PHARMACOVIGILANCE

WHO Definition:
Pharmacovigilance (PV) is the detection, assessment, understanding and
prevention of adverse effects or any other medicine-related (WHO) problem.
Mission Statement of GPV:
To provide high quality science-based proactive risk management strategies and
operational excellence in a fully compliant global pharmacovigilance system with
the ultimate goal to safeguard patients well-being and thus protect the company
Pharmacovigilance is a science contributing to the protection of patients and public
health.
We need an efficient Pharmacovigilance system to...

Fulfill our manufacturer's responsibility towards patients and health care

professionals.

Fulfill all regulatory reporting requirements worldwide.

Anticipate or minimize risks and to take appropriate measures accordingly.

The European Medicines Agency's (EMA) main responsibility is the protection and
promotion of public and animal health, through the evaluation and supervision of
medicines for human and veterinary use. But also :

The scientific evaluation of applications for EU marketing authorizations for

human and veterinary medicines in the centralized procedure.

Coordinating the EU's safety-monitoring or pharmacovigilance system for

medicines.

Coordinating inspections with the assessment of marketing-authorization

applications.
FDA is responsible for protecting the public health by assuring:

Safety

Efficacy

Security

WHO is the directing and coordinating authority for health within the United
Nations system.

Responsible for providing leadership on global health matters, shaping the

health research agenda, setting norms and standards, articulating evidence-based
policy options, providing technical support to countries and monitoring and
assessing health trends.

The World Health Organization set up its international drug monitoring

program after the thalidomide incident. Since 1978 the Program has been carried
out by Uppsala Monitoring Centre (UMC) in Sweden.
Uppsala Monitoring Centre priorities are:
1.
The safety of patients and the safe and effective use of medicines in every
part of the world.
2.
To coordinate the WHO Program for International Drug Monitoring and its
more than 100 member countries.

3.
To collect, assess and communicate information from member countries
about the benefits, harms and risks of drugs and other substances used in medicine
to improve patient therapy and public health worldwide.
4.
To collaborate with member countries in the development and practice of the
science of pharmacovigilance.
The International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH) brings together the regulatory
authorities and pharmaceutical industry of EU/EEA , Japan and the US to discuss
scientific and technical aspects of drug registration.
ICH CATEGORIES

Quality Guidelines Harmonisation achievements in the Quality area based on

Good Manufacturing Practice (GMP) risk management.

Safety Guidelines to uncover potential risks like carcinogenicity, genotoxicity

and reprotoxicity.

Efficacy Guidelines Design, conduct, safety and reporting of clinical trials.

Multidisciplinary Guidelines Cross-cutting topics which do not fit uniquely into

one of the Quality, Safety and Efficacy categories. It includes the ICH medical
terminology.
Local PV legislation
In each country there are legal requirements which have to be followed.
Local Pharmacovigilance personnel must be familiarized with the local
requirements.
Global PV personnel must evaluate the local requirements for potential global
impact (e.g. setting up reporting rules for expedited case reporting to Health
Authorities, writing of aggregated safety reports).
Quality Documents are essential to ensure consistency in processes, and must be :

Clear and concise

Complete

Consistent

Controlled

Current
A BI employee must read the Quality Documents, based on global and local
Curricula defining the mandatory Quality Documents per function. In many
Countries/departments the Quality Documents are distributed via Learning Once
Source (LOS). It is worked on a global roll out plan.

The overall quality objectives of a pharmacovigilance system are:

Complying with the legal requirements

Preventing harm from adverse reactions in humans arising from the use of
authorised medicinal products

Promoting the safe and effective use of medicinal products

Contributing to the protection of patients and public health

QUALITY AND COMPLIANCE

1.
Quality Planning
2.
Quality Adherence
3.
Quality Control/ Assurance
4.
Quality Improvement

The Quality System is an integral part of the pharmacovigilance system and

therefore the EU-QPPV has to have the overview of the quality system.

Clear responsibilities and communication lines have to be established so that

the EU-QPPV can fulfil her/his tasks.

