Section 3

PV

Section 3

3.1: management of adverse events reports from spontaneous reporting • 3.1.1: Single case Processing Activities:• SOP 202 defines the responsibilities of LSU• For case processing from spontaneous sources• Responsibilities of LSUs are as follows

– Documentation and tracking of spontaneous adverse events for J&J authorized products within the territory or from other countries.

– Record follow up request with original reporter.– Review and document adverse events for the minimal criteria

and translation’s correctness and overall case consistency.– Double checks for any new information to existing case report.– Processing of the adverse event reports to BRM.– Reconciliation with LQD for any PQC with or without AE

3.1: management of adverse events reports from spontaneous reporting • Main responsibility undertaken by BRM after case

receipts:– Case entry and acknowledgement to senders.– Medical review, AE coding, Assessment on seriousness– Determination of labelledness of company's casualty.– Identifying the report as serious unexpected associated.– Align with the LSO if specific follow up is needed– Processing of the report and ensuring that company’s

regulations are met.– Inform LSU for any report updates.– LOCs perform single case processing towards BRM by

using SCEPTRE; if no SCEPTRE, use fax

3.1: management of adverse events reports from spontaneous reporting • MAH should implement PV system so that all

responsible parties are aware of their duties of reporting AE information within 24 hours to LSU

• In case LSU is not available appoint a single contact.• After receiving spontaneous AE report to LSU, assess

the information for the presence of four basic elements for validity. Elements are:– Identify the patient– Identify the reporter– Identify the J&J suspect drug– Adverse event

3.1: management of adverse events reports from spontaneous reporting • If one of the elements is missing carry out a follow up

process with the reporter to obtain them, record all the efforts and file them with source documents until missing information is received or is not likely to be received.

• Receipt of the report is indicated by the company became aware date.

• This date is the day zero for the regulatory compliance timelines.

• All reports are documented with the original source documents.

• Late report receipts from employees or third parties are subjected to root cause analysis.

3.1: management of adverse events reports from spontaneous reporting • Reports are viewed on the basis of timeline, seriousness

and need to follow up using BRM decision tree.• Database tool is used for double checks review of follow up

report and scheduling. • LSU without BRM safety system are given a local case

number, tracking sheet number and global AE data collection form before being faxed to ARM.

• BRM after reviewing may ask for additional information.• Authorized LSOs enter data in BRM system.• Before sending the report to BRM, LSO approves it.• Lso should ensure PV report receipts.

3.2 Management of Serious Adverse Event Reports originating from Company Sponsored/Supported Interventional Clinical Trials• 3.2.1 Case Processing:• Responsibilities of the LSO are as follows:• • The collection of serious adverse event reports from

company sponsored/supported interventional Clinical Studies and Activities in areas for which LSU is responsible.

• • Review all the contents of the reports.• • Transmission to BRM.• • Ensure the availability of clinical trials conducted in

LSO’s areas • • Review monthly study overview listings and take

action to meet compliance requirements

• SAEs from interventional Clinical follows a process which is similar to Spontaneous AEs with the following differences:

• • The GCO /GCO-MAO clinical staff trains investigational staff on (S)AE and safety reporting requirements.

• • Investigator makes an initial report which is transferred on a Global Clinical SAE form to GCO/ GCO-MAO

• •GCO / GCO-MAO Clinical stamp date and will review the report for completeness before forwarding it to LSU.

• • The reviewed report is forwarded to LSU within 1 calendar day of

• • Missing information or clarification of previous information is collected by LSO with the help of GCO/GCO MAO

• •GCO or GCO-MAO conducts regular reviews of study data to find safety trends and issues

• Timelines for forwarding reports to BRM by the LSU are as follows:

• a) LSU not using the SCEPTRE e-platform: • Fatal/Life Threatening SAE reports within two (2)

calendar days following Day 0, the regulatory clock start date.

• All non Fatal/Life Threatening SAE reports within three (3) calendar days following Day 0.

• b) LSU using the SCEPTRE e-platform: Fatal/Life Threatening SAE reports within two (2) calendar days following Day 0, the regulatory clock start date.

• All non Fatal/Life Threatening SAE reports within six (6) calendar days following Day 0

• For reporting of Partnered Products cases special arrangements are made.

• And its reporting to CA of is governed by the PV Agreement between BRM/LOC and the Partner.

• The LSO will use PV Agreement if the LOC is the clinical trial sponsor or has the delegated reporting responsibility.

• 3.2.2 Reporting of Serious Adverse Events from Company Sponsored/Supported Interventional Clinical Trials

• Following are the responsibilities of the LSO:• • Reporting of SAEs/ SUSARs to the local CA • • The reporting of SUSARs to IRB is clinical

team’s responsibility. • This procedure may be transferred to the GCO

Safety Unit based on the Service Level Agreement

• GCO SU may also provide SUSAR line listings / Annual Safety Report to IECs/ IRBs.

• 3.3 Management of Solicited Serious Adverse Event Reports originating

• from Company Sponsored/Supported Non-Interventional Programs

• SOP 209 describes the responsibilities of the employees in the case processing and reporting of SAEs , which are as follows:

• • Review of the PV paragraphs and other such documents for the confirmation that all required data is recorded.

• • Collection to completion of serious adverse events• • Review of all the contents of the reports • • The transmission of these reports to BRM.• SUSAR reporting to IRBs is mandatory and is done by GCO

Safety Unit • SUSAR distribution to IRBs participating incase of non-

interventional programs may not happen depending on the local laws.

• 3.4 Overview of the Investigator Initiated Study Process:• These studies are handled according to the J&J points to consider

on IIS, J&J International Health Care Compliance Guide, and other such laws and codes.

• LSO should review the given safety reporting flow as described in Contract and receive SAEs from Investigators and submit it to BRM.

