Healthcare students' knowledge, attitude and perception of pharmacovigilance: A systematic review

Monira Alwhaibi; Noha A Al Aloola

doi:10.1371/journal.pone.0233393

. 2020 May 20;15(5):e0233393. doi: 10.1371/journal.pone.0233393

Healthcare students' knowledge, attitude and perception of pharmacovigilance: A systematic review

Monira Alwhaibi ^1,^2,^*, Noha A Al Aloola ^1,²

Editor: Lisa Susan Wieland³

PMCID: PMC7239457 PMID: 32433649

Abstract

Objective

The objective of this review is to evaluate the existing evidence about the knowledge, attitude, and perceptions (KAP) of healthcare students towards pharmacovigilance and adverse drug reactions reporting (ADRs).

Methods

A systematic literature search was conducted using MEDLINE, CINAHL, EMBASE, ERIC, and Cochrane Database of Systematic Reviews via OVID. This review restricted the search to studies published in English from inception until December 2019.

Primary and secondary outcome measures

The primary outcome was healthcare students’ knowledge, attitude, and perceptions of pharmacovigilance.

Results

Of the 664 articles identified, twenty-nine studies were included in the review. Overall, healthcare students vary in their knowledge and attitude towards pharmacovigilance and ADRs reporting. There was inconsistency in measuring KAP between the studies and the main drawback in the literature is lacking validated KAP measures.

Conclusions

In summation, optimal KAP assessment can be achieved through developing a standard validated measure. Our future healthcare providers should have basics pharmacovigilance knowledge in order to rationally reporting ADRs and preventing serious health problems.

Introduction

Pharmacovigilance is an important discipline worldwide to ensure patient safety and the appropriate use of medicines [1]. World Health Organization (WHO) defines pharmacovigilance (PV) as “the science and activities relating to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem.”[2] Pharmacovigilance and adverse drug reactions (ADRs) reporting education are important competencies all healthcare school students need to obtain before they graduate and be involved in clinical practice as healthcare professionals [3]. Therefore, educating healthcare students in the school of medicine, pharmacy, dentistry, or nursing and involving them early in clinical practice to prescribe, administer, and/or monitor medications is essential to ensure the safe use of medications [4].

Healthcare students may not recognize the importance of post-marketing ADR and may not have received sufficient knowledge and skills to recognize and adequately report the ADRs during their education. Literature indicated that many healthcare students missed the training on this topic, and inadequately prepared during their education for their role in monitoring and reporting ADRs [3, 5]. In addition, previous studies have shown that pharmacy students have insufficient knowledge of pharmacovigilance and ADRs reporting [3, 5].

Unfamiliarity with pharmacovigilance and ADR-reporting have been associated with ADRs underreporting by healthcare professionals [6, 7]. Further, underreporting and the lack of understanding of ADRs could lead to a greater burden on patients, payers, and healthcare systems. Therefore, knowledge and perception toward the safety profile of medications are essential. Educating healthcare professionals on the possible existence of unexpected adverse reactions and how to report them to the local regulatory authorities can facilitate the detection and assessment of drug safety signals.

The purpose of this systematic review is to evaluate the literature that measures the level of healthcare students’ knowledge, attitude, and perception of pharmacovigilance and ADRs reporting. This can help to identify the current need for education/training on pharmacovigilance and the research need to improve our understanding of healthcare students’ knowledge, attitude, and perception of pharmacovigilance.

By summarizing the published literature in this area it should be possible to grasp a more understanding of the existing evidence and understand future needs for research in this area. Our review research questions are:

What is known about healthcare students’ pharmacovigilance knowledge?
What is known about healthcare students' attitudes and perceptions of pharmacovigilance?
Are there any validated measures to assess students’ knowledge, attitude, and perception toward PV in the existing literature, and what could future studies add to our understanding of the healthcare students' knowledge, attitude and perception of pharmacovigilance?

Methods

Eligibility criteria

Study inclusion criteria were as follows: (1) study population consisting of healthcare students (medical, pharmacy, dental, and nursing) at any stage of their undergraduate training, (2) the study outcome is the knowledge, attitude or perception of pharmacovigilance, and (3) study design is cross-sectional.

Exclusion criteria were as follows (1) study population consisting of postgraduate or healthcare professionals, (2) qualitative study design, and (3) report language is non-English.

