GUIDANCE FOR INDUSTRY ON

PHARMACOVIGILANCE REQUIREMENTS
FOR
HUMAN VACCINES

Effective Date:
Version: 2.0

Published by;
Central Drugs Standard Control Organization,
Ministry of Health & Family Welfare, Government of India
 PREFACE

This is in consonance with the objective of the Drugs & Cosmetics Act
1940 and Rules made thereunder and New Drugs and Clinical Trial
Rules 2019 and other functions of CDSCO wherever applicable. These
guidelines are intended for the guidance of the Marketing Authorization
Holders (MAHs) i.e. manufacturers and importers of Human Vaccines.
The procedure set out to facilitate the industry to submit the documents
as per the requirements of Drugs and Cosmetics Act and Rules.
Guidance documents may be amended from time to time as per
requirements after obtaining necessary approval from the Competent
Authority.
 FOREWORD

The Central Drugs Standard Control Organization (CDSCO), being the

apex regulatory authority for approval of drugs in India, is committed
to safeguard and enhance the Public Health by assuring the safety,
efficacy and quality of drugs including vaccines, cosmetics and
medical devices.
India has extensive Pharmacovigilance activities for vaccines as part
of post licensure submissions in form of PSURs, PMS studies, AEFI
case reports and Individual Case Safety Reports (ICSRs). The present
document is developed to provide the guidance to all the stakeholders
including the Marketing Authorization Holders on the coordinated
activities of the various departments within the Ministry of Health &
Family Welfare to work together and enhance the pharmacovigilance
of vaccines.
The present document is developed to provide the guidance to all the
stakeholders including the Marketing Authorization Holders about
Vaccine Safety Monitoring, Audits and Inspection; Risk Management
Plan (RMP) wherever applicable and Periodic submission of Risk
Benefit Evaluation Report i.e., PSUR to the Licensing Authority.
The guidance document has been prepared in line with the Drugs &
Cosmetics Act 1940 and Rules made thereunder and NDCT Rules,
2019 to provide guidance for the MAH to perform specific safety study
throughout the product life cycle and to define the roles and
responsibilities of all the stake holders namely CDSCO, PvPI at IPC,
Immunization Division, MAH, private and public practitioners and
outlines the Risk Minimization Action Plan. This could provide
guidance to the manufacturers and importers of vaccines in the
country to strengthen their AE/AEFI monitoring and reporting and
pharmacovigilance department to ensure patient safety.
 CONTENTS
ABBREVIATIONS
1. INTRODUCTION
1.1 Objective
1.2 Background
1.3 Rationale
1.4 Scope
2. ROLES AND RESPONSIBILITIES OF AUTHORITIES
2.1 CDSCO
2.2 PvPI, Indian Pharmacopoeia Commission
2.3 AEFI Secretariat, Immunization Division of Ministry of
Health and Family Welfare
2.4 Pharmacovigilance Division (Human Vaccine) at CDSCO
3. PHARMACOVIGILANCE PLAN
3.1 Pharmacovigilance Methods
3.2 Post marketing surveillance/ Periodic Safety Update Report
3.3 Post marketing trials (Phase – IV)
4. PHARMACOVIGILANCE CHAPTERS
4.1 Chapter 1: Pharmacovigilance System Master File
4.2 Chapter 2: Collection, Processing and Reporting of
Individual Case Safety Report (ICSR) by Marketing
Authorization Holder (MAH)
4.3 Chapter 3: Preparation & Submission of Periodic Safety
Update Report by MAH
4.4 Chapter 4: Quality Management System at MAH site
4.5 Chapter 5: Audits & Inspections of Pharmacovigilance
System at MAH site
4.6 Chapter 6: Submission of Risk Management Plan
5. PROCEDURES FOR IMPLEMENTING AN EFFECTIVE
PHARMACOVIGILANCE SYSTEM
6. DEFINITIONS
7. REFERENCES
8. APPENDICES
ABBREVIATIONS:
AE Adverse Event
ADR Adverse Drug Reaction
AEFI Adverse Event Following Immunization
CDL Central Drugs Laboratory
CDSCO Central Drugs Standard Control Organization
CIOMS Council for International Organizations of Medical
Sciences
CRF Case Report Form
DCG(I) Drugs Controller General (India)
DIO District Immunization Officer
DOV Date of Vaccination
EPI Expanded Programme on Immunization
FCIF Final Case Investigation Form
GCP Good Clinical Practices
GMP Good Manufacturing Practices
GLP Good Laboratory Practices
ICSR Individual Case Safety Reports
IPC Indian Pharmacopoeia Commission
ITSU Immunization Technical Supportive Unit
MAH Marketing Authorization Holder
NCC National Coordinating Centre
NRA National Regulatory Authority
PBRER Periodic Benefit Risk Evaluation Report
PCIF Preliminary Case Investigation Form
PSUR Periodic Safety Update Report
PhFI Public Health Foundation of India
Pv Pharmacovigilance
PVMF Pharmacovigilance System Master File
PVOIC Pharmacovigilance Officer-In charge
PvPI Pharmacovigilance Programme of India
SEPIO State EPI Officer
UIP Universal Immunization Programme
1. INTRODUCTION:

Over the last three decades, India has become a vibrant hub of vaccine
manufacturing units with state-of-the-art facilities at par with the International
manufacturing standards. India can now boast of producing safe, effective and
affordable vaccine products which safeguard millions of children at domestic and
International level. This responsibility warrants additional efforts of constant
vigilance of vaccine products moving in the market.
The pre-market mandatory clinical trial has little scope to assess the
inherent risks associated with the nature of antigens /excipients formulation or
that cropping up due to specific manufacturing process and raw materials used.
Risk assessment during product development should be conducted in a
thorough and rigorous manner; however, it is impossible to identify all safety
concerns during clinical trials. Once a product is marketed, there is generally a
large increase in the number of patients exposed, including those with co-morbid
conditions and those being treated with concomitant medical products.
Therefore, post marketing surveillance which may be passive or stimulating have
major role to assess the actual safety aspects of the vaccine product. Safety data
collection and risk assessment based on observational data are critical for
evaluating and characterizing a product’s risk profile and for making informed
decisions on risk minimization.
This guidance document focuses on pharmacovigilance activities on a
vaccine product circulating in the market throughout its life cycle post licensure
period. This guidance uses the term pharmacovigilance to mean all scientific and
data gathering activities relating to the detection, assessment, understanding and
prevention of adverse events. Pharmacovigilance principally involves the
identification and evaluation of safety signals. In this guidance document, safety
signal refers to a concern about a new risk or a new aspect of an already known
risk or excess of adverse events compared to what would be expected to be
associated with a product’s use.
Signals can be identified from post marketing data and other sources, such
as preclinical data and events associated with other products in the same
pharmacological class. It is possible that even a single well documented case
report can be viewed as a signal, particularly if the report describes a positive re-
challenge and de-challenge or if the event is extremely rare in the absence of
drug use. Signals generally indicate the need for further investigation, which may
or may not lead to the conclusion that the product caused the event. After a
signal is identified, it should be further assessed to determine whether it
represents a potential safety risk and whether other action should be taken.

1.1 OBJECTIVE:
This document intends to be an aid for the Marketing Authorization Holder and
for other allied stakeholders who play active role in launching, distribution and
bringing the vaccine products to end users, to implement an effective PV System
for ensuring patient safety. The main focus of this guideline is to identify the risks,
formulate the risk profile of a vaccine and its administration programme, design of
appropriate pharmacovigilance plan to mitigate such risks and to explore the
missing critical information which did not emerge during pre- market phase-I/II/III
trials and therefore safety profile had not been established.

1.2 BACKGROUND
The decision to approve a vaccine is based on its having a satisfactory balance
of benefits and risks within the conditions specified in the product labeling. This
decision is based on the information available at the time of approval. The
knowledge related to the safety profile of the vaccine can change over time
through expanded use in terms of subject characteristics and the number of
patients exposed. In particular, during the early post marketing period, the
product might be used in settings different from clinical trials and a much larger
population might be exposed in a relatively short timeframe.
Once a vaccine is marketed, new information might emerge, which may have an
impact on the risks/benefits ratio of the product. Evaluation of this information
should be a continuous process in consultation with regulatory authorities.
Detailed evaluation of the information generated through pharmacovigilance
activities is important for all vaccine products to ensure their safe use. The risk-
benefit balance can be improved by reducing risks to patients through effective
pharmacovigilance system that can enable information feedback to the users of
medicines in a timely manner.
1.3 RATIONALE
This document rationally places guidance that all Marketing Authorization Holder
(MAH) of Human vaccines (importers and manufacturers) should establish and
implement an appropriate effective pharmacovigilance system with adequate
number of qualified, trained, experienced manpower to collect, collate and
analyze all AEFI (minor, severe and serious) as per V Schedule of New Drugs
and Clinical Trial Rules, 2019. This Pharmacovigilance system within the
company should conduct decisive causality assessment (Refer AEFI Surveillance
and Response – Operational Guidelines 2024) of the collated AEFI cases, after
due investigation and prepare case closure report. In a comprehensive PSUR, all
such information shall have to be placed as per the norms stipulated in Fifth
Schedule of New Drugs and Clinical Trial Rules, 2019 and submitted to the
Licensing Authority i.e. DCG (I) in CDSCO (HQ) within the stipulated time period.
After review of the submitted PSUR, CDSCO shall convene the meeting of PSUR
committee within a reasonable time period and give opportunities to the
concerned Marketing Authorization Holder (MAH) to present their case and
PSUR in general. Based on the recommendation of the PSUR committee the
vaccine Licensing Authority i.e. DCG(I) will take appropriate regulatory action in
accordance with Drugs & Cosmetics Act and Rules made thereunder, so as to
monitor the safety and effectiveness of human vaccine in the market so as to
safeguard the public health. MAHs must have a Pharmacovigilance system in
place that enhances the overall quality of the receipt, processing and reporting of
AE/ AEFI while ensuring that accurate and complete information with respect to
patient safety is provided to CDSCO.

1.4 SCOPE
This document has been framed in compliance with the provisions made under
Fifth Schedule of New Drugs and Clinical Trial Rules 2019, Schedule M of Drugs
& Cosmetics Act 1940 and Good Clinical Practices (GCP) Guidelines of India,
AEFI Surveillance and response operational Guidelines to provide guidance to
Marketing Authorization Holders (Importers and Manufacturers of Human
Vaccine) of India to establish their Pharmacovigilance System for collection,
detection, assessment, monitoring, and prevention all AE/ AEFI cases pertaining
to vaccine products across the domestic and export market, after due
investigation & causality assessment at their end and collate all such cases in
PSUR for periodic reporting to the Licensing Authority i.e. DCG(I) in CDSCO.
This document does not include all other new Drugs and animal vaccine moving
in the market.
This document is designed to facilitate compliance by the industry and to
enhance consistency in the implementation of the regulatory requirements
regarding Good Pharmacovigilance Practices.
This document provides adequate information in a systematic manner for
reporting serious adverse event or adverse event following immunization when
the product is in the market and would enable the systematic sharing of
information between CDSCO, Pharmacovigilance Programme of India (PvPI) and
the Expanded Programme on Immunization (EPI), Ministry of Health and Family
Welfare.
The roles and responsibilities of the CDSCO are as per the Drugs and Cosmetics
Act, 1940 and Rules made thereunder.
In case, the Pharmacovigilance Programme of India receives AEFI
information from any reporting source, the same shall be shared with the AEFI
Secretariat under the Immunization Division (MoHFW). The AEFI Secretariat will
process the AEFI cases for causality assessment and signal detection and
management and present the data to the National AEFI Committee (for approval
of results of causality assessment) and the Signal Review Panel (for signal
assessment) and further recommendations to CDSCO for regulatory actions. The
Licensing Authority may also advise the MAH to conduct Phase IV trial in case of
demonstration of product safety, efficacy and dose definitions. 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 product use. They may be
of any type but should have valid scientific objectives, for example,
epidemiological studies etc.
Similarly, the Immunization Division under Ministry of Health and Family
Welfare collects information on adverse event related to Universal Immunization
Program (UIP) vaccines on a regular basis through the AEFI surveillance system.
Information on serious adverse events is collected in the Case Reporting Form
(CRF) and details of the investigation of the reported event are collected in the
Case Investigation Form (CIF) by the DIO with all supporting documents such
hospital records, post mortem reports, etc. These are then shared with the SIO
who presents it to the state AEFI committee which assigns the causality.
 The AEFI Secretariat will share line-listing in excel (.xls) format with CDSCO
for deaths and clusters on a weekly basis and all serious and severe cases on a
monthly basis. Limited line list will be in excel format and will have state, age,
sex, date of vaccination (DOV), antigens administered, manufacturing details
(name, batch number and expiry date) and reason for reporting. CDSCO will
share linelist details for vaccines relevant to the particular manufacturer with
instructions that these are being shared with the MAH for internal review and not
for investigations in the field.
In addition to the state AEFI committee, causality assessments are also
done at the national level by AEFI Secretariat. The causality assessment results
in the form of a linelist are shared with the CDSCO for further analysis and
necessary regulatory actions. In tandem is the process of signal management for
vaccines being done at the AEFI Secretariat. A Signal Review Panel for vaccines
assesses and reviews the detailed signal assessments bimonthly and the
recommendations are then forwarded through the proper channel to CDSCO for
further dissemination to MAHs. A detailed process is outlined in further sections.

2. ROLES AND RESPONSIBILITIES OF AUTHORITIES:

2.1 CENTRAL DRUGS STANDARD CONTROL ORGANIZATION:
The Central Drugs Standard Control Organization (CDSCO) under DGHS in
Ministry of Health and family welfare (Govt. of India) acts as the nodal agency
(NRA) for regulation of “Drugs” as defined in section 3(b) (i-iv) in Drugs &
Cosmetics Act 1940 to ensure the Quality, safety, efficacy of all human vaccines
(defined as Drugs). CDSCO is empowered under Drugs & Cosmetics Act 1940
to grant permission, licenses for marketing within the country. CDSCO is also
mandated by Ministry of Health and Family Welfare, Govt. of India, to conduct a
nation-wide pharmacovigilance programme in coordination with the Indian
Pharmacopoeia Commission (IPC) located at Ghaziabad which is the National
Coordinating Centre (NCC) of many ADR monitoring centers established in
various medical colleges across the country.
The Roles and Responsibilities of CDSCO are as per the Drugs and Cosmetics
Act and Rules. CDSCO is responsible to take appropriate regulatory decision
and actions on the basis of recommendations of NCC-PvPI at IPC Ghaziabad
and AEFI programme of Immunization division of Ministry of Health and Family
Welfare, New Delhi.
CDSCO is also responsible to take regulatory decisions on the basis of
recommendations shared by Signal Review Panel of Vaccines where-in a
detailed analysis of the PMS, PSUR, AEFI data is done by expert committee.
CDSCO (HQ) then reviews the recommendations and shares them with MAHs
for necessary actions.
The regulatory recommendations are disseminated to MAHs through proper
channel by CDSCO. As a part of the condition of the Marketing Authorization,
the MAH is also required to submit PMS/PSUR after licensure of the product.
The PSURs is to be submitted every six months for first two years of the
approval and annually for subsequent years, till the product is categorized as
‘New Drug’. The Licensing Authority may extend the total duration of submission
of PSURs if it is considered necessary in the interest of public health. PSUR
furnished by the Importers/Manufacturers of vaccines holding marketing
authorization is deliberated in PSUR Expert Committee Meetings conducted by
CDSCO. The PSUR data is also considered while reviewing the UIP vaccine
safety database for signals by the AEFI Secretariat.
The Licensing Authority may also advise the MAH to conduct Phase IV trials
which go beyond the prior demonstration of product safety, efficacy and dose
definitions. These trials may not be considered necessary at the time of new
vaccine approval but may be required by the Licensing Authority for optimizing
the vaccine’s use. They may be of any type but should have valid scientific
objectives.

