[000012]

Presented By,
Jatin Nagar
PG Diploma (CDM & PV),
B.Pharm (Department of Pharmaceutical
Sciences,
MDU University,
Rohtak
Department Of Pharmaceutical Sciences,
Saurashtra University, Rajkot
1

GUIDELINES UNDER
THIS
 E1 Guideline
 E2 Guideline
a) E2A Guideline
b) E2B Guideline
c) E2C Guideline
d) E2D Guideline
e) E2E Guideline
f) E2F Guideline
Saurashtra University, Rajkot 2

E1 Guideline
The Extent Of Population
Exposure To Assess Clinical
Safety For Drugs Intended For
Long Term Treatment Of Non-
life Threating Condition

Objective
 To present an accepted set of principles for the safety
evaluation of drugs for the long-term treatment (longer
than 6 months) of non-life-threatening diseases.
 The safety evaluation during clinical drug development
is expected to characterise and quantify the safety profile
of a drug over a reasonable duration of time.
 Thus, duration of drug exposure and its occurrence of
adverse events are important considerations in
determining the size of the data base necessary to achieve
such goals.

Purpose
 It is useful to distinguish between clinical data on
adverse drug events derived from studies of shorter
duration of exposure and data from studies of longer
duration.
 It is expected that short-term event rates (cumulative
3-months) will be well characterised.
 The clinical studies judgements about the
relationships between the drug and adverse events.
 A placebo-controlled trial allows the drug-treated
group to be compared directly with the background
event rate in the patient population being studied.

General Agreement
1. A harmonised regulatory standard covers many
indications and drug classes, there are exceptions.
2. Regulatory standards for the safety evaluation of
drugs should be based on previous experience
with the occurrence and detection of adverse drug
events, statistical considerations, and practical
considerations.
3. Information about the occurrence of ADEs in
relation to duration of treatment for different drug
classes is incomplete, and further investigations to
obtain this information would be useful.

4. Available information suggests that most ADEs first
occur, and are most frequent, within the first few
months of drug treatment. The number of patients
treated for 6 months at dosage levels intended for
clinical use, should be adequate to characterise the
pattern of ADEs over time.
5. Some ADEs may increase in frequency or severity
with time or that some serious ADEs may occur only
after drug treatment for more than 6 months.
Therefore, some patients should be treated with the
drug for 12 months. 100 patients exposed for a
minimum of one-year is considered to be acceptable
to include as part of the safety data base.

6. The total number of individuals treated with the
investigational drug, including short-term exposure,
will be about 1500. Japan currently accepts 500-
1500 patients: the potential for a smaller number of
patients is due to the post-marketing surveillance
requirement
7. Filing for approval will usually be possible based
on the data from patients treated through 6 months.
Data on patients treated through 12 months must be
submitted as soon as available and prior to approval
in the United States and Japan. In the U.S. the
initial submission for those drugs designated as
priority drugs must include the 12-months patient
data.

E2A
GUIDELINE
DEFINITIONS AND
STANDARDS FOR
EXPEDITED
REPORTING

1. INTRODUCTION
There are two issues within the broad
subject of clinical safety data
management that are appropriate for
harmonisation:
 The development of standard
definitions and terminology, and
 The appropriate mechanism for rapid
reporting, in the investigational (i.e.,
pre-approval) phase.

2.DEFINITIONS AND
TERMINOLOGYA. Basic Terms
1. Adverse Event (or Adverse Experience)
Any untoward medical occurrence in a patient or clinical
investigation subject administered a pharmaceutical product
and which does not necessarily have to have a causal
relationship with this treatment.
2. Adverse Drug Reaction (ADR)
All noxious and unintended responses to a medicinal
product related to any dose should be considered adverse drug
reactions.
As found in WHO Technical Report 498 [1972]
A response to a drug which is noxious and unintended and
which occurs at doses normally used in man for prophylaxis,
diagnosis, or therapy of disease or for modification of
physiological function.

