DRUG REGULATION IN WORLD &

INDIA
(US) Historical perspective of
human research conducts
1. Nuremberg Code, 1946
2. Kefauver Amendments, 1962 – Thalidomide
3. Declaration of Helsinki, 1964
4. National Research Act, 1974 - Tuskegee Syphilis
Study (1932-1972)
5. Belmont Report, 1979
Nuremberg Code
• December 9, 1946 - American military tribunal opened criminal
proceedings against 23 leading German physicians and
administrators for crimes against humanity – 16 found guilty
• German Physicians conducted medical experiments on thousands
of camp prisoners without their consent.
• Most of the participants of these experiments died or were
permanently crippled.
• The Nuremberg Code was established in 1948, stating that "The
voluntary consent of the human participant is absolutely
essential,"
• It did not carry the force of law, but the Nuremberg Code was the
first international document which advocated voluntary participation and
informed consent.

• Video Link: https://www.youtube.com/watch?v=ula7dzU2umw

Kefauver Amendments
• 1960s – Thalidomide as sedative in pregnancy used in Europe (but
not approved by US FDA)
• Deformities in foetus
• No informed consent (not approved by FDA)
• 1962 US Senate hearings Kefauver Amendments passed into law -
For the first time, drug manufacturers were required to prove to
the FDA the effectiveness of their products before marketing
them

• Link : https://www.youtube.com/watch?v=y2lhmSCunrI
Declaration of Helsinki
• World Medical Association - recommendations guiding
medical doctors in biomedical research involving
human participants
1. Research with humans should be based on the results from
laboratory and animal experimentation
2. Research protocols should be reviewed by an independent
committee prior to initiation
3. Informed consent from research participants is necessary
4. Research should be conducted by medically/scientifically
qualified individuals
5. Risks should not exceed benefits
• Revised - 1975, 1983, 1989, 1996, 2000, 2002, 2004,
2008
Tuskegee Syphilis Study
• Study on 600 low income African-American by U.S.
Public Health Service
• Free medical examination – but not told of diagnosis
• Many died of syphilis
• Stopped in 1973 by the U.S. Department of Health,
Education, and Welfare
• 1974 National Research Act passed - National
Commission for the Protection of Human Subjects of
Biomedical and Behavioural Research established
• The commission produce Belmont Report (1979)

• Link: https://www.youtube.com/watch?v=J3tQ93fQf8U
Belmont Report
• Three basic ethical principals
1. Autonomy/respect for persons (Individuals should be treated as
autonomous agents & Persons with diminished autonomy are entitled to protection)
2. Beneficence (Human participants should not be harmed & Research should
maximize possible benefits and minimize possible risks) and

3. Justice (benefits and risks of research must be distributed fairly)

which are the cornerstone for regulations involving
human participants.
What is GCP
A standard for designing,
Designing
conducting, recording and
reporting of studies involving
Reporting Conducting
human subjects.
Public assurance that the
Clinical Trials
rights, safety and well-being
or Studies
of trial subjects are
protected.
Analysis Monitoring

Recording
What is ICH?
• International Conference on Harmonisation
• Realisation to have independent evaluation of medical products mostly
driven by tragedy
• 1960-1970s - rapid increase in laws, regulations and guidelines for
reporting and evaluating the data on safety, quality and efficacy
• Varied from country to country – need to harmonise
• Pioneered by European Community (EC) (now the European
Union) in 1980s
• WHO Conference of Drug Regulatory Authorities (ICDRA), in Paris,
in 1989
• ICH was initiated on April 1990, in a meeting hosted by EFPIA
(European Federation of Pharmaceutical Industries and Associations) in Brussels

• Main outcome - Tripartite ICH Guidelines on Safety, Quality and

Efficacy
Aims of ICH
1. Unify registration requirements for new products
2. Reduce medicinal product development costs:
more economical use of animal, human and
material resources.
3. Accelerate medicinal product licensing times:
avoid repeat testing in different regions.
4. Increases patent protection times through
reducing delay in licensing times.
Principles of ICH GCP
2.1 Clinical trials should be conducted in accordance
with the ethical principles that have their origin in
the Declaration of Helsinki, and that are consistent
with GCP and the applicable regulatory
requirement(s).
2.2 Before a trial is initiated, foreseeable risks and
inconveniences should be weighed against the
anticipated benefit for the individual trial subject and
society. A trial should be initiated and continued only
if the anticipated benefits justify the risks.
Principles of ICH GCP
2.3 The rights, safety, and well-being of the trial
subjects are the most important considerations and
should prevail over interests of science and society.
2.4 The available nonclinical and clinical information
on an investigational product should be adequate to
support the proposed clinical trial.
Principles of ICH GCP
2.5 Clinical trials should be scientifically sound, and
described in a clear, detailed protocol.

2.6 A trial should be conducted in compliance with

the protocol that has received prior institutional
review board (IRB)/independent ethics committee
(IEC) approval/favourable opinion.
Principles of ICH GCP
2.7 The medical care given to, and medical decisions
made on behalf of, subjects should always be the
responsibility of a qualified physician or, when
appropriate, of a qualified dentist.

2.8 Each individual involved in conducting a trial

should be qualified by education, training, and
experience to perform his or her respective task(s).
Principles of ICH GCP
2.9 Freely given informed consent should be
obtained from every subject prior to clinical trial
participation.

