Risk analysis and postmarketing pharmacovigilance activities

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Risk analysis and post-marketing
pharmacovigilance activities

• Hilde Rodseth
• Boehringer Ingelheim (Pty) Ltd
• Acknowledgement thanks
• Dr. Mark Hopley Medical Director of BI

ABCD
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Outline References

• Definitions
• History
• Current process
• Performance
• Risk analysis risk minimisation
• Need
• Components and timing
• Specification
• Plan
• Activities

• ICH E2E
• www.ich.org
• EMEA
• www.emea.europa.eu
• FDA
• www.fda.gov
• Health Industry forum
• healthforum.brandeis.edu

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Definitions
PhamacovigilanceThe process of monitoring,
evaluating and improving the safety of medicines
in use and the prevention of adverse drug
reactions
Adverse Drug Reaction A response to a drug which
is harmful and unintended, and which occurs at
doses normally used
Safety Signal Reported information on a possible
causal relationship between an adverse event and
a drug
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History of pharmacovigilance

• 1848
• The Lancet starts collecting notifications of
  side effects after a death caused by anaesthesia
• 1906
• US Federal Food and Drug Act requires that
  pharmaceuticals be pure and free of any
  contamination
• 1937
• USA 107 lethal cases after diethylenglycol
  was mistakenly used to solubilise sulphanilamides

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History of pharmacovigilance (cont)

• 1959-61Reports of foetal abnormalities in
  relation with the use of a new sleep-inducing
  drug thalidomide
• 1962USA revised law requiring to prove safety
  and efficacy before issuing marketing
  authorisation
• 1967WHOs International Drug Monitoring Programme

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Current process

• Application - ISS
• Clinical trials to phase III - SADRs / AEs /
  Frequencies
• Laboratory/pre-clinical/other data
• Benefit versus risk conclusions
• Approval by HA
• Labelled use/indication
• Satisfactory risk benefit relationship
• Risks included in label (disclosure)
• Wait and see
• ADR surveillance and signal assessment (PSUR)
• Update label (restrictions)
• Ad hoc HCP communications (Dear Dr. letters)
• Withdrawal

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Pharmacovigilance Process
Traditional Methods
Data Mining
Detect Signals
Generate Hypotheses
Insight from Outliers
Health Impact Benefit/Risk
Refute/Verify
Estimate Incidence
Act
Misuse ? Overuse ? Off label use ?
Inform
Restrict use/ withdraw
Change Label
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Finding LARGE counts

• Many thousands of cells
• Most are empty, even with large number of AEs
• Data mining by Companies, HAs and WHO

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Limitations of spontaneous ADR reporting

• Underlying background rate of event within
  population
• Under-reporting in general
• Reports generated in uncontrolled environment can
  be biased
• Variable quality of reports
• Lack of denominator data

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Safety data
Pre-market
Post-market
Quality of patient information
Use in settings different from registration
trials Large population exposed in a short time
Quantity of patients
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Outline References

• Definitions
• History
• Current process
• Performance
• Risk analysis risk minimisation
• Need
• Components and timing
• Specification
• Plan
• Activities

• ICH E2E
• www.ich.org
• EMEA
• www.emea.europa.eu
• FDA
• www.fda.gov
• Health Industry forum
• healthforum.brandeis.edu

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ICH E2E Pharmacovigilance planning

• Planning of pharmacovigilance activities
• Throughout product life-cycle
• Esp. early postmarketing period
• Document risks
• Science-based risk identification
• Collaboration
• Regulators, industry and academia
• Proposes pro-active mechanisms to decrease risk
• Aim widen riskbenefit ratio
• Adopted in EU and FDA guidelines in 2005
  currently in implementation

ICH E2E at ICH6 Osaka (14 November 2003)
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Components and timing Prior to license
application - planning and dialogue with
regulators
Clinical Trials
Application
Review
Available Data/information
Approval
Pharmacovigilance Specification
Postmarketing
Pharmacovigilance Activities
Pharmacovigilance Plan
Phase IV Trials
Ongoing dialogue with regulators with every
safety review iterative cycle
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Pharmacovigilance (safety) specification