The main function of the quality system is to monitor the implemented

processes and to conduct regular quality controls.
What has to be monitored?
1.
Processing and reporting of Individual Case Safety Reports (ICSR)
2.
Signal Management
3.
Risk Management System described in the Risk Management Plan (RMP)
4.
Preparation and reporting of Periodic Safety Reports
5.
Implementation of safety variations and communication of safety concerns
6.
Communicating information to patients and healthcare professionals about
changes to the risk-benefit balance of products
7.
Business continuity plans
Monitoring of processes
The Quality System covers also :

The SOP System

The document management system

PV Training

Facilities and systems

Personnel and Resources

Audit- and inspection reports

CAPA
If a non compliance is detected, GPV Quality&Compliance must be informed in
order to improve and correct the processing and avoid the occurrence of an error
or a discrepancy and to perform:

An impact and root cause analysis to identify the underlying reason

And define corrective and preventive actions (CAPA)

Corrective Action (CA)- Action to eliminate the root cause of a detected noncompliance or other undesirable situation; to prevent the recurrence of the noncompliance
Preventive Action (PA)- Action to eliminate the root cause of a potential noncompliance or other undesirable situation; to prevent the occurrence of a noncompliance
Pharmacovigilance System Master File (PSMF)
PSMF is a detailed description of the Pharmacovigilance System used by the
marketing authorisation holder with regard to one or more authorised products.
BI is legally required as MAH for medicinal products authorised in the EU to maintain
and make available upon request a Pharmacovigilance System Master (PSMF) File
describing the Global PV System operated by BI.


Contributes to the appropriate management and improvement of the global
pharmacovigilance system
PSMF Supports

Planning and conduct of Audits

Preparation of inspection

Competent authorities during Marketing Authorization procedures and postmarketing.

Documentation Management System
IDEA (International Document management and Electronic Archiving) is BI's
Approach to Electronic Document Management.

IDEA for CON is the system for Quality Documents .A viewer self-training is to
be done within the first days after job start (precondition for access to LOS).

IDEA for GEN is the system for filing Official Documents that are to be filed
either due to regulatory requirements or business needs (record retention).

BIRDS is the Boehringer Ingelheim document management system for

submission documentation to the Authorities. All submission chain activities are
unified in this system. Periodic Reports are also stored here.
Training Management System
LOS (Learning One Source) system is a learning management system. It is used to
administer, monitor and oversee employee training of all types, e.g. self-training of
Quality Documents and other controlled documents or e-learnings.
Tasks:

Learning items based on Curricula are automatically assigned to user

depending on the function, and must be completed on or before due date.

E-learnings and Quality Documents are to be confirmed per e-signature after

completion.

New employees have a timeline of 42 days for completion of Quality

Documents trainings as of access to LOS. For e-learnings the timeline is specified
per training item.
GDSS System
GDSS is a virtual system which consists of several individual systems for Adverse
Event processing and reporting.
ARISg Adverse Reaction Information System global supports the collection,
evaluation, reporting and analyses of adverse event data in accordance with
international regulations.
E2B E2B module supports the standardized electronic data exchange between the
Marketing Authorization Holder (MAH) and the regulatory authorities as laid down in
ICH Multi-disciplinary Group 2 Expert Working Group documents. BI is an E2B
gateway user.
System which allows:
- Automated and manual selection of specific Individual Case Safety Reports (ICSRs)
for transmission to specific recipients
- Customized mapping of ICSR data from ARISg to the E2B file
- Tracking of receipt and acceptance of transmitted E2B files

DSIS is the data retrieval system for GPV.

This environment includes an Ad Hoc and Standard reports environment that will
retrieve data primarily from the data warehouse, and is used to address any
internal/external requests for aggregated data.
Signal Detection Risk Management Therapeutic Area Physicians will receive
data from Empirica on a pre-defined basis to detect signals of potential new adverse
events for BI drugs. RM TA Physician will evaluate the signals, and appropriate
actions will be implemented.
DETECT DATABASE
Data Entry STandards for the Entry of Suspect Drugs in Clinical Trials.
Contains all the information required for entering a clinical trial case into ARISg
The information is sorted by trial number.
Non PV SYSTEMS
CTMS
The Clinical Trial Management System is a global system in BI Medicine for the
management of clinical trials from the pre-trial clinical stage to the end of marketing
for a substance.
Non PV SYSTEMS Oracle Clinical
Provides an integrated Clinical Data Management (CDM) and Remote Data Capture
(RDC) solution that includes functionality in key areas such as integration, data
collection, localization, and reporting.

