Pharmacovigilance

– Aggregate Reports
P V D RU G S A F E T Y A CA D E MY
 Topics to be Covered
 Purpose of this Course  DSUR and Its different
sections
 Pharmacovigilance and Its
objectives  PADER and Its different
sections
 Aggregate Reports & Its
types Guidance Session:
 How to Switch from
 How ICSR & Aggregate ICSR to Aggregate,
Reports are interrelated Signal and Risk
 Difference between PSUR Management Role
and PBRER  What Next ?
 Sections of PBRER
 Purpose of this Training Course
 PV Aggregate Reporting Role – Niche Skill
 High Demand and Less Resources in Pharma
Industry
 Saturation in ICSR Role
 Automation in PV ICSR Role
 To advance your Career Growth in
Pharmacovigilance domain
 To make your Basics of Aggregate reports very
clear
 To help you to crack your Interview
 To make this course available at very
affordable price
 Pharmacovigilance - Definition

The World Health Organization (WHO)

has defined Pharmacovigilance as
“science and activities relating to the
detection, assessment, understanding
and prevention of adverse effects or
any other medicine-related problem.
 Pharmacovigilance Objectives
Pharmacovigilance covers the entire life-cycle of a
medicinal product.
The objectives of Pharmacovigilance are:
 Preventing harm from adverse reactions in
humans arising from the use of authorised
medicinal products within or outside the terms
of marketing authorisation or from occupational
exposure
 Promoting the safe and effective use of
medicinal products, through providing timely
information about the safety of medicinal
products to patients, healthcare professionals,
and the public.
 It is an activity contributing to the protection of
patient’s and public health.
 What are Aggregate Reports? (1/2)
 Aggregate report is the process that reviews
the cumulative safety information from a wide
range of sources, on a periodic basis and
submits the findings to regulators worldwide.
 The aggregate report examines and
summarizes all existing safety experience with
a medicinal product.
 Cumulative or Aggregate reporting, also
known as Periodic Reporting, plays a key role
in the safety assessment of drugs.
 What are Aggregate Reports? (2/2)
Aggregate reporting involves the compilation of
safety data for a drug over a prolonged period of
time (months or years), as opposed to single case
reporting which, by definition, involves only
individual AE reports.
 The periodic reports play an important role in risk-
benefit evaluation of the drug and involves
collective analysis of cases in the database,
monitoring regulatory actions, literature searches
etc.
 They are required to be submitted to various
regulatory agencies to comply with the regulatory
requirements. The advantage of aggregate
reporting is that it provides a broader view of the
safety profile of a drug.
 Types of Aggregate Reports
Pre-Marketing Reports Post-Marketing Reports
IND Annual Reports PSUR (Periodic Safety Update Report)/ PBRER
(Periodic Benefit-Risk Evaluation Report)

Clinical Study Reports (CSR) PADER (Periodic Adverse Drug Experience Report)

Development Safety Update Report ACO (Addendum to Clinical Overview)

(DSUR)

Annual Safety Reports (ASR) NDA (New Drug Application) and

ANDA (Abbreviated New Drug Application) Reports
 How ICSR & Aggregate Reports
are Interrelated?
 ICSR (Individual Case Safety Report)
involves single patient case ICSR
 ICSRs are processed individually in
safety database e.g., ARGUS or ARISg
Aggregate Reports
 No clear picture of relationship of
Product and event in ICSR
 Aggregate Reports gives more clarity Signal Detection
to assess relationship of Product and
event
 ICSR plays important role in signal
detection Risk Management
 Difference between PSUR and
PBRER
PSUR PBRER
A PSUR primarily served as an interval A PBRER is meant to be a cumulative benefit-
safety report risk report
No data on efficacy and effectiveness from It includes data on efficacy and effectiveness
ongoing or updated clinical trials and from ongoing or updated clinical trials and
cohort studies cohort studies
No Benefit evaluation Benefit evaluation
Risk evaluation (risk minimization Risk evaluation (risk minimization procedures
procedures for limited products) for all significant risks associated with all
products)
No integrated risk benefit analysis Integrated risk benefit analysis
 Basic Terminologies
DIBD: Developmental International Birth Date (DIBD) is the date of
approval of the first authorization for conducting an interventional clinical
trial in any country. The first data lock point for the DSUR is the first
anniversary of the DIBD.

IBD: International Birth Date (IBD) is the date of the first marketing
authorisation for any product containing the active substance granted to
any company in any country in the world. If a marketing authorisation
holder has no information on the actual IBD for a product, it should first
refer to listings of birth dates that some regions develop and make publicly
available. If the product is not included in any listing, it should propose to
the regulatory authority a birth date that is based on the earliest known
marketing authorisation of the substance and then obtain the regulatory
authority’s agreement.
 Basic Terminologies
DLP: The Data Lock Point (DLP) represents the cutoff date for data
and analyses presented in a document.

• For a periodic safety update report (PSUR), the date designated as the cut-
off date for data to be included in a PSUR.
• For a periodic benefit-risk evaluation report (PBRER), the date designated
as the cut-off date for data to be included in a PBRER, based on the
international birth date (see GVP Annex IV, ICH-E2C(R2) Guideline).
• For a development safety update report (DSUR), the date designated as
the cut-off date for data to be included in a DSUR, based on the
development international birth date (see ICH-E2F Guideline, Volume 10 of
the Rules Governing Medicinal Products in the EU).
 Periodic Benefit-Risk
Evaluation Report (PBRER)
 Part I - Title page
The title page of PBRER should include the following information:

1. Name of the medicinal product(s) and substance

2. International birth date (IBD)

3. Reporting interval
4. Date of the report
5. Marketing authorisation holder details
6. Statement of confidentiality of the information

 The title page shall also contain the signature

 Part II - Executive Summary
An executive summary should be placed immediately after the title page and before the
table of contents.
The purpose of the executive summary is to provide a concise summary of the content
and the most important information in the PSUR and should contain the following
information:

 Introduction and reporting interval;

 Medicinal product(s), therapeutic class(es), mechanism(s) of action, indication(s), pharmaceutical
formulation(s), dose(s) and route(s) of administration;
 Estimated cumulative clinical trials exposure;
 Estimated interval and cumulative exposure from marketing experience;
 Number of countries in which the medicinal product is authorised;
 Summary of the overall benefit-risk analysis evaluation (based on sub-section 18.2 “benefit-risk
analysis evaluation” of the PSUR);
 Actions taken and proposed for safety reasons, (e.g., significant changes to the reference product
information, or other risk minimisation activities);
 Conclusions
 Part III - Table of Contents
1. Introduction
The marketing authorisation holder should briefly introduce the product(s) so
that the PSUR “stands alone” but it is also placed in perspective relative to
previous PSURs and circumstances.

