Regulatory framework of India, Acts and Regulations for conduct of clinical trial in India, Schedule Y, approval of new chemical entity and recent amendments

1. REGULATIONS IN CLINICALREGULATIONS IN CLINICAL
TRIALTRIAL
Dr. Siddhartha Dutta

2. Contents
• Introduction
• Regulatory framework in India
• Act and Rules
• Important components of D & C act, 1940
• Schedule Y
• Regulations of FDCs’
• Appendices
• Recent regulatory changes
• Future in CT

3. CLINICAL TRIAL(WHO)
• Any research study that prospectively assigns human
participants or groups of humans to one or more
health-related interventions to evaluate the effects on
health outcomes
• Interventions include but are not restricted to drugs,
cells and other biological products, surgical
procedures, radiological procedures, devices,
behavioural treatments, process-of-care changes,
preventive care, etc.

4. CLINICAL TRIAL
• 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) effects

And/or Adverse effects

With the objective of determining safety and/or efficacy of the
new drug

5. INDIA: A Hub
• Skilled and well trained
manpower
• Low operational cost
• Huge patient load
• Wide variety of diseases
• Good infrastructure

6. Regulatory Framework in India

7. CENTRAL DRUG STANDARD CONTROL
ORGANISATION
(CDSCO)
• CDSCO is main body which works on development of
regulatory procedures and standards for drugs,
cosmetics, diagnostics and devices
• Lays down regulatory guidance by amending acts and
rules; and regulates new drug approval process
• Main objective is to standardize clinical research and to
assure safety, efficacy, quality of drugs, cosmetics
and medical devices

8. Drugs Controller General of India
[DCGI]
• Responsible for giving regulatory permissions for the
conduct of clinical trials and is responsible for approval of
marketing licenses for drugs in India
• Inspections of trial sites
• Inspections of sponsors of clinical research and manufacturing
facilities in the country
• Oversight of the Central Drugs Testing Laboratory (Mumbai)
and the Regional Drugs Testing Laboratory
• Heads the Indian Pharmacopeia Commission
• DCGI is advised by the Drug Technical Advisory Board (DTAB)
and the Drug Consultative Committee (DCC)

9. Categorization: A road towards
faster approval
• To expedite the approval process, for studies already
approved by other countries’ regulatory agencies, DCGI has
divided all applications into 2 categories
• Cat A- Clinical trials whose protocols have been approved by
EMEA or regulatory agencies in the US, UK, Switzerland
Australia, Canada, Germany, South Africa or Japan
• Cat B- Reviewed following the regular approval system by an
expert committee

10. • Law: A rule of conduct enforced by a controlling
authority
• Regulation: An interpretation of how to implement a
law schedule
• Guideline: An interpretation of the regulations which
has no legal binding and may not be universally
accepted

11. • Drug and Cosmetic Act 1940 (D/C Act) & Drug and
Cosmetic rules 1945
• Pharmacy Act , 1948
• Drugs Control Act, 1950
• Ethical guidelines for Biomedical Research on Human
Participants, 2000, 2006 by ICMR
• Indian GCP Guidelines,2001
• Amendments to Drug and Cosmetic Act,2002
• Revised Schedule Y, 2005

12. ACT vs. RULES ??
The Drugs and Cosmetics Act, 1940
•It is an Act of the Parliament of India which regulates the
import, manufacture and distribution of drugs in India
The Drugs and Cosmetics Rules, 1945
•It contains provisions for classification of drugs under
given schedules
•Guidelines for the storage, sale, display and
prescription of each schedule

13. Forms of D & C Act
Form 44 Application for grant of permission to import or
manufacture a New drug or to undertake clinical trial
Form 12 Application for license to import drugs for the purpose of
examination, test or analysis
Form 11 License to import drugs for the purpose of examination, test
or analysis(1 yr validity)
Form 4 Issue of import certificate(6 months validity)
Form 1 Application for the issue of import certificate for import of
import of narcotic drugs and psychotropic substances(6
months validity)

14. Rules of D & C Act
RULES PERMISSION FOR
122 A To import New drugs
122 B To manufacture New drugs
122 D To Import or Manufacture fixed dose combinations
122DA To conduct clinical trials for New Drug/Investigational
New drug
122 DAA Definition of Clinical Trial
122 DAB Draft guidelines for registration of all clinical research
organizations involved in the clinical trials in India(5 yr)
122-E Definition of New Drug

