NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019

New Drugs and Clinical
Trials (NDCT) rules, 2019
An Overview
Akash Agnihotri
Tutor
Department of Pharmacology
Amrita School of Medicine, Faridabad
NDCT 2019 by Akash Agnihotri 1

NDCT 2019
• Draft copies of new clinical trials rules on public domain: 7th February, 2018
• Objections and suggestions invited from all stakeholders
• Central Government notified “New Drugs and Clinical Trials Rules, 2019” on
19th Mar 2019
• New Drug and Clinical Trial Rules, 2019 are applicable from 19th Mar 2019,
except Chapter 4 [Ethics Committee for Biomedical and Health Research],
which came into force after 180 days (i.e. 21st Sep 2019)
2
NDCT 2019 by Akash Agnihotri

The New Drugs & Clinical Trial Rules, 2019
New rules are structured around:
• 13 chapters, which includes 107 rules and 8 schedules
Will apply to:
• All new drugs
• Investigational new drugs
• Clinical trials
• Biomedical and health research
• Ethics committees
3

The New Drugs & Clinical Trial Rules, 2019
New rules override part XA and Schedule Y of medicine and
cosmetics rules, 1945
Earlier regulations and schedule Y will still be applicable for
veterinary use drugs
4
Schedule Y was a law that
outlined the requirements and
guidelines for conducting clinical
trials and importing or
manufacturing new drugs in
India
Part XA As per Drugs and cosmetic Rules
1945, part X-A, import or manufacture of
new drug for clinical trials or marketing

NDCT 2019, Aimed
Promoting clinical research within the country by implementing:
• Time-bound review of applications
• Allowing increased predictability and transparency of regulatory pathway
• Providing clarity on many complex subjects, including post-trial access
After a series of media allegations of unethical practices, in
2013 the CDSCO office made stricter regulations for
conducting clinical trials

Highlights in the 2019 NDCT
Amendments of drugs and cosmetics rules, 1945:
• Rule 97 includes 122DAA in the drugs and cosmetic rules 1945, which
consists:
Non-application of certain rules for new drugs and investigational new
drugs for human use
Part XA and schedule Y shall not be applicable with regard to new drugs
and investigational new drugs for human use

New Definitions in NDCT Rule 2019

New Definitions: Clinical Trial
• “Clinical trial” in relation to a new drug or investigational new drug means,
any systematic study of such new drug or investigational new drug in
human subjects to generate data for discovering or verifying its:
 Clinical or
 Pharmacological, including pharmacodynamics, pharmacokinetics or
 Adverse effects
• With the objective of determining the safety, efficacy or tolerance of such
new drug or investigational new drug

New Definitions: Academic Clinical Trial
Rule 2(a)
• Clinical trial of a drug already approved for a certain claim
• Initiated by any investigator, academic or research institution
• For a new indication or new route of administration or new dose or new
dosage form
• Results of such a trial are intended to be used only for academic or
research purposes and not for seeking approval of the central licensing
authority or regulatory authority of any country for marketing or
commercial purpose

New Definitions: Biomedical & Health Research
Rule 2(h)
• Research including studies on:
• Basic, applied and operational research
• Clinical research
• Designed primarily to increase scientific knowledge about diseases and
conditions (physical or socio-behavioural) their detection and cause
• Evolving strategies for health promotion, prevention or amelioration of
disease
• Rehabilitation but does not include clinical trial

New Definitions: Biomedical & Health Research
(BHR)
• BHR to be conducted in accordance with “National Ethical Guidelines for
Biomedical and Health Research involving Human Participants” by ICMR
• EC for BHR is required to be registered with DHR, MoH&FW
• Observational & non interventional study of a drug which is not a new
drug, however it is advisable to submit such protocols to CDSCO for
confirmation

New Definitions: Orphan Drugs
Rule X
• Means a drug intended to treat a condition which affects not more than
five lakh persons in India, without any financial gain foreseen by pharma
company but for benefit of humanity

Newly Approved Orphan Drugs
• Approved in 2024:
• Fidanacogene elaparvovec-dzkt (Treatment of adults with moderate to severe
hemophilia B (congenital factor IX deficiency)
• Atidarsagene autotemcel (Treatment of children with pre-symptomatic late
infantile (PSLI), pre-symptomatic early juvenile (PSEJ) or early symptomatic early
juvenile (ESEJ) metachromatic leukodystrophy (MLD)
• Approved in 2023:
• Donislecel-jujn (Treatment of adults with Type 1 diabetes who are unable to
approach target HbA1c because of current repeated episodes of severe
hypoglycemia despite intensive diabetes management and education

Top 5 Selling Orphan Drugs in the World (Feb, 2022)
(Ibrutinib)
(Daratumumab
)
(Elexacaftor/
tezacaftor/ivacaftor)
(Emicizumab
)
(Olaprib)
(Drug Name)