Records and organizes data for clinical studies

Allows to define the data the study captures, and how to view the data
during analysis

Gives methods to generate and manage queries on data returned from

investigator sites
Non PV SYSTEMS CPD3
The Corporate Product Database is the leading information source for country
specific regulatory information of medicinal products.

It contains information on registration of human and veterinary medicinal

products as well as drug master files.
Non PV SYSTEMS GCOMS
Global Complaint Management System, is an application System which support the
Complaint Process.
Main tasks are to:

ensure reliable and fast exchange of information on complaints

standardise terms used for the management of complaints and the

description of defects

track the status of complaint evaluation and timelines

archive finalised complaints

Non PV SYSTEMS BILit+

The BI Literature Database BILit+ is a database that holds publications on BI
products, including pre-publications, reviews, congress posters and abstracts.
AE COLLECTION Which information is to be collected?
All PV relevant information is to be collected including the following special case
situations:

AE Information

Reports where the embryo or foetus may have been exposed to the
medicinal product with and without AEs (Drug Exposure During
Pregnancy (DEDP)).

Drug abuse / misuse

Overdose with and without event

Medication Error with and without event

Off-label use with and without event

Therapeutic response increased and/or Unexpected Benefit

Lack of efficacy

Occupational Exposure

Interactions with adverse events

Adverse Event (AE) Definition

Any untoward medical occurrence in a patient or clinical investigation subject

administered a pharmaceutical product and which does not necessarily have to
have a causal relationship with this treatment.

Any new illness, disease or worsening of an existing illness or a disease after

exposure to the drug or initiation of the clinical trial (CT).

Clinically significant laboratory values could constitute an adverse event, if

explicitly reported as AE or in spontaneous case reports if the lab test result is in the
focus of the report.
Adverse Drug Reaction (ADR) Definition
An adverse event is considered to be an adverse drug reaction if there is a
reasonable causal relationship between administration of the drug and the event. It
could also arise from occupational exposure.
Examples:

4 hours after vaccination patient developed injection site reaction. The

reporter sees a causal relationship between drug and AE.

A mother treats her baby with an ointment and she herself develops skin
rash on the hands. The reporter sees a causal relationship between drug and AE.
Drug Exposure During Pregnancy, DEDP
Whenever pregnancy associated with the administration of a BI drug is reported to
BI, be it with or without an AE, (through maternal or paternal exposure) a Drug
Exposure During Pregnancy (DEDP) report must be completed by using the
following forms:

For Post Marketed Sources: Use the Pregnancy Monitoring Form for DEDP
information collection. Use the AE reporting form for AE data collection.

CT Sources: Use the Pregnancy Monitoring Form for CTs.


For both sources: Pregnancy and outcome of a pregnancy must be followed
up (reporter is to be contacted after birth/delivery); this applies to maternal and
paternal cases.
Abuse/Misuse - Definition

Drug abuse is the intentional sporadic or persistent drug use for an

unlabelled, non-therapeutic purpose to exert a distinct effect inconsistent with or
unrelated to acceptable medical practice.
Overdose Definition

Overdose is the accidental or intentional use of a drug in an amount higher

than normally used or prescribed.

A dose is considered an overdose as reported term if more than the PI

(reference document) recommended maximal daily dose (adjusted for age and
weight) was given or taken, regardless of prescription.

Clinical judgement should always be applied.

Medication Error Definition

A medication error is a principally preventable event related to product

nomenclature, labelling, prescribing, dispensing, dosage, administration, or use. For
BI, the concept includes unintentional misbehaviour in good faith of the prescriber,
pharmacist, or user.

Medication error is to be collected even if no further adverse event occured.

Off-Label Use Definition
Off-label use without AEs refer to situations reported spontaneously where the drug
is prescribed or used outside the authorised product information as described in the
local PI (Patient Information), be it for another indication or patient population as
follows:
Off-label use is explicitly reported
The indication reported is not part of the symptoms and/or medical concept of the
labelled indication
The drug is administered in contradiction to contraindications as stated in the PI

Off-label use information must be collected for suspected BI drugs

independent if an AE occurred in addition or not.
Off-Label Use

Reports of Off-label use of 2 or more patients will be entered as a cumulative

report in ARISg.

