Question and Answers of General principles of Aggregate Reporting

Question-1 Give any five sources of Information of PSUR?

Answers- Non-clinical studies;

Clinical trials, including research in unapproved indications or populations;

Spontaneous reports (for example, on the MAH’s safety database);

MAH-sponsored websites;

Observational studies such as registries.

Question-2 How does a PBRER facilitate?

Answer- Summarizes relevant new safety information that may impact the benefit risk profile

Summarizes important new efficacy / effectiveness information

Examines if new information is in accord with previous knowledge of the benefit risk profile

Integrates Benefit / Risk Evaluation where new important safety information has emerged.

Question 3 -what are the Common PSUR inspection findings?

Answer - Poor quality reports, Incorrect format of the document

New safety signals not or poorly assessed

Medication errors not highlighted

Absence of use of standardized medical terminology (MedDRA)

Published literature not properly reviewed

Omission of required information e.g., Update of Regulatory or MAH Actions taken for Safety Reasons,
Changes to Reference Safety Information

Question 4 - What is the Periodicity / Submission of the PSUR/ PBRER Report?

Answer- Immediately upon requests

Every 6 months from authorization until vaccine is placed on the market

Every 6 months for the first 2 years on the market

Annually for the next 2 years

Thereafter every 3 years Submission of PSUR:

By day 70 after data lock point (DLP) for intervals up to 12 months

By day 90 after DLP for intervals > 12 months.

Question - 5 What is full form of PSUR AND PBRER?

Answer - Periodic safety update reports (PSURs)/ Periodic Benefit Risk Evaluation Report

Question - 6 What are the safety parameters of interest while preparing ISS?

Answer: Safety parameters of interest typically include those specified in FDA guidance, those that are a
priori special interest or concern for the program or compound, and those identified during data review.
Some examples of safety parameters are exposure, concomitant medications, deaths, adverse
experiences (occurrence, relatedness, severity, seriousness, duration, timing, etc.), laboratory measures,
and vital signs. A good test of whether one has selected the right parameters is to ask whether the
summary of the estimates of these parameters sufficiently describes the overall drug safety profile.

Question - 7 What is summary bridging report?

Answer: The different frequency and periodicity requirements of different regulatory authorities in
different countries create potential problems for the production of PSURs. Under ICH E2C provisions,
regulators who do not wish to receive a 6-month report are expected to accept two 6-month reports as
an annual report or the appropriate series of reports as a 5-year report. CIOMS V therefore proposed
the use of the summary bridging report to facilitate the review of a series of reports. This is a concise
document integrating the information presented in two or more PSURs that is submitted to a regulatory
authority to cover a specified period over which a single report is required.

Question - 8 Define sections of risk management plan

Answer: sections of the risk management plan include:

1. Safety Specifications: Describes the significant information on identifies and potential risks and
missing information and on safety concerns which need to be managed proactively.

2. Pharmacovigilance Plan: Provides planning of PV activities to characterize and quantify clinically

relevant risks and to identify new adverse reactions.

3. Risk Minimization Plan: Planning and implementation of risk minimization measures (RMM), including
the evaluation of effectiveness of RMM activities.

Question - 9 Describe signal detection.

Answer: Signal detection in Pharmacovigilance involves looking at the adverse reaction data for patterns
that suggest new safety information which arises from one or multiple sources (including observations
and experiments), which suggests a new potentially causal association, or a new aspect of a known
association, between an intervention and an event or set of related events, either adverse or beneficial,
that is judged to be of sufficient likelihood to justify verificatory action”.

Question - 10 What is Aggregate Reporting?

Answer. Aggregate reporting or Periodic Reporting 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.

Question - 11 What are the benefits of Aggregate Reporting?

