1

Pharmacovigilance
Process Work Flow

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Process of PV 2
4 ELEMENTS DETERMINING VALIDITY OF A

CASEPHARMACOVIGILANCE
WORKFLOWTYPES OF CASES
SOURCES OF CASE REPORTS AND REPORTING FORMS

SINGLE CASE PROCESSING-ICSRS

Basic Steps in the Case Handling Process

Case Management Workflow
Case Receipt
Triaging
Case Processing
Medical review
Follow up of adverse events
Case completion
AGGREGATE REPORTING

SIGNAL DETECTION

RISK MANAGEMENT PLAN

 3

A Valid Adverse Event Report:

4 Minimum data elements required

1- An identifiable patient
(initials, age, sex, birthday, or simply the knowledge that a patient exists)

2- An identifiable suspected company product

3- An identifiable reporter (patient, physician, nurse, etc.)
4- An adverse event*

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 5

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1- An Identifiable Patient

Yes No
Enough evidence that a patient exists Medical inquiries about AEs with no patient

any knowledge of an Batch reports: specific patient number

individual patient: “Ten patients developed rash while on Diovan”
age (or age
category, e.g., adolescent,
adult, elderly), gender, Unspecified Number of patients
initials, date of birth, name, or patient “some patients had anaphylaxis”
identification
number.
Non-human subject (pet)
 7

2- An Identifiable Reporter

Yes No
Initials, name of a person or Email Address with no other identifiers
relationship to the patient (e.g.
Telephone number with no other identifiers
parent),
A reporter who refuses to give his/her name
name of an institution
or address, professional qualifications
and/or relationship to the
complete mailing address with
patient
no other information
A letter not meeting the criteria
The reporter’s professional of column “yes”
qualification (e.g. MD, Dr.)
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 8
3- A Suspect Product:

Yes No
Any product registered, in-licensed, or co- A generic formulation of a company
promoted by company or MAH (globally product (manufacturer known)
or locally)

A generic formulation of a company

product (manufacturer unknown)

A product from an unblinded SAE

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 9
4- An Adverse Event:

Yes:
• a specific symptom or diagnosis laboratory finding kinetic interaction
with plasma level change lack of efficacy or lack of expected therapeutic
effect (as defined in the product label).
• Death with no other information pregnancy, overdose, abuse,
accidental administration, disease aggravation.

No:
• ambiguous claims “patient suffered an injury” “irreparable damage” “patient
hospitalized”, with no symptoms or diagnosis that led to the injury hospitalization.

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 10
Desired Information:

 
Patient: Initials, age, sex
 
 Company medication (therapy dates, dose, formulation, indication etc.)
 
 Adverse event (onset date, lab data, treatment, outcome)
 
Reporter correspondence details

In addition:

 
Medical history
 
 Concomitant medication (therapy dates, dose, indication, etc)
 
Action taken (dechallenge/rechallenge, intervention)

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 11
Follow-Up Information:

 
Any new information, or change in previous information
 
 provided by the reporter, or requested by local or central IMS

Significant
follow-up information expeditable within the SOP
timelines*

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 12

Receipt of a Valid Adverse Event Report:

Date received by manufacturer

(Initial receipt date (IRD or MRD)):

Date of receipt of a valid report with the 4

minimumdate elements by any company employee or
a designated person (e.g. a distributor)

Triggers the regulatory clock!

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 13
Pharmacovigilance Workflow:

AE Case Aggregate Signal Risk

Reports Reporting Detection Management
To monitor any
To review the Process of reported AE of the
Serious and
cumulative safety determining AEs product on a patient
unexpected AEs are
information from a associated with and to seek
subject to expedited
wide range of particular drugs methods to
reporting
sources, on a and comparing the minimise or remove
periodic basis and same to that for such AE from the
submit to regulators other similar drugs. patient.
worldwide.

