PLOS ONE

RESEARCH ARTICLE

Increasing adverse drug reaction reporting—

How can we do better?
Miri Potlog Shchory ID1,2☯*, Lee H. Goldstein3, Lidia Arcavi4, Renata Shihmanter4,
Matitiahu Berkovitch5‡, Amalia Levy1‡
1 Department of Public Health, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva,
Israel, 2 Assaf Harofeh School of Nursing, Faculty of Medicine, The Hebrew University of Jerusalem,
Jerusalem, Israel, 3 Clinical Pharmacology Unit, Haemek Medical Center, Afula affiliated to The Bruce
Rapapport School of Medicine, Technion, Haifa, Israel, 4 Clinical Pharmacology Unit, Kaplan Medical Center,
a1111111111 Hebrew University and Hadassah Medical School, Rehovot, Jerusalem, Israel, 5 Clinical Pharmacology Unit,
Shamir Medical Center (Assaf Harofeh), Zerifin, Affiliated to Sackler School of Medicine, Tel-Aviv University,
a1111111111
Tel-Aviv, Israel
a1111111111
a1111111111 ☯ These authors contributed equally to this work.
a1111111111 ‡ These authors also contributed equally to this work.
* [email protected]

OPEN ACCESS
Abstract
Citation: Potlog Shchory M, Goldstein LH, Arcavi Adverse drug reactions (ADRs) are associated with morbidity and mortality worldwide.
L, Shihmanter R, Berkovitch M, Levy A (2020) Although national systems for reporting ADRs exist there is a low reporting rate. The aim of
Increasing adverse drug reaction reporting—How
the current study was to evaluate an intervention plan for improving ADRs reporting among
can we do better? PLoS ONE 15(8): e0235591.
https://doi.org/10.1371/journal.pone.0235591 medical professionals (physicians and nurses). A multicentre intervention study was con-
ducted, in which one medical centre was randomly assigned to the intervention group and
Editor: Karen Cohen, University of Cape Town,
SOUTH AFRICA two medical centres to the control group. The study consisted of 3 phases: baseline data
collection, intervention and follow-up of the reporting rate. The questionnaire that was filled
Received: September 1, 2019
in at base line and at the end of study, contained questions about personal/professional
Accepted: June 19, 2020
demographic variables, and statements regarding knowledge of and behaviour toward
Published: August 13, 2020 ADRs reporting. The intervention program consisted of posters, lectures, distant electronic
Peer Review History: PLOS recognizes the learning and reminders. An increase in the number of ADRs reports was noted in the inter-
benefits of transparency in the peer review vention group (74 times higher than in the control group) during the intervention period,
process; therefore, we enable the publication of
which was gradually decreased with as the study progressed (adjusted O.R = 74.1, 95%
all of the content of peer review and author
responses alongside final, published articles. The CI = 21.11–260.1, p<0.001). The changes in the "knowledge related to behaviour” (p = 0.01)
editorial history of this article is available here: and in the "behaviour related to reporting" (p<0.001) score was significantly higher in the
https://doi.org/10.1371/journal.pone.0235591 intervention group. Specialist physicians and nurses (p<0.001), fulfilling additional positions
Copyright: © 2020 Potlog Shchory et al. This is an (p<0.001) and those working in other places (p = 0.05) demonstrated a high rate of report.
open access article distributed under the terms of Lectures were preferable as a method to encourage ADRs reporting. The most convenient
the Creative Commons Attribution License, which
reporting tools were telephone and online reporting. Thus, implementation and maintenance
permits unrestricted use, distribution, and
reproduction in any medium, provided the original of a continuous intervention program, by a pharmacovigilance specialist staff member, will
author and source are credited. improve ADRs reporting rates.
Data Availability Statement: All data files are
available from the ICPSR database - project ID-
openicpsr-119582.

Funding: The author(s) received no specific

funding for this work.

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PLOS ONE Increasing adverse drug reaction reporting

