schedule y

1. Dr.Roohana Hasan
Moderator:
Dr.Fardan Qadeer

2. • 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
DRUG REGULATION IN INDIA

3. • 1. Schedule X – Narcotics
2. Schedule H – Prescription drugs
3. Schedule C and C1- Biological Products (Serums and
Vaccines)
Retail and Distribution
• 1. Schedule N
List of the equipment for the efficient running of manufacturing
wing, Qualified personnel
2. Schedule M-GMP
Manufacturing Practice
• Schedule Y
Clinical Trials and new drug development

4. MINISTRY OF HEALTH AND FAMILY
WELFARE Introduced THE DRUGS AND
COSMETICS ACT (1940) AND RULES (1945)
An Act to regulate the import, manufacture,
distribution and sale of drugs and cosmetics in
India.
The drugs and cosmetics act and rules

5. SCHEDULE Y
Rules 122 A, 122 B, 122 D, 122 DA, 122 DAA, 122 DAB, 122 E, 122 DD.
REQUIREMENTS AND GUIDELINES FOR
PERMISSION TO IMPORT AND / OR
MANUFACTURE OF NEW DRUGS FOR SALE OR
TO UNDERTAKE CLINICAL TRIALS
Includes
•Responsibilities
•Applications
•Appendices
•Refinements

6. Appendices in Schedule Y
I. Data required for import/manufacture/ conduct CT of new drugs
IA. 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

7. • 122-A Application for permission to import
new drug.
• 122-B Application for approval to manufacture
new drug.
• 122-D Permission to import or manufacture
FDC.

8. 1. APPLICATION FOR PERMISSION:
Application for permission to import or manufacture new
drugs shall be made in the form along with following data:
 Introduction
 Chemical and pharmaceutical information
 Animal Pharmacology
 Animal toxicology
 Human / Clinical pharmacology (Phase I)
 Therapeutic exploratory trials (Phase II)
 Therapeutic confirmatory trials (Phase III)
 Special studies
 Regulatory status in other countries
 Prescribing information

9. Chemical and pharmaceutical information
• Information on active ingredients
– Drug information (Generic Name, Chemical Name)
• Physical and chemical properties of drug
• Analytical Data
• Complete monograph specification including
• Validations
• Stability Studies
• Data on Formulation
– Dosage form
– Composition
– Excipient compatibility study
– Packing specifications
– Process validation

10. Animal Pharmacology
General Principles
• Specific and general pharmacological studies
should be conducted to support use of
therapeutics in humans.
• Safety pharmacology studies are studies that
investigate potential undesirable
pharmacodynamic effects of a substance on
physiological functions in relation to exposure
within the therapeutic range or above.

11. • Summary
• Specific pharmacological actions
• General pharmacological actions
• Follow-up and Supplemental Safety
Pharmacology Studies
• Pharmacokinetics: absorption, distribution;
metabolism; excretion
Includes

12. SPECIFIC PHARMACOLOGICAL ACTONS
Actions which demonstrate the therapeutic potential for
humans.
Scientifically validated methods should be used.
The use of new technologies and methodologies in accordance
with sound scientific principles should be preferred.
GENERAL PHARMACOLOGICAL ACTIONS
Essential Safety Pharmacology
Safety pharmacology studies need to be conducted to
investigate the potential undesirable pharmacodynamic effects
of a substance on physiological functions in relation to exposure
within the therapeutic range and above.
Effects on different organs

13. ANIMAL TOXICOLOGY
• Toxicity studies should comply with the norms
of Good Laboratory Practice (GLP).
• Toxicokinetic studies should be conducted to
assess the systemic exposure achieved in
animals and its relationship to dose level and
the time course of the toxicity study.

