INTRODUCTION

Pharmacovigilance
Pharmacovigilance (PV) was born in 1963 after the disaster caused by thalidomide in 1961,
with the 16th World Health Assembly (WHA 16.36) that adopted a resolution, which
reiterated the need for early intervention with regard to the rapid dissemination of information
on adverse drug reactions (ADRs). This led, later, in 1968, to the creation through World
Health Organization (WHO) of a pilot research project for international drug monitoring.[1]
The purpose of this was to develop a system, applicable internationally, for detecting
previously unknown or poorly understood adverse effects of medicines.[2] From this, practice
and science of PV emerged.[3]
PV is defined as the science and activities relating to the detection, assessment, understanding
and prevention of adverse effects and of all other drug problems.[1] Furthermore, the WHO
program for international drug monitoring aims at developing comprehensive global PV
strategy that responds to the health-care needs of all countries.[4] As previously stated by the
WHA , the WHA 16.36 (1963) led to the creation of the WHO program for international drug
control. Under this program, systems have been created in Member States for the collection
and evaluation of individual case safety reports (ICSRs). [5]
ADRs knowledge led to increased recognition and reporting of the events. In developed
countries, 12% of admissions is caused by ADRs and these are the fourth and the sixth most
common cause of death.[6] Furthermore, the increase in the average age of the population is
related to a proportional increase in the number of drugs used (due to the prevalence of
chronic diseases, such as hypertension, heart failure, glaucoma, prostatic hyperplasia,
diabetes, etc.) resulting in an exponential increase of the ADRs.[7] Other possible causes are
the rapid development of new molecules for diseases previously intractable and new
treatment alternatives for other common pathologies with a significant growth in the number
of drugs commercially available. This can generate a lack of health professionals’ knowledge
about the potential adverse effects due to drug-drug interactions or contraindications of some
dugs caused by improper use. [8-10] Furthermore, the introduction of generic drugs has also
increased the number of patients not responding to treatments or with ADRs due to increased
bioavailability. [11,12]
In all countries, PV systems rely on spontaneous (or voluntary) communication, in which
suspected ADRs are reported by the medical staff or by patients themselves to a national
health coordinating centre. The spontaneous reporting systems provide the highest volume of
information at the lowest maintenance cost[13] and have established their value in the early
diagnosis of problems related to safety in patients or their products or their use.[14] Most
important function of the spontaneous reporting systems is the early identification of
signals[15] and the formulation of hypotheses, which leads to further investigations, in order
to confirm or refute any possible risks related to the use of a medication, any possible changes
in the package insert and give updated information product.[16 ]
In some cases, the withdrawal of marketing authorizations are also based on ICSRs, for
example, in the case of cerivastatin, an association (a “signal”) among cerivastatin, myopathy
and rhabdomyolysis has been published on the basis of ICSRs, from the Uppsala Monitoring

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Centre in 1999 and various regulatory decisions were announced between 1999 and 2001in
different countries.[17] Unfortunately not in all countries, the voluntary reporting reaches
standard levels set by the WHO(300 reported ADRs/1 million people),[18] under-reporting,
according to literature data, appear to be due to: Lack of knowledge (it is believed that only
serious adverse reactions should be reported), lack of interest or time, the indifference to the
problem, the uncertainty about the causal link between a drug and an ADR; the mistaken
belief that only safe drugs are marketed. For these reasons, Agenzia Italian del Farmaco
(AIFA) has been promoting several projects on the whole national territory and managed at
regional level, in order to increase “PV Culture”.

Oncology
Oncology is the branch of medicine that focuses on the prevention, diagnosis, and treatment
of cancer. Cancer is a disease characterized by uncontrolled cell growth, which can invade
nearby tissues and spread (metastasize) to other parts of the body.
A hundred years ago, cancer was not so common; however, since the last couple of decades,
its incidence has been rising alarmingly, probably due to our changing lifestyle, habits, and
increased life expectancy. Cancer is one of the most dreaded diseases of the 20th century and
spreading further with continuance and increasing incidence in the 21st century. The situation
is so alarming that every fourth person is having a lifetime risk of cancer. India registers more
than 11 lakh new cases of cancer every year, whereas, this figure is above 14 million
worldwide. We are constantly exposed to a variety of cancer-causing agents, known as
carcinogens.
What is cancer? Put simply; cancer is the abnormal growth of cells. Cancers arise from any
organ or body structure and are composed of tiny cells that have lost the ability to stop
growing. Occasionally, cancer may be detected “incidentally” by a laboratory test or
radiological routine test or for an entirely different reason. In general, cancer must reach a
size of 1 cm, or be comprised of 1 million cells, before it is detected. At this point, it may be
referred to as a “‘mass,” a “growth,” a “tumour,” a “nodule,” a “lump,” or a “lesion.”
Exceptions to this general rule include cancers of the blood and bone marrow (leukaemia’s
and lymphomas) – which frequently do not produce a “mass,” but will be evident on
laboratory tests.
Transformation of a normal cell into a cancerous cell is probably not such a critical event in
the genesis of cancer; rather it is the inability of immune cells of the body to identify and
destroy the newly formed cancer cells when they are a few in numbers. The risk of cancer is
multiplied in those persons, whose immune system is suppressed due to any factor including
chronic stress, old age, chronic debilitating disease, previous use of chemotherapy, and abuse
of drugs such as analgesics, antibiotics, and corticosteroids.[19].

