TransCelerate Safety Issue Notification Guide · 2. Provide insight on interpretation of several country guidances for implementation to help make operationalizing compliance more

Final: July 1, 2019

Interpretations of Guidances & Regulations

TransCelerate Safety Issue Notification Guide

Australia

Turkey Canada

Israel

New Zealand

Saudi Arabia

Switzerland

Copyright ©2019 TransCelerate BioPharma Inc., All rights reserved. 2

Australia

Canada

Israel

New Zealand

Saudi Arabia

Switzerland

Turkey

01 Introduction

02 Approach

03 Challenges

04 Definitions & Processes Relevant for Signals & Safety Issues

05 Proposals for Challenges

06 Conclusions

07 Country Specific Sections

TABLE OF CONTENTS

NOTE: These materials are provided for informational purposes only and ‘AS IS’ WITHOUT WARRANTY OF ANY KIND, EITHER EXPRESSED OR IMPLIED, INCLUDING, BUT NOT LIMITED TO, THE IMPLIED WARRANTIES OF FITNESS FOR A PARTICULAR PURPOSE OR NON-INFRINGEMENT. TransCelerate and its members do not accept any responsibility for any loss of any kind, including loss of revenue, business, anticipated savings or profits, loss of goodwill or data, or for any indirect consequential loss whatsoever, suffered by any person using these materials or acting or refraining from action as a result of the information contained in these materials. Any party using these materials bears sole and complete responsibility for not only complying but determining how best to comply with all applicable laws and regulations in all relevant jurisdictions. The content set out herein

should not be construed or taken as legal advice.

Introduction


In recent years, Health Authorities (HA) around the world are rapidly evolving their expectations for safety issue* notifications. These vary by country and may include expectations that information is shared earlier, and with varying levels of detail and formats.

While Marketing Authorization Holders (MAHs) recognize the importance of meeting HA expectations for safety issue notifications, there are challenges with interpreting and operationalizing these guidance's to meet HA expectations in an efficient manner.

This guide is intended to aid industries‘ ability to meet safety issue notification requirements (2019) for in scope Health Authorities. The guide intends to provide awareness to the industry to enable successful safety issues notification submission to these Health Authorities. In addition it

describes methods that aid in interpretation and implementation that may be helpful, particularly as guidelines and Health Authority expectations continue to evolve.

Introduction Problem Statement/Opportunity

NOTE: This guide is intended for use in connection with for implementation of applicable Health Authority legislation published prior to January 2019 as subsequent legislation (e.g. new or altered regulations) is not reflected or considered.

*Safety issue is an overarching term used to capture various country requirements for safety signals and notifications.


Introduction Notification Guide Objectives

1. Provide greater understanding of safety issue notification requirements, which include signals and safety issues, and providing awareness and guidance for submissions to Health Authorities

2. Provide insight on interpretation of several country guidances for implementation to help make operationalizing compliance more efficient and effective

3. An aid to MAHs ability to meet signal and safety issue notification requirements for in scope countries*

The Guide can be used in a highly flexible manner, as described below:

Australia

Turkey Canada

Israel

New Zealand

Saudi Arabia

Switzerland

*Selection of countries is based on those countries that have relevant guidancesand are a variation from other markets (i.e. EU/US) regulatory requirements.

Approach


ApproachOverview of Methodology

1. Scoped Project

2. Reviewed Guidance

Documents

3. Proposed Reference Definitions

4. Gathered MAH insights

5. Created Notification Guide

In creating this guide, the following approach was used.


ApproachScoped Project

• Early or additional notification of safety issues which may include emerging safety issues and signals

• In-scope countries: Australia, Canada, Israel, New Zealand, Saudi Arabia, Switzerland, Turkey

• Selection of countries is based on those countries that have relevant legislation and are a

variation from major markets (i.e. EU/US) regulatory requirements.

• Patient safety issues associated with approved products (marketed drugs)

The following were defined as key elements for the scope of this project


ApproachReviewed Guidance Documents

1. Identified and reviewed relevant guidance documents for each country

2. Identified terminology used in different countries and examples of safety

issues cited by individual regulatory authorities

3. Identified two broad categories:

• Signals

– Sub-set of countries require signals that have not progressed to safety issues

• Safety issues

– Different terminology used by HAs to request notification of safety information identified by MAHs that requires communication and/or pharmacovigilance or risk management actions or that results in such actions due to a HA request

The following steps were taken in reviewing the relevant guidance documents.

Link to Country Guidances Reviewed


ApproachProposed Reference Definitions

Goal: Leverage established, widely accepted definitions to interpret/clarify country requirements

1. Reviewed country guidances to identify safety issues and signal terminology

2. Identified commonality and differences in terminology definitions(among countries’ guidances)

3. Leveraged terminology from EMAGVP Annex 1, that included all concepts required by country specific terms

4. Applied common terms to country terms, qualifying country specific nuances

Problem Statement: Differing uses of terminology make it challenging to interpret, apply and meet Health Authority expectations

Opportunity to better operationalize country specific requirements

The following process was used in proposing the reference definitions.