In a report fulfilling the criteria of off-label without an AE reported, enter the

reported facts describing the off-label use in the reported term on the event screen
and flag the case on screen Case Information with the Type Incomplete Case.
Lack of Efficacy Definition

Lack of efficacy is defined as failure of a drug to evoke the expected and

claimed therapeutic response if administered within the indication.

Interactions - Definition

An interaction takes place between two or more drugs, which are given or
taken simultaneously or subsequently, and leads to a increase or decrease of the
pharmacological effect.

Apart from drug-drug interactions; there can also be drug-alcohol

interactions, drug-food interactions, drug-radiation interactions, drug-tobacco
interactions.

A pure question about a possible interaction in an otherwise completely

eventless report that does not qualify for entering interaction as an event would not
be considered a case.
Technical Product Complaint /Falsified Medicinal Products
A Technical Product Complaint, is any indication of a product defect involving
the possible failure of a drug or medical device to meet any of its specifications or
functionalities.
Examples:

Cardboard box or blister are printed or marked incorrectly

Capsules or blisters are damaged/empty

Tablets are brittle or discoloured

Syrup is cloudy

Damaged or defective packaging

Patient information leaflet is missing or incorrect

Function defects of the metered dose aerosol, Respimat or HandiHaler

Complaints may be received from an external source, and must be forwarded to the
Local Pharmaceutical Complaint Officer (LPCO) who is responsible for the
assessment and forwarding of complaints to GPV in case of a related AE.
Complaints without adverse event wont be captured in the AER form or in ARISg.

Minimum Criteria
1.
Existence of a reporter
2.
Existence of Patient
3.
A BI drug or IMP
4.
Adverse Event
BI DRUGS

Marketed Products under International Responsibility

Marketed products under Non-International responsibility

Non International Products
NIP/DIP

Investigational products
IMPs
IMP - Investigational medicinal product
An investigational medicinal product is a pharmaceutical form of an active
substance (BI drug or comparator) or placebo being tested or used as a reference in
a clinical trial; including products already with a marketing authorization, but used

or assembled (formulated or packaged) in a way different from or when used for an

unauthorized indication or when used to gain further information about the
authorized form.
NIMP - Non-investigational medicinal product
A Non-investigational medicinal product is a medicinal product which is not classed
as an IMP in a trial, but is provided to subjects in a clinical trial and used according
to the study protocol. Usually an NIMP is a marketed drug.
Examples of a NIMP:

rescue medication

background medication

concomitant medication

radiopharmaceutical drugs to measure endpoint

challenge drugs to measure endpoint

any medication (other than the trial drug) provided by BI.

BI Forms

AE /ADR case reports will be forwarded from local PV to GCM by using the BI
standard forms as follows:

Forms can be found in the GPV Compendium, IDEA for CON.

1.
Adverse event Report Form
2.
Standard (SAE) form for Clinical Trials
3.
Customised (S) AE reporting forms for Non-Trial Activities
Company Receipt Date (clock start) - Definition
The receipt date must reflect the date on which the company* receives the
information, without consideration of business hours, holidays or weekends. For
example, if the information is received on a Saturday, the receipt date is Saturday
and not the next business day.
*company includes Company Research Organizations (CROs) working on behalf of BI
and Licence Partners (LP).
The day of receipt will be considered as day zero and is relevant to define the
reporting timelines for ICSR submission to health authorities, Investigators, Ethic
Committees.
General Comments on Case Collection
Source documentation includes:
All information pertaining to a case report, i.e. hand written notes, phone notes,
forms, medical records received from the reporter (lab tests, hospital discharge
letters), correspondence with the reporter.

The local Case ID and the BI Case ID as well as initial received date/latest
received date by the company must be carefully documented.

The received date by PV is to be entered on the source documents.

Patient and reporter information has to be treated with care ensuring data
privacy rules are kept.

No interpretation of data is permitted; information is to be entered on the

AER form / ARISg according to source documents.