Competing interests: The authors have declared Introduction

that no competing interests exist.
An integral part of drug therapy is the adverse reactions associated with the drug [1]. These
reactions can cause personal injury, hospitalization overload and increase in health costs,
thereby creating a heavy burden on national healthcare systems [2–5]. Studies around the
world have demonstrated that 3–7% of all hospitalizations are a result of adverse drug reac-
tions (ADRs) and 10–20% of inpatients suffer from drug-related adverse reactions [3, 6–8].
Serious ADRs were found to be the fourth to sixth causes of death in hospitalized patients in
the US, leading to extended hospitalization and doubling of the cost of treating these patients
[9,10]. Therefore, both healthcare teams and patients share a common goal of early detection
and prevention of ADRs.
Pharmacovigilance is defined by the WHO as the science and activities relating to the detec-
tion, assessment, understanding and prevention of adverse reactions or any other drug-related
problem. National systems for reporting drugs’ adverse reactions can be found in almost every
country [10–12]. Spontaneous reporting of medical staff regarding the occurrence of adverse
reactions is the major source for monitoring and investigating adverse reactions of marketed
drugs. However, only 1 in 20 adverse reactions is actually detected and defined as a real side
effect; this leads to the erroneous assumption that the incidence of adverse reactions is much
lower than it actually is [13–15]. Inadequate ADR reporting may lead to loss of clinical informa-
tion that could prevent substantial damage to patients and consequently minimize health costs.
Hence, it is very important to encourage medical staff to report any definite or suspected
ADR, as well as to establish and maintain an accurate database which can be used for analyzing
and processing of accumulated data, drawing conclusions and providing further recommenda-
tions. This series of actions could optimize patients’ wellbeing and safety and improve the
functioning of the healthcare system.
Israel has been an official member of the World Health Organization international program
for monitoring drugs since 1973. In August 2012, the Israeli ministry of health (MOH) pub-
lished guidelines for reporting adverse events and new safety information. This document
specifies the type of information that the Marketing Authorization Holder (MAH) requires
reporting and enables the MAH to appoint a pharmacist to serve as a qualified person respon-
sible for matters related to the reports included in this standard operating procedure, accord-
ing to the standard worldwide practice. Those regulations were update at February 2013 in
order to clarify the work processes related to reporting ADRs and new safety information, to
update the definitions of the SOP and to update the types of information requiring reporting
by the MAH. The aim of additional update from May, 2013 was to adjust the SOP to the Phar-
macists Regulations [16]. A new regulation was launched at October, 2014, in which a report-
ing system in medical institutions for both common and severe ADRs was established. In July
2019, a new portal for reporting adverse events to the Risk Management Department was
established. The purpose of all these regulations was to raise the awareness of the healthcare
teams to the importance of reporting ADRs [17]. Nevertheless, the reporting rate in Israel, as is
worldwide, is still quite low. Schwartzberg el al., identified 16,409 of Individual Case Safety
Reports (ICSRs) submitted to the MOH’s ADRs central database between September 2014 and
August 2016. However, of these reports, only 5.5% were submitted by health care professionals
from medical institutions, while 94.3% were submitted by pharmaceutical companies (MAH
and importers) and only 0.2% of the reports have been submitted by patients and the general
public [18].
The purpose of the present study was to establish and evaluate an intervention plan in
order to improve the reporting norms of ADRs among medical professionals (physicians and
nurses).

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PLOS ONE Increasing adverse drug reaction reporting

Materials and methods

Study design
The study was conducted over a period of 17 months (August 2012 to December 2013) and
included the healthcare teams (physicians and nurses) of internal medicine divisions from three
public medical centers in Israel: "A", "B" and "C", while each division served as a cluster. The med-
ical centers selected for the study were public hospitals serving an urban and rural population of
0.5–1 million people each. In Israel, a high percentage of physicians and nurses are from the Com-
monwealth States and Russian is their first language. In order to make it easier for them to com-
plete the questionnaire and to increase the response rate it was translated into Russian. Staff
members who lacked sufficient knowledge of Hebrew or Russian to fill in the questionnaires were
excluded from the study. Medical Center "A" was randomly selected to be the intervention group.
Medical centers "B" and "C" were merged and served as the control group. The randomization
among the centers was raffled by an external person who was not related to the study. ADRs
reports were collected from the Israeli Ministry of Health computerized website for all three medi-
cal centers, and reports from medical center "A" (the intervention group) were also collected from
the physical reporting binders available in the departments. The study was approved by the insti-
tutional review board of each medical center respectively. "A"—Ethics ("Helsinki") Committee;
(protocol Number 180/10); "B"—Committee Helsinki; (protocol Number EMC-0107-10); "C"—
Ethics ("Helsinki") Committee (protocol Number ver:1 KAP 1). In the introduction to the ques-
tionnaire a detailed explanation regarding the research and its rational was provided (See Supple-
ment 1 in the S1 File). In this section the participant was required to give consent to be included
in the research. Verbal consent was received during a meeting in which the research was pre-
sented to each participant. As part of the consent procedure the interviewer explained to each
medical staff member (physicians and nurses) about the study. Potential participants were
informed that taking part in the study was voluntary. Those who agreed to participate gave their
oral consent. A record of all participants who provided oral consent was kept by the principal
investigator. Every local IRB approved the use of verbal consent. Written consent was not
obtained from the participants because the participants were staff members and not patients.
The study consisted of 3 phases: The first phase of baseline data collection lasted three
months and included handing out a questionnaire to the healthcare teams. The questionnaire
contained questions about personal and professional demographic data, and statements
regarding the knowledge of and behavior toward ADRs reporting.
The second phase of the study was a 5-month intervention phase. The purpose of the
intervention plan was to improve the staff reporting rate of ADRs. Site "A" was randomly
selected as the medical center for intervention. The intervention program consisted of the fol-
lowing: a) posters for raising the awareness of the medical staff; these were placed at various
locations throughout the departments, such as: physicians’/ nurses’ rooms, medication rooms,
and dining areas; b) Forty-five minute lectures that were given during divisional meetings of
physicians and nurses separately. The lectures included: definitions of ADRs and pharmacov-
igilance, an explanation about the importance of the issue, data from international studies in
the field, information about the relationship between adverse drug events and morbidity/mor-
tality rates, incidence and prevalence of ADRs during hospital admission, the costs of ADRs
for the healthcare system and the patients, presenting the reasons of ADR under reporting and
a description of the current practices in Israel and around the world; c) Program promotion.
This included: visiting the departments and talking with the medical staff twice weekly, pre-
senting the program in the medical center portal and homepage and sending text messages to
the participants on their mobile phones every two weeks (a total of 8 text messages were sent);
d) introduction of distant electronic learning into the medical center portal.