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 Case Management Flow:

What is PV
Duplication Logging the
Receive Case
Adverse
Check Case
Drug
reactions

Regulation
s

Perform
Medical Data Entry in
Single Case
Triage to
Review database
Aggregate
Assess Case
Reporting

Signal
Detection

Validation &
Risk Close Case
Generate Report 1
4
Managemen
t
 15

Overview of Pharmacovigilance System:

Issue and Crisis

PMS and Spontaneous Risk Management Management
Epidemiological Report Plans
Data Amend
Prescribing
Information
Clinical Trial

Data in Database entry Data Review Output Action

Licensing
Licensing
Submission & Partner
Partner Enquiry
Study Reports
Signal response
Detection and Worldwide
Literature Regulatory Review regulatory reports
generation
Reports Reports Marketing Expedited and
Status Reported
Follow Up
Data

Collect….. Collate…… Analyze…… Communicate…...

 16
SOURCES of AE Reports:

 Spontaneous reports (SRs): • Medical literature/ media


 Health Care Professionals (HCPs) • Stimulated reports:

 Non Health Care – Patient support programs
Professionals (non-HCPs) – Disease management

 Internet – Marketing surveys

– Patient Registries
 Solicited reports: – Health outcome studies

 Clinical trials phases I-IV – Lawsuits

 Observational Post-Marketing – Quality of life questionnaires
Surveillance (PMS) studies – Medical chart reviews

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Sources of Individual Case Safety Reports

 Spontaneous report acc. to ICH E2D:

A spontaneous report is an unsolicited communication by healthcare
professionals or consumers to a company, regulatory authority or other
organization (e.g. WHO, Regional Centers, Poison Control Center) 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.

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Definitions:

 Healthcare professional (HCP):

Healthcare professionals are medically-qualified persons
such as physicians, dentists, pharmacists, nurses, coroners, or
as otherwise specified by local regulations.
 Consumer (non-HCP):
A consumer is defined as a person who is not a healthcare
professional.
Examples: user, spouse, relative, neighbor

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Source of Individual Case Safety Reports:

 Literature:
The Marketing Authorization Holder (MAH) is expected to
regularly screen the worldwide scientific literature. Cases of ADRs
from the scientific and medical literature, might qualify for
 expedited reporting.
 Internet:
MAHs are not expected to screen external websites for ADR
information but should regularly screen their websites for potential
 ADR case reports.
 Regulatory Authorities:
Individual serious unexpected adverse drug reaction reports
originating from foreign regulatory authorities are always subject to
expedited reporting.

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Spontaneous Reporting:

Strengths Weaknesses
 Cornerstone of ‘PV’
  Underreporting

 Cheap & Easy

 Quality of reporting

 Encompass all clinical  No denominator

 settings  Subject to bias

 Life-time span

 Delayed effects go
 Detection of rare ADRs undetected
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How to Report:

 CIOMS-I form

 MedWatch 3500 – voluntary reporting

 MedWatch 3500A – mandatory reporting by MAHs

 CDSCO ADR form (India)

1. Patient Details
2. Suspected Medicinal Product(s)
3. Other Treatment(s)
4. Details of Suspected Adverse Drug Reaction(s)
5. Details on Reporter of Event
6. Administrative and Sponsor/Company Details

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 Pharmacovigilance Case Management Workflow: 22
2. AE Case Triage
a. Identify duplicate AE cases 3. Event Assessment
b. Assign case priority a. Prepare company narrative for review
c. Enter other case data b. Assess case from
into AERS system medical perspective
d. Perform preliminary c. Perform final review of
QA of data entered case for reportability

1. AE Case Reception
a. Receive AE Case
b. Document receipt 4. Processing Follow-
c. Index, file source documents Up Information
a. Identify additional
Information required to
analyze / report the case
b. Follow-up with case
reporter to obtain
additional information
c. Update additional case
information in AERS

5. Risk/Benefit Analysis
6.Regulatory
Submission a. Perform risk benefit analysis
based on AERS data
a. Prepare safety report b. Perform risk benefit analysis based
b. Facilitate final review by on data provided by regulatory agencies
Regulatory Affairs c. Prepare analysis reports
c. Submit report to Regulatory Agency
d. Track submission date of report
 23
Single Case Processing-ICSRs:

Basic Steps in the Case Handling

ProcessCase Management
WorkflowCase Receipt
Triaging
Case Processing
Medical review
Follow up of adverse
eventsCase completion
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 24
What is PV
AE Case Reception:
Adverse
Drug
reactions AEs received from variety of sources via wide range of
methods (Telephone calls, Fax, Mail, Electronic Media). The
Regulations
following information is captured:
 Case details

