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 legislationIn 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• CurrentA 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 COMPLIANCE1. Quality Planning2. Quality Adherence3. Quality Control/ Assurance4. 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 Management3. Risk Management System described in the Risk Management Plan (RMP)4. Preparation and reporting of Periodic Safety Reports5. Implementation of safety variations and communication of safety concerns6. Communicating information to patients and healthcare professionals about changes to the risk-benefit balance of products7. Business continuity plans

Monitoring of processesThe Quality System covers also : The SOP System The document management system PV Training Facilities and systems Personnel and Resources Audit- and inspection reports

CAPAIf 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 non-compliance or other undesirable situation; to prevent the recurrence of the non-compliancePreventive Action (PA)- Action to eliminate the root cause of a potential non-compliance or other undesirable situation; to prevent the occurrence of a non-compliancePharmacovigilance 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 post-marketing.

Documentation Management SystemIDEA (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 DATABASEData 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 SYSTEMSCTMS 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 ClinicalProvides 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 – CPD3The 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 – GCOMSGlobal 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, DEDPWhenever 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 – DefinitionOff-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 ProductsA 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 HandiHalerComplaints 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 won‘t be captured in the AER form or in ARISg.

Minimum Criteria1. Existence of a reporter2. Existence of Patient3. A BI drug or IMP4. Adverse Event

BI DRUGS• • Marketed Products under International Responsibility • Marketed products under Non-International responsibilityNon International Products NIP/DIP• Investigational products IMPs

IMP - Investigational medicinal productAn 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 productA 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 Form2. Standard (SAE) form for Clinical Trials3. Customised (S) AE reporting forms for Non-Trial Activities

Company Receipt Date (clock start) - DefinitionThe 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 CollectionSource 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 ClassificationUnsolicited 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)

SpontaneousSpontaneous ReportsInformation 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 LiteratureWorldwide 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 productAdditional 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 ActivitiesNon-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

RegistriesA 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 Sponsor-Investigator • 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 ThreateningWITHIN 1 DAYMeet formal seriousness criterion and received during business hours NEXT BUSINESS DAYMeet formal seriousness criterion and received outside business hours 3 CALENDAR DAYS

All other ICSRs Timelines (Japanese OPU Only)1 calendar dayFetal or Life Threatening3 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 timelinesIf 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. Seriousness2. Listedness3. Casual Relationship

Adverse Event Classification - Serious Criteria (according to ICH E2A definitions*)1. Results in death2. Is immediately Life threatening3. Results in persistent or significant disability /incapacity4. Results in prolong an existing inpatient hospitalisation5. Is a congenital anomaly6. 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 sponsor’s product or program and has to be defined as such in the clinical trial protocol.

ListednessDefinition 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 Investigator’s 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).

ExpectednessAn 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 company’s 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 RelationshipFor 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: RELATEDThe analysis of the facts/evidence or arguments available suggests a reasonable possibility of a causal relationship between the adverse event and the drugNOT RELATEDThe 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 UPHealthcare ProffesionalConsumerPregnancy

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 receiptRemaining 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 COLLECTIONMonitor effectiveness and collect new data • IDENTIFY&ANALYSERisk quantification and benefit assessment • EVALUATE Benefit risk balance and oppertunities to increase and/or characterise • SELECT & PLANRisk characterisation / minimisation and benefit maximisation techniques • IMPLEMENT Risk minimisation / characterisation and benefit maximisation

ABBAE Adverse EventAESI Adverse event of Special InterestADR Adverse Drug Reaction API Active Pharmaceutical Ingredient ARISg Adverse Reactions Information System globalBI Boehringer IngelheimBILit Boehringer Ingelheim Literature Database CAPA Corrective and Preventive Actions CCDS Company Core Data Sheet CDM Clinical Data ManagementCML Clinical Monitor Local

CRO Clinical Research Organization CT Clinical TrialCTMS Clinical Trial Management System CUP Compassionate Use ProgramsDAC Disease Awareness CampaignDEDP Drug Exposure During PregnancyDIP Delegated International ProductDMO Document Management OptionDMP Disease Management ProgramsDS Drug SafetyDSIS Drug Safety Intelligence System DSUR Development Safety Update ReportDWH Data warehouse EMA European Medicine AgencyEU-QPPV European Union Qualified Person for

Pharmacovigilance FDA Food and Drug AdministrationGCM Global Case ManagementGDSS Global Drug Safety SystemGMP Good Manufacturing Practices GPV Global PharmacovigilanceHA Health AuthoritiesIB Investigator BrochureIC Informed ConsentICH International Conference on HarmoniationICSR Individual Case Safety Report IDEA International Document management

and Electronic ArchivingIEC Independent Ethic Committee IIS Investigator Initiated StudiesIND Investigational New DrugIMP Investigatinal Medicinal Product IRB Independent Review BoardLOS Learning One Source LP License PartnerLPCO Local PharmaceuticalComplaint OfficerLPVM Local Pharmacovigilance Manager MA Medical AffairsMAH Marketing Authorisation HolderNIP Non International ProductNIS Non Intervencional StudiesNPU Named Patient UseNTA Non Trial ActivitiesO*C Oracle ClinicalOPU Operative UnitPADER Periodic Adverse Drug Event Report PAC Patient Activation Campaign

PAP Patient Adherence Programs PASS Post Authorisation Safety StudiesPBRER Periodic Benefit Risk Evaluation ReportPI Patient Information PIL Patient Information LeafletPQG Product Quick GuidePSMF Pharmacovigilance System Master FilePSP Patient Support Program PSUR Periodic Safety ReportPT Preferred Term PV Pharmacovigilance PVWG Pharmacovigiance Working GroupQRPE Quality Management, Regulatory Affairs,

Pharmacovigilance, Epidemiology RA Regulatory Affairs RCC Regional Coordinator Center RDC Remote Data CaptureREP Residual Effect Period RLC Regional Labeling CommitteeRMP Risk Management PlanRMTA Risk Management Therapeutic Area RPV Regional Pharmacovigilance SAE Seriuos Adverse Event SPC Summary of Product CharacteristicsSOP Standard Operational Procedure SUSAR Suspected Unexpected Serious Adverse Reaction UMC Uppsala Monitoring Centre WHO World Health Organization WI Working Instruction