Multidisciplinary Aspects
Cancer cells continue to grow unless one of four things occur: [20] The cancerous mass is
removed surgically; [21] using chemotherapy or another type of cancer-specific medication,
such as hormonal therapy; using radiation therapy; or the cancer cells shrink and disappear

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on their own. This last event, while extremely rare, can occur with some melanomas or some
kidney cancers.
Surgery, radiotherapy, and chemotherapy from the conventional approaches are used to treat
cancer. Surgery was the first modality used successfully in the treatment of cancer. It is the
only curative therapy for many common solid tumours. The most important determinant of a
successful surgical therapy is the absence of distant metastases and no local infiltration.
Chemotherapy is the administration of cytotoxic agents (orally or intravenously, usually in
combinations) resulting in cytotoxicity to both resting and dividing cells. The objective of
cancer chemotherapy is to prevent cancer cells from multiplying, invading, metastasizing, and
killing the patient. Systemic chemotherapy is the main treatment available for disseminated
malignant diseases. Radiation therapy is a local modality used in the treatment of cancer.
Other conventional techniques used in the treatment of cancer including bone marrow
transplantation, peripheral stem cell transplantation, hormone therapy, photodynamic therapy,
cryosurgery, immunotherapy, and gene therapy.
Is cancer curable? The short answer to this question is “Yes.” In fact, all cancers are curable
if they are caught early enough. That is the justification for screening tests (such as
mammograms, colonoscopies, and Pap smear examination). When cancers are caught early,
they tend to be smaller; they are thus either easier to remove surgically or more likely to
shrink in response to chemotherapy or radiation therapy. When cancer is localized, it can be
totally removed by surgery but in most of the cases, it is practically impossible to detect
cancer at such an early stage. Early detection is often the key to surviving any form of cancer.
The diagnosis and treatment of cancer have come a long way in the last 50 years. In the past,
cancer, the “C-word,” was a death sentence. Today, we can treat and cure several types of
cancer; however, it is evident that these cancers need to be found at an early stage. More than
7 out of 10 children are cured of cancer. Testicular cancer, Hodgkin’s lymphoma and many
cases of leukaemia can all be cured in adults with current treatments. Most skin cancers are
cured with surgery. Moreover, many cases of thyroid cancer and cancer of the larynx are
cured with radiotherapy. Many other types of cancer are also cured if they are found early
enough – for example, 75% of breast cancers found at an early stage. Of course, there is still a
long way to go before we can cure most cancers. The difficulty is that different cancers are
caused by different things, so there is not one strategy that can prevent them. They also
respond to different treatments, so not one kind of treatment can cure them all. Even though
we can cure several types of cancers, it is important to maintain vigilance about screening for
cancer.
Some forms of cancer are curable no matter when they are detected, and some are only
curable if they are caught at any early stage. For example, acute leukaemia and some types of
lymphoma can be curable with chemotherapy. Certain lymphomas such as Hodgkin’s disease
require radiation therapy for a cure. Other common cancers such as colon cancer, breast
cancer, prostate cancer, lung cancer, and pancreatic cancer are all curable, but only if they are
detected in early stages (Stage I or II).
Some cancers have high survival rates with early detection. Six highly treatable cancers
among others are – cancers of breast, skin (nonmelanomas), colon, prostate, testes, and
cervix. Most of the childhood malignancies (both solid and haematolymphoid) are curable.
Breast cancer is the most common nonskin cancer among women, as one out of every eight
women will be diagnosed in her lifetime. In patients whose breast cancer is detected while