15. New Drug(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
• Approved for use but in the market for less than 4 yrs after
approval
• FDC, individually approved, to be combined for the first time in
a fixed ratio or if ratio is changed
• All vaccines and r-DNA drugs

16. SCHEDULE YSCHEDULE Y
• Requirements and guidelines for permission to import
and/ or manufacture of new drugs for sale or to
undertake clinical trials

17. Requirement and guidelines on Clinical Trials
for importing and manufacture of New drug

18. APPLICATION
FOR
PERMISSION

19. 1. Application for permission
Application is made in FORM 44 accompanied with following data
in accordance with appendices, namely
1. Chemical and pharmaceutical Information
2. Animal pharmacology data
3. Animal toxicology data
4. Human clinical pharmacology data
5. Regulatory status in other countries
6. Prescribing Information

20. Chemical and pharmaceutical
Information
• Information on active ingredients
• Drug information (Generic Name, Chemical Name)
• Physicochemical properties of drug
• Analytical Data
• Complete monograph specification
• Validations
• Stability Studies
• Data on Formulation
• Dosage form
• Composition
• Excipient compatibility study

21. Animal pharmacology data
(Item 3 of Appendix I and Appendix IV)
• Specific pharmacological actions
• General pharmacological actions
• Follow-up and Supplemental Safety Pharmacology
Studies
• PK

22. 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

23. Phase 1 trial
• Systemic Toxicity studies
(i) Single dose toxicity studies (ii) Dose Ranging Studies
(iii) Repeat-dose systemic toxicity studies of appropriate
duration to support the duration of proposed human exposure
• Male fertility study
• In-vitro genotoxicity tests
• Relevant local toxicity studies with proposed route of clinical
application
• Allergenicity/Hypersensitivity tests
• Photo-allergy or dermal photo-toxicity test

24. Phase 2 trial
• In case of an application for directly starting a Phase II trial -
complete details of the nonclinical safety data needed for
obtaining the permission for Phase I trial, as per the list
provided above must be submitted
• Repeat-dose systemic toxicity studies of appropriate duration to
support the duration of proposed human exposure
• In-vivo genotoxicity tests
• Reproductive/developmental toxicity study (if female patients of
child bearing age are going to be involved)

25. Phase 3 trial
• In case of an application for directly initiating a Phase III trial -
complete details of the non-clinical safety data needed for
obtaining the permissions for Phase I and II trials
• Repeat-dose systemic toxicity studies of appropriate duration to
support the duration of proposed human exposure
• Reproductive/developmental toxicity studies
• Carcinogenicity studies (when there is a cause for concern or
when the drug is to be used for more than 6 months)

26. Human clinical pharmacology
data
For new drug substances discovered in India
•Clinical trials are required to be carried out in India right from
Phase I and data should be submitted as required under items 1,
2, 3, 4, 5 (data, if any, from other countries) , and 9 of Appendix I
For new drug substances discovered in countries other than India
•After submission of Phase I data generated outside India to the
Licensing Authority, permission may be granted to repeat Phase I
trials and/or to conduct Phase II trials and subsequently Phase III
trials concurrently with other global trials for that drug
•Phase III trials are required to be conducted in India before permission to
market the drug in India is granted

27. NCE
1) NCE discovered in India
2) NCE that are already approved/marketed in other
countries-
Phase III trials are conducted in a large number of
patients with multiple site and compared with a standard
drug, to confirm efficacy and safety would be sufficient
3) NCE that are not approved/marketed in other
countries- Permission for clinical trials is given with a
“phase lag”

28. Regulatory status in other countries
(Item 9.2 of Appendix I)
• Information in respect to restrictions imposed(if any), on the
use of the drug in other countries, e.g.
• Dosage limits
• Exclusion of certain age groups
• Warning about ADRs
• Withdrawal of drug in any country by the manufacturer or by
regulatory authorities, such information should also be
furnished along with the reasons and their relevance
&
• To be submitted by the sponsor to the Licensing Authority
during the course of marketing of the drug in India

