Q. Organisation and objective of ICH and Expedited reporting.

Unique
harmonization project involving regulatory authorities and pharmaceutical
industry started in 1990 with well-defined objectives: To improve efficiency of
new drug development and registration processes. To promote public health,
prevent duplication of clinical trials in humans and minimize the use of animal
testing without compromising safety and effectiveness. Accomplished through
the development and implementation of harmonized guidelines and
standards. #objective:- To develop a stand-alone document for regions that
prefer this approach, or To provide guidance on incorporation of elements of
the Safety Specification and Pharmacovigilance Plan into the Common
Technical Document (CTD).* The guideline describes a method for
summarizing: • The important identified risks of a drug, Important potential
risks, and
*expedited reporting:- it is important to harmonize the way to gather and, if
necessary, to take action on important ant clinical safety information arising
during clinical development. Thus, agreed definitions and terminology, as well
as procedures, will ensure uniform Good Clinical Practice standards in this area. The
initiatives already undertaken for marketed medicines through the CIOMS-1 and CIOMS-2
Working Groups on expedited (alert) reports and periodic safety update reporting,
respectively, are important precedents and models. However, there are special
circumstances involving medicinal products under development, especially in the early
stages and before any marketing experience is available. Conversely, it must be recognized
that a medicinal product will be under various stages of development and/or marketing in
different countries, and safety data from marketing experience will ordinarily be of interest
to regulators in countries where the medicinal product is still under investigational-only
(Phase 1, 2, or 3) status. For this reason, it is both practical and well-advised to regard pre-
marketing and post-marketing clinical safety reporting concepts and practices as
interdependent, while recognizing that responsibility for clinical safety within regulatory
bodies and companies may reside with different departments, depending on the status of
the product (investigational vs There a are two issues within the broad subject of c clinical
safety data management that are appropriate for harmonization at this time: 1. The
development of standard definitions and terminology for key aspects of clinical safety
reporting, and 2. The appropriate mechanism for handling expedited (rapid) reporting, in the
investigational (i.e., pre-approval) phase. The provisions of this guideline should be used in
conjunction with other ICH Good Clinical Practice guideline’s.
Q. Safety Data Generation Pre clinical phase. Clinical phase. Post
approval phase (PMS). :-safety data is generated throughout the drug
development process, including pre-clinical, clinical, and post-approval (PMS)
phases. Pre-clinical studies in animals provide initial toxicity and
pharmacokinetic data. Clinical trials, which are divided into phases, further
assess safety and efficacy in humans. Post-approval monitoring, including
periodic safety update reports and spontaneous reporting, continues to gather
data on long-term safety and efficacy. 1)Pre-clinical Phase: This phase
involves extensive laboratory and animal studies to evaluate the safety and
potential risks of a new drug before it enters human testing. Researchers
assess pharmacokinetics (absorption, distribution, metabolism, and
excretion) and toxicology (acute, chronic, and reproductive toxicity). These
studies help establish a safety profile before human trials, taking 1.5-2 years.
*Clinical Phase:Clinical trials are divided into four phases (I, II, III, and IV) to
evaluate safety and efficacy in humans. Phase I studies involve a small group
of healthy volunteers to determine the drug’s dosage, safe range, and how the
body absorbs and eliminates it.* Phase II studies are conducted in a larger
group of patients with the condition being treated to assess efficacy and further
evaluate safety. * Phase III studies are large, controlled trials to confirm
efficacy, assess risks and benefits, and compare the drug with other
treatments.* Phase IV studies are conducted after the drug is approved and on
the market, focusing on monitoring long-term safety and effectiveness,
identifying rare side effects, and comparing the drug to other treatments in real-
world settings.
*Post-approval Phase (PMS):Post-marketing surveillance, also known as
Phase IV, continues to monitor the drug’s safety and effectiveness after it’s
approved. *This phase helps identify adverse events, rare side effects, and
long-term effects that may not have been detected during clinical trials. *Data
is collected through various methods, including spontaneous reporting,
periodic safety update reports, and non-interventional studies.
*The goal is to ensure that the drug remains safe and effective for its intended
use and to identify any new safety issues that may arise.
Q. Individual case safety reports:- An ICSR is a document that contains
information about a single patient who has experienced an adverse event or
suspected adverse reaction (ADR) after exposure to a drug or other medicinal
product. *ICSRs are typically submitted to regulatory authorities, such as the
FDA in the United States, or the EMA in Europe. *These reports are used to
monitor the safety of medicinal products and to identify potential safety
concerns.* Pharmacovigilance professionals review the reports and assess the
causality of the adverse event, determine the severity of the event, and decide
on any necessary regulatory action * These four elements for valid
assessment of an ICSR are: 1.An identifiable patient *An identifiable reporter
A suspect drug and An adverse event. *Importance of ICSR: To provide critical
information on the safety profile of drugs and medical products. *In post-
marketing surveillance, it helps to ensure that any safety concerns that may
arise after approval are identified and addressed in a timely manner. *To
improve patient safety by providing valuable information on the risks
associated with particular drugs or medical product Uses of ICSR: Signal
detection: Signals can indicate the need for further investigation or regulatory
action. Risk assessment: It invoves evaluating the severity, frequency, and
potential outcomes of a particular adverse event or suspected adverse
reaction based on the available evidence.

