The document provides guidelines for adverse drug reaction (ADR) reporting and statistical methods used for safety data analysis. It defines ADRs and different types of ADR reporting such as spontaneous reporting, expedited reporting, and aggregate reporting. It also describes various pharmacovigilance methods used for ADR reporting including passive and active surveillance. Statistical analysis methods covered include measures of central tendency, variability, and parametric and non-parametric tests. Common scales for assessing ADR causality and severity are also mentioned.

1. GUIDELINES FOR ADR REPORTING
AND STATISTICAL METHODS FOR
SAFETY DATA ANALYSIS
By Tanushree Karmakar
M.Pharm Pharmacology 1st Year

2. Adverse Drug Reaction
• ADR can be defined as a response to a drug which is
noxious and unintended, and which occurs at doses
normally used in man for the prophylaxis, diagnosis,
or therapy of disease, or for the modifications of
physiological function.
• Whereas, Adverse event is any untoward medical
occurrence in a patient or clinical investigation
subject administered a pharmaceutical product and
which does not necessarily have a causal relationship
with this treatment.
• Therefore, an adverse drug reaction is an adverse
event with a causal link to a drug.

4. Adverse drug reaction (ADR)
monitoring
• Identifying Adverse Drug Reaction
• Assessing Causality (Relationship between
drug and suspected reaction)
• Documentation of ADR
• Reporting Serious ADRs to Pharmacovigilance
centres /ADR Regulating Authorities

5. OBJECTIVE OF ADR REPORTING
• To detect the nature and frequency of ADRs including periodic re-
evaluation of the benefit-risk ratio of medicinal products,
• Assist the drug regulatory authority, public health programs,
scientists and consumer society take appropriate action to minimise
risks of ADR
• Providing updated drug safety information to health care
professionals
• Upgrading package insert, design appropriate package insert
information and dissemination of information which may constitute
withdrawal of the product in the market or restrictions for
marketing
• Prevention of relapse or study of new indication, overuse, possible
mechanism underlying the adverse reaction observed or misuse.
• To identify risk factors that may predispose, induce or influence the
development, severity and incidence of adverse reactions in the
population .

8. REPORTING of ADR
• Spontaneous reporting: Clinician's normal diagnosis of a patient.
Relies on vigilant physicians and other healthcare professionals,
generate a suspicion of an ADR, but also report it.
• Expedited reporting: Involve a serious and unlisted event. The
timeframe for reporting expedited cases is 7 to 15 calendar days.
• Clinical trial reporting: Also known as SAE (serious adverse event)
reporting .It is the key component that drug regulatory authorities
consider in the decision-making - to grant or deny market
authorization for a drug. SAE reporting occurs as a result of study
patients (subjects) who experience serious adverse events during the
conducting of clinical trials.
• Aggregate reporting: Also known as periodic reporting. Performs
the key role in the safety assessment of drugs .Includes compilation
of safety data for a drug over a prolonged period of time (months or
years)

9. Pharmacovigilance methods Of
Reporting ADR
 Passive Surveillance
• Spontaneous reporting
• Case Series
 Stimulated Reporting
 Active Surveillance
• Sentinel Sites
• Drug Event Monitoring
• Registries
 Comparative Observational Studies
• Cross-sectional Study (Survey)
• Case-control Study
• Cohort Study
 Targeted Clinical Investigations
• Descriptive Studies
• Natural History of Disease

10. Adverse drug reaction and causality
assessment scales
• Naranjo’s Algorithm
• Kartch Lasagna’s Algorithm
• WHO-UMC probability scale
• Spanish quantitative imputation scale
• Kramer’s scale
• Jones scale
• European ABO system
• Bayesian System

11. Hartwig ADR Severity assessment scale

12. Regulatory actions on the basis of ADR
reports
• Summary of Product Characteristics (SPC) – basis of
information for Healthcare Professionals on how to use
the medicinal product safely and effectively
• Patient Information Leaflets (PIL) – drawn up in
accordance with the SPC
• Changes in classification:
– From Over the counter to Prescription only Medicine
– From renewable prescription to non-renewable
– Special medical prescription
– Restricted prescription
• Marketing Authorization withdrawal
• Batch recall based on clustering of ADRs

13. ADR Reporting through Vigiflow
• VigiFlow is a web-based Individual Case Safety Report
(ICSR) management system that is specially designed for use
by national centres in the WHO Programme for International
Drug Monitoring.
• Can be used by both national authorities and companies for
management of their own reports
– Data entry
– Assessment
– Storage – Retrieval (e.g. for follow-ups)
– Communication with other parties
• It is web-based
• It is E2B compatible

14. • Other tools:
 ARISg : ARISg is a leading pharmacovigilance and
clinical safety system that helps companies efficiently
process all safety cases and generate appropriate global
reports for distribution to regulatory authorities and
partners.
 Argus : Argus is a scalable end-to-end safety process
providing automated global case processing, periodic
reporting, E2B intake and submission, comprehensive
reporting, detailed analytics, and Japanese safety
operations from within a single system.
 Vigibase: It is a World Health Organization’s (WHO)
global Individual Case Safety Report (ICSR) database
that contains ICSRs submitted by the participating
member states enrolled under WHO’s international
drug monitoring programme. It is the single largest
drug safety data repository in the world.

16. Statistical Methods for Data Analysis
• Statistics in relation to biological experiments deals with
collection,presentation,analysis of data , interpretation of results with
an aim to draw meaningful inference.
• Categories:
1. Central Tendency: Arithmetic Mean,Median,Mode.
2. Variability : Standard Deviation, Variance
3. Tests of Significance: Parametric tests
Non- Parametric tests
• Parametric Tests: Student’s t-test, Paired t-test, Analysis of
Variance Test (ANOVA),Chi Square test, Fisher's Exact test.
• Non-Parametric test: Kruskal-Wallis H test, Wilcoxon’s Signed rank
test

17. Central Tendency
• The goal of central tendency is to identify the value
that is most typical or most representative of the
entire group.
• The arithmetic mean is the arithmetic average. It is
calculated by adding up individual observation
divided by number of observation.
• Median is the central value of all observations
arranged from lowest to highest.
• Mode is the most frequently occurring value in a
series of observations.

18. Variability
Variability is a measure of the spread of scores in a distribution.
• Standard deviation describes the average distance from the
mean.
• Where X= Observation , X = mean ,n = no of observation.
• Variance measures variability by computing the average
squared distance from the mean.
Variance =

19. Tests of Significance: Parametric
Test
• Parametric test are performed if the parent population
from which the samples are drawn follows a normal
distribution or the sampling distribution approaches to
normal distribution as the sample size is made increase
indefinitely.
1. Student’s t- test : This test is applied to assess the
statistical significance of the difference between two
independently drawn sample means (unpaired means)
obtained from two series of data.
2. Paired t- test : used for analysis of paired data.
3. Analysis of variance test (ANOVA) : Applied when
there is a comparison between more than two samples.

20. 4. Chi square test : generally applied in analysis
of quantal or all or none responses.
5. Fisher’s Exact test : Applied to verify all or
none response to determine the significance.
Non-Parametric tests
Applied if the distribution is not known regarding the
parent population or if it is not possible to make the
distribution to follow normal distribution.
Also known as distribution free statistics

21. 1. Kruskal- Wallis H test : Used to compare
groups.
2. Wilcoxon’s Signed Rank Test : Applied when
the measurements are continuous and have
the strength of only the ordinal scale.