2.2 PHARMACOVIGILANCE PROGRAMME OF INDIA (PVPI) -

INDIAN PHARMACOPOEIA COMMISSION (IPC):
The Central Drugs Standard Control Organization (CDSCO), Directorate General
of Health Services under the aegis of Ministry of Health & Family Welfare,
Government of India has initiated a nation-wide Pharmacovigilance programme
for protecting the health of the patients by assuring drug safety. Later the
MoHFW recasted these programmes on 15th April 2011 vide an order number
X.11035/7/2011-DFQC shifting the National Coordination Centre from AIIMS,
New Delhi to IPC Ghaziabad. The programme is coordinated by the Indian
Pharmacopoeia Commission, Ghaziabad as the National Coordination Centre
(NCC). The center operates under the supervision of a Steering Committee.
Indian Pharmacopeia Commission, Ghaziabad is an autonomous organization
under the MoHFW, having mandate for preparation of standards for all drugs
including bulk antigens and vaccine products, publication of Indian
Pharmacopoeia (IP) with monographs for all drugs including vaccines,
publication of National Formulary of India (NFI), preservation of reference
standards for Drugs, however, the vaccine reference standards on behalf of IPC
are maintained by CDL (Kasauli). IPC is also the National Coordination Centre
for all ADR Monitoring Centers across the country to collect, collate AE/ADRs for
all drugs, including vaccines.

Major roles and responsibilities of PvPI at IPC includes development and

implementation of pharmacovigilance system in India, enrolment of all
hospitals/medical colleges in the program covering north, south, east and west of
India, encouraging healthcare professionals in reporting of adverse reaction to
drugs, vaccines, medical devices and biological products and collection of case
reports and data in the suspected adverse drug reaction reporting form.

The long-term goal of PvPI at IPC includes developing and implementing

electronic reporting system (e-reporting), to develop reporting culture amongst
healthcare professionals.

The adverse events following vaccinations, which are reported from the AMCs,
are shared with the AEFI Secretariat, for examination and after validation for
signal assessments. The AEFI Secretariat has established a Signal Review
Panel for vaccines which share the recommendations and updates to the
National AEFI Committee and CDSCO for regulatory actions.

Role of PvPI at IPC:

• To monitor Adverse Drug Reactions (ADRs) in Indian population.
• To create awareness amongst health care professionals about the
importance of ADR reporting in India.
• To monitor benefit-risk profile of medicines and vaccines
• Generate independent, evidence based recommendations on the
safety of medicines.
• Support the CDSCO for formulating safety related regulatory
decisions for medicine.
• Communicate findings with all key stakeholders.
 • To share the Adverse reaction reported for UIP vaccines to AEFI
Secretariat for data triangulation, analysis and discussion in the
Signal Review Panel of vaccines (MoHFW) for further action.

2.3 AEFI SECRETARIAT, IMMUNIZATION DIVISION OF MINISTRY OF HEALTH

AND FAMILY WELFARE:
Immunization is one of the most cost effective public health interventions resulting
in reduction of morbidity and mortality of children. Under the Universal
Immunization Programme (UIP), Govt. of India is providing vaccination to prevent
seven vaccine preventable diseases (VPDs) namely, Diphtheria, Pertussis,
Tetanus, Polio, Measles, Hepatitis B and Tuberculosis.

IMMUNIZATION SCHEDULE IN UNIVERSAL IMMUNIZATION PROGRAM:

Vaccine VPD Due Age Max age
BCG Tuberculosis At birth till one year of age
Hepatitis B - BirthHepatitis B within 24 hours
At birth
dose
OPV-0 Polio within the first 15
At birth days
At 6 weeks, 10 weeks &
till 5 years of age
OPV 1, 2 & 3 14 weeks
Pentavalent 1, 2 & Diphtheria, Pertussis ,
3** (Diphtheria+ Tetanus , Hepatitis B , At 6 weeks, 10 weeks & 1 year of age
Pertussis + Haemophilus 14 weeks**
Tetanus + Hepatitis Influenzae B
B + Hib)
Fractional IPV
Polio At 6 ,14 weeks and 9 1 year of age
(Inactivated Polio
month
Vaccine)
Rotavirus
Rotavirus At 6 weeks,10 weeks &
1 year of age
14 weeks

Pneumococcal Pneumococcal At 6 weeks & 14 weeks 1 year of age

Conjugate Vaccine Disease
At 9 completed months
(PCV)
- booster
Measles / Rubella Measles , Rubella At 9 completed months- 5 years of age
1st dose ## 12 months.

Japanese Japanese At 9 months-12 15 years of age

Encephalitis – 1 @ Encephalitis months@
(Where applicable)

Vitamin A (1st dose) 5 years of age

At 9 months ( 1 lakh IU)

DPT Booster-1 16-24 months 7 years of age

Diphtheria, Pertussis ,
Tetanus

Measles / Rubella 16-24 months

Measles , Rubella
2nd dose ## 5 years of age

16-24 months
OPV Booster Polio 5 Years
Japanese 16-24 months @
Japanese
Encephalitis
Encephalitis – 2 @
till 15 years of age
(Where applicable)

At 16 months. Then, one

Vitamin A $ (2nd to
dose every 6 months. up to the age of 5
9th dose)
years

7 Years of age
DPT Booster-2 Diphtheria, Pertussis , 5-6 years
Tetanus
10 years &
Td Tetanus 16 Years
16 years
Td-1 Tetanus Early in pregnancy Give as early as
possible in
pregnancy
Td-2* Tetanus 4 weeks after TT-1*

Td- Booster Tetanus If received 2 TT doses in

a pregnancy within the
last 3 years*
IMMUNIZATION DIVISION BRIEF FROM MoHFW -
In 2012, AEFI Secretariat was established with due approval of MoHFW with
mandate of collection, collation, line listing, reporting, sharing with partner
organizations (e.g. CDSCO), investigation, causality analysis and signal
assessment of AEFIs.
Adverse events following use of vaccine, whether in the Universal
Immunization Programme (UIP) or private sector, pediatric vaccines or
vaccines used in adults or for international travel, etc. should be reported to
the AEFI surveillance system and CDSCO. All cases involving serious
unexpected adverse reactions must be reported to the licensing authority
within fifteen days of initial receipt of the information by the applicant (MAH).
AEFI Secretariat manages AEFI data (adverse events reported as
hospitalizations, deaths, etc. following vaccination), follows up with states for
investigations, and facilitates causality assessments of cases at national
level. The Secretariat provides strategic vision to improve AEFI surveillance
and vaccine safety under overall guidance of the National AEFI Committee
and National AEFI Technical Collaborating Centre at Lady Hardinge Medical
College (LHMC), New Delhi. Signal management is another core function of
the secretariat and regular bimonthly meetings of the signal review panel are
conducted to review the signals. It supports MoHFW in taking policy decisions
related to AEFI surveillance and vaccine safety. The national AEFI
surveillance guidelines are developed and updated by the AEFI Secretariat
with support of WHO-India Country Office.
Adverse events after immunization can be serious or non-serious. Serious
AEFIs such as death, hospitalization, disability, and cluster or community
concern need to be reported immediately through CRF and investigated
timely in the CIF. Serious AEFIs are reported on SAFE-VAC directly or
through UWIN. Non-Serious AEFIs are reported in UWIN. Numbers of minor
and serious AEFI are also reported every month through Health Management
Information System (HMIS). For COVID-19 vaccines also AEFIs have been
collected routinely from Co-WIN Chapter. A self-reporting Chapter also is
functional for reporting AEFIs by the vaccine recipients.
Serious AEFIs are investigated by Drug inspectors deputed by the concerned
State Drug Control Department and the concerned CDSCO (zonal) office as
members of the district AEFI committee which investigates AEFIs with the
DIO. The drug inspectors are responsible for collecting samples of implicated
vaccine vials and other concomitant drugs, diluents, etc. after a decision has
been made to do so by the district AEFI committee in consultation with the
State Immunization Officer. The collected vaccine samples are sent to CDL,
Kasauli for testing and analysis.
The state AEFI committee conducts a causality assessment to the report and
sends to the National level within pre- defined timelines. These are then
collated and are put up to the National AEFI Committee for review and
assessment. The role of the AEFI Committees at different administrative
levels is to strengthen AEFI reporting, conduct thorough investigation, reduce
program error and timely detection of signals.
The reporting can occur from any level of government or private sector
including the private practitioner in the CRF form. Refer to the National AEFI
Surveillance and Response Operational Guidelines of Ministry of Health &
Family Welfare, Govt. of India for details.

Each serious event (s) should be followed up to determine the cause for its
occurrence (causality assessment). The causality assessment is done by the
state AEFI committee/ National AEFI committee depending on the urgency of
the situation.
The AEFI Secretariat shares a linelist in excel format with CDSCO for deaths
and clusters on a weekly basis and all serious and severe cases on a monthly
basis. linelist will be in excel format and will have state, age, sex, DOV,
antigens administered, manufacturing details (name, batch number and expiry
date) and reason for reporting. Based on the causality assessment report
detailed inspection related to GMP, product etc. and further regulatory action
are initiated by CDSCO as and whenever required.
Also as mentioned in the AEFI operational guidelines, in case of an urgent
situation, the state AEFI committee along with the state drug control
authorities should immediately inform AEFI Secretariat, Immunization
Division to take the following steps together with the CDSCO.
 Report the findings of the investigation of the state government & Govt.
of India.
 The details of the implicated vaccine or product should be submitted to
Govt. of India immediately so that regulatory decision could be
considered by CDSCO in accordance with Drug and Cosmetics Act and
rules made thereunder.
 CDSCO along with CDL, Kasauli & Immunization division will co-ordinate
a re-evaluation of the
 Quality of the vaccine & communicate to the manufacturer (by CDSCO),
if necessary.

SIGNAL DETECTION AND MANAGEMENT FOR VACCINES

A structured approach for spontaneous reporting (active and passive
surveillance) of AEFI is an important element of vaccine safety monitoring.
The evaluation of safety signals is part of vaccine safety vigilance and is
essential to ensure that regulatory authorities and immunization programme
have the most up-to-date information on benefits and risks. The benefit-risk
balance of many vaccines is dynamic and may change over time, or may
appear to change over time, and this may impact pharmacovigilance activities.
Council for International Organizations of Medical Sciences 2010 defines
Signal as “Information that arises from one or multiple sources (including
observations or experiments), which suggests a new, potentially causal
association, or a new aspect of a known association between an intervention
[e.g., administration of a vaccine] and an event or set of related events, either
adverse or beneficial, that is judged to be of sufficient likelihood to justify
verification action.” The rapid detection of vaccine safety signals of global
importance is complemented by a scientifically sound assessment of the
signals through signal management process performed to determine whether
there are new risks associated with vaccine or whether known risks have
changed, and includes any related recommendations, decisions,
communications and tracking. A database is created of all the adverse events
(AEs) reported and this database is assessed for trend analysis and safety
signals regularly. A trend analysis report on evaluation of AEFIs (minor,
serious and severe, causality assessed cases and global updates is prepared
to monitor the trends for different vaccines over a period of time in different
age groups on fortnightly basis.
The signal management process includes the following steps: signal
detection, validation, confirmation, analysis, prioritization, evaluation, and
recommended actions, tracking of follow-up activities, communication, and
risk minimization. AEFI database considers proportional reporting ratio (PRR),
chi-square (χ2) statistics, Information Component (IC) and IC025; followed by
detailed qualitative assessment of the vaccine-event combinations. A Signal
Review Panel which is an independent body at the national level consisting of
experienced professionals in the field of clinical pharmacology, medicine,
infectious diseases, pediatrics, dermatology, neurology, cardiology, regulatory
authority members (CDSCO), (including a Chairperson and a Member
Secretary) assesses information on potential signals of possible importance
for public health, drug regulation, and science from the data base for both
regular UIP and COVID-19 vaccines on a bi-monthly basis. The Panel reports
its findings and recommendation to the National AEFI Committee, and the
Ministry of Health and Family Welfare (MOHFW). The regulatory
recommendations are then forwarded through the proper channel to CDSCO
for further dissemination to MAHs.
Signal Management Process for Vaccines: At National Level

MOHFW: Ministry of Health and Family Welfare (Immunization Division); AEFI

Sect, ITSU: Adverse Events Following Immunization Secretariat,
Immunization Technical Support Unit, Immunization Division, MOHFW; NAC:
National AEFI Committee; CDSCO: Central Drugs Standard Control
Organization (DCGI office); NTAGI: National Technical Advisory Group on
Immunization; PI: Prescribing Information; SmPC: Summary of Product
Characteristics; RMP: Risk Management Plan; PSUR: Periodic Safety Update
Report

The Signal review Panel and National AEFI Committee may recommend any
or combination of the following:
1) No need for further evaluation or action at this point of time, other than
routine pharmacovigilance.
2) Seek additional information such as:
a) Manufacturer will submit additional data regarding the signal
available with it;
b) Manufacturer will report specifically regarding this signal at the
time of submission of regular PSUR or submit an ad-hoc PSUR to
CDSCO;
c) Manufacturer will conduct a post-authorization safety study and
submit its final results to CDSCO
3) Ask manufacturer to
a) Update product information, PSURs and/or risk management plan
(RMP) with specific recommended changes.
b) Implement additional risk minimization measures such as the
preparation of educational materials, etc.
The regulatory recommendations from the signal review panel are shared with
CDSCO to be shared with Marketing Authorization Holders (MAHs) for further
action which includes inclusion of recommended adverse events in the
Summary of Product Characteristics for the said vaccine. Considerations of
risk-benefit with regards to the impact on patients’ or public health are kept in
mind throughout the decision-making process.

Strengthening Safety Surveillance for New Vaccine Introduction or

pandemic preparedness -
New vaccines may be introduced by following the due regulatory and
programmatic processes (in the case of routine vaccines) or through
emergency use authorization (as for COVID-19 vaccinations). Preparations
are required for both situations to enable improved monitoring of vaccine
safety. One of the major challenges faced when a new vaccine is introduced
is the non-availability of a complete safety profile of the vaccine. Safety data
available at the time of introduction is usually limited to clinical trial data. The
regulators determine that the potential benefits outweigh the potential risks of
the vaccine and a final analysis will include all safety data accumulated from
phase 1, 2 and 3 studies. After approval of a vaccine, stringent follow-up is
essential to monitor vaccine safety in routine use through phase IV (Post
Marketing Trial), Post Marketing Surveillance or observational or non-
interventional study for active surveillance, Post Marketing Surveillance
including assessment of Adverse Events Following Immunization (AEFI) and
Adverse Events of Special Interest (AESI).
COVID-19 vaccines were new vaccines, were granted Emergency Use
Authorization /approval for restricted use in emergency situations due to the
threat of the pandemic. These vaccines underwent modified but rigorous
processes of safety assessment prior to their approval. In order to further
ensure monitoring of safety and efficacy, the drug regulator directed
manufacturers to put in place systems for post-marketing assessment of
vaccines in accordance with the general guidelines specified in the Fifth
Schedule of the New Drugs and Clinical Trials Rules, 2019. Well-functioning
regular passive AEFI surveillance systems can identify rare, serious adverse
events following the introduction of new vaccines. Passive Adverse Events
Following Immunization (AEFI) surveillance system captures minor, severe,
and serious adverse events and can provide trends and potential signals
requiring further studies and assessments. Many new vaccines/COVID-19
vaccines are built using novel platforms or platforms rarely used on a mass
scale. Based on the experiences from existing/past vaccines or vaccine
platforms on which vaccines are developed, a list of potential AESIs are
identified to prioritize enhanced vaccine safety surveillance. For COVID-19
vaccines in India, the Immunization Technical Support Unit (ITSU) under the
guidance of a Technical Advisory Group (TAG) has undertaken a multi-centric
AESI sentinel surveillance study involving 16 medical colleges across India to
understand the risk of occurrence of select AESIs following COVID-19
vaccines. From the list of 23 AESIs shortlisted by SPEAC/CEPI, ten AESIs
were studied. From a public health perspective, timely and effective
communication of signal information to relevant stakeholders is the linchpin
upon which effective pharmacovigilance practice rests. Understanding the
balance between the benefits and risks of vaccination is essential to ensure
informed and adequate public health decision-making.