• The key policies from the LSO are:• • Review IIS initiative before deciding on the contract.• • Explain reporting procedure of AEs, SAE and pregnancies to the

LOC• • Review PV section(s) of the protocol, project descriptions• • Support will be provided when an agreement made between the

investigator-sponsor and the J-C OC• • Monitor investigator-sponsor outbound safety reporting duties to

participating parties.• • The sponsor-investigator should reconcile between the study

database with safety database and perform safety analysis

3.5 Processing and Reporting Pregnancy Reports following Exposure to Johnson & Johnson Medicinal Products

• 3.5.1 Case Processing:• LSO’s responsibilities are as follows:• • The collection and follow-up to completion of

pregnancy reports from all company sponsored / supported interventional and noninterventional trials

• • Review all contents of the reports • • Transfer these reports to BRM.• • Report pregnancy reports to the local CA

• The process for handling pregnancy reports is similar to handling AEs/SAEs with following differences:

• •Both maternal and paternal exposure to J&J products and pregnancy outcomes are collected.

• • Pregnancy with or without SAE is recorded and reported to BRM under SAE timelines.

• • Pregnancy Reports with non-fatal SAEs, AE/non AE Reports are processed following non fatal SAE timelines.

• • For pregnancy reports use forms referenced in Cross- Pharma SOP 09410, and for AEs/SAEs use conventional forms

• • Incase of paternal exposure, the male patient is given an “Authorization for Disclosure of Medical Information Form” for pregnant female partner for the approved follow up.

• • Case will be serious event when pregnancy occurs during the use of a J&J contraceptive product, it will be considered as a serious event. This applies to clinical and spontaneous reports.

• • All pregnancy reports are followed up in order to report its outcome.

• 3.6 Detecting and Reporting AE from Published Literature• Regular literature searches is done for product with MAH

responsibilities • Marketed products without generic name but with active substance

is also included for reporting • Search those journals not included in company web based. • Local literature searches may be outsourced to a Third Party • Responsibilities of the LSO are as follows:• • Maintain an updated list of local journals including the frequency

of issuance and review this list every time there is any change – • • On a weekly basis* search for potential AE information in the

local medical/ scientific literature• • Document the performed literature search• • If the literature article meets the criteria for a literature report

proceed with case processing and provide it to BRM in10 days• • If the company receives the literature article. It will be signed,

stamped and reviewed by LSO , • • If no reportable information that mark it as Not reportable • • Request for follow-up information from the author.

3.7 Outbound Reporting• 3.7.1 Expedited Reporting of Individual Case Safety Reports

(ICSR) to the• Competent Authorities (CA)• Outbound activities regarding ICSR are handled by

MAHs/LOCs/Sponsors of clinical trials• Customers are:• • Local CAs,• • European Medicines Agency ,• • Independent Ethic Committee (IECs), investigators.• LSO is responsible for ICSR submission to local CAs and for

SUSARS submissions to IECs and investigators, responsibility may be delegated to another J-C LOC

• For ICSR submissions, LSO must have training and have access to all databases of reportable ICSRs.

• Based on the queries by LSO, BRM supported products are made available to them which reflect the concerned products and regulatory requirements.

• LSO forwards draft queries to BRM for implementation.

• Queries are maintained by LSO, e.g., new investigational/new marketed products inclusion new local reporting requirements.

• Responsibilities of the LSO to meet J-C LOC compliance:• • Supervise products, investigational new drugs and regulatory

requirements• • Access to all relevant databases • • Monitor all the database regularly to retrieve cases, submit reason

incase of of non-submission.• •Communicate new local CA requirements to the QPPV• • Regular documentation of reviews on marketed products and study

listings• • Arrange intra/cross country back-ups• • Update delegation contracts• • Supervise changes in reg. reporting processes• • Oversight on exceptions in product-specific outbound responsibilities• • After sending preliminary reports, record submission date database

after receiving BRM version• • look for CAs’ acknowledgement • • immediate actions incase of electronic submission failure

• The two modes of reporting spontaneous events are:• A. Paper-based reporting through expedited reports

from the BRM Worldwide Safety System • B. Electronic E2B reporting from the BRM Worldwide

Safety System • Special reporting arrangements for partnered

products• Regularly checking of safety to retrieve any

reportable case. • LSO will make report submission decision • All submission data is recorded in the BRM Safety

database.

• 3.7.2 Delegation of Outbound Activities• 3.7.2.1. To the European Electronic Reporting Group• E2B submissions of expedited ICSRs to EEA CAs responsibility

may be given to the European Electronic Reporting Group (EERG) based on PV Agreement.

• LSO has to provide the following information: • • Local regulatory reporting requirements table• • A list of marketed and investigational products• • Correctness confirmation of the database queries• • Notify BRM about updates to existing queries and

Regulations• Global LSO maintains records of appendices and queries

Share Point site.

• 3.7.2.2. To other J-C LOC – Back-up• The LSO may delegate another LOC from different J-C for ISCr submission

in case of the original LSO’s absence, which should be mentioned in the agreement , specifying:

• • Databases for ICSRs retrieval• • Concerned products/INDs• • The time period for delegated responsibilities • • The way of transmission • • CA(s) and regulatory requirements details• At the end of back-up period all reports are sent to original LOC.• 3.7.2.3. To Global Clinical Organization Safety Unit (GCO SU)• LSOs are not responsible for SUSAR submission to customers other than

CAs• For SUSAR submission to IECs and investigators all regulatory

requirements should be fulfilled by study sponsors

• 3.7.3. LSOs Oversight on Outbound Metrics• For LSO supervision the following information

is available:• • List of submissions to EMEA and CAs• • Monthly EERG and LOC compliance

dashboards for EMEA and CAs submissions • • Single Case Timelines Deviation Memos for

late reports

• 3.8 Overview of Compliance Tracking Process.• Responsibilities of the LSO are the following:• • Give attention to non-compliance of inbound/outbound

expedited reporting and record it in target system• • Regular review of expedited single case reporting

Compliance Reports and request corrections to BRM• • Root cause analysis for non-compliance issues due to late

local case processing, document the analysis with corrective/preventive actions

• • Train employees to detect trends in non-compliance causes• • Communicate the agreed corrective actions• • Follow-up of CAPAs

• Evaluate whether the reports both outbound and inbound are submitted within allotted timelines to CA and BRM

• Record a Single Case Timelines Deviation Memo (SCTDM) in the TARGET system for non-compliance due to late case processing.