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The third phase of the study lasted 9 months and included following up on the monthly
reporting rates. ADRs were reported through the Ministry of Health computerized website
(for both the intervention and the control group) or documented in binders available only in
the departments of the intervention group. At the end of this phase the participants from both
groups were asked to fill in the same questionnaire again.

The questionnaire (Supplement 1 in S1 File)

The questionnaire design was based on the causes for underreporting of ADRs among profes-
sionals, known as the “seven deadly sins” and on the combined theoretical model of the factors
affecting the conditions for ADR reporting by healthcare professionals [17,19–32].
Demographic data included profession and degree, date and place of birth, gender, country
of professional training, years of experience, expertise, as well as additional roles and positions
in other medical institutions.
"Knowledge related to behavior" was intended to explore the knowledge of the participants
about the ADR reporting procedure and its importance. It was investigated using the following
general question which dealt with identification of ADRs and the reasons for reporting/not
reporting: "You may notice an irregular adverse reaction from drug treatment and not report
it since:" Then the participants were prompted to choose one of 5 statements: "A. I know the
adverse drug reaction has already been documented by the pharmaceutical company"; "B. I do
not know that there is a center for reporting adverse drug reactions"; "C. I am not aware of the
need for reporting adverse drug reactions"; "D. I don’t know how to report adverse drug reac-
tions"; and "E. Reporting one adverse drug reaction does not significantly contribute to the
reporting mechanism". The answers were ranged on a scale from 1 point—no reason for not
reporting to 10 points—good reason for not reporting. This means that a staff member who
reports ADRs will receive a lower score.
The score of "behavior related to reporting" was constructed from two items that analyzed
the patterns of reporting to the National Center of pharmacovigilance and to pharmaceutical
companies. The statements were: "A. I spoke with pharmaceutical companies about the possi-
bility of adverse drug reactions with their drugs"; and "B. Have you ever reported adverse drug
reactions to a national reporting center?". The average of this score ranged from 1 point—non
reporting behavior—through 10 points—reporting behavior. The higher rate of reporting
achieved a higher score.
The main hypothesis: after the intervention program there would be more ADRs reporting
among medical professionals (physicians and nurses) in the intervention group compared to
the control group and to ADRs reporting base line.

Data analysis
Data analysis was carried out using the SPSS 21 software (PASW inc., USA). The statistical
analysis was conducted according to the phases of the study. Means and standard deviation
were used for continuous variables and examined by T or One-Way ANOVA/Mann Whitney
tests based on the variables distribution. The score of "Knowledge related to behavior" and the
score of "behavior related to reporting" didn’t distribute normally, thus we used a- parametric
test (Mann Whitney). Percentages and numbers were used for categorical variables and were
tested by chi square or Fisher’s exact tests as appropriate. Statistical significance was estab-
lished as p�0.05. The multi-variable models examined the independent effect of the interven-
tion program on reporting. The difference (change) was viewed as the dependent variable, and
factors forecasting change were examined through multi-variable linear regression models.

