ICH Guidelines for

Pharmacovigilance
Prepared and Presented by –
Ms. Neha Jain
(Associate Professor)

Ms. Neha Jain (Associate Professor) 1

Organization and objectives of ICH:
 INTERNATIONAL CONFERENCE ON HARMONISATION (ICH)
of Technical Requirements for Pharmaceuticals for Human Use -

 Established in April 1990

 Initiative for regulators and pharmaceutical industries
 Reformed as a non-profit legal entity under Swiss Law on 23 October
2015.
 Formed to assure safety, quality and efficacy of medicines, the
members of ICH who include members from drug regulatory authorities
and research based industries of European Union, US and Japan will
discuss on the technical procedures and documents required.

Ms. Neha Jain (Associate Professor) 2

Organization and objectives of ICH: Continued...

 Need for harmonization –

 The difference in the technical requirements and the procedures
followed by different countries made the global marketing of drugs as
time consuming and expensive
 To reduce the cost and time required for the global marketing of
drugs
 Harmonization of technical requirements has to be promoted
 Special guidelines to be framed to ensure the quality, safety and the
efficacy of the drugs

Ms. Neha Jain (Associate Professor) 3

Organization and objectives of ICH: Continued...

 Purpose or Objectives of ICH –

 Harmonized interpretation and application of technical guidelines

and requirements for marketing authorization to:
 Reduce duplication of testing of the drugs under investigation
Increase economical use of resources
 Eliminate unnecessary delay in availability of new medicines
Safeguarding quality, safety and efficacy
Accomplished through Technical Guidelines that are implemented by
the regulatory authorities.

Ms. Neha Jain (Associate Professor) 4

Organization and objectives of ICH: Continued...

 Categories agreed for Harmonization –

 New types of medicinal products
 Lack of harmonization of current technical requirements
 Transitions to technically improved testing procedures
 Review of existing ICH guidelines resulting in major changes
 Maintenance of existing ICH guidelines requirement minor changes

Ms. Neha Jain (Associate Professor) 5

Organization and objectives of ICH: Continued...

 Categories agreed for Harmonization –

 New types of medicinal products
 Lack of harmonization of current technical requirements
 Transitions to technically improved testing procedures
 Review of existing ICH guidelines resulting in major changes
 Maintenance of existing ICH guidelines requirement minor changes
 ICH Members:- (ICH covers 3 regions)
 European Union
United States of America
Japan
Ms. Neha Jain (Associate Professor) 6
Organization and objectives of ICH: Continued...

 "Six Parties” of ICH:–

1. The European commission, (representing 28 members states of EU)
2. The European federation of pharmaceutical industries and associations
(IFPMA)
3. The Ministry of Health, Labour and Welfare of Japan
4. The Japanese Pharmaceutical Manufactures Association (JPMA)
5. The US Food and drug Administration (FDA)
6. The Pharmaceutical Research and Manufacture of America (PhRMA)

Ms. Neha Jain (Associate Professor) 7

Organization and objectives of ICH: Continued...

ICH Members (18)

Regulatory Members:
Founding Regulatory Members: ANVISA, Brazil
European Union HSA. Singapore
MFDS, Republic of Korea
FDA, United States of America
NMPA, China
MHLW/PMDA, Japan SFDA, Saudi Arabia
TFDA, Chinese Taipei
TITCK, Turkey

Industry
Founding Industry Members:
Members: BIO Standing Regulatory Members:
EFPIA Global Self-Care Health Canada, Canada
JPMA Federation Swiss medic, Switzerland
PhRMA IGBA

Ms. Neha Jain (Associate Professor) 8

ICH Guidelines for Pharmacovigilance
Introduction:
 ICH Guidelines for Pharmacovigilance –

 The ICH has published a number of documents setting standards for

safety, both clinical and pre-clinical.
 Pre-clinical guidelines have an "S" designation e.g. S1, S2 etc. It should
be noted that the clinical safety guidelines are designated as "E“
 These documents provide a high degree of detail about the expected
manner, method, timing, frequency and circumstances in which
pharmaceutical companies and other relevant parties need to report
suspected adverse reactions and other vital clinical data to the regulatory
authorities.