The introduction should contain the following information:

• IBD, and reporting interval;

• Medicinal product(s), therapeutic class(es), mechanism(s) of action,
authorised indication(s), pharmaceutical form(s), dose(s) and route(s) of
administration;
• A brief description of the population(s) being treated and studied
 2. Worldwide Marketing Authorisation
Status
This section of the PSUR should contain a brief narrative overview
including:

 Date of the first authorisation worldwide

 Indications(s)
 Authorised dose(s) and
 Where authorised
 3. Actions taken in the reporting
interval for safety reasons (1/3)
This section of the PSUR should include a description of significant actions related to
safety that have been taken worldwide during the reporting interval, related to either
investigational uses or marketing experience by the marketing authorisation holder,
sponsors of clinical trial(s), data monitoring committees, ethics committees or
competent authorities that had either:

 A significant influence on the risk-benefit balance of the authorised medicinal

product; and/or
 An impact on the conduct of a specific clinical trial(s) or on the overall clinical
development programme

If known, the reason for each action should be provided and any additional relevant
information should be included as appropriate.
Relevant updates to previous actions should also be summarised in this section.
 3. Actions taken in the reporting
interval for safety reasons (2/3)
Examples of significant actions taken for safety reasons
Actions related to investigational uses:
• Refusal to authorise a clinical trial for ethical or safety reasons;
• Partial or complete clinical trial suspension or early termination of an ongoing clinical
trial because of safety findings or lack of efficacy;
• Recall of investigational drug or comparator;
• Failure to obtain marketing authorisation for a tested indication including voluntary
withdrawal of a marketing authorisation application;
• Risk management including protocol modifications, restrictions in study population or
indications, changes to the informed consent document, formulation changes, etc.
 3. Actions taken in the reporting
interval for safety reasons (3/3)
Examples of significant actions taken for safety reasons
Actions related to marketing experience:
• Failure to obtain or apply for a marketing authorisation renewal;
• Withdrawal or suspension of a marketing authorisation;
• Actions taken due to product defects and quality issues;
• Suspension of supply by the marketing authorisation holder;
• Risk management including significant restrictions on distribution or introduction of
other risk minimisation measures; significant safety-related changes in labelling
documents including restrictions on use or population treated; communications to
health care professionals; and new post-marketing study requirement(s) imposed by
competent authorities
 4. Changes to reference safety
information
 This section should list any significant changes made to the
reference safety information within the reporting interval.
 Such changes might include information relating to
contraindications, warnings, precautions, serious adverse drug
reactions, interactions, important findings from ongoing or completed
clinical trials and significant non-clinical findings (e.g., carcinogenicity
studies).
 Specific information relevant to these changes should be provided in
the appropriate sections of the PSUR.
 5. Estimated exposure and use
patterns (1/7)
 This section should provide an accurate estimate of the population exposed
to the medicinal product, including all data relating to the volume of sales
and volume of prescriptions. This estimate of exposure shall be accompanied
by a qualitative and quantitative analysis of actual use.
 This section should provide estimates of the size and nature of the
population exposed to the medicinal product including a brief description of
the method(s) used to estimate the subject/patient exposure and the
limitations of that method.
 Consistent methods for calculating subject/patient exposure should be used
across PSURs for the same medicinal product. If a change in the method is
appropriate, both methods and calculations should be provided.
 5. Estimated exposure and use
patterns (2/7)
5.1. Cumulative subject exposure in clinical trials
This section of the PSUR should contain the following information on the patients studied in clinical trials
sponsored by the MAH:
 Cumulative numbers of subjects from ongoing and completed clinical trials
 Detailed cumulative subject exposure in clinical trials should be presented if available
 Important differences among trials in dose, routes of administration, or patient populations can be
noted
 Appropriate exposure date to be provided for special populations involved in clinical trials
 Substantial differences in time of exposure between subjects randomised to the investigational
medicinal product or comparator
 Investigational drug exposure in healthy volunteers should be presented separately
 If the serious adverse events from clinical trials are presented by indication in the summary
tabulations, the patient exposure should also be presented by indication
 For individual trials of particular importance, demographic characteristics should be provided
separately
 5. Estimated exposure and use
patterns (3/7)
Examples of tabulations for estimated exposure and adverse events/reactions data
 5. Estimated exposure and use
patterns (4/7)
5.2. Cumulative and interval patient exposure from marketing experience
 Separate estimates should be provided for cumulative exposure (since the IBD), when possible,
and interval exposure (since the data lock point of the previous PSUR).
 Justification should be provided if it is not possible to estimate the number of patients exposed.
 Alternative estimates of exposure, if available, should be presented along with the method(s)
used to derive them.
Examples: patient-days of exposure and number of prescriptions.
 If such measures are not available, measures of drug sales, such as tonnage or dosage units,
may be used. The concept of a defined daily dose may also be used to arrive at patient exposure
estimates.
 5. Estimated exposure and use
patterns (5/7)
5.2. Cumulative and interval patient exposure from marketing experience
The data should be presented according to the following categories
1. Post-authorisation (non-clinical trial) exposure
The data should be routinely presented by sex, age, indication, dose, formulation and region,
where applicable.
2. Post-authorisation use in special populations
Populations to be considered for discussion include but might not be limited to: • paediatric
population; • elderly population; • pregnant or lactating women; • patients with hepatic and/or
renal impairment; • patients with other relevant co-morbidity; • patients with disease severity
different from that studied in clinical trials; • sub-populations carrying relevant genetic
polymorphism(s); • populations with specific racial and/or ethnic origins.
 5. Estimated exposure and use
patterns (6/7)
3. Other post-authorisation use
Examples of such patterns of use may include evidence of overdose, abuse, misuse and use
beyond the recommendation(s) in the reference product information.
Such information may be received via spontaneous reporting systems, medical information
queries, customer’s complaints, screening of digital media or via other information sources
available to the MAH.
5. Estimated exposure and use
patterns (7/7)
 6. Data in summary tabulations (1/6)
 The objective of this section is to present safety data through summary
tabulations of serious adverse events from clinical trials, spontaneous serious and
non-serious reactions from marketing experience (including reports from
healthcare professionals, consumers, scientific literature, competent authorities
(worldwide)) and serious reactions from non-interventional studies and other
non-interventional solicited source.
 When MedDRA terminology is used for coding the adverse event/reaction
