MEDICAL EVALUATION OF ADVERSE EVENTS IN

PHARMACOVIGILANCE

Quality system in pharmacovigilance

The pharmacovigilance quality management system (QMS) can be defined as the the
framework of the policies, procedures and systems that are necessary to ensure that
the activities relating to the detection, assessment, understanding and evaluation of
adverse effects or any other medicine-related problem relating to medicinal products
are handled in compliance with applicable laws, regulations and company
expectations . The quality system is having activities:

• Quality planning: establishing structures and planning integrated and consistent

processes
• Quality adherence: carrying out tasks and responsibilities in accordance with
quality requirements
• Quality control and assurance: monitoring and evaluating how effectively the
structures and processes .
• Quality improvements: correcting and improving the structures and processes where
necessary .
quality objectives of a pharmacovigilance system
 Complying with the legal requirements for pharmacovigilance tasks and
responsibilities
 Preventing harm from adverse reactions in humans arising from the use of
authorized medicinal products within or outside the terms of marketing
authorization , occupational exposure
 Promoting the safe and effective use of medicinal products, in particular through
providing timely information about the safety of medicinal products to patients,
healthcare professionals and the public
 Contributing to the protection of patients' and public health.

Quality requirements for pharmacovigilance activities

Quality requirements are those characteristics of a system that are likely to

produce the desired outcome, or quality objectives. It shall cover organizational
structure, responsibilities, procedures, processes and resources of the
pharmacovigilance system as well as appropriate resource management,
compliance management and record management.
For the systematic approach towards quality in accordance with the quality cycle
managerial staff in any organization should be responsible for ensuring that the
organization documents the quality system as described
 ensuring that the documents describing the quality system are subject to
document control in relation to their creation, revision, approval and
implementation
 ensuring that adequate resources are available and that training is provided
 ensuring that suitable and sufficient premises, facilities and equipments
 ensuring adequate compliance management
  ensuring adequate record management
 reviewing the pharmacovigilance system including its quality system at
regular intervals in risk based manner to verify its effectiveness and
introducing corrective and preventive measures where necessary
 ensuring that mechanisms exist for timely and effective communication,
including escalation processes of safety concerns relating to medicinal
products within an organization
 identifying and investigating concerns arising within an organization
regarding suspected no adherence to the requirements of the quality and
pharmacovigilance systems and taking corrective, preventive and escalation
action as necessary.
 ensuring that audits are performed .

Expedited reporting criteria

The purpose of expedited reporting is to make regulators, investigators, and other
appropriate people aware of new, important information on serious reactions. It
involve events previously unobserved or undocumented, and a guideline is needed on
how to define an event as "unexpected" or "expected" . Expected / Unexpected from
the perspective of previously observed, not on the basis of what might be anticipated
from the pharmacological properties of a medicinal product.
Single Cases of Serious, Unexpected ADRs
• Reports from spontaneous sources and from any type of clinical or epidemiological
investigation, independent of design or purposes
• It also applies to cases not reported directly to a sponsor or manufacturer.
• The source of a report (investigation, spontaneous, other) should always be
specified.
• Information obtained from any source should be submitted to appropriate regulatory
authorities if the minimum criteria for expedited reporting can be met.
• Causality assessment is required for clinical investigation cases.
• All cases, having a reasonable suspected causal relationship and the medicinal
product qualify as ADRs..
• Many scales used are WHO and Naranjo.
• Phrases - "plausible relationship," "suspected causality," or "causal relationship
cannot be ruled out"
Inappropriate expedited reporting
Serious but expected, Serious events from clinical investigations that are considered
not related to study product, whether the event is expected or not. Non-serious,
whether expected or not.
Reporting Time Frames
Fatal or Life-Threatening Unexpected ADRs
 Occurring in clinical investigations - very rapid reporting.
 Regulatory agencies should be notified.

All Other Serious, Unexpected ADRs

Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must
be filed as soon as possible but no later than 15 calendar days.