2.4 PHARMACOVIGILANCE DIVISION (HUMAN VACCINE) AT CDSCO

Pharmacovigilance Division monitors all post licensure activities of vaccine
related to AEFI surveillance, PSUR review, Pv Inspection, Audit and any other
data on vaccine safety as and whenever required as per Drugs and
Cosmetics Act 1940 and Rules made thereunder.
Pharmacovigilance Division shall be responsible for (i) the coordination with
NCC-PvPI (IPC-Ghaziabad) and AEFI Secretariat, Immunization Division,
Ministry of Health and Family Welfare for the various AEFI reported in the field
(ii) to attend various meeting with the stake holders for coordination purpose
or whenever situation arises (iii) collecting all the adverse events/ SAE
reported by the immunization division and IPC, which shall be reviewed by the
expert committee constituted for this purpose for taking further regulatory
action.
PMS/PSUR being conditions for Market Authorization and Licensing and
therefore to ensure the regulatory conformance and proper design of post-
marketing studies, this division shall work with coordination of the licensing
division. This division is responsible for collecting, compiling and collating the
data received from the MAH as per the requirements of Fifth Schedule of New
Drugs and Clinical Trial Rules 2019. The compiled PMS/ PSUR data will then
be reviewed by the advisory committee constituted by the Drugs Controller
General of India. Based on the analysis of the advisory expert committee,
regulatory decision will be taken by CDSCO.
Further, 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 industry. The regulatory decision shall be taken in
accordance with Drug & Cosmetics Act and rules made thereunder. If
marketing of the new drug is delayed by the applicant after obtaining approval
to market, such data will have to be provided on a deferred basis beginning
from the time the new drug is marketed.

Sharing of AEFI with Marketing Authorization Holder:

The AEFI Secretariat will share limited linelist in excel format with CDSCO for
deaths and clusters on a weekly basis and all serious and severe cases on a
monthly basis. Limited linelist will be in excel format and will have state, age,
sex, DOV, antigens administered, manufacturing details (name, batch number
and expiry date) and reason for reporting. CDSCO will share linelist details for
vaccines relevant to the particular manufacturer with instructions that these
are being shared with the MAH for internal review and assessment.

3. PHARMACOVIGILANCE PLAN

The MAH will develop a comprehensive pharmacovigilance plan as outlined

below.

3.1 PHARMACOVIGILANCE METHODS

The best method to address a specific situation can vary depending on the
product, the indication, the population being treated and the issue to be
addressed. The method chosen can also depend on whether an identified
risk, potential risk or missing information is the issue and whether signal
detection, evaluation or safety demonstration is the main objective of further
study. When choosing a method to address a safety concern, the MAH should
employ the most appropriate design. Following are the key methods used in
pharmacovigilance.

3.2 INDIVIDUAL CASE SAFETY REPORT:

After obtaining either a manufacturing license and/or Import registration and

/or import license from the office of DCG (I) at CDSCO (HQ), all MAHs shall
place the vaccine products in the market and simultaneously initiate
collection, collation and monitoring of all serious & severe and minor AEFI
cases across the country by choosing an appropriate method of vigilance
activities as follows:

A) Passive Surveillance - Spontaneous Reports

A spontaneous report is an unsolicited communication by healthcare

professionals or consumers to a MAH, regulatory authority that describes one
or more adverse drug reactions in a patient who was given one or more
biological products and that does not derive from a study or any organized
data collection scheme.

Spontaneous reports play a major role in the identification of safety signals

once a drug is marketed. In many instances, a MAH can be alerted to rare
adverse events that were not detected in earlier clinical trials or other pre-
marketing studies. Spontaneous reports can also provide important
information on at-risk groups, risk factors, and clinical features of known
serious adverse drug reactions. Caution should be exercised in evaluating
spontaneous reports, especially when comparing drugs. The data
accompanying spontaneous reports are often incomplete, and the rate at
which cases are reported is dependent on many factors including the time
since launch, pharmacovigilance-related regulatory activity, media attention,
and the indication for use of the drug.

B) Stimulated Reporting
Several methods have been used to encourage and facilitate reporting by
health professionals in specific situations (e.g., in-hospital settings) for new
products or for limited time periods. Such methods include online reporting of
adverse events and systematic stimulation of reporting of adverse events
based on a pre-designed method. Although these methods have been shown
to improve reporting, they are not devoid of the limitations of passive
surveillance, especially selective reporting and incomplete information.
During the early post-marketing phase, MAH might actively provide health
professionals with safety information and at the same time encourage
cautious use of new products and the submission of spontaneous reports
when an adverse event is identified. A plan can be developed before the
product is launched (e.g., through site visits by MAH representatives, by
direct mailings or faxes, etc.). Stimulated adverse event reporting in the early
post-marketing phase can lead MAH to notify healthcare professionals of new
therapies and provide safety information early in use by the general
population. This should be regarded as a form of spontaneous event
reporting, and thus data obtained from stimulated reporting cannot be used to
generate accurate incidence rates, but reporting rates can be estimated.

C) Active Surveillance
Active surveillance, in contrast to passive surveillance, seeks to ascertain
completely the number of adverse events via a continuous pre-organized
process. An example of active surveillance is the follow-up of patients treated
with a particular drug through a risk management program. Patients who fill a
prescription for this drug may be asked to complete a brief survey form and
give permission for later contact In general; it is more feasible to get
comprehensive data on individual adverse event reports through an active
surveillance system than through a passive reporting system.
All the SAE during the period of PMS/PSUR shall be reported within 15
days to the Licensing Authority.

3.2.1 Periodic Safety Update Report:

PSUR are important pharmacovigilance documents. They provide an
opportunity for MAHs to review the safety profile of their products and ensure
that the SmPC and Package Leaflet within reasonable time frame. Periodic
Safety Update Reports (PSUR) present the world-wide safety experience of a
medicinal product/vaccines at defined times post-authorization, in order to
report all the relevant new safety 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; create
periodically the opportunity for an overall safety re-evaluation; indicate
whether changes should be made to product information in order to optimize
the use of the product. The MAH shall submit the PSUR report as per fifth
schedule of New Drugs and Clinical Trial Rules 2019. A detailed description
of PSURs is presented in chapter 4.3.
 4.1 CHAPTER 1: Pharmacovigilance System Master File
(PSMF)

Contents:

4.1.1 Introduction

4.1.2 Scope

4.1.3 Contents of the PSMF

4.1.3.1 Pharmacovigilance personnel and their

responsibilities

4.1.3.2 Pharmacovigilance organization structure

4.1.3.3 Sources of safety data

4.1.3.4 Pharmacovigilance processes

4.1.3.5 Pharmacovigilance system performance

4.1.4 Annexures to the PSMF

Pharmacovigilance System Master File

4.1.1 Introduction
The Pharmacovigilance System Master File (PSMF) provides a description of
the pharmacovigilance system used by the MAH with respect to
pharmaceutical products marketed by them. The PSMF is not a part of the
marketing authorization (MA) dossier and is maintained independently by the
MA.

4.1.2 Scope

The scope of this chapter is to provide guidance to MAH to create and maintain
the PSMF at their site. This describes the different documents to be created,
updated, controlled, archived and traceable, whenever required.

4.1.3 Contents of the PVMF

The PSMF should contain all information related to MAH’s PV system

and cover the following sections:

4.1.3.1 Pharmacovigilance personnel and their responsibilities: -

A qualified and trained personnel should be authorized by the company

management as Pharmacovigilance Officer In-charge (PVOIC) with
responsibilities for dealing PV activities at MAH's organization. The PVOIC
should be a medical or pharmacy professional trained in the collection and
analysis of AE reports. The PVOIC shall be responsible for the following:
 Development of training Chapters and organizing training for staff of PV
department;
 Identification of PV activities and framing of SOPs, revision of SOPs;
 Establishment and maintenance of QMS of PV department;
 The PVOIC should reside in India and respond to queries of
regulatory authorities. The information related to the PVOIC
provided in the PSMF should include:
• Contact details (Name, address, phone, e-mail);
• Summary, curriculum vitae with the key information on the role of
the PVOIC;
• A description of the responsibilities stating that the PVOIC has
sufficient authority over the PV system in order to promote,
 maintain and improve compliance;
• Details of Person-in-charge to work in the absence of PVOIC;

4.1.3.2 Pharmacovigilance Organization Structure

4.1.3.2.1 Marketing Authorization Holder

The Pharmacovigilance system organogram at MAH site should be included in

the PSMF. The authorized signatory should be clearly indicated. The
description of PV system at MAH site should be provided in PSMF.

4.1.3.2.2 Contract Research Organization (CRO)

If, MAH assigns the responsibilities of PV activities of their pharmaceutical

products to any CRO, then the information of the company (ies) including their
allied PV departments involved and the relationship(s) between Contract
Research Organizations & operational units relevant to the fulfilment of PV
obligations should be provided. It should include:
 The PV organizational structure of the CRO's showing the organogram
of the PV department.;
 Name & address of the organization, where the PV functions are
undertaken such as collection of AEs, ICSRs processing, preparation &
submission of PSURs, signal detection, Risk Management Plan (RMP),
post-marketing surveillance and management of safety variations;
 Delegated activities (contracts and agreements as per Indian law);
 Service providing system (e.g., medical information, auditors, patient
support programme providers, study data management etc.);
 Commercial arrangements (distributors, licensing partners, co-marketing
etc.);
 Technical providers (hosting of computer systems and validation etc.)

4.1.3.3 Sources of safety data

The PVOIC will be responsible to collect data, reports, publications related to

safety of all pharmaceutical products marketed by the MAH. The main sources
for safety data will be as follows:
 Medical information inquiries;
 "Contact us" emails, website inquiry forms and helpline etc.;
 Pharmaceutical Product market complaints-Receipt, handling and
 disposal;
 MAH employees involved in PV activities;
 Spontaneous information from patient or their care givers and follow up
of information;
 Published literature;
 Spontaneous reporting by HCPs including pharmaceutical sales
representatives;
 Reports from internet, digital media or social media;
 Patient-support programmes;
 Reports from National Regulatory Authorities;
 Contract partners involved in PV activities;

4.1.3.4 Pharmacovigilance Processes

4.1.3.4.1 Description

A description and flow-diagram of the entire PV process, data handling, records

control and archives of PV performance and covering the following aspects
should be included in the PSMF:

 The procedures for ICSR collection, collation, processing, assessment,

reporting and follow-up; should clarify the activities;
 Compilation of all ICSRs and preparation & submission of PSURs of
new drugs in accordance with the New Drugs and Clinical Trials Rules,
2019 as amended from time to time;
 Review of ICSR, detection of signal (if any), Drug Safety Alerts, CAPA;
 Communication of Drug safety concerns to Consumers, HCPs and the
National Regulatory Authorities;
 SmPCs and PILs with history of updates and revisions.

4.1.3.4.2 SOPs should include the following:

 Description of the process, data handling and records of PV
performance;
 ICSR collection, collation, follow-up, assessment and reporting;
 Risk Minimization Plan for safety concerns identified;
 Causality Assessment of reported AE/AEFI;
 PSUR scheduling, preparation and submission;
 Quality issue, recall or withdrawal of pharmaceutical products;
  Training procedures, evaluations and documentations;
 Signal detection and evaluation process;
 Communication of safety concerns to consumers, HCPs and regulatory
authorities;
 Implementation of safety variations in PILs/SmPCs;
 Safety data exchange agreements, if any;
 Safety data archival and retrieval;
 PV audit & inspections;
 Routine PV Self-Inspection/Audit;
 Quality Control for PV activities;

4.1.3.4.3 Computerized systems and database

The location, functionality and operational responsibility for computerized

systems and databases for receiving, collating and reporting safety information
should be described in PVMF. Validation status of computer system
functionality with change control, if any; nature of testing; back-up procedures
should also be described. The MAH can have data collection in Excel
spreadsheets to record and track the data.

4.1.3.4.4 QMS in Pharmacovigilance

The QMS should be established in PV activities, which should include:
• Document and record control: The MAHs should retain the soft copy
back-up of all PV documents for indefinite time and hard copies for at least
10 years. The MAHs shall maintain a logbook for recording primary
information received for every Adverse Events reported.
• Trainings: A summary of trainings records and files should be
available at the PV site of MAH. Staff should be appropriately trained
for performing PV- related activities, including any individual, who
may receive safety reports.
• Auditing: The QA of the company should supervise/facilitate the
internal & external audits of PV system. The audit report must be
documented within the quality system; with a brief description of the
CAPA associated with the significant findings, the date it was
identified and the anticipated resolution date(s) with cross reference
to the audit report and the documented CAPA plan(s).
4.1.3.5 Pharmacovigilance System Performance

The key indicators for the performance of PV system e.g., number and
quality of ICSRs, CAPA needs to be identified and measured for annual
trend analysis.

The should contain evidence of the ongoing monitoring of the PV system

performance including compliance of the main PV output. The PSMF
PVMF should include a description of the monitoring methods applied
and contain as a minimum the following:
 An explanation of how the correct reporting of ICSRs is
assessed. In the annexure, figures/graphs should be
provided to show the timelines of submission;
 A description of any metrics used to monitor the quality of
submissions and performance of PV. This should include
information provided by the regulatory authority regarding
the quality of ICSR reporting, PSURs or other
submissions;
 An overview of the timelines of PSUR reporting;
 An overview of the methods used to ensure the timelines
of safety variation submissions compared to internal and
competent authority deadlines including the tracking of
required safety variations that have been identified but not
yet submitted;
 Wherever applicable, an overview of adherence to RMP
commitments, or other obligations or conditions of
marketing authorization(s) relevant to PV.

4.1.4 Annexures to the PSMF

 A list of biological products including the name of the
pharmaceutical product, active substance(s) and
excipients;
 A list of contract agreements covering delegated activities
including the pharmaceutical products;
 A list of tasks delegated by the PVOIC for PV;
 A list of all completed audits (regulatory as well as internal)
and a list of audit schedules
 4.2 CHAPTER-2: Collection, Collation, Processing &
Reporting of Individual Case Safety Reports

Contents:

4.2.1 Introduction
4.2.2 Structure & Processes
4.2.3 Literature monitoring
4.2.4 Follow-up of ICSR
4.2.5 Processing of ICSR
4.2.6 Reporting of ICSR
4.2.7 Coding of Adverse Event & Indication
4.2.8 Reporting time lines
4.2.9 Causality assessment
4.2.10 Special Population
4.2.1 Introduction

This section highlights the general principles for the Collection, Collation,
Processing & Reporting of Individual Case Safety Reports associated
with pharmaceutical products for human use.

4.2.2 Structure & Processes

4.2.2.1 Collection and Collation of ICSR

The MAHs will collect the Adverse Events of their marketed vaccine from
different sources. The AE data collection tool for ICSR reporting to
CDSCO by MAH is annexed in appendix D. The following
sources/methods required to be established by MAHs to strengthen
spontaneous reporting.

4.2.3 Medical inquiries

The MAHs should have a process in place to record all the medical
inquiries related to their vaccine and documents including follow-up
information or clarifications with a patient/consumer or HCPs. For
inquiries that relate to safety of the vaccine, MAHs should ensure that
there is a mechanism in place to transfer details of such cases to the PV
point of contact.

4.2.4 “Contact us”, e-mails and website inquiry forms

The MAH should consider the mechanism(s) by which incoming

information via "Contact us" on their MAH portal, through e mail
addresses and website inquiry forms is monitored to allow the
identification and transfer of PV data to the designated PV person in an
appropriate time frame to meet the regulatory requirement.

4.2.2.2 MAH’s employees

The employees of the MAH designated for the PV work, should be

trained timely on the type of the information received and data collected
from the various sources. These employees should be well versed in
dealing with the information i.e., how to report particular Adverse
Events? The data captured manually by the medical representative
during a discussion with HCP regarding an AE or other safety related
issue should be retained and he/she should be aware of reporting the
same to the PV personnel of the respected MAHs.

4.2.2.3 Contractual partners

There could be different types of contractual arrangements existing in

the pharmaceutical industry like loan licensing, contract manufacturing,
distribution etc. The responsibilities regarding PV activities among
partners should be clearly defined in a drug safety data exchange
agreement. Contractual partners are a potential source of ICSR and
mechanisms should be in place for the exchange of these ICSR in an
appropriate manner & timeframe to meet regulatory requirements.

4.2.2.4 Information on Adverse Events from the internet or digital

media

The MAHs should regularly screen relevant websites or digital media

(including newspapers) or social media under their management or
responsibility for potential reports of Adverse Events. The frequency of
the screening should allow for potential valid ICSR to be reported to the
competent authorities within the appropriate reporting timeframe based
on the date of the information was posted on the website/digital media.
MAHs may also consider utilizing their websites/portals to facilitate the
collection of Adverse Events.

4.2.2.5 Solicited reports

Solicited reports of suspected AE/AEFI are those derived from organized

data collection systems, which include clinical trials, non- interventional
studies, registries, post-approval named patient use programmes, other
patient support and disease management programmes, surveys of
patients or healthcare providers, compassionate use or name patient
use, or information gathering on efficacy or patient compliance. Reports
of suspected AE/AEFI obtained from any of these data collection systems
should not be considered spontaneous.

