Industry Industry Industry Industry pharmacovigilancepharmacovigilancepharmacovigilancepharmacovigilance practicespracticespracticespractices

Symposium: ‘’Current Regulatory Aspects Symposium: ‘’Current Regulatory Aspects Symposium: ‘’Current Regulatory Aspects Symposium: ‘’Current Regulatory Aspects in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and in the Field of Medicinal Products and Medical Devices in Human and Veterinary Medical Devices in Human and Veterinary Medical Devices in Human and Veterinary Medical Devices in Human and Veterinary Medicine’’, 14Medicine’’, 14Medicine’’, 14Medicine’’, 14thththth &&&& 15151515th th th th November 2014, November 2014, November 2014, November 2014, VršacVršacVršacVršac

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Roche Croatia Roche Croatia Roche Croatia Roche Croatia

Innovative global pharmaceutical industryInnovative global pharmaceutical industryInnovative global pharmaceutical industryInnovative global pharmaceutical industry…and all stakeholders……and all stakeholders……and all stakeholders……and all stakeholders…

PATIENTPATIENTPATIENTPATIENT

PhysicianPhysicianPhysicianPhysician

PharmacistPharmacistPharmacistPharmacist

NurseNurseNurseNurseMinistryMinistryMinistryMinistry ofofofof

HealthHealthHealthHealth

Health Health Health Health insuranceinsuranceinsuranceinsurancefoundfoundfoundfound

PATIENTPATIENTPATIENTPATIENT

Health Health Health Health AuthorityAuthorityAuthorityAuthority

Pharma Pharma Pharma Pharma IndustryIndustryIndustryIndustry

AgencyAgencyAgencyAgency for for for for MedicinalMedicinalMedicinalMedicinalProductsProductsProductsProducts

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Our priority is to make sure that the therapeutic benefits of the medicine outweigh the throughout the lifecycle of a medicine.

Innovative global pharmaceutical industryInnovative global pharmaceutical industryInnovative global pharmaceutical industryInnovative global pharmaceutical industry…and all stakeholders……and all stakeholders……and all stakeholders……and all stakeholders…

Patient safety is of paramount importance to us. Patient safety is of paramount importance to us. Patient safety is of paramount importance to us. Patient safety is of paramount importance to us.

We should ensure that use of (innovative) medicines is safe.We should ensure that use of (innovative) medicines is safe.We should ensure that use of (innovative) medicines is safe.We should ensure that use of (innovative) medicines is safe.

Focus on Focus on Focus on Focus on PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance

First of all, How do we work?

UNDER LEGAL FRAMEWORKUNDER LEGAL FRAMEWORKUNDER LEGAL FRAMEWORKUNDER LEGAL FRAMEWORK: local, global (e.g. EU legislation)

Focus on Focus on Focus on Focus on PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance

CROSS FUNCTONALCROSS FUNCTONALCROSS FUNCTONALCROSS FUNCTONAL: safety, regulatory, quality…

Focus on Focus on Focus on Focus on PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance

EMA webpages

‘’ The new The new The new The new pharmacovigilancepharmacovigilancepharmacovigilancepharmacovigilance legislation, which started to come legislation, which started to come legislation, which started to come legislation, which started to come into effect in July 2012, into effect in July 2012, into effect in July 2012, into effect in July 2012, was the biggest change to the was the biggest change to the was the biggest change to the was the biggest change to the regulation of human medicines in the European Union (EU) since regulation of human medicines in the European Union (EU) since regulation of human medicines in the European Union (EU) since regulation of human medicines in the European Union (EU) since 1995.1995.1995.1995. It had significant implications for applicants and holders It had significant implications for applicants and holders It had significant implications for applicants and holders It had significant implications for applicants and holders of EU marketing of EU marketing of EU marketing of EU marketing authorisationsauthorisationsauthorisationsauthorisations.’’.’’.’’.’’