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still in localized form have a 5-year survival rate of 98%, compared with a survival rate of
72% by Stage III and just 22% by Stage IV. [22,23]
Skin cancers (basal cell carcinoma and squamous cell carcinoma) are the most common form
of all human cancers, and if found early, skin cancer is nearly 100% treatable. Likewise,
diagnosing cervical cancer while the lesions are precancerous leads to a near 100% survival
rate, but the rate drops to just 32% if diagnosed in Stage III and 16% if diagnosed at Stage IV.
Testicular cancer is treatable in 99% of the time when detected early, but only 73% are
cancer-free after 5 years if diagnosed in advanced stages. Similarly, 5-year survival rate when
colon cancer is detected early is 90%, yet only 39% of cases are diagnosed before cancer has
begun to spread. According to the Surveillance, Epidemiology, and End Results Program, it is
98% survivable for 5 or more years if prostate cancer diagnosed at stages when the disease is
confined to the prostate gland (Stage I and II).[20] The survival rate drops to about 28% if
diagnosed at Stage IV.
Cancers cells not only have mutations that result in dysregulated expression of oncogenes
and tumour suppressor genes, but these changes result in the alteration of expression of
hundreds of genes. Looking at this, we have various forms of “targeted” therapy directed at
specific single molecular targets or a class of molecular targets in cancer cells. With targeted
therapy, the specific mechanism of action of the drug results in an increase in its therapeutic
index. Currently, the two major classes of targeted therapy are the small molecule tyrosine
kinase inhibitors and monoclonal antibodies (MABs). Imatinib, for instance, has been
amazingly successful as a targeted agent directed against several members of a class of
enzyme known as tyrosine kinases, and by that mechanism, it has been phenomenally
successful as a treatment of chronic myeloid leukaemia and gastrointestinal stromal tumors.
Tamoxifen is a targeted therapy directed at the estrogen receptor (ER), and it still remains a
mainstay of treatment for ER-positive breast cancers, along with a newer class of drugs
known as aromatase inhibitors.[24]
Cancer researchers work on developing new and more effective surgery techniques,
radiotherapy and chemotherapy drugs all the time. Biological therapies such as MABs, cancer
vaccines, and gene therapies are all active areas of research. There are various anti-angiogenic
drugs that can stop cancers from growing the blood vessels that they need. Research is also
looking into developing cost-effective ways of screening for the different common cancers so
they can be diagnosed early enough to be cured.
Avoiding immune destruction is now considered a hallmark of cancer, and the
immunotherapy arena has exploded with the recent advances demonstrating an improvement
in survival and a durability of response in patients with different cancer types, like in
melanoma, which translates into an improved overall survival benefit.[25] To name those
immunotherapeutic strategies that include the adoptive transfer of ex vivo activated T cells,
immunomodulatory MABs, and cancer vaccines. Advances in molecular pathology will
provide the means to identify the targets and will be used to subtype tumours and will provide
predict response to therapy and provide prognostic information.[26]

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In recent years, anticancer treatments have seen an enormous evolution. Targeted therapies
are a new generation of anticancer drugs which interfere with specific molecules that are
involved in the growth, progression, and spread of cancer, and are expressed by specific
cancer types. These drugs have introduced the concept of individually-tailored cancer
treatment. The specific mechanism of action of target therapies should cause fewer toxic
effects than conventional chemotherapy drugs [20]. The specific safety profile of each new
drug, which is the information known about its safety at the time of marketing, has always
been based on pivotal clinical trials. For this reason, the adverse drug reactions (ADRs)
reported in the Summary of Product Characteristics (SPC) cannot be exhaustive [21–23],
because the potential new drugs are tested under controlled conditions, with a small sample of
selected patients, and often with a short follow-up time. The differences between selected
patients enrolled in clinical trials and the real-world patients regard the characteristics of the
latter [2]. Often, the real-world patients in oncology are represented by elderly patients which
may be considered as a “special population”. Elderly patients are at a high risk of ADRs,
medical errors, and drug interactions, because of comorbidities, polypharmacy, greater
vulnerability, and age-related changes in pharmacokinetics and pharmacodynamics [23].
In everyday clinical practice, there is a significant list of side-effects that can be ascribed to
targeted drugs; indeed, although they are different from the well-known side effects caused by
chemotherapy, they can severely compromise patients’ quality of life, and can even cause
discontinuation of therapy or changes in the therapeutic strategy [24].
Pharmacovigilance aims to improve patients’ safety through the detection of ADRs.
Spontaneous reporting is the best method for highlighting adverse drug reactions outside
clinical trials [25].
In oncology, under-reporting of adverse reactions is a common phenomenon, because ADRs
are generally considered inevitable [26]. In addition, there is a relevant decrease of patient’s
satisfaction during anticancer treatment as a consequence of ADRs. A shift in the trend of
reporting ADRs by health professionals and patients is considered to be an important element
to improve patient’s safety and adherence to targeted therapies. The involvement of patients
in Pharmacovigilance reporting systems (PVRS) is a potential strategy to increase the
knowledge of oncological ADRs, increase patient’s satisfaction, and reduce the phenomenon
of under-reporting [27–29].

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 Aim and Objectives

Aim:

To evaluate the role of Pharmacovigilance in oncology by assessing the awareness,

Knowledge, and attitude towards adverse drug reactions and safety monitoring of cancer
drugs.

Objective:

1. To assess the awareness and understanding of pharmacovigilance among the general

public, pharmacy students, and cancer patients.
2. To evaluate the knowledge and perception regarding adverse drug reactions (ADRs)
associated with cancer therapy.
3. To identify common side effects and safety concerns reported during cancer
treatment.
4. To highlight the importance of ADR reporting systems in improving cancer patient
care and drug safety.
5. To promote awareness about the role of pharmacovigilance in ensuring the safe and
effective use of oncology medications.
6. To analyze data collected through surveys to identify gaps in knowledge and areas
needing awareness campaigns.