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PLOS ONE Increasing adverse drug reaction reporting

Identifying independent predicting factors of reporting adverse reactions was done through
multi-variable logistic regression models.
Quantitative variables, such as the differences between groups, comparison between physi-
cians and nurses and between medical centers, were analyzed by chi square or Fisher’s exact
tests. The differences and changes between the various parameters (knowledge and reporting
patterns) were calculated by comparing the data collected after the intervention phase with the
baseline data (change). The differences in knowledge and reporting among the study groups
were compared separately by T tests with independent samples or through One-Way
ANOVA. The building strategy for multivariable models was forced all the independent vari-
ables to one block. Both statistical and clinical justifications were considered. The models
included all the variables that were found to be significant (p<0.05) in the univariate data anal-
ysis, and covariates that were important to controlling for, as a baseline characteristic, accord-
ing to the research questions. All the independent variables that were included in the analyses
were presented in the results of the multivariable models. The multivariate models examined
the effect of the intervention program on knowledge and reporting. The difference (change)
was defined as the dependent variable and factors forecasting change were examined through
linear regression. The adjusted factors of reporting adverse reactions (with 95% confidence
intervals, 95% CI) were performed through multivariate logistic regression models. The inde-
pendent effect of every measure index of the questionnaire was adjusted to demographic and
professional variables.

Results
433 (81.5%) medical staff members, physicians and nurses, completed the questionnaire twice,
before and after the intervention. 47.8% of the participants were from the "A" medical center,
28.4% from "B" and 23.8% from "C". Distribution by gender was 69.1% females and 30.9%
males. 73% were nurses and 27% physicians. No selection bias was found between the staff
members completed the questionnaire the first time and those completed it twice. No differ-
ences in personal or professional variables were found between the intervention group ("A"
medical center) and control group ("B" and "C" medical centers), except for the ratio between
physicians and nurses and the subjects country of origin and average age."
During the research period, 336 ADRs were reported, of which 288 (85.7%) were reported
in Medical Center “A”, with 285 ADRs from the reporting binders and 3 ADRs from the Min-
istry of Health’s computerized website. The ADRs reports from the control groups comprised
10 reports (3%) in center “B” and 38 reports (11.3%) in center C; these were reported to the
Health Ministry’s computerized website. The reports were checked and there were no dupli-
cate reports by the staff members on both reporting channels in the intervention group.
The number of ADRs reports in the intervention vs. the control groups during the study
period is presented in Fig 1.
A rapid and substantial increase in the number of ADR reports was noted in the interven-
tion group during the 5-month intervention period, which gradually decreased toward the end
of the study. The reporting in the intervention group went nearly back to baseline and was
even lower than in the control group. On the other hand, there was almost no change in the
number of ADR reports in the control group during the entire study duration. After the inter-
vention period the reporting rate in the intervention group reverted to almost baseline and
was lower than the control group, similarly to the trend that was observed in the baseline.
Comparison of the rate of ADRs reports received from physicians vs. nurses indicated that
in both groups a substantial increase in the number of ADR reports was observed during the
intervention period, which gradually decreased toward the end of the study.

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PLOS ONE Increasing adverse drug reaction reporting

Fig 1. Number of ADR reports in the intervention vs. the control groups during the study period. A rapid and
substantial increase in the number of ADR reports was noted in the intervention group during the 5-month
intervention period, which gradually decreased toward the end of the study.
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Comparison of the score of "knowledge related to behavior" showed that before any inter-
vention the mean score of the control group was significantly lower than that observed in the
intervention group (3.84±2.20 and 4.37±2.27 respectively, p = 0.02), demonstrating that the
control group was more aware of ADRs reporting. Nevertheless, the changes in the "knowledge
related to behavior” score was significantly higher in the intervention than in the control
group (a change of -0.69±2.58 in the intervention group vs. -0.11±2.19 in the control group,
P = 0.01)) Table 1).
When the score of "behavior related to reporting" was compared between the intervention
and control groups upon intervention, a statistically significant increase in the score "behavior
related to reporting" was observed in the intervention group, with a mean change of 0.65±2.22
(2.21±1.88 before intervention and 2.37±2.87 after intervention, P<0.001). No significant dif-
ference in the score of "behavior related to reporting" was noted in the control group (Table 2).
Comparison of patterns in "behavior related to reporting" was conducted according to vari-
ous demographic and professional-related variables. The results revealed that the nurses dem-
onstrated less changes in "behavior related to reporting" than physicians (P = 0.003). A
significant positive correlation was found between the numbers of patients treated per day by
the medical staff (nurses and physicians) and "behavior related to reporting", i.e. as the number