• identify root cause and make corrective/preventive measures • BRM Compliance Science generated monthly Compliance Reports are

used by LSO or them with local case management records.• If discrepancies are detected, the LSO may ask for change in compliance

report within 5 business days from the receipt of the report • Find out the cause of delay when more than one non-compliance cases

are notified.• In case a non-compliant timeline is determined between the receipt of a

case report at BRM and the availability of the completed report for CA reporting by the LSOs,

• BRM will generate a deviation report.• If a non-compliant case has no Single Case Timelines Deviation record,

than LSO must create a new one in TARGET system

• Area PV Head will review all CAPAs ,gather information, analyze root cause and will identify trends.

• information of non-compliance trends will be distributed to Area Medical Directors (AMD) and (VP EMEA PV & MC).

• Reviews and analysis of non-compliance reports will be conducted for developing corrective action plans

• VP EMEA PV & MC will provide a summary of CAPAs and trends to (QPPV) and the BRM Regional Head EMEA.

• LSO must manage CAPA after its execution. • If actions fails to meet the target, CMD/ LM and the Area PV

Head must be informed and new actions must be decided

• 3.9 Overview of process to respond to a safety-related request for• information from a Competent Authority• SOP307 covers all spontaneous/non-solicited product-related queries/requests

from HAs/CAs but not originating from MAs submitted to HAs/CAs. • The queries or requests may relate to:• safety (will be handle by LSO)• efficacy,• quality, or • availability of the product. • manufacturing issues (arising from (PSURs), related aggregate and single case

reports)• This SOP is not for queries or that are expected from HA/CA review of :• New Drug Application• Lifecycle line extension application,• Company Core Data Sheet (CCDS) • local label submissions.• Clinical trial application• post marketing commitments or product complaints

• Anticipated queries arising as part of planned regulatory procedures should be recorded as part of the applicable submission.

• LSO should acknowledge the receipt and respond immediately

• Responsibilities of the LSO (or designee) are as follows:

• • Immediate forwarding of safety-related requests/assessments of safety information, received from LSU to:

• - The BRM Support Desk for distribution to responsible parties within BRM

• - Regulatory Affairs department• - Local Regulatory Affairs Head• - VP EMEA PV & MC• - Area PV Head• • local Regulatory Affairs employees must know that

they must forward all information on safety-related requests from (CA) to the LSO

• The LSO should inform extended team of any safety-related question.

• extended team includes:• a member of the Office of the EEA QPPV Systems, • the Product Safety Expert• member of Regulatory Affairs department • The team will decide the management of response from Local

response. • And than a local response team will be developed to decide

actions, and the LSO will arrange for necessary resources needed.

• The Product Issue Management procedure will be refereed when decision about the status of the question is under consideration.

• If question is not an issue develop response approval from stake holders submit it to CA via local regulatory affairs

• LSO will keep the track of the feedback from CA and will close or restart the case on the basis of the response.

• The LSO must ensure that following are documented and filled:

• original CA request, the • data submitted in response and• final conclusion • All CA requests should be properly tracked in• WRAT (Worldwide Regulatory Affairs Tracking) in

collaboration with the Regulatory Affairs Head

3.10 Management of Safety Information

• Reconciliation is done when one information is available in two systems or in different functional groups.

• Either confirm the receipt of information or compare the key data elements between sending and receiving systems.

• Clinical Studies and Related Activities• Inbound Activities Reconciliation• Clinical Study Team perform reconciliation of the clinical studies and

activities from clinical study database or BRM WWSS• LSO will manage SAE’s from local studies and• ongoing reconciliation is done and recorded.• For study in progress, compare the reconciliation results of SAE’s with

clinical database at the end of the study must be performed and documented for all such studies whilst the

• This should be completely documented before study database lock

• Outbound Activities Reconciliation• SUSAR determination from different sources is performed by

BRM, based on the applicable Reference Safety Information. • Through queries, SUSAR reports are retrieved from SCEPTRE.• Based on the agreement , either the LSO submits reportable

cases to CA while GCO-SU reports to or the local OC will submit them to CA and investigators both.

• The GCO-SU has a system (CTSRS) for tracking of such reports and makes timely submission to investigators and like parties

• For using GCO-SU services by OC, written agreements must be documented

• OC should develop a process to supervise all delegated duties and make sure of compliance. The SUSAR submission ECs may differ from

• Medical Information, Call Centres & Local Quality Designee (LQD)

• Sources of AE are: • Medical professional • consumers to Medical Information • call centres. • LQD may receive product quality complaints with or without

AE. • For Third Party products, AEs are reported to the LSU. • All sources of AE information should be regularly reconciled

LSU processed reports and transmitted to BRM.• Reconcile reports within timescale so that processing newly

identified cases can take place.• And for this purpose establish close connection with all

parties involved in the collection and processing of AEs

• 3.10.2 Procedures for Unblinding SUSARs/SUAs• The Unblinding Designee unblinds the report before it is send

to LCR in SCEPTRE which is later retrieved by:• Clinical groups, • Regulatory Affairs groups, • GCO Safety Unit and • LSOs. • If the administered treatment is the Company product, global

expectedness is assessed against the Reference Safety Information.