3. Unexpected Adverse Drug Reaction
An adverse reaction, the nature or severity of which is not
consistent with the applicable product information (e.g., Investigator's
Brochure for an unapproved investigational medicinal product).
B. Serious Adverse Event or Adverse Drug Reaction
The term "severe" is used to describe the severity of a specific event
(as mild or moderate) while "serious," which is based on event
outcome or action criteria associated with events that pose a threat to a
patient's life or functioning.
A serious adverse event (experience) or reaction is any untoward
medical occurrence that at any dose:
* Results in death,
* Is life-threatening (risk of death at the time of the event)
* Requires inpatient hospitalisation or prolongation of
existing hospitalisation,
* Results in persistent or significant disability/incapacity

C. Expectedness of an Adverse Drug Reaction
The purpose of expedited reporting is to make
regulators, investigators, and other appropriate people
aware of new, important information on serious
reactions.
And a guideline is needed on how to define an event as
"unexpected" or "expected“.

3. STANDARDS FOR
EXPEDITED REPORTING
A. 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 reporting.
 This applies to reports from spontaneous
sources and from any type of clinical or
epidemiological investigation.
 Information obtained by a sponsor or
manufacturer on serious, unexpected reports should
be submitted to an appropriate regulatory
authorities.

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; appropriate medical
and scientific judgement should be applied for each situation.
B. Reporting Time Frames
1. Fatal or Life-Threatening Unexpected ADRs
~ Fatal or life-threatening, unexpected ADRs
occurring in clinical investigations.
~ 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 first knowledge
by the sponsor that a case qualifies, followed by as
complete a report as possible within 8 additional
calendar days.
~ This report must include an assessment of the
importance and implication of the findings,
including relevant previous experience with the same or
similar medicinal products.

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 that the case meets the minimum criteria for
expedited reporting.
3. Minimum criteria for reporting
For regulatory purposes, initial reports should be
submitted within the prescribed time as long as the
following minimum criteria are met:
> 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.

3. 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 (as
appropriate for the local situation) in countries
where the drug is under development.

D. Managing Blinded Therapy Cases
 When the sponsor and investigator are blinded
to individual patient treatment (as in a double-
blind study), the occurrence of a serious event
requires a decision on whether to open (break)
the code for the specific patient.
 If the investigator breaks the blind, then it is
assumed the sponsor will also know the
assigned treatment for that patient.
 When the blind is eventually opened, which
may be many weeks or months after reporting
to regulators, it must be ensured that company
and regulatory data bases are revised.

E. Miscellaneous Issues
1. Reactions Associated with Active Comparator or
Placebo Treatment
~ It is the sponsor's responsibility to decide whether active
comparator drug reactions should be reported to the other
manufacturer and/or directly to appropriate regulatory
agencies.
~ Sponsors must report such events to either the
manufacturer of the active control or to appropriate
regulatory agencies.
2. Products with More than one Presentation or Use
~ To avoid uncertainties, an ADR that qualifies for
expedited reporting with one presentation of a product
(e.g., a dosage form, formulation, delivery system) or
product use (e.g., for an indication or population),
should be reported to regulatory filings across other
product presentations and uses.

~It is not uncommon that more than one dosage form,
formulation, or delivery system (oral, IM, IV, topical,
etc.) of the pharmacologically active compound(s) is
under study or marketed; for these different
presentations there may be some marked differences
in the clinical safety profile.
3. Post-study Events
Although such information is not routinely collected
by the sponsor, serious adverse events that occurred
after the patient had completed a clinical study
(including any protocol-required post-treatment
follow-up) will possibly be reported by an
investigator to the sponsor. Such cases should be
regarded for expedited reporting purposes as though
they were study reports.

E2B
GUIDELINE
DATA ELEMENTS FOR
TRANSMISSION OF
INDIVIDUAL CASE
SAFETY REPORTS

SCOPE
 To standardize the data elements for transmission of
individual case safety reports by identifying, and
where necessary or advisable, by defining the data
elements for the transmission of all types of
individual case safety reports.
 This includes case safety reports for both pre and
post approval periods and covers both adverse drug
reaction and adverse event reports.
 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.