Single Case  Drug Details

 Patient Details

 Case Reporter Details
Aggregate
Reporting

 Case details

Signal  Case number
Detection 
 Initial report or follow up report

 Companies the drug belong to

Risk
Management  Seriousness about the case

 Date of receipt by the company becomes the Regulatory Clock start date
 25
What is PV
AE Case Reception:
Adverse
Drug

Drug details:
reactions


 The reporter suspects that one of the drug is the cause. It is called Suspect Drug.
Regulations 
 The other associated drugs are called Concomitant Drugs. Along with the name of the drugs,
 dose, frequency, regimen, indication are recorded where ever possible.
 
Single Case Patient Details:
• Patient’s age, country, ethnicity, medical history , etc.
 
 Case Reporter Details:
Aggregate
Reporting • About the person who reported the case.
 When the case is reported when the drug is in clinical trial, it is Clinical Trial Reporting.

Signal  When the case is reported when the drug is in market, it is Spontaneous Reporting.
Detection 
 When the case is reported through publication, it is Literature Reporting.

The reporters of cases are categorized : HCP and Non-HCP.

Risk
Management

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What is PV
Triaging:
Adverse
Drug
reactions
Triage is the assessment, classification & prioritization of the information
received according to key regulatory, scientific and medical criteria.
Regulations

Triage errors if not corrected in time can result in:

Single Case

Seriousness

 Late regulatory reports

Aggregate

Reporting
 Missed safety signals
Triage
Signal
Detection

Expectedness Relatedness

Risk
Management

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 27
Methods of Causality Assessment:


 Kramer scale


 Bayesian Neural network


 Yale algorithm


 Spanish quantitative imputation system


 WHO assessment scale


 Naranjo's scale


 European ABO system
 Karch and Lasagna's scale
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 Relatedness/Causal Relationship 28
Doctors review the data and finds out the causality of the
case, i.e., why this adverse event happened.
What is PV

Adverse No
Event has reasonable Temporal
Drug Remote
Reactions association with drug?
Yes
Regulations
No
Event stops after Dechallenge Possible

Single Case Yes

No No
Event due to existing
Rechallenge
Clinical Condition? Possible
Aggregate
Reporting Yes No
Event reappears after
Possible
Signal Rechallenge
Detection

Yes
1/11/2017
Risk
Management
High Probable Katalyst Healthcares & Life Sciences
 29
What is PV
Relatedness:
Adverse
Drug
reactions

“Suspect Causal Relation” WHO Causality Algorithm

Regulations
Classification Definition
Definitely related Events have no uncertainty in their relationship to test drug administration:
meaning that a re-challenge was positive.
Single Case

Probable Event follows a reasonable temporal sequence from drug administration,

increases upon discontinuation of the drug

Aggregate
Reporting
Possible Event may or may not follow a reasonable temporal sequence from drug
administration but seems to be the type of reaction that cannot be
dismissed as unlikely.
Signal
Detection
Unlikely No reasonable temporal association between the study drug and the
suspected event
Risk

Definitely unrelated Events which occur prior to test drug administration or events which cannot
Management

be even remotely related to study participation

 30
What is PV
Causality:
Adverse
Drug
To determine likelihood of a causal relationship between drug & adverse events:
reactions

 Association in time/place between drug use and event.

Regulations  Pharmacology (current knowledge of nature ).
 Medical/pharmacological plausibility (signs, symptoms, tests, mechanism).
 Likelihood or exclusion of other causes.
Single Case
Common Questions to assess causality:
Are there previous conclusive reports on this reaction?

Aggregate
Did the ADR appear after the suspected drug was administered?
Reporting
Did the ADR improve when the drug was discontinued?

Did the ADR appear with re-challenge?

Signal
Detection Are there alternative causes for the ADR?
Did the reaction appear when placebo was given?
Was the drug detected in blood at toxic levels?
Risk
Management Was the reaction more severe when the dose was increased, or less severe when the dose
was decreased?
Did the patient have a similar reaction to the same or similar drug in any previous exposure?
 31
NARANJO Algorithm

For assessing the causality-



definite = 9


probable = 5-8


possible = 1-4
 doubtful =  0

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 33

Hartwig and Seigels Scale:

For assessing the severity-
1. Mild ADRs-are self limiting and do not contribute to prolongation
of length of hospital stay.
2. Moderate ADRs- require therapeutic intervention or hospital admission
or prolonged hospital stay by at least one day.
3. Severe ADRs- life threatening, requiring intensive medical care
or produce disability or lead to death.

