Miss. Shraddha Anil Naik
M.Pharmacy, Appasaheb Birnale
College of Pharmacy, Maharashtra, Sangli 416416.
*Corresponding Author E-mail: nshraddha211@gmail.com
ABSTRACT:
Pharmacovigilance definition given by WHO, it
is “The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other possible
drug-related problems. The number of Adverse Drug Reactions (ADRs) reported,
have also resulted in an increase in the volume of data handled. It is a
challenge to standardize the act of signal detection and risk management in the
context of clinical trials and post-marketing pharmacovigilance. However, with
more clinical trials and clinical research activity being conducted in India,
and also conducted in phase of clinical trials, Pharmaco epidemiologic study
there is an immense need to understand and implement pharmacovigilance. This
review describes the various strategies and proposals to build, maintain and
implement a robust pharmacovigilance system for various take holders and
eventually make it happen in India!
KEYWORDS: Adverse drug
reaction, clinical trials, Pharmacoepidemiologic Studies
INTRODUCTION:
Pharmakon (Greek) = drug
Vigilare (Latin) = to keep
watch; awake, alert; watchfulness in respect of care, danger, caution,
circumspection; process of paying close and continuous attention.
According to the
Pharmacovigilance definition given by WHO, it is “The science and activities
relating to the detection, assessment, understanding and prevention of adverse
effects or any other possible drug-related problems. Recently, its concerns
have been widened to include herbals, traditional and complementary medicines, blood
products, biological, medical devices and vaccines”.
These adverse drug
reactions (ADRs) not only add to the suffering of patients but also increase
morbidity and mortality along with a financial burden on society. The overall
incidence of ADRs in hospitalized patients is estimated to be 6.7 %and that of
fatal ADRs (0.1–0.85%). Data indicates that in patients who experience ADRs
death rates are 19.18% higher and the length of hospital stay is 8.25% higher.
Total medical costs for patients with ADRs are increased by an average
of19.86%. However, the lack of ability of clinicians to suspect or detect such
adverse events related to drugs might lead to inappropriate management of
adverse events thus exposing the patient to additional drug hazards. To minimize
the suffering of the patients from ADRs, it is essential though difficult to
establish causal relationship between the drug and the event which is nothing
but the causality assessment. By definition, causality assessment is the
evaluation of the likely hood that a particular treatment is the cause of an
observed adverse event which assesses the relationship between a drug treatment
and the adverse event. It is an important component of pharmacovigilance,
contributing to better evaluation of the risk-benefit profiles of medicines and
evaluating ADR reports in early warning systems and for regulatory purposes.
Historical
Background of Pharmacovigilance:
Severe disaster led to
an awareness that drugs not only can heal but also can harm including sudden death
caused by chloroform anaesthesia in 1877 and fatal hepatic necrosis due to
arsenicals in 1922. Food, Drug and Cosmetic Act, the Kefauver-Harris
Amendments, gave the FDA the power to approve or disallow the introduction of
new drugs and the continued marketing of established compounds based on
substantial evidence of their therapeutic efficacy as well as safety. Around
1980 it became compulsory to record side effects (adverse drug reactions) by
the regulatory authorities in many countries to allow for a continual
monitoring of the risk and benefit of products both in the investigational
phase before authorization and as post marketing surveillance when the product
is commercialised as an authorized product. The consequences of this are that
over the last 30 years there have been continued instances of drug recalls or
precautionary statements due to the discovery of potential hazards during their
use, some more notable examples include: practolol and the mucocutaneous
syndrome, benoxaprofen and hepatic disorders / deaths in the elderly,
temafloxacin and haemolytic anaemia, fenfluramine/phentermine and valvulopathy
or pulmonary hypertension, terfenadine or cisapride and potential cardiac
arrhythmias (especially in association with interacting agents), cerivastatin
(Lipobay) and rhabdomyolysis, Vioxx with increased risk of cardiovascular
events.
Many companies have developed
innovative and efficient monitoring systems that have contributed to the
detection of new safety signals. Encouraged by the 1998 Erice Declaration on
Communicating Drug Safety, communication and exchange of information between
the industry, regulatory authorities and the public has improved, which has
more recently been further supported by the establishment of the community
database (Eudravigilance Database) in December 2001, in London.