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 LITERATURE REVIEW

3.1. Pharmacovigilance in oncology

Background Side effects of cancer therapy are one of the most important issues faced
by cancer patients during their illness. Pharmacovigilance, namely the science and activities
aimed at monitoring the safety of drugs, is particularly important in oncology, due to the
intrinsic biologic toxicity of antineoplastic agents, their narrow therapeutic windows, and the
high doses and rigid timing of treatment regimens. Aim of the review to identify the main
issues in carrying out an effective pharmacovigilance activity in oncology. Method, we
searched PubMed for articles about pharmacovigilance in relation to chemotherapy,
radiotherapy and targeted therapy for cancer, using Mesh terms and text words. We also
searched Embase, CINAHL, Scopus, Micromedex, the Cochrane Library, two
pharmacovigilance databases and the Gray literature for articles published in 2012–2018.
Overall, 137 articles were considered potentially relevant and were critically appraised
independently by two authors, leading to the inclusion of 44 relevant studies, guidelines and
reviews. Another 10 important research reports were included in the review. Results Eight
critical issues of pharmacovigilance in oncology were identified. These issues pertain to:
terminology; range of side effects; targeted therapy and immunotherapy; chemoradiotherapy;
generic drugs and biosimilars; drug interactions, pharmacogenetics and polypharmacy;
special patient categories; and under-reporting of ADRs. Conclusion The importance of
pharmacovigilance in oncology must be highlighted with every effort, to improve safety and
offer cancer patients every possible help to improve their quality of life during such a critical
period of their lives. [30]

3.2. Pharmacovigilance in oncology: evaluation of current practice and future

perspectives
Pharmacovigilance (PV), or drug safety monitoring, aims to improve patient safety
through the detection and management of drug-related adverse reactions. It is implemented
both by spontaneous reporting of adverse drug reactions (ADRs) and by careful detection of
signals suggestive of drug toxicity. PV is an important clinical topic in clinical practice and
pharmacotherapy, assuring the maintenance of a safe risk/benefit ratio throughout the
commercial life cycle of a drug
We conducted a structured literature search on PubMed, Scopus, Cinahl and the Cochrane
Library. We also performed manual searches in international databases of ADR individual
reports to outline a structured profile on the topic. Our goal was to review key elements that
affect safety monitoring of cancer drugs and their appropriate use, highlighting the strengths
and weaknesses of PV in oncology.
This paper provides an understanding of the methodologies used by PV in current clinical
practice and particularly in cancer drug therapy; a focus upon reporting of ADRs by health
professionals and patients; and a focus upon methods used by PV to detect new signals of
risk/harm related to medicines utilization.

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To our knowledge, few articles focus upon the importance of PV and post-marketing
surveillance of cancer drug therapies. Structured management of spontaneous reports of
ADRs and data collection is essential to monitoring the safe use of drugs in this field in which
pharmacotherapy is affected by high incidence of drug-related complications and by a narrow
benefit/risk ratio. [31]

3.3. Relevance of the Weber effect in contemporary pharmacovigilance of oncology

drugs
Numerous reporting biases have been known to affect spontaneous reporting
databases. The Weber effect, which constitutes a peak in adverse event (AE) reporting of a
drug at the end of second year after regulatory approval followed by a continuous decline
thereafter, has been considered an important bias for a long time. The existence of this bias in
AE reporting of oncology drugs remains an under evaluated area, prompting a targeted
examination.
The US Food and Drug Administration (USFDA) Adverse Event Reporting System (FAERS)
was studied for AE reporting patterns of 5 years of 15 new molecular entities (NMEs) and
biologics used in oncology. This 5-year period started from the USFDA date of approval for
the NMEs and biologics. The number of AEs reported for each of the drugs was plotted
against time (years). The AE reporting patterns were specifically examined for the existence
of the Weber effect. In addition, AE reporting rate patterns of 5 years of seven NMEs and
biologics used in oncology were examined.
A total of 50,630 AE reports were logged in to the FAERS for all 15 drugs examined for AE
reporting patterns. We observed five distinct AE reporting patterns for 15 drugs; however,
none of the AE patterns were identical to the Weber effect. We did not observe a consistent
AE reporting rate pattern for the seven drugs examined for AE reporting rates. With the
exception of one drug (cetuximab), none of the drugs exhibited a second-year peak in AE
reporting rates. This peak was not followed by continuous decline in AE reporting rate
thereafter.
This study does not support the existence of the Weber effect in AE reporting of oncology
drugs. The contemporary AE reporting of oncology drugs does not exhibit a consistent
pattern. [32]

