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TITLE & SYNOPSIS

Sr.
Item Guidelines
No.

Evaluation of suspected Adverse Drug Reaction Profile at a Tertiary Care

01) Title:-
Teaching Hospital of central India: An Observational, Cross sectional study

The aim of pharmacotherapy is to provide maximum benefits with

02) Introduction :-
minimal risk due to adverse effects. Real-life use of drugs is very different from
the controlled clinical trial environment in which drugs are tested prior to
marketing. Clinical trials are short in duration and exclude vulnerable individuals
such as the elderly, women of child-bearing age, children, and those with
concurrent illnesses. Therefore, when a drug is launched in the market not all of
its adverse effects may be known, thereby making post-marketing surveillance
of drugs extremely important. An example is that of cardiovascular events with
rofecoxib, a drug which was indicated for the treatment of osteoarthritis. After
being marketed for 5 years and being used by millions of patients, the drug was
withdrawn as a result of the APPROVe trial that showed a doubling of risk of
myocardial infarctions and ischemic cerebrovascular events in patients taking
rofecoxib as compared to those taking placebo. [1]
The WHO defines Adverse Drug Reactions (ADRs) 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.” [2] Adverse Drug Reaction (ADR) is a
major limitation in providing health care to patients at a global level. It affects
patient’s recovery as well as the economy of health care. In various studies
adverse drug reactions have been implicated as a leading cause of considerable
morbidity and mortality. The incidence of ADRs globally varies with studies
which show incidences ranging from as low as 0.15% to as high as 30%. Indian
reports on ADR monitoring have been very few. This may be because ADR
monitoring is still developing here. [3] Hospital based ADR monitoring and
reporting programs

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aim to identify and quantify the risks associated with use of drugs. This
information may be useful in identifying and minimizing preventable ADRs while
generally enhancing the knowledge of prescribers to deal with ADRs more
efficiently.
There is a tremendous need of ADR database especially in
developing countries like ours. It leads to the earliest possible detection of
various unknown ADRs and drug interactions. It also helps in estimation and
analysis of the risk: benefit ratio and dissemination of the information for
improving drug prescribing and drug regulation. Therefore, Pharmacovigilance
Programme of India was initiated for protecting the health of the patients by
assuring drug safety. The World Health Organization (WHO) defines
pharmacovigilance as “the science and activities relating to the detection,
assessment, understanding and prevention of adverse effects or any other
possible drug-related problems”.[4] The science is essential for maintaining
optimal risk–benefit profile of marketed drugs and hence for safeguarding
public health.
The present study will be conducted at a tertiary care teaching
hospital which is also designated as ADR monitoring center. Spontaneous
reporting systems provide the highest volume of information at the lowest
maintenance cost of all the sources of data for drug safety monitoring and have
proven their value in the early detection of patient safety issues. [5,6] The most
important function of spontaneous reporting systems is the early identification
of signals and formulation of hypotheses, leading to further confirmatory
investigations or sometimes regulatory warnings and changes of product
information leaflets.[7] In some instances, withdrawals of marketing
authorizations are also based on Individual case safety reports.
Considering the scarcity of information available regarding the ADRs
profile, we are going to conduct this study with the objective, to assess the
inpatients and outpatients ADR profile reported to ADR monitoring center from
various clinical departments at a tertiary care teaching hospital using
spontaneous reporting method and evaluation of causality, preventability,
severity and outcome of reported ADRs.

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3.1) Primary
How many ADRs which will be evaluated in this study have causality relationship
Research
with drug ?
Question :-

3.2) Secondary
How many ADRs which will be evaluated in this study will be preventable ?
Research
What will be the severity pattern of reported ADRs ?
Question 1 :-

(if any)

3.3) Secondary
What will be the outcome pattern of reported ADRs ?
Research
Question 2 :-

(if any)

4.1) Primary Not applicable

Hypothesis :-

4.2) Other Not applicable

Hypothesis 1:-

(if any)

4.3) Other Not applicable

Hypothesis

2 :-

(if any)

05) Review of 1. Prospective observational study conducted at ADR monitoring centre of

Literature :- Santhiram Medical College & Hospital, Nandyal by TY Sree Sudha 1 ,
Yakaiah Vangoori et al . Study was conducted to identify, analyse the
causality, and severity of adverse drug reactions and to find out the
factors associated with ADR related factors. Total 145 ADR reports were
analysed. Most of the ADRs were observed in females (60%). Majority of
ADRs were caused by NSAIDs (32.4%), followed by antimicrobials (20%).
Most common organ systems involved was skin (38%). Causality