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 34

Reporting Time Frames

Post-marketing 15-day "Alert reports“

The applicant shall report each adverse drug experience that is both serious
and unexpected, as soon as possible but in no case later than 15 calendar
days of initial receipt of the information by the applicant.

SUSAR (suspected unexpected serious adverse reaction)

This reporting needs to be done not later than seven days after the Sponsor
was first aware of the reaction. Any additional relevant information should be
sent within eight days of the report.
-FDA

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 38

Data Processing:

 The main functions of these steps are:





• Data entry into safety database from source document
• Coding (AEs & Products)
• Writing the case narrative
• Identifying missing information that should be pursued as
queries for Follow Up

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 39
Case Processing:

 Duplicate search: Due to, greater awareness , stringent

regulations and multiple reporting sources, duplicate reports is a
common phenomenon. Every safety management software has a
facility to identify and delete duplicates. Certain characteristics of
a case (sex, age or date of birth, dates of drug exposure, clinical
trial code, country, etc.) may be used to identify duplicate
reporting. This action is of significance for further processing of
the case. The duplicate could actually be follow up information
that could alter the seriousness and hence reporting timeline of
the case. Missed out duplicates could send misleading
information to signal detection systems.

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 40

 Data Entry: Details of the four pillars of a valid case have to be reported
meticulously. Patient information has to follow the HIPPA code for
confidentiality. Reporter information has to clear and detailed enough to be
able to contact the person if necessary. Drug identifiers like name,
formulation and dose have to be captured correctly. Event report has to be
detailed enough for the evaluator to decide on the cause of the adverse
event. This would include chronological description of the event or events,
nature, localization, severity, characteristics of the event, results of
investigations and tests, start date, course and outcome, concomitant
medications and other risk factors .

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 41
Dictionary Coding:

Medical classification, or medical coding, is the process of

transforming descriptions into universal medical diagnoses &
Procedure terms.

Purpose:
 To code new and amended dictionary terms for purpose of
 standardization
 These terms could be Drug terms, Adverse Events, Diseases,
 Medical Procedures.
 To ensure consistent data classification across all protocols within
 a project as well as globally across all projects
 To classify similar verbatim text into predefined categories that
represent medical concepts so that statistical reports can be
generated for data analysis.
 42
Dictionary Category:

Medical
World Health
Dictionary for World Health
Organization -
Regulatory Organization -
Activities Drug Dictionary
Adverse Reaction
Terminology

MedDra WHO Drug WHO -ART

• Symptoms
• Signs Adverse Events
• Diseases
•Study Drugs • Serious
• Diagnosis
•Concomitant Drugs • Non-Serious
• Therapeutic Indications
•Previous Drugs
• Names & Qualitative results of investigations
• Surgical & Medical Procedures -Maps to COSTART for
reporting purposes
• Medical/Social/Family History
 43

WHOART-WHO:
Adverse Reaction Terminology is dictionary for coding
adverse reactions . This system is maintained by the UMC.
COSTART:
COding Symbols for a Thesaurus of Adverse Reaction
Terms developed by USFDA . But recently COSTART was
replaced by MedDRA.
 44

 MedDRA is managed by MSSO (Maintenance and Support Services

Organization)



 MSSO releases new version in twice a year (March & September)



 March release is the main ,contains changes at the HLT level & above



 September release contains changes at the PT level

 Latest version (17.1) was updated in sept 2014
 45
Example of Coding an Event:

Verbatim MedDRA
redness at the injection site Erythema

itchiness at injection site Pruritis

lack of efficacy Drug inefficient

reduced effect Drug nefficient

reflux Acid reflux

 46

Coding for drugs: Both the suspect drug and concomitant

medication have to be coded. The principle is again to be talking
the same language across countries, companies and regulatory
bodies. Most common dictionary is the WHO Drug Dictionary
enhanced. This is provided as a product by the Upsala
Monitoring centre of the WHO. Entries are updated 4 times a
year. The majority of entries refer to prescription-only products,
but some over-the-counter (OTC) preparations are included. The
dictionary also covers biotech and blood products, diagnostic
substances and contrast media. For chemical and therapeutic
groupings the WHO drug record number system and ATC
classifications are considered.
 47