14. Animal toxicology
• Systemic Toxicity studies
– Single dose toxicity studies
– Repeated dose toxicity studies
• Male fertility studies
• Female Reproduction and Developmental Toxicity
Studies
• Local toxicity
• Allergy/Hypersensitivity
• Genotoxicity
• Carcinogenicity

15. Single-dose Toxicity Studies
• These studies should be carried out in 2 rodent
species (mice and rats)
• Each group should contain at least 5 animals of
either sex.
• At least four graded doses should be given.
• Animals should be exposed to the test substance in
a single bolus or by continuous infusion.
• Animals should be observed for 14 days after the
drug administration
• Minimum lethal dose (MLD) and Maximum
tolerated dose (MTD) should be established.
• If possible, the target organ of toxicity should be
determined.

16. Repeated-dose Systemic Toxicity Studies
• Should be carried out in 1 non rodent and 1
rodent species.
• Dose ranging studies should precede the 14-, 28-,
90- or 180- day toxicity studies.
• 5 animals in each group and at least 4 graded
doses should be given.
• Highest dose should be the maximun tolerated
dose of the single dose toxicity study.
• It is given consequently for 10 days
• Organ specific toxicity is established.

17. Male Fertility Study
• Each group should consist of 6 adult male
animals.
• Animals should be treated with the test
substance for minimum 28 days and maximum
70 days before they are paired with female
animals of proven fertility in a ratio of 1:2 for
mating.
• Pairing should be continued till the detection
of vaginal plug or 10 days, whichever is earlier.

18. • Females getting thus pregnant should be
examined for their fertility index after day 13
of gestation.
• All the male animals should be sacrificed at
the end of the study and organs for
reproduction are examined.

19. Female Reproduction and Developmental
Toxicity Studies
• These studies need to be carried out for all
drugs proposed to be studied or used in
women of child bearing age.
• 3 segments
SEGMENT I Albino mice or rat Female Fertility Study
SEGMENT II Albino mice or rat
+
Albino rabbits
Teratogenicity Study
SEGMENT III Albino mice or rat Perinatal Study

20. • Dose selection: administered to both males and
females, beginning a sufficient number of days before
mating
• Groups: 15 males and 15 females per dose. Control
and the treated groups should be of similar size.
• Dosing interval: Three graded doses. The route of
administration should be the same as intended for
therapeutic use. Drug treatment should continue
during mating and, subsequently, during the gestation
period.
• Dams should be allowed to litter and their medication
should be continued till the weaning of pups.

21. Observations should be carried out for
• Mating behavior
• Survival
• Growth parameter
• Length of gestation
• Parturition
• Post-partum health & gross pathology of affected organ
• Progress of gestation/ parturition periods
• Signs of intoxication
• Body weight
• Food intake

22. Local toxicity
These studies are required when the new drug is proposed
to be used by some special route (other than oral) in
humans:
It includes:
• Dermal toxicity
• Photo-allergy or dermal photo-toxicity:
• Vaginal toxicity
• Rectal tolerance test
• Parenteral toxicity: injection site toxicity
• Ocular and inhalational toxicity studies

23. Allergenicity / Hypersensitivity
Any one of the standard tests:
• Guinea pig :
– Maximization test (GPMT)
• Mouse :
– Local lymph node assay (LLNA)

24. Genotoxicity Studies
• Genotoxicity tests are in vitro and in vivo tests
conducted to detect compounds which induce
genetic damage directly or indirectly.
• These tests should enable a hazard identification
with respect to damage to DNA and its fixation.
• Genotoxicity data are not required before Phase I and
II trials. But these studies should be completed before
applying for Phase III trials.

25. The following standard test battery is generally
expected to be conducted:
• (i) A test for gene mutation in bacteria.
• (ii) An in vitro test with cytogenetic evaluation of
chromosomal damage with mammalian cells or an in vitro
mouse lymphoma tk assay.
• (iii) An in vivo test for chromosomal damage using rodent
hematopoietic cells.