terms, the preferred term (PT) level and system organ class (SOC) should be
presented in the summary tabulations.
 The seriousness of the adverse events/reactions in the summary tabulations
should correspond to the seriousness assigned to events/reactions included in the
ICSRs using the criteria established in ICH-E2A.
 Seriousness should not be changed specifically for the preparation of the
PSURs.
 6. Data in summary tabulations (2/6)
6.1. Reference information
This sub-section of the PSUR should specify the version(s) of the coding
dictionary used for presentation of adverse events/ reactions.
 6. Data in summary tabulations (3/6)
6.2. Cumulative summary tabulations of serious adverse events from clinical trials
This sub-section should provide background for the appendix that provides a
cumulative summary tabulation of serious adverse events reported in the marketing
authorisation holder’s clinical trials, from the DIBD to the data lock point of the current
PSUR.
The tabulation(s) should be organised by MedDRA SOC.
The following points should be considered:
 Causality assessment is generally useful for the evaluation of individual rare
adverse drug reactions.
 In general, the tabulation(s) of serious adverse events from clinical trials should
include only those terms that were used in defining the case as serious and non-
serious events should be included in the study reports.
 The tabulations should include blinded and unblinded clinical trial data.
 Certain adverse events can be excluded from the clinical trials summary
tabulations, but such exclusions should be explained in the report.
 6. Data in summary tabulations (4/6)
Example of summary tabulation of serious adverse events from clinical trials
 6. Data in summary tabulations (5/6)
6.3. Cumulative and interval summary tabulations from post-marketing data sources
 This sub-section of the PSUR should provide background for the appendix that provides
cumulative and interval summary tabulations of adverse reactions, from the IBD to the
data lock point of the current PSUR.
 These adverse reactions are derived from spontaneous ICSRs including reports from
healthcare professionals, consumers, scientific literature, competent authorities
(worldwide) and from solicited non-interventional ICSRs including those from non-
interventional studies.
 Serious and non-serious reactions from spontaneous sources, as well as serious adverse
reactions from non-interventional studies and other non-interventional solicited sources
should be presented in a single table, with interval and cumulative data presented side-by-
side.
 As described in ICH-E2D11 (see Annex IV) guideline, for marketed medicinal products,
spontaneously reported adverse events usually imply at least a suspicion of causality by
the reporter and should be considered to be suspected adverse reactions for regulatory
reporting purposes.
 6. Data in summary tabulations (6/6)
Example of summary tabulations of adverse drug reactions from post-marketing
data sources
 7. Summaries of significant findings from clinical
trials during the reporting interval (1/6)
 This section should provide a summary of the clinically important emerging
efficacy and safety findings obtained from the MAH sponsored clinical trials
during the reporting interval.
 When possible and relevant, data categorised by sex and age (particularly
paediatrics versus adults), indication, dose, and region should be presented.
 Information on lack of efficacy from clinical trials for treatments of non-life-
threatening diseases in authorised indications should also be summarised.
 The MAH should include an appendix listing with following information.
Study ID, Study title, Study type, population studied, including country and
other relevant population descriptors (e.g., paediatric population or trial
subjects with impaired renal function), study start and status of clinical trial
study (ongoing or completed).
 7. Summaries of significant findings from clinical
trials during the reporting interval (2/6)
7.1. Completed clinical trials
This sub-section of the PSUR should provide a brief summary of clinically
important emerging efficacy and safety findings obtained from clinical trials
completed during the reporting interval. This information can be presented in
narrative format or as a synopsis12. It could include information that supports
or refutes previously identified safety concerns as well as evidence of new
safety signals.
 7. Summaries of significant findings from clinical
trials during the reporting interval (3/6)
7.2. Ongoing clinical trials
If the marketing authorisation holder is aware of clinically important
information that has arisen from ongoing clinical trials (e.g., learned through
interim safety analyses or as a result of unblinding of subjects with adverse
events), this sub-section should briefly summarise the concern(s). It could
include information that supports or refutes previously identified safety
concerns, as well as evidence of new safety signals.
 7. Summaries of significant findings from clinical
trials during the reporting interval (4/6)
7.3. Long-term follow-up
Where applicable, this sub-section should provide information from long-term
follow-up of subjects from clinical trials of investigational drugs, particularly
advanced therapy products (e.g., gene therapy, cell therapy products and
tissue engineered products).
 7. Summaries of significant findings from clinical
trials during the reporting interval (5/6)
7.4. Other therapeutic use of medicinal product
This sub-section of the PSUR should include clinically important safety
information from other programmes conducted by the marketing authorisation
holder that follow a specific protocol, with solicited reporting as per ICH-
E2D13 (e.g., expanded access programmes, compassionate use programmes,
particular patient use, and other organised data collection).
 7. Summaries of significant findings from clinical
trials during the reporting interval (6/6)
7.5. New safety data related to fixed combination therapies
Unless otherwise specified by national or regional regulatory requirements, the
following options can be used to present data from combination therapies:
• If the active substance that is the subject of the PSURs is also authorised or
under development as a component of a fixed combination product or a multi-
drug regimen, this sub-section should summarise important safety findings from
use of the combination therapy.
• If the product itself is a fixed combination product, this PSUR sub-section should
summarise important safety information arising from the individual components
whether authorised or under development.
The information specific to the combination can be incorporated into a separate
section(s) of the PSUR for one or all of the individual components of the
combination.
 8. Findings from non-interventional
studies
 This section should summarise relevant safety information or information with
potential impact in the benefit-risk assessment from MAH - sponsored non-
interventional studies that became available during the reporting interval (e.g.,
observational studies, epidemiological studies, registries, and active surveillance
programmes).
 The MAH should include an Appendix listing MAH-sponsored non-interventional
studies conducted.
 Final study reports completed during the reporting interval for the studies mentioned
in the paragraph above should also be included in the regional appendix.
 Summary information based on aggregate evaluation of data generated from patient
support programs may be included in this section when not presented elsewhere in the
PSUR.
 9. Information from other clinical trials
and sources
9.1. Other clinical trials
Summarise information relevant to the benefit-risk assessment of the medicinal
product from other clinical trial/study sources which are accessible by the MAH during
the reporting interval (e.g., results from pool analysis or meta-analysis of randomised
clinical trials, safety information provided by co-development partners or from
investigator-initiated trials).