• Comparator product reports are assessed for expectedness against the corresponding SmPC. The SUSAR/SUA is then promoted to Local Case Reporting (LCR) in SCEPTRE

• 3.10.3 Determining Expectedness of Adverse Reactions• Once the processing of event starts, use Reference Safety Information

(RSI) for expectedness determination• A reported Adverse Drug Reaction (ADR) is considered expected when it is

mentioned in RSI document • LOC must assess expectedness against the local label.• RSI document sections are as follows::• • Contra-indications• • Precautions• • Adverse Reactions/Undesirable Effects• • Overdose• • Drug interactions.• Only those AE experienced during clinical studies are considered expected

when there is an association between the events and the drug • Documented events with titles specifying that they are associated with

product use are considered expected. • It will be considered implied if the table list only number of events

occurred during clinical trial against active comparator or placebo, and the number is greater than comparator or placebo.

• An ADR is considered unexpected if it occurs with a greater specificity or severity than that documented in the RSI.

• FDA requests an assessment for listedness be done based on ADR as defined by the Council for International Organisations of Medical Sciences (CIOMS).

• During a transition period, Update RSI with new ADRs

3.11 Review and Reporting of Company Activities generating patient data on J&J Products initiated, conducted or supported by Janssen-CilagEMEA Operating Companies

• 3.11.1 Review of Company Activities• patient data may be organized locally or

internationally Irrespective of their source• a project description is needed for each Company

Activity to start the evaluation• If the project is in scope for ReCAP, use complete

ReCAP process • projects should undergo local review, and each step

must be documented in Recap system

• OC generates patient data related to the use of drugs in compliance with J&J requirements and local laws

• Review of the Research Concept done by:• the Country Medical Director (CMD), • Area Medical Director (AMD),• the Local Safety Officer (LSO) and • the Health Care Business Integrity Officer (HCBI Officer) (for

Single Country Activities)• Therapeutic Area Leader (ETAL) or EMEA Medical Affairs

Director (EMAD),• The Vice-President EMEA Pharmacovigilance and Medical

Compliance (VP EMEA PV & MC) • The EMEA Health Care Business Integrity Leader (EMEA HCBI

Leader) (for Pan-EMEA activities)

• EMEA Decision Tree will be used for Safety Reporting procedures.

• In case of unclear safety reporting requirements refer to PV Policy Committee (PvPC) can be consulted.

• To maintain compliance with J&J requirements a process must be placed at LOC that will assist in generating patient

• All employees involved in generating patient data should receive training.

• All activities must undergo an initial and properly documented review, where the potential for patient data collection is evaluated.

• 3.11.2 Review of Safety Reporting Procedures• SOP 108 also describes “Standard PV Paragraphs” for

all non-interventional protocols/project descriptions. • This Paragraphs explains necessary procedures to be

followed for generating patient data under non-interventional clinical study or related activity.

• All such project description should include this PV Para

• Project submitted by the Project Owner will be reviewed by the LSO or by the VP EMEA PV & MC to decide the nature project and the reporting procedure to followed.

• 3.11.3 Safety Monitoring Plan (SMP) / Study Specific Responsibility Form (SSRF)

• SMP or SSRF explains responsibilities of the parties involved in clinical studies inline with the safety profile of the compound

• These document outlines sponsors’ regulatory responsibilities and company’s compliance, processing of safety data and forwarding them to the applicable parties

• SMP/SSRF is prepared by LSO representative• The Global Trial Manager (GTM) ensures availability of

updated SMP/SSRF, to Local Trial Managers (LTM) and to BRM and also to R&D Heads incase of outsourced studies

• The Local Trial Manager (LTM) forward it to LSO, LQD and GCO Local R&D Heads

• LSO reviews SMP/SSRF for responsibilities delegated to LSU. • Special attention are given to:• inbound and outbound activities• aggregate report submissions responsibilities• Outsourced activities to CROs • The review should focus on:• • Availability of a Safety Processing Flow availability • • Responsibility for inbound and outbound reporting activities• • Responsibilities for aggregate report (ASR/SLL) submissions to CAs, investigators• • Safety Database owner• • Any agreed unexpected activities assigned• The reviews responsibilities should be documented, such as:• • New study information to LSU• • Access to the study protocol and reference safety information• • Update SCEPTRE LCR queries and Pharma SLA Appendix and inform EERG • • Include new product/investigational drug to the local product list • • Check aggregate report submission responsibility,and forward to the relevant• parties.

• 3.11.4 Overview of Related Key Processes and governance that ensures appropriate review and approval of proposed safety reporting procedures Global Medical Affairs Council - Research Concept Approval Process (GMAC - ReCAP)

• The Research Concept Approval Process a cooperative between marketing and medical units of the organization to align research and product related concerns at all level.

• The ReCAP review global approval process for research and medical studies for meeting compliance

• After the approval of protocol, ReCAP supervises local medical

• The scope covers all countries and therapeutic areas. • Medical Affairs studies and HE activities generating safety

data for all types products

• This includes:• Clinical studies, • surveys, • prospective and retrospective field-based studies, • Post Authorisation Safety Studies (PASS), • re-analysis work, • post-hoc analysis,• limited access programmes,• named patient programs,• investigator-initiated or cooperative group studies• and animal or in vitro laboratory studies

• Protocol Review and Approval Process (PRAP) for Medical Affairs Protocols

• Protocol Review committee must approve MA study protocols before initiating the study.

• Submit Pan-EMEA Interventional/non-interventional studies to the R&D Protocol Review Committee (R&D PRC)

• Submit Single Country interventional to the EMEA Protocol Review and Approval (PRAP); and Single Country non-interventional studies to the Country PRAP.

• Ensure consistency of Research concept, during PRAP review • Also ensure correct safety reporting procedures and Standard PV

Paragraph are present• EMEA Decision Tree on Reporting Safety Information Arising From J&J• Pharmaceuticals Company Activities on Pharmaceutical Products• Decision Tree provides guidance to LOC/MAH on reporting of AE related

SOPs that should be considered for activities involved in the collection of AEs

• Pharmacovigilance Policy Committee (PvPC) is available to provide additional guidance.