3.4. Pharmacovigilance of anti-cancer medicines: opportunities and challenges

The foundations of pharmacovigilance are the monitoring of drug safety in real-world
medicine, and identification of new adverse effects, unknown at the time of market approval.
Cancer patients are prone to adverse drug reactions due to the complexity of the neoplastic
disease and its treatment. Pharmacovigilance of anti-cancer medicines is further complicated
because patients have comorbidities, as for elderly patients. It is even more challenging when
complete safety and risk data for a drug are lacking, as may occur for new molecules or when
it comes to drugs for children.
This article introduces the field of pharmacovigilance of anti-cancer drugs, describing the
various layers of complexity that make the recognition of adverse drug events in oncology

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particularly problematic, including the type of medicines, the phenomenon of underreporting
and polypharmacy. Finally, it reviews new digital tools to help pharmacovigilance activities in
oncology.[33]

3.5. Pharmacovigilance in oncology: pattern of spontaneous notifications, incidence of

adverse drug reactions and under-reporting
The high toxicity and narrow therapeutic window of antineoplastic agents makes
pharmacovigilance studies essential in oncology. The objectives of the current study were to
analyze the pattern of spontaneous notifications of adverse drug reactions (ADRs) in
oncology patients and to analyze the incidence of ADRs reported by outpatients on
antineoplastic treatment in a tertiary care teaching hospital. To compose the pattern of ADR,
the notification forms of reactions in oncology patients in 2010 were reviewed, and the
reactions were classified based on the drug involved, mechanism, causality, and severity. To
evaluate the incidence of reactions, a questionnaire at the time of chemotherapy was included,
and the severity was classified based on the Common Terminology Criteria. The profiles of
the 10 responses reported to the Pharmacovigilance Sector were type B, severe, possible, and
they were primarily related to platinum compounds and taxanes. When the incidence of
reactions was analyzed, it was observed that nausea, alopecia, fatigue, diarrhea, and taste
disturbance were the most frequently reported reactions by oncology patients, and the grade 3
and 4 reactions were not reported. Based on this analysis, it is proposed that health
professionals should be trained regarding notifications and clinical pharmacists should
increasingly be brought on board to reduce under-reporting of ADRs.[34]

3.6. Targeted therapies and adverse drug reactions in oncology: the role of clinical
pharmacist in pharmacovigilance
Background The majority of adverse drug reactions (ADRs) reported in the summary
of product characteristics (SPCs) are based on pivotal clinical trials, performed under
controlled conditions and with selected patients. Objectives (1) to observe ADRs in the real-
world setting and to evaluate if the supervision of the pharmacist impacts on the management
of ADRs and on the satisfaction of patients; (2) to sensitise health professionals and patients
on the need to increase the reporting of ADRs, in compliance with
Pharmacovigilance. Setting CRO Aviano, Italian National Cancer Institute. Method From
February 2013 to April 2015, we conducted an observational study enrolling 154 patients (≥
18 years) undergoing treatment with at least one of ten targeted-therapies included in the
study. Main outcome ADR reporting in the real-world setting. Patient satisfaction with
clinical pharmacist support. Results Reported ADRs in the real setting do not always
correspond with data described in the respective SPCs. Unknown ADRs were also identified
such as hyperglycaemia with lenalidomide and sorafenib; and hypomagnesaemia with
bevacizumab. We also observed a 124.3% increase in spontaneous reports. Conclusion This
study shows the high value of active pharmacovigilance programs, and our results might be a
starting point for developing a randomised trial which should aim to demonstrate the impact
of the pharmacist on improving patient’s adherence and in measuring the difference in ADRs
reports in the different arms followed or not by the pharmacist.[35]

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3.7. Pharmacovigilance Practices by Healthcare Providers in Oncology: A Cross-
Sectional Study
patient safety in oncology settings. This study aimed to assess the awareness,
attitudes, and practices towards PV and identify barriers to effective adverse drug reaction
(ADR) reporting for HCPs working in oncology-related settings. Employing a cross-sectional
survey design, we collected data from 65 HCPs, focusing on their experiences with ADR
reporting, education on ADR management, and familiarity with PV protocols. The results
showed that about half of the responders were pharmacists. Around 58.9% of the respondents
reported ADRs internally, and 76.9% had received some form of ADR-related education.
However, only 38.5% were aware of formal ADR review procedures. Methotrexate and
paclitaxel emerged as the drugs most frequently associated with ADRs. The complexity of
cancer treatments was among the common reasons for the low reporting of ADRs by the
study participants. The findings highlight the need for enhanced PV education and
standardized reporting mechanisms to improve oncology care. We conclude that reinforcing
PV training and streamlining ADR-reporting processes are critical to optimizing patient
outcomes and safety in oncology, advocating for targeted educational interventions and the
development of unified PV guidelines.[36]

