Mircea Ciuca, MD

Global Head Medical & Clinical Drug Safety

Disclaimer

The views and opinions expressed in this presentation are solely those of the presenter and do not necessarily reflect those of Vifor, or any of its affiliated organizations.

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Objectives

Draft GVP Module IX (overview of

changes)

New terminology (EVDAS, eRMR)

MAH's obligations - access to EV,

training, changes to current procedures

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Introduction

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Introduction

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Signal Management

Introduction

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Introduction

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Benefit-riskmanagement

MHRA GPvP Symposium 02 September 2016

Draft revision Module IX GVP

First revision after 2012 implementation of new PV legislation

Released for public consultation August 2016

Expected to be effective Q1 2017

New elements introduced in the signalmanagement process

*Guideline on good pharmacovigilance practices (GVP). Module IX –Signal management EMA/827661/2011 Rev 1* DRAFT for public consultation 04AUG2016

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Draft revision Module IX GVP Revised definition and process for emerging safety issues,

previously addressed in GVP Module VI Streamlined information on scientific aspects of signal

management Statistical aspects now addressed in Addendum I Clarifications on terminology, roles and responsibilities, and

processes Criteria for access by marketing authorisation holders to case

narratives held in EudraVigilance Updated guidance on the periodicity of monitoring of

EudraVigilance data Procedural options for signals validated by marketing

authorisation holders

*Guideline on good pharmacovigilance practices (GVP). Module IX –Signal management EMA/827661/2011 Rev 1* DRAFT for public consultation 04AUG2016

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Draft revision Module IX GVP Definitions

Scientific aspects

Steps in the process

Timelines

Communication

*Guideline on good pharmacovigilance practices (GVP). Module IX –Signal management EMA/827661/2011 Rev 1* DRAFT for public consultation 04AUG2016

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IX.C.3.1 Emerging safety issues (definition)

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GVP Module IX – Signal management (rev1)

Module VI – rev 1 - VI.C.2.2.6 Module IX - rev1 – IX.A.1 Terminology

Events may occur, which do not fall within the definition ofreportable valid ICSRs, and thus are not subject to the reportingrequirements, even though they may lead to changes in the knownrisk-benefit balance of a medicinal product and/or impact onpublic health. Examples include:• major safety findings from a newly completed non-clinical study;• major safety concerns identified in the course of a non-interventional post-authorisation study or of a clinical trial;• signal of a possible teratogen effect or of significant hazard topublic health;• safety issues published in the scientific and medical literature;• safety issues arising from the signal detection activity (seeModule IX) or emerging from a new ICSR and which impact on therisk-benefit balance of the medicinal product and/or haveimplications for public health;safety issues related to the use outside the terms of the marketingauthorisation;• safety issues due to misinformation in the product information;• marketing authorisation withdrawal, non-renewal, revocation orsuspension outside the EU for safety-related reasons;• urgent safety restrictions outside the EU;• safety issues in relation to the supply of raw material;• lack of supply of medicines.

A safety issue considered by a marketingauthorisation holder in relation to an authorisedmedicinal product under its responsibility torequire urgent attention of the competent authoritybecause of the potential major impact on the risk-benefit balance of the product and/or on patient orpublic health, that could warrant prompt regulatoryaction and communication to patients andhealthcare professionals (see also GVP Module VIand IX.C.3.1.).

IX.C.3.1 Emerging safety issues (process)

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GVP Module IX – Signal management (rev1)

Module VI – rev 1 - VI.C.2.2.6 Module IX. - rev 1 - C.3.1

Reportable to :P-PV-emerging-safety-issue@ema.europa.eu

Should be reported immediately whenbecoming aware of them.

The document should indicate the points of concern and the actions proposed in relation to the marketing application/authorisation for the concerned medicinal product.

Reportable to :P-PV-emerging-safety-issue@ema.europa.eu

This should be reported within 2 working days of becoming aware of the issue.When notifying an emerging safety issue, the marketing authorisation holdershould describe the safety concern, the source(s) of information, any plannedor taken actions, and should provide any relevant documentation. In suchinstances, a standalone signal notification (see IX.C.3.4.) is not required.

Upon being notified of an emerging safety issue, national competentauthorities and/or the Agency as appropriate should promptly assess theurgency and potential impact of the issue and agree on appropriate next stepsand the potential regulatory procedure to address the matter raised (seeEuropean Union Regulatory Incident Management Plan for Medicines forHuman Use).

In order to ensure its effectiveness, the system should not be saturated by thetransmission of less urgent information. Marketing authorisation holdersshould only communicate as emerging safety issues those safety concernswhich meet the definition provided in IX.A, i.e. whose urgency andseriousness cannot permit any delay in handling, for instance validated signalsthat cannot wait up to 30 days for confirmation by Member States.