Search strategy

The present systematic review was reported according to the Preferred Reporting Items for the Systematic Reviews and Meta-Analyses (PRISMA) guidelines (S2 Appendix) [8].

Research articles were retrieved from six databases (MEDLINE via EBSCO, Cumulative Index to Nursing and Allied Health Literature (CINAHL®) via EBSCO, EMBASE, ERIC via EBSCO, and Cochrane Database of Systematic Reviews via OVID) with database-specific queries. These databases were searched using both controlled and free-text language. In terms of free-text search, the keywords included the following terms/combination of terms: (knowledge OR attitude OR perception) AND (healthcare students OR medical students OR pharmacy students OR dental) AND (pharmacovigilance OR adverse drug reactions reporting). For the controlled language search included the following exploded Medical Subject Headings (MeSH) terms: "knowledge”, “attitude”, “perception", "Students, Medical", "Students, Pharmacy", "Students, Nursing", "Students, Dental", "Pharmacovigilance" and " Drug-Related Side Effects and Adverse Reactions” as recommended for each databases. S1 Appendix shows the complete search strategy used in MEDLINE.

Articles search of the four databases was conducted independently by two review authors (MA and NA), any disagreement was resolved by consensus. Besides, bibliographies from the selected articles were searched manually for relevant articles. Limits that were applied included selecting studies published in English from inception until December 2019; studies pertaining to the evaluation of pharmacovigilance knowledge, attitude or perception and where the participants are healthcare students.

Study selection

At first, literature screening of the extracted articles involved examining the titles and abstracts for relevant articles for inclusion was conducted independently by two review authors (MA and NA). Then, the review authors evaluated the full-text articles against the inclusion/exclusion criteria. The article selection process resulted in twenty-nine studies included in this systematic review (Fig 1).

Fig 1 — *From*: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi: 10.1371/journal.pmed1000097 For more information, visit www.prisma-statement.org.

Data extraction and quality assessment

The two review authors (MA and NA) independently extracted the included data. Information about the study characteristics, methodological details, main outcome measures, and findings were extracted from the selected articles and organized in an excel table to facilitate the assessment of their quality using STROBE (Strengthening The Reporting of OBservational Studies in Epidemiology) checklist [9]. This tool covers twenty-two criteria for study design quality and biases in the study. For each criterion met, the study gets one point; the highest score indicates the highest quality of the study. Besides, we have used the five items risk of bias in cross-sectional surveys of attitudes and practice [10].

Statistical analysis

The published literature was analyzed qualitatively and the results (number and percentage) were reported in a narrative way, focusing on common findings that we identified across the included studies.

Patient and public involvement

Patients and the public were not involved in the design or conduct of this study.

Results

Selection process

A total of 664 articles were identified from all searches, with 636 remaining after the removal of duplicates. Based on the title and abstract screening, 39 full-text articles were retrieved. Of these, twenty-two studies met the inclusion criteria and included in the final review (Fig 1).

General characteristics of included studies

The characteristics of the included studies are displayed in Table 1. Studies that evaluated pharmacovigilance knowledge, attitude or perception of healthcare students started to appear since 2011. The majority of the included studies involved pharmacy students [11–19], while few studies specifically focused on healthcare students [20–22], nursing students [23], and dental students [24, 25]. The total number of included studies was twenty-nine, with sample sizes ranging from 30 to 874. Response rates across the studies varied from 24% to 100%. Twenty-seven studies examined the Pharmacovigilance knowledge [11–35], twelve studies evaluated attitudes towards pharmacovigilance [14, 16, 19–21, 23–26, 29, 30, 33], and fourteen studies measured the perception of pharmacovigilance [11–15, 17, 18, 21–23, 26–28, 31, 36]. Around 50% of the included studies (n = 15) were pilot tested among the students that were not included in the final analysis. A pilot test was used to evaluate the validity and reliability of the instrument with an overall reliability coefficient, Cronbach’s alpha, ranging from 0.69–0.82 suggesting that the items included in these studies have relatively high internal consistency.

Table 1. Characteristics of included studies that measures knowledge, attitude, and perceptions of medical students.