Elements for the inclusion in expedited reports of serious ADR

 Patient details: gender ,age ,height, weight etc
 Suspected medicinal product: Brand name ,Batch number etc
 Other treatments : concomitant products, non medical product therapies.
 Details of suspected ADR
 Outcome
 Company details :source of report ,date event report was first received by sponsor
or manufacturer, name address and details of manufacturer or company or
sponsor.
PSUR AND PBRER

PSUR

They are Periodic Safety Update Reports . PSURS are Pharmacovigilance

documents intended to provide an evaluation of the risk-benefit product at
defined time points after its authorization.

Goal of PSUR
It is to present a comprehensive and critical analysis of the risk-benefit balance
of the product, taking into account new information in the context of cumulative
information on risk and benefits balance of a medicinal or emerging safety .It is
done usually After Phase III and during Phase IV The medicinal product remains
a New one for first 4 years after marketing First 2 years, submit PSUR at an
interval of 6 months Next 2 years at an interval of 12 months

PBRER
It is a Periodic Benefit Risk Evaluation Report . PBRER is an analysis of the
safety, efficacy, and efficiency of a drug, once it is already in the market.

Goal of PBRER

The PBRER submission is intended to present a periodic, comprehensive, brief

and critical evaluation of new or emerging information on the risks of the health
product and the product's overall benefit-risk profile. It is done when , once drug
is already in the market every 6 months for the first 2 years after the product is
marketed once a year for the following 2 years

PSUR PBRER
  Primarily served as an interval
safety report
 Includes cumulative information
on risk and benefit balance of a
medicinal or emerging safety.
 Cumulative benefit-risk report
 Includes data on efficacy and
effectiveness from ongoing or
updated clinical Trials and
cohort studies.

PV database and signal detection

Pharmacovigilance database is usually practiced by agencies and pharmaceutical
companies by focusing on SD in large databases
 These databases are of huge sizes, e.g.
• USFDA database, AERS:> 6.2 million records
• WHO database, VIGIBASE: > 7.2 million records
• GSK database, OCEANS:> 2 million records
 Based on a study, the highest power for finding a true signal is achieved by
combining those databases with the most drug-specific data
 Also early safety SD should involve the use of multiple large global databases
Reliance on a single database may reduce statistical power and diversity of ADRs
Desirable attributes of AE database software
 Should be well integrated with Clinical data management software
 User friendly
 Individual reports management features
 Easy for query
 Line listing of the entire database or part is possible and easy
 Data extraction is easy, with desirable filters
 May also keep track of post marketing Rx utility and complaints data
Signal detection
Signal "Information that arises from one or multiple sources which suggest a new
potentially causal association, or a new aspect of a known association, between an
intervention and an event or set of related events, either adverse or beneficial, that is
judged to be of sufficient likelihood to justify verificatory action
 Signal detection :The act of looking for and / or identifying signals„ Detection using
event data from any source.

 Sources for the detection of signals:

 Spontaneous reporting
 Active monitoring systems
 Interventional studies (clinical trials)
 Non-interventional studies (pharmacoepidemiology studies)
 Non-clinical studies (e.g. animal toxicology studies)
 Systematic reviews (i.e. thorough review of the published literature)
 Meta-analyses (i.e. mathematical pooling of all the clinical trial data
 Signal prioritization
• Confirmed signal: Results in the movement of the signal to the evaluation process
• Unconfirmed signal: Results in the monitoring of this event over time and regularly
re-prioritizing based on new information
• Refuted signal Results in the closing of the signal Disease progress ons, Known
issues
 Signal evaluation
Risk assessment and management
A Risk Management Plan is a document based on: Safety profile of the medicine,
Plan of all pharmacovigilance activities. . Planning and implementation of different
measures in order to minimize risk; and evaluation of effectiveness of those
measures.
Objectives of RMP
Early identification of any risk taking into consideration all the existing
information ,Identification of areas where it is necessary to perform an in depth
evaluation , Project new studies to characterize and identify scientific-based risks.
Pharmacovigilance starts before marketing authorization and it continues during all
the life-cycle.