New Definitions: Post-Trial Access
Rule CC
Making a new drug or investigational new drug available to a trial
subject after completion of clinical trial through which the said drug
has been found beneficial to a trial subject during clinical trial

New Definitions: New Drug Rule W

Ethics Committee for Clinical Trials

4 pillars of principle of medical ethics
Autonomy: Person’s right to make choices and hold view
Justice: Everyone should be treated equally and benefits are shared
equally
Nonmaleficence (Do not harm): There should be obligations of not
to harm anyone intentionally
Beneficence (Do good): Benefits should be provided to everyone
and one should contribute to the welfare of the society

Ethics Committee Constitution
Ethics
Committee
Members
1 Lay person
1 Women
Member
1 Legal
Expert
1
Independent
Member
1 From Non-
Scientific
Area
1 From
Scientific
Area
1 From
Medical
Field
7 Members Minimum 50% of
members must be
from outside

Ethics Committee for Clinical Trials
• Deals with Regulatory CT as well as Academic CT & BA/BE
• Constitution: Minimum 50% of members must be from outside
• Compensation: Regulatory trial DCGI, Academic trial  guidelines by
ICMR
• Registration with CDSCO: 5 years validity
• Independent ethics committee: According with rule 7,same site/radius of
50 kms
• EC approving BHR,BA/BE, CT  register with CDSCO & DHR

Ethics Committee for Clinical Trials (continued)
Time line
• 60 Days Timeline: Clinical trial as part of discovery, research, manufacture
and marketing
• 90 Days Timeline: For other applications of CT and new drug
• Permission from Central Licensing Authority (CLA) needed
• CLA permission not needed in: Trials solely for academic research

Ethics Committee approval for Clinical Trials
• Multicentric CT: EC approval from each site
• EC not present at site:
• Other site can give approval & bear all responsibilities
• Independent EC approval
• After approval: Inform Central Licensing Authority (CLA) within 15
days
• If rejected and applying to another EC: details of rejection to be submitted
to CLA

Accelerated approval to new drug
• Approval after phase 2 if it shows remarkable efficacy
• For life threatening disease, unmet medical needs
• Surrogate endpoints considered
• Phase 4 CT needed for validation of clinical benefit

Serious Adverse Event (SAE) reporting and
assessment
• A Serious Adverse Event (SAE) is defined as any adverse drug event that is
life threatening or associated with:
• Death
• Inpatient hospitalization
• Prolonged hospitalization
• Persistent or significant disability or incapacity
• A congenital anomaly or birth defect
• Causality assessment: Scales- WHO, Naranjo’s

Timeline for reporting SAE
• Investigator to Sponsor, EC, CDSCO: Initial report < 24 hrs
• Full analyzed report, investigator must submit a report 14 days of
event
• Sponsor must also provide free medical management for the
appropriate time
• Recommendation for compensation:
• Chairperson of Ethics committee to DCGI : <30 calendar days
• Chairperson of Expert committee to DCGI: <60 days of receipt of report
from ethics committee
• Order of compensation from DCGI to Sponsor :<90 days of receipt of
report
• Final compensation paid by sponsor to patient/relative:< 30 days of
receipt of order

Compensation and Formulas

Quantum of compensation and formulas
1. Formula in Case of clinical trial related death:

Quantum of compensation and formulas
2. For permanent disability: Compensation = (DX90XC)/(100X100)
• C= Quantum of compensation in case of death
• D= Percentage of disability
3. SAE causing life-threatening disease: Compensation = N x W
• N=Number of days for life-threatening situation requiring medical care,
irrespective of days of hospitalization
• W=Minimum wage per day of the unskilled worker (in Delhi)
4. Reversible SAE in case it is resolved: Compensation = 2 x W x N
• W = Minimum wage per day of the unskilled worker (in Delhi)
• N = Number of days of hospitalization

Some Important Changes and Alterations
of New Rule

Important Points of NDCT 2019
1. New and Old License Application Fee Structure
Application fees for Phass-1-4 clinical trials now increased up to 6-8 folds
30

2. After approval of a Clinical Trial, it is now valid for 2 years from the date of
its approval
3. There are two typed of Ethics Committees (EC):
• One for Clinical Trials & BA/BE studies (Under CDSCO)
• One for Biomedical & Health Research (Under ICMR)
4. The Validity of EC registration is now 5 years
5. DCGI should be informed about the approval granted by the EC within 15
working days of the grant of such approval

6. In case of rejection of trial application, the applicant may request to
reconsider the application within a period of 60 days from the date of
rejection of the application.
7. A 6 monthly report of clinical trial should be submitted to DCGI through
SUGAM portal. But enrollment status should be submitted to DCGI every
3 months.
8. The termination of the clinical trial and BA/BE study should be notified to
CLA within 30 days with detail of its cause for termination.

