Adverse drug reporting

What is pharmacovigilance?
Pharmacovigilance is defined as the pharmacological science relating
to the detection, assessment, understanding and prevention of
adverse effects, particularly long-term and short-term adverse
effects of medicines.
Need for pharmacovigilance (PvPI)
 Before registration and marketing of medicine in the country, its
safety and efficacy experience are based primarily on the use of
medicine in clinical trials.
 These trials also detect adverse reactions, but some of the
important reactions which take long time to develop or those
which occur rarely may not be detected in clinical trials.
 The controlled conditions in which the medicines are used in
clinical trials necessarily do not reflect the way they will be used in
clinical practice.
 For a medicine to be considered safe, its expected benefits should
be greater than any associated risks of harmful reactions.
 So, in order to gain a comprehensive safety profile of the
medicinal product, a continuous post-marketing monitoring
system is essential.
 PvPI provides such a system to collate the data and use the
inferences to recommend regulatory interventions, besides
communicating risks to the health care professionals and the
public.
 The medical colleges and hospitals are the cornerstone of the
PvPI. They act as AMC’s which are responsible for collecting the
Individual case safety reports (ICSR’s)
 The data is then entered into the database by using the VigiFlow
software and constitutes the Indian patient safety database.
 VigiFlow also facilitates submission of Indian ICSR’s to the WHO
global ICSR database – VigiBase
There are multiple reasons for this increasing necessity of
pharmacovigilance. Some of these are as follows:
1. Unreliability of pre-clinical safety data
• Well-controlled conditions
• Small and specific sample size
• Pressure from various groups to reduce time to approval.
2. Changing pharmaceutical marketing strategies
• Aggressive marketing
• Direct advertising to consumer
• Launch in many countries at a time.
3. Changing physician’s and patient’s preferences
• Increasing use of newer drugs
• Increasing use of drugs to improve quality of life
• Shift of supervised to self-administered therapy.
4. Easy accessibility
• Increasing conversion of prescription drugs to over the
counter drugs
• Easy access to drug information on the internet
• Easy availability of complementary medicines
• Easy availability of substandard drugs.
Communication in PvPI
What is an adverse drug reaction?
An adverse drug reaction is ‘an appreciably harmful or unpleasant
reaction, resulting from an intervention related to the use of a
medicinal product, which predicts hazard from future administration
and warrants prevention or specific treatment, or alteration of the
dosage regimen, or withdrawal of the product’ (Edwards and
Aronson, 2000).
This has to be contrasted with the term adverse drug event, which
refers to untoward occurrences following drug exposure but not
necessarily caused by the medicine (Asscher, Parr and Whitmarsh,
1995).
A causal relationship between the drug and the occurrence is
suspected.
ADRs frequently mimic ordinary diseases and, if they are uncommon,
may easily be overlooked.
A high index of suspicion is needed if ADRs are to be successfully
diagnosed. The clinician always has to think: ‘Could this be drug-
induced – is this an ADR’. The question is important, for withdrawal
of the cause of an ADR is usually essential.
What is a serious adverse reaction?
A serious adverse event is one that results in any one of the following
outcomes
a. Death
b. A life-threatening adverse drug experience
c. Inpatient hospitalization
d. Prolongation of existing hospitalization
e. A persistent or significant disability/incapacity
f. A congenital anomaly/birth defect
Reporting of adverse drug reactions
Adverse drug reactions can be monitored through two ways
 Active surveillance system – Active surveillance requires
continuous preorganised process
Eg: Cohort event monitoring
 Passive surveillance system – Passive surveillance means no
active measures are taken to look for adverse effects other
than the encouragement of health care professionals and
others to report safety concerns.
Eg: Spontaneous or voluntary reporting
 Presently PvPI is following spontaneous reporting system to
collect data on drug safety.

The 4 essential elements for an ADR are as follows

(1) Identifiable reporter
(2) Identifiable patient
(3) Adverse reaction
(4) Suspected product
Essentially required items (ERI) for a quality ICSR

For a valid case report mandatory fields are the minimum

requirement.

Who can report?

All health care professionals, non-healthcare professionals including
consumers can report suspected adverse drug reaction.
Pharmaceutical companies also send the ICSR’s specific for their
product to the National coordination centre (NCC)
Why to report?
 Moral responsibility of the health care professional
 Safety of the population and the occurrence of ADR’s constitute
a significant economic burden
 India has vast genetic and ethnic variability with difference
disease prevalence
 Use of multi-modal practices and poor patient compliance
What to report?
Reporting of all types of suspected ADR’s irrespective of whether
they are known or unknown, serious or not serious, frequent or rare
and regardless of an established causal relationship.
 Although pharmacovigilance is primarily concerned with
pharmaceutical medicines and vaccines, drugs used in traditional
medicine, medical devices, contrast media and other
pharmaceuticals will also be considered.
 Special fields of interest – Outcome in pregnancy, lactation,
pediatric and geriatric population.
 In addition, ADR’s due to lack of efficacy, overdose, antibiotic
resistance and pharmaceutical defects (spurious or adulterated
drugs) is also recommended
 Not included – ADR’s associated with drug abuse, misuse,
occupational exposure or off-label use is not included under PvPI
 PHYSICIAN JUDGEMENT SHALL BE FINAL