• Common Technical Document (CTD)
• Overview of Safety 2.5.5
• Benefits and Risks Conclusions 2.5.6
• Summary of Clinical Safety 2.7.4
• Safety Specification Summary
• Important identified risks
• e.g. No. pts, age, gender, stratification
• AE requiring further investigation
• Important potential risks
• Potential for overdose (e.g. antidepressants)
• Misuse for illegal purposes
• Important missing information
• children
• elderly
• pregnancy lactation
• ethnicity

ICH E2E at ICH6 Osaka (14 November 2003)
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Pharmacovigilance Plan

• Methods to address each of the issues identified
  in the Pharmacovigilance Specification
• No special concerns
• Routine pharmacovigilance
• Risk identified (potential) / missing information
• Actions designed to address these,
• Routine pharmacovigilance

ICH E2E at ICH6 Osaka (14 November 2003)
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Risk Minimisation Action Plans - RiskMAPs

• Specific issue / missing information
• Action(s)
• Objective
• Rationale
• Milestones for evaluation / reporting
• Until exposure is adequate
• Identification / characterization risk
• Refute an identified concern

ICH E2E at ICH6 Osaka (14 November 2003)
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RiskMAP Goals and Objectives

• Example
• Risk ? Drug X is teratogenic
• Goal ? Prevent foetal exposure to Drug X
• Objectives
• For women who are or may become pregnant
• Lower risk of doctor prescribing
• Lower risk of pharmacist dispensing
• Tools
• Targeted education and outreach
• Reminder systems and processes
• Performance-linked access systems

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Examples of RiskMap Tools

• Targeted education and outreach
• Prescriber education
• Continuing medical education
• Reminder Systems
• Patient consent
• Programs that document knowledge / understanding
• Specialised packaging to enhance safe use (e.g.
  only one month supply)
• Performance-Linked Access Systems
• Systems that link product access to laboratory
  results (e.g. negative pregnancy test)
• Other documentation

FDA guidance on ICH E2E
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Thalidomide High risk drug or high risk use?

• Being used
• Multiple myeloma erythema nodosum leprosum
  Crohn's disease graft-versus-host reactions
  after bone marrow transplantation AIDS-related
  aphthous stomatitis Behcet's syndrome
  Waldenstrom's macroglobulinemia Langerhans cell
  histiocytosis rheumatoid arthritis, discoid
  lupus erythematosus erythema multiforme
• New adverse effects still being found
• Thrombosis and embolism

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Anti-TNF medication in RA

• Risk ? TNF important in defence against TB
• Goal ? Prevent use in patients with active TB
• Objectives
• For patients who have active TB
• Prevent doctor prescribing
• Prevent pharmacist dispensing
• Tools
• CXR and PPD prior to starting Rx
• Review by Specialist Association
• Data base capture and follow up, e.g. pt registry

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Potential for medication errors/misuse/abuse to
be considered

• Naming
• Date rape potential? colour and flavour
• Abuse or overdose limit pack size?
• Prevention of accidental ingestion e.g. children
• Visually impaired patients
• Life threatening if administered by wrong route?
  (consider route of concomitant meds)

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Future developments?

• Increased transparency e.g. CT databases and
  publication of and CT results
• Use of pharmacogenomics to ID genetic variations
  that impact on drug safety, e.g. cytochrome P450
  mutation
• More phase IV clinical trials mandated by HAs
  penalties for non-compliance
• Incentives for additional clinical trials, e.g.
  patent extension on paediatric use
• Development of common standards for Good
  Vigilance Practice (GVP)
• Evolution of IT systems for better
  epidemiological assessments

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Changing priorities
Risk Management
Risk Management
Signal Detection
Aggregate reporting
Signal Detection
Aggregate reporting
AE Mgt
AE Case Management
Now (Passive)
Future (Pro-active)
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Risk Management - embracing change
It is not the strongest of the species that
survive, nor the most intelligent, but the one
most responsive to change. Charles Darwin 1859
On the Origin of Species by Means of Natural
Selection, or the Preservation of Favored Races
in the Struggle for Life.
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Optimistic pharmacovigilance
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• Thank you