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

Advanced Methodologies in Pharmacovigilance

V Sai Kruthika, Sarvani Ekathmika, Prathamesh Golapkar
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ABSTRACT How to cite this paper: V Sai Kruthika |

The World Health Organization defines pharmacovigilance as "the Sarvani Ekathmika | Prathamesh
science and actions connected to the detection, evaluation, Golapkar "Advanced Methodologies in
understanding, and prevention of adverse effects or any other drug- Pharmacovigilance"
Published in
related problem." Pharmacovigilance is critical in ensuring that
International Journal
patients receive safe pharmaceuticals. We can learn more about a
of Trend in
drug's side effects through a variety of methods, including Scientific Research
spontaneous reporting, diligent monitoring, and database research. and Development
Novel mechanisms are being established at both the regulatory and (ijtsrd), ISSN: 2456- IJTSRD55052
scientific levels to increase pharmacovigilance. They include 6470, Volume-7 |
conditional approval and risk management strategies on a regulatory Issue-2, April 2023, pp.510-514, URL:
level, and openness and increasing patient engagement on a scientific www.ijtsrd.com/papers/ijtsrd55052.pdf
one.
Copyright © 2023 by author (s) and
OBJECTIVE International Journal of Trend in
To review and discuss various aspects of pharmacovigilance, Scientific Research and Development
including new methodological developments. Journal. This is an
Open Access article
KEYWORDS: spontaneous reporting, data mining in spontaneous distributed under the
reporting, intensive monitoring, general practice research data base, terms of the Creative Commons
developments, international developments Attribution License (CC BY 4.0)
(http://creativecommons.org/licenses/by/4.0)

INTRODUCTION:
The topic of medication safety has recently pharmacovigilance is to deliver medications to the
received a lot of attention. Nearly frequently, public with a favourable benefit-harm profile. In
stories in tabloids and scholarly publications are this context, several regulatory post-marketing
published about medications that induce monitoring difficulties will be explored, followed
unanticipated adverse drug responses (ADRs). by a description of the methods utilised to
These stories have had the regrettable effect of discover new ADRs and a review of the
raising concerns about the usage of these advantages and cons of each strategy.
medications among both patients and health
There are three stages to pre-marketing clinical
professionals. A more significant outcome might
testing. Phase III investigations are frequently
be that the patient discontinues taking the
double-blind randomised controlled trials, which
recommended drug, which could lead to a condition
are regarded as the most rigorous method of
even worse than the ADR he was initially
assessing if a treatment-effect association exists.
concerned about. The World Health Organization
(WHO) defines pharmacovigilance as "the However, when it comes to monitoring the safety
science and activities relating to the detection, of a drug, this study design is not optimal. Due to
assessment, understanding, and prevention of the limited number of patients participating, it is
adverse effects or any other drug-relatedproblem," generally not possible to identify ADRs that occur
and it plays a critical role in ensuring that doctors, only rarely. The relatively short duration of clinical
in collaboration with the pharmaceutical industry. trials makes it difficult to detect ADRs with a long
latency. Another limitation of clinical trials is the
METHODS USED IN population in which a drug is tested. In order to
PHARMACOVIGILANCE study rare ADRs, ADRs with a long latency and
Pharmacovigilance efforts are broadly classified
ADRs in specific populations, careful monitoring
into three categories: regulatory, industry, and
of the drug in the post-marketing phase is essential.
academia. The goal of regulatory