26.  For expected clinical use more than 6 months
 For drugs used frequently in an intermittent manner
 If concern about the carcinogenic potential due to :
Previous demonstration in the product class
Structure-activity relationship suggests carcinogenic risk
Preneoplastic lesions in repeated dose toxicity studies
Long-term tissue retention results in reactions
Carcinogenicity

27. • 122-DA Permission to conduct clinical trials
for new drug / investigational new drug.
– 122 - DAA Definition of CLINICAL TRIAL.
– 122- DAB Reports of Serious Adverse Events
(SAEs) including deaths.
– 122- E New Drug

28. Clinical Trial
• “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.
122 - DAA

29. New Drug
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 recognised in the country as
effective and safe for the proposed claims.
122-E

30. • Clinical trial on a new drug shall be initiated only after
the permission has been granted by the
 Licensing Authority
 Respective ethics committee(s).
• 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.
Approval for clinical trial

31. Responsibilities of Sponsor
• Implementing and maintaining quality
assurance systems.
• submit a status report on the clinical trial
• in case of studies prematurely discontinued
for any reason including lack of commercial
interest in pursuing the new drug application,
a summary report should be submitted within
3 months.
• Report SAE

32. Responsibilities of the Investigator
• Conduct of the trial according to the protocol and
the GCP Guidelines
• Follow the SOP’s.
• Ensure that adequate medical care is provided to
the participant for any adverse events.
• Report SAE.

33. • 122 – DD Registration of Ethics
Committee (EC).

34. ETHICS COMMITTEE
It is the responsibility of the ethics committees that reviews
and accords its approval to a trial protocol to safeguard the
rights, safety and well being of all trial subjects.
• Care of the vulnerable group in the study: patients with
incurable diseases, unemployed or impoverished persons,
patients in emergency situation, others incapable of
personally giving consent
• Ethics Committee(s) should make, at appropriate intervals,
an ongoing review of the trials for which they review the
protocol
122 – DD

35. • The number of persons in an Ethics
Committee should have at least seven
members
Chairperson
outside the institution
Member Secretary
(a)basic medical scientists (preferably one
pharmacologist).
(b) clinicians
(c) legal expert
(d) social scientist/ representation of non-
governmental voluntary agency /
philosopher / ethicist / theologian or similar
person
(e) lay person from the community

36. INFORMED CONSENT
In all clinical trials freely given, informed written
consent is required to be obtained from each study
subject
• Verbal information of the study using a patient
information sheet
• Language that is nontechnical and understandable
by the study subject.
• Where a subject is not able to give informed
consent, the same may be obtained from a legally
acceptable representative.

37. • Where a subject is not able to give informed consent,
same may be obtained from a legally acceptable
representative .
• If the Subject or his/her legally acceptable
representative is unable to read/write – an impartial
witness should be present during the entire informed
consent process who must append his/her signatures
to the consent form.

39. 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.

40. Post Marketing Trials (Phase IV)
Post Marketing trials are studies (other than routine
surveillance) performed after drug approval and
related to the approved indication(s).
It is done to detect unexpected adverse effects and
drug interactions dose-response or efficacy ,safety
studies and trials designed to support use under the
approved indication(s), e.g. mortality/morbidity
studies, epidemiological studies .

41. • for new drug substances discovered in
countries other than India, Phase I data should
be submitted along with the application.
• After submission of Phase I data generated
outside India to the Licensing Authority,
• Phase 1 Phase 2
Phase 3
Phase III trials are required to be
conducted in India before
permission to market the drug in
India is granted

42. Post Marketing Surveillance
• Subsequent to approval of the product, new
drugs should be closely monitored for their
clinical safety once they are marketed.
• The report is to be submitted every six months
for the first two years after approval of the
drug is granted to the applicant. For
subsequent two years need to be submitted
annually and may be extended if necessary.

43. • The applicants shall furnish Periodic Safety
Update Reports (PSURs) in order to-
• report all the relevant new information from
appropriate sources;
• relate these data to patient exposure ;
• summarize the market authorization status in
different countries and any significant variations
related to safety;
• indicate whether changes should be made to product
information in order to optimize the use of the
product.