• Pharmacovigilance Policy Committee (PvPC)• The Pharmacovigilance Policy Committee (PvPC) guides safety community

on interpreting and understanding of PV regulation for establishing PV operational policies

• The PvPC reviews PV regulations to interpret them according to global regulations for maintaining compliance.

• PvPC also act as forum for the safety community • Policy on Trial Master Source• The Policy on “Trial Master Source” describes the scope and condition of

using it• The objective of this is to provide a single repository for all types of studies,

activities and programs. • In this way data is centralized for answering Regulatory authorities queries

and forwarding them to internal customers. • The policy is for all clinical studies ongoing/started since 1-Jan-2007 • all related research activities, access programs and non J&J sponsored

clinical activities started/ongoing since 1-Jan-2008.• Company sponsored/supported activities are first entered in CTMS.• Direct data entry will be necessary for all other required TMS data

• Policy for the Registration & Reporting of Results of J&J Pharmaceutical Company Sponsored Clinical Studies

• “Global SOP for Registration, Assessment and Disclosure of Clinical Studies and Related Clinical Activities” is for supervising and monitoring clinical study results

• The objective is to provide a process that aligns the following areas:• • Protocol registration• • Assessing study to find out whether safety reporting procedures were

followed• • Disclosure of study results• Clinical Registry contain all Clinical Studies and Related Clinical by

Marketing and Development Partners, single country activities, and Investigator-Initiated Studies

• Protocol information maintained in the Clinical Registry• J&J’s obligation to disclose both protocol and result summaries is assessed

for each clinical activity. • The disclosure depends on the medical importance of the study

• 3.12 Overview of Process for Aggregate Report Preparation and Submission to Competent Authorities (PSUR, Bridging report, addendum, ASR, SUSAR Line Listings)

• A. Preparation/Planning• Regulatory Medical Affairs Writing Prepares Annual Safety Reports and SUSAR

Line Listings • Other types of periodic reports are written by Pharmacovigilance Aggregate

Reporting• BRM Pharmacovigilance Alliance Management is responsible for making PV

agreement available to the BRM PVAR/RMAW for access to third-party requirements and contact details.

• BRM PVAR and RMAW groups are responsible for maintenance of the EU CTD Calendar Update and BRM Aggregate Report Calendar Update respectively which are distributed to LSO

• The LSO gathers local updates report requirements within 2 weeks. • If new reports are required between quarterly updates, the LSO should inform

the BRM PVAR/RMAW group for updating their calendars within three business days

• BRM PVAR/RMWA should be given at least six months notice for requests for PSURs and at least 90 days notice prior to HA due date

• B. Call For Information• The BRM PVAR or RMAW group identifies individuals

with information that can be included in the PSUR/ASR.

• If different departments are working on aggregate reports, one single contact point is decided.

• LOCs are emailed about rewuired information to be delivered to BRM by what time. The email is send one month prior to the data lock date for the PSUR and ASR. This is referred to as a Call for Information (CFI).

• C. Planning Meeting, Creation, Review and Publication

• The Report Owner plans a meeting for deciding topics to be addressed besides standard PSUR/ASR topics.

• meeting minutes along with due date for all steps of PSUR/ASR are distributed

• Draft report is written when the case is processed. • Data is run from the BRM WWSS for quality check

and will be re-run for corrections • Before finalizing the report, its draft will be reviewed

by others and feedback will be added • The final version is signed indicating its completeness

and accuracy

• D. Distribution and Submission• The final report is available by calendar day 48 (PSURs) or 53

(ASRs) to Global Regulatory Operations/Affairs or Study Responsible Regulatory Operations (SRRO) Department respectively which they will forward to CA and others within 60 days

• For submission responsible employee must prepare cover letter.

• Review by this employee may not be necessary but in EU countries for PSUR comparison of local label with CCDS will be made and the difference is noted in Cover letter

• In case of Annual Safety Reports, the responsible employee should check listing of local studies and inform BRM in case of discrepancies

• If BRM’s report don’t meet local regulation than LOC must notify this to BRM in order to make changes.

• E. Compliance• BRM Quality Systems generates compliance metrics

for local submission of reports to CA • LSO must provide report submission information to

BRM compliance science• Late submission reason must be documented along

with CAPA • In countries that do not have an obligation to submit

PSURs to CAs, the LSO confirms with BRM on a monthly basis that the PSUR was received and not submitted.

• F. J-C Operating Company Roles and Responsibilities and governing SOPs

• Responsibilities of LSO in relation to aggregate reports are as follows:

• • PREPARATION/PLANNING: Making sure that BRM support Desk and QPPV are informed of any request from CA

• • CALL FOR INFORMATION: Forwarding Individual case reporting to BRM before data lock

• • PLANNING MEETING, CREATION, REVIEW AND PUBLICATION: Develop PSUR for Products of Local Opportunity

• • DISTRIBUTION AND SUBMISSION: review documents, forward them to CA and provide additional information if required.