OBJECTIVES OF PHARMACOVIGILANCE:
·
Improve
patient care and safety in relation to the use of medicines and all medical and
Para medical interventions.
·
Research
the efficacy of drug and by monitoring the adverse effects of drugs right from
the lab to the pharmacy and then on for many years.
·
Pharmacovigilance
keeps track of any drastic effects of drugs.
·
Improve
public health and safety in relation to the use of medicines.
·
Contribute
to the assessment of benefit, harm, effectiveness and risk of medicines,
encouraging their safe, rational and more effective (including cost-effective)
use.
·
Promote
understanding, education and clinical training in pharmacovigilance and its
effective communication to the public.
ROLES OF
PHARMACOVIGILANCE:
·
The safety of complementary and traditional medicines, vaccines and
biological medicines;
·
The receipt, processing and reporting of adverse event reports;
·
Following-up with reporters to obtain further details about a case
report;
·
Providing an information service to healthcare professionals and
patients on product safety; and Providing safety expertise to internal
cross-functional colleagues.
GOOD
PHARMACOVIGILANCE PRACTICES:
Risk assessment and
risk minimization form what FDA calls risk management. It is an iterative
process of:
·
Assessing
a product’s benefit-risk balance
·
Developing
and implementing tools to minimize its risks
·
Evaluating
tool effectiveness and reassessing the benefit-riskbalance
·
Making
adjustments as appropriate to the risk minimization toolsto further improve the
benefit-risk balance.
ADVERSE DRUG
MONITORING:
Adverse drug
reactions (ADRs) are common, often unrecognised and typically under-reported.
However, update knowledge and skills related to detection, assessment,
prevention, management and transparent notification / reporting of ADR is
essential for an efficient Pharmacovigilanceeverywhere on the globe.
ADR INCLUDES:
1) ADRs associated
with newly marketed medications
2) Serious,
life-threatening, or fatal reactions.
3) According to the
Food and Drug Administration, a serious adverse event is one in which the
patient outcome is death, life-threatening), disability, hospitalization
(initial or prolonged), a congenital anomaly, or necessitates medical or
surgical intervention to prevent permanent impairment or damage.
4) Unusual
increases in numbers or severity of reactions.
5) Allergic
reactions and idiosyncratic reactions are also considered ADRs, if they are
deemed to be serious, life threatening, or fatal, as described above.
However, the
definition of ADR shall not include:
a. Adverse effects of
the drug which are related to the size of the dose, expected, well-known
reactions and do not result in changing the care of the patient.
b. Drug withdrawal,
drug-abuse syndromes, accidental poisoning, and drug-overdose complications
(e.g., drowsiness from diphenhydramine)
c. Reactions which are
extensions of the pharmacologic effect for which the drug is given (e.g., bone
marrow suppression with antineoplastic agents).
d. Disturbances
totally dependent on the pathological state (e.g., diarrhoea from cancer and
not from a laxative).
SOME TYPES OF ADRS:
·
Serious Adverse
Event (SAE):
An adverse drug
reaction or adverse event that Results in death or is life threatening or
requires in-patient hospitalization or prolongation of existing hospitalization
or Results in persistent or significant disability or incapacity, or Causes
congenital malformation.
·
Unexpected
Serious Adverse Drug Reaction:
A serious adverse
drug reaction that is not identified in nature, severity or frequency in the
risk information set out in the investigator’s brochure or on the label of the
drug.
·
Expected
Adverse Reaction:
There is a
reasonable possibility that the reaction or event may have been caused by the
drug or research intervention (i.e. a causal relationship between the reaction
and the drug or research intervention cannot be ruled out by the investigator).
·
A Suspected
Unexpected Serious Adverse Reaction (SUSAR): is an adverse
reaction that is both serious and unexpected (i.e. the nature and severity
Absence of ADRs and freedom from unintended, unwanted negative or excessive
effects of drugs).