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Post-marketing studies can be descriptive or while selective reporting of suspected concerns
analytical. Descriptive studies generate hypotheses might create the impression of a risk that does not
and attempt to describe the occurrence of events exist. Underreporting and selective reporting, on
related to drug toxicity and efficacy. Analytical the other hand, might be viewed as benefits.
studies test hypotheses and seek to determine When only the most severe and unexpected
associations or causal connections between occurrences are reported, it is simpler to discover
observed effects and particular drugs, and to new ADR signals because the individual
measure the size of these effects. Descriptive reporting the response has already identified what
studies are widely used in post-marketing may be a new safety risk.
surveillance because they are able to generate
DATA MINING IN SPONTANEOUS
hypotheses that will become starting points for
REPORTING
analytical studies. Two forms of descriptive
In the past, signal identification in spontaneous
studies— spontaneous reporting and intensive
reporting was mostly accomplished by case-by-
monitoring—will be discussed here. Analytical
case analysis of reports. Yet, data mining
studies can be conducted using a variety of
techniques have grown in popularity in recent
approaches, including case–control studies, cohort
years. The phrase 'data mining' refers to the
studies and clinical trials. In order to be able to
process of analysing data from many angles and
conduct retrospective cohort and case–control
extracting important information.
studies, data which have been collected in a
reliable and routine manner needs to be available. Algorithms are frequently employed in huge
databases to discover hidden patterns of
SPONTANEOUS REPORTING
correlations or unexpected occurrences, i.e.,
In 1961, a letter from the Australian physician WG
signals. Although the methodology of the various
McBride was published in Lancet. In this letter, he
data mining methods applied in pharmacovigilance
shared his observation that babies whose mothers
differ, they all share the characteristic that they
had used thalidomide during pregnancy were born
express to what extent the number of observed
with congenital abnormalities more often than
cases differs from the number of expected cases.
babies who had not been exposed to thalidomide in
Several approaches of data mining are currently in
utero [33]. In the years to come it became evident
use. Proportional reporting ratios (PPRs), compare
that thousands of babies had been born with limb
the proportion of reports for a specific ADR
malformations due to the maternal use of
reported for a drug with the proportion for that
thalidomide. In order to prevent a similar disaster
ADR in all other drugs.
from occurring, systems were set up all over the
world with the aim of regulating and monitoring The calculation is analogous to that of relative risk.
the safety of drugs. Spontaneous reporting systems Using the same information, it is also possible to
(SRS) were created, and these have become the calculate a ‘reporting odds ratio’. The Bayesian
primary method of collecting post marketing confidence propagation neural network (BCPNN)
information on the safety of drugs. The main method is used to highlight dependencies in a data
function of SRS is the earlydetection of signals of set. This approach uses Bayesian statistics
new, rare and serious ADRs. A spontaneous implemented in a neural network architecture to
reporting system enables physicians and, analyse all reported ADR combinations.
increasingly more often, pharmacists and patients Quantitatively unexpectedlystrong relationships in
to report suspected ADRs to a pharmacovigilance the data are highlighted relative to general
centre. The task of the pharmacovigilancecentre is reporting ofsuspected adverse effects. The WHO
to collect and analyse the reports and to inform Collaborating Centre for International Drug
stakeholders of the potential risk when signals of Monitoring uses this method for data mining. A
new ADRs arise. related approach is the Multi-Item Gamma
Spontaneous reporting is also used by the Poisson Shrinker (MGPS) usedby the FDA for data
pharmaceutical industry to collect information mining of their spontaneous report’s database.
about their drugs. By using an SRS, it is feasible to The MGPS algorithm computes signal scores for
monitor all medications on the market for a pairs, and for higher-order (e.g., triplet,
relatively modest cost over their full life cycle. The quadruplet) combinations of drugs and events that
fundamental critique of this technique is the are significantly more frequent than their pair-wise
possibility of selective reporting and associations would predict [44]. All data-mining
underreporting, which can lead to the incorrect approaches currently cannot distinguish between
conclusion that a genuine danger does not exist, associations that are already known and new

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

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

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limits on direct consumer marketing and adverse events. The system is totally web- based;
requirements for post-marketing studies. The FDA consequently, questionnaires can be sent via email
could impose monetary penalties for non- to participating patients at different points,
compliance. A third aspect of the reform is the allowing the collection of longitudinal data. The
improvement of post marketing surveillance. A high level of automation also allows a rapid
routine systematic approach to active population- collectionand analysis of data.
based drug surveillance that could identify
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