Ms. Neha Jain (Associate Professor) 9

ICH Guidelines for Pharmacovigilance
Continued...
Introduction:
 ICH Guidelines for Pharmacovigilance –
 Each of the following clinical safety guideline has an identifying
code, and during the lifetime of the ICH the codes have already been
revised to reflect the development and evolution of those standards
documents:
 E1 Clinical Safety for Drugs Intended for Long-Term Treatment of
Non-Life Threatening Conditions
E2A Clinical Safety Data Management: Definitions and Standards
for Expedited Reporting
E2B (R2) Maintenance of the Clinical Safety Data Management
including Data Elements for Transmission of Individual Case Safety
Reports
Ms. Neha Jain (Associate Professor) 10
ICH Guidelines for Pharmacovigilance
Continued...
Introduction:
 ICH Guidelines for Pharmacovigilance –

 E2B (R3) Clinical Safety Data Management: Data Elements for

Transmission of Individual Case Safety Reports
 E2C (R1) Clinical Safety Data Management: Periodic Safety
Update Reports for Marketed Drugs
E2C (R2) Periodic Benefit-Risk Evaluation Report
E2D Post - Approval Safety Data Management: Definitions and
Standards for Expedited Reporting
E2E Pharmacovigilance Planning
E2F Development Safety Update Report

Ms. Neha Jain (Associate Professor) 11

EXPEDITED REPORTING:
 CLINICAL SAFETY DATA MANAGEMENT: DEFINITIONS AND
STANDARDS FOR EXPEDITED REPORTING (E2A) -
It is important to harmonies the way to gather and, if necessary, to take
action on important 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.
This guideline addresses the following:
 The development of standard definitions and terminology for key aspects
of clinical safety reporting,
 The appropriate mechanism for handling expedited (rapid) reporting, in
the investigational (i.e., pre-approval) phase.

Ms. Neha Jain (Associate Professor) 12

EXPEDITED REPORTING: Continued...

 Expedited Report: SAEs which are unexpected (not labelled), be

reported in 15 Calendar days from the first notification of anyone in the
company including its agent, business partners, contractors, distributors,
and vendors. Also known as alert report, 15-day report.
 7-day report: Patient in question has died or had life threatening SAE
which is also unexpected and possibly related. This report should be sent to
the health authorities within 7 calendar days.
Note: All 7-day reports are also 15-day report. It must also be followed up
as a 15 day report

Ms. Neha Jain (Associate Professor) 13

EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

What Should be Reported?
1. Single Cases of Serious, Unexpected ADRs:
 All adverse drug reactions (ADRs) that are both serious and unexpected
are subject to expedited reporting.
 This applies to reports from spontaneous sources and from any type of
clinical or epidemiological investigation, independent of design or
purpose.
 Information obtained by a sponsor or manufacturer on serious,
unexpected reports from any source should be submitted on an
expedited basis to appropriate regulatory authorities if the minimum
criteria for expedited reporting can be met.
 Causality assessment is required for clinical investigation cases.
Ms. Neha Jain (Associate Professor) 14
EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

What Should be Reported?
2. Other Observations:
 There are situations in addition to single case reports of "serious"
adverse events or reactions that may necessitate rapid communication to
regulatory authorities
Examples include:
 For an "expected," serious ADR, an increase in the rate of occurrence
which is judged to be clinically important.
 A significant hazard to the patient population, such as lack of efficacy
with a medicinal product used in treating life-threatening disease.

Ms. Neha Jain (Associate Professor) 15

EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

Whom should be Reported?

Determination Sponsor Investigator

Serious/Life- Yes Yes

Threatening

Causality (Responsible Yes Yes

Possibility)

Expectedness Yes Yes

(Labeled/Unlabeled)

Ms. Neha Jain (Associate Professor) 16

EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

Reporting Time Frames:
1. Fatal or Life-Threatening Unexpected ADRs
 Fatal or life-threatening, unexpected ADRs occurring in clinical
investigations qualify for very rapid reporting. Regulatory agencies should
be notified (e.g., by telephone, facsimile transmission, or in writing) as
soon as possible but no later than 7 calendar days after first knowledge by
the sponsor that a case qualifies, followed by as complete a report as
possible within 8 additional calendar days.
2. All Other Serious, Unexpected ADRS
 Serious, unexpected reactions (ADRs) that are not fatal or life- threatening
must be filed as soon as possible but no later than 15 calendar days after
first knowledge by the sponsor.
Ms. Neha Jain (Associate Professor) 17
EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

Reporting Time Frames:
3. Minimum criteria for reporting
 An identifiable patient; a suspect medicinal product; an identifiable
reporting source; and an event or outcome that can be identified as
serious and unexpected, and for which, in clinical investigation cases,
there is a reasonable suspected causal relationship.