Author (Publication Year)	Country	Study Design	Student Type	Total Students	Response Rate	Questionnaire Development	Outcomes	Main Findings	Quality ^*
Katyal et al (2019)[33]	India	Cross-sectional study	Medical students	253		Was developed based on reviewing the literature	Knowledge and Attitude	Around 60% were familiar with the term ‘Pharmacovigilance’	>75%
Marko (2019)[29]	India	Cross-sectional study	2^nd year, pre-final year, and intern Medical students	228		Pretested questionnaire.	Knowledge and Attitude	> 60% of responders have knowledge about PV and ADRs. Around 80% have positive attitude toward ADR reporting.	<75%
Yu et al (2019)[32]	South Korea	Cross-sectional study	Pharmacy students	303		The survey was developed based on a mixed theoretical model	Knowledge and Attitude	Around 67% have knowledge regarding PV, attitude towards ADRs range from 30% to 78%	>75%
Khan et al (2018)[34]	Pakistan	Cross-sectional study	Final year pharmacy students	122		Well designed and structured questionnaire	Knowledge	Overall mean score of knowledge about ADRs and PV was 7.46 ± 2.19	<75%
Gaude et al (2018)[30]	India	Cross-sectional study	Final year medical students	95	73%	Predesigned questionnaire	Knowledge and Attitude	Around 55% of student answered the questions related to knowledge correctly and 67.3% had a positive attitude	>75%
Ajantha et al (2018)[31]	Chennai	Cross-sectional study	Dental students	200		A validated questionnaire	Knowledge and Attitude	The knowledge regarding PV and ADRs was low ranging from 29% to 32%	<75%
Aamir et al (2018)[35]	Pakistan	Cross-sectional study	Pharmacy and Medical Students	2010		Well-structured questionnaire	Knowledge	Poor knowledge towards PV and ADRs reporting was noticed among medical and pharmacy students	>75%
Tadvi et al (2018)[20]	Saudi Arabia	Cross-sectional study	3^rd and onwards medical students	148	59%	Was developed based on the information obtained from previous studies	Knowledge and Attitude	The knowledge regarding PV and ADRs was low ranging from 28% to 57%.	>75%
Limaye et al (2018)[38]	India	Cross-sectional study	Pharmacy students	352	88%	Was developed based on reviewing the literature and pilot tested among 30 students	Knowledge and perception	PV knowledge (44%) and perception (58%)	<75%
Chhabra et al (2017)[24]	India	Cross-sectional study	3^rd and final year dental students	241	88%	Was developed from Theory, research, observation, and expert opinion and pilot tested among 35 students (Cronbach’s alpha was 0.72 for knowledge; 0.86 for attitude)	Knowledge and Attitude	The total median PV knowledge score was 6, total median attitude score was 35	>75%
Alkayyal et al (2017)[16]	Saudi Arabia	Cross-sectional study	4^th, 5^th, and 6^th year pharmacy students	259		Was developed based on extensive literature search and pilot tested among 10 students	Knowledge and Attitude	The mean PV knowledge score was 4.15	>75%
Othman et al (2017)[39]	Yemen	Cross-sectional study	Final year pharmacy students	385	92%	Was developed based relevant literature and pilot tested among 20 students	Knowledge and Perception	The knowledge regarding PV and ADRs range from 20% to 81%, perceptions range from 60% to 97%	>75%
Al-Shekaili et al (2017)[17]	Oman	Cross-sectional study	Final year pharmacy students	118	79%	Was developed based on reviewing the literature	Knowledge and Perception	The PV knowledge range from 17% to 78%, perceptions range from 39% to 80%	>75%
Osemene et al (2017)[15]	Nigeria	Cross-sectional study	Final year pharmacy students	342	98%	The study adapted the survey instruments used in similar studies, Pilot tested (Cronbach alpha = 0.72)	Knowledge and Perception	The mean PV knowledge score was 4.3, mean perception scores range from 1.8–4.6	>75%
Schutte et al (2017)[21]	Netherlands	Cross-sectional study	3^rd to 6^th year medical students	874	7–24%	Was developed and pilot tested	Knowledge and Attitudes	Knowledge regarding PV and ADRs range from 28% to 95%	>75%