IX.A.1 Terminology

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GVP Module IX – Signal management (rev1)

Annex I – Rev3 Module IX - rev1 – IX.A.1 Terminology

SignalInformation arising from one or multiple sources, including observations and experiments, whichsuggests a new potentially causal association, or a new aspect of a known association between an intervention and an event or set of related events, either adverse or beneficial, that is judged to be of sufficient likelihood to justify verificatory action [IR 520/2012 Art 19(1)].

For the purpose of monitoring data in the EudraVigilance database, only signals related to an adverse reaction shallbe considered [IR 520/2012 Art 19(1)].

For the purpose of Section 16.2 of the periodic benefit-risk evaluation report, signals relate to adverse effects (seeAnnex IV, ICH-E2C(R2) Guideline)

SignalInformation arising from one or multiple sources,including observations and experiments, whichsuggests a new potentially causal association, or a newaspect of a known association between an interventionand an event or set of related events, either adverse orbeneficial, that is judged to be of sufficient likelihoodto justify verificatory action [IR Art 19(1)].New aspects of a known association may includechanges in the frequency, duration, severity oroutcome of the adverse event.For the purpose of monitoring data in theEudraVigilance database (also referred to as‘EudraVigilance’), only signals related to an adversereaction shall be considered [IR Art 19(1)].A signal often relates to all medicinal productscontaining the same active substance, includingcombination products. Certain signals may only berelevant for a particular medicinal product or in aspecific indication, strength, pharmaceutical form orroute of administration whereas some signals mayapply to a whole class of medicinal products.

IX.A.1 Terminology

Amended definitions (vs GVP Annex I)

- Signal management process

- Signal validation

New definitions (vs GVP Annex I)

- Signal detection

- Signal confirmation

- Signal analysis and prioritisation by PRAC

- Signal assessment by PRAC

- Lead MS for signal assessment

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GVP Module IX – Signal management (rev1)

Draft revision Module IX GVP Definitions

Scientific aspects

Steps in the process

Timelines

Communication

*Guideline on good pharmacovigilance practices (GVP). Module IX –Signal management EMA/827661/2011 Rev 1* DRAFT for public consultation 04AUG2016

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Addendum 1- Methodological Aspects of Signal Detection from Spontaneous Reports of Suspected Adverse Reactions

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GVP Module IX – Signal management (rev1)

Addendum 1 - General concept

- Should allow routine signal detection

- Based on the concept of Drug-Event Combinations (DECs)

- Proposed statistical approach : Disproportionate reporting

- Specific implementation in Eudravigilance is described in the Guidance «Screening for Adverse Drug Reactions in Eudravigilance» (available in Q4 2016)

- The tools and their use will be described in separate user manuals (User Manual of the electronic Reaction Monitoring Report and EVDAS User Manual).

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GVP Module IX – Signal management (rev1)

Factors that may affect the performance of signal detection systems :

* MedDRA hierarchy :

Preferred Term (PT), has been shown to be a good choice in terms of sensitivity and positive predictive value,

A subset of MedDRA terms judged to be important medical events (IMEs) is considered a useful tool in statistical signal detection,

Other levels of MedDRA terms (HLT, SMQ) may be used for targetedmonitoring of potential risks,

Use of synonyms may be appropriate

The definition of a synonym in this context is the pragmatic one that two PTs are considered synonyms if it is reasonable to suppose that a primary reporter of a suspected adverse reaction, presented with a single patient and without a specialist evaluation, would not necessarily be able to decide which term to use.

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GVP Module IX – Signal management (rev1)

Addendum 1 – Methods aimed at specific groups of events

• Designated Medical Events

It is recommended that these designated medical events (DME) are drawn to the attention of signal detection assessors irrespective of any other statistical methods used and that they are prioritised for clinical review.

• Serious events

Due to their impact, serious events should be prioritised in Signal Detection.

Complementary to the creation of a list of DMEs and in addition to the use of lists of IMEs, a simple approach to such prioritisation is to highlight new ICSRs in which a death is reported and to give separate counts of those ICSRs for each DEC.

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GVP Module IX – Signal management (rev1)

Addendum 1 – Methods aimed at specific patients populations

When ICSR databases are sufficiently large :

- Paediatric populations

- Geriatric populations

Addendum 1 – Methods aimed at underlying causal processes

In addition to the description of the clinical manifestation of the suspected adverse reaction, ICSRs may include information on the potential causal mechanisms for the reaction. This applies to the situation of Abuse, misuse, overdose, medication error or occupational exposure.

Thus, it is recommended that the numbers of ICSRs with the respective MedDRA codes should be displayed for each DEC in signal detection listings.