Answer

 Helps in studying benefit/risk balance of medicinal products throughout product life cycle.
 Presents wider perspective of drug safety profile
 Allows collective analysis of cases in database tracking of regulatory actions literature search
etc.
 Reviews the cumulative safety information from a wide range of sources, on a periodic basis and
submits the findings to regulators worldwide.
 Examines and summarizes all existing safety experience with a medicinal product.
 Outline plans for signal or risk evaluations including timelines and/or proposals for additional
pharmacovigilance activities.

Question -12 What are the principles of Aggregate reporting?

Answer - Aggregate reports are the reports that emphasize evaluation of safety profile and benefit risk
and do not focus much on individual cases. 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.

Principle based on the-

1. - Benefit- risk evaluation

2. -Reference information
3. -Single DSUR for an active substance.
4. -Single PBRER for an active substance.

Question - 13 In which year GVP VII first version for ICH guideline E2C (R2) on periodic benefit- risk
Evalution report (PBRER) came into effective?

Answer - 2012

Question - 14 What is Development Safety Update Report (DSUR)?

Answer: Development Safety Update Reports (DSUR) are new, internationally harmonized, safety
documents covering the safety summary of medicinal products during their development or clinical trial
phase.

Question - 15 What is the difference between DSUR and PSUR?

Answer: The Developement Safety Update Report (DSUR) is used for drugs still under development to assess
risk to the subjects enrolled in the study, while the Periodic Safety Update Report is used for drugs already on
the market to assess long term safety.

Question - 16 What is Data Lock Point?

Answer: Data Lock Point means for a periodic safety update report (PSUR), the date designated as the
cut-off date for data to be included in a PSUR.

Question - 17 What should a DSUR contain?

Answer:
-The progress of clinical investigation.
-Safety information of the product.
-Issues which may impact the safety of the trial participants.
-Brief statement about the present understanding and management of identified and potential risks.
-Statements indicating whether the data from the current reporting period aligns with the known safety
information of the investigational product or not.

Question - 18 What is PADER?

Answer: 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.
Question - 19 What are the required documents for PADER?
Answer:

Domestic ICSRs

SUSAR cases (15- day reports)

Analysis document

Regulatory Actions/changes to the RSI

Question - 20 Give any 2 differences between PADER & PBRER?

Answer:

PADER
It consists of individual case narratives for cases
with fatal outcome and/events of special interest
It is prepared per US 21 CFR 314.80 and is
submitted to US FDA
It consists of around 5 sections and is a relatively
less complex document
It includes case presentation of serious unlisted
events and regulatory updates
A separate PADER is to be submitted with each
NDA approval (for different indications and/or
formulations of an investigational medicinal
product) though sometimes MAH can prepare
one PADER for different NDAs for different
strengths of a formulation with appropriate
justification
The frequency of submission is quarterly for the
first 3 years followed by annually
PBRER
It consists of detailed analysis on the benefit-risk
evaluation of the given medicinal product
It is prepared per ICH E2C R2 and European
Medicines Agency Module VII guidelines and is
submitted to the European Union and the rest of
the world
It consists of 20 sections and is a more complex
document
It mainly includes sections on regulatory updates,
cumulative and interval exposure, interventional
and noninterventional clinical trials, overview of
signals, and benefit-risk assessment
Usually, one PBRER is prepared for an
investigational product with different
formulations, dosage forms, or indications. In
exceptional cases with provision of appropriate
justification, for example, entirely different
indications, submission of separate PBRERs might
be acceptable
For newly approved products, PBRERs are
submitted 6 months for first 2 years followed by
 annually (with exception of ad hoc requests)
Quarterly and annual PADERs are submitted
Annual or multiyear PBRERs are submitted within
within 30 and 60 calendar days of DLP,
70 or 90 calendar days of DLP, respectively
respectively

Question –-21 Timelines of different types of reports: DSUR, PSUR, PBRER &PADER?
Answer:

60 calendar days- DSUR

60 calendar days- PSUR
70 calendar days (Annual)
90 calendar days (multiyear) -PBRER
30 calendar days
(Quarterly)
60 calendar days (Annual) -PADER