9. Post-trial access of drug to the patients (should be provided by the
sponsor at free-of-cost to the trial subject after the trial is over), which
completely depends on recommendation of the investigator and its
approval by EC.
10. For conducting an academic clinical trial (intended solely for academic
research purposes) only Ethics Committee approval is mandatory (no
permission is required from DCGI) and such clinical trial should not used
for promotional or approval purposes.

11. The Sponsor should provide free medical management to the “subject as
long as required as per the opinion of investigator, or till such time it is
established that the injury is not related to” the clinical trial or BA/BE
study.
12. “ The sponsor or its representative and the investigator shall forward their
reports on Serous Adverse Events (SAE) of death after due analysis” to
DCGI, HOI, Chairperson of EC within 14 days of the “Knowledge of
occurrence of SAE of death”

13. Periodic Safety Update Report (PSUR): Timeline is reserved as per old
regulation but content & structure is now should be arranged with very
detailed and exhaustive EU PBRER (ICH) format.
EU PBRER: European Union Periodic Benefit Risk Evaluation Report
As per the Drugs and Cosmetics Act, 1940 & Rules, 1945 including
NDCT Rules, 2019
PSURs are required to be submitted every six months for first two
years from the date of approval and for subsequent two years
annually

Overall comparison of new rules with former
rules
36

Overall comparison of new rules with former rules
NDCT 2019 by Akash
Agnihotri
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NDCT 2019 by Akash
Agnihotri 39

NDCT 2019 by
Akash Agnihotri
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NDCT 2019 by Akash
Agnihotri
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NDCT 2019
by Akash
Agnihotri
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NDCT 2019
by Akash
Agnihotri
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Flow chart on the
compensation
procedures in case
of serious adverse
events and death
during the clinical
trials

Flow chart on
general
procedure of
grant of
approval to
conduct clinical
trials in India
48

References
I. Dubey A, Kotian B, Ravi GS. New Drugs and Clinical Trials Rules, 2019: Towards Fast-track
Accessibility of New Drugs to the Indian Population. Indian J of Pharmaceutical Education and
Research. 2019;53(4s):s451-s459.
II. NDCT Rule 2019. Accessed by: https://cdsco.gov.in/opencms/export/sites/CDSCO_WEB/Pdf-
documents/NewDrugs_CTRules_2019.pdf
III. Singh N, Madkaikar NJ, Gokhale PM, Parmar DV. New drugs and clinical trials rules 2019:
Changes in responsibilities of the ethics committee. Perspect Clin Res. 2020 Jan-Mar;11(1):37-
43. doi: 10.4103/picr.PICR_208_19. Epub 2020 Jan 31. PMID: 32154148; PMCID:
PMC7034142.
IV. Annapurna SA, Rao SY. New drug and clinical trial rules, 2019: an overview. Int J Clin Trials
2020;7(4):278-84.
V. Urooj M, Husain GM, Khan MA, Kazmi MH. Compensation to clinical trial participants in India:
A gap analysis. Int J Pharm Investig. 2017 Apr-Jun;7(2):41-46. doi: 10.4103/jphi.JPHI_31_17.
PMID: 28929045; PMCID: PMC5553263.
VI. Postgraduate Pharmacology by Sougata Sarkar, Paras Medical Publisher, 2020.
VII. Orphan Drug Report 2022, by By Melanie Senior and Andreas Hadjivasiliou, April 2022

MCQs on NDCT 2019

MCQ No. 01
The renewal of the ethics committee must be
completed ____________
a) 60 days before the expiry of the license
b) 90 days prior to the expiry of the license
c) 30 days before the expiry of the license
d) 120 days prior to the expiry of the license

MCQ No. 02
The validity period of Ethics Committee
registration is ____________
a) 1 Year
b) 3 Years
c) 5 Years
d) 10 Years

MCQ No. 03
In cases where patients have an expected mortality
of 90% or more within 30 days, the quantum of
compensation should be:
a) ₹ 1 Lakh
b) ₹ 2 Lakh
c) ₹ 5 Lakh
d) ₹ 10 Lakh

MCQ No. 04
Before initiating a study involving primary data collection,
the Principal Investigator must ensure that various
approvals are obtained. Which of the following approvals is
absolutely mandatory?
a) Scientific committee approval
b) Ethics committee approval
c) Technical committee approval
d) Regulatory authority approval

MCQ No. 05
According to the timeline for reporting Serious Adverse
Events (SAEs) and the order of compensation from DCGI
to the Sponsor, the compensation order should be issued:
a) Within 30 days of receipt of the SAE report
b) Within 60 days of receipt of the SAE report
c) Within 90 days of receipt of the SAE report
d) Within 120 days of receipt of the SAE report

MCQ’s Answer Key
1. b) 90 days prior to the expiry of the license
2. c) 5 Years
3. b) 2 Lakh
4. b) Ethics Committee Approval
5. c) Within 90 days of receipt of the SAE report

Thank you

NDCT Rules, 2019: An Overview | New Drugs and Clinical Trial Rules 2019

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