Q. Post approval expedited reporting:- - Post-approval expedited reporting

is the prompt reporting of serious, unexpected adverse drug reactions (ADRs)
to regulatory authorities after a drug has been approved for sale. It's a crucial
aspect of post-marketing surveillance, ensuring the ongoing safety monitoring
of pharmaceutical products. This reporting helps identify new safety concerns
and allows for timely regulatory action. , Key Aspects of Post-Approval
Expedited Reporting:Prompt Reporting:Reports should be submitted to
regulatory authorities as soon as possible, often within specific timeframes
(e.g., 7 days for fatal or life-threatening reactions, 15 days for other serious
unexpected reactions). Serious and Unexpected ADRs:The reporting focuses
on single cases of serious, unexpected ADRs.
Definitions:“Serious” refers to events that result in death, are life-threatening,
require hospitalization, or result in persistent or significant
disability/incapacity. “Unexpected” refers to ADRs that are not consistent with
information in the drug’s source documents. *Importance:-Expedited
reporting allows regulatory agencies to quickly assess new safety information,
potentially leading to updates to product labeling, warnings, or even
restrictions on use.* ICH Guidance:The International Conference on
Harmonisation (ICH) provides guidelines for post-approval safety data
management and expedited reporting, including ICH E2D. *Case
Management: Post-approval safety data management also includes good case
management practices, ensuring that individual case safety reports are
properly processed and reviewed.
Q. Periodic safety update report:- Periodic Safety Update Report (PSUR) is a
pharmacovigilance document submitted by marketing authorization holders to
regulatory authorities, providing a comprehensive evaluation of a drug’s safety
profile after it has been authorized for use. The PSUR assesses the risk-benefit
ratio of a medicine, considering new and emerging safety information.
*Purpose and Content: * Risk-Benefit Assessment: The primary goal is to
analyze the risk-benefit balance of a medicinal product, ensuring that its
benefits outweigh the potential risks.