4.2.2.6 Miscellaneous sources for reporting

The MAH should have other methods like e-mail, fax, online submission,
mobile app, helpline, postal letters etc. to report Adverse Events. Patient
identity should be kept confidential.

4.2.3 Literature Monitoring

The scientific and medical literature is a significant source of information

for monitoring the safety and benefit-risk profile of pharmaceutical
products, particularly in relation to the detection of new safety signals or
emerging safety issues. MAHs should perform monthly literature review
of their pharmaceutical products by using electronic literature data base
(such as PubMed, Science Direct, and Scopus etc.). Any AE identified
by this process need to be processed as per spontaneous ICSR. The
MAHs are advised to submit vaccine ICSR to CDSCO along with the
complete literature reference including Digital Object Identifier (DOI) or
copy of full-length article, wherever feasible.

4.2.4 Follow-up of ICSR

When initial ICSR is received, the information on Adverse Event may be

incomplete. Thus, the ICSR should be followed up as necessary to
obtain the required information (Refer section 2.6.1, Essential data
element of ICSR) required for clinical evaluation of the ICSR.

For serious ICSRs, at least two follow-up attempts must be made and
documented. For non-serious ICSRs, at least one follow-up attempt
must be made and documented. While reporting to PvPI, the MAH
should clearly indicate that the reported ICSR is either initial or follow up.

4.2.5 Processing of ICSR

4.2.5.1 ICSR receipt
4.2.5.2 Date of receipt

The MAH should record the date of receipt for each Adverse Events; this
applies to both initial notification and any follow-up communication.

4.2.5.3 Validation of reports

All reports of Adverse Events should be validated by authorized

signatories of MAHs before reporting them to the NCC-PvPI, IPC &
National Regulatory Authority.

4.2.6 Reporting of ICSR

Only valid ICSR would qualify for reporting to National Regulatory

Authority. Each valid ICSR should have the following minimum criteria
for reporting: -
1. An identifiable patient (one or more identifier such as, patient
initial, age, gender, weight);
2. An Adverse Event
3. A suspected pharmaceutical product (along with manufacturer
details and batch number, including brand name if any);

An identifiable reporter (source); the fields to describe the above four

criteria are as follows: -

4.4.6.1 Identifiable patient should have the following

information:

 Patient Initials: Write first letters of name & surname e.g., Vipin
Sharma should be written as VS.
 Age or date of birth: Write either the date of birth (DD/MM/YYYY)
or age of the patient at the time of an Adverse Event occurred.
 Gender: Male/Female/Transgender
 Weight: In case of adult (in Kg) and in case of infant use value up
to two decimals.

Note: If any of this information is missing, the ICSR will still be

considered. Any one of the above can define the identifiable patient for
case processing.

4.4.6.2 An Adverse Event

 Date of onset of adverse event
 Date of stop of adverse event
 Describe adverse event: Provide the description of the reaction in
terms of nature, localization, etc.

4.4.6.3 A suspected pharmaceutical product

1. The details of suspected vaccine(s) such as vaccine name (brand

 or generic), Batch No/Lot No., expiry date, marketing authorization
holder/ manufacturer, dose, route, frequency, dates of therapy
started & stopped, and indication should be provided.

2. Action Taken with respect to suspected vaccine after adverse

event:

Mention the status of action taken at the time of Adverse Event

reporting as-

 Vaccination withdrawn –Was the suspected vaccine

discontinued?

 Dose reduced – Was the dose of suspected vaccine reduced

after the occurrence of Adverse Event?
 Dose increased – In certain situations; there may be lack of
therapeutic efficacy of a medication. They are not normally
reported. Medical products used in critical conditions or for life
threatening diseases, vaccines, contraceptives, etc. non
effectiveness is also regarded as an adverse event.
 Dose not changed – Was the suspected vaccine
continued?
 Unknown – Where information is not known?
 Not Applicable – Such as case of, one dose vaccination,

3. Re-challenge details: Mention the status on re-challenge as-

 'Yes'-If, the AEFI reappeared after re-introduction of suspected
vaccine.
 'No'- If, the AEFI did not reappear after re-introduction of suspected
vaccine.
 'Effect unknown'- When the above information is not available
 Dose - In some cases, when the suspect product is re-introduced, in
those cases the dose given to the patient must be specified.

4. Concomitant drugs: The details like dose, route, and frequency of

all concomitant drugs should be provided in the same manner as that of
suspected drugs including self-medication, Over the Counter medication,
herbal medications, etc. with therapy dates.
5. Relevant tests/ laboratory data/investigation: Mention
relevant laboratory tests /investigation data before & after Adverse
Events.

6.Other relevant history: The relevant medical history of patient

including pre-existing medical conditions (e.g., allergies, pregnancy,
smoking, alcohol use, hepatic/ renal dysfunction) and concurrent condition,
if any.

7. Seriousness of the reaction: If, any adverse drug reaction is serious

in nature, tick the appropriate reason for seriousness as-
 Death: If, the patient died, mention the cause and date of death.
 Life-threatening: If, the patient was at substantial risk of dying at
the time of Adverse Events.
 Hospitalization /prolongation of existing hospitalization: If,
Adverse Events caused hospitalization or increased the hospital
stay of the patient.
 Disability: If, Adverse Events resulted in a substantial disruption
of a person's ability to conduct normal life functions.
 Congenital anomaly: If, exposure of the drug prior to conception
or during pregnancy may have resulted in a birth defect.
 Other medically important condition: When the event does not fit
to above conditions, but the event may have put the patient at risk
and required medical or surgical intervention to prevent any one
of the above conditions.

8. Outcomes: Tick the outcome of the adverse event at the time of

reporting as-
 Recovered/resolved: If, the patient recovered/resolved from the
adverse event.
 Not recovered/not resolved: If, the patient did not
recover/resolve from the adverse event.
 Recovering/resolving: If, the patient is recovering/resolving from
the adverse event.
 Fatal: If, the patient died.
 Recovered/resolved with sequelae: If, the patient has
completely recovered from the adverse event (mention the date of
 recovery) or recovered with sequelae (e.g., scar).
 Unknown: If, the outcome is not known.

4.4.6.4 An identifiable reporter (source);

 Name & address: A reporter must mention his/her name, address

and contact details. The identity of the reporter will be maintained
confidential.
 Date of report: Mention the date on which he/she reported the
Adverse Events.
 Reporter qualification: Qualification of the reporter needs to be
mentioned.

4.2.7 Coding of Adverse Event

For the purpose of ICSR reporting (expedited and periodic) to
National Regulatory Authority, Marketing Authorization Holders are
required to code Adverse Events, Indication preferably using latest
version of MedDRA.

4.2.8 Reporting time lines

All Serious Adverse Events Following Immunization must be reported
by MAH within 15 calendar days of receipt of information from any
source, to National Regulatory Authority (NRA), i.e, CDSCO through
email - [email protected], [email protected], [email protected]
All Non-Serious Adverse Events must be reported by MAH within 30
calendar days of receipt of information from any source, to National
Regulatory Authority (NRA), i.e, CDSCO through email – [email protected],
[email protected]
Note: The adverse events due to lack of efficacy, medication error etc. must
also be reported to national regulatory authority.

4.2.9 Causality assessment

The MAHs should preferably follow WHO-UMC AEFI causality
assessment scale (as applicable) for establishing a causal
relationship between the suspected vaccine and Adverse Events by
trained healthcare professionals. For WHO-UMC AEFI causality
assessment scale, refer ANNEXURE-5.
4.2.10 Special population
4.2.10.1 Use of a biological product during pregnancy or
breastfeeding
Where during pregnancy, a woman has been exposed to any potential
teratogenic medication, the follow up should be done till the delivery or
child birth to assess the adverse outcome of maternal exposure

When an active substance (or one of its metabolites) has a long half-life,
this should be taken into account when assessing the possibility of
exposure of the embryo, if the pharmaceutical product was taken before
conception.

Reports of exposure to biological products during pregnancy should

contain as many detailed elements as possible in order to assess the
causal relationship between any reported Adverse Events and the
exposure to the suspected pharmaceutical product.

Individual cases with an adverse outcome associated with a

pharmaceutical product following exposure during pregnancy are
classified as serious reports and should be reported:
 Reports of congenital anomalies or developmental delay in foetus
or child;
 Reports of fetal death and spontaneous abortion;
 Reports of serious suspected adverse reactions in the neonate.

However, in certain circumstances, reports of pregnancy exposure with

no suspected reactions may necessitate reporting. This may be a
condition of the marketing authorization or stipulated in the risk
management plan; for example, pregnancy exposure to pharmaceutical
products contraindicated in pregnancy or pharmaceutical products with a
special need for surveillance because of a high teratogenic potential
(e.g., thalidomide, isotretinoin). A signal of a possible teratogenic effect
(e.g., through a cluster of similar abnormal outcomes) should be notified
immediately to the regulatory authority/NCC-PvPI, IPC.

Note: AEs which occur in infants following exposure to a biological

product from breast milk should be reported.
 4.2.10.2 Use of a biological product in pediatric or elderly
population

The collection of safety information in pediatric or elderly population is

important. Reasonable attempts should therefore be made to obtain and
submit the age or age group of the patient when a case is reported by a
healthcare professional, or consumer in order to be able to identify
potential safety signals specific to a particular population.
 4.3 CHAPTER-3: Preparation and Submission of
Periodic Safety Update Report

Contents:

4.3.1. Introduction
4.3.2. Objective
4.3.3. General Principles
4.3.4. Structure & Content
4.3.1. Introduction

The Periodic Safety Update Report is a document for evaluation of the

benefit- risk profile of a pharmaceutical product submitted by the MAH at
defined time points as per Drugs and Cosmetics Act, 1940 and New
Drugs & Clinical Trial Rules, 2019 there under during the post-marketing
phase.

4.3.2. Objective

This chapter defines the recommended format, content and timelines of

PSUR submission in conformity with New Drugs and Clinical Trial Rules-
2019 of the Drugs and Cosmetics Act, 1940. PSURs are intended to be
submitted to national regulatory authority i.e. CDSCO in order to monitor
the safety and efficacy of pharmaceutical products marketed in India.

The main objective of a PSUR is to present a comprehensive, concise

and critical analysis of new or emerging information on the risks and
benefits of the pharmaceutical products in approved indications. The
PSUR, is therefore, a tool for post-marketing evaluation at defined time
points in the life cycle of a pharmaceutical product.

4.3.3. General Principles

4.3.3.1. Post marketing assessment of new drug –

(1) When a new drug is approved for marketing, assessment of safety

and efficacy of the drug are generally based on data from a limited
number of patients, many studied under the controlled conditions of
randomized trials. Often, high risk patients and patients with
concomitant illnesses that require use of other drugs are excluded
from clinical trials, and long-term treatment data are limited.
Moreover, patients in trials are closely monitored for evidence of
adverse events.
(2) In actual clinical practice, monitoring is less intensive, a broader
range of patients are treated (age, co-morbidities, drugs, genetic
abnormalities), and events too rare to occur in clinical trials may be
observed. Therefore, subsequent to approval of a new drug, the drug
 shall be closely monitored and post marketing assessment of its
benefit-risk profile shall be carried out.
(3) A person intending to import or manufacture any new drug for sale or
distribution shall have a pharmacovigilance system in place for
collecting, processing and forwarding the adverse drug reaction
report to the Central Licencing Authority emerging from the use of the
drug imported or manufactured or marketed by the applicant in the
country.
(4) The pharmacovigilance system shall be managed by qualified and
trained personnel and the officer in-charge of collection and
processing of data shall be a medical officer or a pharmacist trained
in collection and analysis of adverse drug reaction reports.
(5) Post marketing assessment of new drug may be carried out in
different ways as under: -
(A) Phase IV (Post marketing) trial- Phase IV (Post marketing)
trial include additional drug-drug interactions, dose-response or
safety studies and trials designed to support use under the
approved indications, e.g. mortality or morbidity studies etc. Such
trial will be conducted under an approved protocol with defined
scientific objectives, inclusion and exclusion criteria, safety and
efficacy assessment criteria etc. with the new drug under
approved conditions for use in approved patient population. In
such trial the ethical aspects for protection of rights, safety and
well-being of the trial subjects shall be followed as per the
regulatory provisions including that for compensation in case of
clinical trial related injury or death and good clinical practices
guidelines. In such study, the study drug may be provided to the
trial subject free of cost unless otherwise there is specific
concern or justification for not providing the drug free of cost, to
the satisfaction of the Central Licencing Authority and the
ethics committee.
(B) Post marketing surveillance study or observational or non-
interventional study for active surveillance- Such studies are
conducted with a new drug under approved conditions of its use
under a protocol approved by Central Licencing Authority with
 scientific objective. Inclusion or exclusion of subject are decided as
per the recommended use as per prescribing information or
approved package insert. In such studies the study drugs are the
part of treatment of patient in the wisdom of the prescriber included
in the protocol. The regulatory provisions and guidelines applicable
for clinical trial of a new drug are not applicable in such cases
as drugs are already approved for marketing.

(C) Post marketing surveillance through periodic safety update

reports- As part of post marketing surveillance of new drug the
applicant shall furnish periodic safety update reports (PSURs) in
accordance with the procedures as follows;

i. The applicant shall furnish periodic safety update reports

(PSURs) in order to-

a) report all relevant new information from appropriate sources;

b) relate the data to patient exposure;
c) summarize the market authorization status in different
countries and any significant variations related to safety;
and
d) Indicate whether changes shall be made to product information
in order to optimize the use of product.

ii. Ordinarily all dosage forms and formulations as well as

indications for new drugs should be covered in one periodic
safety update reports. Within the single periodic safety update
reports separate presentations of data for different dosage forms,
indications or separate population need to be given.

iii. All relevant clinical and non-clinical safety data should cover
only the period of the report (interval data). The periodic safety
update reports shall be submitted every six months for the first
two years after approval of the drug is granted to the applicant.
For subsequent two years – the periodic safety update reports
need to be submitted annually. Central Licencing Authority may
extend the total duration of submission of periodic safety
 update reports if it is considered necessary in the interest of
public health. Periodic safety update reports due for a period
must be submitted within thirty calendar days of the last day of
the reporting period. However, all cases involving serious
unexpected adverse reactions must be reported to the Licencing
Authority within fifteen 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. Vaccines and biologicals always
considered as new drugs, unless specified, otherwise, by the
Licensing Authority.

iv. New studies specifically planned or conducted to examine a

safety issue should be described in the periodic safety update
reports.

v. A PSUR should be structured as follows:

(1) Title Page: The title page of periodic safety update

reports should capture the name of the drug; reporting interval;
permitted indication of such drug; date of permission of the drug;
date of marketing of drug; licensee name and address.

(2) Introduction: This section of periodic safety update

reports should capture the reporting interval; drugs intended
use, mode of action, therapeutic class, dose, route of
administration, formulation and a brief description of the
approved indication and population.

(3) Current worldwide marketing authorization status:

This section of periodic safety update reports should capture
the brief narrative over view including details of countries where
the drug is currently approved along with date of first approval,
date of marketing and if product was withdrawn in any of the
countries with reasons thereof.

(4) Actions taken in reporting interval for safety

reasons: This section of periodic safety update reports should
 include a description of significant actions related to safety that
have been taken during the reporting interval, related to either
investigational uses or marketing experience by the licence holder,
sponsor of a clinical trial, regulatory authorities, data monitoring
committees, or ethics committees.

(5) Changes to reference safety information (RSI): This

section should include any significant changes in reference
safety information within the reporting interval. Such changes
include information relating to contraindications, warnings,
precautions, adverse events, and important findings from
ongoing and completed clinical trials and significant non-clinical
findings, if any.

Note: Even if there is no significant change in RSI (Prescribing

Information Leaflet & Company Core Data Sheet/Summary of
Product Characteristics), MAHs should submit recent dated
approved RSI as an Annexure.