3.8. Intensive safety monitoring program of antineoplastic medicines: A pilot study in a

Portuguese oncology hospital
The aim of this study was to test the feasibility and the usefulness of an intensive
safety monitoring program to identify adverse drug reactions for medicines under additional
monitoring that are used to treat cancer patients within a Portuguese oncology hospital.
This pilot intensive safety monitoring program was a three-month prospective, observational
study. Patients undergoing treatment with one of the following medicines were included:
nivolumab, olaparib, palbociclib, pembrolizumab, pertuzumab, ramucirumab, ribociclib,
trastuzumab emtansine, or trifluridine/tipiracil. Potential eligible patients were identified by
pharmacists based on prescription data. Clinicians used proper paper-based reporting forms to
record adverse drug reactions. Clinical secretariats sent those reports through an electronic
platform to the pharmacovigilance department for analysis.
Seventy-five patients were on treatment with selected medicines. Of those, 33 (44%)
experienced adverse drug reactions: 23 (69.7%) cases were serious and 5 (15.2%)
unexpected. Considering the number of patients exposed to each medicine and the number of
patients experiencing adverse drug reactions, trifluridine/tipiracil (72.7%; 8/11) was
associated with the highest rate of toxicity, followed by olaparib (66.7%; 2/3), trastuzumab
emtansine (50.0%; 3/6), pertuzumab (47.8%; 11/23), pembrolizumab (45.5%; 5/11),
palbociclib (25.0%; 1/4), and nivolumab (18.8%; 3/16). A total of 59 adverse drug reactions
were identified (i.e. 1.8 adverse drug reactions/patient), mainly gastrointestinal disorders (n =
15; 25.4%), and blood and lymphatic system disorders (n = 14; 23.7%).
This intensive safety monitoring program was feasible and allowed identifying serious and
unexpected adverse drug reactions, adding value to pharmacovigilance and therefore

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contributing to improve patient safety. Further research is needed to confirm the findings of
this pilot study.[37]
.

3.9. Pharmacovigilance Safety Monitoring in Clinical Trials

Pharmacovigilance is that the science and activities associated with the gathering,
detection and assessment of adverse event data. Major purpose of pharmacovigilance is to
gauge the benefit- risk profile of drug for better efficacy and safety to be used in patients.
Pharmacovigilance plays a major role in rationale use of drug which provides the information
about the adverse drug reactions which seen in patients. In terms of volume Indian Pharma
industry is third largest in world and in terms of value id thirteen largest in world. India is also
known as a hub for clinical research and drug development. There is a requirement of a global
and standardized pharmacovigilance system in India for better safety assessment in India. In
drug development process the only priority of clinical trials is to make sure patient safety
during and after the trials. A critical component throughout the drug development life-cycle is
monitoring patient safety. Patient must be treated consistent with the requirements and illness
of patient therefore the utmost value is given to monitoring of patient safety in the least levels
of drug development. Such monitoring may be a dynamic process so to approach safety
monitoring. To ensure a systematic approach to safety monitoring pharmaceutical sponsor
must work proactively and collaboratively with all stakeholders. We have to focus upon all
the aspects of drug safety in clinical trials including basics of drug safety, regulatory aspects
of drug safety, patient suitability for safety in trials, post marketing safety and causality risk
assessment of the drug products.[38]

3.10. A real-world pharmacovigilance study of FDA Adverse Event Reporting System

(FAERS) events for osimertinib
Osimertinib was a third-generation, irreversible epidermal growth factor receptor
tyrosine kinase inhibitor (EGFR-TKI), which approved by the US Food and Drug
Administration (FDA) in 2015 for treatment of non-small cell lung cancer (NSCLC). Our
study was to explore the adverse events (AEs) caused by osimertinib through data mining of
the US FDA Adverse Event Reporting System (FAERS), and provide reference for clinical
safety. Data of osimertinib were collected from the FAERS database covering the period from
first quarter of 2016 to the fourth quarter of 2021. Disproportionality analyses was employed
to quantify the associated AE signals of osimertinib and detect the risk signals from the data
in the FAERS database. Reporting odds ratio (ROR) was used to detect the risk signals from
the data in the FAERS database. The definition relied on system organ class (SOCs) and
preferred terms (PTs) by the Medical Dictionary for Regulatory Activities (MedDRA).
Totally, 9,704,33 reports were collected from the FAERS database, 10,804 reports of
osimertinib were identified as the ‘primary suspected (PS)’ AEs. Osimertinib induced AEs
occurred in 27 organ systems. 68 significant disproportionality PTs satisfying with the four
algorithms were retained at the same time. Unexpected significant AEs such as scrotal
volvulus, hepatic function abnormal, venous thromboembolisms might also occur. The
median onset time of osimertinib-associated AEs was 58 days (interquartile range [IQR] 14–

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212 days), and the majority of the AEs occurred within the first 30 days after osimertinib
initiation. Our study found significant new AEs signals of osimertinib and might provide
support for clinical monitoring and risk identification of osimertinib.[39]