PHARMACOVIGILANCE PROGRAMME:
The national
pharmacovigilance system plays a vital role in increasing public awareness of
drug safety. How is the Pharmacovigilance system set-up Pharmacovigilance
systems are usually established at the national level? The following bodies
play a role in all Pharmacovigilance systems:
·
Drug
regulatory agencies (DRA)
·
Manufacturers
/ producers
·
Health
care professionals
·
Pharmacovigilance
units
CLINICAL TRIALS:
Pharmaceutical companies are required by law in all countries to perform
clinical trials, testing new drugs on people before
they are made generally available. The manufacturers or their agents usually
select a representative sample of patients for whom the drug is designed at
most a few thousand along with a comparable control group. The control group
may receive a placebo and/or another drug that is already marketed for the
disease. Clinical trials do, in general, tell us a good deal about how well a
drug works and what potential harm it may cause. Clinical trials, also known as
clinical studies, are designed to help us find out how to give a new treatment
safely and effectively to people. A clinical trial is an organized research
study designed to investigate new methods ofpreventing, detecting, diagnosing,
or treating an illness ordisease and attempt to improve a patient’s quality of
life
Mainly 4 phases of clinical trialsare
Phase I: Inthis phase, primarily provide information on acute
tolerability and safety, dose-plasma concentration profiles, maximum safe doses
and concentrations, routes of metabolism and elimination and initial estimates
of the variability associated with these measurements.
Phase II: In this phase, establish clinical efficacy
and incidence ofside effects in patient population define most appropriate dose
schedule and provide detailed pharmacological date for optimum use of the drug.
Phase III: In this phase, check whether the
treatment is effective, compare it with a vailable and established treatment,
and determine optimum dosage, frequency of administration, usefulness of drug
in patients, safety of treatment and common adverse reactions of the compound.
Phase IV: In this phase, designed to reveal adverse reactions
related to prolonged usage, drug efficacy in long term use, newuses, an
assessment of misuse or overuse liability, druginteractions and compatibility
with other agents. Thereare certain steps and protocols, which needed to
befollowed while carrying out the actual clinical trials. Today FDA’S main aim
is, by using new diagnostic, imaging, and clinical evaluation techniques, to
bring new drugs and medical products in market. These new “toolkits” include
advances in basic sciences such as inbioinformatics, genomics, and imaging
technologies. These technologies make drug discovery anddevelopment cheaper,
faster, and more predictable. Apart from the technologies, new advances are
emergingin clinical trials. Some of them are - Model-based drug development
offers significant opportunity to improve drug development decision-making.
Clinical Trial Modeling and Simulations observations regarding pharmacological
actions is embedded in mathematical equations and set of assumptions embedded
in amathematical equation and give “virtual” information about the analysis of
the pharmacological observations of patients.
PHARMACOEPIDEMIOLOGIC STUDIES:
Pharmacoepidemiology is defined as “The study of effects of and use of
drugs in large populations. It is the use of epidemiological methods to address
issues from clinical pharmacology, usually questions about the balance between
beneficial and adverse effect of drugs.” It also takes into account patient
compliance and other factors that apply when drug is used under real-life
conditions. They are not experimental but observational in nature.
Pharmacoepidemiologic studies can be of various designs, including cohort
(prospective or retrospective), case-control, nested case-control, case
crossover, or other models.
Fig.1. Cohort study
Fig2. Case-control study.
CASE REPORT:
In medicine, a case report is a detailed report of the symptoms, signs, diagnosis, treatment, and follow-up of an
individual patient. Case reports may contain a demographic profile of the patient, but usually describe an
unusual or novel occurrence. Some case reports also contain a literature
review of
other reported cases.
Good case reports include the following elements:
·
Description
of the adverse event
·
Suspected
and concomitant product therapy details
·
Patient
characteristics
·
Documentation
of the diagnosis of the events
·
Clinical
course of the event and patient outcomes
ADVERSE DRUG
REACTION (ADR):
Aresponse which is
noxious and unintended, and which occurs at doses normally used in humans for
the prophylaxis, diagnosis, or therapy of disease, or for the modification of
physiological function. An adverse drug reaction, contrary to an adverse event,
is characterized by the suspicion of a causal relationship between the drug and
the occurrence, i.e. judged as being at least possibly related to treatment by
the reporting or a reviewing health professional.