Rajiah et al (2016)[18]	Malaysia	Cross-sectional study	Final year pharmacy students	108		Was designed after a detailed review of relevant literature was pilot-tested among 20 pharmacy students (Cronbach’s alpha = 0.82)	Knowledge and Perception	Knowledge regarding PV and ADRs range from 7.4% to 92% and perception range from 3% to 75%	>75%
Abubakar et al (2015)[22]	Nigeria	Cross-sectional study	4^th and 5^th year medical students	108	74%	The questions were extracted from previous literature and pilot-tested among 20 medical students (Cronbach’s alpha = 0.69)	Knowledge and Perception	Knowledge regarding PV and ADRs range from 10% to 94%, perception range from 6% to 98%	>75%
Farha et al (2015)[27]	Jordan	Cross-sectional study	4^th, 5^th, and 6^th year pharmacy students	225	67%	A questionnaire previously developed by the study	Knowledge and Perception	The knowledge regarding PV and ADRs was ranging from 5% to 65%	>75%
Kothari et al (2015)[28]	Anand district in Gujarat, India	Cross-sectional study	5^th, and 6^th year pharmacy students	300		Was developed based on the literature and pilot-tested among 25 pharmacy students	Knowledge and Perception	Knowledge regarding PV and ADRs range from 13% to 61%	<75%
Khan et al (2015)[26]	Pakistan	Cross-sectional study	Final-year pharmacy and medical students	91		Was designed by the authors after an extensive literature review and pilot tested among 10 students (Cronbach’s alpha = 0.81)	Knowledge, attitude and Perception	PV knowledge range from 31–91% for pharmacy and 7–84% for medical students, Attitude range from 47–98% for pharmacy and 35–98% for medical students	>75%
Shalini et al (2015)[25]	Malaysia	A pilot study	Pre-final and final year dental students	61	76%	Was adapted from the previously published paper and pilot-tested among 20 students (Cronbach’s α = .73)	Knowledge and Attitude	Knowledge regarding PV range from 3% to 50%	<75%
Jha et al (2014)[40]	Nepal	Cross-sectional study	Pharmacy students			Was developed after consulting previous studies	Knowledge		>75%
Sivadasan et al (2014)[12]	Malaysia	Cross-sectional study	Pre-final and final year medicine and pharmacy students	479	63%	Questionnaire was prepared from the literature and pilot-tested among 20 pharmacy students (Cronbach’s alpha = 0.72)	Knowledge and Perception	Knowledge regarding PV range from 21% to 59% for pharmacy students and 6% to 72% for medical students,	>75%
Reddy et al (2014)[14]	India	Cross-sectional study	Pharmacy students	225	90%	Was generated and adapted from previous studies and pilot-tested among 15 students (Cronbach’s alpha = 0.72)	Knowledge, Attitude and Perception	The knowledge regarding PV and ADRs was ranging from 5% to 65%, perceptions from 40% to 95%	<75%
Sivadasan et al (2014)[23]	Malaysia	A pilot study	Pre-final and final year Nursing Students	32	100%	The questionnaire was adapted from the previously published paper and pilot-tested among 20 students (Cronbach’s alpha = 0.73)	Attitude	The mean score on PV knowledge was found to be 12.31, for attitude was 15.1, for perception was 15.06.	>75%
Sharma et al (2012)[13]	Punjab, India	Cross-sectional study	Final year pharmacy students	30		The questionnaire was adapted from the previously published study	Knowledge and Perception	The knowledge regarding PV and ADRs was ranging from 10% to 90%.	<75%
Gavaza et al. (2012)[19]	United States	Pilot study	Final year pharmacy students	58	91%	A survey instrument adapted from previous research	Knowledge and Attitude	The PV knowledge score range from 29% to 82% and mean score on PV attitude was 5.2.	>75%
Elkalmi et al (2011)[11]	Malysia	Cross-sectional study	Final-year (fourth-year) pharmacy students	510	84%	Was developed from the literature and a qualitative study a pilot-tested to a sample of 20 pharmacy students (Cronbach’s alpha = 0.76).	Knowledge and Perception	The knowledge regarding PV and ADRs was ranging from 17% to 96%, perceptions from 40% to 95%	~75%
Kalari et al. (2011)[36]	United States	Cross-sectional study	Second and third year pharmacy students	228	65%		Perception	The perception regarding PV and ADRs was ranging from 25% to 84%	<75%