44. Serious Adverse Events
• Any undesirable experience associated with the
use of a medical product in a patient
• It should be reported within 14 days by the
Sponsor to the Licensing Authority and to the
other Investigator(s) participating in the study
Death Life-threatening
Hospitalization Disability or Permanent Damage
Congenital Anomaly/Birth Defect Required Intervention to Prevent
Permanent Impairment or Damage
(Devices)
Other Serious (Important Medical
Events)
122- DAB

46. Geriatrics
• Geriatric patients should be included in Phase III
clinical trials (and in Phase II trials, at the Sponsor's
option)
– Geriatric patients should only if the disease intended to be
treated is characteristically a disease of aging
– The conditions to be treated should be common in the
elderly are likely to be encountered
– When the new drug is likely to alter the geriatric patient’s
response compared with that of the non-geriatric patient.
– the population to be treated is known to include
substantial numbers of geriatric patients

47. 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
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.

48. Paediatrics
• When clinical development is to include studies in
children, it is usually appropriate to begin with
older children before extending the trial to
younger children and then infants.
• If the new drug is for diseases predominantly or
exclusively affecting paediatric patients.
• Initial safety and tolerability data should be
obtained from the adult population data before
starting trial in children.
• Written informed consent should be taken from
the legal guardians.

49. Bioavailability / Bioequivalence Studies
• For drugs approved elsewhere in the world and
absorbed systemically, bioequivalence with the
reference formulation should be carried out wherever
applicable.
• 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.

50. PRESCRIPTION INFORMATION
The full
prescribing
information
should be
submitted as
part of the
new drug
application
for marketing

52. The Drugs and Cosmetics Rule made an amendment
GSR 53(E) dated 30-01- 2013 inserting a Rule 122DAB
and a new Appendix-XII in Schedule Y
It determine the quantum of compensation, if any, to
be paid by the Sponsor or his representative,
whosoever have obtained permission from the Drugs
Controller General(India) in a time bound manner.
B = Base amount (i.e. 8 lacs)
F = Factor depending on the age of the
subject (based on Workmen
Compensation Act)
R = Risk Factor

53. Age……………..F Factor Age……………..F Factor Age……………..F Factor
>16 . . . . . . . . 228.54
17 . . . . . . . . . 227.49
18 . . . . . . . . . 226.38
19 . . . . . . . . . 225.22
20 . . . . . . . . . 224.00
21 . . . . . . . . . 222.71
22 . . . . . . . . . 221.37
23 . . . . . . . . . 219.95
24 . . . . . . . . . 218.47
25 . . . . . . . . . 216.91
26 . . . . . . . . . 215.28
27 . . . . . . . . . 213.57
28 . . . . . . . . . 211.79
29 . . . . . . . . . 209.92
30 . . . . . . . . . 207.98
31 . . . . . . . . . 205.95
32 . . . . . . . . . 203.85
33 . . . . . . . . . 201.66
34 . . . . . . . . . 199.40
35 . . . . . . . . . 197.06
36 . . . . . . . . . 194.64
37 . . . . . . . . . 192.14
38 . . . . . . . . . 189.56
39 . . . . . . . . . 186.90
40 . . . . . . . . . 184.17
41 . . . . . . . . . 181.37
42 . . . . . . . . . 178.49
43 . . . . . . . . . 175.54
44 . . . . . . . . . 172.52
45 . . . . . . . . . 169.44
46 . . . . . . . . . 166.29
47 . . . . . . . . . 163.07
48 . . . . . . . . . 159.80
49…………….....156.47
50………………..153.09
51…………...…..149.67
52………………..146.20
53…………………142.68
54………………..139.13
55………………..135.56
56………………..131.95
57………………..128.33
58………………..124.70
59………………..121.05
60………………..117.41
61………………..113.77
62………………..110.14
63 . . . . . . . . . 106.52
64 . . . . . . . . . 102.93
65 or above … 99.37

54. RISK FACTOR INDEX(R) RISK FACTORS
0.50 terminally ill patient (expected survival
not more than (NMT) 6 months)
1.0 Patient with high risk (expected
survival between 6 to 24 months)
2.0 Patient with moderate risk
3.0 Patient with mild risk
4.0 Healthy Volunteers or subject of no risk