How to report?
Use of “Suspected Adverse Drug Reaction Reporting Form” available
on the official website of Indian Pharmacopoeia Commission. (IPC)
Whom to report?
Coordinator or technical associate of the respective AMC or directly
to the NCC.
NCC-PvPI helpline number  1800-180-3024 (9:00 AM to 5:30 PM
on weekdays)
 Data flow of an ICSR

Assessment of ICSR
i. Quality of documentation – Completeness and integrity of data,
quality of diagnosis and follow up
ii. Coding – Drug name and reaction term (WHO dictionary or WHO
Adverse Reaction Terminology)
iii. Relevance – Detection of new reaction, drug regulation, scientific
or educational value, unknown reaction or serious reaction
New drug – Up to 4 years from the date of approval
iv. Identification of duplicate reports – Sex, age, date of exposure to
drug
v. Causality assessment – Likelihood of a causal relationship
between drug exposure and adverse events must be validated
Why causality assessment?
 Most case reports concern suspected adverse drug reactions.
 Adverse reactions are rarely specific for the drug, diagnostic tests
are usually absent and a rechallenge is rarely ethically justified.
 In practice few adverse reactions are ‘certain’ or ‘unlikely’; most
are somewhere in between these extremes, i.e. ‘possible’ or
‘probable’.
How to solve the problem?
 Development for a structured and harmonised assessment of
causality
 None of these systems, however, have been shown to produce a
precise and reliable quantitative estimation of relationship
likelihood.
 Advantages and limitations of standardised case causality
assessment
What causality assessment can do What causality assessment cannot
do
Decrease disagreement between Give accurate quantitative
assessors measurement of
relationship likelihood
Classify relationship likelihood Distinguish valid from invalid cases
Mark individual case reports Prove the connection between drug
and event
Improvement of scientific evaluation; Quantify the contribution of a drug
educational to the development of an adverse
event
Change uncertainty into certainty

The WHO-UMC causality assessment system

 It is a combined assessment taking into account the clinical-
pharmacological aspects of the case history and the quality of the
documentation of the observation.
 Other criteria such as previous knowledge and statistical chance
play a less prominent role in the system.
WHO-UMC assessment criteria
Causality term Assessment criteria
Certain  Event or laboratory test abnormality, with
plausible time relationship to drug intake
 Cannot be explained by disease or other
drugs
 Response to withdrawal plausible
(pharmacologically, pathologically)
 Event definitive pharmacologically or
phenomenologically (i.e. an objective and
specific medical disorder or a recognised
pharmacological phenomenon)
 Rechallenge satisfactory, if necessary

Probable/Likely  Event or laboratory test abnormality, with

Possible
Unlikely
Conditional/Unclassified
Unassessable/Unclassifiable
reasonable time relationship to drug intake
 Unlikely to be attributed to disease or other
drugs
 Response to withdrawal clinically reasonable
 Rechallenge not required
 Event or laboratory test abnormality, with
reasonable time relationship to drug intake
 Could also be explained by disease or other
drugs
 Information on drug withdrawal may be
lacking or unclear
 Event or laboratory test abnormality, with a
time to drug intake that makes a relationship
improbable (but not impossible)
 Disease or other drugs provide plausible
explanations
• Event or laboratory test abnormality
• More data for proper assessment needed, or
• Additional data under examination
• Report suggesting an adverse reaction
• Cannot be judged because information is
insufficient or contradictory
• Data cannot be supplemented or verified
Naranjo’s algorithm for causality assessment
NARANJO’S ALGORITHM Yes No Do not
(Questions asked) know or
not done
Are there previous conclusive reports on this 1 0 0
reaction?

Did the adverse event occur after the suspected drug 2 -1 0

was administered?

Did the adverse reaction improve when the drug was 1 0 0

discontinued or a specific antagonist was
administered?
Did the adverse reaction reappear when the drug 2 -1 0
was re-administered?

Are there alternative causes (other than drug) that -1 2 0

could have on their own caused the reaction?

Did the reaction reappear when a placebo was -1 1 0

given?

Was the drug detected in the blood (or other fluids) 1 0 0

in concentrations known to be toxic?

Was the reaction more severe when the dose was 1 0 0

increased or less severe when the dose was
decreased?

Did the patient have a similar reaction to the same or 1 0 0

similar drugs in any previous exposure?