• • COMPLIANCE: Complete aggregate report submission compliance form and supervise products compliance

• G. EU PSUR harmonisation and work share scheme• A PSUR work sharing project has been initiated by the EU Heads of Medicines

Agencies.• For all medicinal products, with the same active ingredient, this offers the

possibility of• having the same Harmonized Birth Date and Data Lock point for the compilation of• PSURs. For marketing authorisation holders this means that for all pharmaceutical

forms• and strengths of products with the same active ingredient, the same PSUR

submission• procedure can be followed. For the Agencies this project allows the PSUR

assessment• process to be more efficient. The latest version of the list of adopted EU

Harmonized• “virtual” Birth Dates (EU HBDs), related Data Lock Points (DLPs) for the

forthcoming• PSURs and allocated PSUR Reference Member State (P-RMS = Member State in

charge• of making the PSUR assessment report) can be found on the Heads of Medicines• Agencies (HMA) website: http://www.hma.eu/80.html

• Within the EU, it is mandatory for Marketing Authorisation Holders (MAHs) to follow the• PSUR harmonisation process in order to have a similar submission cycle and a• harmonisation of the safety sections of the SmPC. A guidance document for MAHs on• submission under the EU PSUR synchronization scheme can be found on HMA website:• http://www.hma.eu/human.html• The J&J team working on Birth Date Harmonisation is using the following Birth Date• definitions:• 1. The International Birth Date (IBD) is defined as the date of the first marketing• authorisation for a medicinal product (active ingredient) granted to the MAH in any• country in the world.• 2. The European Harmonized Birth Date (EUHBD) is defined as a 'virtual birth date'• that has been agreed between the MAH(s) and the Member States (of the EU).• The EU HBD may or may not be the same date as the IBD. The EU HBD relates• to the active substance. (However, MAHs are encouraged to agree the same EU• HBD for various salts and esters related to a single base).• 3. Operational Birth Date (OBD) is a J&J term and is defined as a 'virtual birth date'• which may coincide with either IBD or EU HBD or may be some other internally• derived date.

3.13: overview of Surveillance , signal detection and watch list:

• 3.13.1: surveillance & Signal Detection:• Safety signal are detected by employees concerned

with PV, and globally this is BRM’s responsibility, which is mentioned in many SOPs.

• BRM LOC Surveillance Guide Document provides guidelines to LOCs or J&J organization involved in Surveillance.

• Which is to be used when there are specific regulations posted by local bodies.

• Local surveillance are crafted according to the local needs otherwise when there is no specific requirements use BRM.

• For serious cases BRM PV physicians handles the signal detection (ata signle case level) which later forwarded to Safety surveillance Phyisican and Post marketing safety expert for further evaluation.

• Internal database surveillance is done by Analytic information management and reports are submitted to meet PSUR cycle

• SSP checks these reports for the variation that needs updating

• AIM prepares quality assurance reports to detect product quality issues.

• Data mining is done y using external database.• SSP reviews the statistical variations of drug

event combinations • Signals are detected from both data mining

and SCEPTRE.• If its indicated after first review that further

detection is required and information are needed to be added than it will be conducted to meet the requirement.

• SSP prepares topic reviews with the help of BRM resources, which after completion is shared on the decided forum.

• PSE has decision making authority on the basis of surveillance findings.

• Safety Franchise Surveillance Activity:• Safety related questions may arise from the following sources:• Client development• Periodic label review• Events described in Class labelling• Protocol review• Pharmacoepidemiology review• Literature review• Product quality issues• Market research• Outcome studies• Medication error reports• Peer-to-Peer communication• While preparing and reviewing Risk management reports and CA reports

• CA safety information question are forwarded to BRM desk support who will further forward It to EEA QPPV and PSE. Safety related question are handles by PSE and product quality scientist.

• BRM assess risk and than makes benefit risk decisions

• For this purpose following are the steps to be followed:

• Gather necessary information from both internal and external sources.

• Analyze and interpret the data.• Forward it to peer and EEA QPPV for the

review before finalizing it• Internal PV customers by BRM those parties

involved in Clinical studies and activities, and in this regard BRM submits repots and analysis to health agencies, and makes recommendations to labelling committees.

• Local signal Detection Activities:• LOC’s should report potential safety issues

and AE to BRM, including:• Withdrawal of a product in the local market.• New contraindication apart from the

approved one• And modification in the contraindications• Immediate transfer of such detections to BRM

is very important.

• Signal detection is MAH responsibility. And if the signal happens to be true than it is a safety concern, and MAH must take actions.

• LOC should report information to BRM when:• It might alter the benefit risk assessment• It would be important enough to change medicinal

product administration and conditions of MA• It could change overall clinical investigation process• Immediate drug safety concern should be reported

to QPPV and safety franchise

• 3.13.2: Watch Lists• BRM owns product specific watchlist and is managed

by PVP and global watchlist team• BRM Regional centers produces product specific

watchlist. It provides input to the queries and record feedbacks.

• Authorized LSO’s can view watchlist when specific product or MedDRA Preferred Terms are entered in the case.

• LCR outbound activities are monitored by watchlist content.

• BRM world wide safety system is incorporated in SCEPTRE which provides the details of the requirements for drug specific events to BRM single case processing staff.

• 3.14: Labelling Activities: • SOP “ development and maintenance of labelling

documents" shares the responsibility related to development of local and regional labelling documents, which is applied to label J&J products

• Issue realting to product label is handled by cross pharma regulaotry affairs by assmebling a cross functional labelling working group. And SOP 07925 describes labelling realted committes resposnibilities

•

• BRM is also the part of the labelling group and the labelling working group responsible for writing updated product labelling and deciding timeline for the global labelling globally, and which is later submitted to labelling review committee.

• LRC reviews the propsoed lables before submitting them to CA, and may make recommendations.

• LRC also recognizes local label deviations

• regulatory affairs distributes labelling updates to LOCs, and for tracking and auditing compliance.

• Submission of the updated labels to CA via MAH’s regulaotry functions.

• MAH should ensure their SmPCs are consistent with company core data sheets, meeting CAs requirements and patient information leaflets are also consistent

• Investigator Brochures:• IB’s should be available to all J&J employees involved

in clinical studies.• IB eRoom conatins necesaary folders that are used in

IB. it has two folders, one for full development of product and another one for early development of product (with restricted access)

• LCR case retrieval by the LSO for expedited report, is guided by SCPTRE.

• Incase of uncertain events all LSO have access to IB.