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PV: Pharmacovigilance

*Quality of the studies was evaluated using the STROBE (Strengthening The Reporting of OBservational Studies in Epidemiology) checklist

Quality assessment

Overall, the included studies scored well for clearly stating the study aims, design, target population, risk factors and outcomes measurement, result explanation, and discussion and conclusion justified by the results (Table 1). The main issues were mainly related to failure to address the sample size calculation or addressing the non-response rate. Besides, many studies have no information about the missing data within completed questionnaires and have not conducted pilot testing.

Main findings

Key information form selected articles were extracted and tabulated using the following categories: pharmacovigilance knowledge, attitude or perception (Table 1).

Pharmacovigilance knowledge

Knowledge about pharmacovigilance and ADR reporting was mainly evaluated using multiple-choice response options ranging from 10 to 15 questions [11, 12, 14–17, 19, 20, 23, 26, 29–35]. A score of 1 was given for each correct answer and 0 for each wrong answer. The most common questions asked about PV, ADR definitions and the local regulatory body of ADR reporting, while few studies asked about the ADR causality assessment, types of ADR, and the online WHO PV database (S3 Appendix). Generally, knowledge of healthcare students about the local regulatory body and local reporting system of ADR reporting was inadequate. One study conducted by Khan et al compared the knowledge between medical and pharmacy students and found that pharmacy students have a significantly higher knowledge of pharmacovigilance compared to medical students [26]. Another study by Sivadasan et al had also compared medical to pharmacy students and found that pharmacy students have better knowledge and perception towards pharmacovigilance and ADR reporting compared to medical students [12].

Pharmacovigilance attitude

Attitude towards pharmacovigilance and ADR reporting was measured using multiple-choice response options ranging from 2 to 5 questions [20, 30], and using a 5-point Likert scale [16, 24]. Although only a few studies evaluated attitude; it should be noted that some questions used were related to measuring the perception rather than attitude [16, 22, 26, 31]. The most commonly asked question was about the willingness of students to report any ADR in their future practice (S3 Appendix). The attitude towards PV and ADRs from the included studies ranged from 25% to 97% [16, 20, 24].

Pharmacovigilance perception

Perception about pharmacovigilance and ADR reporting was measured using a 5-point Likert-scale format (1 strongly agree to 5 strongly disagree) [11–13, 15, 17, 21, 23], questions range from 5 to 13 questions [11–13, 23, 31]. However, some studies evaluated perceptions using multiple-choice response options [14]. The majority of included studies evaluated perceptions by asking students about their belief of PV, i.e. if they think that PV should be included in the curriculum, if they think ADR reporting should be made compulsory, and if they are allowed or trained to perform ADR reporting during the clerkship (S3 Appendix). The perception regarding PV and ADRs from the included studies was ranging from 25% to 97% [11–13, 15, 17, 21, 23]. Khan et al compared the perceptions between medical and pharmacy students and found that pharmacy students reported more positive responses to all of the perceptions statements than the medical students (P<0.05) [26].

Discussion

The present systematic review identified the available literature that evaluated KAP of PV and ADR reporting of any healthcare school students. Most of the published studies evaluated KAP among pharmacy students, while few focused on medical, dental, and nursing students. A summary of different measures used to assess KAP among different healthcare students was provided in this review.

Our review highlights the main drawback in this area, which is the lack of standardized validated measures to assess knowledge, perception, and attitude toward PV and ADR reporting. There were variations in items used in different studies to assess KPA of students. The survey instruments were pilot tested in fifteen studies and the internal consistency measured using Cronbach’s Alpha. However; no item analysis in the form of difficulty and discrimination was reported in any of these studies.

Moreover, findings from this review highlight the variation in KAP of different healthcare students towards pharmacovigilance and ADRs reporting. This variation could be attributed to the following factors: i) inconsistency in tools/measured used to evaluate KAP between the studies; ii) lacking validated KAP measures, iii) different study setting, and iv) different PV and ADR reporting experiences during their education. Therefore developing a standard validated measure is needed to optimize KAP assessment.