Risk Management Plan: It includes all the existing and missing information about
the safety profile of the medicine; certainty level of the effectiveness shown in
clinical trials, measures to prevent any risk associated to the medicine including
evaluation of effectiveness of these measures and it is the detailed description of the
Risk Management System.
Presentation
Forensic pharmacovigilance
Forensic Pharmacovigilance is a branch of pharmacovigilance uses the expert
knowledge of adverse drug effects related to illicit drugs and resolve events, questions
or a cover criminal act.
Goal
provide risk assessment, signal detection and collection of evidence the drug which
are misuse / abuse / nonapproved.
Scope of forensic pharmacovigilance
• Illicit drug use: To prevent the usage of dangerous substances, drug monitoring
program was passed in Maryland in 2011
• Role in solving civil or criminal cases
• Differentiation between adverse drug reaction and adverse event casuality
assessment scales like
1. Naranjo's scale
 2. WHO casuality assessment scale
3. Bayesian scale are used by the experts to assign the level of correlation
• Discrimination between serious and severe adverse drug reactions A reaction is said
to be serious if it
 Result in death
 Life threatening
 Requires inpatient hospitalization
 Persistent or significant Disability or incapacity
 Congenital abnormality
 0ther medical important conditions.
 Other than this other cases can be severe.
• Identification of counterfeit or substandard drugs. E.g.: contamination of heparin in
USA in 2009
Drugs with their possible ADRS of forensic significance
• Trazadone
It is an antidepressant, anxiolytic and hypnotic .its ADR include suicidal
ideation.
Forensic significance: while mining the evidences in death of such cases
suicidal ideation may be considered.
• Methadone
it is a opioid analgesic, its ADR include respiratory depression
Forensic significance: respiratory arrest
Challenges in forensic pharmacovigilance

 Reluctance of medical professionals

 Fear of litigation
 Fear of being twisted by the lawyer
 Loss of productivity
 Extrapolation of data does not always produce the real figures
 Uniformity and non uniformity
 Ethics in forensic pharmacovigilance

Steps involved;
 Forensic pharmacokinetics
Biological samples should be collected to assess the presence of the drug.
The ADR should be identified. It helps to find out the presence of the drug.

Temporal relationship :The time lag between the administration of drug and
the occurrence of ADR.
E.g. immediate reactions are having low temporal relationship.
Casuality assessment of the case ,It is done by
1. Naranjo's scale
2. WHO scale etc
 Cautious extrapolation of facts to every case
 It must be avoided which leads to the misleading judgement based upon
inaccurate data
 Presenting evidence for the court.
The report should be submitted clearly and should not include the comments
which is beyond the expertise who submitting the report.
Medical error and medical negligence cases can be solved by forensic
pharmacovigilance
e.g.: 10 year old leukemia patient in Britain who had to be given a chemotherapy
injection died due to the wrong injection given to him. The boy ate food that was
prohibited during the procedure. For solving such cases of death, pharmacovigilance
plays a great role.
Forensic pharmacovigilance plays a great role to solve medico legal cases.

Conclusion
Pharmacovigilance system, like any system, is characterized by its structures,
processes and outcomes. The Quality System is part of the Pharmacovigilance System
and consists of its own structures and processes. Expedited reporting refers to ICSRs
(individual case safety reports) that involve a serious and unlisted event that is
considered related to the use of the drug . PSUR primarily served as an interval safety
report whereas a PBRER is meant to be a cumulative benefit‐risk report.
pharmacovigilance databases is one approach that has become increasingly popular
with the availability of extensive data sources and inexpensive computing resources.
The data sources (databases) may be owned by a pharmaceutical company, a drug
regulatory authority, or a large healthcare provider. Forensic pharmacovigilance is a
budding branch of pharmacovigilance to solve medico legal cases.