Adoption of new Directive and Regulation new Directive and Regulation new Directive and Regulation new Directive and Regulation by the European Adoption of new Directive and Regulation new Directive and Regulation new Directive and Regulation new Directive and Regulation by the European Parliament and Council of Ministers in December 2010, bringing about significant changes in the safety monitoring of medicines across the EU:

• Directive 2010/84/EU

• Regulation (EU) No 1235/2010

• Regulation (EU) No 1027/2012 (applicable since 5 June 2013)

• Directive 2012/26/EU (applicable since 28 October 2013)

Focus on Focus on Focus on Focus on PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance

EMA webpages…

VolumeVolumeVolumeVolume 9A9A9A9A

‘’ Practical measures to facilitate the performance of pharmacovigilance in accordance with the legislation are available in the guideline on guideline on guideline on guideline on GGGGoodoodoodood pharmacopharmacopharmacopharmacoVVVVigilanceigilanceigilanceigilance PPPPracticesracticesracticesractices (GVP)(GVP)(GVP)(GVP). GVP apply to marketing-authorisation holders, the European Medicines Agency and medicines regulatory authorities in EU Member States, and cover medicines authorised centrally via the Agency as well as and cover medicines authorised centrally via the Agency as well as medicines authorised at national level.’’

GVP modules I to XVIGVP modules I to XVIGVP modules I to XVIGVP modules I to XVI cover major pharmacovigilance processes.

The chapters on productchapters on productchapters on productchapters on product---- or populationor populationor populationor population----specific considerationsspecific considerationsspecific considerationsspecific considerations are currently under development. (public consultation is ongoing for P II Biological medicinal products )

Guidelines should be followed!Guidelines should be followed!Guidelines should be followed!Guidelines should be followed!

GVP GVP GVP GVP ModulesModulesModulesModules

I I I I PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance systems and their quality systemssystems and their quality systemssystems and their quality systemssystems and their quality systems

II II II II PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance system master filesystem master filesystem master filesystem master file

III III III III PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance inspectionsinspectionsinspectionsinspections

IV IV IV IV PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance auditsauditsauditsaudits

V V V V Risk Risk Risk Risk management systemsmanagement systemsmanagement systemsmanagement systems

VI VI VI VI Management Management Management Management and reporting of adverse reactions to medicinal and reporting of adverse reactions to medicinal and reporting of adverse reactions to medicinal and reporting of adverse reactions to medicinal productsproductsproductsproducts

VII VII VII VII Periodic Periodic Periodic Periodic safety update reportsafety update reportsafety update reportsafety update report

VIII VIII VIII VIII PostPostPostPost----authorisation authorisation authorisation authorisation safety studies safety studies safety studies safety studies

IX IX IX IX Signal Signal Signal Signal managementmanagementmanagementmanagement

X X X X Additional monitoringAdditional monitoringAdditional monitoringAdditional monitoring

GVP GVP GVP GVP ModulesModulesModulesModules

XI Public participation in pharmacovigilance (public consultation 4Q 2014/1Q 2015)

XII Continuous pharmacovigilance, ongoing benefit-risk evaluation, regulatory action and planning of public communication (public consultation 4Q 2014)

XIII (Incident Management � Module XIII on incident management

is no longer under development. All topics originally intended to be covered in this module are now to be included in module XII.)be covered in this module are now to be included in module XII.)

XIV International cooperation (public consultation 1/2Q 2015)

XV XV XV XV Safety Safety Safety Safety communicationcommunicationcommunicationcommunication

XVI XVI XVI XVI RiskRiskRiskRisk----minimisation minimisation minimisation minimisation measures: selection of tools and measures: selection of tools and measures: selection of tools and measures: selection of tools and effectiveness effectiveness effectiveness effectiveness indicatorsindicatorsindicatorsindicators

+ annexes

PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance processesprocessesprocessesprocesses

Nowadays we do not just report and processing adverse events/adverse drug reactions but we are deeply involved in and do we are deeply involved in and do we are deeply involved in and do we are deeply involved in and do also:also:also:also:

- Signal detectionSignal detectionSignal detectionSignal detection

- Risk Management PlanRisk Management PlanRisk Management PlanRisk Management Plan

- Safety CommunicationSafety CommunicationSafety CommunicationSafety Communication

- Study and Program OversightStudy and Program OversightStudy and Program OversightStudy and Program Oversight

- Aggregate ReportsAggregate ReportsAggregate ReportsAggregate Reports

- PV QualityPV QualityPV QualityPV Quality

- PV AgreementsPV AgreementsPV AgreementsPV Agreements

- Labeling and PV Commitments Labeling and PV Commitments Labeling and PV Commitments Labeling and PV Commitments

Signal detectionSignal detectionSignal detectionSignal detection

DATA SOURCES: data from the clinical and safety database, pre-clinical data, Phase 1 data in healthy volunteers or patients, spontaneous reports, internet or social media sites created or sponsored by the Company, Registries, Epidemiological databases, health care databases

Signal Detection Plan

RMPRMPRMPRMPRisk management activitiesRisk management activitiesRisk management activitiesRisk management activities

We want to have a safe treatment as much as possibleWe want to have a safe treatment as much as possibleWe want to have a safe treatment as much as possibleWe want to have a safe treatment as much as possible… … … … wewewewe needneedneedneed to to to to createcreatecreatecreate a Plan (a Plan (a Plan (a Plan (RiskRiskRiskRisk Management Plan)Management Plan)Management Plan)Management Plan)

Risk Minimization Activities are present in all industries not just pharma!

The aim of a risk minimization activity is to reduce the probability or severity of an adverse reaction. probability or severity of an adverse reaction.

- routine risk minimization (e.g., product labeling)

- additional risk minimization activities (e.g., professional or patient communications/educational materials).

RMPRMPRMPRMPEducationalEducationalEducationalEducational MaterialsMaterialsMaterialsMaterials

• Approved by national Agencies

Have we distributed the right educational material to relevantHCPs and patients with valid outcome?

We need to monitor and measure effectiveness, the process (distribution) and outcome.

Safety CommunicationSafety CommunicationSafety CommunicationSafety Communication

- Report in a timely manner

- Providing timely, evidence-based information on the safe and effective use of medicines and effective use of medicines • Dear Healthcare Professional Communication (DHPC)• Dear Investigator Letter (DIL) • To Whom it May Concern Letter (TWIMCL) • Safety Queries• Local/global crisis management

• MEDIA…The media is also a target audience for safety communication!

The way safety information is communicated through the media will influence the public perception

Study and Program OversightStudy and Program OversightStudy and Program OversightStudy and Program Oversight

Organised data collection

Solicited reports (classified as study reports + causalityassessment)

• ClinicalClinicalClinicalClinical – clinical trials, non interventional studiesincluding non-interventional post-authorisation safety studies

• MarketingMarketingMarketingMarketing – Market Research Programs, Patient Support• MarketingMarketingMarketingMarketing – Market Research Programs, Patient SupportPrograms

- Local activities related to ongoing studies and programs can potentially trigger receipt of safety information

- One of the key responsibilities of the Local SafetyResponsible is safety oversight of these activities

- Safety relevant activities may be outsourced to serviceprovider (e.g.CRO) - appropriate reporting processes should be set up

Aggregate ReportsAggregate ReportsAggregate ReportsAggregate Reports

• Periodic Safety Update Reports (PSURs)/ Periodic Benefit-Risk Evaluation Reports

(PBRERs)

• Development Safety Update Reports (DSURs)

• Six Monthly Suspected Unexpected Serious Adverse Reactions Line Listing (SSRs

Each report must be compiled, reviewed and distributed to the required Each report must be compiled, reviewed and distributed to the required Regulatory Authorities according to a schedule.

