Transcript Postmarketing Pharmacovigilance

Postmarketing
Pharmacovigilance
English D. Willis, MD
Clinical Risk Management
Merck Research Laboratories
June 1, 2012
Definition of Pharmacovigilance
(PV)
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The study of the safety of marketed drugs under practical conditions of
clinical use in large communities.
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A clinical science whose objectives are the surveillance, evaluation, and
signaling of the undesirable effects of pharmaceutical products used for
medical therapy and whose major sources of new information are
spontaneous notification and reporting of such effects.
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It also includes the diffusion of this information and the regulatory
measures taken to prevent future adverse drug reactions, to ensure
safer use of drug products as well as improvement in the risk/benefit
ratio.
Ref: Mann R D, Andrews E B (2007) Pharmacovigilance 2nd ed. John Wiley and Sons, Ltd, England
Cobert BL, Biron P (2002) Pharmacovigilance from A to Z Adverse Drug Event Surveillance. Blackwell
Science, Michigan
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Postmarketing PV Activities
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Designed to monitor the safety profile throughout the life-cycle of the product
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Adverse Event Reporting System (AERS)
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Periodic Safety Update Reports (PSURs)
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For the identification and assessment of previously unrecognized (unlabeled) AEs
Worldwide, passive, spontaneous and voluntary AE reporting system
Reports received from healthcare professionals (HCP), consumers, literature and serious reports from
study environment
Provides an update of the worldwide safety experiences of a medicinal product to Competent Authorities at
defined points post-authorization. It includes succinct summary information with a critical evaluation of the
risk-benefit balance of the product in the light of new or changing information. The evaluation helps to
determine if further investigation or changes to the Company Core Data Sheet (CCDS) or company label
are needed.
Included is a comprehensive review of regulatory and exposure data, risk information and reports of AE
temporally associated with use of a product
Risk Management Systems
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Risk management ≠ risk elimination
Risk management is intended to optimize the benefit risk balance, by minimizing risks while preserving the
benefits
Basic activities include:
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Risk identification
Risk evaluation and characterization
Risk communication
Risk minimization
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Key International Organizations in the
Development of Safety Regulations
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International Conference on Harmonization (ICH) of Technical
Requirements of Registration of Pharmaceuticals of Human Use
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Topic areas of focus:
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Participants:
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Safety: relating to in vitro and in vivo preclinical studies
Efficacy: relating to clinical studies in human subjects
Quality: relating to chemical and pharmaceutical quality assurance
EU: CHMP/EMEA
US: FDA and PhRMA
Japan: WHLW and JPMA
Regulatory observers from WHO, Therapeutic Products Programme (Health
Canada) and European Free Trade Assoc.
Several ICH Documents to include:
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E2C-PSUR for marketed products
E2D-Postapproval Safety Drug Management: Definitions and Standards for
Expedited Reporting
E2E-Pharmacovigilance Planning
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Key International Organizations in the
Development of Safety Regulations
(con’t)
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Council of International Organizations of Medical Sciences
(CIOMS)
 Established by the WHO and UNESCO as an international, nongovernmental, non-profit organization
 Regulatory and industry working group or “think tanks”
 Primary objectives:
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To facilitate and promote international activities in the field of
biomedical sciences
To maintain collaborative relations with UN and specialized agencies
To serve the scientific interest of the international biomedical
community in general
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Safety Profile at Approval
This is why PV is necessary
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Safety data at time of drug/vaccine approval
 Randomized controlled clinical trials are rigorous in
design but they have limitations
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Limited numbers of patients studied (range is 1500 to 10,000 for a
new drug; vaccine trials ~ 20,000 or more)
Select patient population intended to limit variability to be able to
demonstrate efficacy without confounders
Duration of exposure to the drug or vaccine is limited
In summary, clinical trials are not “real world” use
Post-approval data expands the understanding of the
safety profile
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Detects rare events
Monitor for and encourage safe use of the product
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Spontaneous Reports of
Adverse Drug Events
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HCPs role in the continuous monitoring for
safety and risk identification is crucial
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Medically confirmed reports from HCPs are
preferred by industry
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Regulatory guidelines for reporting of AEs to
agencies; company shares all AE reports with
agencies; companies and agencies each have
their own database.