ApproachGathered MAH Insights

Goal of survey: Assess ambiguous parts of country regulations in order to best focus the Notification Guide on areas of value

What: Survey designed in 8 parts (Global/Headquarters and 7 countries)

When: Survey issued February 2019

Who: 16 member companies surveyed with 11 respondents

Why: Survey was created to understand the impact of the recent local regulations for MAHs to develop and implement processes for compliance based on the role of Global/Headquarters and local affiliates

MAH Insights of Safety

Issue Notification

Australia

Global/ Headquarters

Turkey

Canada

Israel

New Zealand

Saudi Arabia

Switzerland

A survey was conducted to facilitate collection of MAH insights on safety issue notifications.


ApproachCreated Notification Guide

The following steps were taken to develop this guide.

Input

•Analyzed relevant guidance documents that required further clarity and inconsistencies in interpretation

•Requested TransCelerate Member Company feedback regarding challenges relevant for global vs local affiliates

Analysis

•Reviewed & analyzed survey results

•Collated MC responses while maintaining the blind

•Reviewed for Global/Headquarters: 1) Highest ranking challenges identified and 2) Difference for internal vs external signals

•Reviewed for local affiliate countries: 1) Ambiguity in guidance's and country specific challenges identified and 2) Health authority acceptance or rejection

Output

•Tailored guide to address areas that required further clarity and incorporate TransCelerate team’s expert review

•Presented application of reference definitions by country

•Developed a flowchart to highlight a proposed communication workflow

•Provided a country-specific analysis

Purpose

•Applicable to global office or can be tailored to each country office

•Use as basis to compare company processes to general industry approach

•Inform MAHs regarding general industry challenges and practices

•Create awareness among health authorities

•Provide transparency among all relevant stakeholders

Challenges


ChallengesHighest Rated Challenges

Total Respondents: 11

Total Skipped: 0

AreaSignal

NotificationEmerging

Safety Issues

Determining the decision maker within the company 27.3% 18.2%

Timelines (e.g. receiving notification of signal in timely manner, communication of signals)

72.8% 63.6%

Identification of qualified signals (determination of relevant signal for Health Authority notification)

54.6% 45.5%

Communication process between appropriate local affiliates and global/headquarters

72.7% 54.6%

Communication within functions across local affiliates 45.5% 54.6%

Follow-up questions received from Health Authorities 36.4% 18.2%

Determining the action owner (e.g. Safety vs Regulatory) 45.5% 27.3%

Amount of information to provide to Health Authority 63.7% 63.6%

Tracking the notifications to the Health Authority 81.8% 45.5%

Member Companies were surveyed and asked to rate the most significant challenges associated with implementing signal and emerging safety issues notification requirements on a scale from 1 (not challenging) to 5 (challenging). The rows highlighted in blue were identified as the highest rated challenges (challenging and somewhat challenging).

All survey responses were collected by a 3rd party consultant, blinded and aggregated before dissemination to TransCelerate Member Companies.


ChallengesAspects of Highest Rated Challenges

>60% of member company respondents identified timelines were challenging (e.g. receiving notification of signal in timely manner, communication of signals)

Understanding of triggers and endpoints for timelines

1. Timelines

>50% of member companies surveyed identified that communication of actions imposed by a specific regulatory agency was challenging

Information shared in a format ready for onward external communication

Need for clear communication process between local affiliates & global/headquarters

3. Communication

>80% of survey respondents stated tracking notifications to the health authority was challenging

All responding companies considered it necessary to have awareness of signals submitted to local Health Authorities

2. Tracking

>60% of responding member companiesidentified the amount of information to submit to Health Authorities was challenging

Where feedback was received from the agency, this was related to content that was lacking

5. Amount of Information

>60% of responses identified that the determination of relevant signal for health authority notification was challenging

Actions imposed by regulatory authorities and labeling updates were identified as the most difficult safety actions to communicate.

4. Identification of Relevant Signals

Challenges

*Data collected from member company survey

Additional aspects of highest rated challenges from MAH insights survey.

Definitions & Processes Relevant for Signals & Safety Issues


Definitions & Processes Relevant for Signals & Safety IssuesProposed Reference Definitions

Validated Signal (Internal):An internally (e.g. within company) generated signal for which the signal validation process has confirmed that available documentation contains sufficient evidence demonstrating a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis (amended from Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4)).

Validated Signal (External):An externally (e.g. HA) generated signal for which the external validation process has confirmed that available documentation contains sufficient evidence demonstrating a new potentially causal association or a new aspect of a known association, and therefore justifies further analysis (amended from Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4)).

Emerging Safety Issue (ESI):Safety issues identified by the MAH or a competent authority that require urgent attention because of potential major impact on the risk-benefit balance of the medicinal product and/or on patients’ or public health and the potential need for prompt regulatory action and communication to patients and healthcare professionals (amended from Guideline on good pharmacovigilance practices (GVP) Annex I - Definitions (Rev 4)).

Refuted Signal:Validated signal which, with further assessment has been determined to be “false”, (e.g. causal association cannot be established at that point). It is noted that for the purpose of the periodic benefit-risk evaluation report (PBRER) ICH describes refuted signals as signals that, following evaluation, have been refuted as “false” signals based on medical judgment and a scientific evaluation of the current available information (GVP Annex IV, ICH-E2C(R2) Guideline).

Due to variability in language used by various HAs, the below reference definitions are proposed in order to qualify the individual HA terms by utilizing broadly understood terminology for signals and emerging safety issues from GVP Modules. The purpose of usingreference definitions is to help reduce operational challenges to meet these countries' guidances.