Causality assessment:
 Non spontaneous case reports usually indicate whether an adverse drug
 reaction is suspected due to the administered drug.
 In these circumstances and even otherwise, a causality assessment is required
 to be conducted.
 Various approaches have been developed for the structured determination of
the likelihood of a causal relationship between drug exposure and adverse
events.
These systems are largely based on following considerations:
 the chronology or association in time (or place) between drug administration
and event current knowledge of nature and frequency of adverse reactions
 due to the suspect molecule; or the pharmacology
 medical or pharmacological plausibility based on signs and symptoms,
 laboratory tests, pathological findings, mechanism of action
 likelihood or exclusion of other causes for the same adverse events; often the
disease condition or concomitant medication.
 48
Listedness/Labeldness/Expectedness:

 Listedness is based on the CCSI which is the core information on

safety profile of molecule available with MAH.

 Expectedness is based on SmPC or PI which is a local label and is
related to particular nation.

 It may happen that molecule A is having 10 SmPCs but as a rule
each molecule is always has one CCSI. Also, CCSI may contain the
less safety information which is available in each and every SmPC
but vice-a-verse is not true. So rarely it may happen the event is
unlisted but may be expected as per the local label (SmPC).

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 49

 CIOMS V provides a very elaborate explanation of

Listedness/Labeldness/ and Expectedness.

 The purpose of Expectedness/Labeldness is to assess
the reportability of the case to health authorities,
whereas listedness, based on CCSI is for the
generation of line-listings for PSURs.

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 50
Case Review:
 All cases should be reviewed after processing to ensure regulatory,
scientific and medical standards are met





Case review is a 2 step process:
- Quality review
- Safety Assessment

Focus of Case Review:



Completeness and Accuracy of data.


Consistency of data entry with source documents


Confirmation of the triage assessment of regulatory reportability


Consistency with established report standards (ICH)
 Queries and Follow up information
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 51
What is a Narrative?

 Summary of all relevant clinical information relating to an

adverse event
• Relevant information*
• Presented in logical time sequence (medical story)
• Comprehensive details of individual cases (stand alone)

*Electronic reporting currently limit on characters (20,000

characters)

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 52
Key Elements of a Narrative:

 This is a spontaneous non serious report.


 A nurse reported that a 29 year old male consumer
experienced stomach ache on 14Jun2008. while on
therapy with oral aspirin

 The patient stated that he experienced burning type of
stomach ache. The patient could not eat due to the pain
in the stomach. The patient also could not sleep until
early morning due to the stomach pain.

 He was taking aspirin 75mg two times a day orally for the
treatment of low back pain from an unknown date.
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 53

Key Elements of a Narrative...Contd

 Medical history included high blood pressure and ulcerative

colitis from an unknown date.

 Concomitant medications included oral acetaminophen 500mg,
Vitamin B complex 180mg, from an unknown date.

 Investigations data; endoscopy was carried out on 19Jun2008
and the results were normal.

 Therapy with Aspirin was continuing at the time of the report.

 At the time of the report the clinical outcome of the event was
unknown.

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 54
Medical Review:


 Adverse Event (AE) Capture
• Appropriateness of the AE terms selected

 Sequencing of the AEs

 Confirmation of Coding

 Confirmation of the Seriousness classification of the AE Terms

 Confirmation Listedness/Expectedness classification of AE Terms

 Reviews concurrent conditions, medical history
 Identification of any specific additional information needed for
 medical assessment

 Company causality assessment, wherever appropriate
 Identification of potential safety signals

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 55

• Timely reporting to authorities: this is the end goal for which all
the above has to be done in a timely manner. The reporting could
be by sending data back to the sponsor or by a click of a button
based on the software used. The latter will provide an extra couple
of days for case processing

• Safety data management is the most basic step in

pharmacovigilance. This is often outsourced so that internal
company resources can focus on the domain related, mentally
stimulating activities like signal detection, regulatory responses,
information to stakeholders