3.11. Genetic Therapy and Molecular Targeted Therapy in Oncology: Safety,

Pharmacovigilance, and Perspectives for Research and Clinical Practice
The impressive advances in the knowledge of biomarkers and molecular targets has
enabled significant progress in drug therapy for crucial diseases such as cancer. Specific areas
of pharmacology have contributed to these therapeutic outcomes—mainly targeted therapy,
immunomodulatory therapy, and gene therapy. This review focuses on the pharmacological
profiles of these therapeutic classes and intends, on the one hand, to provide a systematic
definition and, on the other, to highlight some aspects related to pharmacovigilance, namely
the monitoring of safety and the identification of potential toxicities and adverse drug
reactions. Although clinicians often consider pharmacovigilance a non-priority area, it
highlights the risk/benefit ratio, an essential factor, especially for these advanced therapies,
which represent the most innovative and promising horizon in oncology.[40]

3.12. Pharmacovigilance, Drug Interactions, Pharmacogenetics And Therapeutic Drug

Monitoring Of Anticancer Agents: A Valuable Support For Clinical Practice
Clinical Pharmacology is an integral part of Oncology, especially in the modern era of
precision medicine. The innovations introduced in drug development (conditional accelerated
tumor-agnostic approvals through adaptive trials) and clinical practice (liquid biopsy, tumor
molecular board) underline the pressing need for clinical pharmacologists, who play a catalyst
and translational role in a synchronized multidisciplinary team. This review describes the
latest advancements and challenges in actually implementing the precision medicine approach
in oncology: pharmacovigilance, drug interactions, pharmacogenetics and therapeutic drug
monitoring are often overlooked valuable tools for the understanding, detection, assessment,
and prevention of adverse drug reactions, thus supporting safe prescribing in Oncology.[41]

3.13. Improving medication safety in oncology care: impact of clinical pharmacy

interventions on optimizing patient safety
Background Adverse drug reactions (ADRs) monitoring in cancer patients is
important to ensure early detection, effective management and possible prevention
subsequently. Objectives This study was conducted to detect and monitor ADRs to anti-
cancer agents, and to assess impact of clinical pharmacists (CPs)’ interventions in minimizing
ADRs to anti-cancer agents. Setting Private, specialty oncology care hospital in South
India. Methods CPs prospectively followed cancer patients admitted to inpatient wards and
treated at ambulatory care in order to identify ADRs, for a period of 3 years.
Identified/reported ADRs were discussed with concerned oncologists and/or nurses,
documented electronically and assessed further for their causality, severity, preventability and
grading. Based on study findings during year 1, interventions (educational, therapeutic and
system based) were developed by CPs and implemented in order to minimize preventable
ADRs. Impact of CPs’ interventions was studied during year 2 and year 3. Main outcome

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measure(s) Preventable factors contributing to ADRs and percentage of preventable ADRs
before and after CPs’ interventions. Results A total of 1279 ADRs were reported in 1133
patients from a cohort of 1328 patients. Vomiting (23.22%), alopecia (9.53%), diarrhoea
(8.67%) and myelosuppression (7.42%) were the common ADRs reported. Inappropriate
administration frequency and regimen of anti-emetics (22%), lack of/suboptimal supportive
care (18%) and administration errors (16%) were identified as common contributing
(preventable) factors for ADRs in year 1. Percentage of preventable ADRs was 81% during
year 1 (pre-intervention), and 45% and 34% in year 2 and year 3 respectively (post-
interventions). Conclusion Interventions by CPs helped to minimize preventable ADRs to
anti-cancer agents.[42]

3.14. Identification of anticancer drugs associated with atrial fibrillation: analysis of the
WHO pharmacovigilance database
The explosion of novel anticancer therapies has meant emergence of cardiotoxicity
signals including atrial fibrillation (AF). Reliable data concerning the liability of anticancer
drugs in inducing AF are scarce. Using the World Health Organization individual case safety
report database, VigiBase®, we aimed to determine the association between anticancer drugs
and AF.
A disproportionality analysis evaluating the multivariable-adjusted reporting odds ratios for
AF with their 99.97% confidence intervals was performed for 176 U.S. Food and Drug
Administration (FDA)- or European Medicines Agency (EMA)-labelled anticancer drugs in
VigiBase®, followed by a descriptive analysis of AF cases for the anticancer drugs identified
in VigiBase®. ClinicalTrial registration number: NCT03530215. A total of 11 757 AF cases
associated with at least one anticancer drug were identified in VigiBase® of which 95.8%
were deemed serious. Nineteen anticancer drugs were significantly associated with AF of
which 14 (74%) are used in haematologic malignancies and 9 (45%) represented new AF
associations not previously confirmed in literature including immunomodulating agents
(lenalidomide, pomalidomide), several kinase inhibitors (nilotinib, ponatinib, midostaurin),
antimetabolites (azacytidine, clofarabine), docetaxel (taxane), and obinutuzumab, an anti-
CD20 monoclonal antibody.
Although cancer malignancy itself may generate AF, we identified 19 anticancer drugs
significantly associated with a significant increase in AF over-reporting. This
pharmacovigilance study provides evidence that anticancer drugs themselves could represent
independent risk factors for AF development. Dedicated prospective clinical trials are now
required to confirm these 19 associations. This list of suspected anticancer drugs should be
known by physicians when confronted to AF in cancer patients, particularly in case of
haematologic malignancies.[43]

