Advanced Methodologies in Pharmacovigilance

International Journal of Trend in Scientific Research and Development (IJTSRD)
Volume 7 Issue 2, March-April 2023 Available Online: www.ijtsrd.com e-ISSN: 2456 – 6470
@ IJTSRD | Unique Paper ID – IJTSRD55052 | Volume – 7 | Issue – 2 | March-April 2023 Page 510
Advanced Methodologies in Pharmacovigilance
V Sai Kruthika, Sarvani Ekathmika, Prathamesh Golapkar
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ABSTRACT
The World Health Organization defines pharmacovigilance as "the
science and actions connected to the detection, evaluation,
understanding, and prevention of adverse effects or any other drug-
related problem." Pharmacovigilance is critical in ensuring that
patients receive safe pharmaceuticals. We can learn more about a
drug's side effects through a variety of methods, including
spontaneous reporting, diligent monitoring, and database research.
Novel mechanisms are being established at both the regulatory and
scientific levels to increase pharmacovigilance. They include
conditional approval and risk management strategies on a regulatory
level, and openness and increasing patient engagement on a scientific
one.
OBJECTIVE
To review and discuss various aspects of pharmacovigilance,
including new methodological developments.
KEYWORDS: spontaneous reporting, data mining in spontaneous
reporting, intensive monitoring, general practice research data base,
developments, international developments
How to cite this paper: V Sai Kruthika |
Sarvani Ekathmika | Prathamesh
Golapkar "Advanced Methodologies in
Pharmacovigilance"
Published in
International Journal
of Trend in
Scientific Research
and Development
(ijtsrd), ISSN: 2456-
6470, Volume-7 |
Issue-2, April 2023, pp.510-514, URL:
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International Journal of Trend in
Scientific Research and Development
Journal. This is an
Open Access article
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INTRODUCTION:
The topic of medication safety has recently
received a lot of attention. Nearly frequently,
stories in tabloids and scholarly publications are
published about medications that induce
unanticipated adverse drug responses (ADRs).
These stories have had the regrettable effect of
raising concerns about the usage of these
medications among both patients and health
professionals. A more significant outcome might
be that the patient discontinues taking the
recommended drug, which could lead to a condition
even worse than the ADR he was initially
concerned about. The World HealthOrganization
(WHO) defines pharmacovigilance as "the
science and activities relating to the detection,
assessment, understanding, and prevention of
adverse effects or any other drug-relatedproblem,"
and it plays a critical role in ensuring that doctors,
in collaboration with the pharmaceutical industry.
METHODS USED IN
PHARMACOVIGILANCE
Pharmacovigilance efforts are broadly classified
into three categories: regulatory, industry, and
academia. The goal of regulatory
pharmacovigilance is to deliver medications to the
public with a favourable benefit-harm profile. In
this context, several regulatory post-marketing
monitoring difficulties will be explored, followed
by a description of the methods utilised to
discover new ADRs and a review of the
advantages and cons of each strategy.
There are three stages to pre-marketing clinical
testing. Phase III investigations are frequently
double-blind randomised controlled trials, which
are regarded as the most rigorous method of
assessing if a treatment-effect association exists.
However, when it comes to monitoring thesafety
of a drug, this study design is not optimal. Due to
the limited number of patients participating, it is
generally not possible to identify ADRs that occur
only rarely. The relatively short duration of clinical
trials makes it difficult to detect ADRs with a long
latency. Another limitationof clinical trials is the
population in which a drug is tested. In order to
study rare ADRs, ADRs with a long latency and
ADRs in specific populations, careful monitoring
ofthe drug in the post-marketing phase is essential.
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Post-marketing studies can be descriptive or
analytical. Descriptive studies generate hypotheses
and attempt todescribe the occurrence of events
related to drug toxicity and efficacy. Analytical
studies test hypotheses and seek to determine
associations or causal connections between
observed effects and particular drugs, and to
measure the size of these effects. Descriptive
studies are widely used in post-marketing
surveillance because they are able to generate
hypotheses that will become starting points for
analytical studies. Two forms of descriptive
studies— spontaneous reporting and intensive
monitoring—will be discussed here. Analytical
studies can be conducted using a variety of
approaches,including case–control studies, cohort
studies and clinical trials. In order to be able to
conduct retrospective cohort and case–control
studies, data which have been collected in a
reliable and routine manner needs to be available.