Ms. Neha Jain (Associate Professor) 18

EXPEDITED REPORTING: Continued...

 STANARDS FOR EXPEDITED REPORTING –

How to Report?
 The CIOMS-I form has been a widely accepted standard for expedited
adverse event reporting. However, no matter what the form or format
used, it is important that certain basic information/data elements, when
available, be included with any expedited report, whether in a tabular or
narrative presentation.
 All reports must be sent to those regulators or other official parties
requiring them in countries where the drug is under development

Ms. Neha Jain (Associate Professor) 19

EXPEDITED REPORTING: Continued...

 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG REACTIONS –
1. Patient Details:
 Initials
 Other relevant identifier (clinical investigation number, for example)
 Gender
 Age and/or date of birth
 Weight
 Height

Ms. Neha Jain (Associate Professor) 20

EXPEDITED REPORTING: Continued...

 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG REACTIONS –
2. Suspected Medicinal Product(s) :
 Brand name as reported
 International Non-Proprietary Name (INN)
 Batch number
 Indication(s) for which suspect medicinal product was prescribed or
tested
 Dosage form and strength
 Daily dose and regimen (specify units e.g., mg, ml, mg/kg)
 Route of administration
 Starting date and time of day
 Stopping date and time, or duration of treatment
Ms. Neha Jain (Associate Professor) 21
EXPEDITED REPORTING: Continued...

 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG REACTIONS –
3. Other Treatments :
 For concomitant medicinal products (including non-prescription/OTC
medicinal products) and non-medicinal product therapies, provide the
same information as for the suspected product

4. Details of Suspected Adverse Drug Reaction(s):

 Full description of reaction(s) including body site and severity, as well as
the criterion (or criteria) for regarding the report as serious should be
given. In addition to a description of the reported signs and symptoms,
whenever possible, attempts should be made to establish a specific
diagnosis for the reaction.
 Start date (and time) of onset of reaction
 Stop date (and time) or duration of reaction
Ms. Neha Jain (Associate Professor) 22
EXPEDITED REPORTING: Continued...

 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG REACTIONS –

 Dechallenge and rechallenge information

 Setting (e.g., hospital, out-patient clinic, home, nursing home)
 Outcome: information on recovery and any sequelae: what specific tests
and/or treatment may have been required and their results; for a fatal
outcome, cause of death and a comment on its possible relationship to the
suspected reaction should be provided. Any autopsy or other post-mortem
findings (including a coroner's report) should also be provided when
available. Other information: anything relevant to facilitate assessment of
the case, such as medical history including allergy, drug or alcohol abuse;
family history: findings from special investigations.

Ms. Neha Jain (Associate Professor) 23

EXPEDITED REPORTING: Continued...

 KEY DATA ELEMENTS FOR INCLUSION IN EXPEDITED

REPORTS OF SERIOUS ADVERSE DRUG REACTIONS –
5. Details on Reporter of Event (Suspected ADR)
 Name
 Address
 Telephone number
 Profession (specialty).

6. Administrative and Sponsor/Company Details

 Source of report was it spontaneous, from a clinical investigation
(provide details), from the literature (provide copy), other?
 Date event report was first received by sponsor/manufacturer
 Country in which event occurred
Ms. Neha Jain (Associate Professor) 24
ndividual Case Safety Reports (ICSR):
 It is a document providing the most complete information related to an
individual case at a certain point of time.
 An Individual Case Study Report (ICSR) is a safety service document
which includes information required for reporting the adverse events and
problems related to products and complaints filed by consumers with
respect to any product.
 It is an important facet of adverse event reporting which is a source of
data in PV (pharmacovigilance).
Sources of individual case safety reports
1. Unsolicited Sources
 Spontaneous reports
 Literature
 Internet
 Other sources- such as lay press and other media
Ms. Neha Jain (Associate Professor) 25
 2. Solicited sources3. Contractual Agreements4. Regulatory
ndividual Case Safety Reports (ICSR): Continued...