Table 1. Comparison of the changes in the mean score of "knowledge related to behavior" of the intervention group vs. the control group. The changes in the
"knowledge related to behavior” score was significantly higher in the intervention than in the control group.
Score before the intervention Score after the intervention Differnce in score changes
Mean ±SD (n) Mean ± SD (n) Mean ±SD(n)
Intervention group 4.37±2.27 (206) 3.67±2.16 (205) - 0.69±2.58 (205)
Control group 3.84±2.20 (220) 3.73±2.14 (225) - 0.11±2.19 (221)
P value 0.02 0.79 0.01
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PLOS ONE Increasing adverse drug reaction reporting

Table 2. Comparison of the changes in the mean score of "behavior related to reporting" of the intervention group vs. the control group.
Score before the intervention Score after the intervention Differnce in scores changes
Mean ± DS (n) Mean ± DS (n) Mean ± DS (n)
Intervention group 2.21±1.88 (207) 2.87±2.37 (207) 0.65±2.22 (207)
Control group 2.54±2.13 (226) 2.48±2.12 (226) - 0.06±2.16 (226)
p value 0.09 0.79 0.001
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of patients per caregiver increased, the change in "behavior related to reporting" score was
higher (P = 0.02). In addition, the results revealed that the more aware the caregiver is of the
fact that the patients are consuming more than one medication per day, a larger change in
"behavior related to reporting" score is observed (P = 0.02, r = 0.13) (Table 3).
The demographic and the professional variables and reporting/non reporting behavior
were later examined within the intervention group. As seen in Table 4, physicians reported
more than nurses (56.9% vs. 36.5%, p = 0.009). Specialists, both nurses and physicians,
reported more than non-specialists (60.6% vs. 32.6%, p<0.001). Those (both physicians and
nurses) fulfilling additional positions and those working in other places beside the hospital
demonstrated high rates of reports (66.7% vs. 33.6%, p<0.001 and 60.0% vs. 39.8%, p = 0.05,
respectively) (Table 4).
Further analysis of the previous data to physicians and nurses revealed that the demo-
graphic and professional variables among the physicians did not have any effect on the per-
centage of ADRs reports. However, among the nurses, specialty (56.1% vs 29.6%, p = 0.02) and
fulfilling additional positions (63.3% vs. 28.8%, p<0.0001) indeed increased reporting rates,
while no difference was observed with regard to working in other places besides the hospital
(37.5% vs. 36.6%, p = 0.96).
The intervention plan had a strong, independent and statistically significant effect on
"behavior related to reporting" (p = 0.008). In addition, profession and number of patients
treated per day by the caregiver also had a significant effect on the "behavior related to report-
ing" (p = 0.01 and p = 0.02, respectively) (Table 5).
In order to examine the independent effect of the intervention plan on reporting (yes / no),
a logistic model was constructed. We found that the intervention plan had a strong, indepen-
dent, statistically significant effect on the staffs’ actual ADRs reporting. After standardization
for specialist, expertise, holding managerial positions and those who work in other places, sub-
jects in the intervention group reported 74 times higher than their counterparts in the control
group (O.R = 74.1, 95% CI = 21.11–260.1, p<0.001) (Table 6).
Education and lectures were preferable, while payment for reporting was the least desirable
method for encouraging medical staff to report side effects. The most convenient reporting
tools were found to be the telephone and an internet site.

Discussion
The purpose of this study was to establish and evaluate an intervention plan for increasing
ADR reporting rate among physicians and nurses. This study demonstrates that the rate of
ADR reporting increased significantly during the intervention period, and declined gradually
thereafter. However, almost no change in the numbers of reports was observed in the control
group during the entire duration of the study. The trend presented in the data that the rate of
reports decreased over time after the intervention program was discontinued implies that con-
tinued intervention may be required to maintain the high rate of reports. Interestingly, the
reporting rate in the control group was higher than in the intervention group at base line,

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PLOS ONE Increasing adverse drug reaction reporting