All source documents must be archived and filed in chronologic order by the
Local OPU.

Source Classification
Unsolicited sources

Spontaneous reports from:

Healthcare professionals, patients, consumers

Literature reports

Health Authority reports

Solicited sources

Clinical trials (CT)

Compassionate use programs (CUP) that actively collect AEs

Named patient use programs (NPU)

Non-interventional studies (NIS)

Registries

Non trial activities (NTAs)

Spontaneous
Spontaneous Reports
Information on AEs reported spontaneously (where reporter actively and voluntarily
contacts BI) is collected, followed up on and processed regardless of the time
elapsed since patients exposure. Information could be received from, e.g.
consumer, patient or Healthcare Professional
Health Authority Reports
Authority Reports are to be processed as received and assessed by the reporting
authority.
Scientific Literature
Worldwide scientific, medical literature, congress materials, abstracts must be
screened to identify pharmacovigilance information associated with a Boehringer
Ingelheim active ingredient or its generic equivalent

for review of worldwide experience with the product as part of continuous

safety screening activities

for the preparation of Periodic Benefit-Risk Evaluation Report (PBRER)

for detection, processing and reporting of Individual Case Safety Reports

(ICSRs) from literature
Screening is performed at a global level for: GCM

All BI products, international and non international products

Developmental drugs

Non BI active ingredients which are part of a core BI combination product

Additional sources:

Local literature screening

Scientific literature a BI employee is becoming aware of

Detailed searches in external databases to identify literature relating to class

effects or monitoring topics as defined by the Pharmacovigilance working group

Any publication identified as PV relevant should be forwarded to Global Case

Management according to the defined timelines.

All articles identified are stored in the BI Literature database (BILIT), checked
for PV relevance and flagged accordingly to ease retrieval for safety monitoring

purposes. Safety Information fulfilling the minimal criteria for an ICSR is entered
into ARISg.
Clinical Trials ( Interventional studies)
A clinical trial is any investigation (of one or more investigational medicinal
product(s)) in human subjects intended to:

discover or verify the clinical, pharmacological and/or other

pharmacodynamic effects

identify any adverse reactions

study absorption, distribution, metabolism and excretion with the objective of

ascertaining its (their) safety and /or efficacy.
This includes clinical trials carried out in either one site or multiple sites, whether in
one or more member states.
According to the EMA, AE reporting begins with the signed Informed Consent (IC)
and ends with the end of the Residual Effect Period (REP)/ end of follow-up period.
Emergency and Compassionate Use (CUP)
Compassionate Use (CUP)
Making a medicinal product available for compassionate reasons to a group of
patients with a chronically or seriously debilitating disease or whose disease is
considered to be life-threatening, and who cannot be treated satisfactorily by an
authorized medicinal product (the medicinal product concerned must either be
subject of an application for a central marketing authorization or must be
undergoing clinical trials) [REG (EC) No 726/2004 Art 83(2)].
Named Patient Use (NPU)

Specific to one single patient, who cannot enter a clinical trial

BI has to approve every single patient request

To be verified whether based on local requirements an approval by the local

health authorities is required.
Expanded Access Program (EAP)

For patient cohorts expected to be treated with the drug upon approval

Protocol defining inclusion / exclusion criteria, no randomisation

For each patient verification that they cannot enter a clinical trial and match
inclusion criteria

Notification of the protocol to local health authorities and ECs.

Non-Interventional Studies (NIS) Studies where the medicinal product(s) is (are)
prescribed in the usual manner in accordance with the terms of the marketing
authorization. The assignment of the patient to a particular therapeutic strategy is
not decided in advance by a trial protocol.
Any prospective collection of clinical and individual patient data with a BI marketed
product is to be considered a NIS unless it meets the criteria for a clinical trial.
Non Trial Activities
Non-trial activities (NTAs) are activities relating to both Prescription Medicines and
Consumer Health Care projects that are not defined as:
NIS
Interventional Clinical Trials
Non-interventional (observational studies) using existing data handled by Global
Epidemiology

Registries
A registry is a Public Health Surveillance System that collects and maintains
structured patient records relating to specific disease or condition for a specified
time period and population.
For the purpose of processing in ARISg these will be treated as Solicited report
(Primary Source)
Investigator Initiated Studies (IIS)
IIS are clinical trials and health outcomes studies involving Boehringer Ingelheim
drugs or therapeutic areas of interest

Types of IIS:

Interventional Clinical Studies

Non Interventional Studies: e.g. Epidemiology studies, Outcome research,

Post Authorization safety study (PASS)

A third party Investigator proposes the study and acts as the SponsorInvestigator

The Sponsor-Investigator has all responsibility for the conduct of the study.