3.15 risk management• LSO must implement risk managements plans within

LOC.• RMP is used for the mitigation strategies for any risk

associated with the product use.• RMP is developed for new MAA in EU and for older

products it is needed when risk are identified. • RMP is used to maintain risk benefit balance by

communicating risk based on the safety profiles of the product

• RMP is developed in the following manner:• Background: description and understanding of

the product• Safety specification: safety profile of the drug• PV plan: routine surveillance activities which

includes AE reporting and signal detection in database and also review of lot-related events

• In US FDA may ask for Risk minimization plans

• According to the FDA every company should have Risk evaluation and mitigation strategies to ensure that the drug benefits outweighs the risk associated with the product.

• And FDA may impose REMS at pre or post marketing.• However if further mitigation strategies are needed

than risk minimization action plan is needed.• RiskMAP gives tool to reduce identified risk which is

based on the type of product. And later this process is evaluated.

• Once need of REMP or RiskMAP is realized than R&D safety head will prepare its document and compound development team will establish risk management team.

• Leader of the team is usually CDTL who is responsible for implementing this process and during the whole process BRM is facilitating the program. Each RMT member is responsible for one area.

• After the report is combined BRM is responsible for submitting it to QPPV for the review

• Upon the finalization the document is submitted to CA.

• During RMP implementation the process is continuously evaluated to make necessary adjustments if required.

• RMP is shared with LOC people.When LSO are needed in RMP, REMS or RiskMAP:Data collection of AEExpedited reporting of certain eventsTraining of relevant OC personnelCommunication with HCPs

• 3.16: Overview of Product Issue Management Process:• SOP 308 explains the responsibilities of the personnel

involved in product related issues that may affect safety, efficacy or availability of J&J or partnered products.

• All employees should inform their Heads about product related issues

• HOD or line managers should inform local contact point within 2 days of awareness.

• Issue contact point can be VP, Medical Affairs Office.• ICP with issue evaluation panel should allocate the necessary

resources and appoint a leader.• Product issue team is established once VP Medical affairs and

Chairman Pharma EMEA decides

• 3.17: PV business Continuity plan:• LOCs must have BCP for PV. According to the “WW BC and

disaster recovery policy”.• BCP is a plan that ensures that even in the case of major

disaster the business continues to operate uninterrupted.• SOP 110, describes activities to ensure continuation of

business incase of disruption where PV procedures may be affected.

• Sop covers HR, technical and communication areas.• Also provide guidance for PV critical process. And a team with

a leader is also established to handles interruption when PV critical process are affected

• All processes must be document before the resolution is made.

• LSO handles following responsibilities:• Inbound and outbound activities are done in case of

disruption• Training of all employees involved in PV BCP• Documentation of all reports received during

disruption.• Country Medical Director’s responsibilities are:• Local departments (involve in PV) are following BCP.• Workplace outside J-C facilities are available for

employees of SU• Communication plan to inform all internal and

external partners• Replacement of LSO incase of his absence

3.18: 24-hour emergency coverage for Urgent medical phone calls:

• 3.18.1: Summary:• MAH/OC must maintain a 24-hr contact list of

people to be contacted in case of medical emergency and it should be update. It should also include contacts of people handling non-PV calls too.

• 3.18.2: Overview of Key accountabilities and governance that ensures appropriate 24-hour coverage for receipt of urgent medical phone calls

• OC should handle the process of forwarding in-out office hours calls and making sure the QP is involved.

• Special attention must be given to out-office hours calls which may include emergencies other than AE.

• Further actions are decided after receiving the calls

• After receiving the call, decide the main concern of the call e.g. AE, PQC, combination of both, pregnancies or other urgent matters. If call concern AE, forward the call to LSU.

• If there are out of office hours call centers, they should be provided a document in which the minimal information is to be recorded and also to whom it should be forwarded, and also place a verification process

• Request for urgent call to QPPV must follow the prescribed document available at BRM portal

• People receiving calls should be trained to document necessary information, name of receiver and forward the call to LSO

• Country medical director will test 24-hour urgent call process and relevant employees will be informed of such test. And on the basis of its result it will be decided whether further training is required or not

• 3.19: Products of Local Opportunities:• 3.19.1: Introduction:• POLO are the products not supported by BRM,

and the PV responsibilities are handled by LOC.

• 3.19.2: Activities undertaken by LOC:• As MAH/clinical trial sponsor, J&J LOC fulfills

all PV responsibilities, and it should meet both local and J&J corporate standards.

• LOC must develop a system for POLOs which may include the followings:

• For EEA nominate a EEA QPPV, and for any other countries nominate a local contact.

• Develop safety data base for these products• Medical evaluation for POLO ICSRs.• Submission of ICSR to CA, and compliance with legislation.• Develop and approve aggregate reports.• Ensure signal detection for concerned products.• Review global literature• Incase of safety related questions, provide responses from CA• Develop process for proper POLO labelling• Develop training program for these products, and monitor

their compliance with legal standards

• Precisely all activities handles by BRM will be handled by LOC alone

• All these responsibilities are ensured by LOC through a process by LOC however these responsibilities can be delegated to third parties and for that a agreement must be developed.

• 3.19.3: In-or-Out Licensed Products Of local Opportunity:

• For in-or-out product PV responsibilities are shared between two parties.

• Incase of global products, partied responsibilities are outlined in global agreements.

• In case of in-or-out licensed POLOs the PV agreement development is LOC’s responsibility.

• However sharing of responsibilities may differ from LOC to Loc.

• 3.20: Overview of Product Quality Complaint Process:• SOP 206 explains the responsibilities of LQD and LSO for

handling product related complaints.• A system is to be developed to record such complaints and

forward them to their respective departments.• LOC’s responsibilities regarding PQC are as follows:• Initial evaluation whether it is AE, Technical or combination of

both or a design complaint• Document batch number or ask for it incase of missing batch

number• Determine whether manufacturing investigation is required

or not• Forward these investigation results to BRM for AE reports

with Local QA reference numbers

• First evaluation is to be done quickly. Seriousness of AE will be assessed BY LSO who will forward it to BRM

• Seriousness assessment is done on all information available

• If a manufacturing evaluation is required for AE, Technical or for combination, inform Global Pharma Supply with in 2 days from the notified day

• For marketed products use the PQSM system.• Incase of three off business days inform immediately

on 4th day

• LQD forwards the conclusion of investigation, tracking numbers, date of review of AE, or AE/PQC to LSO who later forwards it to BRM.