Definitions & Processes Relevant for Signals & Safety IssuesRationale for selection of definitions

Validated signal

• All signals received or generated by a MAH undergo validation

• Assumption is that external signal requests received from a HA are automatically considered as 'validated' by MAHs

• Definition of ‘validated signal’ encompasses all types of signals required by in-scope HAs

• For example, in Israel The Ministry of Health refer to 'AEs observed outside of Israel, which are considered as AEs affecting product safety and requiring attention (signal)'*

• A different sub-set of validated signals required in each impacted country

• For example, refuted signals vs. signals resulting in changes to the product information

* State of Israel – Ministry of Health SOP Title 'Reporting Adverse Events and New Safety Information', section 3.2.2.5

Below are the rationale for the proposed reference definitions.



Validated signal (Internal)

• EMA definition of validated signal modified to include source of signal to accurately capture HA requirements

• Routine internal signal detection activities which result in identification of a validated signal that warrants

further investigation

• Internal signals are available via signal management system

Validated signal (External)

• EMA definition of validated signal modified to include source of signal to accurately capture HA requirements

• Includes:• Questions from regulatory authorities that require analysis of safety data by the company

• Questions from regulatory authorities that have undergone analysis for validity by the Agency

• Includes HA requests and negotiations that may impact safety, including labeling updates

• Examples of external validated signals include PRAC requests to analyse data, or FDA issuance of a Notification of Tracked Safety Issue (TSI)

• Does not include:

• Questions related to individual cases e.g. follow-up questions

• External signals are available via signal management system and/or may be tracked as regulatory

correspondence




Emerging safety issue (Amended)

• EMA definition of emerging safety issue has been modified to include issues identified by both the MAH and a competent

authority

• Specific focus of HA is regarding action taken in another specified country. For example, Health Canada refer to 'The intended outcome is.....early knowledge of regulatory actions that are taken in foreign jurisdictions'*.

• A variety of language is used but the spirit consistent with intent of ‘emerging safety issue’

• For example, TGA define significant safety issues as those with 'potential major impact on the benefit-risk balance of the medicine and/or on patient or public health'**.

• Includes:

• Emerging safety issues identified through routine internal signal detection activities• Emerging safety issues notified via regulatory authorities• Actions taken in other specified countries that the MAH may not agree with and will not result in a change to the core RMP

or data sheet

• Emerging safety issues are available via signal management system and/or may be tracked as regulatory correspondence or

actions e.g. update of local label, issuance of additional risk minimisation measures

• Issues are notified to impacted innovator company or are identified by monitoring of the external environment

• MAHs should clearly understand how an ESI is defined relevant to their internal definitions of types of safety issues and how

actions taken in one country may be communicated to additional affiliates

* Health Canada 'Notifying Health Canada of Foreign Actions – Guidance Document for Industry', section 1.1

**TGA 'Pharmacoviglance responsibilities of medicine sponsors. Australian recommendations and requirements'.



CountryValidated Signal

(Internal)Validated Signal

(External)Emerging Safety Issue

(Amended)

Australia Yd Ya

Canada Ya

Israel Ye Yd Ya

New Zealand Yd Ya

Saudi Arabia Yb Yb Y

Switzerland Yc Yd Ya

Turkey Yd Ya

Definitions & Processes Relevant for Signals & Safety IssuesNotification Requirements of Reference Definitions By Country

a For ESI, safety issues identified by the marketing authorization holder or a specified competent authority.b All valid signals, including confirmed and refuted signals, received from any competent authority or identified internallyc All valid signals resulting in changes to the product informationd Receipt of notification of a signal evaluation or safety- or efficacy-related procedure by a specified competent authoritye All valid signals possibly related to the medicationNote: Y = Yes, notify the health authority; blank cell = denotes no requirement or not applicable

Below are the notification requirements of the proposed reference definitions by country.


Process FlowchartSafety Issue Notification (SaIN) to Relevant Regulatory Authorities Process

Affili

ate

(I

nitia

tin

g)

Glo

ba

l Sa

fety

Te

am

Imp

ac

ted

Aff

ilia

tes

(Wh

ere

no

tific

atio

n

ma

yb

e r

eq

uire

d)

Receives Safety Query/Notice from local authority and submits to

Global Safety (External validated signal)

No further actionDoes the local HA agree with

conclusion

Evaluate Safety Request/Notice

Does any other country need to

be notified?

Internal validated

signal

Document Rationale

Is this a query/notice for a signal evaluation?

No

Send Safety Assessment to local Authority

Create Safety Response

No action needed

Re-assess company position

No

Yes Initiate & Complete

Safety Assessment

Yes

Do you need to notify local

authority?Document Rationale

Yes

NoSend Response to local

authority and track

Yes

NOTE: Further explanation of flowchart on next slide

No


Process Flowchart - FootnotesSafety Issue Notification to Relevant Regulatory Authorities Process

The flowchart provides a high-level mapping from the time a signal is received or identified, validated (internally or externally) and a response sent to a HA. At various points in the evaluation process a signal may be provided to a country based on their signal reporting requirements.

These points are as follows:

• Notification of the initial request or safety query

• Notification of the completed assessment for confirmed and/or refuted signals.

• Notification of the agreed actions between the HA and the MAH, if different than what is stated in the conclusion of the completed assessment

Throughout this process safety queries or notices should always be assessed to determine if they qualify as Emerging Safety Issues. If so, notification is provided to impacted HAs per local reporting timelines.