2.10 All clinical trial information should be recorded,

handled, and stored in a way that allows its accurate
reporting, interpretation and verification.
Principles of ICH GCP
2.11 The confidentiality of records that could identify
subjects should be protected, respecting the privacy and
confidentiality rules in accordance with the applicable
regulatory requirement(s).

2.12 Investigational products should be manufactured,

handled, and stored in accordance with applicable good
manufacturing practice (GMP). They should be used in
accordance with the approved protocol.

2.13 Systems with procedures that assure the quality of

every aspect of the trial should be implemented.
The summary of the principles
1. Conduct trials according to GCP
2. Weigh risks vs. benefits
3. Subjects wellbeing exceed the science
4. Have adequate information to justify trial
5. Write a sound protocol
6. Receive IRB/IEC approval
7. Use qualified physicians
8. Use qualified & trained support staff
9. Obtain informed consent
10. Record information appropriately
11. Confidentiality & data protection
12. Handle investigational products appropriately
13. Quality assurance
 DRUG REGULATION SYSTEM
Ministry of Health and Family
Welfare

• Directorate General of Health Services

CDSCO-Central Drugs Standard

Control Organization

• Drugs Controller General of India.

Retail and Manufacturing Clinical Trials and

new drug
Distribution Practice development
Retail and Distribution

• 1. Schedule X – Narcotics
2. Schedule H – Prescription drugs
3. Schedule C and C1- Biological Products (Serums and
Vaccines)

Manufacturing Practice

• 1. Schedule N
List of the equipment for the efficient running of manufacturing
wing, Qualified personnel
2. Schedule M-GMP

Clinical Trials and new drug development

• Schedule Y
The drugs and cosmetics act and
rules:
• GOVERNMENT OF INDIA 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.
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
 SCHEDULE Y

Rules 122 A, 122 B, 122 D, 122 DA, 122 DAA, 122 DD, 122 DAC & 122 DAB.
Rules
• 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
New Rules
• 122 DD
Registration of Ethics Committee
• 122 DAC
Audio-Visual Recording of Inform Consent Process
• 122 DAB
Determine the quantum of compensation in case of
clinical trial related death
• 122- E New Drug
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
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
DRUG DISCOVERED DRUG DISCOVERED
IN INDIA OUTSIDE INDIA

PREVIOUS PHASE I
DATA
STARTED FROM
PHASE I
APPROVED

PHASE II TRIAL

PHASE II TRIAL
2. CLINICAL TRIAL
PERMISSION
The ethics committee.
SPONSER
• Quality assurance
• Submission of status report.
• Reporting of any serious
adverse effect
• To ensure that laboratories
used for generating data for
clinical trials should be
compliant with Good
Laboratory Practices
Licensing Authority
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.
Serious Adverse Events
• Any undesirable experience associated with the use of
a medical product in a patient
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)

• It should be reported within 14 days by the Sponsor to

the Licensing Authority and to the other
Investigator(s) participating in the study

122- DAB
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
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
Age……………..F Factor
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
Age……………..F Factor
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
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
Submission of reports of SAEs to CDSCO
◼ The sponsor or his representative are requested to prepare the SAE reports as per
Appendix-XI of Schedule-Y of D&C Rules along with checklist.

◼ Clear and unequivocal information should be provided in the SAE report.

◼ All items mentioned in the checklist may not be applicable in all the cases of SAE’s.
The items not relevant to a particular SAE should be marked with “Not Applicable
(NA)”.
Desired Information in a SAE Report
▪ Trial Identifier – Study Protocol Number
▪ Trial drug – Name, Dates of administration, Dose
▪ Subject identifier – center, screening/enrolment number, sex, initials.
▪ Name of Investigator
▪ SAE onset date
▪ SAE Description
▪ Baseline status and medical History
▪ Expedited reporting criteria
▪ Action taken
▪ Outcome
▪ Investigator signature and date
PRINCIPLE OF PRIVACY AND CONFIDENTIALITY

◼ The Investigator must safeguard the confidentiality of trial data, which might
lead to the identification of the individual subjects.

◼ Data of individual subjects can be disclosed only in a court of law under the
orders of the presiding judge or in some cases may be required to
communicate to Drug Regulatory/ Health Authority. In order to maintain the
confidentiality, the videographer should be engaged as part of the study
team.

◼ Prior to initiation of the study, the Investigator should define and allocate the
activities of audio-video recording of informed consent process to the
respective identified person as videographer.

◼ The Investigator shall maintain the details of the person to whom he has
delegated the duties of audio video recording.
Appendices In Schedule Y
• APPENDIX I- Data to be submitted along with the application to conduct clinical trial/import/
manufacture of new drugs for marketing in the country.

• APPENDIX I- 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 II- Structure , contents and format for clinical Study Reports.

• APPENDIX III- Animal toxicology (Non- Clinical Toxicity studies

• APPENDIX IV- Animal Pharmacology

• APPENDIX V- Informed Consent

• APPENDIX VI- Fixed Dose combinations (FDC)

• APPENDIX VII- Undertaking by Investigator

• APPENDIX VIII- Ethics Committee

• APPENDIX IX- Stability testing of New Drugs

• APPENDIX X- Contents of the proposed protocol for conducting clinical trials

• APPENDIX XI- Data elements for reporting serious adverse events occurring in a Clinical trial

• APPENDIX XII- System for pre-screening of SAE reports (New)

Thank You!