2. Solicited sources
3. Contractual Agreements
4. Regulatory Authority Sources
 Because of national and international agreements, rules, and
regulations, individual case safety reports of adverse drug reactions
and adverse events need to be transmitted
 from identified reporting sources to regulatory authorities and
pharmaceutical companies
 between regulatory authorities
 between pharmaceutical companies and regulatory authorities
 within authorities or pharmaceutical companies
 from clinical investigators, via the sponsor, to ethics committees
 from authorities to the World Health Organization (WHO)
Collaborating Center for International Drug Monitoring
Ms. Neha Jain (Associate Professor) 26
ndividual Case Safety Reports (ICSR): Continued...

2. Solicited sources
3. Contractual Agreements
4. Regulatory Authority Sources
 Because of national and international agreements, rules, and
regulations, individual case safety reports of adverse drug reactions
and adverse events need to be transmitted
 from identified reporting sources to regulatory authorities and
pharmaceutical companies
 between regulatory authorities
 between pharmaceutical companies and regulatory authorities
 within authorities or pharmaceutical companies
 from clinical investigators, via the sponsor, to ethics committees
 from authorities to the World Health Organization (WHO)
Collaborating Center for International Drug Monitoring
Ms. Neha Jain (Associate Professor) 27
ndividual Case Safety Reports (ICSR): Continued...

 The transmission of such individual case safety reports currently

relies on paper-based formats (e.g., Yellow cards, CIOMS forms,
Med Watch) or electronic media.
 Considering the large number of potential participants in a world-
wide exchange of information, there is a need for an electronic
format capable of accommodating direct database to database
transmission
 Successful electronic transmission of information relies on the
definition of common data elements and standard transmission
procedures
 The format for individual case safety reports includes provisions for
transmitting all the relevant data elements useful to assess an
individual adverse drug reaction or adverse event report. Structured
data are strongly recommended in electronic transmission.

Ms. Neha Jain (Associate Professor) 28

ndividual Case Safety Reports (ICSR): Continued...

Minimum information:
 The minimum information for the transmission of a report should
include at least one identifiable patient (section B.1), one identifiable
reporter (section A.2), one reaction/event (section B.2), and one
suspect drug (section B.4).
 Because it is often difficult to obtain all the information, any one of
several data elements is considered sufficient to define an
identifiable patient or an identifiable reporter.
 It is also recognized that the patient and the reporter can be the same
individual and still fulfill the minimum reporting criteria.
 In addition, to properly process the report, the following
administrative information should be provided: the sender's (case)
safety report unique identifier (A.1.0.1), the date of receipt of the
most recent information (A.1.7), the worldwide unique case
identification number (A.1.10) and the sender identifier (A.3.1.2).
Ms. Neha Jain (Associate Professor) 29
ndividual Case Safety Reports (ICSR): Continued...

GUIDELINE - CONTENT OF THE DATA ELEMENTS:

 The data elements are divided into sections pertaining to:
 A: Administrative and Identification Information
 Identification of the case safety report
 Primary source(s) of information
 Information on sender and receiver of case safety report
 B: Information on the Case:
 Patient characteristics
 Reaction(s)/event(s)
 Results of tests and procedures relevant to the investigation of
the patient
 Drug(s) information
 Narrative case summary and further information
Ms. Neha Jain (Associate Professor) 30
ndividual Case Safety Reports (ICSR): Continued...

