Studies
1.2) Dose Ranging Study
1.3) Male Fertility Study
1.4) Female Reproduction and Development Toxicity Studies.
1.5)Local toxicity
1.6)Allergenicity /Hypersensitivity
1.7)Genotoxicity and Carcinogenicity

40. APPENDIX IV: ANIMAL PHARMACOLOGY
General Principles
1.1 Specific Pharmacological actions
1.2 General Pharmacological Actions
1.3 Follow-up and Supplemental Safety Pharmacology
Studies
1.4 Conditions Under Which Safety Pharmacology
Studies Are Not Necessary
1.5 Timing Of Safety Pharmacology Studies In Relation
To Clinical Development
1.6 Application Of Good Laboratory Practices (GLP)

41. APPENDIX V: INFORMED CONSENT
Checklist for study Subject's informed consent documents.
APPENDIX VI: FIXED DOSE COMBINATIONS (FDCs)
Fixed Dose Combinations refer to products containing one or
more active ingredients used for a particular indications.
APPENDIX VII: UNDERTAKING BY THE
INVESTIGATOR
APPENDIX VIII: ETHICS COMMITTEE
The number of persons in an Ethics Committee should have at
least seven members.
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
temperature, humidity and light, and to establish shelf life for
the formulation and storage conditions.

42. APPENDIX X: CONTENTS OF THE PROPOSED
PROTOCOL FOR CONDUCTING CLINICAL TRIALS
1. Title Page
2. Table of Contents
3. Study Objective(s)
4. Study Design
5. Study Population
6. Subject Eligibility
7. Study Assessments
8. Study Conduct stating the types of study activities
9. Study Treatment
10. Adverse Events.
11. Ethical Considerations
12. Investigational Product Management
13. Study Monitoring and Supervision:

43. APPENDIX XI: Data Elements for reporting serious adverse
events occurring in a clinical trial
1. Patient Details
2.Suspected Drug(s)
3. Other Treatment(s)
4. Details of Suspected Adverse Drug Reaction(s)
5. Outcome
6. Details about the Investigator*
- Name
- Address
-Telephone number
- Profession (speciality)
- Date of reporting the event to Licensing Authority
- Date of reporting the event to Ethics Committee
- Signature of the Investigator

44. Loopholes in Schedule Y:
 New drug remains new for 4 years. Thus, Phase IV trials
require permission. However, Approved drug and indication
need not require permission.
 Approval of Amendment could be a problem.
 SOPs for investigators and documentation of tasks –
Template required.
 Unmet medical needs to be added to CT waiver.
 EC chairman outside institute is a rarity.
 Exhaustive species data (App .I-A)and comparative
evaluation (App. I) not helpful for differentiation.
 All CT supplies to be included in Form 11.
 Requirement to support data protection

45. Unattended Areas
Regulations for :
1. Biologics : vaccines
Blood products
Tissue Cellular/gene therapy
2. Herbals
3. Medical devices
4. Pharmacovigilance
5. Electronic records

46.  Dr Reddy's Laboratories on Wednesday said it has launched its
generic Lamotrigine extended-release tablets, used for treating
epilepsy, in the American market following approval by the US
health regulator.
 Hyderabad-based pharma major Dr Reddy's Laboratories
( DRL) on Friday said it had launched anti-cancer drug
Decitabine in the injectable form, a copy cat version of Dacogen,
in the US market on July 11. The brand is manufactured and sold
by Japanese drug giant Eisai Inc under license from Astex
Pharmaceuticals Inc.
 SUN PHARMA announced that the US FDA has granted its
subsidiary final approval for its abbreviated new drug application
for generic version of diabetes drug Prandin. Repaglinide tablets,
1mg and 2mg are therapeutic equivalents of Novo Nordisk's
Prandin.

47. No Drug Name Active
Ingredient
Date Use
1 Tivicay Dolutegravir 8/12/13 Treat HIV-1 infection
2 Simponi Aria golimumab 7/18/13 In Rheumatoid Arthritis
3 Gilotrif afatinib 7/12/13 Non-small lung cancer
4 Mekinist trametinib 5/29/13 Treat tumors
5 Tafinlar dabrafenib 5/29/13 Treat melanoma
6 Xofigo Radium Ra 223
dichloride
5/15/13 treat symptomatic late-stage
(metastatic)
prostate cancer
7 Breo Ellipta fluticasone
furoate
5/10/13 airflow obstruction in
patients with chronic
obstructive pulmonary
disease (COPD).
8 Nesina a alogliptin 1/25/13 To improve blood sugar
control in adults with type
2 diabetes
9 Invokanac canagliflozin 3/29/13 to improve glycemic

48. The Clinical Trials Innovation Core develops, tests and
implements new methodological and technological innovations to
enhance clinical trial designs in neurodegenerative diseases. The
Core designs algorithms to identify the best subjects, measures,
time intervals and statistical approaches to detect the slightest yet
important changes in subjects during a clinical trial.
The Program will:
 Investigate and implement methodological and technological
innovations for neurodegenerative disease clinical trials.
 Develop novel approaches to subject selection, study design,
and data analysis, to maximize power.
 Provide direction of how to install and operate the most
appropriate tools.
 Provide expert core staff members to actively support
investigators designing new trials.
 Continually import and refine new algorithms and other tools to
enable clinical trials.

49. References:
 Dr. B.S. KUCHEKAR ,Mr. A. M. KHADATARE ,
Mr . SACHIN C . ITKAR; Forensic Pharmacy , Sixth
edition , Nirali Prakashan,pg.no:5.270-5.301.
 http://www.slideshare.net/pgpritigupta1/schedule-y-pritigupta
http://www.scribd.com/doc/7211784/Schedule-Y
http://www.authorstream.com/Presentation/Malarkodi-
863587-schedule-y-guidelines/