29. Prescribing Information

30. CLINICAL TRIAL

31. 2.Clinical Trial(CT)
• Approval for clinical trials
• Responsibilities of sponsor
• Responsibilities of Investigator
• Informed Consent
• Responsibilities of Ethics Committee
• Human Pharmacology (Phase l)
• Therapeutic Exploratory Trials (Phase ll)
• Therapeutic confirmatory Trials (Phase lll)
• Post Marketing Trials (lV)

32. Responsibility of Sponsor
• Implementation and Quality assurance to ensure compliance to
protocol and GCP guidelines of CDSCO
• Submission of status report of the CT at prescribed periodicity
• In case of premature discontinuation of the study a summary
report to be submitted within 3 months
• Serious adverse event(SAE) to be communicated promptly
(within 14 calendar days) to the licensing authority and other
investigators

33. Responsibilities of Investigator
• Conduct of trial according to protocol and GCP
• Standard operating procedures are required to be
documented
• During and following a subject's participation in a trial, the
investigator should ensure that adequate medical care is
provided to the participant for any adverse events
• SAE & unexpected adverse events reporting to Sponsor
within 24 hrs. EC within 7 days of occurrence

34. Informed Consent
• Freely given, informed, written consent is required to be
obtained from each study subject
• Both the PIS as well as the ICF 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
• 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.

35. Responsibilities of Ethics Committee
• Reviews and accords its approval to a trial protocol to
safeguard the rights, safety and well being of all trial subjects
• Should exercise particular care to protect the rights, safety and
well being of all vulnerable subjects participating in the study
• Document standard operating procedures and should maintain
a record of its proceedings
• EC should make, at appropriate intervals, an ongoing review of
the trials for which they review the protocol(s)
• If EC revokes its approval, it must record the reasons and
communicate to the Investigator as well as to the Licensing
Authority

36. Human Pharmacology (Phase l)
• Objective of study- Estimation of safety and tolerability with the
initial administration of an IND into human
• Non-therapeutic objectives and may be conducted in healthy
volunteers subjects or certain types of patients
• Maximum tolerated dose
• Pharmacokinetics
• Pharmacodynamics

37. 5.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
• 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

38. 6.Therapeutic confirmatory
Trials (Phase lll)
• Primary objective
Demonstration or confirmation of therapeutic benefit(s)
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
• 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

39. Post Marketing Trials (lV)
• Performed after drug approval and related to the approved
indication(s)
• These trials go beyond the prior demonstration of the drug's
safety, efficacy and dose definition
• Include additional drug-drug interaction(s)
• Dose-response or safety studies
• Trials designed to support use under the approved
indication(s), e.g. mortality/morbidity studies, epidemiological
studies etc.

40. STUDIES
IN
SPECIAL POPULATION

41. 3. 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

42. Studies in Elderly
Geriatric patients should be included in Phase III clinical trials (and
in Phase II trials, at the Sponsor's option) in meaningful numbers,
if
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; or
When there is specific reason to expect conditions common
in the elderly are likely to be encountered; or
When the new drug is likely to alter the geriatric patient's
response (with regard to safety or efficacy) compared with that of
a non-geriatric patient

43. Studies in Pediatrics
• CT 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
 Clinical trials
 Relative bioequivalence studies(paediatric vs. adult formulation)
 PK studies for dose selection in the age ranges of paediatric patients
• Written informed consent should be obtained(parent/LAR)

44. Studies in Pregnant &
Nursing Women
• When the drug is intended for use by pregnant/nursing women
or foetuses/nursing infants, the data generated of non pregnant
or nursing, is not suitable
• For new drugs, follow-up data (pertaining to a period
appropriate for that drug) on the pregnancy, foetus and child
will be required
• Where applicable, excretion of the drug or its metabolites into
human milk should be examined
• Infant should be monitored for predicted pharmacological
effects of the drug

45. POST MARKETING SURVEILLANCE

46. 4.Post Marketing Surveillance
Periodic Safety Update Reports (PSURs)
submitted in order to monitor for the clinical safety of the new drug
•Report all the relevant new information (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
•New studies specifically planned/conducted to examine a safety
issue should be described in the PSURs

47. BA/BE studies

48. Special Studies- BA/BE studies
• For drugs approved elsewhere in the world and
absorbed systemically, bioequivalence with the
reference formulation should be carried out
• Evaluation of the effect of food
• Dissolution and bioavailability data to be submitted
• All bioavailability and bioequivalence studies
should be conducted according to the Guidelines
for Bioavailability and Bioequivalence studies as