(6) Estimated patient exposure: This section of periodic

safety update reports should provide the estimates of the size and
nature of the population exposed to the drug. Brief descriptions of
the methods used to estimate the subject or patient exposure
should be provided,

Cumulative subject exposure in clinical trial -

This section of the PSUR should include the following information in

tabular format as referred below:

 Cumulative numbers of subjects from ongoing and

completed clinical trials exposed to the investigational
pharmaceutical product, placebo, and/or active comparator(s)
since the date of first approval for conducting an interventional
clinical trial in any country (Refer Appendix-B, Table 01).
 More detailed cumulative subject exposure in clinical
trials should be presented, if available (e.g. sub- grouped by
age, sex, and racial/ethnic group) important differences among
trials in dose, routes of administration, or patient populations
 can be noted in the tables, if applicable, or separate tables can
be considered (Refer Appendix-B, Table No. 02 & 03);
 Important differences among trials in dose, routes of
administration, or patient populations can be noted in the
tables, if applicable, or separate tables can be considered.
 If, clinical trials have been or are being performed in special
population (e.g. pregnant women; patients with renal, hepatic, or
cardiac impairment; or patients with relevant genetic
polymorphisms), exposure data should be provided as
appropriate.
 When, there are substantial differences in the time of
exposure between subjects randomized to the investigational
pharmaceutical product or comparator(s), or disparities in length
of exposure between clinical trials, it can be useful to express
exposure in subject-time (subject-days, -months, or - years).
 New drug exposure in healthy volunteers might be less
relevant to the overall safety profile, depending on the type of
AE/AEFI, particularly, when subjects are exposed to a single
dose. Such data can be presented separately with an
explanation as appropriate.
 If, the SAEs from clinical trials are presented by
indication in the summary tabulations, the patient exposure
should also be presented by indication, where available.
 For individual trials of particular importance, demographic
characteristics should be provided separately, if available.

6.1 Cumulative and interval patient exposure from Marketing

Experience from India

Interval patient exposure refers as the patient exposure occurring

between two data lock points of PSUR. Separate estimations should be
provided for interval exposure and, when possible, cumulative exposure
(since the date of marketing authorization) from India. (Refer Appendix-
B, Table No. 04 and 05). The estimated number of patients exposed
should be provided, when possible, along with the method(s) used to
determine the same. If an estimate of the number of patients is not
 available, alternative estimated measures of exposure should be
presented along with the method(s) used to derive them, if available.
Examples of alternative measures of exposure include patient-days of
exposure and number of prescriptions. If applicable, data of special
population and vulnerable population should be identified and
submitted.

The data should be presented according to the following categories:

6.1.1 Post-approval exposure

An overall estimation of patient exposure should be provided. In

addition, the data should be presented by indication, sex, age, dose,
formulation, and region, wherever applicable. Depending upon the
product, other relevant variables, such as vaccinations, etc. should be
described. Whenever, there are patterns of reports indicating a safety
signal, exposure data within relevant subgroups should be presented,
if possible. Some industries may be running some programmes for
ensuring patient safety such as patient support programme, if in this
programme, any safety concern or serious AE/AEFI is observed, it
should also be communicated to CDSCO.

6.1.2 Post-approval use in special population

Where the approved drug has been used in special population, the
cumulative estimated patient exposure should be provided with method
of calculation.

Sources of such data may include non-interventional studies designed

to obtain this information, such as registries.

The following are the examples of special population:

• Pediatric population;
• Elderly population;
• Pregnant or lactating women;
• Patients with hepatic and/or renal impairment;
• Patients with other relevant co-morbidity;
• Patients with disease severity different from that studied in clinical
trials;
 • Sub-population carrying relevant genetic polymorphism(s);
• Patients of different racial and/or ethnic origin;
• Any other vulnerable population.

6.1.3 Other post-approval use

If the MAH becomes aware of any specific pattern of use of a

pharmaceutical product, which may be relevant for assessment of
product safety, a brief description should be provided. Examples of such
patterns of use are drug abuse (for example, some cough syrups, anti-
histamines, pregabalin, are used for sedation), misuse (such as use of
antibiotics in viral infection) and use beyond that recommended in the
reference product information (e.g., an anti-epileptic drug used for
neuropathic pain and/or prophylaxis of migraine headaches).

6.2 Cumulative and interval estimated patient exposure from

Marketing Experience from rest of the world.

The estimations should be provided separately for interval exposure

(since the data lock points of the previous PSUR) and, when possible,
cumulative exposure from the date of approval in the rest of the world.
(Refer Appendix-B, Table 06 and 07). The data should be presented as
mentioned in the section 6.2.

7. Presentation of individual case histories: This section of Periodic

Safety Update Reports should include the individual case information
available to a license holder and provide brief case narrative, medical
history, indication treated with suspect drug, causality assessment.
Provide following information:

7.1 Reference prescribing information

In this section, updated reference prescribing information of a new drug

should be provided by the MAH.

7.2 Individual cases received from India (Line listing of ICSRs)

The line listing of ICSRs should at least contain the following information:
age, gender, seriousness criteria, AE/AEFI start/stop date, therapy start/stop
date of suspected/concomitant drug, dose, route of administration,
indication of suspected/concomitant drug, relevant past medical history,
outcome & causality assessment in tabulated form.

7.3 Individual cases received from rest of the world

In this section Individual cases received from rest of the world should be
provided by the MAH.

7.4 Cumulative and interval summary tabulations of serious

adverse events from clinical investigations -

This section of the PSUR should provide a brief narration of the serious
adverse events as mentioned in the Appendix B background for the
Appendix (example of Format need to be provided) that provides a
cumulative summary tabulation of SAE reported in the MAHs, clinical
trials, from the first authorization to conduct a clinical trial in any country
worldwide to the data lock point of the current PSUR. The MAHs should
explain any omission of data (e.g., clinical trial data might not be
available for pharmaceutical products marketed for many years). The
tabulation(s) should be organized by SOC, for the new drug, as well as
for the comparator arm(s) (active comparators, placebo) used in the
clinical development programme. Data can be integrated across the
programme. Alternatively, when useful and feasible, tabulations of SAEs
can be presented by trial, indication, route of administration, or other
variables.
This section should not serve to provide analyses or conclusions based on
the SAEs.
• Appendix B, Table 8 provides cumulative tabulations of SAEs from
clinical trials.
• While tabulating SAEs from clinical trials only those criteria should
be used which are defined in NDCT Rules, 2019. This should not
include non- serious adverse events.
• The causality assessment, where has been done should also be
mentioned as related and not-related.
• While coding SAE (Table 8) and AE/AEFI (TAB), Preferred Term (PT)
and System Organ Class (SOC) should be used.

7.5 Cumulative and interval summary tabulations from post-

marketing data sources
This section of the PSUR should provide background for the Appendix
that provides cumulative and interval summary tabulations of AE/AEFI
from the date of marketing authorization to the data lock point of the
current PSUR.
The tabulation should include:
• Serious and non-serious AE/AEFI from spontaneous ICSR, including
reports from HCPs, consumers, scientific literature, and regulatory
authorities
• Serious adverse drug reactions from non-interventional studies
• Solicited reports of serious AE/AEFIs

For special issues or concerns, additional tabulations of adverse drug

reactions can be presented by indication, route of administration, or other
variables. This section should not serve to provide analyses or conclusions
based on the data presented (Refer Appendix-B, Table 09).

8. Studies
This section of periodic safety update reports should capture the brief
summary of clinically important emerging efficacy or effectiveness and
safety findings obtained from the licence holder, sponsored clinical trials
and published safety studies that became available during the reporting
interval of the report which has potential impact on product safety
information.
(i) Summaries of significant safety findings from clinical trials
during the reporting period;
(ii) Findings from non-interventional Studies;
(iii) Findings from non-Clinical Studies;
(iv) Findings from literature

Completed clinical study

A brief summary of clinically important safety and efficacy findings

obtained from completed trial during the reporting interval should be
provided. This information can be presented in a narrative format or as a
synopsis (Refer ICH- E3). It could include information that supports or
refutes previously identified safety concerns, as well as evidence of new
safety signals.
8.1.1 Ongoing clinical study

If the manufacturer and/or importer is aware of clinically important

information that has arisen from ongoing clinical trials (e.g. learned
through interim safety analyses or as a result of unbinding of subjects
with Adverse Events), this sub- section should briefly summarize the
concern(s). It could include information that supports or refutes
previously identified safety concerns, as well as evidence of new safety
signals.

8.1.2 Long-term follow-up

Wherever applicable, this sub-section should provide information from long-

term follow-up of subjects from clinical trials of new drugs, particularly
advanced therapy products (e.g. gene therapy, cell therapy products and
tissue engineering and biotech products). These are referred as
Advanced Therapy Medicinal Products (ATMPs).

8.1.3 Other therapeutic uses of biological product

This should include clinically important safety information from other

programmes, if and when conducted by the manufacturer and/or importer
that follow a specific protocol (e.g., expanded access programmes,
compassionate use programmes, particular patient uses and other
organized data collection).

8.1.4 New safety data related to Fixed Dose Combination

therapies
Unless otherwise specified by national regulatory authority requirements,
the following data from combination therapies:
• If the product that is the subject of a PSUR is also approved or under
development as a component of a combination product or a multi-drug
regimen, this section should summarize important safety findings from
the use of the fixed dose combination therapy
• If this PSUR is a combination product, this section should summarize
important safety information arising from the individual components
• The information specific to the combination can be incorporated into
a separate section(s) of the PSUR for one or all of the individual
 components of the combination.

8.2 Findings from non-interventional Studies

This section should summarize relevant safety information or

information with potential impact on the benefit or risk evaluations,
from MAH - sponsored non-interventional studies that became
available during the reporting interval (e.g., observational studies,
epidemiological studies, registries, and active surveillance
programmes). This should include relevant information from drug
utilization studies, when applicable to multiple regions.

8.3 Information from other clinical trial sources

8.3.1 Other clinical trials

This sub-section should summarize information accessible with

reasonable effort from any other clinical trial/study sources to the MAH
during the reporting interval (e.g. including results from pooled analyses
or meta-analyses of randomized clinical trials, and safety information
provided by co- development partners or from investigator-initiated
trials).

8.3.2 Medication errors

This sub-section should summarize relevant information on patterns of

medication errors and potential medication errors, even when not
associated with adverse outcomes. This information may be received by the
manufacturer and/or importer via spontaneous reporting systems, medical
information queries, customer complaints, screening of digital media,
patient support programmes, or other available information sources.

8.4 Findings from non-Clinical Studies;

This section should summarize major safety findings from non-clinical in

vivo and in vitro studies (e.g., carcinogenicity, reproduction, or
immunotoxicity studies) ongoing or completed during the reporting
interval.

8.5 Findings from literature

This section should summarize new and significant safety findings,
either published in the scientific literature, Alerts published by
USFDA/EMEA or other regulatory agencies, relevant to the approved
pharmaceutical product that the manufacturer and/or importer became
aware of during the reporting interval.
Literature searches for PSUR should be as wide as possible and should
also include studies reporting safety outcomes in groups of subjects and
other products containing the same active substance.
This should include:
• Pregnancy outcomes (including termination) with or without adverse
outcomes
• Use in pediatric populations
• Compassionate supply, named patient use
• Lack of efficacy
• Asymptomatic overdose, abuse or misuse
• Medication error where no adverse events occurred Important non-
clinical safety findings

9. Other Information: This section of PSURs should include the details

about signal and Risk Management Plan in place by licence holder (if
any). (For detail please refer Chapter 6)

(a) Signal and risk evaluation: In this section, licence holder will
provide the details of signal and risk identified during the
reporting period and evaluation of signals identified during the
reporting period.

(b) Risk management plan: In this section, licence holder will

provide the brief details of safety concern and necessary action
taken by him to mitigate these safety concerns.

9.1 Lack of efficacy in controlled clinical trials

Data from clinical trials indicating lack of efficacy, or lack of efficacy

relative to established therapy(ies), for pharmaceutical products
intended to treat or prevent serious or life-threatening illnesses (e.g.,
excess cardiovascular AEs in a trial of a new anti-platelet drug for Acute
Coronary Syndromes) could reflect a significant risk to the treated
population and should be summarized in this section.
9.2 Late-breaking information

This section should summarize information on potentially important safety

and efficacy/effectiveness findings that arise within 15 days after the data
lock point of the PSUR in preparation. Examples include clinically significant
new publications, important follow-up data, clinically relevant toxicological
findings and any action that the manufacturer and/or importer, a data
monitoring committee, or a regulatory authority has taken for the safety
reasons.

Any significant change proposed to the reference product information

which has occurred after the data lock point of the report, but before
submission should also be included in this section, where feasible. Such
changes could include a new contraindication, warning/precaution, or new
AE/AEFI.

9.3 Overview of signals: new, ongoing, or closed

A new signal is a signal that the MAH became aware of during the
reporting interval. A new clinically important information on a previously
closed signal that became available during the reporting period of the
PSUR (i.e., a new aspect of a previously refuted signal or recognized risk
likely to warrant further action to verify) would also constitute a new
signal. New signals may be classified as closed or ongoing, depending
on the status of signal evaluation at the data lock point of the PSUR.
Examples would include new information on a previously:
• Closed and refuted signal, which would result in the signal being re-
opened; Identified risk which is indicative of a clinically significant
difference in the severity of the risk, e.g., transient increase in liver
enzymes are identified risks and new information is received indicative
of a more severe outcome such as hepatic failure; neutropenia is an
identified risk and a well- documented and unconfined case report of
agranulocytosis is received;
• Identified risk for which a higher frequency of the risk is newly found,
e.g., in a sub population; and
• Potential risk which, if confirmed, would warrant a new warning,
 precaution, a new contraindication or restriction in indication(s) or
population or other risk minimization activities.
Refer Appendix-C, include a tabular listing of all signals ongoing or
closed at the data lock points of the PSUR.
When a regulatory authority has requested that a specific safety concern
(not considered a signal) be monitored and reported in a PSUR, the
MAH should summarize the result of the analysis of such safety concern
in this section even if it is negative.

10. Overall Safety Evaluation: This section of PSURs should capture

the overall safety evaluation of the drug based upon its risk benefit
evaluation for approved indication.
The purpose of this section is to provide:
• Important identified risks;
• Important potential risks;
• Important missing information.
• In case a signal was indicated in previous interval report and now has
been refuted because of new evidences which resulted in closure,
should be specifically mentioned here.
• An evaluation of new information with respect to previously recognized
identified and potential risks
• An updated characterization of important potential and identified
risks, where applicable and
• A summary of the effectiveness of risk minimization activities (if any)
in any country or region, which may have utility in other countries or
regions.

These evaluations of subsections should not summarize or repeat

information presented in previous sections of the PSUR, but should
instead provide an interpretation of the information, with a view towards
characterizing the profile of those risks assessed as important.
10 Benefit Evaluation

10.2.1 Important baseline efficacy/effectiveness information

This section summarizes information on the efficacy/effectiveness of the

pharmaceutical product as of the beginning of the reporting interval, and
provides the basis for the benefit evaluation. This information should
relate to the approved indication(s) of the pharmaceutical product listed in
the reference product information

For pharmaceutical products with multiple indications, population, and/or

routes of administration, the benefit should be characterized separately
by these factors, wherever relevant. The level of detail provided in this
section should be sufficient to support the characterization of benefit in
PSUR and the benefit-risk assessment.

10.2.2 Newly identified information on efficacy/effectiveness

Wherever necessary, for some products new information on

efficacy/effectiveness in approved indications that may have become
available during the reporting interval should be presented in this section.

New information about efficacy/effectiveness in uses other than the

approved indication(s) (off-label use) should not be included, unless
relevant for the benefit-risk evaluation in the approved indication.

Information on additional indications approved during the reporting interval

should also be included in this section. New information on efficacy
/effectiveness might also include changes in the therapeutic environment
that could impact efficacy/effectiveness over time, e.g., vaccines,
emergence of resistance to anti- infective agents.

10.2.3 Characterization of benefits

This sub-section provides an integration of the baseline benefit
information and the new benefit information that has become available
during the reporting interval, for authorized indications. When there are
no new relevant benefit data, this sub-section should provide a
characterization of the information in sub-section "Important baseline
efficacy and effectiveness information".
When there is a clear information about the benefit and no significant
change in the risk profile in this reporting interval, the integration of
baseline and new information in this sub-section should be provided.
This sub-section should provide a concise but critical evaluation of the
strengths and limitations of the evidence on efficacy and effectiveness,
as follows:
• A brief description of the strength of evidence of benefit, considering
comparator(s), effect size, statistical rigor, methodological strengths
and deficiencies, and consistency of findings across clinical
trials/studies
• New information that challenge the validity of a surrogate endpoint, if
used
• Clinical relevance of the effect size
• Generalizability of treatment response across the indicated patient
population, e.g., information that demonstrates lack of treatment
effect in a sub-population
• Adequacy of characterization of dose-response
• Duration of effect
• Comparative efficacy
A determination of the extent to which efficacy findings from clinical trials
are generalizable to patient populations treated in medical practice.