Table 3. Comparison of patterns in "behavior related to reporting" according to various demographic- and professional-related variables of the intervention group
vs. the control group. Nurses demonstrated less changes in "behavior related to reporting" than physicians A significant positive correlation was found between the num-
bers of patients treated per day by the medical staff (nurses and physicians) and "behavior related to reporting", as well as between the awareness of the caregiver that the
patients are consuming more than one medication per day, and the change in "behavior related to reporting" score.
Variable Number Change in "behavior related to reporting" (Mean±SD) P-value
Total No
Gender Female 299 0.20±2.04 P = 0.27
433 Male 134 0.46±2.57
Profession Nurse 316 0.06±1.91 P = 0.003
433 Physician 117 0.89±2.79
Country of origin Israel 200 0.11±2.37 P = 0.25
421 Eastern Europe 184 0.49±1.96
Other 37 0.38±2.52
Country of professional training
Israel 291 0.18±2.07 P = 0.31
422 Eastern Europe 89 2.48±2.24
Other 42 0.62±3.05
Specialty Yes 144 0.42±2.79 P = 0.40
433 No 289 0.21±1.93
Fulfilling other positions Yes 91 0.38±2.89 P = 0.51
392 No 301 0.17±1.91
Working in other places Yes 47 0.70±3.01 P = 0.29
423 No 376 0.22±2.11
Age 404 r = 0.04 P = 0.40
404
Age �35 143 0.17±2.21 P = 0.70
404 36–45 131 0.32±2.23
�46 130 0.40±2.41
Years of seniority in the profession 392 r = 0.04 P = 0.49
392
Years of seniority in the profession <7 110 0.17±2.21 P = 0.48
392 7–20 172 0.18±2.13
>21 110 0.50±2.38
Years of seniority in the profession in Israel 213 r = 0.06 P = 0.42
213
Years of seniority in the profession in Israel �20 113 0.45±1.76 P = 0.72
213 >21 96 0.35±2.21
Years of Seniority in the internal division 414 r = 0.03 p = 0.57
414
Years of Seniority in the internal division �3 137 0.16±1.97 P = 0.31
414 3.1–13 140 2.55±2.22
�13.1 137 0.23±2.43
Number of patients treated per day 382 r = 0.12 P = 0.02
382
Number of patients treated per day �12 195 0.06±2.11 P = 0.02
382 >13 187 1.56±2.34
No. of drugs distributed/examined per day 319 r = -0.04 P = 0.50
319
No. of drugs distributed/examined per day �50 190 2.42±0.41 P = 0.71
319 >51 129 2.09±0.31
% of Patients taking more than one drug per day 380 r = 0.13 P = 0.02
(Continued )

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PLOS ONE Increasing adverse drug reaction reporting

Table 3. (Continued)

Variable Number Change in "behavior related to reporting" (Mean±SD) P-value

Total No
380
Patients taking more than one <90% 82 0.41±2.40 P = 0.77
drug per day >90% 298 0.38±2.34
380
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though it was not statistically significant. The intervention plan increased the reporting rate
and the differences between the control and the intervention rose and were statistically signifi-
cant throughout the intervention period. However, as distance from the intervention period
increased, the amount of reports decreased eventually reverting to the trend that was observed
at the baseline. The impact of the intervention waned with time. An example to this trend was
demonstrated also in an educational intervention program to improve physicians’ reporting of
ADRs. In this study the reporting rate in the intervention group increased during the interven-
tion, while it gradually decreased through 13 months of follow-up [9].
The compliance rate of the participants in the present study for filling in both question-
naires was rather high (81.5%). A lower rate of compliance was reported in similar studies, in
which 22.8% (Biagi 2013) or 47% (Passier 2009) of the physicians answered questionnaires
regarding ADRs reporting [33, 34]. Another study from Venezuela (Garciani 2011) reported
higher compliance rate of 65.4% among physicians and pharmacists and 60% among nurses
[35]. Interestingly, a much lower compliance rate was found in studies in which the question-
naires were sent to the participants by e-mail or regular mail [36]. The relatively high rate of
compliance in the current study may be associated with the constant presence of the investiga-
tor at the medical centers and the personal contact with the study participants.
According to the results of the current study, physicians reported ADRs more than nurses.
In addition, the change in the “Behavior related to reporting” score in the intervention group
was higher among physicians compared to the nurses. The changes in the “Behavior related to
reporting” is also demonstrated by the increase in the rate of ADRs in the intervention group
compared the control group. This finding is consistent with other studies [1, 37–39]. In a
study that took place in Korea, spontaneous reports of ADRs by e-mail were 13% among
nurses vs. 53% reports by physicians. Some studies demonstrated that nurses mostly tend to
report an ADR to a physician. Hanafi et al. have shown that 89% of the nurses who participated
in the study said that they reported the ADR to the physician [40]. The Hajebi’s study found
that 56% of the nurses that come across a drug-related side effect reported to the department
physician, 26% to the head nurse and 13% to a pharmacist [41]. The availability and accessibil-
ity of physicians to nurses who work in hospitals probably encouraged the reporting to physi-
cians. This tendency could explain the difference in ADR reporting rates between nurses and
physicians. Contrarily, in a research that was conducted in an Israeli public hospital where the
medical staff was encouraged to report ADRs to the clinical pharmacology unit, the nurses
were found to have reported more ADRs than the physicians [42]. In the present study, despite
the fact that the nurses reported less than the physicians, their rate of reports peaked more
quickly and decreased more slowly than that of the physicians.
We also found that professionals who fulfill additional positions in the department or in
other health institutions (such as: community health services or treating senior citizens at
nursing homes) demonstrated higher rates of ADR reporting. In addition, the results of the
present study showed that specialists reported more ADRs than non-specialists and that the