9.2. Medication errors

Summarise relevant information on patterns of medication errors and potential
medication errors, even when not associated with adverse outcomes.
Such information may be relevant to the interpretation of safety data or the overall
benefit-risk evaluation of the medicinal product.
 10. Non-clinical Data
 This PSUR section should summarise major safety findings from non-clinical
in vivo and in vitro studies (e.g., carcinogenicity, reproduction or
immunotoxicity studies) ongoing or completed during the reporting interval.

 Results from studies designated to address specific safety concerns should

be included in the PSUR, regardless of the outcome.

 Implications of these findings should be discussed in the relevant evaluation

sections of the PSUR.
 11. Literature
This section should include a summary of new and significant safety findings, either
published in the peer-reviewed scientific literature or made available as unpublished
manuscripts that the MAH became aware of during the reporting interval.

The special types of safety information that should be included:

• Pregnancy outcomes (including termination) with no adverse outcomes
• Use in paediatric populations
• Compassionate supply, named patient use
• Lack of efficacy
• Asymptomatic overdose, abuse or misuse
• Medication error where no adverse events occurred
• Important non-clinical safety results

The publication reference should be provided in the style of the “Vancouver Convention”.
 12. Other periodic reports
 This section will only apply in certain circumstances concerning fixed
combination products or products with multiple indications and/or
formulations where multiple PSURs are prepared in agreement with the
competent authority.
 The MAH should prepare a single PSUR for a single active substance (unless
otherwise specified by the competent authority).
 However, if multiple PSURs are prepared for a single medicinal product, this
section should also summarise significant findings from other PSURs if they
are not presented elsewhere within the report.
 Based on the contractual agreements, the MAH should summarise
significant findings from periodic reports provided during the reporting
interval by other parties (e.g., sponsors, other MAHs or other contractual
partners).
 13. Lack of efficacy in controlled
clinical trials
This section should summarise data from clinical trials indicating lack of
efficacy, or lack of efficacy relative to established therapy(ies), for products
intended to treat or prevent serious or life-threatening illnesses (e.g., excess
cardiovascular adverse events in a trial of a new anti-platelet medicine for
acute coronary syndromes) that could reflect a significant risk to the treated
population.
 14. Late-breaking information
 The MAH should summarise the potentially important safety, efficacy and
effectiveness findings that arise after the data lock point but during the period of
preparation of the PSUR.
 Examples include clinically significant new publications, important follow-up data,
clinically relevant toxicological findings and any action that the marketing
authorisation holder, a data monitoring committee, or a competent authority
(worldwide) has taken for safety reasons.
 New individual case reports should not be routinely included unless they are
considered to constitute an important index case (i.e., the first instance of an
important event) or an important safety signal or where they may add information to
the evaluation of safety concerns already presented in the PSUR.
 Any significant change proposed to the reference product information (e.g., new
adverse reaction, warning or contraindication) which has occurred during this period,
should also be included.
 15. Overview of signals: new, ongoing
or closed (1/4)
 The purpose of this section is to provide a high-level overview of signals that
were closed (i.e., evaluation was completed) during the reporting interval as well
as ongoing signals that were undergoing evaluation at the end of the reporting
interval.
 Signals may be qualitative (e.g., a pivotal individual case safety report, case
series) or quantitative (e.g., a disproportionality score, findings of a clinical trial
or epidemiological study).
 Decisions regarding the subsequent classification of these signals and the
conclusions of the evaluation, involve medical judgement and scientific
interpretation.
 A new signal refers to a signal that has been identified during the reporting
interval. Where new clinically significant information on a previously closed signal
becomes available during the reporting interval of the PSUR, this would also be
considered a new signal on the basis that a new aspect of a previously refuted
signal or recognised risk warrants further action to verify.
 15. Overview of signals: new, ongoing
or closed (2/4)
Examples of new signals would therefore include new information on a
previously

• Close and refuted signal, which would result in the signal being re-opened.

• Identified risk where the new information suggests a clinically significant difference
in the severity or frequency of the risk.
• Identified risk for which a higher frequency or severity of the risk is newly found
(e.g., in an indicated subpopulation).

• Potential risk which, if confirmed, would warrant a new warning, precaution, a new
contraindication or restriction in indication(s) or population or other risk
minimisation activities.
 15. Overview of signals: new, ongoing
or closed (3/4)
MAH should provide a tabulation of all signals ongoing or closed at the end of the reporting
interval. This tabulation should include the following information (refer next slide):

• a brief description of the signal

• date when the marketing authorisation holder became aware of the signal
• status of the signal at the end of the reporting interval (close or ongoing)
• date when the signal was closed, if applicable
• source of the signal
• a brief summary of the key data
• plans for further evaluation
Note: When a competent authority (worldwide) has requested that a specific topic (not considered a signal) be
monitored and reported in a PSUR, the marketing authorisation holder should summarise the result of the
analysis in this section if it is negative. If the specific topic becomes a signal, it should be included in the signal
tabulation and discussed in sub-section 16.2 (“Signal evaluation”).
 15. Overview of signals: new, ongoing
or closed (4/4)
Example of tabular summary of safety signals that were ongoing or closed during the reporting
interval.
 16. Signal and Risk evaluation
The purpose of this section is to provide:
 Succinct summary of what is known about important identified and potential risks
and missing information at the beginning of the reporting interval covered by the
report
 An evaluation of all signals closed during the reporting interval
 An evaluation of new information with respect to previously recognised identified
and potential risks
 An updated characterization of important potential and identified risks, where
applicable
 A summary of the effectiveness of risk minimisation activities in any country or
region which may have utility in other countries or regions
 The evaluation of sub-sections should provide interpretation and critical appraisal of
the information, with a view towards characterizing the profile of those risks assessed
as important
 16. Signal and risk evaluation
16.1. Summaries of Safety concerns
 The purpose of this sub-section is to provide a summary of important safety
concerns at the beginning of the reporting interval, against which new
information and evaluations can be made.