SPONTANEOUS REPORTING
In 1961, a letter from the Australian physician WG
McBride was published inLancet. In this letter, he
shared his observation that babies whose mothers
hadused thalidomide during pregnancy were born
with congenital abnormalities more often than
babies who had not been exposed to thalidomide in
utero [33]. In the years to come it became evident
that thousands of babies had been born with limb
malformations due to the maternal use of
thalidomide. In order to prevent a similardisaster
from occurring, systems were set up all over the
world with the aim of regulating and monitoring
the safety ofdrugs. Spontaneous reporting systems
(SRS) were created, and these have becomethe
primary method of collecting post marketing
information on the safety of drugs. The main
function of SRS is the earlydetectionof signals of
new, rare and serious ADRs. A spontaneous
reporting system enables physicians and,
increasingly more often, pharmacists and patients
to report suspected ADRs to a pharmacovigilance
centre.The taskof the pharmacovigilancecentreis
to collect and analyse the reports and to inform
stakeholders of the potential risk when signals of
new ADRs arise.
Spontaneous reporting is also used by the
pharmaceutical industry to collect information
about their drugs. By using an SRS, it is feasible to
monitor all medications on the market for a
relatively modest cost over their full life cycle. The
fundamental critique of this technique is the
possibility of selective reporting and
underreporting, which can lead to the incorrect
conclusion that a genuine danger does not exist,
while selective reporting of suspected concerns
might create the impression of a risk that does not
exist. Underreporting and selective reporting, on
the other hand, might be viewed as benefits.
When only the most severe and unexpected
occurrences are reported, it is simpler to discover
new ADR signals because the individual
reporting the response has already identified what
may be a new safety risk.
DATA MINING IN SPONTANEOUS
REPORTING
In the past, signal identification in spontaneous
reporting was mostly accomplished by case-by-
case analysis of reports. Yet, data mining
techniques have grown in popularity in recent
years. The phrase 'data mining' refers to the
process of analysing data from many angles and
extracting important information.
Algorithms are frequently employed in huge
databases to discover hidden patterns of
correlations or unexpected occurrences, i.e.,
signals. Although the methodology of the various
data mining methods applied in pharmacovigilance
differ, they all share the characteristic that they
express to what extent the number of observed
cases differsfrom the number of expected cases.
Severalapproaches of data mining are currently in
use. Proportional reporting ratios (PPRs), compare
the proportion of reports for a specific ADR
reported for a drug with the proportion for that
ADR in all other drugs.
The calculation is analogous to that of relative risk.
Using the same information, itis also possible to
calculate a ‘reporting odds ratio’. The Bayesian
confidence propagation neural network (BCPNN)
method is used to highlight dependencies in a data
set. This approach uses Bayesian statistics
implemented in a neural network architecture to
analyse all reported ADR combinations.
Quantitatively unexpectedlystrong relationships in
the data are highlighted relative to general
reporting ofsuspected adverse effects. The WHO
Collaborating Centre for International Drug
Monitoring uses this method for data mining. A
related approach is the Multi-Item Gamma
Poisson Shrinker (MGPS) usedby the FDA for data
mining of their spontaneous report’s database.
The MGPSalgorithm computes signal scores for
pairs, and for higher-order (e.g., triplet,
quadruplet) combinations of drugs and events that
are significantly more frequentthan their pair-wise
associations would predict [44]. All data-mining
approachescurrently cannot distinguish between
associations that are already known and new

associations. Moreover, clinical information
described in the case reports is not taken into
account; consequently, there is still the need for a
reviewer to analyse these events.
INTENSIVE MONITORING
In the late 1970s and early 1980s a new form of
active surveillance was developed in New Zealand
(the Intensive Medicines Monitoring Programme)
and the UK (Prescription Event Monitoring). These
intensive monitoring systems use prescription data
to identify users of a certain drug. The prescriber
of the drug is asked about any adverse event
occurring during the use of the drug being
monitored.These data are collected and analysed
for new signals. The methodology of these
intensive monitoring systems has been described in
depth elsewhere [45–48]. The basis of intensive
monitoring is a non-interventional observational
cohort, which distinguishes it from spontaneous
reportingbecause the former only monitors selected
drugs during a certain period of time.
Through its non-interventional character,intensive
monitoring provides real world clinical data
involving neither inclusion nor exclusion criteria
throughout the collection period. It is unaffected by
the kind of selection and exclusion criteria that
characterise clinical trials, thereby eliminating
selection bias. Another strength of the
methodology is that it is based upon event
monitoring and is therefore capableof identifying
signals for events that were not necessarily
suspected as being ADRs ofthe drug being studied.