• AE and combined complaints are forwarded in BRM case processing system and if manufacturing evaluation is requested than use QA number.

• If no investigation is required AE will be forwarded to BRM as usual, but if BRM ask for investigation than it will be communicated via LSO

• 3.21: PV responsibilities in Contractual Agreements:

• Contractual parties responsibilities regarding PV activities must be specifies in PV agreements.

• The applicable SOP applies to:• Single Country or Multi-Country, • new and updated,• in-licensing and outlicensing agreements with

pharmacovigilance implications within the EMEA region.

• Out of scope of this SOP are:• contracts with clinical research organisations, • clinical trial contracts with investigators and

cooperative groups, • contracts with consultants and• service contracts relating to non-interventional

activities. • internal service level agreements • All agreements must be entered in the International

Contract Database (ICD) by the ICD Administrator

• Single Country Agreements• Contract Owner and LSO decide whether the

Agreement needs a separate PV Agreement. • The contract owner, LSO and BRM Head PV Alliance

Management (Head PAM) will decide the PV agreement type

• The Head PAM or LSO may review it. • The LSO provides a copy of the signed PV Agreement

to all stakeholders and ensures training of the appropriate staff at the LOC

• Multi-Country Agreements• BRM reviews them to ensure that it has proper PV

agreement in place• The Contract Owner distributes it to LOC before the

agreement takes effect.• The LSO provides a copy of the signed PV agreement

all stakeholders and ensures training the staff of LOC Partner.

• Validation of the list of Agreements with PV obligations

• ICD will forward relevant agreements to LSO • The LSO must return it with their verfification

• Documentation maintained at the LSU• The LSO should update the following lists in the of the PV

Handbook appendix with information specified in third party the Agreements

• • The local list of Agreements relevant to the LOC • • The list of marketed and/or clinical research products

involved• • The list of local nominated person and Qualified Persons for

PV system • Check the Agreement for deviations from the standard

procedures, such as:• • Deviations from the local safety data collection and

processing process• • Deviations from the safety reporting process• Update working instructions of the LSU for PV compliance • Train LSU personnel and document this training

• 3.22 Case Closure• Monitor individual safety reports for the follow-up of reports

and case can be closed when no further information is expected

• LSO must regularly check due diligence in BRM WWSS • Unauthorized LSOs, must monthly review the local Tracking

Tool for deciding the closure of the case, which includes evaluation of the processing and completeness of the data

• The following criteria can be used:• • No outstanding questions• • No outstanding follow-up information awaited• • Outcome is known • • No outstanding administrative activities • • Reporter declined

• Collect information and send decided numbers of due diligence letters before closing invalid/incomplete reports.

• Collect all information and ensure no follow-up information will have impact before closing pregnancy reports.

• The LSO will review information and decide case closure and will document the date of closing

• Authorized LSOs will close all active due diligence schedules. Nonauthorized

• LSOs will indicate the status ”Case Closed” in the local Tracking Tool.

• After case closure, all report documentation must be properly filed.

• 3.23 Safety and Security of Business Sensitive Information• Information available to personnel in Medical Affairs and LSU is

important since:• • the information fowarded to partners may include personally

identifiable information • Information communicated may need to be limited to certain level of employees

• 3.23.1 Premises and Accesses Main Offices• offices have secure entrances.• Visitors pass through office attendants • Employees carry cards.• Visitors obtain a visitor identity card. • Visitors are accompanied by an office employee • Also offices are equipped with anti-fire devices and breakage

alarms. • These devices tested twice per year. • Maintenance and testing logs are archived in administration offices.

• The LSU is equipped with a fire and waterproof area/cabinets.

• The LSU are accessible to the LSU employees,• 3.23.2 Network Safety and Security Main Server• The main server is in the main office area • All information on the servers are backed-up on daily

basis • The back-up tapes and logs are stored in fire and

waterproof premises away from the main office

• Employees can to access network by going through the verification system.

• Certain company network addresses are accessible to specific job functions

• Encryptions and Firewall• The network is also secured with encryption

systems and firewalls to prevent unauthorized users

• Anti-Viruses• The whole network are equipped with

antivirus programs

• 3.23.3 Security of Communication with LSU• All employees and partners are communicate

information to the LSU only via secure communication systems:

• • designated fax and/or supervised fax• • secure e-mail system• The LSU has a designated e-mail address. All archived

e-mails are backed-up on the main server. • The LSU e-mail folder is backed-up on tapes • All safety communication received by e-mail is

printed and archived in case files, in the fire and waterproof cabinet

• 3.24 Shared PV Services for Consumer Medicines acquired from Pfizer• All effective J-C EMEA-MA-PV-SOPs are applicable and should be followed by J-C• EMEA Local Safety Officers (LSOs) who are providing pharmacovigilance services for• consumer medicines acquired from Pfizer.• Additional instructions to the existing pharmacovigilance processes for the situations• where an exception to the current J-C EMEA-MA-PV procedures should be followed with• regards to the legacy Pfizer Consumer Health (PCH) products, are described in the J-C• EMEA-MA-PV-SWP -001.• In general, the following applies for the legacy PCH Products:• • Cases with legacy PCH products will be sent (e-mailed) to a different address• within BRM compared to other J&J product cases.• • Because legacy PCH products are not maintained in the SCEPTRE database the• standard case tracking procedures cannot be used. LSOs are to use a local case• tracking system instead.