 It should provide the following safety information:

 Important identified risks;
 Important potential risks and
 Missing information
 16. Signal and risk evaluation
16.1. Summaries of Safety concerns
 The following factors should be considered when determining the importance of
each risk:
• Medical seriousness of the risk, including the impact on individual patients; • Its
frequency, predictability, preventability, and reversibility; • Potential impact on
public health (frequency; size of treated population); and • Potential for avoidance
of the use of a medicinal product with a preventive benefit due to a
disproportionate public perception of risk (e.g., vaccines).

 Important identified and potential risks may include, for example:

• Important adverse reactions; • Interactions with other medicinal products; •
Interactions with foods and other substances; • Medication errors; • Effects of
occupational exposure; and • Pharmacological class effects.
 16. Signal and risk evaluation
16.2. Signal evaluation
This sub-section of the PSUR should summarise the results of evaluations of all
safety signals (whether or not classified as important) that were closed during the
reporting interval.
The two main categories to be included in this sub-section are:
1. Those signals that, following evaluation, have been refuted as “false” signals
based on medical judgement and scientific evaluation of the currently available
information.
2. Those signals that, following evaluation, have been categorised as either a
potential or identified risk, including lack of efficacy.

It is recommended that the level of detail provided in the description of the signal
evaluation should reflect the medical significance of the signal and potential public
health importance and the extent of the available evidence.
 16. Signal and risk evaluation
16.2. Signal Evaluation
 Signals can be presented as
• Closed and refuted signals
• Closed signals that are categorised as important potential risks
• Closed signals that are categorised as important identified risks
• Closed signals that are potential risks not categorised as important
• Closed signals that are identified risks not categorised as important

 Each signal evaluation should include source or trigger of the signal; background relevant
to the evaluation; method(s) of evaluation, including data sources, search criteria, results
- a summary and critical analysis of the data; discussion and conclusion
 16. Signal and risk evaluation
16.3. Evaluation of risks and new information
 This sub-section should provide a critical appraisal of new information relevant to previously
recognised risks that is not already included in sub-section 16.2 (“Signal evaluation”).
 New information can be organised as follows:
1. New information on important potential risks
2. New information on important identified risks
3. New information on other potential risks not categorised as important
4. New information on other identified risks not categorised as important
5. Update on missing information

 The focus of the evaluation(s) is on new information which has emerged during the reporting
interval of the PSUR. This should be concise and interpret the impact, if any, on the
understanding and characterisation of the risk.
 16. Signal and Risk evaluation
Each evaluation should include the following information as appropriate:

 Source of the new information;

 Background relevant to the evaluation;
 Method(s) of evaluation, including data sources, search criteria, and analytical
approaches;
 Results – a summary and critical analysis of the data considered in the risk
evaluation;
 Discussion;
 Conclusion, including whether or not the evaluation supports an update of the
characterisation of any of the important potential and identified risks in sub-section
16.4 (“Characterisation of risks”)
 16. Signal and risk evaluation
16.4. Characterisation of risks
 This sub-section should characterise important identified and potential risks based
on cumulative data (i.e., not restricted to the reporting interval) and describe missing
information.
 Depending on the nature of the data source, the characterisation of risk may
include, where applicable:

• frequency; • numbers of cases (numerator) and precision of estimate, taking into account
the source of the data; • extent of use (denominator) expressed as numbers of patients,
patient-time, etc., and precision of estimate; • estimate of relative risk and precision of
estimate; • estimate of absolute risk and precision of estimate; • impact on the individual
patient (effects on symptoms, quality or quantity of life); • public health impact; • patient
characteristics relevant to risk (e.g. patient factors (age, pregnancy/lactation, hepatic/renal
impairment, relevant co-morbidity, disease severity, genetic polymorphism); • dose, route of
administration; • duration of treatment, risk period; • preventability (i.e. predictability, ability
to monitor for a “sentinel” adverse reaction or laboratory marker); • reversibility; • potential
mechanism; and • strength of evidence and its uncertainties, including analysis of conflicting
evidence, if applicable.
 16. Signal and Risk evaluation
16.4. Characterisation of risks

 For PSURs for products with several indications, formulations, or routes of

administration, where there may be significant differences in the identified and
potential risks, it may be appropriate to present risks by indication, formulation, or
route of administration. It may include:

 risks relating to the active substance;

 risks related to a specific formulation or route of administration (including
occupational exposure);
 risks relating to a specific population; and
 risks associated with non-prescription use (for compounds that are available as
both prescription and non-prescription products).
 16. Signal and risk evaluation
16.5. Effectiveness of risk minimisation (if applicable)
 Risk minimisation activities are public health interventions intended to prevent the occurrence of an
adverse drug reaction(s) associated with the exposure to a medicinal product or to reduce its severity.

 The aim of a risk minimisation activity is to reduce the probability or severity of an adverse drug
reaction.

 Risk minimisation activities may consist of routine risk minimisation (e.g., product labelling) or
additional risk minimisation activities (e.g., Direct Healthcare Professional Communication/ educational
materials).

 Relevant information on the effectiveness and/or limitations of specific risk minimisation activities for
important identified risks that has become available during the reporting interval should be
summarised in this sub-section of the PSUR.