*Comprehensive Evaluation:PSURs analyze safety and efficacy data,

including adverse drug reactions (ADRs), emerging risks, and any new
information received after the drug’s approval
. *Signal Detection: They help identify and evaluate potential new risks or
safety concerns, which may require changes to product information, risk
mitigation strategies, or further investigations.
*Compliance: PSURs are a regulatory requirement for maintaining a
medicine’s authorization and ensuring ongoing safety monitoring. Frequency
and Submission:Periodic Updates:PSURs are submitted at predefined
intervals, typically annually or bi-annually, depending on the drug and
regulatory requirements.
Q. ICH GUIDELINE FOR PHARMACOVIGILANCE Good clinical practice in
pharmacovigilance Studies:- *Good clinical practices is a set of
internationally recognized ethical and scientifically quality requirements which
must be observed for designing. Conducting, recording and reporting clinical
trials that involves the participation *of human subjects. Compliance with this
good practice provides assurance and the rights, safety and well-being of trial
subjects are protected and that results of clinical trial are credible.*A standard
for the design, conduct, monitoring, auditing, recording. Analyses and
reporting of clinical trials that provides assurance that the data and reported
results are credible and accurate and that the rights, integrity, and
confidentially of trial subjects are protected. * ICH-GCP is an International
Conference on Harmonization Good Clinical Practices the guidelines was
developed with consideration of the current good clinical practices of the
European Union, japan, and the United States as well as those of Australia,
Canada, the Nordic countries and the world health organization. *
objectives:- *To harmonize the regulations and the guidelines for the drug
development. *To ensure the scientific validity and credibility of the data
collected inhuman clinical studies. *To protect the rights of human subjects
participating in the clinical trials.More economical use of human, animal and
material resources.Minimizing the risks and maximizing benefits associated
with investigational drugs.
Q. Upsala monitoring centre:- The Uppsala Monitoring Centre (UMC) is a
global organization that operates under the World Health Organization (WHO)
as the coordinating body for the WHO Programme for International Drug
Monitoring. Based in Uppsala, Sweden, the UMC collects, analyzes, and
disseminates data related to pharmacovigilance (the science and activities
related to the detection, assessment, understanding, and prevention of
adverse effects or any other drug-related problems). * functions
include:Adverse Drug Reaction (ADR) Monitoring: Collects and analyzes
reports of adverse drug reactions (ADRs) from member countries, contributing
to global safety surveillance.* VigiBase Database: *Data Analysis and Signal
Detection : Analyzes ADR data to detect potential safety signals, patterns, or
Q. Vaccine safety surveillance:- vaccine:- A complex biological formulation
that gives acquired immunity to a particular infectious disease is called
vaccine. * The process of ingestion of antigenic agents to stimulate an
individuals immune system for against particular pathogen is called
vaccination. It is one of the most effective way, * Vaccine safety surveillance
involves monitoring the safety of vaccines after they are released for public use,
to identify and investigate any potential adverse events. This is done through
both passive and active surveillance systems. Passive surveillance relies on
reports from healthcare providers, while active surveillance involves the
proactive collection of data.
*vaccine Pharmacovigilance:- Pharmacovigilance of vaccines involves
monitoring, detecting, assessing, understanding, preventing, and
communicating adverse events related to immunization. It’s crucial for
identifying and addressing potential risks associated with vaccine use,
ensuring public health and safety. Objectives:- Minimize negative effect. * To
promote safe use of vaccines. * Detect the adverse event early. * To Make sure
that healthy people usually receive the vaccines. * To ensure that infants and
children consume most of the vaccines. * To administer the vaccines globally
STEPS OF VACCINE PHARMACOVIGILANE * Detect signal suggesting AEFI is
related to vaccine * Develop hypothesis about casual association b/w an AEFI
and vaccination*Test hypothesis through appropriate epidemiological
methods “
vaccine pharmacovigilance include: Adverse Events Following
Immunization (AEFI) Detection: This involves identifying and reporting any
adverse events occurring after vaccination, even if a causal relationship is not
definitively established. *AEFI Assessment:Evaluating the nature, severity,
and potential risk of reported adverse events to determine if they are related to
the vaccine. *Understanding Vaccine Risks: Analyzing data from AEFI reports
and other sources to better understand the causes and mechanisms of
vaccine-related adverse events.
Q. Vaccine failure :- When the disease occurs in a person despite being
vaccinated for it, this is called vaccine failure * Vaccine failure occurs when a
vaccine does not provide adequate protection against a disease, despite being
properly administered.
CAUSES OF VACCINE FAILURE ,Manufacture, Incorrect vaccination timing,
Poor vaccine storage, Ageing, Vaccine administration method, Vaccine
transportation, Improper duration of vaccination, Use of expired vaccine,
➤Light exposure, Poor health status, Genetic resistance,
Immunosuppression, Lack of maintenance, Inappropriate choice of vaccine
*Q.adverse event following immunization:- Adverse Events Following
Immunization (AEFI) are untoward medical occurrences that follow
immunization, but may not necessarily be caused by the vaccine. AEFI can be
classified by severity (minor, severe, serious) and by the reason for the event
(vaccine-related, error-related, coincidental, anxiety-related, or unknown). The
significance of AEFI reporting and surveillance is to ensure the quality and
safety of vaccines, maintain public confidence, and improve immunization
programs. Classification of AEFI: * Severity: Minor: Common, self-limiting
reactions that resolve quickly and pose little danger, like pain or swelling at the
injection site. Severe: Reactions that are not life-threatening, but may require
medical attention, such as a high fever or a severe rash. Serious: Events that
are life-threatening, result in death, require hospitalization, or lead to a
permanent disability. * Reason for Event: Vaccine-Related: Reactions due to
the vaccine product, a defect in the vaccine, or an allergic reaction. *Error-
Related: Events caused by an error in vaccine handling, preparation, or administration.
Coincidental: Events that occur after immunization but are unrelated to the vaccine, such
as a pre-existing condition or a different illness. Significance of AEFI Reporting and
Surveillance: Public Confidence: AEFI surveillance helps to identify and address
potential vaccine safety issues, which is crucial for maintaining public trust in
immunization programs. *Vaccine Safety:Surveillance allows for the
monitoring of vaccine safety, identifying rare adverse events, and ensuring that
vaccines are safe and effective.
Q. PHARMACOVIGILANCE METHODS 1) PASSIVE SURVEILLANCE -
SPONTANEOUS REPORTING, CASE SERIES * spontaneous reporting :-
*Voluntary reporting or Mandatory reporting * An Unsolicited reports from healthcare
professionals or consumers to a company, regulatory authority or other organization that
describes one or more ADRs in a patient who was given one or more medicinal products is
called spontaneous reports. * Physicians, other healthcare professionals- provided with
forms for filling suspected ADR details- once filled, they are notified to drug regulatory
authority. (eg: DCGI for India, USFDA for United States of America, TGA (Therapeutic and
Goods Administration) for Australia) * Forms are generated by regulatory authorities or by
organizations under aegis of regulatory authorities. * Forms are circulated through web
sites or distributed to healthcare professionals through training programs
conducted. * case series:- Collection of case reports that share some
common characteristics such as being exposed to the same drug; and, in
which same outcome is observed. * A case series, Involves reports on two or more
people with common exposure to a drug, or a common outcome. *Series of case reports
can provide evidence of an association between a drug and an adverse event.Used generally
for generating an hypothesis than for verifying an association between drug exposure and
outcome. Advantage:- Easy to write, Generate hypothesis, Observations are useful
for other researchers.,DISADVANTAGES:, Chances of bias, Lack of comparison
group. 2) ACTIVE SURVEILLANCE – SENTINEL SITES, DRUG EVENT
MONITORING, REGISTRIES 1. SENTINEL SITES ,Active surveillance can be
achieved by reviewing medical records or interviewing patients and/or physicians in a
sample of sentinel sites to ensure complete and accurate data on reported adverse events
from these sites. * The selected sites can provide information such as data from specific
patient sub groups that would not be available in a passive spontaneous reporting system.
* Weaknesses of sentinel sites: selection bias, small number of patients, increased costs.2.
DRUG EVENT MONITORING * In this system, patients are first identified from
electronic prescription data or automated health insurance claims. * A follow
up questionnaire can then be send to each prescribing physician or patient at
pre-specified intervals to obtain outcome information. * Relevant information
including demographics, indication for treatment, duration of therapy, dosage,
clinical events, and reasons for the discontinuation of therapy can be included
in the questionnaire.
3) COMPARATIVE OBSERVATIONAL STUDIES – COHORT, CASE-CONTROL,
AND CROSS SECTIONAL STUDIES ‘ do itself.