Our knowledge findings are consistent with the previously published review, which investigates the pharmacovigilance competencies of all healthcare students [3]. Knowledge about PV is poor, despite the good perception about PV importance and the good attitude toward PV and ADR reporting. Based on Reumerman et al. review many factors could influence PV competencies such as; type of healthcare school, academic level of study and previous training [3]. This review shows that educational interventions such as; short lectures, workshops, training in ADR reporting and assessment have improved healthcare students’ knowledge, perception and positive attitude toward PV [3]. However, it is unknown which education intervention was the best to improve students’ PV knowledge and competences, due to variation in questions or outcomes scores that have been used by the authors.

In our review, students’ satisfaction towards PV coverage in their curriculum varied from 21 to 85%. This finding indicates variation in PV integration in the curriculum between different healthcare schools. Besides, the finding highlights the need for uniform PV educational intervention. Given the importance of PV and ADR reporting in preventing serious health problems, more education in the field of PV and ADRs is needed. Moreover, standards for teaching PV have been developed by experts working in different fields of medication safety worldwide in the World Health Organization (WHO and the International Society of Pharmacovigilance (ISoP). The WHO-ISoP group had created core elements of a comprehensive PV curriculum to guide the PV integration into the healthcare schools' curriculum [37]. Besides, Stakeholders’ initiated on behalf of the WHO an agreement about PV competencies and key aspects of subjects that should be taught with a focus on clinical Aspects [4]. The five main aspects that were identified include 1) understanding the importance of PV; 2) preventing; 3) recognizing; 4) managing and; 5) reporting ADRs. These competencies should be integrated into the curriculum of healthcare students to improve their knowledge about PV. This review has helped us gather evidence about the absence of standardized validated measure to evaluate the KAP of PV and ADR reporting of any healthcare school students. Our search strategy was comprehensive, including studies published in English, and a manual search of relevant studies. Besides, quality assessment was conducted to evaluate the quality of the design of the included studies and the presence of potential bias. The main limitation in our review is the heterogeneity of assessment measures used between different included studies, which made a meta-analysis impossible. However, this heterogeneity directs the future need for a standardized validated assessment measure and a unified PV educational intervention for healthcare students in different healthcare schools. Besides, many studies have no information about the missing data within completed questionnaires and have not conducted pilot testing. Another limitation was that the searches developed and carried out without collaboration with a trained information specialist.

Conclusions

This review demonstrated the lack of PV knowledge among healthcare students and identified several research gaps that need to be focused on future research. These include; developing a standard validated measure to assess students’ knowledge, attitude, and perception toward PV. Further, the development of a unified PV education intervention to adequately prepare our future healthcare providers to rationally report ADR of drugs is crucial.

Supporting information

S1 Appendix. Search strategy used in MEDLINE.

(DOCX)

Click here for additional data file.^{(14.6KB, docx)}

S2 Appendix. PRISMA 2009 checklist.

(DOCX)

Click here for additional data file.^{(20.1KB, docx)}

S3 Appendix. Questions used to measures knowledge, attitude, and perceptions of medical students in the included studies.

(DOCX)

Click here for additional data file.^{(33.9KB, docx)}

Data Availability

All data generated or analysed during this study are included in this published article.

Funding Statement

This research project was supported by a grant from the “Research Center of the Center for Female Scientific and Medical Colleges”, Deanship of Scientific Research, King Saud University.

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PLoS One. doi: 10.1371/journal.pone.0233393.r001

Decision Letter 0

Lisa Susan Wieland

10 Feb 2020

PONE-D-20-00501

Medical Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review

PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: No

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: I Don't Know

Reviewer #3: N/A

**********

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript is technically sound, however this manuscripts aim is not consistent with the outcome of the search and the results. The authors claim to have only included MEDICAL students, however most included articles are NOT about medical students (ie pharmacy, dental or nursing). The conclusion, where you claim knowledge and perceptions about PV in MEDICAL students is insufficient, should therefore be changed.

2. Has the statistical analysis been performed appropriately and rigorously?

The manuscript doesn’t include a section on statistical analysis, although some descriptive statistical tests were probably done.

3. Have the authors made all data underlying the findings in their manuscript fully available?

Yes.

4. Is the manuscript presented in an intelligible fashion and written in standard English?

Yes, most of the manuscript is written in standard English, although many parts should be looked over because of spelling errors or non-fluent sentences (my comments are presented down below).

More specific remarks

Introduction

Page 5, line 8: “Have the above questions adequately… “:This sentence is too complicated and doesn’t flow, please rewrite.