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 56
Case Completion:

 Case considered ready for completion when it has gone through

triage, processing, review and approval




 Case completion process includes:
- any updates to the case as required by the review cycle
- incorporation of additional information requests into standard
follow-up requests
- generation of final report & distribution of the final report to
appropriate internal & external parties, including regulatory
submission
- Archiving the report and accompanying source documents (both
paper & electronic documents)*
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 57

Follow up Information:
Recommendation to prioritize case reports by importance:
 Serious and unexpected
 Serious and expected

 Non-Serious and unexpected
 Cases of special interest (ADRs under surveillance; non-serious ADRs which
may develop into serious ADRs (mild blood alterations indicating
dyscrasias; liver enzyme fluctuations etc..)

Follow up can be obtained by:

 Telephone; site visit; written request

 Written confirmation should be obtained wherever possible for the
data supplied

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Follow up Information:
 Judgement should be exercised for the extent of follow up and should be
placed

 alongside the seriousness of the reported reaction and the known
outcome

 (condition stabilized; resolved)

 It is recommended that MAHs should collaborate together if there is more
than

 one MAHs drug suspected as a causal agent (interactions)

 ICH E2D has a list of key data elements which should be included wherever

 possible in expedited reports

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Follow up related to pregnancy:

 Any pregnancy outcome where the reporter or Company decides may be
related

 to the Company product, this should be reported as an expedited report

under 15
 calendar day rules

 All pregnancy cases should be followed to term

 If the Company product has long half life (or metabolites) even though the

 product was stopped before conception there is a possibility that

drug/metabolite
 exposure could occur and recommendations in the label and for Company

 monitoring should occur
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What is Aggregate Reporting:

 Aggregate Reporting is the process that reviews the cumulative safety
information from a wide range of sources, on a periodic basis and submit
the findings to regulators worldwide.




 Aggregate report examines and summarize all existing safety experience with a
medicinal product. Report includes benefit risk assessment of SAEs and ADRs,
pregnancy reports, overdose and Lack of Efficacy reports.




 The aggregate safety reports are submitted to regulators for as long as the
medicine is marketed anywhere in the world and enables understanding of risk
benefit profile of product over a period of time.

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Examples of Aggregate Reports

Pre-marketing Reports Post-marketing Reports

Periodic Safety Update Report (PSUR)
NDA Annual Reports
 IND annual reports  Summary Bridging Report (SBR)
Clinical Study Reports (CSR)  Development Safety Update Report (DSUR)
Annual Safety Reports (ASR)
 Periodic Adverse Drug Experiences Reports
(PADER)

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Periodic Reporting in US 62

(PADER)

 PADER- Periodic adverse drug experience report or

PAER- Periodic adverse experience report _periodic
report in US. The U. S. Food and Drug Administration
(FDA) generally requires NDA Periodic Reports






Quarterly during the first 3 years and
 Annual reports thereafter SUR may be submitted to
U.S. FDA in lieu of PADER with prior exemption
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Periodicity of reporting In Europe (PSUR)

The European Medicines Evaluation Agency (EMEA)

requires Periodic Safety Update Reports (PSURs)



Every 6 months for 2 years


Annually for the 3 following years, and then
 Every 5 years
Each PSUR should be submitted within 70 or 90
days of the last data lock point.
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Periodicity of reporting In Japan:
(Anzenteikihoukoku)

In Japan, the authorities require a survey on a cohort by a

number of identified institutions
 Annually for 6 years on this cohort

Adverse reactions that are non serious, but both mild in

severity and unlabeled, must be reported
 Every 6 months for 3 years and
 Annually thereafter

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What is PSUR:

 The Periodic Safety Update Report (PSUR) is a report that summarizes

interval safety data covering short periods of time and is used in overall
safety evaluation of a product.

 It is a tool for Marketing Authorization Holders (MAHs) to conduct
systematic analyses of safety data on a regular basis.

The deadlines for the submission of PSURs are as follows:

 Every 6 months in the first two years following authorization and/or marketing.

 Every year in the next two years.

