From Signal Detection to Safety Assessment and Selection

3/13/2017

HEALTH CANADA’S PHARMACOVIGILANCE ACTIVITIES FOR MARKETED PHARMACEUTICAL PRODUCTS: FROM SIGNAL DETECTION TO SAFETY ASSESSMENTS AND SELECTION OF RISK MITIGATION STRATEGY

Nadiya Jirova M.Sc. Marketed Pharmaceuticals and Medical Devices Bureau Marketed Health Products Directorate Health Canada CAPRA meeting, January 2017

Outline

Overview of Pharmacovigilance at MHPD Signal Detection • Signal Detection Working Groups • Prioritization of safety issues Signal assessment • Work process • Sources of data • Considerations • Options • Recommendations • Examples of Signal Assessments Summary Safety Reviews http://www.hc-sc.gc.ca/ewh-semt/pubs/occup-travail/balancing_six-equilibre_six/index-eng.phpQuestions 2

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MPMDB within Health Canada

Health Canada

Health Products Branches and Food Branch

Directorates Marketed Health Products Directorate

Marketed Pharmaceuticals Bureaux and Medical Devices Bureau

Lifecycle Approach to Product Vigilance

MPMDB activities span the lifecycle of a Health Product in Canada

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MPMDB Activities within MHPD

Medication PSUR Policy InfoWatch Complementary Advertising Incidents Review Development Activities

Signal Signal Risk RMP Review Detection Assessment Minimization review Activities

AE Risk Comms Risk Comms Risk Comms Risk Comms Basic Reg. collection Pharmac. Biologics NHPs Med. Dev. Activities

Pharmacovigilance at MHPD

Signal detection working groups • Safety literature • Canada Vigilance database • Foreign agency actions • Info submitted by MAH • TPD Bureau requests Other Emerging safety issues Possible outcomes/ risk mitigation strategies: Signal detection and labelling, risk Assessment Prioritization communication, publication to raise awareness and stimulate reporting, etc. Do we need to investigate it further?

Is it a signal? (validation step) • Possible causal relationship • Previously unknown or incompletely documented • Generate sufficient suspicion of an association • Warrant further investigation 6

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SIGNAL DETECTION ACTIVITIES AT MPMDB

WHO Definition of a Safety Signal

“Reported information on a possible causal relationship between an adverse event and a drug, the relationship being unknown or incompletely documented previously. Usually more than a single report is required to generate a signal, depending upon the seriousness of the event and the quality of the information”

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Characteristics of a Signal • A working hypothesis

• May point to unknown (or new aspects of a known) adverse reaction associations for: • Old or new drugs • Drug-drug interactions • General or restricted group populations

• Not a proof of causal relationship and require further evaluation

• May or may not lead to regulatory action

Overview of Pharmacovigilance Activities Note: RMPs “changed the game” Sources Signal Risk management somewhat identification Scanning: Other regulatory actions: •Media Market withdrawal, •Medical and scientific labelling change, RMPs literature Risk Management Int. Regulatory Agencies: Signal Detection •Databases Strategy •Warnings/Advisories •Pharmacovigilance Forums Manufacturer: •Phase IV studies •PSURs Risk communication •Registries Prioritization •RMPs and related activities •Public Advisory Health Canada: •Health Professional Communication •CanadaVigilance & Public Communication •WHO •Notice to Hospitals Evaluation •Pre-market safety •Product Information Update information •Media •InfoWatch ------Signal evaluation Drug Safety & •MedEffect/MedEffet Effectiveness Network •It’s Your Health

MONITORING 11

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Signal Detection Working Groups (SD-WG) • Four working groups at MPMDB based on signal sources: • Safety Literature Scanning Working Group • Signal Identification from Foreign Agencies Working Group • Market Authorization Holder Submitted Information Working Group • Pharmaceutical Program Signal Detection Working Group

• Each group consists of a blend of scientific evaluators and medical officers.

Literature scanning at MPMDB

. About 8500+ medical journals are weekly being scanned by Health Canada library

. About 949 literature / media article screened by evaluators annually

. If related to an active ingredient combined to a medical device, then it is assigned to the appropriate group according to the issue at stake (e.g., testosterone pump)

. 85% of items dismissed without further group discussion (predominantly due to sufficient labelling)

. Remaining items are brought for discussion (i.e., 6 articles per meeting, most items are dismissed due to insufficient evidence to support a signal or methodological issues )

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Signal IdentificationSignal Identification from fromForeign Foreign Agencies Agencies WG

Communications issued by the following are systematically screened:

• WHO (World Health Organization) • FDA (Food and Drug Administration), USA • EMA (European Medicines Agency) • ANSM (Agence nationale de sécurité du médicament et des produits de santé), France • MHRA (Medicines and Healthcare products Regulatory Agency), U.K. • TGA (Therapeutic Goods Administration), Australia • Medsafe (Medicines and Medical Devices Safety Authority), New Zealand • SwissMedic (Swiss Agency for Therapeutic Goods) • PMDA (Pharmaceutical and Medical Devices Agency), Japan