Elements of the specifications in the ICSR :

 Pre-Clinical:
 Toxicity
 General Pharmacology
 Drug Interactions
 Other toxicity related information
 Clinical:
 Limitations of the Human Safety Database
 Populations not studied in the pre-approval phase
 Adverse events/adverse drug reactions
 Identified risks that require further evaluation
 Potential risks that require further evaluation
 Identified and potential interactions
Ms. Neha Jain (Associate Professor) 31
PERIODIC SAFETY UPDATE REPORTS:
 The periodic safety update report (PSUR) is a document that allows
a periodic, comprehensive assessment of the worldwide safety data of
a marketed drug or biological product.
 The concept evolved from the Council for International
Organizations of Medical Sciences (CIOMS) Working Group II report
(CIOMS, 1992).
 The PSUR creates the opportunity for a periodic overall safety
evaluation to show whether a product's safety profile has remained the
same or has undergone change since it was authorized and to indicate
whether changes should be made to product information to optimize
the use of a product.

Ms. Neha Jain (Associate Professor) 32

PERIODIC SAFETY UPDATE REPORTS: Continued...

Purpose of the PSUR:

 The reason such a review is needed periodically is because clinical
trials tend to be of short duration and to include a limited number of
patients.
 Moreover, clinical trials have inclusion and exclusion criteria. After a
product is launched, it may be used by patients not studied in clinical
trials, for example children, the elderly, pregnant or breastfeeding
women or patients with co morbidities such as hepatic or renal disease.
 After approval, a drug becomes so available for immediate use in
large populations, so rare adverse drug reactions (ADRs) can be more
easily identified. The drugs also become available for indefinite use
(unless prescribing information indicates otherwise), and delayed onset
ADRS become easier to identify.
Ms. Neha Jain (Associate Professor) 33
PERIODIC SAFETY UPDATE REPORTS: Continued...

General Principles of PSUR:

 ONE REPORT FOR PRODUCTS CONTAINING ONE ACTIVE SUBSTANCE
AUTHORISED TO ONE MARKETING AUTHORISATION HOLDER
 Ordinarily, all dosage forms and formulations as well as indications for a given
pharmacologically active substance authorized to one marketing authorization holder
(MAH) may be covered in one PSUR.
 Within the single PSUR, separate presentations of data for different dosage forms,
indications or populations (e.g. children versus adults) may be appropriate.
 PRODUCTS AUTHORISED TO MORE THAN ONE MAH
 Each MAH is responsible for submitting PSURs, even if different companies market
the same product in the same country.
 COMBINATION PRODUCTS
 Safety information for the fixed combination may be reported either in a separate
PSUR or included as separate presentations in the report for one of the separate
components, depending on the circumstances.

Ms. Neha Jain (Associate Professor) 34

PERIODIC SAFETY UPDATE REPORTS: Continued...

General Scope of Information:

 All relevant clinical and non-clinical safety data should cover only the period of the
report (interval data). Exception- Regulatory status information on authorization
application and data on serious unlisted ADRs- can be provided with cumulative
summary tabulations.
 The safety information contained within the PSUR comes from a variety of different
sources. These include spontaneous reports of adverse events from different countries, the
literature, clinical trials, registries, regulatory ADR databases and important animal
 Reports of lack of efficacy specifically for drugs used in the treatment of life-
threatening conditions and for certain other medicinal products, such as contraceptives
and vaccines, may represent a significant hazard, and in that sense may be a safety issue.
These types of cases should be discussed in the PSUR.
Frequency of reporting:
 Each PSUR should cover the period since the last update report. The need for a report
and the frequency of report submission to authorities are subject to local regulatory
requirements. The age of a medicinal product on the market may influence this process.
Ms. Neha Jain (Associate Professor) 35
PERIODIC SAFETY UPDATE REPORTS: Continued...

 In the EU, reports be submitted every 6 months for the first 2 years
after authorization, annually for the three following years and then five
yearly
 In the United States, the FDA requires quarterly reports during the
first 3 years, then annual reports
 In Japan, the authorities require annual survey report on a cohort of a
few thousand patients established by a certain number of identified
institutions during the 6 years following authorization.
 Regarding other marketing experience, adverse reactions which are
non-serious, but both mild in severity and unlabeled, must be reported
every 6 months for 3 years and annually thereafter

Ms. Neha Jain (Associate Professor) 36

PERIODIC SAFETY UPDATE REPORTS: Continued...