BI has very limited involvement in the design and execution of these trials;
however, may provide drug supply, financial and/or other support.

BI is informed via the unique entry point (defined in PV Agreement) on

adverse events and relevant PV information as specified in the study protocol,
depending on study type and study particularities.
OPU level SPONTANEOUS REPORTS

Receipt of the Information

Verify if minimal criteria are fulfilled

Duplicate check based on the Local tracking Sheet

Create a local case ID number

Determine Company receipt date

Stamp of case id

Send Queries if needed, using the Product Quick Guide (PQG)

Enter all data in AER (Adverse Event Reporting) form in English language

Perform quality check on the AER form incl. documentation

Forward the AER form to GCM for processing in ARISg

Archive the source documents

GCM level For fatal, life-threatening, serious, significant initial cases, or regulatory
relevant Follow/Ups:

CASE RECEIPT

TRIAGE

DATA ENTRY

SCIENTIFIC REVIEW

MEDICAL REVIEW

DISTRIBUTION
For all non-serious or not regulatory relevant Follow/Ups and DEDP cases:

CASE RECEIPT

TRIAGE

DATA ENTRY
TECHNICAL COMMIT

Timelines for forwarding of ICSRs to GPV (Except Japanese OPU)

DAY OF RECEIPT
Fetal or Life Threatening
WITHIN 1 DAY
Meet formal seriousness criterion and received during business hours
NEXT BUSINESS DAY
Meet formal seriousness criterion and received outside business hours
3 CALENDAR DAYS
All other ICSRs
Timelines (Japanese OPU Only)
1 calendar day
Fetal or Life Threatening
3 Calendar Days
Meet formal seriousness criterion or containing AESI
7 Calendar Days
Non-serious ICSRs
Clinical Trial Cases timelines
Post Marketed Cases timelines incl. Literature

License Partner Cases if outside corporate timelines

If reports from License Partner are received outside the corporate timelines:

A fatal/life-threatening LP case is due on the next calendar day of BI receipt.

A Serious/AESI LP case is due on the next working day of BI receipt.

A non-serious LP case is due within 5 calendar days.

Adverse Event Classification

AE classification is needed for determination of regulatory reportability and

prioritisation of reporting timelines.

An adverse event is to be classified

with regard to:
1.
Seriousness
2.
Listedness
3.
Casual Relationship
Adverse Event Classification - Serious Criteria (according to ICH E2A definitions*)
1.
Results in death
2.
Is immediately Life threatening
3.
Results in persistent or significant disability /incapacity

4.
Results in prolong an existing inpatient hospitalisation
5.
Is a congenital anomaly
6.
Any other reason representing a significant hazard w/c is comparable to the
aformentioned criteria
Adverse Events of Special Interest (AESI)
AESI are processed in the same way and according to the same timelines as serious
events, although they may be non-serious.
Post Marketed Experiences:
An AESI is an event processed like a serious event although it might be non serious
due to dedicated requirements from health authority for expedited reporting, refer
to the reference document Adverse Events of Special Interest.
Clinical trials:
An AESI can be serious or non-serious and is one of scientific and medical concern
specific to the sponsors product or program and has to be defined as such in the
clinical trial protocol.
Listedness
Definition of Listedness:
An adverse event is listed if it is adequately described with regard to nature,
severity and frequency in the Company Core Data Sheet (CCDS) or Investigational
Brochure as a known adverse event to the drug. Listed events must be clearly
defined in the CCDS.

Listedness reflects the knowledge of, and assessment by BI; thus the
listedness is one and the same worldwide.

The CCDS is used for the listedness of marketed medical products and the
Investigators Brochure (IB) for investigational products.