International Collaboration in Signal Detection

Bilateral arrangements with foreign regulators: • United States, Europe, Singapore, Switzerland, Australia, New Zealand, etc. (ad-hoc regulatory information sharing)

SignalEngaged Assessments in multilateral 130 initiatives:days Serious• Heads Adverse of Agency Reactions International 15 days Pharmacovigilance Work sharing Group (Canada, Australia, Singapore, Switzerland) • Teleconference (Canada, United States, Australia, New Zealand) for signal detection • World Health Organization (WHO) Uppsala Collaborating Centre: adverse drug reaction monitoring

Participates in networks of interest: • European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, Pharmacoepidemiological Research on Outcomes of Therapeutics, and U.S. FDA MedSUN Sentinel Initiative

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Market Authorization Holder Submitted Information • Signal detection based on review of safety information submitted by the MAH • Preliminary screening of data to determine if in depth review is warranted • Identification of important updates to CCDS

Scope of Activities • MAH (submitted directly to MHPD) e.g. ‘ad hoc’ information (e.g. study results, PSURs, position statements …) solicited Periodic Safety Update Reports (PSURs) (e.g. follow-up to an RMP or other review) and solicited study reports and any other information requested by MPMDB

• MAH (forwarded to MHPD internally) e.g. information from TPD (unsolicited RMPs submitted with SNDS) or from another signal detection working group

Number of PSURL1 completed per year

FY 2011‐2012 FY 2012‐2013 FY 2013‐2014 FY 2014‐2015 FY 2015‐2016 # of PSUR L1 completed 75 164 167 149 133

Pharmaceutical Program Signal Detection WG

• Sources of information:

• ad hoc safety information and recommendations provided by pre-Marketing review bureaux. Safety information may originate from a Notifiable Change (NC) submission, a New Drug Submission (NDS) or a Supplemental New Drug Submission (SNDS).

• Safety information originating from other stakeholders e.g. Drug Safety and Effectiveness Network (DSEN) or Canadian Network for Observational Drug Effect Studies (CNODES)

• Safety information originating from the Canadian Agency for Drugs and Technologies in Health (CADTH).

• Additional activities: screening of NCs and SNDs submissions for potential risk communication issuance including InfoWatch updates.

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Considerations during signal detection

Corroboration from other sources? Publications on same issue, actions from other regulatory agencies, Canadian or international cases in Pharmacovigilance databases, class effect, etc.

Potential impact on clinical practice Anticipated change in prescribing behaviour (e.g., increased frequency or severity of AE, potential for risk management, shift in benefit-risk profile, etc.)

Public health related issue? Involvement of vulnerable populations, wide use of health product, etc.

Canadian context and experience? How the practice described in the article relates to the Canadiansituation (e.g., health risk applicable in Canada, domestic case reports, etc.)

Identify issues that are relevant to Canadians

Detection and Triage of Signals

Other – Media, Pre-Marketing International **Literature MAH Submitted, Academia, Review Bureaux / Regulatory (Environmental) PSURs, etc Conferences, Office of Clinical Agencies Scanning DSEN etc Trials

Signal Identification/Coordination Drug / Med Dev Signal Identification Canada Combo Products WorkingCoordination Group Vigilance

Signal Prioritization Meeting

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SIGNAL PRIORITISATION

Weekly meetings of the management team 1-3 potential signals /meeting

Considerations during signal prioritization

New AE ( unknown)

Unlabelled AE

Clinical characteristics of AE (e.g. lab. results, rare or low natural frequency)

New Health Product (HP) (2 years or less)

Public Health aspect (e.g. Amount of HP use, number of adverse event cases )

Vulnerable populations involved

Risk perception by media / by the general population:

Potential Shift in the benefit/risk ratio

Preventability by regulatory or risk management intervention

Strength of the association between the AE and the HP ( e.g. biological plausibility / inherent toxicity. compatible temporal relationship) 21

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Signal Prioritization Activities by Fiscal Year (Pharmaceuticals)

FY 2011‐ FY 2012‐ FY 2013‐ FY 2014‐ FY 2015‐ 2012 2013 2014 2015 2016

# of potential signals screened 3216 2697 2402 2842 4486

# of potential signals discussed 284 173 # of total signals prioritized 50 41 28 20 36 # of signals screened out after prioritization 23 28 23 17 10

Issue Related Summary Reports (IRSRs)

During the prioritization meeting the decision is made if a request for an IRSR should be sent ( to one or several MAHs)

In accordance with the Food and Drug Regulations (C.01.019):

Health Canada may, for the purposes of assessing the safety and effectiveness of a drug, request in writing that the MAH submit an issue-related summary report which contains a concise, critical analysis of the adverse drug reactions and serious adverse drug reactions to a drug.