 Insights into the effectiveness of risk minimisation activities in any country or region that may have
utility in other countries or regions are of particular interest. Information may be summarised by
region, if applicable and relevant.
 17. Benefit evaluation
PSUR sub-sections 17.1 (“Important baseline efficacy and effectiveness information”)
and 17.2 (“Newly identified information on efficacy and effectiveness”) provide the
baseline and newly identified benefit information that support the characterisation of
benefit described in sub-section 17.3 (“Characterisation of benefits”) that in turn
supports the benefit-risk evaluation in section 18 (“Integrated benefit-risk analysis for
authorised indications”).
 17. Benefit evaluation
17.1. Important baseline efficacy and effectiveness information
 This sub-section of the PSUR summarises information on both efficacy and
effectiveness of the medicinal product at the beginning of the reporting interval and
provides the basis for the benefit evaluation. This information should relate to
authorised indication(s) of the medicinal product listed in the reference product
information.
 For medicinal products with multiple indications, populations, and/or routes of
administration, the benefit should be characterised separately
 The level of detail provided in this sub-section should be sufficient to support the
characterisation of benefit in the PSUR sub-section 17.3 (“Characterisation of
benefits”) and the benefit-risk assessment in section 18 (“Integrated benefit-risk
analysis for authorised indications”).
 17. Benefit Evaluation
17.2. Newly identified information on efficacy and effectiveness
 For some products, additional information on efficacy or effectiveness in authorised
indications may have become available during the reporting interval. Such information
should be presented in this sub-section of the PSUR.
 For authorised indications, new information on efficacy and effectiveness under
conditions of actual use should also be described in this sub-section
 Information on indications newly authorised during the reporting interval should
also be included in this sub-section.
 Particular attention should be given to vaccines, anti-infective agents or other
medicinal products where changes in the therapeutic environment may impact on
efficacy/effectiveness over time.
 17. Benefit Evaluation
17.3. Characterisation of benefits
 This sub-section provides an integration of the baseline benefit information and the
new benefit information that has become available during the reporting interval, for
authorised indications.
 The level of detail provided in this sub-section should be sufficient to support the
analysis of benefit-risk in section 18 (“Integrated benefit-risk analysis for authorised
indications”).
 When there is new positive benefit information and no significant change in the risk
profile in this reporting interval, the integration of baseline and new information in
this sub-section should be succinct.
 17. Benefit Evaluation
This sub-section should provide a concise but critical evaluation of the strengths and
limitations of the evidence on efficacy and effectiveness, considering the following:

 A brief description of the strength of evidence of benefit, considering comparator(s),

effect size, statistical rigor, methodological strengths and deficiencies, and consistency
of findings across trials/ studies;
 New information that challenges the validity of a surrogate endpoint, if used;
 Clinical relevance of the effect size;
 Generalisability of treatment response across the indicated patient population (e.g.,
information that demonstrates lack of treatment effect in a sub-population);
 Adequacy of characterization of dose-response;
 Duration of effect;
 Comparative efficacy; and
 A determination of the extent to which efficacy findings from clinical trials are
generalisable to patient populations treated in medical practice.
18. Integrated Benefit-Risk Analysis for
Authorised Indications
 The marketing authorisation holder should provide in this PSUR section an overall
appraisal of the benefit and risk of the medicinal product as used in clinical practice.

 The sub-sections 16.4 (“Characterisation of risks”) and 17.3 (“Characterisation of

benefits”) present the risks and benefits, this section should provide a critical analysis
and integration of the key information in the previous sections and should not simply
duplicate the benefit and risk characterisation presented in the sub-sections
mentioned above.
18. Integrated Benefit-Risk Analysis for
Authorised Indications
18.1. Benefit-risk context – Medical need and important alternatives
This sub-section of the PSUR should provide a brief description of the medical need for
the medicinal product in the authorised indications and summarised alternatives
(medical, surgical or other; including no treatment).
 18. Integrated Benefit-Risk Analysis for
Authorised Indications
18.2. Benefit-risk analysis evaluation
The benefit-risk evaluation should be presented and discussed in a way that facilitates the
comparison of benefits and risks and should take into account the following points:
 The key benefits and risks considered in the evaluation should be specified. The key
information presented in the previous benefit and risk section/sub-sections should be carried
forward for integration in the benefit-risk evaluation.
 Consider the context of use of the medicinal product: the condition to be treated, prevented, or
diagnosed; its severity and seriousness; and the population to be treated (relatively healthy;
chronic illness, rare conditions).
 With respect to the key benefit(s), consider its nature, clinical importance, duration, and
generalisability, as well as evidence of efficacy in non-responders to other therapies and
alternative treatments. Consider the effect size. If there are individual elements of benefit,
consider all.
 With respect to risk, consider its clinical importance, (e.g., nature of toxicity, seriousness,
frequency, predictability, preventability, reversibility, impact on patients), and whether it arose
from clinical trials in unauthorised indications or populations, off-label use, or misuse.
 The strengths, weaknesses, and uncertainties of the evidence should be considered when
formulating the benefit-risk evaluation. Limitations of the assessment should be discussed.
18. Integrated Benefit-Risk Analysis for
Authorised Indications
Provide a clear explanation of the methodology and reasoning used to develop the
benefit-risk evaluation:

 The assumptions, considerations, and judgement or weighting that support the

conclusions of the benefit-risk evaluation should be clear.

 If a formal quantitative or semi-quantitative assessment of benefit-risk is

provided, a summary of the methods should be included.