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assessment showed 85.5% ADRs as probable. 18.6% of ADRs were of

severe type and 51% moderate. Study generated a data of ADRs, which
will give information to the clinicians for optimum and safe use of drugs
in day to day practices and helps in creating their own ‘P’ drug list.
2. A non-interventional observational study was conducted over 1 year
from January to December 2015 by Shivaraj Basavaraj Patil, Shrinivas R.
Raikar et al . The yellow forms dropped in the red ADR boxes are
collected and analysed for demographic data, causality, severity, drugs
implicated, and organ system affected. The data were presented as
numbers and percentages. 175 ADRs were reported, which shows
reporting was adequate. Antimicrobials are the most common drug class
implicated in ADRs, and the dermatological system was the most
common system affected by ADRs. All the reactions either belonged to
the probable or possible category. Majority of reactions were non-
serious.
3. A prospective, spontaneous reporting study was conducted over a
period of 9 months by R. Arulmani, S.D. Rajendran & B. Suresh et al. Of
the total of 187 adverse drug events (ADEs) reported, 164 reports from
121 patients were confirmed as ADRs, giving an overall incidence of
9.8%. This included 58 (3.4%) ADR related admissions and 63 (3.7%)
ADRs occurring during the hospital stay. About two thirds of the
reactions (102, 62.2%) were classified as probable. The majority of the
reactions (88, 53.7%) were mild. Most patients (119, 72.6%) recovered
from the incidence. The majority of the reactions were of type H (100,
61%) which indicates that they were not predictable and not potentially
preventable. An average cost of 481 rupees (£6) was spent on each
patient to manage ADRs.
4. Retrospective, observational, record-based study was conducted in the
ADR monitoring centre (AMC) of Travancore medical college, working
under Pharmacovigilance Programme of India (PvPI) using suspected
ADR monitoring form by Jihana Shajahan, Abdul Aslam Parathoduvil et
al. The total number of ADRs reported was 300. Among this 39%
reactions were serious, and 69% reactions were non-serious. only 0.3%
ADRs were definitely preventable, 18% were probably preventable. So,

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total preventability was found to be 18.3%. Majority of the reactions

(142) i.e. 47.3%) had level 2 severity. There were 81 reactions (27%)
belonging to level 3 severity. Assessment of outcome showed 64.3%
patients recovered from the reaction and 30% were recovering at the
time of reporting ADR. In 3% reports, patients had not recovered from
ADR and in 1.7% cases recovery happened with some sequelae. In 0.7%
reports outcome was unknown.

6.1) Primary
To evaluate suspected Adverse drug reaction (ADR) profile in outpatients and
Objectives :-
inpatients of a tertiary care teaching hospital.

1. To assess causality by Naranjo adverse drug reaction probability scale.

6.2) Other Objectives
2. To assess preventability according to Schumock and Thornton Criteria.
1:-
3. To assess severity assessment according to Modified Hartwig and Seigel
(if any)
Criteria.
4. To assess outcome of reported ADRs.

6.3) Other Objectives

2:-

(if any)

07) Methodology :-
Study Design
An observational, cross sectional study
Study Period
December 2022 to May 2024
Study site:
ADR monitoring center, tertiary care teaching hospital
Study population
ADRs reported to ADR monitoring center from inpatient and outpatient

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departments of tertiary care teaching hospital.

Inclusion criteria:
1. All completed CDSCO suspected ADR reporting forms version no 1.4/1.2
reported to the ADR monitoring centre of the institution
2. ADR reported by healthcare professionals
3. ADR reported by MBBS and nursing students of the institution
Exclusion criteria:-
1. ADR reported by non-health care professionals
2. ADR reported by patients

Study procedure :
The study will be initiated after approval from the Institutional Ethics
Committee.
Our institute has approved an ADR monitoring center in the department of
pharmacology under the pharmacovigilance program of India. Regular activities
are conducted by the ADR monitoring center in the hospital such as: conducting
sessions to create awareness about ADR monitoring for clinicians, residents,
interns, nursing students/staff, and undergraduate students. The Central Drug
Standard Control Organization’s (CDSCO) Suspected Adverse Drug Reaction
Reporting Form (ADR forms) of version 1.4/1.2 contains the patient details, drug
details, the description of the reaction, concomitant medication, co-existing
illness, any rechallenge, dechallenge, etc. are distributed to all the clinical
departments and also training to fill ADR form properly are carried out on a
regular basis. The suspected ADRs reported to the ADR monitoring center in
the study period will be carefully analyzed and documented. Regular visits will
be conducted to collect the forms and follow up wherever possible.