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IRSRsPurpose – General of IRSRs Overview

• Purpose of assessing the safety and effectiveness of a drug • Includes an analysis of the risk of the drug and conclusions regarding the safety of the product as marketed in Canada • Used in MHPD primarily in signal assessment • Not specific format required (no ICH guidelines)

The Ideal IRSR *

 Submitted when requested, within the timelines provided, using the latest data lock point (DLP)  Stand-alone document that is easy to read and follow  Provides the specific information as requested  Uses the MAH’s Global Safety Database including clinical trials post-marketing data and literature reports  Uses ADR search strategies that are not too wide or too narrow, following suggested MedDRA terminology.  Includes CIOMS reports, narratives and causality when possible  Provides Canadian context when available: exposure data in both patient-years and total number of patients exposed in cumulative form as well as a breakdown by year.  Provides a clear rationale for all safety conclusions  Proposes Pharmacovigilance and Risk Minimization activities  Important reference publications are included

*According to MPMDB

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SIGNAL ASSESSMENT

130 business days for a standard review and 90 days for a MHPD priority review

Signal Assessment : True collaboration

• Scientific team • Epidemiologists • Medical team • Pre-market Bureaus (TPD)

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Number of Signals Completed by Fiscal Year and Source

Sources/FY FY 2011‐2012 FY 2012‐2013 FY 2013‐2014 FY 2014‐2015 FY 2015‐2016 Literature 13 14 5 7 3 Media 00001 Foreign Regulatory Agency 12 17 8 3 2 PRAC 07454 Previous Reviews 6 14 6 13 8 CV 21131 1 MAH 54340 Pre‐market or Partner Directorate 75654 Other 00000 Total4572353823

Components of the Signal Assessment

1. Identification of the issue 2. Purpose of the assessment 3. Background 4. Issue Analysis 5. Summary 6. Considerations 7. Option analysis 8. Recommendations 9. References 31

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Signal Assessment : Components

1. Identification of the issue • This section focuses on identification/description of the issue, and how it originated. 2. Purpose of the assessment • The purpose clearly identifies the specific focus of the signal assessment document. 3. Background • Product Indication(s) in Canada • Marketing Status • Product Class • Background characterisation of the safety risk • Biological Plausibility

Signal Assessment : Issue Analysis

Previous regulatory assessments and/or actions in Canada and internationally • Previous assessments • Labelling updates • Risk communications • Ongoing safety studies Analysis of Adverse Events in Canada and internationally • Canada Vigilance database • WHO database (including Information Component (IC values)) • Cases reported by the MAH (in PSURs or IRSR if requested)

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Signal Assessment : Issue Analysis (continued)

• Causality Assessment – performed by a Medical Team • In most instances, the WHO causality algorithm will be used to assess relevant cases. A focus is put on the serious “possible” and “probable” (and the very rare “certain”) case reports, with an analysis that may include evidence for a dose-dependence relationship or lack thereof; relevant clinical features of this condition; any identified population at risk, and description of limitations of the causality assessment.

Signal Assessment : Issue Analysis (continued) • Scientific Literature • Review of the literature provided by the MAH ( if the IRSR has been requested) • Health Canada’s review of Scientific literature • Performed by a HC specialised librarian • Includes relevant publications on particular adverse reaction/safety issue in association with a product of interest; known mechanism of AR, potential class effect, drug utilization (may include off-label use). • Product Utilisation • IMS data and utilisation data provided by the MAH ( if an IRSR has been requested)

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Classification of evidence

Systematic Reviews meta-analysis

Randomized controlled trials

Epidemiological studies (Cohort, Case-control, Cross-sectional)

Case report/series

Media, expert opinion, animal research

Is the type of evidence presented well-suited to answer questions on a possible link between reported AE-Drug?

Signal Assessment

• Conclusions and risk mitigation strategies proposed by the MAHs ( if an IRSR has been requested).

• Brief summary of the signal assessment

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Signal Assessment: Considerations

• Shift in the benefit/risk ratio of the product based on the new information • Strength and limitations of available data • Need for a precautionary approach • Use in vulnerable population or identifiable subpopulation • Availablilty of other therapeutic options • Actions by other regulatory agencies • Feasability of risk mitigation actions • Public interest

Signal Assessment: Option Analysis

• Standard monitoring (issue would not be readdressed unless new information is obtained); • Request to continue monitoring issue through Canada Vigilance database for reassessment in specific time periods (e.g. 6 months, 1 year, 2 years); • Request a PSUR or annual summary report, using Food and Drug Regulation C.01.018; • Request submission of a Pharmacovigilance and/or Risk Management Plan;

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