10.2.4 Benefit risk analysis evaluation

This section should provide an integration and critical analysis of the key
information. This section also provides the benefit-risk analysis, and
should not simply duplicate the benefit and risk characterization presented
in subsections mentioned above.

10.2.5 Benefit-Risk context- medical need and important alternatives

This sub-section should provide a brief description of the medical need

for the pharmaceutical product in the approved indications, and
summarize alternatives (medical, surgical, or other; including no
treatment).

10.2.6 Benefit-Risk analysis evaluation

A benefit-risk balance is specific to an indication and population. For
products approved for more than one indication, benefit-risk profiles
should be evaluated and presented for each indication individually. If
there are important differences in the benefit-risk profiles among
populations within an indication, benefit-risk evaluation should be
presented by population, if possible.
The benefit-risk evaluation should be presented and discussed in a way
that facilitates the comparison of benefits and risks, and should take into
account the following points:
• Whereas previous sections included all important benefit and risk
information, not all benefits and risks contribute importantly to the
overall benefit-risk evaluation. Therefore, the key benefits and risks
considered in the evaluation should be specified. The key
information presented in the previous benefit and risk sections should
be carried forward for integration in the benefit-risk evaluation.
• Consider the context of use of the pharmaceutical product: the
condition to be treated, prevented, or diagnosed; its severity and
seriousness; and the population to be treated.
• With respect to key benefit(s), consider its nature, clinical
importance, duration, and generalizability, as well as evidence of
efficacy in non- responders to other therapies and alternative
treatments. Consider the effect size. If there are individual elements
of benefit, consider all (e.g., for therapies for arthritis: reduction of
symptoms and inhibition of radiographic progression of joint
damage).
• With respect to risk, consider its clinical importance, e.g., nature of
toxicity, seriousness, frequency, predictability, preventability,
reversibility, impact on patients, and whether it arose from off-label
use, a new use, or misuse.
• The strengths, weaknesses, and uncertainties of the evidence
should be considered when formulating the benefit-risk evaluation.
Describe how uncertainties in the benefits and risks impact the
evaluation. Limitations of the assessment should be described.
Provide a clear explanation of the methodology and reasoning used for
benefit- risk evaluation:
 • The assumptions, considerations, and judgement or weighing that
support the conclusions of the benefit-risk evaluation, should be
clear.
• If a formal quantitative or semi-quantitative assessment of benefit-
risk is provided, a summary of the methods should be included.
• Economic considerations (e.g., cost-effectiveness) should not be
included in the benefit-risk evaluation.
Note: When there is important new information or an ad hoc PSUR has
been requested, a detailed benefit-risk analysis is warranted.
Conversely, where little new information has become available during
the reporting interval, the primary focus of the benefit-risk evaluation
might consist of an evaluation of updated interval safety data.

11. Conclusion:

This section of PSURs should provide the details on the safety profile of
drug(s) and necessary action taken by the license holder in this regard.

Based on the evaluation of the cumulative safety data, and the benefit-risk
analysis, the manufacturer and/or importer should assess the need for
further changes to the reference product information and propose changes
as appropriate. In addition, and as applicable, the conclusion should include
preliminary proposal(s) to optimize or further evaluate the benefit-risk
balance, for further discussion with the national regulatory authority. This
may include proposals for additional risk minimization activities. These
proposals should also be considered for incorporation into the Risk
Management Plan.

12. Appendix:

The appendix includes the copy of marketing authorization in India, copy

of prescribing information, line listings with narrative of Individual Case
Safety Report.
 4.4 CHAPTER- 4: Quality Management System at
Marketing Authorization Holder Organization

Contents:

4.4.1. Introduction

4.4.2. Scope

4.4.3. Structures and Processes

4.4.4. Specific quality system procedures and processes

4.4.1. Introduction

This Chapter contains guidance for the Marketing Authorization Holders

for the establishment, maintenance, performance, performance and
quality assurance of PV system.

4.4.2. Scope

This guidance document is applicable to all MAHs who hold marketing

authorization for manufacture or import of pharmaceutical products in
Indian market.

4.4.3. Structures and Processes

4.4.4. Pharmacovigilance system

All MAH should have the PV system which should comply with the
quality management system including requirements of NDCT Rules
2019, revised Schedule M of the Drugs & Cosmetics Act, 1940, and
Rules made thereunder.

The PV system at MAH should have an organogram describing PV

personnel’s roles and responsibilities, procedures, processes and
resources, including management of resources, compliance and records
(Refer Chapter 1 for more details).

4.4.5. Quality Management System (QMS) of PV

The QMS in PV is a framework of policies, procedures and system

necessary to ensure quality related to detection, assessment,
understanding, evaluation and prevention of adverse events on
pharmaceutical products.

The quality management system is based on the following activities:

 Quality planning: Establishing structures of PV system, planning,

effective integration and consistent processes for safety;
 Quality adherence: Carrying out tasks and responsibilities in
accordance with quality requirements such as collection of ICSRs,
completeness of report, case narrative, data management, causality
assessment, signal management, etc.;
 Quality control and assurance: By monitoring the parameters
described under quality adherence;
 Quality improvements: Taking Corrective and Preventive measures,
as and when required, to ensure patient safety.

4.4.4.4. Requirements and Responsibilities of QMS at MAH site

MAH should have a sufficient number of competent and appropriately

qualified, and trained personnel for the performance of PV activities.

In case, where MAH has completely outsourced the PV activities, through

a valid contract, the outsourced agency/institution should comply with the
above statement. It should be notified to CDSCO with authorized legal
documents. The responsibility of adhering to PV QMS will ultimately lie with
MAH.

The managerial staff in the organization should be responsible for

compliance of PV Guidance Document for MAHs of Pharmaceutical
Products.

4.4.4.5. Training of MAH personnel for PV

The personnel involved in PV activities should receive induction (within

one month of joining and continued trainings with proper evaluation of
performance, thereafter. The organization should maintain the training
plans and records of trainings. The organization should keep identifying
the continued training needs.
4.4.4.6. Facilities and equipment for PV

Achieving the required quality for the conduct of PV processes and their
outcomes is also intrinsically linked with appropriate facilities and
equipment used to support the processes. Facilities and equipment
should include office space, Information Technology (IT) systems and
storage space (electronic). They should be located, identified, designed,
constructed, adapted and maintained to suit their intended purpose in
line with the quality objectives for PV System.

Facilities and equipment which are critical for the conduct of PV should
be subject to appropriate checks, qualification and/or validation activities to
prove their suitability for the intended purpose.

4.4.4. Specific quality system procedures and processes

4.4.4.1. Compliance management by MAH
For the purpose of compliance, MAHs should have specific quality
system procedures and processes in place in order to ensure the
following:
• Continuous monitoring of PV data, the examination of options for
risk minimization and prevention and that appropriate measures are
taken by the MAH (refer Chapter 6 for detailed information)
• Scientific evaluation of all information on the risks of pharmaceutical
products as regards patients or public health, in particular as regards
adverse reactions in human beings arising from use of the product
within or outside the terms of its marketing authorization or
associated with occupational exposure (refer Chapters 2, 3 and 6 for
detailed information)
• Submission of accurate and verifiable data on all AEFIs to the
regulatory authority within the legally required time-limits
• Quality, integrity and completeness of the information submitted on
the risks of pharmaceutical products, including processes to avoid
duplicate submissions and to validate signals
• Effective communication with regulatory authority, including
communication on new or changed risks, the PSMF, risk management
systems, PSURs and CAPAs.

4.4.4.2. Record management

The MAH shall record all PV information and ensure that it is handled
and stored so as to allow accurate reporting, interpretation and
verification of that information.

As part of a record management system, specific measures should,

therefore be taken at each stage in the storage and processing of PV
data to ensure data security and confidentiality. This should involve strict
limitation of access to documents and to databases to authorized
personnel respecting the medical and administrative confidentiality of the
data. The electronic copies of the PV records should be stored indefinitely.
It is expected that the MAHs should retain the soft copy back-up of all
PV documents for indefinite time and hard copies for at least 10 years.
The MAHs shall maintain a logbook for recording primary information
received for every Adverse Events reported.

4.4.4.3. Documentation of the quality system

All elements, requirements and provisions adopted for the quality system
should be documented in a systematic and orderly manner in the form of
written policies and procedures. For the requirements of documenting the
quality system (refer Chapter 1 for detailed information).

4.4.4.4. Critical PV processes

The following PV processes should be considered as critical:

• Benefit-risk evaluation;
• Establishing, assessing & implementing risk management systems
and evaluating the effectiveness of risk minimization;
• Collection, processing, management, quality control, follow-up for
missing information, coding, classification, duplicate detection,
evaluation and timely electronic transmission of ICSRs from any
source;
• Signal management;
• Scheduling, preparation (including data evaluation and quality
control), submission and assessment of PSURs;
• Interaction between the PV and product quality defect systems;
• Communication about safety concerns between MAHs and licensing
authority in particular notifying changes to the benefit-risk balance of
pharmaceutical products;
• Communicating information to patients and healthcare professionals
about changes to the benefit-risk balance of pharmaceutical products
for the aim of safe and effective use of pharmaceutical products;
• Keeping product information up-to-date with the current scientific
knowledge, including the conclusions of the assessment and
recommendations from the regulatory authority;
• Implementation of variations to marketing authorizations for safety
reasons according to the urgency required.
 • Provisions for events that could severely impact on the organization's
staff and infrastructure in general or on the structures and processes
for PV in particular; and
• Back-up systems for urgent exchange of information within an
organization, amongst organizations sharing PV tasks as well as
between MAHs and competent authorities.

4.4.4.5. Monitoring the effectiveness of QMS in PV

The QMS in PV should be continuously monitored for its

effectiveness by the MAH through the following processes:

 System reviews by those responsible for management

 Audits
 Compliance monitoring
 Inspections
 Evaluating the effectiveness of actions taken with biological
products for the purpose of minimizing risks and supporting
their safe and effective use in patients.

The organization may use performance indicators to continuously

monitor the good performance of PV activities in relation to the
quality requirements. The requirements for the quality system itself
are laid out in this Chapter and its effectiveness should be monitored
by managerial staff, who should review the documentation of the
quality system at regular intervals with the frequency and the extent
of the reviews to be determined in a risk-based manner.
Reviews of the quality system should include the review of SOPs and
work instructions, deviations from the established quality system, audits
and inspections reports as well as the use of the indicators referred to
above.

4.4.4.6. Responsibilities of the MAH in relation to the PVOIC for PV

The pharmacovigilance system shall be managed by qualified and

trained personnel and the officer in-charge of collection and processing
of data shall be a medical officer or a pharmacist trained in collection
and analysis of adverse drug reaction reports.
A qualified and trained personnel should be authorized by the company
management as Pharmacovigilance Officer In-charge (PVOIC) with
responsibilities for dealing PV activities at MAH's organization. The PVOIC
should be a medical or pharmacy professional trained in the collection and
analysis of AE reports. The PVOIC shall be responsible for the following:
 Development of training modules and organizing training for staff of
PV department;
 Identification of PV activities and framing of SOPs, revision of SOPs;
 Establishment and maintenance of QMS of PV department;
The PVOIC should reside in India and respond to queries of regulatory
authorities including PvPI, IPC whenever required. The information related
to the PVOIC provided in the PSMF should include:
 Contact details (Name, address, phone, e-mail);
 Summary, curriculum vitae with the key information on the role of the
PVOIC;
 A description of the responsibilities guaranteeing that the PVOIC has
sufficient authority over the PV system in order to promote, maintain
and improve compliance;
 Details of Person-in-charge to work in the absence of PVOIC;
 4.5 CHAPTER- 5: Audit & Inspection of
Pharmacovigilance System at Marketing Authorization
Holder Organization

Contents:

4.5.1. Introduction

4.5.2. Objectives

4.5.3. Inspection Types

4.5.4. Inspection Procedure

4.5.5. Regulatory Actions

4.5.6. Training Inspectors

 4.5.1. Introduction
This chapter provides insights into planning, conducting, reporting and
follow-up of PV inspections by regulatory authorities/officials responsible
for inspection.

4.5.2. Objectives
The objectives of PV audits and inspections are as below:
 To verify by examination and evidence, the appropriateness of the
implementation and operation of the PV system including its
quality systems.
 To assess and establish that the MAH has qualified personnel,
robust system and facilities to conduct PV activities
 To identify, record and address non-compliance, which may
pose a risk to public health
 To take regulatory action, wherever considered necessary based
on the result of the inspections/audits.

The results of an inspection will be provided to the inspected MAH,

who will be given the opportunity to comment on any non-compliance
identified. Any non-compliance should also be rectified by the MAH
within stipulated time period through the implementation of CAPA
plan.

4.5.3. Inspection Types

The Inspections of PV can be routine or targeted to MAHs suspected

of being non-compliant.

4.5.3.1. Routine inspection

These are planned and informed inspection of the PV system of MAH.

The focus of these inspections is to determine that the MAH has
personnel, systems and facilities in place to meet the regulatory PV
obligations for the marketed pharmaceutical products in India.

4.5.3.2. Targeted inspections

These inspections are conducted as and when there is trigger and the
 regulatory authority determines that inspection is the only way. Triggering
factors for such type of inspections are as below (but not limited to):

 Continuous delays or omission and poor-quality reporting of

ICSRs/PSURs/RMPs.
 Failure to provide the asked information or data within the
deadline specified by regulatory authority.
 Delays or failure to carry out specific obligations related to the
monitoring of pharmaceutical product safety, identified at the
time of the marketing authorization.
 Delays in the implementation or inappropriate implementation of
CAPAs.
 Sudden pharmaceutical product withdrawal and recall.
 Any major changes in PV system.
 Any emerging safety issue relating to any drug product held by the
MAH.

4.5.4. Inspection Procedure

4.5.4.1. Inspection Planning

PV inspection should be based on a systematic and risk-based

approach to make the best use of surveillance and enforcement
resources whilst maintaining a high level of public health protection. A
risk-based approach to inspection planning will enable the frequency
and scope of inspections to be carried out.
The PV inspection team will comprise CDSCO Officials and
representative from PvPI & other experts if required.
The inspection will be planned based on the following:
 Compliance history identified during previous PV inspections, if
any.
 Re-inspection date recommended by the inspectors as a result of
compliance of previous inspection submitted by MAH,
 MAH with sub-contracted/ outsourced/ Third Party PV activities
(qualified person responsible for PV functions in India, reporting
of safety data, etc.) and multiple firms employed to perform PV
 activities;

 Changes to the PV safety database(s), which could include a

change in the database itself or associated databases, the
validation status of the database as well as information about
transferred or migrated data;
 Changes in contractual arrangements with PV service
providers or the organizations at which PV is conducted;
 Delegation or transfer of PSMF management.

4.5.4.2. Organization to be inspected

Any party carrying out PV activities in whole or in part, on behalf of, or in

conjunction with the MAH may be inspected, in order to confirm their
capability to support the MAH's compliance with PV obligations.

4.5.6. Regulatory Actions:

In the event of non-compliance, the regulatory authority shall take the

necessary measures to ensure that a MAH is in compliance with
NDCTR-19 of D&C Act 1940 and Rules made thereunder.
 4.6 CHAPTER- 6: Submission of Risk Management
Plan

Contents:

4.6.1. Introduction

4.6.2. Objectives

4.6.3. Contents of RMP

4.6.1. Introduction
At the time of marketing authorization, information on the safety of a
biological product is relatively limited as the clinical studies are
carried out in relatively small number of subjects, restricted
population in terms of age, gender, ethnicity, restricted co-morbidity,
restricted co-medication, restricted conditions of use, relatively short
duration of exposure and follow up.
A biological product is authorized on the basis that at the time of
authorization, the benefit-risk balance is positive. The product may
have multiple risks of varying degree associated with it and individual
risks will vary from product to product. All actual or potential risks
might not have been identified at the time of initial authorization.
Many risks will only be discovered and characterized during post-
marketing phase.
The aim of Risk Management Plan (RMP) is to document the risk
management system considered necessary to identify, characterize
and minimize a pharmaceutical product’s important risks. The Risk
Minimization strategy involves continuous monitoring of efficacy and
safety profile-Risk Identification, Risk Assessment, Risk
Characterization, Risk Communication and Risk Mitigation.