3.15. A bibliometric analysis of research progress on pharmacovigilance and cancer

from 2002 to 2021
The complexity of cancer itself and treatment makes pharmacovigilance critical in
oncology. Despite rapid progress on pharmacovigilance and cancer research in the past two

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decades, there has been no bibliometric analysis in this field. Therefore, based on the Web of
Science database, we used CiteSpace, VOS-viewer and R-bibliometrix to analyze and
visualize publications, and described the development trend and research hot spots in this
field. 502 publications were included. The development of pharmacovigilance and cancer
research has continued to grow. The USA has the largest number of publications and citations,
followed by France and UK. Vanderbilt University and Sorbonne University are the
institutions that contribute the most papers, and 5 of the top 10 high-yield institutions are
from France. Salem JE and Lebrun-Vignes B of Sorbonne University have published the most
papers, and they have a strong cooperative relationship. Salem JE has the highest H
index. Drug Safety has the largest number of publications in the field of pharmacovigilance
and cancer, with a high impact factor (IF). In recent years, immune checkpoint inhibitors
(ICIs) have been identified as a hot topic and will continue to be maintained. This paper can
help researchers get familiar with the current situation and trend of pharmacovigilance and
cancer research, and provide valuable reference for the selection of future research directions.
[44]

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 TOOLS AND METHODS

4.1. Study Design

A descriptive, cross-sectional survey-based study was conducted to evaluate
awareness, understanding, and attitudes towards pharmacovigilance in oncology and the
safety monitoring of cancer drugs.
4.2. Study Population
The study targeted three groups:
General public
Pharmacy students
Cancer patients
4.3. Structured Questionnaire
A pre-designed questionnaire was created using Microsoft Word. It consisted of both
open-ended and close-ended questions, including multiple-choice and Likert scale questions.
Hospital records and case studies
4.4. Online Platform
Google Forms or similar tools were used to circulate the questionnaire digitally.
Patient Medical Records Clinical data, lab results, and prescription history

4.5. Data Recording Tools

Responses were collected and managed using Microsoft Excel for preliminary sorting
and analysis.
4.6. Method of Data Collection
Participants were selected using a non-probability convenience sampling technique.
The survey link was shared through social media platforms, email, and in-person
communication. Participants were informed about the purpose of the study, and consent was
obtained prior to their participation.

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 Results and Discussion

A total of 48 participants responded to the survey, which included individuals from the
general public (28), Pharmacy students (9), and cancer patients (2). The key findings from the
survey are summarize below
5.1.1 Age Range:
Majority of participants were between 19-35 years (79.6%)
5.1.2. Gender:
67.3% Male & 32.7% female
5.1.3. Awareness of Pharmacovigilance and ADRs:
67% (33 participants) had heard of the term pharmacovigilance, while 33% (16) had
not.
65% (32 participants) were aware of what an adverse drug reaction (ADR) is, and
35% (17) were not.
5.1.4. Awareness of Cancer Drug Side Effects:
A significant 84% (41 participants) were aware that cancer treatments often have
serious side effects.
76% (37 participants) believed it is important to monitor the side effects of cancer
drugs, while 18% were unsure, and 6% said no.
5.1.5. Beliefs about Reporting and Its Importance:
An overwhelming 94% (46 participants) agreed that reporting side effects can help
improve healthcare
73% (36 participants) were willing to report a side effect, 16% (8) said maybe, and
10% (5) said they wouldn’t report it
5.1.6. Experience with Cancer Drug Side Effects:
Nearly half of the participants (24 out of 49) had either experienced or knew someone
who experienced side effects from cancer treatment
Among them, 52% (25 participants) confirmed it was reported to a healthcare
provider, while 26% (13) said it wasn’t, and 22% (11) were not sure

5.2. This section includes screenshots of the key questions used in the survey form designed
for project and responses obtained

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Fig: 5.1.1

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Fig: 5.1.2

Fig: 5.1.3

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Fig: 5.1.4

Fig: 5.1.5

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Fig: 5.1.6

Fig: 5.1.7

Fig: 5.1.8

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Fig: 5.2.1

Fig: 5.2.2

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Fig: 5.2.3

Fig: 5.2.4

Fig: 5.2.5

Fig: 5.2.6

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Fig :5.2.7

Fig:5.2.8

Fig: 5.2.9

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Fig: 5.2.10

Fig: 5.2.11

Fig: 5.2.12

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Fig: 5.2.13

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