Section Number Section

1.1 Executive summary Introduction
1.2 Worldwide market authorisation
1.3 Update on regulatory authority or marketing authorisation holder
actions taken for safety reasons
1.4 Changes in reference safety information
1.5 Patient exposure
1.6 Presentation of individual case histories
1.7 Studies
1.8 Other information
1.9 Overall safety evaluation
1.10 Conclusion
Appendix 1 Company core data sheet
Appendix 2 Marketing authorisation status
Appendix 3 Line listings of case reports
Appendix 4 Summary tabulations of events (complement to Appendix 3)

Ms. Neha Jain (Associate Professor) 37

PERIODIC SAFETY UPDATE REPORTS: Continued...

PSUR Content:
 TITLE - PSURs contain proprietary information, so the title page should
contain a statement on the confidentiality of the data and conclusions included
in the report.
 EXECUTIVE SUMMARY - The executive summary should consist of a
brief overview providing the reader with a description of the most important
information.
 INTRODUCTION - The introduction puts the report in context, describing
those products/formulations that are included and excluded, outlining the
pharmacology of the product, its indications (both marketed and in clinical
trials)
 WORLDWIDE MARKETING AUTHORISATION STATUS - The
PSUR should include a short summary of the worldwide marketing
authorisation status
Ms. Neha Jain (Associate Professor) 38
PERIODIC SAFETY UPDATE REPORTS: Continued...

PSUR Content:
 PATIENT EXPOSURE –
 Patient exposure refers to both market exposure and clinical trials (if
relevant). Estimates of patient exposure for marketed drugs often rely
on gross approximations of in-house or purchased sales data or volume.
 PRESENTATION OF INDIVIDUAL CASE HISTORIES –
 There is no specific guidance in E2C on the presentation of individual
case histories, but because it is impractical to present all case reports for
the reporting period, a brief description of the criteria used to select
cases for presentation should be given.
 This section of the PSUR should contain a description and analysis of
selected cases, including fatalities, presenting new and relevant safety
information and grouped by medically relevant headings

Ms. Neha Jain (Associate Professor) 39

PERIODIC SAFETY UPDATE REPORTS: Continued...

PSUR Content:
 STUDIES –
 Studies refer to only those company-sponsored studies and published safety
studies, including epidemiology studies, that produce findings with potential
impact on product safety information.
 OTHER INFORMATION –
 Other information may include risk management programmes the MAH has
put in place and/or a benefit-risk analysis report.
 If such an analysis has been conducted separately, a summary of the analysis
should be included in this section.
 This section can also include important information received after the DLP
(data lock point).

Ms. Neha Jain (Associate Professor) 40

PERIODIC SAFETY UPDATE REPORTS: Continued...

PSUR Content:
OVERALL SAFETY EVALUATION –
 The overall safety evaluation should highlight new information on serious and
non-serious unlisted ADRs. If there are no new safety issues, this should be
stated with a note that the information is in keeping with the established safety
profile. This section should also review reports of
 Drug interactions
 Overdose
 Deliberate or accidental and treatment
 Abuse or misuse
Pregnancy or lactation
 Positive and negative experiences
 Special patient groups (e.g. Children, elderly, organ impaired)
 Defects of long-term treatment.
Ms. Neha Jain (Associate Professor) 41
PERIODIC SAFETY UPDATE REPORTS: Continued...

PSUR Content:
Conclusion –
 The conclusion should indicate safety data which are not in accordance with
previous experience and/or with the CCSI and specify and justify any action
recommended or initiated.
 Intake of ADR information
 Case processing
 Data retrieval
 Data analysis
 Medical review and risk assessment.

Ms. Neha Jain (Associate Professor) 42

Post approval safety management guideline:
 Post approval safety management (E2D) guideline was finalized in 2003 and
provides a standardized procedure for post approval safety data management,
including post approval expedited reporting to the concerned authority.
 It parallels and adds to the E2A document, which covered preapproval
(clinical trial) safety data management, by covering post marketing safety data
management.
 This document standardizes data management of cases from consumers,
literature, internet, and other types of post marketing cases.

Ms. Neha Jain (Associate Professor) 43

Post approval safety management guideline: Continued...

DEFINITIONS:
i. Adverse Event
ii. ADR
iii. Serious AE/ADR
iv. Unexpected ADR.
v. Healthcare professional: Any medically-qualified person such as a
physician, dentist, pharmacist, nurse, coroner, or as otherwise specified by
local regulations.
vi. Consumer: A person who is not a healthcare professional, such as patient,
lawyer, friend or relative of the patient.