4.6.2. Objectives
 Identification and characterization of risk to update the
safety profile of the pharmaceutical product(s);
 Indicate how to characterize further the safety profile
of the pharmaceutical product(s);

 Document measures to prevent or minimize the risks

associated with a pharmaceutical product, including an
assessment of the effectiveness of interventions;
 Document post-marketing obligations that have been imposed
as a condition of the marketing authorization;
 Document any change in the risk profile of a pharmaceutical
product(s) after marketing authorization.
The RMP document is a dynamic, stand-alone document which
should be updated throughout the life-cycle of pharmaceutical
products.
The License holder will provide the details of safety concern and
necessary actions taken by him to mitigate any safety concern in the
applications of PSUR.

4.6.3. Description of RMP

4.6.3.1. Pharmaceutical product overview
The MAH should provide an overview of a pharmaceutical product
including:
 Active Pharmaceutical Ingredient(s) information, name of MAH,
date and country of first launch/authorization worldwide (if
applicable), chemical class, indication (s), mechanism of action,
route of administration, pharmaceutical form and strength.
 Information on the excipients used in the formulation of a
pharmaceutical product should be provided.
 Administrative information on the RMP such as data lock
point, date submitted and version number of all parts of RMP.

4.6.3.2. Safety specifications

The MAH should provide a synopsis of the safety profile of a
pharmaceutical product(s) and should include, what is known and
unknown about the pharmaceutical product(s) safety. The safety
specification consists of following subsections:

4.6.3.3. Epidemiology, indication (s) and target population(s):

This section should include incidence, prevalence, mortality and
relevant co- morbidity, and should whenever possible be stratified by
age, sex, and racial and/or ethnic origin.

4.6.3.2.1. Non-clinical part of the safety specifications:

This section should present a summary of important non-clinical
safety findings like toxicity related information, interactions etc.
4.6.3.2.2. Clinical trial exposure:

This section includes the data on the patients studied in clinical

trials. This should be stratified for relevant categories (age, gender,
indication, ethnicity, exposure to special population-pediatric,
geriatric etc.) and also by the type of clinical trial.

4.6.3.2.3. Populations not studied in clinical trials:

This section describes, which sub-populations within the expected
target population have not been studied or have only been studied to a
limited degree in the clinical trial population. Limitations of the clinical
trials should also be presented in terms of the relevance of exclusion
criteria such as pediatric population, geriatrics population,
pregnant/lactating women, hepatic /renal impairment patients etc.

4.6.3.2.4. Post-marketing experience:

This section should provide information on the number of patients
exposed during post-marketing phase; how the pharmaceutical
product has been used in clinical practice, labelled and off-label use
including use in the special populations mentioned above? This should
also include any action taken by any regulatory authority/MAH for safety
reason.

4.6.3.2.5. Identified and potential risks:

This section provides information on the important identified and
potential risks associated with the use of a pharmaceutical product and
potential Adverse Events/Adverse Reactions with other pharmaceutical
products, foods, other substances, and the important pharmacological
class effects.
The risk data should include frequency, public health impact, risk
factors, preventability, potential mechanism, evidence
source/strength.

4.6.3.2.6. Summary of the safety concerns:

At the end of the RMP document, summary of the "Safety
concerns/measures" of pharmaceutical products should be provided.
4.6.3.4. PV activities
MAH should list the various PV activities involved to identify a new
safety concern or further characterize known safety concerns or
investigation of potential safety concerns, whether it is real or not
and how missing information will be sought? PV activities can be
divided into routine PV activities and additional PV activities. For
each safety concern, the MAH should list their planned PV activities
for that concern. PV plans should be proportionate to the risks of the
product. If routine PV is considered sufficient for post-marketing
safety monitoring, without the need for additional actions (e.g. safety
studies) "routine PV" should be carried out against the safety
concern.

4.7. Nature and rate of known Risks versus Benefits:

Comparing the characteristics of the product’s adverse effects and

benefits may help clarify whether a Risk MAP could improve the
product’s benefit-risk balance. The characteristics to be weighed
might include the
1) types, magnitude, and frequency of risks and benefits;
2) populations at greatest risk and/or those likely to derive the
most benefit;
3) existence of treatment alternatives and their risks and
benefits; and
4) Reversibility of adverse events observed.

4.7.1. Preventability of adverse effects:

Serious adverse effects that can be minimized or avoided by
preventive measures around drug prescribing are the preferred
candidates for Risk MAPs.
Probability of benefit: If factors are identified that can predict
effectiveness, a Risk MAP could help encourage appropriate use to
increase benefits relative to known risks. A risk minimization tool is a
process or system intended to minimize known risks. Tools can
communicate particular information regarding optimal product use
and can also provide guidance on prescribing, dispensing, and/or
using a product in the most appropriate situations or patient
populations. A number of tools are available and may be used as
required. A variety of tools are currently used in risk minimization
plans. These fall within three categories:
(1) Targeted education and outreach: targeted education and
outreach to communicate risks and appropriate safety
behaviors to healthcare practitioners or patients.
(2) Reminder systems: processes or forms to foster reduced-risk
prescribing and use, and
(3) Performance-linked access systems: that guide prescribing,
dispensing, and use of the product to target the population and
conditions of use most likely to confer benefits and to minimize
particular risks.

4.7.2. Targeted education and outreach

It is recommended that MA holders consider tools in the targeted
education and outreach category.
(a) When routine risk minimization is known or likely to be
insufficient to minimize product risks or
(b) As a component of Risk MAPs using reminder or performance-
linked access systems.
Sponsors are encouraged to continue using tools, such as education
and outreach, as an extension of their routine risk minimization efforts
even without a Risk MAP.
Tools which may be used as routine risk minimization efforts even
without a Risk MAP may be:
• Training programs for healthcare practitioners or patients
• Continuing education for healthcare practitioners such as
product-focused programs developed by sponsors and/or
sponsor-supported accredited CE programs
• Prominent professional or public notifications
• Patient labeling such as Medication Guides and patient package
inserts Promotional techniques such as direct-to-consumer
advertising highlighting appropriate patient use or product risks
• Patient-sponsor interaction and education systems such as
 disease management and Patient access programs
• Healthcare practitioner letters

In addition to informing healthcare practitioners and patients about

conditions of use contributing to product risk, educational tools can
inform them of conditions of use that are important to achieve the
product’s benefits.
On the other hand, deviations from the labeled dose, frequency of
dosing, storage conditions, or other labeled conditions of use might
compromise the benefit achieved, yet still expose the patient to
product related risks. Risks and benefits can have different dose-
response relationships. Risks can persist and even exceed benefits
when products are used in ways that minimize effectiveness.
Therefore, educational tools can be used to explain how to use
products in ways that both maximize benefits and minimize risks.
It is recommended that tools in the reminder systems category be
used in addition to tools in the targeted education and outreach
category when targeted education and outreach tools are known or
likely to be insufficient to minimize identified risks. Tools in the
reminder system include systems that prompt, remind, double- check
or otherwise guide healthcare practitioners and/or patients in
prescribing, dispensing, receiving, or using a product in ways that
minimize risk. Examples of tools in this category are as follows:
• Patient education that includes acknowledgment of having read
the material and an agreement to follow instructions. These
agreements are sometimes called consent forms.
• Healthcare provider training programs that include testing or
some other documentation of physicians’ knowledge and
understanding.
• Enrolment of physicians, pharmacies, and/or patients in special
data collection systems that also reinforce appropriate product
use.
• Limited number of doses in any single prescription or limitations
on refills of the product.
• Specialized product packaging to enhance safe use of the
 product.
• Specialized systems or records that are used to attest that
safety measures have been satisfied (e.g. Prescription stickers,
physician attestation of capabilities).

4.7.3 PERFORMANCE-LINKED ACCESS SYSTEMS

Performance-linked access systems include systems that link
product access to laboratory testing results or other
documentation. Tools in this category, because they are very
burdensome and can disrupt usual patient care, should be
considered only when
1. Products have significant or otherwise unique benefits in a
particular patient group or condition, but unusual risks also
exist, such as irreversible disability or death, and
2. Routine risk minimization measures, targeted education and
outreach tools, and reminder systems are known or likely to
be insufficient to minimize those risks.

4.7.4. Selecting and Developing the Best Tools:

• Maintain the widest possible access to the product with the
least burden to the healthcare system that is compatible with
adequate risk minimization (e.g., a reminder system tool
should not be used if targeted education and outreach would
likely be sufficient).
• Identify the key stakeholders who have the capacity to
minimize the product’s risks (such as physicians,
pharmacists, pharmacies, nurses, patients, and third party
payers) and define the anticipated role of each group.
• Seek input from the key stakeholders on the feasibility of
implementing and accepting the tool in usual healthcare
practices, disease conditions, or lifestyles, if possible.
Examples of considerations could include (but would not be
limited to) patient and healthcare practitioner autonomy,
time effectiveness, economic issues, and technological
feasibility.
• Acknowledge the importance of using tools with the least
 burdensome effect on Healthcare practitioner- patient,
pharmacist-patient, and/or other healthcare relationships.
It is recommended that MA holders periodically evaluate
each Risk MAP tool to ensure it is materially contributing to
the achievement of Risk MAP objectives or goals.

4.7.5. Risk minimization activities

The MAH should have the approved & updated Package inserts,
Product labelling, Product Information Leaflet (PIL), pack size,
risk minimization activities. The MAH should also consider when
appropriate to have additional Risk minimization activities like
educational material, communication letter to Healthcare
Professionals (HCPs) etc.
For each safety concern, the following information should be
provided:
 Objectives of the risk minimization activities;
 Routine risk minimization activities;
 Additional risk minimization activities (if any), individual
objectives and justification,
 How the effectiveness of each (or all) risk minimization
activities will be evaluated in terms of attainment of their
stated objectives?
 What the target is for risk minimization? i.e. what are the
criteria for judging success?
 Milestones for evaluation and reporting.
5. Procedures for implementing an effective
Pharmacovigilance System

(a) Obligations for MAH:

In accordance with the Govt. Gazette Notification No. GSR 227 (E) dated
March, 19th March 2019, for the purpose of Post Market Surveillance, the
MAH shall have a pharmacovigilance system in place for collecting,
processing and forwarding the reports to the Licensing Authorities for
information on Adverse Event Following Immunization (AEFI) emerging from
the use of the vaccine manufactured and marketed by the MAH in the
country. The system shall be managed by qualified and trained personnel
and officer-in-charge of collection and processing of data shall be a Medical
Officer or apharmacist trained in collection and analysis of AE/AEFI.

Hence, the Marketing Authorization Holder (MAH) should establish an

appropriate pharmacovigilance system by assuming the responsibilities and
liabilities for its vaccine product(s) circulating in the market and should
ensure that appropriate action may be taken whenever safety concerns arise
after due investigation and scientific evaluation. The Marketing Authorization
Holder (MAH) should appoint as per the norms laid down in Fifth Schedule
of New Drugs and Clinical Trial Rules 2019 under Drugs & Cosmetics Act
1940 ., a qualified and trained personnel with duly given responsibilities for
continuously monitoring of the vaccine products at his disposal

(b) AEFI Case Reporting:

Documented standard procedure should compile but not be limited to the

following:
i. Provisions for timely and thorough review to determine whether the
complaint represents an AE/AEFI;
ii. Personnel responsible to receive the incoming correspondence
(phone calls, letter, email, etc.) relating to potential AE/AEFI through
product complaints;
iii. How an unique identifier is assigned to each case; and
iv. Clear and defined processes on AE/AEFI complaint, evaluation and
follow-up.
c) Manufacturers and importers should have in place systems and
procedures for the receipt, handling, evaluation and reporting of AE/AEFIs
that are adequate to effectively sustain AEs/AEFI reporting. All cases
involving serious unexpected adverse reactions must be reported to the
licencing authority within fifteen 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.
In case of manufacturer, distributing countries specific PSUR should be
compiled and submitted in a separate section within the PSUR data. All the
SAE reported in the distributing countries shall be reported within 15 days.

d) MAHs should have in place adequate procedures for AE/AEFI receipt,

handling, evaluation and reporting and should include but not be limited to
the following.
i. Requirement to report to CDSCO within 15 days of receipt by the MAH,
reports of serious AE/AEFI occurring within India, and serious
unexpected AE/AEFI occurring outside of India and any unusual failure
in efficacy for new drugs occurring within India, if applicable;
ii. Address all the specific Indian regulatory requirements such, as when
notification is required, serious and non-serious adverse reactions,
unusual failure in efficacy of new drugs, if applicable, retention of all
records associated with AE/AEFIs, etc.;
iii. Requirement to have a qualified health care professional to evaluate
and assess AE/AEFI reports, including the process to review AEs.
iv. Identifying the 4 minimum criteria (an identifiable reporter (source), an
identifiable patient, a suspect product and an adverse reaction) for
submitting a case;
v. Identifying key personnel who are responsible for forwarding the AE
reports to the Licensing Authority;
vi. Procedure on how complaints and AEs are tracked/logged in;
vii. Procedure on how the MAH is to be notified of foreign serious
unexpected drug reactions;
viii. The responsibilities for the final approval of AE/AEFI evaluation and
appropriate follow-up;
 ix. Requirement to conduct a critical analysis of AE reports received and
preparation of a summary report on an annual basis, or at the request
of the Licensing Authority (CDSCO). As per Para 6.11 of part I Good
Manufacturing Practices For Pharmaceutical Products: Main Principles
of Schedule M revised vide G.S.R. No. 922(E) dated 28th December
2023 of Drugs and Cosmetics Act and Rules, the licensee shall have a
Pharmacovigilance system in place for collecting, processing and
forwarding the reports to the licensing authorities for information on the
adverse drug reactions emerging from the use of drugs manufactured
or marketed or imported by the licensee. The licensee shall have a
pharmacovigilance system in place for collecting, processing and
forwarding the reports to the licensing authorities for information on the
adverse drug reactions emerging from the use of drugs manufactured
or marketed by the licensee.
e) Importers should have in place adequate procedures for AE/AEFI receipt,
handling, evaluation (for determination of complaints or AE/AEFI) and
forwarding AE/AEFI to the MAH and should include but not be limited to the
following
i. Procedure on how complaints and AE/AEFI are tracked/logged
in;
ii. Procedure on how complaints are assessed in order to
determine if it is an AE/AEFI;
iii. Identifying key personnel who are responsible for forwarding the
AE/AEFI reports to the MAH; Requirement to report AE/AEFI to
the MAH within an appropriate timeframe to allow for expedited
reporting (if required); and all SAEs to be reported within15 days
of receipt of information to CDSCO. This should be read in
conformity with para 4, under heading Post Marketing
Surveillance sub para iii of Fifth Schedule of New Drugs and
Clinical Trial Rules 2019 of Drugs and Cosmetics Rules.
iv. Requirement to follow up with the MAH to ensure that AE/AEFI
have been assessed and sent to Drugs Controller General
(India), if required;
v. Requirement to maintain records of all AE/AEFI received and
AE/AEFI sent to the MAHs and subsequent correspondence;
 and ensure that as per Drugs and cosmetics Rules, As per
Para 6.11 of part I Good Manufacturing Practices For
Pharmaceutical Products: Main Principles of Schedule M
revised vide G.S.R. No. 922(E) dated 28th December 2023
of Drugs and Cosmetics Act and Rules, the licensee shall
have a Pharmacovigilance system in place for collecting,
processing and forwarding the reports to the licensing
authorities for information on the adverse drug reactions
emerging from the use of drugs manufactured or marketed or
imported by the licensee reports of serious adverse drug
reaction resulting from the use of a drug along with
comments and documents are forthwith reported to
concerned Licensing Authority (CDSCO).
f) Procedures should be written, reviewed and approved by qualified
personnel.
g) Procedures should be made available to all relevant personnel involved
in pharmacovigilance activities before the procedures are effective.
h) Procedures should be reviewed on a periodic basis to ensure that they
accurately reflect current practice.
i) Changes to procedures should be tracked and documented.
j) Deviations from procedures relating to pharmacovigilance activities
should be documented
k) When part or all pharmacovigilance activities are performed by a third
party, MAH and importers should review procedures to ensure that
procedures are adequate and compliant with applicable requirements stated
in New Drugs and Clinical Trial Rules 20198. Copies of the procedures
should be readily available to the inspector/ regulator.
l) MAHs
i. The AE/AEFI evaluation, including but not limited to, seriousness and
expectedness assessment should be completed in a manner which
would ensure expedited reporting timelines are met. For both domestic
and foreign reports, the expectedness should be determined from the
relevant labeling such as the product monograph, labeling standards,
information approved for market authorization, or the product label.
ii. Mechanisms should be in place to determine whether an AE/AEFI
 qualifies for 15 day expedited reporting. When a case is found not
reportable, justification is provided and documented.
iii. For AE/AEFI reports that qualify for expedited reporting, the 4
minimum criteria (an identifiable reporter (source), an identifiable
patient, a suspect product and an adverse reaction) for submitting a
case are met.
iv. Process should be in place for determining if a solicited report is to be
submitted to Licensing Authority in an expedited fashion (within 15
days).
v. A qualified health care professional evaluates and assesses AE/AEFI
to determine whether the AE/AEFI qualifies for expedited 15-day
reporting.