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PLOS ONE Increasing adverse drug reaction reporting

Table 4. Comparison of the demographic and the professional variables and reporting/non-reporting behavior in the intervention group vs. the control group.
Physicians reported more than nurses; specialists, reported more than non-specialists; those fulfilling additional positions and those working in other places beside the hos-
pital demonstrated high rates of reports.
Variable (Total No.) Did not report Reported Total p-value
% (n) % (n)
Gender (207) Female 60.8 (96) 39.2 (67) 158 0.23
Male 51.0 (25) 49.0 (24) 49
Profession (207) Nurse 63.5 (99) 36.5 (57) 156 0.009
Physician 43.1 (22) 56.9 (29) 51
Country of origin (202) Israel 47.9 (34) 52.1 (37) 71 0.12
Eastern Europe 63.4 (71) 36.6 (41) 112
Other 64.3 (11) 42.1 (8) 19
Country of Professional Training (200) Israel 55.9 (71) 44.1 (56) 127 0.83
Eastern Europe 60.8 (31) 39.2 (20) 51
Other 59.1 (13) 40.9 (9) 22
Specialty (207) Yes 39.4 (26) 60.6 (40) 66 <0.001
No 67.4 (95) 32.6 (46) 141
Fulfilling other positions (194) Yes 33.3 (15) 66.7 (30) 45 <0.001
No 66.4 (99) 33.6 (50) 149
Working in other places (201) Yes 40.0 (10) 60.0 (15) 25 0.05
No 60.2 (106) 39.8 (70) 176
Age (Mean ±SD) 57.13±7.21 42.87±9.34 103/82 0.92
Age (185) �35 48.8 (21) 51.2 (22) 43 0.08
36–45 66.7 (44) 33.3 (22) 66
�46 50.0 (38) 50.0 (38) 76
Years of seniority in the profession (Mean ±SD) 16.52±10.06 17.14±10.21 103/83 0.68
Years of seniority in the profession (186) <7 54.3 (19) 45.7 (16) 35 0.68
7–20 58.6 (51) 41.4 (36) 87
>21 51.6 (33) 48.4 (31) 64
Years of seniority in the profession in Israel (Mean ±SD) 19.64±9.05 21.4±10.83 81/47 0.32
Years of seniority in the profession in Israel (128) �20 64.8 (46) 35.2 (25) 71 0.69
>21 61.4 (35) 38.6 (22) 57
Years of Seniority in the internal division (Mean ±SD) 11.26±9.49 13.36±10.11 114/84 0.32
Years of Seniority in the internal division (198) �3 65.4 (34) 34.6 (18) 52
3.1–13 60.3 (41) 39.7 (27) 68 0.19
�13.1 50.0 (39) 50.0 (39) 78
No. of patients treated per day (Mean ±SD) 15.92±9.22 16.34±11.19 104/79 0.78
No. of patients treated per day (183) �12 54.5 (54) 45.5 (45) 99 0.50
�13 59.5 (50) 40.5 (34) 84
No. of drugs distributed/examined per day (Mean ±SD) 53.72±43.90 65.04±54.71 91/69 0.15
No. of drugs distributed/examined per day (160) �50 59.1 (55) 40.9 (38) 93 0.50
>51 53.7 (36) 46.3 (31) 67
% of Patients taking more than one drug per day (Mean ±SD) 89.44±19.70 87.19±24.35 102/77 0.56
Patients taking more than one drug per day (179) <90 58.3 (21) 41.3 (15) 36 0.86
>90 56.6 (81) 43.4 (62) 143
https://doi.org/10.1371/journal.pone.0235591.t004

rate of ADR reporting was associated with the number of patients treated per day by the care-
giver. A contrary observation was reported by a study in Ireland, which investigated the rate of
ADR reporting among 118 hospital-based physicians. This study found a higher rate of ADR
reporting among general physicians than among surgeons [43].