Intensive monitoring programmes also enable the
incidence of adverse events to be estimated, thus
enabling quantification of the risk of certain
ADRs. This approach, however, also has
recognised limitations.The proportion of adverse
effects that go unreported to doctors is unknown.
The studies also produce reported event rates
rather than true incident rates. This is the same for
all studies based on medical record data,including
computer databasesand record linkage. There is
no control group in standard intensive monitoring
studies, and the true background incidence for
events is therefore not known.
DATA BASE STUDIES
In order to test a hypothesis, a study has to be
performed. The study can be conductedusing a
variety of methods, including case– control
studies and cohort studies. The limitations of
these methods include power considerations and
study design. In order to be able to conduct
retrospective cohort and case–controlstudies, data
which have been collected in a reliable and
routine fashion needs to be available. The
General PracticeResearch Database (GPRD) and
the PHARMO Record Linkage System, which
will be described in further detail in the
following sections, were chosen here because
they represent two different types of European
databases. Other database- and record linkage
systems are available for research purposes in
both Europe and inNorth America.
GENERAL PRACTICE RESEARCHDATA
BASE
Virtually all patient care in the UK is coordinated
by the general practitioner (GP), and data from this
source provide an almost complete picture of a
patient, his illnesses and treatment. Members of the
GPRD, collect data from about 3 million patients
(about 5% of the UK population). These patients
are broadly representative of the general UK
population in terms of age, sex and geographic
distribution. The data collected include
demographics (age and sex), medical diagnoses
that are part of routine care or resulting from
hospitalisations, consultations or emergency care,
along with the date and location of the event.
There is also an optionof adding free text, referral
to hospitals and specialists, all prescriptions,
including date of prescription, formulation
strength, quantity and dosing instructions,
indication for treatment for all new prescriptions
and events leading to withdrawal of a drug or a
treatment. Data on vaccinations and miscellaneous
information, such as smoking, height, weight,
immunisations, pregnancy, birth, death, date
entering the practice, date leaving the practice and
laboratory results, are also collected. A recent
review of protocols using GPRD datashowed that
the database is used for pharmacoepidemiology
(56%), disease epidemiology (30%) and, to a
lesser degree, drug utilisation,
Pharmacoeconomics and environmentalhazards.
There have been over 250 publications in peer-
reviewed journalsusing the GPRD.
DEVELOPMENTS
Pharmacovigilance and the methods usedneed to
continue to develop in order to keep up with the
demands of society. In recent years, three
publications have been of utmost importance in
terms of providing guidance on the future of
pharmacovigilance. pharmacovigilance experts
from all over the world, representing different
sectors, emphasise the role of communication in
drug safety with the following statements:
1. Drug safety information must serve the health
of the public.

2. Education in the appropriate use of drugs,
including interpretation of safety information,
is essential for the public at large, as well as for
health care providers.
3. All the evidence needed to assess and
understand risks and benefits must be openly
available.
4. Every country needs a system with
independent expertise to ensure that safety
information on all available drugs is
adequately collected, impartially evaluated
and made accessible to all.
5. Innovation in drug safety monitoring needs to
ensure that emerging problems are promptly
recognised and efficiently dealt with, and that
information and solutions are effectively
communicated.
6. The active involvement of patients and the
public in the core debate about the risks and
benefits of medicines, and in decisions about
their own treatment and health.
7. The development of new ways of collecting,
analysing and communicating information
about the safety and effectiveness of
medicines; open discussion about it and the
decisionswhich arise from it.
8. The pursuit of learning from otherdisciplines
about how pharmacovigilance methods can be
improved, alongside wide-ranging
professional, official and public
collaboration.
9. The creation of purposeful, coordinated,
worldwide support amongst politicians,
officials, scientists, clinicians, patients and
the general public, based on the demonstrable
benefits of pharmacovigilance to public health
andpatient safety.
The key values that should underpin
pharmacovigilance are excellence (definedas the
best possible result), the scientific method and
transparency. The paper defines five elements
that are considered tobe essential for achieving
excellence.
Three of these are: process-oriented best
evidence, robust scientific decision-making and
effective tools to deliver protection of public
health. The other two elements, scientific
development and audit, underpinthese processes,
recognising that excellence cannot be achieved
merely byprocess
INTERNATIONAL DEVELOPMENTS
In the past, pharmacovigilance has been most
concerned with finding new ADRs, but
pharmacovigilance should be less focused on
finding harm and more focused on extending
knowledge of safety. In recentyears, regulatory
agencies have been reforming their systems in
order to keep pace with the developments in
pharmacovigilance, with the focus on beingmore
pro-active.