In Clinical trials the reference documents for listedness are defined in the
clinical trial protocol (e.g. for a comparator drug or placebo).

A Listedness assessment is performed during processing of AEs in ARISg (with

an automated function for post-marketed cases, manually for CT cases).

Expectedness
An Adverse Event is expected, if it is adequately described with regard to nature,
frequency and severity in the country specific local Patient Information Leaflet (PIL)
or Summary of Product Characteristics (SPC).

The term Expected reflects the companys view, as approved and then
modified by competent Regulatory Authorities. There is a local PI/SPC in each
country (ideally not differing one from the other).

Based on local regulatory requirements, local PV may have to perform an

assessment on expectedness.
Company Core Data Sheet (CCDS) is a BI proprietary document that contains the
scientific information about efficacy, safety and other data relevant for the
appropriate and safe use of one drug product or several drug products with identical

Active APIs or combination of APIs (Active Pharmaceutical Ingredient) where a

company within the BI Cooperation is the Marketing Authorization Holder (MAH).
CCDS

INCLUDES
Name of the product
Composition
Dosage and administration
Instructions for use
Contraindications
Special warnings and precautions
Interactions
Pregnancy and lactation
Effects on ability to drive and use machines
Side effects

Causal Relationship
For each AE the causality assessment must be provided by the reporter and by the
Company.
The following options for the assessment of the causal relationship (causality
assessment by company) are possible:
RELATED
The analysis of the facts/evidence or arguments
available suggests a reasonable possibility
of a causal relationship between
the adverse event and the drug
NOT RELATED
The analysis of the facts/evidence or arguments
available does not suggest a reasonable
possibility of a causal association between
the adverse event and the drug.

SPONTANEOUS REPORT FOLLOW UP

Healthcare Proffesional
Consumer
Pregnancy
Follow-up general Procedure Relevant Information Needed for Medical Assessment

Patient information (gender, age)

Start and end date of the administration of the BI suspect drug

Daily dose and indication for use of the BI suspect drug

Onset and end date of the event(s)

Outcome of the event(s)

Additional medications (suspect or concomitant) used at time of event

Medical conditions / diseases ongoing at the time of the event (e.g. diabetes)

Important medical history (e.g. myocardial infarction)

Drug specific medically queries in accordance with PQG

The Product Quick Guide is an electronic document updated on a regular basis

which:

Is to be used to ask queries as early as possible in the workflow

Has to be used during case processing by all involved colleagues, i.e.

locally by OPUs, by Global Case Management: TRIAGE & SCIENTIFIC REVIEW and by
MEDICAL REVIEW

Contains general questions, questions on medical concepts and product

specific questions as well as useful links (i.e. to product specific
questionnaires)

Most current version of PQG will be available via a Share Room - Case
processing support
What

is to be reported to Health Authorities?

Individual Case Safety Reports
AE reports as per local law
IND reports
SUSARs reports
Periodic Reports
DSURs
PSUR/PBRER
Quarterly SUSAR Reporting
PADER
Others

Reporting of ICSRs can be performed in different ways, such as:

E2B (electronic data submission). Reporting of valid ICSRs electronically is

mandatory in several countries.

CIOMS (standard paper form). This applies if E2B is not implemented at the
Health authorities.

Manual entry into the local health authority database. Required by local
regulation.
Regulatory timelines valid for US and Europe::
Fatal and life-threatening AEs (in CTs) 7 calendar days after receipt
Remaining serious AEs (in general) 15 calendar days after receipt
Reporting Requirements in Clinical Trials

SUSARs (according to EMA regulations):

SUSAR stands for Suspected Unexpected Serious Adverse Reactions associated with
Investigational Medicinal Products (IMPs)) SUSARs are adverse events which are
considered to be serious, unlisted and related.