Ms. Neha Jain (Associate Professor) 44

Post approval safety management guideline: Continued...

SOURCES:
1. Unsolicited Sources –
 Spontaneous reports
 Literature
 Internet
 Other sources- such as lay press and other media
2. Solicited sources
3. Contractual Agreements
4. Regulatory Authority Sources

Ms. Neha Jain (Associate Professor) 45

Post approval safety management guideline: Continued...

STANDARDS FOR EXPEDITED REPORTING

 Serious ADRs:
 Serious and unexpected cases of ADRs are subject to expedited reporting.
 For reports from studies and other solicited sources, all cases judged by either
the reporting health care professionals or the MAH for causal relationship to the
medicinal product qualifying as ADRs.
 Spontaneous reports associated with approved drugs imply a possible causality
 Other observations:
 Any significant unanticipated safety findings, including in vitro, animal,
epidemiologic, or clinical studies, that suggest a significant human risk and could
change the benefit-risk evaluation should be communicated to the regulatory
authorities as soon as possible.
 Lack of efficacy observations should not be expedited but should be discussed in
PSURs unless local requirements oblige their being expedited.
Ms. Neha Jain (Associate Professor) 46
Post approval safety management guideline: Continued...

STANDARDS FOR EXPEDITED REPORTING

 Overdoses with no associated adverse outcome should not be reported as
adverse reactions.
 Minimum criteria for reporting include an identifiable reporter, an
identifiable patient, an adverse reaction, and a suspect product.
 Reporting time frames for expedited reports are normally 15 calendar days
from initial receipt of the minimal information by any personnel of the
MAH. This is day 0. Additional medically relevant information for a
previously submitted report restarts the clock.
 Non-serious ADRs are not normally expeditable whether expected or not

Ms. Neha Jain (Associate Professor) 47

Pharmacovigilance Planning (E2E):
 This guideline was finalized in 2004 and is intended to aid in planning
pharmacovigilance activities, especially in preparation for the early post
marketing period of a new drug.
 The main focus of this guideline is on a Safety Specification and
Pharmacovigilance Plan that might be submitted at the time of the
application for marketing.
 All three regions of the ICH (United States, European Union, and Japan)
have been turning their attention to risk management and
pharmacovigilance planning throughout the life cycle of a drug.
 This document reflects ICH's views.

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Pharmacovigilance Planning (E2E): Continued...

 Principles of Pharmacovigilance Planning guidelines –

1. Planning of pharmacovigilance activities throughout the
product life cycle
2. Science-based approach to risk documentation
3. Effective collaboration between regulators and industry
4. Applicability of the pharmacovigilance plan across the three
ICH region

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Pharmacovigilance Planning (E2E): Continued...

 Sections of Pharmacovigilance Plan–

1. Safety Specification:
The safety specification is a summary of the important
identified risks of a drug, important potential risks, and
important missing information.
It should refer to the three safety sections in the Common
Technical Document:
 Non-clinical
 Clinical
 Epidemiology.

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Pharmacovigilance Planning (E2E): Continued...

 Sections of Pharmacovigilance Plan–

2. Pharmacovigilance Plan:
The pharmacovigilance plan should be based on the safety
specification and developed by the sponsor.
This includes:
 Summary of ongoing safety issues, including the
important identified risks, potential risks, and missing
information.
 Routine pharmacovigilance practice
 Summary of actions to be completed, including
milestones
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Pharmacovigilance Planning (E2E): Continued...

 Sections of Pharmacovigilance Plan–

3. Pharmacovigilance Methods:
The best method to address a specific situation may vary
depending on the product, indication, population treated.
 Sponsors should choose the most appropriate design.
 Design and conduct of observational studies
 Annexure - A detailed discussion of pharmacovigilance
methods is appended to the document.

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GOOD CLINICAL PRACTICES (GCP):
 GCPs are stand alone document and its guidelines are given in
ICH E6.
 Good Clinical Practice (GCP) is an international ethical and
scientific quality standard for designing, conducting, recording
and reporting trials that involve the participation of human
subjects.
 Compliance with this standard provides public assurance that
the rights, safety, and well-being of trial subjects are protected,
consistent with the principles that have their origin in the
Declaration of Helsinki, and that the clinical trial data are
credible.