m) Reports of AEFI cases from 2 or more sources

i. A mechanism should be in place to identify AEFI data that were

reported to the MAH more than once.
ii. When similar reports are found, verifications should take place to
determine if they are duplicate reports.
iii. Multiple copies of the same AE/AEFI reports should be nullified within
the
iv. Pharmacovigilance system and the record of nullification should be
maintained, allowing for auditing of the nullified record in the future.
v. Documented procedure and process should be in place describing
when AE/AEFI reports may be nullified.
vi. Documentation related to nullified cases should be retained.
vii. Additional information received for previously submitted AE/AEFI
reports
viii. Upon receipt of follow-up information, AE/AEFI reports should be re-
evaluated.
ix. Follow-up information received for previously submitted AE/AEFI
reports must be sent to Licensing Authority within the prescribed
timelines. Reference should be made to the initial report by including
the MAH number specific to the report either in the follow-up report or
on the fax cover sheet.
x. All reportable AE/AEFI that have been upgraded to serious upon
 receipt of follow- up information are to be sent to Licensing Authority
within the prescribed timelines
xi. Rationale for changing the seriousness of an AE/AEFI report should
be documented.
xii. Process for seeking follow-up information and submitting it to
Licensing Authority should be in place. All attempts to obtain follow-up
information should be documented.
n) Reporting of AE/AEFI data
All AEs shall be reported to Licensing Authority (CDSCO) in
accordance with New Drugs Clinical Trial Rules 2019.
o) Importers
All suspected AE/AEFI received should be sent to the MAH within an
appropriate time frame to allow for expedited reporting (if required),
and should therefore be reported to Licensing Authority by the MAH in
accordance with the requirements of the New Drugs Clinical Trial Rules
2019, if required.
Importers should follow-up with the MAH to ensure that AE/AEFI have
been assessed and submitted, if required.
p) Literature Search
MAHs
i. The process, including but not limited to how the search is done, the
database(s) used, and the periodicity of those searches describing
the search in the literature should be written in a procedure.
ii. AE/AEFI found during literature searches should be classified
according to their seriousness and expectedness. These
assessments should be retained and be well documented.
iii. AE/AEFI reports from the scientific and medical literature must be
reported to Licensing Authority in accordance with the New Drugs
Clinical Trial Rules 2019.
iv. Results of the literature searches should be documented.
v. When literature search is performed by a third party, contractual
agreements describing each party’s responsibilities should exist.

q) Periodic Self-inspections

MAHs and Importers

 A self-inspection program that covers all departments that may receive
AE/AEFI reports or that are involved in pharmacovigilance activities may
help to ensure compliance with the appropriate sections of the News and
Drugs and Clinical Trial Rules 2019 applicable to adverse drug reaction
reporting. Self-inspection programs should be in place and should include but
not be limited to the following;
i. A comprehensive written procedure that describes the functions of the
self-inspection program.
ii. Periodic self-inspections that are carried out at defined frequencies,
which are documented. If no AEs have been received, the periodic self-
inspections should include a simulation exercise.
iii. Reports on the findings of the self-inspections and on corrective
actions. These reports should be reviewed by appropriate senior
MAH management. Corrective actions should be implemented in a
timely manner.
r) Periodic self-inspections should be conducted by personnel independent
from the pharmacovigilance department and that are suitably qualified to
perform and evaluate the inspections.

s) Personnel and Training

MAHs and Importers
The individual in charge of the pharmacovigilance department should be
qualified by pertinent training and experience relevant to their assigned
responsibilities
The qualified health care professional;
i. Should have knowledge of all applicable sections of the D&C Act 1940
and Rules made there under, New Drug and Clinical Trial Rules 2019
and GCP Guidelines related to the AEs reporting requirements, and
of key pharmacovigilance activities performed as part of the MAH’s
pharmacovigilance system.
ii. Should be responsible for establishing and managing/maintaining a
system which ensures that information concerning all suspected AEs
that are reported to the personnel of the MAH and to medical
representatives is collected and evaluated.
iii. All personnel involved in pharmacovigilance activities, which may
 include customer service, sales representatives and receptionists,
should have their specific duties recorded in a written description and
have adequate authority to carry out their responsibilities.
iv. All personnel involved in pharmacovigilance activities should be aware
of the principles of pharmacovigilance that affect them, and all
personnel should receive relevant training.
v. When responsible personnel are absent, qualified personnel should be
appointed to carry out their duties and functions.
vi. A qualified health care professional with adequate experience and
training, should be available to evaluate information in respect of a
potential AE/AEFI, assesses the seriousness, expectedness, and
report ability of AE/AEFI, and determine if the AE/AEFI report qualifies
for expedited reporting (within 15 days) and if the report is to be
included in the annual summary
vii. Training should be provided prior to implementation of new or revised
procedures. Records of training should be maintained.
viii. Consultants and contractors should have the necessary qualifications,
training, and experience to fulfill their New Drugs Clinical Trial Rules
2019.

t) Contractual Agreements
MAHs and Importer
i) Contractual agreement should exist with every party that conducts
pharmacovigilance activities, including third- party private label or other MAH
whose name is included in the product information or appears on the label
and should include;
a. who is responsible for determining if a complaint is a potential
AE/AEFI,
b. Who is responsible to report AE/AEFI,
c. Who is responsible for preparing the ASR, including the critical
analysis of the annual summary reports, and what process is utilized
to conduct the critical analysis,
d. Who is responsible for conducting literature searches?
e. Processes by which an exchange of safety information, including
timelines and regulatory reporting responsibilities, are taking place
 between the MAH and its partners (including, but not limited to,
consultants and contractors).
f. To notify other party if changes to procedures are made.
ii) In the case of foreign MAHs, the contractual agreement should specify
to send known AE/AEFI to the local MAH in a timely manner so as to promote
compliance with regulatory reporting obligations.
iii) In the case where the importer is responsible for the pharmacovigilance
activities, the contractual agreement should specify that the foreign MAH is to
send the AE/AEFI data to the importer in a timely manner.
iv) All records (including, but not limited to, contractual agreements and
safety data/ AE/AEFI data) should be available on the premises of the MAH and
the importer for auditing purposes
v) When there is a transfer of market authorization/mergers, contractual
agreement should exist between the previous MAH and the new one outlining
eachparty responsibility.
vi) Contractual agreement should be shared and signed off by each party.
vii) Contractual agreement should be reviewed periodically in order to
reflect current regulations and practices.

u) Validation of Computerized Systems

MAHs, Importer, and all parties involved in pharmacovigilance activities who

use an electronic system.
Data of the validation of system(s) used for recording, evaluating, and tracking
complaints and AE/AEFI should be available.
Computerized systems should be validated and systems are periodically and
suitably backed up at predefined intervals. It should be identified what
electronic data and records will be collected, modified, imported and exported,
archived and how they will be retrieved and transmitted. Electronic source
data, including the audit trail should be directly accessible by investigators,
monitors, auditors, and inspectors without compromising the confidentiality of
participants’ identities.
 6. DEFINITIONS
A. Adverse Event (AE):
Any untoward medical occurrence (including a symptom / disease or an
abnormal laboratory finding) during treatment with a pharmaceutical product
in a patient or a human volunteer that does not necessarily have a
relationship with the treatment being given. Also see Serious Adverse Event.
B.Adverse Event Following Immunization (AEFI):
This is defined as any untoward medical occurrence which follows
immunization and which does not necessarily have a causal relationship with
the use of the vaccine. The adverse event may be any unfavorable or
unintended sign, an abnormal laboratory finding, a symptom or a disease.
C.Adverse Drug Reaction (ADR):
(a) In case of approved pharmaceutical products: A noxious and
unintended response at doses normally used or tested in humans
(b) In case of new unregistered pharmaceutical products (or those
products which are not yet approved for the medical condition where
they are being tested): A noxious and unintended response at any
dose(s).
The phrase ADR differs from AE, in case of an ADR there appears to be a
reasonable possibility that the adverse event is related with the medicinal
product being studied. Adverse drug reactions are type A (pharmacological)
or type B (idiosyncratic). Type A reactions represent an augmentation of the
pharmacological actions of a drug. They are dose-dependent and are,
therefore, readily reversible on reducing the dose or withdrawing the drug. In
contrast, type B adverse reactions are bizarre and cannot be predicted from
the known pharmacology of the drug.
D.Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR)
An AE or ADR that is associated with death, inpatient hospitalization,
prolongation of hospitalization, persistent or significant disability or
incapacity, a congenital anomaly or birth defect, or is otherwise life
threatening.
This is to be read along with the definition as mentioned in Drugs &
Cosmetics Act 1940 and Rules 1945 there under as- A Serious adverse
event is an untoward medical occurrence during clinical trial that is
associated with death, in patient hospitalization, prolongation of
hospitalization, persistent or significant disability or incapacity, a congenital
anomaly or birth defect, or is otherwise life threatening.
E. Suspected Serious Adverse Reaction (SSAR):
An adverse reaction that is classed in nature as serious and which is
consistent with the information about the medicinal product in question set
out.
• In the case of a licensed product, in the summary of product
characteristics (SmPC) for that product.
• In the case of any other investigational medicinal product, in the
Investigator’s Brochure (IB) relating to the trial in question.
F.Suspected Unexpected Serious Adverse Reaction (SUSAR):
An adverse reaction that is classed in nature as serious and which is not
consistent with the information about the medicinal product in question set
out.
• In the case of a licensed product, in the summary of product
characteristics (SmPC) for that product.
• In the case of any other investigational medicinal product, in the IB
relating to the trial in question.
G. Third Party:
For the purpose of this guidance documents means that the entity who is nor
the manufacturer neither the importer.
H. Market Authorization Holder (MAH):
For the purpose of this guidance document means the manufacturer or the
importer of the drug, who has valid manufacturing or import license.
I. Cluster:
Two or more cases of the same event or similar events related in time,
geography, and/or the vaccine administered.

7. REFERENCES

• ICH Guideline. E2E: Pharmacovigilance Planning

• Drugs and Cosmetics Act 1940 & Rules 1945– Fifth Schedule of New
Drugs and Clinical Trial Rules 2019
• Guidance for Industry – Development and Use of Risk Minimization
Action Plans – US FDA
Appendix: A
Annexure-1:
Annexure-2:
Annexure-3:

33
35
36
Annexure-5

37
Appendix B:

Example of summary tabulations

Note: These examples can be modified by manufacturer and/or importer to suit

specific situations, as appropriate.

Table 01: Estimated cumulative subject exposure

from clinical trials

Treatment Number of Subjects

Biological product
Comparator
Placebo

Estimates of cumulative subject exposure, based upon actual exposure data from
completed clinical trials and the enrolment/randomization schemes for ongoing trials.

Table 02: Cumulative subject exposure to “New Drug”

from completed clinical trials by age and sex*

Number of Subjects
Age Range Male Female Total

Table 03: Cumulative subject exposure to “New Drug” from completed

clinical trials by racial/ethnic group*

Racial/Ethnic Group Number of Subjects

Asian
Black
Caucasian
Other
Unknown
Total

*Data from completed trial as of [date]

 Table 04: Cumulative exposure from marketing
experience from India

Indication Sex Age Dose / Strength Formulation

Female
Male

Overall

Indication 1

Indication 2*

Includes cumulative data obtained from month/day /year through month/day/year, where
available

Table 05: Interval exposure from marketing experience

from India
Indication Sex Age Dose/ Strength Formulation
Female
Male

Indication 1

Indication 2*
Includes interval data obtained from month/day /year through month/day/year, where
available

Table 06: Cumulative exposure from marketing

experience from rest of the world
Indication Sex Age Dose/ Formulati ROW
Strength on
(which ever
applicable)

US/Canada
Female

Mexico
Japan

Other
Male

EU
Overall

Indication 1

Indication 2*

Includes cumulative data obtained from month/day/year through month/day/year,

where available

Table 07: Interval exposure from marketing

experience from rest of the world
Indication Sex Age Dose/ Formulati ROW
Strength on
(which ever
applicable)
US/Canada
Female

Mexico
Japan

Other
Male

EU

Indication 1

Indication 2*
 Includes interval data obtained from month/day/year through month/day/year, wherever
available

Table 08: Cumulative tabulations of Serious Adverse Events from

clinical trials
System Organ Investigational Active Placebo* Causality
Class Pharmaceutical Comparator Assessment
Product (Related
(R) and Not
related
(NR)
Preferred Term Listed Not Listed Not
Listed Listed
Blood and
lymphatic
system
disorders

Anemia
Bone Marrow
Necrosis
Cardiac
disorders
Tachycardia
Ischemic
cardiomyopathy
 Table 09: Number of AE/AEFIs using the term (System Organ Class
(SOC) and preferred term (PT) from Post-Marketing Sources
Report Sources (Literature, Spontaneous, Non-
solicited or any other) interventional
post-marketing
sources
Serious Non-serious Total Serious
Spontane
ous
Interv Cumul Interv Cumul Interv Cumula
al ative al ative al tive

SOC 1
PT

SOC 2
PT

Appendix C:
Tabular Summary of Safety Signals that were ongoing or closed
during the reporting Interval (Reporting Interval: DD-MM-YYYY to DD-
MM-YYYY)
Signal Date Status Date Source of Reason for Method of Action(s)
term* detect (ongoin closed Signal** evaluation signal taken or
e g or (for & evaluation planned##
d@ closed) closed summary
# signals) of key data
* @@

Strok e MM/YY Ongoing MM/YY Y Meta Statistically Review Pending

Y analysis significant meta-
(published increase in analysis
trials) frequency and
available
data
TTS MM/YY Closed MM/YY Spontaneo Rash Targeted RSI
Y Y us case already an follow up of updated
reports & identified reports with with a
one case risk SJS not site visit to Warning
report in reported in one and
Phase IV trial pre hospital. Full Precaution
authorization review of DHPC sent to
CTs. 4 cases by oncologists
apparently manufacturer Effectivene
unconfound and/or ss survey
ed reports importer planned 6
within 6 dermatologi months
months of st and post DHPC.
approval; literature RMP
plausible searches updated.
time to onset
*Signal term: A brief descriptive name of a medical concept for the signal. The description may
evolve and be refined as the signal is evaluated. The concept and scope may, or may not, be
limited to specific term(s), depending on the source of signal.
@ Date detected (month/year): Month and year the manufacturer and/or importer became
aware of the signal.
#Status: Ongoing: Signal under evaluation at the data lock point of the PSUR. Provide anticipated
completion date, if known; closed: Signal for which evaluation was completed before the data lock
point of the PSUR

Note: A new signal of which the manufacturer and/or importer became aware during the
reporting interval may be classified as closed or ongoing, depending on the status of signal
evaluation at the data lock point of the PSUR.
$ Date closed (month/year): Month and year when the signal evaluation was
completed.
**Source of signal: Data or information source from which a signal arose. Examples include, but
may not be limited to, spontaneous Adverse Event Reports, clinical trial data, scientific literature,
non-clinical study results, or information requests or inquiries from a regulatory authority.
@@ Reason for evaluation: A brief summary of key data and rationale for further
evaluation.
## Actions taken or planned: State whether or not a specific action has been taken or is planned
for all closed signals that have been classified as potential or identified risks. If any further actions
are planned for newly or previously identified signals under evaluation at the data lock point, these
should be listed. Otherwise leave blank for ongoing signals.
Appendix D: