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Basics of Pharmacovigilance

Regulatory Drug Sciences, LACDR Leiden, Oct 2012
by

Fakhredin Sayed Tabatabaei

on 4 September 2015

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Transcript of Basics of Pharmacovigilance

Basics of Pharmacovigilance
FA Sayed Tabatabaei MD PhD
Medicines Evaluation Board
The Netherlands

Pharmacovigilance
Why do we do that?
Signal Detaction
Risk Management Plan
discovering new safety issues
Structure of the EU-RMP
Database facilitating the sharing of safety information between the National Competent Authorities (NCAs) and the Agency
Objectives:
Safety issues
Safety signals
PSURs
RMPs
Tracking of the Safety Issues and Signals “live cycles” (independently of the authorisation type)

Tracking and monitoring the PSURs cycles and Risk Management Plans together with the implementation of the regulatory actions they require

Easy retrieval of the documents related to the safety of a medicinal product
European Pharmacovigilance Issues Tracking Tool (EPITT)
Regulatory Drug Sciences
Leiden-Amsterdam Center for Drug research
October 2012

Target identification
Receptor binding
Occupancy
Time on target
Drug targeting
Proof of mechanism
Species differences
PK/PD
Safety
Dose ranging
Drug delivery
Efficacy
Clinical validation
Phase I-III trials
Efficacy
Safety
Human PK
Dose selection
Bioavailability
Known risks
Unknown risks
Data collection
Evaluation
Communication
Intervention
Clinical Development
Approval
Discovery
Preclinical Development
Safety Specification
Identified risks
Potential risks
Missing information
Pharmacovigilance Plan
Routine Pharmacovigilance
Spontaneous Reporting, Periodic Safety Update Reports (PSURs), etc.
Additional Pharmacovigilance
Post Authorisation Safety Studies (PASS), etc.
Risk minimisation plan
Routine Risk Minimisation Activities
Summary of Product Characteristics (SPC), Labelling, Packaging, etc.
Additional Risk Minimisation Activities
Educational Materials, Restricted Access, etc.
Interventional studies
Clinical trials
What is the main difference between Case-control and Cohort studies?
Selection of the groups!
is based on patients with and without Adverse Events
is based on users and non-users of the medicinal product
What about Prospective and Retrospective studies?
Adverse Events have already happened before the beginning of the study
Adverse Events would happen after the beginning of the study
But...
which design is better?
How common is the outcome? (Adverse Event)
How frequent is the usage? (Patient Exposure)
How much money and time do we have? (Resources)
Case-control is better for rare events, because we start from the outcome, and not waiting for it to happen!
Cohort is better for lower exposure, because we start from the exposure, and not searching for it!
Cohorts are usually much more expensive and time consuming!
Prospective
Retrospective
Case-Control
Cohort
Case-control
Observational studies
Cohort
Compare outcomes
Draw conclusion
User group
Follow over time
Non-user group
Case group
Control group
Take history
Compare outcomes
Draw conclusion
Proportional Reporting Ratio (PRR)
Spontaneous Reports, and other sources
Random error (chance)
Systematic error (bias)
Sample size
Variability
Response Bias
Non-response Bias
Assessment Bias [clinical trials]
Allocation Bias [clinical trials]
Misclassification Bias
Population admixture [genetic epidemiology]
Berksonian Bias (Admission Bias)
Hawthorne effect (Behavior bias)
Recall Bias
Observer Bias
Interviewer Bias
Loss to follow-up
Surveillance Bias
Publication Bias
Diagnosis Bias
Healthy worker effect

Selection Bias
Information Bias
Confounding Bias
Publication Bias (meta-analyses)
Recall Bias (case-control studies)
effect of a third factor that is related to both the medicine and the adverse event
Allocation Bias (clinical trials)
Non-response Bias (cohort studies)
Diagnosis Bias (cohort studies)
Assessment Bias (clinical trials)
...and what can we do?
Sources of error
in epidemiological studies
Prescription bias (cohort studies)
Diagnosis Bias (case-control studies)
In design:
In analysis:
Restriction
Randomisation
Matching
Multivariate analysis
Stratification
Drug Surviellance
What are the key measures proposed?
1. Providing clear roles and responsibilities for the responsible parties
2. Strengthening companies' pharmacovigilance systems
3. Clear legal base for Risk Management Plans (Penalties for non-fulfillment)
4. Strengthening the reporting system for adverse reactions
5. Proactive and proportionate collection of high quality data
6. Risk-based approach to PSURs
7. Strengthening transparency and communication
Responsibilities of Member States and Companies are clarified

A new scientific committee, the Pharmacovigilance Risk Assessment Advisory Committee (PRAC)

The EU procedure for the assessment of serious safety issues for Nationally Authorised products
Pharmacovigilance system master file
Making Risk Management Plan mandatory

Harmonised guiding principles and a procedure for the supervision of non-interventional Post-Authorisation Safety Studies

Post-Authorisation Efficacy Studies
The EU "Eudravigilance" database will be the single information point


Legal basis for patients to report their side effects

Monitoring of selected scientific literature by the Agency
Database for the collection, verification and presentation of Adverse Drug Reaction reports
Gateway: Single electronic reporting point within EEA
EVMPD: EudraVigilance Medicinal Product Dictionary
EVWEB: Free web-based application for transmission of ICSRs
EVDAS: EudraVigilance Data Analysis System
“Additional Monitoring” for:


Specific symbol and legend in the SPC and PIL

Usually for 5 years (renewal period)
New active substances
New authorisations of biological products (including biosimilars)
Any other, upon request of competent authorities and PRAC
Make the requirements for periodic safety update reports proportional to the risks posed by medicinal products

PSUR waiver for Generics, Homeopathic, and herbal medicines

Would introduce Work-Sharing mechanisms for the assessments
Establishment of a European medicines safety web-portal

Introduction of a new ‘key information' section in the SPC
New pharmacovigilance legislation
Summary of the key changes
New Pharmacovigilance Committee (PRAC)
PSUR worksharing
Pharmacovigilance System Master file

European Medicines Safety Web-portal
New “key information” section in SPC and PIL
Symbol for “products under additional monitoring”

Allow direct patient reporting of Adverse Events
Marketing Authorisation Holders direct reporting to EudraVigilance
National procedure
Mutual Recognition procedure
Centralised procedure
National applications, assessments,
standards, and authorisations
1 assessment
2 to 27 similar national authorisations
1 assessment
1 authorisation in Europe
Same quality, efficacy, and safety standards
EU regulators
Committee for Medicinal Products for Veterinary Use (CVMP)
Committee for Orphan Medicinal Products (COMP)
Committee on Herbal Medicinal Products (HMPC)
Paediatric Committee (PDCO)
Committee for Advanced Therapies (CAT)
Committee for Medicinal Products for Human Use (CHMP)
Responsibility and delegation
European Commision (EC)

European Medicines Agency (EMA)

Reference Member States (RMS)

National Competent Authorities (NCA)
Biologics Working Party (BWP)
Blood Products Working Party (BPWP)
Joint CHMP/CVMP Quality Working Party (QWP)
Patients' and Consumers' Working Party (PCWP)
Scientific Advice Working Party (SAWP)
Vaccine Working Party (VWP)
Efficacy Working Party (EWP)
Safety Working Party (SWP)
Pharmacogenomics Working Party (PgWP)
Committee for Medicinal Products for Veterinary Use (CVMP)
Committee for Orphan Medicinal Products (COMP)
Committee on Herbal Medicinal Products (HMPC)
Paediatric Committee (PDCO)
Committee for Advanced Therapies (CAT)
Pharmacovigilance Risk Assessment Committee (PRAC)
Committee for Medicinal Products for Human Use (CHMP)
Committees (2011)
Interactions with CHMP and Coordination Group:


Explanation on the scientific grounds for differences if opinion/agreement are not in accordance with PRAC recommendation

PRAC recommendation to be made public together with agreement or opinion

EMA ensure appropriate coordination
PRAC will issue recommendations on any question relating to Pharmacovigilance, agreement and monitoring the effectiveness of Risk Management Plans
Current European Pharmacovigilance System
Coordinating bodies
Committees
Mutual Recognition & Decentralised Procedures - Human (CMD(h))
Mutual Recognition & Decentralised Procedures - Veterinary (CMD(v))
Biologics Working Party (BWP)
Blood Products Working Party (BPWP)
Joint CHMP/CVMP Quality Working Party (QWP)
Patients' and Consumers' Working Party (PCWP)
Scientific Advice Working Party (SAWP)
Vaccine Working Party (VWP)
Efficacy Working Party (EWP)
Safety Working Party (SWP)
Pharmacogenomics Working Party (PgWP)
Pharmacovigilance Working Party (PhVWP)
1) Serious adverse drug reactions
– e.g. immune system disorders
2) New (difficult) method of administration
– New patch in neuropathic pain
3) High potential for abuse / off-label use
– Risk for addiction
What kind of products need Risk Minimisation?
1. Health Care Professionals
Prescribers (specialists, general practitioner) Pharmacist
Nursing staff
2. Users
Patients
Parents, care-givers
Who needs to be educated?1
Different ways of communication, depending on the audience
e.g. Direct Healthcare Professional Communication (DHPC), etc.
e.g. new contraindication, suspension, revocation, etc.
Meta-analysis
Descriptive studies
Case reports,
Case series
MedDRA is a clinically-validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation.
MedDRA Definition
*
Lowest Level Term (LLT)
Preferred Term (PT)
High Level Term (HLT)
High Level Group Term (HLGT)
System Organ Class (SOC)
MedDRA Hierarchy
*

Musculoskeletal and connective tissue disorders
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Nervous system disorders
Pregnancy, puerperium and perinatal conditions
Psychiatric disorders
Renal and urinary disorders
Reproductive system and breast disorders
Respiratory, thoracic and mediastinal disorders
Skin and subcutaneous tissue disorders
Social circumstances
Surgical and medical procedures
Vascular disorders

Blood and lymphatic system disorders
Cardiac disorders
Congenital, familial and genetic disorders
Ear and labyrinth disorders
Endocrine disorders
Eye disorders
Gastrointestinal disorders
General disorders and administration site conditions
Hepatobiliary disorders
Immune system disorders
Infections and infestations
Injury, poisoning and procedural complications
Investigations
Metabolism and nutrition disorders
System Organ Classes
Full transcript