Was the adverse event confirmed by any objective 1 0 0

evidence?
Scoring according to Naranjo’s algorithm

Utilization of data
1. Signal generation and strengthening
Signal – Reported information on a possible causal relationship
between an adverse event and a drug, the relationship being
unknown or incompletely documented previously (or) Series of cases
of similar suspected ADR’s reported in relation to a particular drug.
(Quantitatively – more frequent or qualitatively – more serious)
Signal does not imply causation but it can provide preliminary
information about postulating a hypothesis and not for testing it.
2. Risk management – Identification, assessment and prioritisation
of risks followed by approaches to minimise, monitor and control
the probability and impact of adverse drug reactions
3. Drug regulation – Monitoring by CDSCO and market authorisation
holders. Review of product safety information and making
necessary changes in prescribing information or package insert
4. Education – Updating the knowledge associated with use of
medication to health care professionals
Pharmacovigilance programme in India
The National Pharmacovigilance Program established in January
2005, was to be overseen by the National Pharmacovigilance
Advisory Committee based in the Central Drugs Standard Control
Organization (CDSCO).
Many new drugs are being introduced in the country, so there is an
immense need to improve the pharmacovigilance system to protect
the Indian population from potential harm that may be caused by
some of the new drugs.
In the past, India’s regulatory agencies and drug companies based
their safety assessments on experiences derived from long-term drug
use in the Western markets and there was no real urgency for the
government to establish a strong pharmacovigilance system of its
own.
In recent years, India-based drug companies have increased their
capacity to develop and launch new drugs through their own
research efforts and this has heightened the importance of
developing adequate internal pharmacovigilance standards to detect
adverse drug events.
The information obtained to date in the zonal centres from various
peripheral centres is often poor and not well-analyzed. There is
insufficient research on ADRs in India, so the exact incidence of
specific ADRs is unknown.
The reporting forms used by many people engaged in various
pharmacovigilance work are different from the reporting form used
by the National Pharmacovigilance Program, which makes it
extremely difficult to transfer data to the national database, even if
this has been shared by the various parties.
With more and more clinical trials and other clinical research
activities being conducted in India, there is an immense need to
understand the importance of pharmacovigilance and how it impacts
the lifecycle of the product.
A properly working pharmacovigilance system is essential if
medicines are to be used safely. It will benefit all parties including
healthcare professionals, regulatory authorities, pharmaceutical
companies and the consumers. It helps pharmaceutical companies to
monitor their medicines for risk and to devise and implement
effective risk management plans to save their drugs in difficult
circumstances.
Although drugs are passed through a series of trials to establish their
efficacy and safety in human beings before they get marketing
approval, not all the adverse effects caused by a drug can be
detected in clinical trials, especially uncommon ones and those
appear on long‑term administration of that drug because clinical trial
results are limited by strict inclusion criteria; relatively small sample
size (Hanley’s rule of 3) and short study period.

Types of online reporting systems

1. Yellow card form and Yellow card online reporting – UK
2. ADR reporting (Red) form and VigiFlow (software provided by the
WHO) in India, and
3. Form 3500 and US online reporting system
In a spontaneous reporting system, flow of information related to
suspected ADRs occurs through following basic steps
 Information is entered in ADR reporting form by health‑care
professionals at the site of event
 Filled forms are sent to ADR monitoring centres and analyzed
 The information from the filled ADR reporting forms, also
known as Individual Case Safety Reports (ICSRs) is entered in
the respective online reporting systems and are sent to
regulatory authorities
 After due analysis the information is included in a particular
database

 ADR reporting forms and online reporting systems are integral

to spontaneous reporting, one of the most widely used tools of
pharmacovigilance.
 Different countries have adopted different online reporting
systems and different formats of ADR reporting forms which
may differ with each other with regard to type and magnitude
of information captured by them.
 Capturing all the relevant and sufficiently detailed information
related to an adverse event is desirable for appropriate
understanding of its development and to rightly establish its
causality with the suspected drug and its further analysis.
  Although the WHO suggests the ADR reporting form to be short
to improve the voluntary reporting by health‑care
professionals, this might not capture all the relevant, required,
and at least the detailed information related to an ADR.
 Hence, pros and cons of a “short and sweet” reporting form
should be weighed against the extent of its compatibility with
respective online reporting system and action taken
accordingly.

PvPI and WHO-UMC collaboration

In order to participate in International drug monitoring programme,
NCC-PvPI collaborates with WHO-UMC to achieve the objectives of
PvPI in a more efficient way.
 VigiFlow
It is a web based ICSR management system that is specifically
designed for use by national centres in the WHO programme for
International drug monitoring. Maintained by Uppsala Monitoring
Centre (UMC), Sweden.
Once a report is complete and committed, the first version of the
ICSR is generated and it will be automatically saved in VigiBase (WHO
global ICSR database)
 VigiBase
WHO global ICSR database consisting of reports received from
member countries since 1968.
Largest and most comprehensive data resource in the world and is
maintained by UMC on behalf of WHO.
VigiFlow demo chart
Examples of databases
a. WHO International Drug Monitoring Program (VigiBase)
http://www.umcproducts.com/DynPage.aspx?id=73590&mn1=1107
&mn2=1132
b. US FDA ADR Reporting System for Pharmaceutical Products
(FAERS)
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformati
on/Surveillance/AdverseDrugEffects/default.htm
c. Eudravigilance Database in the EU
https://eudravigilance.ema.europa.eu/highres.htm
Figure: Child with thalidomide-induced deformities of the upper and
lower limbs fitted with pneumatic prostheses
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