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PLOS ONE Increasing adverse drug reaction reporting

Table 5. The effect of the intervention program and demographic characteristics on "behavior related to report-
ing". The intervention plan had a strong, independent and statistically significant effect on "behavior related to report-
ing". Profession and number of patients treated per day by the caregiver also had a significant effect on the "behavior
related to reporting".
Variable β p value
Intervention (Yes / No) 0.13 0.008
Professional (physician / nurse) 0.14 0.01
Number of patients treated per day 0.12 0.02
Gender (Male / Female) 0.009 0.87
https://doi.org/10.1371/journal.pone.0235591.t005

The present study demonstrated that the preferred method for increasing the rate of ADR
reporting was lectures and education A study that compared telephone-interview intervention
with a workshop intervention showed that the latter increased ADR reporting rate by a four-
fold on average compared to the control group over 20 months post-intervention. However,
no significant difference vs. the control group in ADR reporting was found in the telephone-
interview intervention [44]. Other studies have shown that improved communication with fel-
low physicians and involvement of pharmacists might be the best ways to improve ADR
reporting [21, 34]. Regular newsletter on current awareness in drug safety, information on
new ADRs, and international drug safety information were also identified as tools or methods
that may motivate ADR reporting in a study conducted by Santosh et al. among 450 healthcare
professionals working at Regional Pharmacovigilance Centers in Nepal [21].
Our research shows that the preferred means of reporting were telephone or website. Other
studies also report these methods as preferential. A study of 500 nurses from a teaching hospi-
tal in Teheran showed that among the 10% who reported an ADR, the majority of the nurses
preferred using the telephone [45]. Among physicians in India and the Netherlands, most of
the ADRs were reported using the computerized system [34, 46].
Payment for reporting was found to be the least favored method to encourage ADR report-
ing in the current study. A survey of 91 practice nurses, health visitors, school nurses and gen-
eral physicians conducted by Pulford et al., has shown that payment for ADR reporting was
indeed the least acceptable out of 14 other options of gratuity [47].

Conclusions
The results of this study indicate that training and educating medical practitioners and provid-
ing them with relevant knowledge regarding ADR reporting is essential. Due to the observa-
tion that the reporting rate decreased with time upon the finalization of the intervention
period, it seems that maintaining a program to encourage reporting, is necessary. Regular
implementation of such a program in the healthcare system will increase the awareness of the
medical staff and improve reporting rates. Maintaining the intervention program could be car-
ried out by nomination of a pharmacovigilance specialist trustee to administer a routine inter-
vention program. This expert could be a physician, a nurse or a pharmacist. Visits, personal

Table 6. The independent effect (adjusted Odd Ratios and 95% CI) of the intervention program on ADR reports.
A logistic model revealed that the intervention plan had a strong, independent, statistically significant effect on the
staffs’ actual ADRs reporting.
Variable O.R CI 95% p value
Intervention (Yes / No) 74.1 21.11–260.1 0.001>
Fulfilling other roles (Yes / No) 3.16 1.45–6.92 0.004
Specialty (Yes / No) 2.32 1.14–4.70 0.02
Professional (physician / nurse) 2.70 1.31–5.57 0.007
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PLOS ONE Increasing adverse drug reaction reporting

discussions, posters, lectures about the importance of ADRs reporting and how to carry it out
and sending text messages to the medical staff on their mobile phones with reminders and rel-
evant information should be used in order to continuously raise their awareness reporting
about ADRs. In addition, the personal contact of the medical staff with the trustee will encour-
age their commitment to report about ADRs. This will probably improve monitoring of medi-
cation use, decrease morbidity/mortality rates and hospitalization duration.

Limitations
The study was carried out in internal divisions of only 3 public medical centers, and therefore
may not have an external validation in other hospitals.
The study included only physicians and nurses, therefore the results cannot be applied to
additional medical professionals.
There were some differences in the basic characteristics between the clusters (hospitals)
which may have affected the quality of the intervention to a certain extent. However, after
adjusting for the demographic variables, we can assume that the results of the study are indeed
due to the effect of the intervention.
We cannot assume from this study that the effect of the intervention would improve safety
of medicine use in the long term and reduce health costs.

Supporting information
S1 Data.
(SAV)
S1 File.
(DOC)
S2 File.
(DOC)

Author Contributions
Conceptualization: Miri Potlog Shchory, Lee H. Goldstein, Lidia Arcavi, Renata Shihmanter,
Matitiahu Berkovitch, Amalia Levy.
Data curation: Miri Potlog Shchory, Matitiahu Berkovitch.
Formal analysis: Miri Potlog Shchory, Amalia Levy.
Investigation: Miri Potlog Shchory.
Methodology: Miri Potlog Shchory, Lee H. Goldstein, Lidia Arcavi, Renata Shihmanter, Mati-
tiahu Berkovitch, Amalia Levy.
Supervision: Amalia Levy.
Validation: Miri Potlog Shchory.
Writing – original draft: Miri Potlog Shchory.
Writing – review & editing: Matitiahu Berkovitch, Amalia Levy.

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