Below is some additional context regarding the flowchart.

Proposals for Challenges


Proposals for ChallengesTimelines

As in the flowchart, safety signal and issue communications may be triggered at different points. For example:

• Receipt of an external signal request may require notification to some countries.

• SwissMedic* should be informed following the initiation of the signal evaluation by specified authorities

• Assessment and conclusion of the safety signal/issue.

• E.g. Saudi Arabia should be notified of all validated signals, confirmed** and refuted.

• Final decision from the originating HA.

• SwissMedic should be informed of the results following the closure of the signal evaluation by specified authorities.

• Every signal should be assessed as a potential emerging safety issue. If it qualifies then all Health Authorities will

be notified in line with their reporting requirements.

• HA guidance as to when safety signal and issue communications should trigger communication are included in

the country specific section

• MAHs need to ensure a mechanism for both initial and any follow-up safety signal and issue communications

to be notified to impacted Health Authorities

*Swissmedic HD- Hilfsdokument Guidance document Drug Safety Signals HMV4

**Confirmed in this context is a signal that remains valid after all available sources of data have been reviewed and affirms the validity of the signal

Countries have various timeline requirements. When creating a process, MAHs should account for the shortest timeframe

Proposals related to timeline challenges.


Proposals for ChallengesTracking

• Create a tracking system of safety issues communicated to Affiliates (and document rationale for those that were not)

• Consider if Global needs to have oversight on what was or was not communicated to local Health Authorities. If oversight is preferred, design the Global tracking system to have access to this information

• Ensure responsibility for notification decision to HA is clearly defined (for example global vs affiliate responsibility)

• Audit/Inspection readiness: Tracking of details of communications and correspondence to the local health authorities (and documenting the rationale if the communication is not sent)

When creating a tracking system, It is important to have transparency in all actions regarding signal notifications including situations where no action is taken and setting clear expectations on tracking

responsibilities.

Proposals related to tracking challenges.


Proposals for ChallengesCommunication

Due to the variety of sources for safety issues, the varying needs of HAs and several functions that may receive or need to action safety information, clear roles and responsibilities for communication of information is essential.

From a global perspective, the following aspects of communication should be considered:

• As a company, each will need to decide how to manage communications, for example, should all affiliates be notified of all safety issues or affiliates who have guidance that requires notification to local HAs

• With consideration of the different sources of safety information, clear roles and responsibilities for communication and understanding of how different safety information is received and disseminated

• Develop Global process documentation that complies with local reporting requirements for notification of safety issues; include timing, and scope and source of safety issues

• Who drafts the communication, who reviews it, and who approves it

• Which functional area sends the communication to the affiliates

• Consider if the roles and responsibilities for the Safety Issue Notification are the same as Emerging Safety Issue Notification

Proposals related to communication challenges.


Proposals for ChallengesCommunication (continued)

From an Affiliate perspective, the following aspects of communication should be considered:

• What is the communication between Affiliate Safety and Affiliate Regulatory and who submits and tracks the communication to the local HA?

• Staff well versed in local regulatory requirements related to safety-related issues, format of response and timeline for notification

• Communicate changing regulatory requirements to Global/Headquarters for awareness, understanding and impact to notification processes

• Ensure availability of local process documentation that complies with local reporting requirement of signals

• Contact Global/Headquarters if clarification of signal notification and company position is required or needed

MAHs should ensure decision points regarding assessment of safety information are clearly documented and understood, leveraging existing process if possible

Proposals related to communication challenges.


CommunicationInternal and External Signals Communicated to Health Authorities

Local Health Authority A

Local Organization A

Global Organization

Local Health Authority C

Requires Internal and External

Decision point for submission of signal to relevant health

authorities**Decision point ownership

varies per company

Externally Initiated

Internally Initiated

Legend

Example of a possible process flow of internal and external initiated signals communicated to HAs based on country requirements and decision point ownership.

Local Organization B

Local Organization C

Local Health Authority B

Requires Internal only


Proposals for ChallengesQualifying Signal Identification

Global• Define scope of internal validated and external validated signals and source of signals that would require

notification to relevant countries• Determine the criteria for what is an Emerging Safety Issue that requires notification with consideration to

local countries regulations

Affiliates

• Establish relationship with local Health Authority and local trade associations to understand regulations when there is ambiguity or challenges

• Understand Global Headquarters safety processes, internal definitions and criteria for communication of the various types of issues

• Validated internal signals confirmed/refuted:• Validated external signals• Emerging Safety Issues (and as it relates to changes in benefit-risk profile)

Whether it's one or multiple processes, MAHs should create a notification process to include internal validated signals, external validated signals and emerging safety issues

Proposals related to qualifying signal identification challenges.


Proposals for ChallengesAmount of Information

• Suggested content for the Communications

– Which Health Authority made the query, Details of the query, Timeline for response to the requesting HA

– The response that was submitted to the requesting HA

– The MAH company stance and action taken by the MAH following HA negotiation

• Consider one format that can be used by multiple countries

• Utilize any required templates per each country’s guidance

• For emerging safety issues, consider including background information of the safety issue and any actions that will be taken by the MAH. If no action will be taken, provide an explanation.