4. STIMULATED REPORTING:-Unsolicited in nature and considered as a

form of spontaneous reporting * Stimulated reports are those that
may have been motivated, prompted or induced and can occur in
certain situations such as: Notifications by authorities concerned,
Literature report, Publication in the press, etc. * Data obtained from
stimulated reporting cannot be used to generate accurate incidence
rates, but can be used to estimate reporting rates.
Limitations:➤Selective Reporting➤Incomplete information
5.TARGETED CLINICAL INVESTIGATIONS:: When significant risks
are identified from pre-approval clinical trials, further clinical studies
might be required to evaluate the mechanism of action for the
adverse reaction. * In some instances, Pharmacodynamics’ and
pharmacokinetic studies might be conducted to determine whether
a particular dose can put patients at an increased risk of adverse
events. * Genetic testing can provide clues about the group of
patients at an increased risk of adverse reaction. * Specific studies to
investigate potential drug-drug interactions and food- drug
interactions might also be required. * Studies can include population
pharmacokinetic studies and drug concentration monitoring in
patients and normal volunteers. * Sometimes, potential risks or
unforeseen benefits in special population might be identified from
pre-approval clinical trials, but cannot be fully quantified due to small
sample size or the exclusion of sub population of patients from these
clinical studies *These populations might include the elderly,
children or patients with renal or hepatic disorder.
Q. Communication in pharmacovigilance:- INTRODUCTION:
Communication in pharmacovigilance refers to the exchange of
information and knowledge between different stakeholders involved
in the monitoring, assessment, and prevention of adverse effects or
other drug-related problems. * Effective communication is essential
for ensuring the safety of drugs and vaccines and improving public
health.
Q. EFFECTIVE COMMUNICATION IN PHARMACOVIGILANCE * Central to
effective and timely communication between FDA and sponsors is the ability
to communicate clearly, both orally and in writing, inside and outside the
formal meeting format. Communication via any of the following best practices
and communication methods (except meetings where numerous attendees
participate) should be conducted via the FDA project manager, typically the
review division RPM, rather than FDA reviewers, team leaders, or senior
management to ensure that the advice is appropriately vetted and
documented. * Meetings between FDA and Sponsors * Sponsors can
request meetings with FDA at any time during drug development to resolve
questions and issues. These meetings may also help to minimize wasteful
expenditures of time and resources. *Written Correspondence from FDA :-
FDA project managers will use established letter templates to ensure
consistency and accuracy in regulatory communications. Project managers
should send a courtesy copy of written FDA correspondence to sponsors when
such communications are time-sensitive or communicate actions *
Submissions from Sponsors:- FDA regulations describe general principles of,
as well as content and format requirements for INDs. *Acknowledging Receipt
of Communications:- FDA project managers will send written
acknowledgment of receipt of certain submissions that have review timelines
* Email between FDA and Sponsors :- Sponsors should establish secure
email with FDA to allow for informal communications that may include
commercial confidential information.
Q. COMMUNICATION IN DRUG SAFETY CRISIS MANAGEMENT: * Expert
responses to public queries * Drug safety communication * Safety labelling
changes * Risk communication research