Side effects:
event secondary to the
therapeutic effect which may actually be beneficial
Classification of adverse reactions:
·
Type
A: Augmented pharmacologic effects
·
Type
B: Bizarre / Idiosyncratic effects
·
Type
C: Chronic effects
·
Type
D: Delayed effects
·
Type
E: End-of-treatment effects
·
Type
F: Failure of therapy
Adverse drug reactions
can be categorised in a number of ways (e.g. by severity, by body systems
affected, or by frequency). The following categorisation is often used:
·
Type A (augmented) reaction
these are based on pharmacological properties of the drug ,which means that
they are augmented, but qualitatively normal response to the drug included side
effects ,toxic effects and consequences of drug withdrawal. They are more common
dose related and mostly preventable and reversible. Eg.anaphylactic reaction
·
Type B (Bizarre) reactions are
effects that are not pharmacologically predictable and can include hypersensitivity
reactions (e.g. anaphylaxis with beta-lactam antibiotics). Additional
categories have been proposed, some to accommodate the time course of the
reaction.
·
Type C (continuing) reactions
describe those that persist for a relatively long time (eg osteonecrosis of the
jaw with bisphosphonates).
·
Type D (delayed) reactions,
which become apparent some time after the use of a medicine (eg leucopenia,
which can occur up to 6 weeks after a dose of lomustine).
·
Type E (end of use) reactions
are associated with the withdrawal of a medicine (eg insomnia, anxiety and
perceptual disturbances following withdrawal of benzodiazepines).
POSSIBLE MECHANISMS OF ADRS
Abnormal pharmacokinetic
mechanisms due to
·
Genetic factors
·
Abnormal drug metabolism may be due to inherited factors of either
Phase I oxidation or Phase II conjugation
·
Phase I: inheriting abnormal alleles of CyP450 can alter drug metabolism;
inheriting abnormal pseudocholinesterase may affect metabolism of drugs like
succinylcholine
·
Phase II: inheriting abnormal N-acetyltransferase which conjugated some
drugs to facilitate excretion may affect the metabolism of INH, hydralazine,
and procainamide
·
Comorbid disease states: Various diseases especially those that cause
renal or hepatic insufficiency may alter drug metabolism.
·
Counterfeit drugs
·
Pharmacodynamic mechanisms due to synergistic effects between
· A drug and a
comorbid disease state
· 2 drugs given
simultaneously
· Counterfeit drugs
·
Risk Management
Risk Management is
the discipline within Pharmacovigilance that is responsible for signal
detection and the monitoring of the risk-benefit profile of drugs. Other key
activities within the area of Risk Management are that of the compilation of
Risk Management Plans (RMPs) and aggregate reports such as the Periodic Safety
Update Report (PSUR), Periodic Benefit Risk Evaluation Report (PBRER), and the
Development Safety Update Report (DSUR).
1.signal detection
2. Causality assessment.
·
Signal
Detection:
Signal means the
first alert about the problem and hazards withadrugit can be generated at the
level of doctors, nursingstaff, pharmacist or adentist in the field. Its the
reported information on possible causal relation-ship between an adverse event
and a drug.
·
Causality
Assessment:
Causality refers to
the relationship of a given adverse event to a specific drug. Causality
determination (or assessment) is often difficult because of the lack of
clear-cut or reliable data.
CONCLUSION:
Pharmacovigilance is not easy, and its errors and problems are repeated.
Of course, by proactively detecting signals and with better risk management
plans, some of the questions may be answered. However, without proper
educational training in this field and good work experience it is difficult to
understand the intricacies that are involved and what to look for
Pharmacovigilance required for systematically identifying and correlating drugs
and side-effects and taking corrective actions, especially for the product
launching first time in India. Pharmacovigilance is the only way to ensure the
safety of drug throughout the lifecycle. Its importance is very much crucial as
the clinical trials have limitation to detect the rare and very rare ADRs. If
all the healthcare professionals take ADR reporting as ethical obligations and
their major responsibilities, we can make our world safer than what is today.
Every reporting by healthcare professionals is important; even though, focus on
the serious unlabelled type of ADRs is more important. There are significant
efforts on the pharmacovigilance to make it more functional after the concept
has emerged, and day by day we are closer to the destiny. It is our
responsibilities to ensure phamacovigilance system is functioning well. ADR
reporting should be taken as a very important duty; not as an extra clinical
burden; by healthcare professions to ensure the safer drug use throughout the
world.
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Received on 03.03.2020
Modified on 30.03.2020
Accepted on 14.04.2020 ©Asian Pharma Press
All Right Reserved
Asian J. Pharm. Res. 2020; 10(2):123-128.
DOI: 10.5958/2231-5691.2020.00024.6