 Economic considerations (e.g., cost-effectiveness) should not be considered in the

benefit-risk evaluation.
 19. Conclusions and Actions
 A PSUR should conclude with the implications of any new information that arose during the
reporting interval in terms of the overall evaluation of benefit-risk for each authorised indication,
as well as for relevant subgroups, if appropriate.
 Based on the evaluation of the cumulative safety data and the benefit-risk analysis, the
marketing authorisation holder should assess the need for changes to the reference product
information and propose changes as appropriate.
 The conclusions should include preliminary proposal(s) to optimise or further evaluate the risk-
benefit balance for further discussion with the relevant competent authority(ies). This may
include proposals for additional risk minimisation activities.
 For products with a pharmacovigilance or risk management plan, the proposals should also be
considered for incorporation into the pharmacovigilance plan and/or risk minimisation plan, as
appropriate.
 Based on the evaluation of the cumulative safety data and the risk-benefit analysis, the
marketing authorisation holder shall draw conclusions in the PSUR as to the need for changes
and/or actions, including implications for the approved summary of product characteristics
(SmPC) for the product(s) for which the PSUR is submitted.
 20. Appendices to the PSUR
A PSUR should contain the following appendices as appropriate

1. Reference information
2. Cumulative summary tabulations of serious adverse events from clinical trials;
and cumulative and interval summary tabulations of serious and non-serious
adverse reactions from post-marketing data sources.
3. Tabular summary of safety signals (if not included in the body of the report).
4. Listing of all the marketing authorisation holder-sponsored interventional and
non-interventional studies with the primary aim of identifying, characterising, or
quantifying a safety hazard or confirming the safety profile of the medicinal
product, or of measuring the effectiveness of risk management measures, in case
of non-interventional studies.
5. List of the sources of information used to prepare the PSUR (when desired by
the marketing authorisation holder).
6. Regional appendix
Development Safety Update
Report (DSUR)
 Introduction - DSUR
DSUR
 Format and content for periodic reporting on drugs under development.
 Development Safety Update Report (DSUR) is Comprehensive, thoughtful annual
review and evaluation of pertinent safety information collected during the reporting
period related to a drug under investigation, whether or not it is marketed.
 A DSUR provides information to assure regulators that sponsors are adequately
monitoring and evaluating the evolving safety profile of the investigational drug.
 The development safety update report (DSUR) proposed is intended to be a common
standard for periodic reporting on drugs under development (including marketed
drugs that are under further study) among the ICH regions.
 U.S. and European Union (EU) regulators consider that the DSUR, submitted
annually, would meet national and regional requirements currently met by the U.S.
investigational new drug application (IND) annual report and the EU annual safety
report, respectively.
 General Terminology
 Data lock point (DLP): The date (month and day) designated as the cut-off for
data to be included in a DSUR. It is based on the Development International Birth
Date (DIBD).
 Development International Birth Date (DIBD): Date of first approval (or
authorization) for conducting an interventional clinical trial in any country.
 Identified risk: An untoward occurrence for which there is adequate evidence of
an association with the medicinal product of interest.
 Potential risk: An untoward occurrence for which there is some basis for suspicion
of an association with the medicinal product of interest but where this association has
not been confirmed.
 Important identified risk; Important potential risk: An identified risk or
potential risk that could have an impact on the risk-benefit balance of the product or
have implications for public health.
 Signal: A report or reports of an event with an unknown causal relationship to
treatment that is recognized as worthy of further exploration and continued
surveillance.
 Objectives of DSUR
The main objective of a DSUR is to present a comprehensive, thoughtful annual
review and evaluation of pertinent safety information collected during the reporting
period related to a drug under investigation, whether or not it is marketed, by:

(1) examining whether the information obtained by the sponsor during the reporting
period is in accord with previous knowledge of the investigational drug’s safety;
(2) describing new safety issues that could have an impact on the protection of
clinical trial subjects;
(3) summarizing the current understanding and management of identified and
potential risks; and
(4) providing an update on the status of the clinical investigation/development
program and study results.
 Relation of DSUR to the PSUR
 Some ICH countries and regions accept submission of a PSUR to fulfill national and
regional requirements for periodic reporting on the safety of approved drugs.
 Although the focus of the DSUR is on investigational drugs, there can be overlap
between the content of the DSUR and PSUR, and some repetition is expected.
 For example,
 Information from marketing experience (reported in the PSUR) might be relevant
to clinical development, and therefore reported in the DSUR.
 Safety findings from clinical trials conducted using marketed drugs would be
included in the DSUR but would also be pertinent to postmarketing safety and
would be reported in the PSUR.
 Both the DSUR and PSUR should be comprehensive and stand alone as they focus
on different subject matter and have differing periodicities and recipients.
 Single DSUR for an Active Substance
 In order to promote a comprehensive analysis and presentation of the safety profile
of the investigational drug, a sponsor should prepare a single DSUR with data
pertinent to all dosage forms and strengths, all indications, and all patient populations
under study with the investigational drug, wherever feasible.
 If this is not possible (e.g., when the data are not available to the sponsor), an
explanation should be provided in the introduction section of the DSUR.
 If more than one sponsor is involved in drug development, particularly in a co-
development or other contractual agreement, a single DSUR can be submitted.
 Periodicity and DSUR Data Lock Point
 The Development International Birth Date (DIBD) is used to determine the start of
the annual period for the DSUR.
 The data lock point of the DSUR should be the last day of the one-year reporting
period. For administrative convenience, if desired by the sponsor, the data lock point
of the DSUR can be designated as the last day of the month prior to the month of the
DIBD.
 When clinical development of a drug continues following a marketing approval in
any country worldwide, both a PSUR and a DSUR should be submitted as specified by
national or regional laws or regulations. If desired by the sponsor, a DSUR can be
prepared based on the PSUR International Birth Date (IBD) so that the DSUR and the
PSUR can be synchronized
 The DSUR should be submitted to all concerned regulatory authorities no later than
60 calendar days after the DSUR data lock point.
 Strategies for preparation of DSURs for
Multi-drug therapies
Multi-drug therapy used in DSUR
clinical trial(s)
Investigational drug (A) + marketed Either a single DSUR focusing on (A+X+Y+Z)
drug(s) (X, Y, Z) or
A single DSUR focusing on (A)
including data on the multi-drug therapy
Two investigational drugs (A) + (B) Either a single DSUR focusing on (A + B)
or
Two separate DSURs (A) and (B), each including
data on the multi-drug therapy
Two (or more) marketed drugs as an A single DSUR focusing on the multi-drug therapy
investigational drug combination (X + Y + Z)
(X, Y, Z)
 Reference Safety Information (RSI)
 The Investigator’s Brochure (IB) in effect at the start of the reporting period should
serve as the reference safety information to determine whether the information
received during the reporting period remains consistent with previous knowledge of
the safety profile of the investigational drug.
 Section 7.1 of the DSUR should clearly indicate the version number and date of the
IB used for this purpose.
 Usually, a single document should serve as the reference safety information.
However, in certain circumstances, it might be appropriate to use more than one
reference document to support the DSUR.
 If the IB has been revised during the reporting period and not previously submitted
to the relevant regulatory authority, the sponsor should provide a copy of the current
version of the IB as an attachment to the DSUR.
 Format and Presentation of DSUR
 Title page
 Executive Summary
 Table of Contents
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 during the Reporting Period
6. Estimated Cumulative Exposure
6.1 Cumulative Subject Exposure in the Development Program
6.2 Patient Exposure from Marketing Experience
 Format and Presentation of DSUR
7. Data in Line Listings and Summary Tabulations
7.1 Reference Information
7.2 Line Listings of Serious Adverse Reactions During the Reporting Period
7.3 Cumulative Summary Tabulations of Serious Adverse Events