The content in the communications to Health Authorities should provide enough information for the HA to understand the safety issue, the data that supports the MAH's conclusion and the MAH's

conclusion.

Proposals related to amount of information to submit to HA challenges.

Conclusions


ConclusionsConcluding Points

• Health Authorities (HA) around the world are rapidly evolving their expectations for safety issue notifications, and requiring the MAH to be more transparent with assessment and communication decisions

• MAHs must be aware of these requirements and have internal processes established to submit safety issues to local regulatory authorities

• Strong communication and clear roles and responsibilities are imperative, within both local affiliates and global functions

• Although the language used and definitions of signals and safety issues varies in the guidelines, the application of standard GVP definitions can aid effective operationalization

• Clear processes and tracking of safety issue communication can aide internal operations as well as compliance

Understanding the specific HA safety issue notification requirements and developing a robust internal process can aid in regulatory compliance.

Country Specific Section


Country Specific SectionIndex

Country Specific Sections:

Australia Link

Canada Link

Israel Link

New Zealand Link

Saudi Arabia Link

Switzerland Link

Turkey Link

The slides represented in these links provide a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on their local regulations. This information is based on current local regulations and interpretation which may change over time. You should confer with your local affiliate to confirm reporting requirements prior to submission.


Country Specific SectionGuidances Reviewed

Country Guidance

Australia Pharmacovigilance responsibilities of medicine sponsors: Australian recommendations and requirements published 27 June 2018Pharmacovigilance inspections: Update on the PVIP, learnings, helpful tips and workshops – held 27 March 2019

Canada Notifying Health Canada of Foreign Actions - Guidance Document for Industry published 20 November 2018

Israel Risk Management and Drug Information Department 1) ‘Ministry of Health SOP 6 Title: Reporting Adverse Events and New Safety Information’ Update No. 3 October 20132) ‘Questions and answers regarding reporting of adverse events and new safety information and risk management

programs and Clarifications for frequently asked questions with respect to SOP 6’ published 28 December 2017

New Zealand Guideline on the Regulation of Therapeutic Products in New Zealand Part 8: Pharmacovigilance Edition 2.1December 2017

Saudi Arabia 1) Saudi Food & Drug Authority Guideline on Good Pharmacovigilance Practices (GVP) Date Implemented 01 September 20152) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Drug Sector, Signal Detection Additional Guidance effective 01January 20183) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Drug Sector Additional Guidance Frequent asked questions (FAQ) effective 01January 20184) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Information about Signal of Cover Letter, effective 01January 2018

Switzerland ‘HD- Hilfsdokument Guidance document Drug Safety Signals HMV4’ published 01 January 2019

Turkey 1) Good Pharmacovigilance Practices Guideline (GVP) Module VII - Signal Management, THE MEDICINES AND MEDICAL DEVICES AGENCY OF TURKEY published 20 December 20162) Turkish Ministry of Health, Turkish Medicines and Medical Devices Agency (TUFAM) Safety Notification Circular (Number:46977249-510.01) published 11 March 2013

https://www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors

https://www.tga.gov.au/presentation-pharmacovigilance-inspections

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/foreign-actions-profile/guidance-document.html

https://www.health.gov.il/hozer/DR_6E.pdf

https://www.medsafe.govt.nz/regulatory/Guideline/GRTPNZ/part-8-pharmacovigilance.pdf

https://www.sfda.gov.sa/ar/drug/resources/DocLib2/Guideline%20on%20Good%20Pharmacovigilance%20Practices%20(GVP).pdf

https://www.sfda.gov.sa/en/drug/about/sector_departments/liicenses/Documents/FAQsv10.pdf

https://www.swissmedic.ch/dam/swissmedic/en/dokumente/marktueberwachung/mu/MU_HMV4/mu101_20_001d_wlarzneimittelsignalehmv4.pdf.download.pdf/MU101_20_001e_WL_Guidance_document_Drug_Safty_Signals_HMV4.pdf

http://farmakovijilansdernegi.org/files/2016.12.20_Guideline_on_Good_Pharmacovigilance_Practices_Module_VII-Signal_management.pdf

AustraliaThese slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Australia

Reviewed Guidance(s): Pharmacovigilance responsibilities of medicine sponsors: Australian recommendations and requirements published 27 June 2018Pharmacovigilance inspections: Update on the PVIP, learnings, helpful tips and workshops –held 27 March 2019

https://www.tga.gov.au/publication/pharmacovigilance-responsibilities-medicine-sponsors

https://www.tga.gov.au/presentation-pharmacovigilance-inspections


Country Specific SectionAustralia

Reference Term

Local GuidanceTerminology

ExamplesTimeline

StartTimeline

Level of Information to Provide

Method of Notification

Emerging Safety Issues (ESI)

A significant safety issue is a new safety issue or validated signal considered by MAH (Sponsor) in relation toMAH’s medicines that requires urgent attention of the TGA.

Based on the seriousness and potential major impact on the benefit-risk balance of the medicine and/or on patient or public health, which could warrant prompt regulatory action and/or communication to patients and healthcare professionals.

• Safety-related actions by comparable international regulatory agencies such as withdrawal or suspension of medicine’s availability; addition or modification for safety reasons of a contraindication, warnings, or precaution statement to the product label

• Changes in the nature, severity or frequency of known serious adverse reactions which are medically significant

• Detection of new risk factors for the development of a known adverse reaction or new serious adverse reaction that may impact on the safety or benefit-risk balance

• A signal of a possible teratogenic effect or of significant hazard to public health

Day 0 = when any personnel including third parties, vendors, or partners become aware

≤ 72 hours of Australian sponsor notification

- Indicate points of concern- Whether plan to take any

regulatory action (e.g. may include changes to RMP, amendments to label or product information document, or distribution of a Dear Healthcare Professional letter)

- If no regulatory action is planned then justification should be provided in Australian context

- Reports of significant safety issues should include:

- A description of the safety issue- Source(s) of information- Your assessment of the risk and

potential impact of the issue- Any actions you propose to take,

or justification for no further action- Any relevant documentation

Email (preferred): [email protected]

Fax: 02 6232 8392

Mail: Signal Investigation CoordinatorPharmacovigilance and Special Product Access Branch Therapeutic Goods AdministrationPO Box 100Woden ACT 2606

Australia

mailto:[email protected]


Country Specific SectionAustralia

Reference Term


Examples Timeline Start TimelineLevel of Information to

ProvideMethod of

Notification

Validated Signal (Internal)

N/A - - - - -

Validated Signal (External)

A significant safety issue is a new safety issue or validated signal considered by MAH (Sponsor) in relation toMAH’s medicines that requires urgent attention of the TGA.

Based on the seriousness and potential major impact on the benefit-risk balance of the medicine and/or on patient or public health, which could warrant prompt regulatory action and/or communication to patients and healthcare professionals.

• validated signals that may impact on the risk-benefit profile

• requests for information by comparable international regulator regarding a potential signal

Day 0 = when any personnel including third parties, vendors, or partners become aware

≤ 72 hours of Australian sponsor notification

- Indicate points of concern- Whether plan to take any

regulatory action (e.g. may include changes to RMP, amendments to label or product information document, or distribution of a Dear Healthcare Professional letter)

- If no regulatory action is planned then justification should be provided in Australian context

- Reports of significant safety issues should include:

- A description of the safety issue- Source(s) of information- Your assessment of the risk and

potential impact of the issue- Any actions you propose to take,

or justification for no further action- Any relevant documentation

Email (preferred): [email protected]

Fax: 02 6232 8392

Mail: Signal Investigation CoordinatorPharmacovigilance and Special Product Access Branch Therapeutic Goods AdministrationPO Box 100Woden ACT 2606

Australia

mailto:[email protected]

Canada CanadaThese slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s): Notifying Health Canada of Foreign Actions - Guidance Document for Industry published 20 November 2018

https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/foreign-actions-profile/guidance-document.html


Country Specific SectionCanada

Reference Term


ExamplesTimeline

StartTimeline




Serious risk of injury to Health

• Serious risks related to a new contraindication or warning

• Recalls in respect of serious risk

• The suspension or revocation of manufacturing authorizations (e.g. site licenses)

Day of the CanadianMAHnotification

Within 72 hours of CanadianMAHnotification

•The action taken by the foreign regulatory authority or the action taken by the company in the foreign jurisdiction;

•The reasons (or information about those reasons) for the action (i.e. product quality/GMP vs. product safety/adverse reaction/unsafe use);

•A description of how the issue that resulted in foreign action is relevant to the safety of product(s) sold in Canada;

•A declaration that the issue related to the action poses a serious risk to human health (see 2.2); and

•Any actions already taken in Canada by the authorization holder in response to the serious safety issue.

•Summary only - refer to guidance document

Electronic on-line form

Canada


CanadaCountry Specific SectionCanada

Reference Term


ExamplesTimeline

StartTimeline




N/A - - - - -


N/A - - - - -

Israel IsraelThese slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s): Risk Management and Drug Information Department 1) ‘Ministry of Health SOP 6 Title: Reporting Adverse Events and New Safety Information’

Update No. 3 October 20132) ‘Questions and answers regarding reporting of adverse events and new safety information

and risk management programs and Clarifications for frequently asked questions with respect to SOP 6’ published 28 December 2017

https://www.health.gov.il/hozer/DR_6E.pdf


Country Specific SectionIsrael

Reference Term


ExamplesTimeline

StartTimeline

Level of Information to

Provide



New safety information

- Prohibition, restriction or alert related to a safety problem (either existing or potential)

- Notice to the healthcare professionals or to the public issued by the manufacturer (DHCP)

Day of the IsraeliMAHnotification

3 working days

Specified for EU only:Relevant information included in the PRAC meetings e.g. DHCP, request for HA investigation

Submitted by email to the ADR mailbox


WHO definition: Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.

AEs observed outside of Israel affecting product safety and requiring attention (signal)


30 calendar days

Description of the signal,information source and background of the signal, reference in the medicinal product leaflets, company’ evaluation and actions planned in view of the signal (includingactivity planned in Israel and expected schedule


Israel


Country Specific SectionIsrael

Reference Term

Local Guidance

TerminologyExamples

Timeline Start

TimelineLevel of Information to

ProvideMethod of

Notification


WHO definition: Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously.

AEs observed outside of Israel affecting product safety and requiring attention (signal)


30 calendar days

Description of the signal,information source and background of the signal, reference in the medicinal product leaflets, company’ evaluation and actions planned in view of the signal (includingactivity planned in Israel and expected schedule


Israel

New Zealand New Zealand

These slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s): Guideline on the Regulation of Therapeutic Products in New Zealand Part 8: Pharmacovigilance Edition 2.1 December 2017

https://www.medsafe.govt.nz/regulatory/Guideline/GRTPNZ/part-8-pharmacovigilance.pdf


Country Specific SectionNew Zealand

Reference TermLocal

GuidanceTerminology

ExamplesTimeline

StartTimeline


ProvideMethod of Notification


Significant Safety Issue

• Modification or removal of an approved indication for safety reasons

• Addition of a contraindication or major changes to warnings, precautions or adverse reactions statements in the product information for safety reasons in any country where the medicine is marketed

• Investigations of safety issues or concerns of the medicine in another country by that country’s medicines regulator (e.g. European Union, EU, referral procedures for safety reasons)

• Withdrawal or suspension of availability of the medicine in another country

• Significant safety results from post-marketing clinical studies• Safety issues due to misinformation in the product information• A lack of efficacy associated with a serious suspected adverse

reaction report• Quality defect, adulteration, contamination or falsified

medicine associated with a serious adverse reaction report• Issues for which the sponsor is considering sending a Dear

Healthcare Professional (or DHCP) letter in any country where the medicine is being marketed

• Issues identified by the sponsor as a result of the sponsor’s own signal management process once assessment has been completed and actions are proposed

From the time a sponsor concludes after review of data that a significant safety issue exists, or from the time a New Zealand sponsor is advised by a parent company that a significant safety issue exists

Report as soon as possible (generally within 72 hours of awareness of the issue)

Sponsors should provide as much information as possible when reporting to Medsafe.

Sponsors must provide any additional information to assist with the evaluation of the impact of the safety issue on the benefits and risks of the medicine, when requested by Medsafe.

Medsafe’s preference is for reporting via email: [email protected]

Post: Clinical Risk Management BranchMedsafePO Box 5013Wellington 6140

Fax: + 64 (04) 819 6806

Telephone: +64 (04) 819 6800

New Zealand


Country Specific SectionNew Zealand

Reference Term

Local Guidance

TerminologyExamples Timeline Start Timeline




N/A - - - - -


Significant Safety Issue

• investigations of safety issues or concerns of the medicine in another country by that country's medicines regulator (e.g. EU referral procedures for safety reasons)

From the time a sponsor concludes after review of data that a significant safety issue exists, or from the time a New Zealand sponsor is advised by a parent company that a significant safety issue exists

Report as soon as possible (generally within 72 hours of awareness of the issue)

Sponsors should provide as much information as possible when reporting to Medsafe.

Sponsors must provide any additional information to assist with the evaluation of the impact of the safety issue on the benefits and risks of the medicine, when requested by Medsafe.

Medsafe’s preference is for reporting via email: [email protected]

Post: Clinical Risk Management BranchMedsafePO Box 5013Wellington 6140

Fax: + 64 (04) 819 6806

Telephone: +64 (04) 819 6800

New Zealand

Saudi Arabia Saudi Arabia

These slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s): 1) Saudi Food & Drug Authority Guideline on Good Pharmacovigilance Practices (GVP) Date Issued 27

May 20152) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Drug Sector, Signal Detection Additional

Guidance 3) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Drug Sector Additional Guidance Frequent

asked questions (FAQ) published July 20124) Kingdom of Saudi Arabia, Saudi Food & Drug Authority, Information about Signal of Cover Letter

https://www.sfda.gov.sa/ar/drug/resources/DocLib2/Guideline%20on%20Good%20Pharmacovigilance%20Practices%20(GVP).pdf

https://www.sfda.gov.sa/en/drug/about/sector_departments/liicenses/Documents/FAQsv10.pdf


Country Specific SectionSaudi Arabia

Reference Term


ExamplesTimeline

StartTimeline




Events that may occur, which do not fall within the definition of reportable valid ICSRs, and thus are not subject to the reporting requirements, even though they may lead to changes in the known risk-benefit balance of a medicinal product and/or impact on public health.

• Major safety concerns identified in the course of a non-interventional post-authorization study or clinical trial• Signal of a possible teratogen effect or significant hazard to public health• Safety issues published in the scientific and medical literature• Safety issues arising from the signal detection activity (see Module IX) or a new ICSR and which impact on the risk-benefit balance of the medicinal product and/or have implications for public health• Safety issues related to use outside the terms of the marketing authorization

Day 0 is day the company decides there is an ESI

Immediately

When notifying an emerging safety issue, the marketing authorization holder should describe the safety issue, the source(s) of information, any planned or taken actions with timelines, and should provide any relevant documentation available at the time of initial notification. Any further information relevant to the issue should be provided to SFDA as soon as it becomes available.

MAH should notify SFDA with all emerging safety issues immediately through NPC email ([email protected]).

Saudi Arabia


Country Specific SectionSaudi Arabia

Reference Term


ExamplesTimeline

StartTimeline




"A signal where the signal validation process of evaluating the data supporting the detected signal has verified that the available documentation contains sufficient evidence demonstrating the existence of a new potentially causal association, or a new aspect of a known association, and therefore justifies further analysis of the signal. "

Validated signals generated from MAH database: Shall validate/ assess the signal and submit signal validation/ assessment report; includes validated & refuted signals

Day 0 is day company validates the signal.

Within 90 days of detection.

- Submit completed cover letter (agency specific) and validated/assessment report.

"Validated signals generated from MAH database: Shall validate/assess the signal and submit signal validation/assessment report to the NPC via email ([email protected]) within 90 days of detection


SIgnals arising from another competent authority or the WHO

Day O is day competent authority or WHO contacts company about the signal.

Validated signals arising from other competent authoring or WHO: Shall notify SFDA within 30 calendar days of receiving validated signal.

Submit completed cover letter (agency specific) &include proposals for action to be received by national PV center. Include all information available on the competent authorities and WHO websites including but not limited to (other competent regulatory safety reviews, competent regulatory signal assessment/validation report, clinical or epidemiological studies, proposals for action).

Email: [email protected].

Saudi Arabia

Switzerland SwitzerlandThese slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s): ‘HD- Hilfsdokument Guidance document Drug Safety Signals HMV4’ published 01 January 2019

https://www.swissmedic.ch/dam/swissmedic/en/dokumente/marktueberwachung/mu/MU_HMV4/mu101_20_001d_wlarzneimittelsignalehmv4.pdf.download.pdf/MU101_20_001e_WL_Guidance_document_Drug_Safty_Signals_HMV4.pdf


Country Specific SectionSwitzerland

Reference Term


ExamplesTimeline

StartTimeline


Provide



Signal with a serious risk potential

Signals involving a serious risk potential (emerging safety issues per the definition of GVP ModuleIX).

Day zero is date the MAH classes a signal as an ESI

5 Days if measuresfor maintaining drug safety are required in the short term

-or-15 days if other risks are not explained in the product information

- All available data on the signal in a summary assessment

- Risk minimizing measures and corresponding timetable for their implementation

The signal reports can be submitted by post (CD) or via the Swissmedic Portal


Signals without a serious risk potential: with or without Implementation of changes to the productinformation

Signals with data origins from other sources besides a Health Authority (SafetyDatabase, Clinical Trial,Longitudinal Data, Literature etc.)

Day zero is closure of signal evaluation by MAH

With implementation of changes to the productInformation:Shortly after the signal is closed

Six months to submit corresponding application

Without implementation of changes to the productInformation:Include in next PBRER/PSUR

- Standard label submission process

- Details of any risk-minimizing measures

- PBRER/PSUR


Switzerland


Country Specific SectionSwitzerland*

Reference Term

Local Guidance

TerminologyExamples

Timeline Start


ProvideMethod of

Notification


Signals evaluated by foreign authorities (countries with a comparable drug regulatory authority) as signals that must be reported to the AgencyApplicable Countries

EU & EFTAcountries USA

– EU PRAC notifications– Responses to PBRER

submissions– Tracked Safety Issues

and Drug Safety Communications from the US FDA

Day zero is the date the MAH is aware of the signal from other Agency

Within 15 days of signal initiation or efficacy-related procedures and following signal closure evaluation/ procedure by the corresponding authority

– Summary of data and findings available to date regarding the signal and/or the procedure in an evaluative summary together with the expected timetable for having the signal processed by the authority concerned

– Following initial signal report, no interim report needed unless requested by Swissmedic

– Specific measures scheduled for Switzerland (including a timetable for implementation) should be defined by the MAH. If the MAH considers that a risk-minimizing measure required by a foreign authority is not appropriate for Switzerland, the MAH should clearly justify this to Swissmedic.


Switzerland

Turkey TurkeyThese slides represent a summary of country specific reporting requirements for Emerging Safety Issues and Signals based on local regulations. This information is based on current local regulations and interpretation which may change over time. MAHs should confer with their local affiliate to confirm reporting requirements prior to submission.

Reviewed Guidance(s):1) Good Pharmacovigilance Practices Guideline (GVP) Module VII - Signal Management, THE

MEDICINES AND MEDICAL DEVICES AGENCY OF TURKEY published 20 December 20162) Turkish Ministry of Health, Turkish Medicines and Medical Devices Agency (TUFAM) Safety

Notification Circular (Number:46977249-510.01)

http://farmakovijilansdernegi.org/files/2016.12.20_Guideline_on_Good_Pharmacovigilance_Practices_Module_VII-Signal_management.pdf


Country Specific SectionTurkey

Reference Term


ExamplesTimeline

StartTimeline


Provide



Signal with a serious risk potential

Signals involving a serious risk potential (emerging safety issues per the definition of GVP ModuleIX).

Receipt of the referred information

15 days

Reports should include a clear description of the safety concern, outcome of action taken in foreign territory and list any pertinent actions that need to be taken in Turkey. These reports should be made even when the marketing authorization holder intends not to take any action with respect to the safety concern.

Electronic Gateway/Hard-copy


N/A - - - - -

Turkey


Country Specific SectionTurkey

Reference Term

Local Guidance

TerminologyExamples

Timeline Start


ProvideMethod of

Notification


Signals raised by EMA or FDA and taking the necessary actions in line with PRAC, FAERS and Periodic Report Assessments

Requests for additional information from PRAC, Periodic Assessment Report requests or posts of signals on FAERS

When received or issued from the requesting agency

15 days of receipt from agency

Reports should include a clear description of the safety concern, and list any pertinent actions that need to be taken in Turkey. These reports should be made even when the marketing authorization holder intends not to take any action with respect to the safety concern.

Electronic Gateway

Turkey