Evaluation of the reports

The reports which will have a minimum of the following information will be
used for analysis - Patient details, the suspected drugs, adverse drug reactions
and the reporter details.
The reactions will be analyzed under the following categories:-
1. Age wise distribution of ADRs
2. Gender wise distribution of ADRs

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3. Department wise distribution of ADRs

4. Drug classes implicated in ADRs
5. Causality of the reactions will be assessed by Naranjo adverse drug
reaction probability scale
6. Preventability by Modified Schumock and Thornton scale
7. Severity of ADR will be evaluated using Modified Hartwig and Seigel
criteria
8. Outcome of reported ADR

Sample Size:
Average numbers of ADRs reported annually to our Adverse drug reaction
monitoring center are 200-225. Considering this fact arbitrary sample size taken
for this study is 260.

Statistical analysis:
 The recorded data will be analyzed by using descriptive statistics.
 The data will be analyzed and presented as numbers and percentages by
using MS Excel 2021

Observation tables :-
1. Age wise distribution of ADRs

Age group Number of ADRs Percentage

1 day – 18 years
19 years- 40 years
41 years- 60 years

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More than 60 years

2. Gender wise distribution

Gender Number of ADRs Percentage

Male
Female

3. Department wise distribution of ADRs

Department Number of ADRs Percentage

4. Drug classes implicated in adverse drug reactions

Drug class Number of ADRs Percentage

5. Causality assessment by Naranjo adverse drug reaction probability

scale
Type Number of ADRs Percentage
Definite ADR
Probable ADR
Possible ADR
Doubtful ADR

6. Preventability by Modified Schumock and Thornton scale

Preventability Number of ADRs Percentage
Definitely preventable
Probably preventable
Not preventable

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7. Severity of ADR using Modified Hartwig and Seigel criteria

Severity Number of ADRs Percentage
Mild
Moderate
Severe

8. Outcome assessment
Outcome Number of ADRs Percentage
Recovered
Recovering
Recovered with sequelae
Not recovered
Fatal
Unknown

8) Reference VANCOUVER STYLE

Style :-

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1. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C,
Riddell R, Morton D, Lanas A, Konstam MA, Baron JA. Cardiovascular events
associated with rofecoxib in a colorectal adenoma chemoprevention trial. N
Engl J Med. 2005; 352(11):1092–102.
2. WHO. Adverse reaction. WHO 1972 [Internet]. Available from:
http://www.who.int/medicines/areas/quality_safetyefficacy/trainingcourses/
defin itions.pdf
3. Arulmani R, Rajendran SD, Suresh B. Adverse drug reaction monitoring in
secondary care hospital in south India. Br J Clin Pharmacol 2008; 65(2):210-6.
4. World Health Organisation Collaborating Centre for International Drug
Monitoring. The Importance of Pharmacovigilance, WHO 2002. Available from:
http://www.who-umc.org
5. Sharma M, Gupta SK. Textbook of pharmacovigilance. New Delhi: Jaypee
Akanksha Mathur et al. ADR Drug Profile At A Tertiary Care Teaching Hospital
International Journal of Research & Review (www.gkpublication.in) 34 Vol.3;
Issue: 9; September 2016 Brothers; 2011. Post marketing surveillance. p. 75-
92.n
6. Alj L, Touzani MDW, Benkirane R, Edwards IR, Soulaymani R. Detecting
medication errors in pharmacovigilance database: capacities and limits. Int J
Risk Saf Med. 2007; 19(4):187-94.
7. Harmark L, van Grootheest AC. Pharmacovigilance: methods, recent
developments and future perspectives. Eur J Clin Pharmacol. 2008; 64(8):743-
52
8. Sudha TYS, Vangoori Y, Varghese AM. A profile of adverse drug reaction in a
tertiary care teaching hospital and associated factors . Biomed and Pharmacol.
J . 2021;14(1): 367-71.