Notes on format of this
document
 The user guidance are presented in
standard type of a slightly smaller font.
 If a data element has a limited set of
choices, they are presented in bold Italic
type.
Definition of data elements
The data elements are sufficiently
comprehensive to cover complex reports
from most sources, different data sets,
and transmission situations or
requirements.

CONTENT OF THE DATA
ELEMENTS
A. ADMINISTRATIVE AND IDENTIFICATION
INFORMATION
A.1 Identification of the case safety report
A.1.0.1 Sender’s (case) safety report unique
identifier.
This identifier should remain constant in subsequent
transmissions of the case by the same sender.
A.1.1 Identification of the country of the primary
source
A.1.2 Identification of the country where the
reaction/event occurred
A.1.3 Date of this transmission

A.1.4 Type of report
- Spontaneous report
- Report from study
- Other
- Not available to sender
A.1.5 Seriousness
=Serious
-Yes/no
=Seriousness criteria
− Results in death
− Is life-threatening
− Requires inpatient hospitalization or prolongation of existing hospitalization
− Other medically important condition
A.1.6 Date report was first received from source
A.1.7 Date of receipt of the most recent information for this report
A.1.8 Additional available documents held by sender
=List of documents held by sender
A.1.9 Does this case fulfil the local criteria for an expedited report?
A.1.10 Worldwide unique case identification number.
=Regulatory authority’s case report number
=Other sender’s case report number

A.1.11 Other case identifiers in previous transmissions
-yes
- Source(s) of the case identifier (e.g., name of the company, name of
regulatory agency)
A.1.12 Identification number of the report which is linked to this
report
A.1.13 Report nullification
- Reason for nullification
A.1.14 Was the case medically confirmed, if not initially from a
health professional?
A.2 Primary source(s) of information
The primary source(s) of the information is a person who reports
the facts. This should be distinguished from senders who are
transmitting the information.

A.2.1 Primary source(s)
- Reporter identifier
- Reporter’s address
- Country
- Qualification
~Physician
~Pharmacist
~Other health professional
~Lawyer
~Consumer or other non health
~professional
A.2.2 Literature reference(s)
A.2.3 Study identification
- Study name
- Sponsor study number

A.3 Information on sender and receiver of case safety
report
1. Sender
= Type
−> Pharmaceutical company
−> Regulatory authority
−> Health professional
−> Regional pharmacovigilance center
−> WHO collaborating center for international drug monitoring
−> Other
= Sender identifier
= Person responsible for sending the report
= Sender’s address, fax, telephone and E-mail
address
2. Receiver
As of sender

B. INFORMATION ON THE CASE
B.1 Patient characteristics
1. Patient (name or initials)
2. Age information
3. Weight (kg)
4. Height (cm)
5. Sex
6. Last menstrual period date
7. Relevant medical history and concurrent
conditions
8. Relevant past drug history
9. In case of death
= Date of death
= Reported cause(s) of death
10. For a parent-child/ foetus report, information
concerning the parent

B.2 Reaction(s)/event(s)
1. Term highlighted by the reporter
1= Yes, highlighted by the reporter, NOT serious
2= No, not highlighted by the reporter, NOT serious
3= Yes, highlighted by the reporter, SERIOUS
4= No, not highlighted by the reporter, SERIOUS
2. Date of start of reaction/event
3. Date of end of reaction/event
4. Duration of reaction/event
5. Time intervals between suspect drug
administration and start of reaction/event
6. Outcome of reaction/event at the time of last
observation

B.3 Results of tests and procedure relevant to the
investigation of the patient
1. Structured information
2. Results of tests and procedures relevant to the investigation.
B.4 Drug(s) information
1. Characterization of drug role
2. Drug identification
3. Batch/lot number
4. Holder and authorization/application number of drug
5. Structured Dosage Information
- dose (number)
- dose (unit) mg
- number of separate dosages
- number of units in the interval
- cumulative dose to first reaction (number)
- cumulative dose to first reaction (unit)
6. Dosage text