49. FIXED DOSE
COMBINATIONS

50. FIXED DOSE COMBINATIONS
(FDCs)
 One or more of the active ingredients is a new drug- Data
to be submitted will be similar to data required for any new drug
(including clinical trials)
 Active ingredients already approved/marketed individually
are combined for the first time, for a particular claim and where
the ingredients are likely to have significant interaction of a PK
or PD nature
 Combination is marketed elsewhere
 Combination is not marketed anywhere in the world but these
drugs are already in use concomitantly (not as an FDC but
individually) for the said claim, marketing permission may be
granted based on chemical, pharmaceutical and stability data

51.  Already marketed, but proposed either to change the ratio
of active ingredients or to make a new therapeutic claim-
appropriate rationale including published reports(if any) should
be submitted to obtain marketing permission
 Individual active ingredients (or drugs from the same
class) have been widely used in a particular indication(s)
for years, their concomitant use is often necessary- no
claim is proposed to be made other than convenience
 The stability of the proposed dosage form need to be
demonstrated and it should be ensured that there is no PK/PD
interaction

52. APPENDICES
APPENDIX l- Data to be submitted along with the application to conduct clinical
trials/import/ manufacture of New drugs for marketing in the country
APPENDIX l-A- 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
APPENDIX ll- Structure, Contents and Format for Clinical Study Reports
APPENDIX lll- Animal Toxicology (Non-Clinical Toxicity studies)
APPENDIX lV- Animal Pharmacology
APPENDIX V- Informed Consent
APPENDIX Vl- Fixed dose Combinations (FDC’s)
APPENDIX Vll- Undertaking by Investigator
APPENDIX Vlll- Ethics Committee
APPENDIX lX- Stability testing of New Drugs
APPENDIX X- Contents of the proposed protocol for conducting clinical trials
APPENDIX Xl- Data elements for reporting serious adverse events occurring in a
Clinical Trial

53. RECENT REGULATORY
CHANGES

54. Three-tier Review Process
• Step 1-- Review in SEC meeting
• Step 2-- Review by Technical Committee(TRC)
• Step 3-- Review by APEX Committee
(if approved, final approval granted by DCGI)

55. Compensation for SAE
• Gazette Notification GSR 53(E) 30th Jan 2013
Amended
• GSR 889 (E), Dec 2014, effective June 2015
• Clarification regarding compensation and free medical
management in case of clinical trial related injury
• Changes in timeline for SAE reporting

56. Ethics Committee Registration
• Feb 2013 – Amendment to D&C Rules vide GSR 72
(E) in the form of Rule 122 DD
• Registration of Ethics Committee with LA mandatory
before it reviews and accords approval to a CT
• Valid for 3 years
• Notice in July 2013 – Independent ECs registered
with LA to oversee only BA / BE studies

57. Audio-Video Recording of
Informed Consent Process
• G.S.R. 364 (E) in June 2013 mandated AV recording
of IC process
• 611 (E) of July 2015 modified AV recording norms
- New Chemical Entity or New Molecular Entity
- Vulnerable subjects

58. Norms for Site Selection
July 2014
•3 trials / investigator
•No clinical trial at sites with < 50 hospital beds
•At least 50% should be govt. sites
Aug 2016(Norms Revoked)
•EC empowered to take a call

59. Academic Research
• G.S.R. 313 (E) of March 2016
• No permission for conduct of clinical trial intended for academic
purposes in respect of approved drug formulation shall be
required for any new indication or new route of administration or
new dose or new dosage form where,-
(a) the trial is approved by the Ethics Committee; and
(b) the data generated is not intended for submission to LA.

60. Inspections by Regulatory
bodies
• G.S.R. 63 (E) of Feb 2013 (New Rule 122 DAC)
• IEC approval, registration with CTRI, submission of annual
status reports
• CDSCO authorized for inspections of clinical trial sites,
including Sponsors and Investigators
• CDSCO office also issued GCP inspection checklist in
Aug 2016

61. SUGAM
• Tool for online applications for clinical trial
• To increase the transparency and efficiency of
processing clinical trial applications

62. Future of CT(INDIA)
• 'Pharma Vision 2020' aimed at making India a global
leader
• Regulations for conduct of CT 2017
• ICMR guidelines- 2017