 Every 3 years thereafter. be received by the competent authority within 70
or 90 days after data lock
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ICH & CIOMS Background:

 CIOMS II Working Group




• Began work in November 1989 after completing CIOMS I
• Harmonize report format for aggregated safety information
• Published Report in 1992

 ICH Topic E2C




• Step 4 November 1996

 ICH E2C Addendum




• Step 4 February 2003
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Source of Information:

Generally, data from the following sources of ADR case information are potentially
available to a MAH and should be included in the PSUR:
 Spontaneous notifications from HCP’s and non-HCP’s

 Clinical Studies

 Literature

 ADR reporting systems of regulatory authorities

 Other sources of data:
(reports on ADRs exchanged between contractual partners (e.g., licensors
licensees), data in special registries, such as maintained in organ toxicity monitoring
centers, reports created by poison control centers and epidemiologic data bases)

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General Principles:

 One report for one active substance

 All indications, dosage forms and
 regimens Separate PSURs
• fixed combinations
• two or more different formulations, e.g., systemic vs topical
• One report to reach regulatory authority for the same time period
• Six-month interval data from international birth date (first approval anywhere)
• Report all relevant new information from appropriate sources
• Use of CCSI as reference product information

Source: ICH E2C PSUR

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PBRER-Periodic benefit risk evaluation report

 PSUR is replaced by PBRER


 The main objective of a PBRER is to present a comprehensive,
concise, and critical analysis of new or

 emerging information on the risks of the medicinal product, and on
its benefit in approved indications,

 to enable an appraisal of the product’s overall benefit-risk profile.

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 The PBRER should contain an evaluation of new information relevant to

the medicinal product that became available to the MAH during the
reporting interval, in the context of cumulative information by:

 Summarizing relevant new safety information that could have an impact
on the benefit-risk profile of the medicinal product;

 Summarizing any important efficacy/effectiveness information that has
become available during the reporting interval;

 Examining whether the information obtained by the MAH during the
reporting interval is in accord with previous knowledge of the medicinal
product’s benefit and risk profile; and

 Where important new safety information has emerged, conducting an
integrated benefit-risk evaluation for approved indications.
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The MAH should continuously evaluate whether any revision of the reference
product information/RSI is needed whenever new safety information is
obtained throughout the reporting interval. Significant changes to the
reference product information/RSI made during the interval should be
described in Section 4 of the PBRER (“Changes to Reference Safety
Information”) and include:
 Changes to contraindications, warnings/precautions sections of the RSI;

 Addition of Adverse Drug Reaction(s) (ADR) and interactions;

 Addition of important new information on use in overdose; and

 Removal of an indication or other restrictions for safety or lack of efficacy
reasons.

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Timelines for PBRER:
Ad hoc (“for cause”) PBRERs
Ad hoc PBRERs are reports outside the routine reporting requirements, and may be
requested by some regulatory authorities. Where an ad hoc report is requested and
a PBRER has not been prepared for a number of years, it is likely that a completely
new report will need to be prepared by the MAH.
Time Interval Between Data Lock Point and the Submission
As a result of the expanded scope of the PBRER, the time interval between the DLP and
submission of PBRERs should be as follows:
 PBRERs covering intervals of 6 or 12 months: within 70 calendar days;

 PBRERs covering intervals in excess of 12 months: within 90 calendar days;

 ad hoc PBRERs: 90 calendar days, unless otherwise specified in the ad hoc request.
The day of DLP is day 0 of the 70- or 90-calendar day interval between the DLP and
report submission.
Where national or regional requirements differ from the above, the MAH should discuss
the timeline for submission with the relevant regulatory authority.
 73

TERMINOLOGY
 SIGNAL-reported information on a possible causal
relationship which is being unknown or incompletely

documented previously.
 Usually more than 1 report is required to generate a signal

 before signals are published they are first clinically
assessed by PV experts at UMC(Uppsala monitoring
Centre ,Sweden)
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 75

There are 3 Types of Signals:

1. Confirmed signals-causal relationship between the drug and adverse event.

2. Refuted(false) signals-no causal relationship.

3. Unconfirmed signals-require further investigation.

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Thank You
&
Questions

Contact:
Katalyst Healthcare’s & Life Sciences
South Plainfield, NJ, USA 07080.
E-Mail: info@KatalystHLS.com 1/11/2017