7. Pharmaceutical form (Dosage form)
8. Route of administration
9. Parent route of administration (in case of a parent
child/foetus report)
10. Gestation period at time of exposure
11. Indication for use in the case
12. Date of start of drug
13. Time intervals between drug administration and start of
reaction/event
14. Date of last administration
15. Duration of drug administration
16. Action(s) taken with drug
− Drug withdrawn
− Dose reduced
− Dose increased
− Dose not changed
− Unknown
− Not applicable
17. Effect of rechallenge
18. Additional information on drug

B.5 Narrative case summary and further
information
1. Case narrative including clinical course,
therapeutic measures, outcome and additional
relevant information.
2. Reporter's comments .
3. Sender's diagnosis/syndrome and/or
reclassification of reaction/event.
4. Sender's comments .

E2C (R1)
GUIDELINE
PERIODIC SAFETY
UPDATE REPORTS
FOR MARKETED
DRUGS

Objectives
 To harmonize technical requirements for registration
or marketing approval. However, because new
products are introduced at different times in different
markets and the same product may be marketed in one
or more countries.
 The regulatory requirements, particularly regarding
frequency of submission and content of periodic
safety updates, are not the same in the three regions
(EU, Japan, USA).
 In order to avoid duplication of effort this guideline on
the format and content for comprehensive periodic
safety updates of marketed medicinal products has
been developed.

Scope
 This guideline on the format and content of
periodic safety update reports(PSUR) covering
short periods (e.g., six months, one year) often
prepared during the initial years following
approval/authorization.
 This guideline might also be applicable for
longer term reporting intervals other options
may be appropriate

General Principles
1. One report for one active substance
All dosage forms and formulations as well as
indications for a given pharmacologically active
substance should be covered in one PSUR.
2. General scope of information
 All relevant clinical and non-clinical safety data
should cover only the period of the report (interval
data) with the exception of regulatory status
information as well as data on serious, unlisted
ADRs which should be cumulative.
 The main focus of the report should be adverse
drug reactions (ADRs).

3. Products manufactured and/or marketed by more than
one company
 Each MAH is responsible for submitting PSURs, even if different
companies market the same product in the same country.
 When companies are involved in contractual relationships (e.g.,
licensor-licensee), arrangements for sharing safety information should
be clearly specified.
 In order to ensure that all relevant data will be duly reported to
appropriate regulatory authorities.
4. International birth date and frequency of review and
reporting
 Each medicinal product should have as an International Birth Date
(IBD), the date of the first marketing authorization for the product
granted to any company in any country in the world.
 Once a drug has been marketed for several years, the need for a
comprehensive PSUR and the frequency of reporting may be reviewed,
depending on local regulations or requests, while maintaining one IBD
for all regulatory authorities
 In addition, approvals beyond the initial one for the active substance
may be granted for new indications, dosage forms, populations, or
prescription status (e.g., children vs. adults; prescription to non-
prescription status)

5. Reference safety information
An objective of a PSUR is to establish whether information
recorded during the reporting period is in accord with previous
knowledge on the drug’s safety, and to indicate whether changes
should be made to product information.
6. Presentation of data on individual case histories
I. Sources of information
a) Direct reports to MAH (or under MAH control)
b) Literature
c) ADR reporting systems of regulatory authorities
d) Other sources of data
II. Description of the reaction
III. Line listings and/or summary tabulations
It does serve to help regulatory authorities identify
cases which they might wish to examine more completely by
requesting full case reports.

MODEL FOR A PERIODIC SAFETY UPDATE
REPORT (PSUR)
1. World-wide Market Authorization Status
− dates of market authorization, and subsequent
renewal;
− any qualifications surrounding the authorization, such
as limits on indications if relevant to safety;
− treatment indications and special populations covered
by the market authorization, when relevant;
− lack of approval, including explanation, by regulatory
authorities;
− withdrawal by the company of a license application
submission if related to safety or efficacy;
− dates of launch when known;
− trade name(s).