The marketing authorisation holder should continuously evaluate continuously evaluate continuously evaluate continuously evaluate whether any revision of the reference product information/reference safety information is needed whenever new safety information is obtained during the reporting interval and ensure that significant changes made over the interval are described in PSUR section 4 (“Changes to the reference safety information”) and where relevant, discussed in PSUR section 16 (“Signal and risk evaluation”).

PV QualityPV QualityPV QualityPV Quality

• QualityQualityQualityQuality is is is is the way of we do the way of we do the way of we do the way of we do thingsthingsthingsthings. . . . Maintain the high quality Maintain the high quality Maintain the high quality Maintain the high quality standards.standards.standards.standards.

• Safety Quality Management system should be in a place

• It is necessary to establish responsibilities and procedures to control

and enhance Drug Safety processes in order to maintain compliance.

Think about…

Inspection Readiness (keep up to date CV, job description, training records)

Pharmacovigilance Business Continuity Management Plan (PV BCM Plan)

-regulatory (EMA) requirement to train and test the BCM plan

Incident

PV AgreementsPV AgreementsPV AgreementsPV Agreements

• Marketing Authorization Holder (MAH) for its products has the responsibility to collect all Adverse Event (AE) reports, including those which arise from commercial Arrangements (e.g. Distribution Agreement, Co-Promotion Agreement, License and Supply Agreement…)

• The Pharmacovigilance activities documented in the PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance Agreement Agreement Agreement Agreement enables the Company to meet its worldwide regulatory safety reporting obligations and Monitor/optimize the safety risk management of its products.Monitor/optimize the safety risk management of its products.

Labeling and PV Commitments Labeling and PV Commitments Labeling and PV Commitments Labeling and PV Commitments

• LabelsLabelsLabelsLabels::::- Local implementation of safety related Core Data Sheet changes and safety

sectionsof updated local labels prior to submission to the Regulatory

Authority- Investigator Brochure (IB) for clinical trials (The CDS is reviewed and

updated periodically in line with IB updates)

Transfer of CDS information Safety VariationTransfer of CDS information Safety Variation

PV PV PV PV Commitments Commitments Commitments Commitments

• The PV commitments PV commitments PV commitments PV commitments are any commitments made to Regulatory Authorities regarding the collection and submission of benefit and/or safety data/information that can have an impact on the benefit-risk balance of the marketed product in the licensed indication, beyond the obligation for spontaneous reporting of adverse events, and the periodic reporting of safety data defined by regulatory requirements.

• Marketing Authorization Holders are required to continuously monitor continuously monitor continuously monitor continuously monitor these commitments and ensure adherence.commitments and ensure adherence.

• EvidenceEvidenceEvidenceEvidence of the continuous monitoring of PV commitment activity must be provided in the Pharmacovigilance System Master File (PSMF).

PharmacovigilancePharmacovigilancePharmacovigilancePharmacovigilance System Master File (PSMF) System Master File (PSMF) System Master File (PSMF) System Master File (PSMF)

• Provides oversight and detailed description of the entire PV system

• Supports and documents compliance with PV requirements• Comprehensive tool for regulatory authorities/inspectors to

oversee the PV system

The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency The regulators are demanding full transparency via the PSMFvia the PSMFvia the PSMFvia the PSMF

Increased immediate external exposure = no time to react.

Therefore, ALL databases and lists must be upTherefore, ALL databases and lists must be upTherefore, ALL databases and lists must be upTherefore, ALL databases and lists must be up----totototo----date at all date at all date at all date at all times! times! times! times!

Key words to keep PV chain strongKey words to keep PV chain strongKey words to keep PV chain strongKey words to keep PV chain strong

# patients # adverse events# patients # adverse events# patients # adverse events# patients # adverse events

Education and training

Quality Check

and Reconciliation

Protection of public health

Compliance

Transparency

Cooperation

Education and training

Tracking

Communication

Doing now what patients need nextDoing now what patients need next

SourcesSourcesSourcesSources

EMA webpages

Roche internal documents

Doing now what patients need nextDoing now what patients need next