IND (according to FDA regulations)

A trial is considered an Investigational New Drug (IND) trial if the CTP (Clinical trial
protocol) has been submitted to and approved by the FDA. IND safety reports must
be submitted to all investigators participating in IND studies with the same IMP
(Investigational Medicine Product).
Periodic safety update reports (PSURs) are cross functional documents
providing an evaluation of the benefit-risk balance of a medicinal product. They
shall be submitted by marketing authorization holders at defined time points during

the post-authorization phase. In the EU and some other countries the reports are
named Periodic Safety Update Reports (PSURs) and are compiled in PBRER format
according to ICH.
A DSUR is a Periodic Safety Report concerning CT or a Post market Product that is
being investigated for other indication.
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 (ICH
E2F)

The DSUR focuses on clinical trials of investigational drugs as well as other

findings that impact the safety and welfare of clinical trial subjects

The DSUR should also provide information on comparators where relevant to

the safety of trial participants

The DSUR should be concise and provide information to assure regulators

that sponsors are adequately monitoring and evaluating the safety profile of their
investigational drug
RISK MANAGEMENT CYCLE

DATA COLLECTION
Monitor effectiveness and collect new data

IDENTIFY&ANALYSE
Risk quantification and benefit assessment

EVALUATE
Benefit risk balance and oppertunities to increase and/or characterise

SELECT & PLAN

Risk characterisation / minimisation and benefit maximisation techniques

IMPLEMENT
Risk minimisation / characterisation and benefit maximisation
ABB
AE
AESI
ADR
API
ARISg
BI
BILit
CAPA
CCDS
CDM
CML
CRO
CT
CTMS
CUP
DAC
DEDP
DIP

Adverse Event
Adverse event of Special Interest
Adverse Drug Reaction
Active Pharmaceutical Ingredient
Adverse Reactions Information System
Boehringer Ingelheim
Boehringer Ingelheim Literature Database
Corrective and Preventive Actions
Company Core Data Sheet
Clinical Data Management
Clinical Monitor Local
Clinical Research Organization
Clinical Trial
Clinical Trial Management System
Compassionate Use Programs
Disease Awareness Campaign
Drug Exposure During Pregnancy
Delegated International Product

global

DMO
DMP
DS
DSIS

Document Management Option

Disease Management Programs
Drug Safety
Drug Safety Intelligence System

DSUR Development Safety Update Report

DWH Data warehouse
EMA European Medicine Agency
EU-QPPV
European Union Qualified Person for
Pharmacovigilance
FDA Food and Drug Administration
GCM Global Case Management
GDSS
Global Drug Safety System
GMP Good Manufacturing Practices
GPV Global Pharmacovigilance
HA
Health Authorities
IB
Investigator Brochure
IC
Informed Consent
ICH
International Conference on Harmoniation
ICSR Individual Case Safety Report
IDEA International Document management
and Electronic Archiving
IEC
Independent Ethic Committee
IIS
Investigator Initiated Studies
IND Investigational New Drug
IMP
Investigatinal Medicinal Product
IRB
Independent Review Board
LOS Learning One Source
LP
License Partner
LPCO Local PharmaceuticalComplaint Officer
LPVM Local Pharmacovigilance Manager
MA
Medical Affairs
MAH Marketing Authorisation Holder
NIP
Non International Product
NIS
Non Intervencional Studies
NPU Named Patient Use
NTA Non Trial Activities
O*C Oracle Clinical
OPU Operative Unit
PADER
Periodic Adverse Drug Event Report
PAC Patient Activation Campaign
PAP Patient Adherence Programs
PASS Post Authorisation Safety Studies
PBRER
Periodic Benefit Risk Evaluation Report
PI
Patient Information
PIL
Patient Information Leaflet
PQG Product Quick Guide
PSMF Pharmacovigilance System Master File
PSP Patient Support Program
PSUR Periodic Safety Report

PT
Preferred Term
PV
Pharmacovigilance
PVWG
Pharmacovigiance Working Group
QRPE Quality Management, Regulatory Affairs,
Pharmacovigilance, Epidemiology
RA
Regulatory Affairs
RCC
Regional Coordinator Center
RDC Remote Data Capture
REP
Residual Effect Period
RLC
Regional Labeling Committee
RMP
Risk Management Plan
RMTA Risk Management Therapeutic Area
RPV Regional Pharmacovigilance
SAE Seriuos Adverse Event
SPC Summary of Product Characteristics
SOP Standard Operational Procedure
SUSAR
Suspected Unexpected Serious
Adverse Reaction
UMC
Uppsala Monitoring Centre
WHO
World Health Organization
WI
Working Instruction