9. Shajahan J, Aslam A, Purushothaman S. An analysis of seriousness,

predictability and preventability of adverse drug reactions reported at a tertiary
care teaching hospital in Kerala, India: a retrospective observational record
based study . IJBCP.2018;7(12): 2433

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10. Mathur A, Goswami N, Shah P, Trivedi N. An Evaluation of Adverse Drug

Reactions Profile at a Tertiary Care Teaching Hospital. International Journal of
Research & Review .2016; 3(9):30-34
11. Dang A, Bhandare P.N. The Profile of Voluntary Reported Adverse Drug
Reactions at a Tertiary Care Hospital: A Fifteen Month Prospective Study.
Journal of Clinical and Diagnostic Research, 2012. 2012 November, Vol-6(9):
1504-1509.
12. Kasliwal R, Spontaneous Reporting in Pharmacovigilance: Strengths,
Weaknesses and Recent Methods of Analysis. Journal of Clinical and Preventive
Cardiology January 2012 | Number 1.
13. Patil S, Raikar S, Janardhan M, Rao V, Vahila N A profile of adverse drug
reactions in a rural tertiary care hospital. National Journal of Physiology,
Pharmacy and Pharmacology . 2016 | Vol 6 | Issue 6
14. Swamy S, Bhanuprakash, Nadig P, Muralimohan, Shetty M (2013) Profile of
Suspect Adverse Drug Reactions in a Teaching Tertiary Care Hospital. J
Pharmacol Clin Toxicol 1(1): 1005.
15. Arulmani R, Rajendran S.D, Sures B. Adverse drug reaction monitoring in a
secondary care hospital in South India. 212 / 65:2 / Br J Clin Pharmacology
DOI:10.1111/j.1365-2125.2007.02993.

9) Timeline/Gantt
Chart :-

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Gantt Chart for study

May Aug Oct- Oct-22- Dec-22- Dec-23- Apr-24-

- 22 - 22 22 Nov -22 Dec-23 Mar- 24 May-24

Registration
Review of
Literature
Topic
Selection
Ethical
Clearance,
Synopsis
Submission
Methodology
, Proforma &
Dummy
tables
presentation
Data
Collection
Data
compilation
& Analysis
Thesis write-
up &
Submission

10) Annexures :-

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Table: 1. Modified Hartwig and Siegel scale

Level Description
1 The ADR requires no change in treatment with the suspected drug.
2 The ADR requires the suspected drug to be withheld, discontinued
or otherwise changed. No antidote or other treatment is required.
There is no increase in length of hospital stay.
3 The ADR requires that the suspected drug be withheld,
discontinued or otherwise changed, and/or an antidote or other
treatment is required. There is no increase in length of hospital
stay.
4 Level 4a - Any level 3 ADR that increases the length of hospital stay
by at least one day.
Level 4b - The ADR is the reason for admission.
5 Any level 4 ADR that requires intensive medical care.
6 The ADR causes permanent harm to the patient.
7 The ADR either directly or indirectly leads to the death of the
patient.

Severity grades Level

Mild level 1,2
Moderate level 3,4
Severe level 5,6,7

Table: 2. The Naranjo ADR Probability Scale

Questions Yes No Don’t
Know

1) Are there previous conclusive reports on this +1 0 0

reaction?

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2) Did the ADR appear after the suspected drug was +2 -1 0

administered?

3) Did the ADR improve when the drug was +1 0 0

discontinued?
(de-challenge)

4) Did the ADR appear with re-challenge? +2 -1 0

5) Are there alternative causes for the ADR? -1 +2 0

6) Did the reaction appear when placebo was given? -1 +1 0

7) Was the drug detected in blood at toxic levels? +1 0 0

8) Was the reaction more severe when the dose was +1 0 0

increased, or less severe when the dose was
decreased?

9) Did the patient have a similar reaction to the same +1 0 0

or similar drug in any previous exposure?

10) Was the ADR confirmed by any objective evidence? +1 0 0

SCORE Causality
>9 Definite ADR
5-8 Probable
1-4 Possible
o Doubtful

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Table: 3. Modified Schumock and Thornton scale

Questions for assessment of preventability

Definitely preventable
1. Was there a history of allergy or previous reactions to the drug?

2. Was the drug involved inappropriate for the patient’s clinical

condition?

3. Was the dose, route or frequency of administration inappropriate for

the patient’s age, weight or disease state?

4. Was a toxic serum drug concentration (or laboratory monitoring test)

documented?

5. Was there a known treatment for the Adverse Drug Reaction?

Probably preventable
6. Was required Therapeutic drug monitoring or other necessary
laboratory tests not performed?

7. Was a drug interaction involved in the ADR?

8. Was poor compliance involved in the ADR?

9. Were preventative measures not prescribed or administered to the

patient?

Not preventable
If all above criteria not fulfilled

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