pharmacovigilance systems & methodologies across the globe

Pharmacovigilance: Systems & Methodologies Across The Globe

ILHAR HASHIM, M PHARM-CLINICAL RESEARCHNATIONAL INSTITUTE OF PHARMACEUTICAL EDUCATION AND RESEARCH (NIPER), MOHALI, INDIA-160062

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2 WHO- UMC- VigiBase- VigiFlow- VigiLyze VigiBase is a World Health Organization’s (WHO) global

Individual Case Safety Report (ICSR) database Contains ICSRs submitted by the participating member states

enrolled under WHO’s international drug monitoring programme

It is the single largest drug safety data repository in the world The Uppsala Monitoring Centre (UMC) on behalf of WHO, is

maintaining VigiBase Vigibase is used to obtain the information about a safety profile of

a medicinal product

3 WHO- UMC- VigiBase- VigiFlow- VigiLyze

These data are used by pharmaceutical industries, academic institutions and regulatory authorities for statistical signal detection, updating periodic reports, ICSR comparisons with company databases and studying the reporting patterns

The data (pre-dominantly post-marketing serious and non-serious cases) is collected from each of its 110 member states which currently comprises to over 10 million ICSRs

About a hundred thousand ICSRs are added each year These submissions are in ICH -E2B standard for electronic transmission of ICSRs


It is mandatory for all the participating countries (125 members states and 28 associate members) to submit ICSRs to UMC via its appointed national centre based in the respective member states

These reports are usually sent to the respective national centre by marketing authorization holders, health care professionals (HCP), consumers or any regional centre


UMC in collaboration with ‘’Swissmedic’’ has developed ‘’VigiFlow’’, a web-based ICSR management system

VigiFlow functions as a national ICSR database management system and analysis tool, through which cases are sent to UMC

VigiFlow supports the collection, processing and sharing of data of ICSRs to facilitate effective data analysis

VigiLyze is an online resource that delivers useful search and analysis functions and provides a quick and clear overview of VigiBase

8 FAERS- MedWatch

The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA

The database is designed to support the FDA's post-marketing safety surveillance program for drug and therapeutic biologic products

The informatic structure of the FAERS database adheres to the international safety reporting guidance issued by the International Conference on Harmonization (ICH E2B)

Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology

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It contains adverse drug reaction reports FDA has received from manufacturers, health proffessionals & consumers/patients as required by regulation &/or voluntarily

MedWatch is the Food and Drug Administration’s Safety Information and Adverse Event Reporting Program

MedWatch is used for reporting an adverse event or sentinel event Voluntary reporting by healthcare professionals, consumers, and patients is

conducted on a single, one-page reporting form- Form FDA 3500

FAERS- MedWatch

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11 EudraVigilance

EudraVigilance is a system for monitoring the safety of medicines in European union

Its components facilitate electronic reporting of suspected adverse reactions related to medicines and the effective analysis of data

This enables the early detection of potential safety issues The system contains different components that perform specific tasks in the process

of electronic reportingof suspected adverse drug reactions

13 EudraVigilance

The EudraVigilance gateway supports the electronic data interchange (EDI) process, which is based on the secure electronic exchange of safety messages between a sender and a receiver

The safety messages contain individual case safety reports(ICSRs) The EudraVigilance web application (EVWEB) is the interface to

the EudraVigilance database management system (EDBMS) and allows registered users to create, send and view ICSRs, safety and acknowledgement messages

EVWEB also enables users to perform queries

14 EudraVigilance

Marketing authorisation holders and sponsors of clinical trials must report and evaluate suspected adverse drug reactions during the development and following the marketing authorization of medicinal products in the European Economic Area (EEA)

Marketing authorisation holders must also electronically submit information on medicinal products authorised in the European Union (EU)

Yellow Card Scheme The Yellow Card Scheme is the UK system for collecting information on

suspected adverse drug reactions (ADRs) to medicines. The scheme allows the safety of the medicines and vaccines that are on the market to be monitored

It is run by the Medicines and Healthcare Products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM).

Suspected ADRs are collected on all licensed medicines and vaccines, from those issued on prescription to medicines bought over the counter from a pharmacist or supermarket

Yellow Cards are available from pharmacies and a few are presented near the back of the BNF as tear-off pages

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17Canada Vigilance

The Canada Vigilance Program is Health Canada's post-market surveillance program that collects and assesses reports of suspected adverse reactions to health products marketed in Canada

A spontaneous reporting system that is designed to detect signals of potential health product safety issues during the post-market period

The data is collected primarily by a spontaneous surveillance system in which adverse reactions to health products are reported on a voluntary basis

Adverse reaction reports are submitted by health professionals and consumers on a voluntary basis either directly to Health Canada or via Market Authorization Holders

19 Blue card

Blue card adverse reaction reporting form

Form to report suspected adverse reactions to vaccines and prescription, over-the-counter and complementary medicines in Australia

Send completed Blue cards to the TGA

By mail to: Pharmacovigilance and Special Access Branch, Reply Paid 100,

Woden ACT 2606

21Pharmacovigilance programme of India (PvPI)

24Data Mining Methodologies for Pharmacovigilance

Data mining the process of extracting previously unknown, valid and actionable information from large information sources or databases

1. Computational methodology-Pre-Marketing surveillance

These research can be categorized intoI. protein target-based. II. chemical structure-based approaches. III. integrative approach.