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GVP Module IX – Signal management (rev1)

Draft revision Module IX GVP Definitions

Scientific aspects

Steps in the process

Timelines

Communication

*Guideline on good pharmacovigilance practices (GVP). Module IX –Signal management EMA/827661/2011 Rev 1* DRAFT for public consultation 04AUG2016

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IX.C.2.1 Principles for access (Eudravigilance Data)

Prior to requesting access to case narratives, the following criteria should be met:

• The review of the electronic reaction monitoring report suggests a signal (see IX.A.);

• To the best of the marketing authorisation holder’s knowledge, the signal is not addressed in the product information of any medicinal product authorised in the EU with the concerned active substance (see also IX.C.3.4.);

• Based on the information published on the European medicines web-portal (see IX.C.8.), the signal was not recently addressed by (a) competent authority(ies) of (a) Member State(s) or by PRAC

See European Medicines Agency Policy on Access to EudraVigilance data for Medicinal Products for Human Use – EMA/759287/2009 rev 2 of 17 Dec 2015.

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GVP Module IX – Signal management (rev1)

IX.C.2.2 Periodicity of monitoring

The appropriate frequency of monitoring of EudraVigilance data may vary with the accumulation of knowledge on the risk profile of a given active substance or medicinal product, taking into account, for example:

• time since first authorisation;

• patient exposure;

• potential risks and missing information documented in the RMP;

• PSUR submission frequency;

• any safety concern of interest in specific situations (e.g. vaccination campaigns).

Thus :

- A 2 weeks interval for products on additional monitoring list unless the sole reason for inclusion on the list is the request of a post-authorisation safety study (PASS),

- A monthly monitoring of EudraVigilance data is routinely applied by the Agency for other active substances,

- It is recommended that the interval between reviews of EudraVigilance data should not exceed 6 months.

- Each organisation should document the frequency of their monitoring of EudraVigilance data06/03/2017 24

GVP Module IX – Signal management (rev1)

The evaluation of the evidence supporting a signal may involve several rounds of expert discussions and different levels of decision-making, within individual organisations. This may result in various decisions, such as:

• closing the signal, when the available data do not support a causal relationship (the signal may be re-opened at a later stage if new evidence arises) or when there is sufficient information on the association in the product information;

• monitoring the signal by reviewing new information from ICSRs or the scientific literature at appropriate time intervals to determine whether the new data are supportive of a causal relationship;

• proposing actions such as changes to the product information by means of a variation, if there is sufficient evidence of a causal relationship.

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GVP Module IX – Signal management (rev1)

IX.B.4 Signal prioritisation

2 new concepts added to help prioritisation :

• the expected extent of the regulatory intervention (e.g. addition of adverse reactions, warnings, contraindications, additional risk minimisation measures, suspension, revocation);

• whether the signal is likely to apply to other substances of the same class of medicinal products.

GVP Module IX – Signal management (rev1)

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IX.C.1 Roles and responsibilities

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GVP Module IX – Signal management (rev1)

IX.C.1 Roles and responsibilities

PRAC List of signalshttp://www.ema.europa.eu/ema/index.jsp?curl=/pages/regulation/document_listing/document_listing_000375.jsp

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GVP Module IX – Signal management (rev1)

New terminology EudraVigilance Data Analysis System (EVDAS)

Module allowing data mining in Eudravigilance

Electronic reaction monitoring report (eRMR)

Output from EVDAS

European Pharmacovigilance Issues Tracking Tool (EPITT)

Signal tracker

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New terminology

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http://www.ema.europa.eu/ema/index.jsp?curl=pages/about_us/document_listing/document_listing_000279.jsp&mid=WC0b01ac05800b6f03

New terminology

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New terminology

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http://www.ema.europa.eu/docs/en_GB/document_library/Work_Instruction_-_WIN/2012/09/WC500132805.pdf

New terminology

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New terminology

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3. ‘Drug info’: this worksheet is automatically updated every 6 months. It is populated with the most used information related to a given active substance,

New terminology

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MAH’s obligations

Access to Eudravigilance (new systems)

Availability of dedicated resources

Appropriate training of people involved in signal management

4200 MAHs (see EMA Annual activity report2015)

Adaptation of internal procedures

Adaptation of SDEA with partners

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MAH’s obligations

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Additonal resources The following documents provide additional guidance

relevant to signal management:

Report of CIOMS Working Group VIII on Practical Aspects of

Signal Detection in Pharmacovigilance

SCOPE Work Package 5 – Signal Management - Best Practice

Guidance

EMA Questions & Answers on Signal Management

Screening for Adverse Drug Reactions in EudraVigilance (Dec2016)

IMI-PROTECT - Pharmacoepidemiological Research on

Outcomes of Therapeutics by a European ConsorTium (Sep2016)

WEB-RADR - use of mobile technologies in pharmacovigilance to

Recognise Adverse Drug Reactions (RADR). 3/6/2017

Take home message

Pharmacovigilance legislations are continuously evolving globally

New methodologies are adopted

Signal management has a great impact on continuous benefit-risk management

Need for a cross-functional approach

Robust process and documentation need to be in place

Heavily scrutinized in audits/inspections

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