* Expert responses to public queries: * As a healthcare professionals respond

to public queries around the world providing expert guidance and respond to
the queries about human drug product * More than 65000 requests receive
annually * Queries receive via phone, electronic mails, and letter from array of
stakeholder * Social media and online tools for DDERs public interface in using
multiple digital * Platform and tools to provide drug safety outreach and
education. *Facebook, twitter, podcast. * Pharmacovigilance in CDERS/FDA
introduction to FDAs medwatch adverse reporting programme.
Drug safety communication: Patients, caregivers, healthcare professionals,
public should be updated on drug safety communication, * This manages from
emerging risks and cautions about medical errors * This contain actionable
recommendations from patients about the drugs and make them more
informed decisions and prevent drug related harm.
Safety labelling changes: *When a drug is approved for safety marketing, not
every safety concern or risk potential can be identified. *Post market safety is
essential to learn more about the effects of a medicine when use by a large no.
of people for long duration. * If new safety concerns emerge after a medicine is
used in a real-world CDER may require ‘safety labelling change' or [SLC]* It
includes contraindications, warnings, and precautions.
Risk communication research: OCOMM houses a number of ongoing
research studies that will allow better understanding of CDER audiences
knowledge, perceptions, needs, desires, and behaviours related to a variety of
drug safety information.
This research efforts also provide the public, including people with limited
health literacy or who face disparities in accessing health services,
opportunities, for input on the effectiveness of CDER drug safety information.
Q. Communication with regulatory agencies, business partners,
healthcare facilities and media. *Pharmacovigilance in regulation of
medicines * Pharmacovigilance in practice * Pharmacovigilance in clinical
practice * Pharmacovigilance in disease control public health programmes
*Pharmacovigilance in regulation of medicines: * They provide the
foundation for a national ethos of medicine safety and for public confidence in
medicines. * The regulatory authorities need to go further than approval of new
medicines to encompass a wider range of issues relating to the safety
medicines, namely * Clinical trails * Safety of complimentary and traditional
medicines, vaccines, and biological medicines. * Pharmacovigilance in
practice: * Cerivastin was first approved as a lipid-regulating agent in 1997.by
2000 a total 549 cases of rhabdomyolysis associated with cerivastatin reported
to WHO centre and also international drug monitoring centre Uppsala,
Sweden. * Then prescribing information changed to include a contraindication
for the combined use of cerivastatin and gemfibrozil another lipid-regulating
medicine. February 2001 in Australia a warning issued to alert prescribers to
the possibility of Rhabdomyolysis occurring with all statins.
Pharmacovigilance in clinical practice: * Safety monitoring of medicine in
common use should be an integral part of clinical practice. * The degree in
which clinicians are informed about the principles of pharmacovigilance and
practice according to them has a large impact on the quality of health care. *
Education and training of health professionals in medicine safety exchange of
information between national and pharmacovigilance centres, the
coordination of such exchange, and the linking of clinical exchange effective
patient care. * Pharmacovigilance in disease control public health
programmes: The monitoring of medicine safety in countries where there is no
regulatory or safety monitoring system in place, or in remote areas with little or
no health care surveillance or by infrastructure, has been identified * The
problems are especially apparent in situation that involve the use of medicines
in specific communities, for example for the treatment of tropical diseases
such as malaria, leishmaniosis and schistosomiasis, and for the treatment of
HIV/AIDS and tuberculosis.