8. Significant Findings from Clinical Trials during the Reporting Period

8.1 Completed Clinical Trials
8.2 Ongoing Clinical Trials
8.3 Long-term Follow-up
8.4 Other Therapeutic Use of Investigational Drug
8.5 New Safety Data Related to Combination Therapies

9. Safety Findings from Noninterventional Studies

10. Other Clinical Trial/Study Safety Information
11. Safety Findings from Marketing Experience
 Format and Presentation of DSUR
12. Nonclinical Data
13. Literature
14. Other DSURs
15. Lack of Efficacy
16. Region-Specific Information
17. Late-Breaking Information
18. Overall Safety Assessment
18.1. Evaluation of the Risks
18.2 Benefit-risk Considerations

19. Summary of Important Risks

20. Conclusions
Appendices to the DSUR
 Periodic Adverse Drug
Experience Report (PADER)
 Introduction - PADER
 A PADER is a type of aggregate safety report required to be submitted by a sponsor
or marketing authorization holder (MAH) to the US Food and Drug Administration
(FDA) after obtaining marketing authorization approval.
 PADER serves the purpose of collating, updating, evaluating, and providing a
summary of post-approval information of a product along with its benefit-risk (B/R)
profile evaluation.
 In PADER, a detailed analysis is not required as per PBRER/ PSUR format.
 The main purpose of a PADER is to update and evaluate a medicine’s global data
and provide information about drug safety.
 It provides a brief summary of changing post-approval information of a drug along
with the benefit-risk profile evaluation.
 This evaluation provides insights, whether further changes are required for a
medicine’s labeling or if additional investigations are required.
 Aim of a PADER
 Report if any new information is obtained from the source medicine
 Evaluate information to find any exposure related to the medicine
 Accumulate the status of the medicine’s approval across various countries
and regions
 Frequency of PADER
 PADERs are required to be submitted quarterly for the first 3 years after
drug approval in the USA, and annually thereafter.
 Waiver not to submit PADER

 An MAH can take waiver from FDA and update the NDA listing and submit
PBRER/ PSUR instead of PADER in ICH regions.
 Table of Content for a PADER
1. A Narrative summary and Analysis of Information in the report
2. A MedWatch form 3500A, for each adverse drug experience not reported
as 15-day expedited report
3. Action taken since the last report
4. Periodic reporting except 15-day alert report
5. Follow up information to adverse drug experiences submitted in a periodic
report
 Key points while drafting a PADER
 Ensure all the ICSR are already submitted during the review period (15 day
reports), and their submission dates are entered in safety database.
 If any ICSR not submitted, then MAH need to submit it ASAP and initiate
CAPA as per internal process.
 The cases/ ICSR that are going to be submitted as part of PADER are closed
in safety database to generate their XML’s.
 The ICSR that needs description should be 15 day expedited cases along
with their clinical significance.
 The Narrative should be brief, with emphasis on data only about serious and
unlisted event, hence avoid copy paste of narratives.
 Key points while drafting a PADER
 The Company comments explaining MAH causality of case should be
retained.
 Explain 15 day expedited and other cases in brief and corelate their
significance in terms of impact on benefit-risk profile of product.
 Attaching the recent USPI and describing a very briefly what were the
changes in USPI made during review period.
 Adding any postmarking studies, regulatory actions and any new safety
measures implemented in respective sections.
 Important differences between PADER
and PBRER
PADER PBRER
1 It consists of individual case narratives It consists of detailed analysis on the benefit-risk
for cases with fatal outcome and/ events evaluation of the given medicinal product
of special interest
2 It is prepared per US 21 CFR 314.80 and It is prepared per ICH E2C R2 and European
is submitted to US FDA Medicines Agency Module VII guidelines and is
submitted to the European Union and rest of the
world
3 It consists of around 5 sections and is It consists of 20 sections and is a more complex
relatively less complex document document
4 It includes case presentation of serious It mainly includes sections on regulatory updates,
unlisted events and regulatory updates cumulative and interval exposure, interventional and
noninterventional clinical trials, overview of signals,
and benefit-risk assessment
 Important differences between PADER
and PBRER
PADER PBRER

5 A separate PADER is to be submitted with Usually, one PBRER is prepared for an

each NDA approval (for different indications investigational product with different
and/or formulations of an investigational formulations, dosage forms, or indications. In
medicinal product) though sometimes MAH exceptional cases with provision of appropriate
can prepare one PADER for different NDAs justification, for example, entirely different
for different strengths of a formulation with indications, submission of separate PBRERs
appropriate justification might be acceptable
6 The frequency of submission is quarterly for For newly approved products, PBRERs are
first 3 years followed by annually submitted 6 months for first 2 years followed by
annually (with exception of ad hoc requests)
7 Quarterly and annual PADERs are submitted Annual or multiyear PBRERs are submitted
within 30 and 60 calendar days of DLP, within 70 or 90 calendar days of DLP,
respectively respectively
 How to Switch from ICSR to Aggregate,
Signal and Risk Management Role

https://pvdrugsafety.com/2021/11/how-to-switch-from-icsr-to-aggregate-reporting-signal-and-risk-
management-role/