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Several limitations inherent in postmarketing
AE reports
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Signal Detection
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For the purpose of identifying:
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New unlabeled AEs
An observed increase in a labeled event in its severity or specificity
New drug, vaccine or food interaction
Newly identified at-risk population
Of consideration are:
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Disease occurrence in expected time
Absence of symptoms prior to exposure
Positive dechallenge and/or rechallenge
Consistent with pharmacological effects or biological plausibility
Consistent with known effects in the class
Event identified in clinical trials
Absence of alternative explanations (co-morbidities or comedications/vaccine)
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Risk Management System
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Process for identifying, characterizing,
evaluating, monitoring, communicating and
mitigating risks that may arise from the
normal conditions of use of a medical
product.
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To ensure a positive benefit/risk balance
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EU Risk Management Plan (RMP)
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Submitted with each NDA filed; when requested by an agency; or with
a significant change in the product
“Living document” that is updated throughout the product life cycle
Part I
 Safety specification
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Describes what is known and not known about the product, the epidemiology of
the condition the drug/vaccine is intended to treat or prevent and the indicated
population
Includes important identified risk, potential risk and missing information
Forms the bases of the PV plan and the evaluation of the need for riskminimization activities
Pharmacovigilance plan
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Describes how the risk will be identified and further characterized
Activities may include: routine PV (AER with reporting), active surveillance
(registries, sentinel sites), pharmacoepidemiology studies (PASS), clinical trials
with safety as an end point, and/or preclinical studies to elucidate the
mechanism of an observed risk
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EU Risk Management Plan (RMP)
(con’t)
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Part II
 Evaluation of the need for risk-minimization activities
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Risk minimization activities are needed if warranted by the particular nature and/or
seriousness of the risk. These are non-routine and beyond the PV plans and local
labeling
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Additional activities (non-routine)
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Educational programs for HCP and consumers
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Patient monitoring programs
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Controlled distribution of the product
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Restricted access programmes
If RMP includes additional activities, a risk minimization plan is needed
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Details the activities for risk reduction of a safety concern
Specific for the safety concern
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RMP - Safety Specification
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Important Identified Risk
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Important Potential Risk
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Adverse reaction (AR) suggestive of an association
with product
AR with some basis for suspicion of an association
with product but not yet confirmed
Important Missing Information
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Safety information not available at the time of
submission and representing a limitation of the
safety data with respect to predicting safety of the
marketed product
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RMP - Pharmacovigilance Plan
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PV plan specific for each safety concern (identified and potential
risk and missing information)
 Routine PV for those with no special concerns
 Additional PV activities for real and potential risks
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Example - registries
Formal action plan for each safety concerns
 Objective of proposed action
 Rationale for proposed action
 Milestones for evaluation and reporting
 Further measures on the basis of findings
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RMP - Risk Minimization
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Product labeling is a standard risk minimization tool for risk
communications
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Sections of Product Circular i.e. product label
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Indications
Dosage and Administration
Contraindications
Warnings/Precautions
Adverse reactions
DD interactions
Use in special populations
Patient Product Information i.e. consumer information
Additional activities to reduce the probability of an AR occurring or its
severity if it occurs
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Examples: DHCP letter, prescribing or dispensing guides, laboratory
monitoring, specific training programs
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Risk Evaluation and Mitigation
Strategy (REMS)
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U.S. FDA specific regulation that describes the use of risk minimization actions
for drugs in the U.S.
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Overall goal of REMS
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Allow safe access to drugs with serious risks for the patients who need them
While minimizing the burden to patients and the healthcare system
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Most medication guides are no longer part of a REMS
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May Include:
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Communication Plan to Health Care Providers
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Dear HCP Letters
Information dissemination to HCP through Professional Societies
Examples of elements to ensure safe use
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Training or certification for HCPs
Certification of dispensing sites (e.g. pharmacies)
Dispensing only in certain settings (e.g. hospitals)
Dispensing drug is conditional on documentation of safe use conditions 9i.e. lab results)
Patients enrolled in Registry
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Risk Communication on Safety
Issues
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Continuous updating of product and patient information labels
Safety-related label changes may include additions to:
 Adverse Reaction section describing clinical findings from newly
completed studies
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Postmarketing Experience sub-section describing new AEs
identified from postmarketing surveillance
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Warnings and Precautions section describing safety concerns
that affect decisions about prescribing the drug,
recommendations for monitoring to ensure safe use and measure
to be taken to prevent or mitigate harm.
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Contraindication section describing situations in which the drug
should not be used because the risk clearly outweighs any
possible therapeutic benefit
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