EUROPE
Implementation of legal tools for monitoring the
safety of medicines and for regulatory actions.
Particular emphasis wasplaced on:
1. Systematic implementation of riskmanagement
plans
2. Strengthening the spontaneous reporting
scheme through improvements of the
EudraVigilancedatabase
3. Launching the European Network of Centres
for Pharmacoepidemiology and
Pharmacovigilance (ENCePP) project to
strengthen the monitoring of medicinal
products
4. The conduct of multi-centre postauthorisation
safety studies
5. Strengthening the organisation and the
operation of the EU Pharmacovigilance
system in the course of the next 2 years,two
main areas will be covered by the European
Risk Management Strategy: further improving
of the operation of the EU Pharmacovigilance
System and strengthening the science that
underpinsthe safety monitoring for medicines
for human use.
The USA
In the USA, the FDA has had a difficulttime since
the withdrawal of rofecoxib. Themain concern is
that the FDA is not able to protect the public from
drug risks as efficiently as it might. In February
2007, on the basis of the IOM report, the FDA
announced several initiatives designed to improve
the safety of prescription drugs [26]. These
initiatives fall into four main categories. The first
is increasing the resources for drug safety
activities.
Perceiving the agency as being overly dependent on
industry funding, some observers propose
eliminating user fees. The second category of
proposed reform isnew authority for the FDA; the
agency needs regulatory tools to help assure drug
safety. This authority would be exercised through a
required risk 748 Eur J Clin Pharmacol (2008)
64:743–752 evaluation and mitigation strategy,
including measuressuch as prescribing restrictions,

limits on direct consumer marketing and
requirements for post-marketing studies. The FDA
could impose monetary penalties for non-
compliance. A third aspect of the reform is the
improvement of post marketing surveillance. A
routine systematic approach to active population-
based drug surveillance that could identify
potential safety problems is needed. Finally,
changes in the FDA management practices and
safety supervision are necessary.
Involvement of patients
Another important development is the recognition
of the patient as an important player in
pharmacovigilance. Patients are the users of
drugs, and it is their use of a drug in a safe manner
is the ultimate goal of pharmacovigilance
activities. In an increasing number of countries
patients are now allowed to report ADRs to the
spontaneous reporting system. The European
Commission acknowledges the role of the patient
in spontaneous reporting.
Patients and patient organisations are becoming
increasingly more involved inpharmacovigilance,
especially when it comes to risk communication.
After introducing patient reporting in the
spontaneous reporting scheme in 2004, the
Netherlands Pharmacovigilance Centre Lareb
took patient reporting one step further and
introduced, in 2006, an intensive monitoring
programme using patients as a source of
information. The Lareb intensive monitoring
programme (LIM), follows the prescription-event
monitoring methodology in that patients are
identified on the basis of prescriptions.
Eligible patients are identified in their pharmacies
when they come and pick upfor the first time the
drug under study. Patients can register at the LIM
website, andduring a certain period of time they
will receive questionnaires asking them about
adverse events. The system is totally web- based;
consequently, questionnaires can besent via email
to participating patients at different points,
allowing the collection of longitudinal data. The
high level of automation also allows a rapid
collectionand analysis of data.
References
[1] World Health Organisation Collaborating
Centre for International Drug monitoring
(2007) the importance of
pharmacovigilance. Available at
http://www.who-umc.org. Cited 18 Dec2007
[2] Bresalier RS, Sandler RS, Quan H et al.
(2005) Cardiovascular events associated
with rofecoxib in a colorectal adenoma
chemoprevention trial. N Engl J Med
352:1092–1102
[3] Topol EJ (2004) failing the public health–
rofecoxib, Merck, and the FDA. N Engl J
Med 351:1707–1079
[4] Horton R (2004) Vioxx, the implosion of
Merck, and aftershocks at the FDA. Lancet
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[5] Hampton T (2005) Experts point to lessons
learned from controversy over rofecoxib
safety. JAMA 293:413–414
[6] Krumholz HM, Ross JS, Presler AH et al.
(2007) What have we learnt from Vioxx? Br
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[7] Nissen SE, Wolski K (2007) Effect of
rosiglitazone on the risk of myocardial
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Cardiovascular risk and the
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JAMA

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