2. Update of Regulatory Authority or MAH
Actions Taken for Safety Reasons
− marketing authorization withdrawal or
suspension;
− failure to obtain a marketing authorization
renewal;
− restrictions on distribution;
− clinical trial suspension;
− dosage modification;
− changes in target population or indications;
− formulation changes.

3. Changes to Reference Safety Information
The version of the company core data sheet (CCDS) with
its company core safety information (CCSI) in effect at
the beginning of the period covered by the report should
be used as the reference. It should be numbered, dated
and appended to the PSUR and include the date of last
revision.
4. Patient Exposure
 It is usually difficult to obtain and validate accurate
exposure data, an estimate of the number of patients
exposed should be provided along with the method used
to derive the estimate. An explanation and justification
should be presented if the number of patients is
impossible to estimate or is a meaningless metric.
 When a pattern of reports indicates a potential problem,
details by country or other segmentation (e.g., indication,
dosage form) should be presented if available.

5. Presentation of Individual Case Histories
I. Summary tabulations
II. MAH’s Analysis of Individual Case Histories
->Used for brief comments on the data concerning individual cases.
6. Studies
I. Newly analyzed company-sponsored studies
II. Targeted new safety studies planned, initiated or continuing
during the reporting period.
III. Published safety studies.
7. Other Information
I. Efficacy-Related Information
II. Late-Breaking Information
III. Overall Safety Evaluation
8. Conclusion
Should ,
− indicate which safety data do not remain in accord with the previous
cumulative experience, and with the reference safety information (CCSI);
− specify and justify any action recommended or initiated.

POST-APPROVAL SAFETY
DATA MANAGEMENT:
DEFINITIONS AND
STANDARDS FOR
EXPEDITED REPORTING
E2D GUIDELINE

INTRO
This guideline is based on the content of ICH E2A
guideline, with consideration as to how the terms and
definitions can be applied in the post-approval phase of
the product life cycle.
SOURCES OFINDIVIDUAL CASE SAFETY
REPORTS
1 Unsolicited Sources
1.1 Spontaneous Reports
It is an unsolicited communication by a healthcare
professional or consumer to a company, regulatory
authority or other organization (e.g. WHO) that
describes one or more adverse drug reactions in a patient
who was given one or more medicinal products and that
does not derive from a study or any organized data
collection scheme.

1.2 Literature
Regularly screen the worldwide scientific literature by accessing widely
used systematic literature reviews or reference databases.
1.3 Internet
1.4 Other Sources
Like media or press note
2. Solicited Sources
Derived from organized data collection systems, include clinical trials,
registries, post-approval named patient use programs, other patient
support and disease management programs, surveys of patients or
healthcare providers, or information gathering on efficacy or patient
compliance.
3. Contractual Agreements
The marketing of many medicines increasingly takes place through
contractual agreements between two or more companies, which may
market same product in the same or different countries/region.
4. Regulatory Authority Sources.

STANDARDS FOR EXPEDITED REPORTING
1. What Should Be Reported?
->Serious ADRs
->Other Observations
- Lack of Efficacy
- Overdose
2. Minimum Criteria for Reporting
It is recommended that as much information as possible be
collected at the time of the initial report.
3. Reporting Time Frames
In general, expedited reporting of serious and unexpected
ADRs is required as soon as possible, but in no case later
than 15 calendar days of initial receipt of the information by
the MAH.

GOOD CASE MANAGEMENT PRACTICES
1. Assessing Patient and Reporter Identifiability
 Important to avoid case duplication, detect fraud, and facilitate
follow-up of appropriate cases.
 Local data privacy laws regarding patient and reporter
identifiability might apply.
2. The Role of Narratives
To summarize all relevant clinical and related information,
including patient characteristics, therapy details, medical history,
clinical course of the event(s), diagnosis, and ADR(s) including the
outcome, laboratory evidence, and any other information that
supports or refutes an ADR.
3. Clinical Case Evaluation
• Is a diagnosis possible?
• Have the relevant diagnostic procedures been performed?
• Were alternative causes of the reaction(s) considered?
• What additional information is needed?