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Protein Target-based Approach Drugs typically work by activating or inhibiting the function of a protein, which in turn

results in therapeutic benefits to a patient. Drugs with similar in vitro protein binding profiles tend to similar side-effects,

Chemical Structure-based Approach The chemical structure-based approach attempts to link ADRs to their chemical

structures

Computational methodology- Pre-Marketing surveillance

26Computational methodology- Pre-Marketing surveillance

Integrative Approach Huang et al. proposed a new computational framework to predict ADRs by

integrating systems biology data that include protein targets, protein-protein interaction network, gene ontology (GO) annotation and reported side effects

Recently, Liu et al. investigated the use of phenotypic information, together with chemical and biological properties of drugs, to predict ADRs

27Post- Marketing Surveillance

Several unique data sources are available for post marketing PhV

1. Spontaneous Reports Spontaneous reporting systems (SRSs) have served as the core data-collection system for post-

marketing drug surveillance since 1960 Some of the prominent SRSs are the Adverse Event Reporting System (AERS) maintained

by the US FDA and the VigiBase managed by the World Health Organization (WHO)

Many post-marketing surveillance analyses are based on these reports voluntarily submitted to the national SRSs, which include disproportionality analysis and data mining algorithms


2. Electronic Medical Records Computerized medical record created in an organization that delivers care, EMRs

contain not only detailed patient information but also copious longitudinal clinical data EMR databases consist of data in two types formats: Structured (e.g., laboratory data)- Several groups have employed computational

methods on structured or coded data in EMRs to identify specific ADR signals


Unstructured Data Data in narrative clinical notes is not readily accessible for data mining, thus

natural language processing (NLP) technique is required to extract the needed information


3. Non-conventional Data Sources Biomedical Literature Biomedical literature can be used as a

complementary resource for prioritizing drug-ADR associations generated from SRSs


Health Forums Data posted by users on health-related

websites may also contain valuable drug safety information

32Data Analysis Techniques in PV

Disproportionality Analysis (DPA)

It involves frequency analyses of 2x2 contingency tables to quantify the degree to which a drug and ADR co-occurs “disproportionally” compared with what would be expected if there were no association

Many approaches are applied, the straight forward method is the calculation of frequentist metrics

Relative Reporting Ratio (RRR), Proportional Reporting Ratio (PRR), Reporting Odds Ratio (ROR)

DPA methods are effective in detecting single Drug-ADR associations


For bayesian approach, algorithms are more complex, such as Gamma-poisson shrinker (GPS) and the Multi-item gamma-poisson shrinker (MGPS) providing Empirical bayesian geometric mean (EBGM) score

Information component (IC) score of Bayesian confidence propagation neural network (BCPNN)

Tatonetti et al applied the Bi clustering algorithm to identify drug groups that share a common set of ADRs in SRS data


Hazard identification

Where a small group of pharmacists reviews all reports, identifies new hazards, and prioritizes them for action. Recommendations are then disseminated to the participants (most hospitals) every two weeks via a newsletter, Medication Safety Alert

Summaries and descriptions

A simple classification scheme can provide summaries and descriptions that permit determination of frequencies or ranking by order of frequency

An example of this would be a reporting system that records medication errors classified by dose, route, patient, etc. Calculating frequencies permits prioritization that can be used by focused systems to allocate further resources.


Trend and cluster analysis

Trend analysis, obtained by calculating and observing rates of events over time, can identify significant changes that suggest new problems (or, if improving, that safety measures are working)

Trends can also be detected using statistical control methodologies

A cluster of events that suddenly arises suggests a need for inquiry

Correlations

An analysis of correlations to evaluate the strength of the relationship between two variables, such as whether dosing errors occur more frequently among chemotherapy patients than among patients undergoing other treatments


Risk analysis

With adequate data, a reporting system can develop valuable information about risk

With a large number of reports, estimations of the probability of recurrence of a specific type of adverse event or error can be calculated

Analysis of reported outcomes can also produce an estimate of the average severity of harm caused by the incident

Causal analysis

If causal factors such as workloads, communication, teamwork, equipment, environment, staffing and the like are included, then correlations among many cause and effect relationships can yield important insights into a health-care system’s vulnerabilities


Systems analysis The ultimate aim of reporting is to lead to systems improvements by

understanding the systems failures that caused the error or injury At the organizational level, this requires investigation and interviews with involved

parties to elicit the contributing factors and underlying design failures A national reporting system must receive this level of information in order to

identify common and recurring systems failures

pharmacovigilance systems & methodologies across the globe

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