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GOOD CLINICAL PRACTICES (GCP): Continued...

1. Clinical trials should be conducted in accordance with the ethical principles

that have their origin in the Declaration of Helsinki, and that are consistent
with GCP and the applicable regulatory requirement(s).
2. Before a trial is initiated, foreseeable risks and inconveniences should be
weighed against the anticipated benefit for the individual trial subject and
society. A trial should be initiated and continued only if the anticipated
benefits justify the risks.
3. The rights, safety, and well-being of the trial subjects are the most
important considerations and should prevail over interests of science and
society.
4. The available nonclinical and clinical information on an investigational
product should be adequate to support the proposed clinical trial.
5. Clinical trials should be scientifically sound, and described in a clear,
detailed protocol.
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GOOD CLINICAL PRACTICES (GCP): Continued...

6. A trial should be conducted in compliance with the protocol that has

received prior institutional review board (IRB)/independent ethics
committee (IEC) approval/favorable opinion.
7. The medical care given to, and medical decisions made on behalf of,
subjects should always be the responsibility of a qualified physician or,
when appropriate, of a qualified dentist.
8. Each individual involved in conducting a trial should be qualified by
education, training, and experience to perform his or her respective task(s).
9. Freely given informed consent should be obtained from every subject prior
to clinical trial participation.
10. All clinical trial information should be recorded, handled, and stored in a
way that allows its accurate reporting, interpretation and verification.

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GOOD CLINICAL PRACTICES (GCP): Continued...

11. The confidentiality of records that could identify subjects should be

protected, respecting the privacy and confidentiality rules in accordance
with the applicable regulatory requirement(s).
12. Investigational products should be manufactured, handled, and stored in
accordance with applicable good manufacturing practice (GMP). They
should be used in accordance with the approved protocol.
13. Systems with procedures that assure the quality of every aspect of the trial
should be implemented.
INVESTIGATOR'S RESPONSIBILITIES:
 All SAEs should be reported immediately by the investigator to the sponsor except
for those SAEs which the protocol or other document identifies not needing
immediate reporting.
 Identify the subject by trial code number rather than by subject name, personal
information and/or address
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GOOD CLINICAL PRACTICES (GCP): Continued...

INVESTIGATOR'S RESPONSIBILITIES:
 Investigator should comply with the applicable regulatory requirement while
reporting unexpected SAEs to the regulatory authorities
 Adverse events or laboratory abnormalities should be reported to the Sponsor within
the time periods specified by sponsor.
 For reported death, the investigator should provide additional information if
requested by sponsor or IRB/IEC.
 If the investigator terminates or suspended trial without prior agreement of the
sponsor, the investigator should promptly inform the institute and where applicable
(such as Institutions, IRB/IEC) by providing detailed information.
 If the sponsor terminates or suspended trial, the investigator should promptly inform
the institutes and where applicable (such as Institutions, IRB/IEC) by providing
detailed information.
 If IRB/IEC terminates or suspends its approval/favorable opinion of a trial, the
investigator should inform the institution where applicable.
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GOOD CLINICAL PRACTICES (GCP): Continued...

SPONSOR'S RESPONSIBILITIES:
 Sponsor is responsible for the ongoing safety evaluation of the investigational
product(s).
 Should notify all concerned investigator(s)/institution(s) and the regulatory
authorities of findings that could adverse affect the safety of subjects, impact the
conduct of trial.
ADR Reporting guidelines:
 Sponsor should expedite the reporting to all concerned investigator(s)/Institution(s)
to the IRB/IEC, where required to the regulatory authority of all ADRs that are both
serious and unexpected.
 Expedited reports should comply with the applicable regulatory requirement and
with the ICH guidelines for clinical safety data management.
 Sponsor should submit to the regulatory authority(ies) all safety updates and periodic
reports as required by applicable regulatory requirement(s).

Ms. Neha Jain (Associate Professor) 58

THANK YOU
~ Ms. Neha Jain
(Associate Professor)

Ms. Neha Jain (Associate Professor) 59