4. 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 recommended that the Medical Dictionary for
Regulatory Activities (MedDRA) be used for coding
medical information.

REFERENCES
1. Current Challenges in Pharmacovigilance: Pragmatic
Approaches (Report of CIOMS Working V), Geneva 2001
2. Rules Governing Medicinal Products in the European Union,
Volume 9, PHARMACOVIGILANCE: Medicinal Products for
Human Use, 2001 http://pharmacos.eudra.org/F2/eudralex/vol-
9/home.htm
3. Guidance for Industry: Postmarketing Safety Reporting for
Human Drug and Biological Products Including Vaccines, Food
and Drug Administration, March 2001 (draft)
http://www.fda.gov/cder/guidance/4153dft.pdf
4. Safety Reporting Requirements for Human Drug and
Biological Products, Proposed Rule, Food and Drug
Administration, March 2003
5. Notification No 421 on Enforcement of the Law Revising
Partially the Pharmaceutical Affairs Law, the Director General,
Pharmaceutical Affairs Bureau, Ministry of Health and Welfare,
March 1997

E2E GUIDELINE
PHARMACOVIGILANCE
PLANNING

Definition
WHO definition of the term ‘pharmacovigilance’ as “the
science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any
other drug related problems.”
Objective
 Preparation for the early post marketing period of a
new drug (in this guideline, the term “drug” denotes
chemical entities, biotechnology-derived products, and
vaccines).
 The main focus of this guideline is on a Safety
Specification and Pharmacovigilance Plan that might be
submitted at the time of licence application.

Scope
 The guideline could be most useful for new chemical entities,
biotechnology-derived products, and vaccines, as well as for
significant changes in established products.
 The guideline is divided into the following sections:
• Safety Specification;
• Pharmacovigilance Plan;
• Pharmacovigilance Methods.
 During the course of implementing the various components of
the Plan, any important emerging benefit or risk information
should be discussed and used to revise the Plan.
 The following principles underpin this guideline:
• Planning of pharmacovigilance activities throughout the
product life-cycle;
• Science-based approach to risk documentation;
• Effective collaboration between regulators and industry;
• Applicability of the Pharmacovigilance Plan across the
three ICH regions.

SAFETY SPECIFICATION
 It should be a summary of the important identified risks of a
drug, important potential risks, and important missing
information.
 The Safety Specification can be built initially during the pre-
marketing phase and, at the time approval is sought, it should
reflect the status of issues that were being followed during
development.
1. Elements of the Specification
Sponsors follow the structure of elements provided below
when compiling the Safety Specification. The elements of the
Safety Specification that are included are only a guide.
The Safety Specification can include additional elements,
depending on the nature of the product.

I. Non-Clinical
• Toxicity (including, nephrotoxicity, hepatotoxicity, genotoxicity,
carcinogenicity );
• General pharmacology (cardiovascular, including QT interval
prolongation; nervous system; etc.);
• Drug interactions;
• Other toxicity-related information or data.
II. Clinical
a. Limitations of the Human Safety Database
• The extent of the world-wide exposure;
• Any new or different safety issues identified;
• Any regulatory actions related to safety.
b. Populations not Studied in the Pre-Approval Phase
• Children;
• The elderly;
• Pregnant or lactating women
• Patients with disease severity different from that studied in clinical
trials
• Patients of different racial and/or ethnic origins.

III. Adverse Events (AEs) / Adverse Drug Reactions
(ADRs)
IV. Identified and Potential Interactions, Including
Food-Drug and Drug-Drug Interactions .
V. Epidemiology
VI. Pharmacological Class Effects
2. Summary
• Important identified risks;
• Important potential risks;
• Important missing information.

PHARMACOVIGILANCE PLAN
1. Structure of the Pharmacovigilance Plan
I. Summary of Ongoing Safety Issues
II.Routine Pharmacovigilance Practices
• The preparation of reports for regulatory authorities:
o Expedited adverse drug reaction (ADR)
reports;
o Periodic Safety Update Reports (PSURs).
III. Action Plan for Safety Issues
IV. Summary of Actions to be Completed
2. Pharmacovigilance Methods
I. Design and Conduct of Observational Studies .

REFERENCES
1. CIOMS, Current Challenges in Pharmacovigilance:
Pragmatic Approaches. Report of CIOMS Working
Group V. Geneva; World Health Organization
(WHO), 2001.
2. Guidelines for Good Pharmacoepidemiology
Practices (GPP), International Society for
Pharmacoepidemiology,
http://www.pharmacoepi.org/resources/guidelines_
08027.cfm, August 2004.

E2F GUIDELINE
DEVELOPMENT
SAFETY UPDATE
REPORT

Agenda
􀂄 Background Information
􀂄 Development Safety Update Report:
Existing Situation –
Opportunities for Improvement
􀂄 General Principles of the DSUR
􀂄 Anticipated Challenges in Implementing
DSURs

Background Information
􀂄 Management of Safety Information from Clinical Trials
(2005)
 Annual
 Cover entire development program
 Common international birth date
􀂄 The Development Safety Update Report: Harmonizing
the Format and Content for Periodic Safety Reporting
During Clinical Trials (2006)
 Defined detail of contents, format, timing
 General principles re: administrative matters, technical
content
 Example DSURs

ICH E2F Expert Working Group
Timelines
 Final Concept Paper: September 20, 2006
 1st ICH Meeting: Oct 2006 (Chicago)
 2nd ICH Meeting: Oct/Nov 2007 (Yokohama)
 Step 2 document: June 2008 (Portland)
 Step 3 – consultation/comment period: June –
December 2008
 Step 4 document: August 2010

Some Constraints/Principles
 ICH documents are guidelines, and cannot
impose new regulatory requirements.
 DSUR should replace existing annual
reporting requirements in US and EU
􀂄 Therefore, DSUR needs to
incorporate all current regulatory
components of those reports.

Existing Situation -
Opportunities for
Improvement
Rationale for DSUR:
 Current periodic safety reports differ,
analyses of safety are not
comprehensive;
 Benefits of harmonizationDepartment Of Pharmaceutical Sciences,

US IND Annual Report Content
Individual studies:
Status of each study:
 Identification – title, protocol number;
purpose,
 patient population: (by age, sex, race)
 planned;
 included;
 completed;
 drop-outs.

US IND Annual Report Content
Summary Information
 Narrative or tabular summary of most frequent and
most serious adverse experiences by body system;
 Summary of all IND safety reports;
 List of subjects who died with cause of death;
 List of drop-outs due to adverse events;
 Pharmacodynamic/pharmacokinetic information;
 List of pre-clinical studies;
 Summary of significant manufacturing/
microbiological changes;
 Other: e.g., Investigational plan for coming year;
changes to IB; Phase I protocol changes.

EU Annual Safety Report Content
Summary Information: individual and
multiple trials
 Concise safety analysis and benefit-risk evaluation;
 Description and critical analysis of all new safety
findings related to Investigational Drug;
 Results of non-clinical studies;
 Other studies likely to affect subjects’ safety;
 Measures to minimise risks;
 Rationale – updating protocol, consent form, Patient
Information Leaflet, IB;
 Implications for trial subjects and tested IMP based
on all available clinical data;

Opportunities for Improvement
 Focus on regulatory compliance instead of
benefit vs. risk analysis;
 Confusing regulatory terminology;
 Inconsistent reference safety information;
 Uncoordinated periodicity of reports;
 Different scope and content for same trials in
different regions;

Benefits of DSUR
 Harmonization of format, content and
scheduling of annual reports in 3
regions:
1. Harmonizes with ICH E2A and E2E
2. Single DSUR for Investigational Drug –
complete picture of evolving safety profile
3. Improved consistency among companies
4. Decrease in number of reports generated
5. Regulators receive the same information at
the same time

CONT….
 Comprehensive, thoughtful annual review
 New concept in Section 19 – Summary of
Important Risks – highlights issues to monitor
(industry and regulators)
 New concept in Section 3 – advice rendered by
regulators that places specific limitation(s) on
current or future development
 Facilitates work sharing ( regulators)

Framework of DSUR Guideline
 Introduction
 Guidance
When, Who, How should DSUR be
prepared?
 DSUR Format/Table of Contents
 Guidance on Contents of DSUR
 Appendices to DSUR
 Glossary

Objective
 Information reported during the current review
period and analysis based on previous knowledge of
the product’s safety;
 Description of new issues that may impact the
overall program or specific clinical trials;
 Summarization of current understanding and
management of known and potential safety risks to
exposed patients;
 Examine changes in the product’s safety profile;
and
 Provide an update on the status of the clinical
development program.Department Of Pharmaceutical Sciences,

Scope
 Clinical trials of investigational drugs (including
vaccines and biologics)
 Other findings that impact the safety and welfare of
clinical trial subjects (e.g., non-clinical studies,
observational studies)
DSUR should,
1. Focus on the investigational drug, providing
information on comparators where relevant to the
safety of trial participants;
2. be concise and provide information to assure
regulators that sponsors are adequately monitoring
and evaluating the safety profile of the
investigational drug

Recipients of DSUR
 Regulatory Authorities: DSUR; within
60 days from the DIBD(Development
International Birth Date)
 EC/IRB, if required: Executive
Summary (plus line listing of SADRs)
 Final DSUR in a Territory: will be
notified with a cover letter.

Content of DSUR
1. Introduction
2. Worldwide Marketing Approval Status
3. Actions Taken in the Reporting Period for Safety
Reasons
4. Changes to Reference Safety Information
5. Inventory of Clinical Trials Ongoing and Completed
6. Estimated Cumulative Exposure
7. Data in Line Listings and Summary Tabulations
8. Significant Findings from Clinical Trials
9. Safety Findings from Non-interventional Studies

CONT…
10. Other Clinical Trial/Study Safety Information
11. Safety Findings from Marketing Experience
12. Non-clinical Data
13. Literature
14. Other DSURs
15. Lack of Efficacy
16. Region-Specific Information
17. Late-Breaking Information
18. Overall Safety Assessment
19. Summary of Important Risks
20. Conclusions

Executive Summary
 Summary of the important information contained in
the DSUR
 Serve as a “stand-alone” document for submission to
stakeholders (e.g., Ethics Committees)
 Includes:
- Introduction
- Investigational drug
- Estimated clinical trial exposure (cumulative)
- Marketing authorization status
- Summary of overall safety assessment
- Summary of important risks
- Actions taken for safety reasons including changes to
IB
- Conclusion.

Other Information
Include relevant findings from:
- Non-interventional, observational and
epidemiologic studies
- Marketing experience
- Other sources/data:
> Non-clinical data
> Long-term follow-up
> Literature
> Other DSURs
> Lack of efficacy

Region-specific Information
 Cumulative summary tabulation of serious adverse
reactions
 List of subjects who died during reporting period
 List of subjects who dropped out of clinical trials in
association with an adverse event
 Significant Phase I protocol modifications
 Significant manufacturing changes
 General investigation plan for the coming year
 Log of outstanding business with respect to US IND

Overall Safety Assessment
 Evaluation of the risks
Changes in previously identified risks
New safety issues
Interactions
Experiences during pregnancy
Other risks
 Benefit Risk considerations
 Conclusions

Summary of important risks
 Cumulative summary list of important identified
and potential risks – those that might lead t
Warnings, Precautions, or Contraindications in
labeling, including:
- Ongoing risks
- Fully addressed or resolved risks
 This information could provide the basis for the
Safety Specification of a risk management plan
(ICH E2E).

Questions….?

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