Methods:

Overall: No section was dedicated to the (descriptive) statistical analysis.

Page 5, line 19/20: “Articles search of the four databases was conducted independently by two review authors (MA and NA), the disagreement was resolved by consensus.”: We suggest changing “the disagreement” to “any disagreement”.

Page 5, line 21: “Limits that were applied included selecting studies those published in English from inception until December 2019 …… “: Incorrect grammar. Possible to delete “those”.

Page 6, line 1: “studies that pertaining to the evaluation …..”: Incorrect grammar. Either: use “studies pertaining to” OR “studies that pertained to the ……”

Page 6, line 2/3: “and where the participants are medical schools students but not healthcare professionals”: Too much information, medical students are not healthcare professionals, so choose either “medical school students’ or “not healthcare professionals”.

Page 6, line 13: “This tool covers twenty-two criteria for Study design quality and biases in the study.“ : No need for a capital letter.

Results:

General remarks: Your aim is to analyze MEDICAL students knowledge and perceptions, you have only included the term MEDICAL STUDENT in your search, however have found studies who only include PHARMACY or DENTAL students. Please elaborate on this strange finding. Do you also think PHARMACY and DENTAL students are MEDICAL students. In this case you should clearly state this.

Page 7, line 6/12: Please add more sourceremarks to these lines. E.g. “Twenty studies examined the Pharmacovigilance knowledge and nine evaluated attitudes towards pharmacovigilance and thirteen studies measured the perception of pharmacovigilance”: has no sources.

Page 7, line 19: Wrong word: “Key information form selected articles were extracted and …”, you probably mean “Key information from selected articles were extracted and …”,

Page 8, line 1/3: “The most common questions asked about PV, ADR definitions and the local regulatory body of ADR reporting, while few studies asked about the ADR causality assessment, types of ADR, and the online WHO PV database (Appendix 2).” Incorrect grammar, is missing a verb and is too long.

Page 8, line 11/12: “Attitude towards pharmacovigilance and ADR reporting was measured using multiple-choice response options range from 2 to 5 questions”, should be “ranging”.

Page 8, line 15/16: and 24/1 “The attitude towards PV and ADRs from the included studies was ranging from 25% to 97%”: should be “…. studies ranged from ……”

Discussion

Page 9, line 11/13: ´Moreover, some studies piloted their instrument and some were face and content validated, around 50% measured the reliability, i.e., internal consistency using Cronbach’s Alpha.”:Incorrect grammar and is too long, try making it into two sentences.

Page 9, line 16/19: “This variation could be attributed to the following factors: i) inconsistency in tools/measured used to evaluate KAP between the studies; ii) lacking validated KAP measures, iii) different study setting, and iv) different experience the students have during their education about PV and ADRs reporting.”: point iv) Incorrect grammar. Try “and iv) different PV and ADR reporting experiences during their education.”

Page 9, line 21/22: You mention that the previous published review investigates all healthcare students (these include medical, pharmacy, dental and nursing). This review also covers these “healthcare students” and mostly focusses on pharmacy students in the text.

Page 10, line 2/5: “In addition, many educational interventions have been implemented among medical schools students to improve PV knowledge to enhance perception and positive attitude toward PV such as; short lecture, multiple training workshops, clinical experience in ADR reporting and assessment [3].”: Last example has incorrect grammar.

Page 10, line 5/7: “These interventions improved students PV knowledge and competences to a different extent, however, due to variation in questions or grouped outcomes scores been used the authors were not able to conclude which intervention was the best.”: Incorrect grammar.

Page 10, line 8/10: “In our review, students satisfaction toward PV coverage in their curriculum was vary from 21 to 85% , which indicates variation in PV integration between different medical schools, highlight the need for uniform PV educational intervention.”: it should be: “student satisfaction towards PV”, it should be: “in their curriculum varied from ….”. Also please make two sentences! Please rewrite the second part of the scentence, it doesn’t flow.

Page 10, line 11: There is a WHO-ISoP core curriculum for pharmacovigilance! Jurgen Backmann et all. Teaching Pharmacovigilance: the WHO-ISoP Core Elements of a Comprehensive Modular Curriculum 2014, drug safety.

Page 10, line 11/14: Too long and malformed sentence. Please rewrite.

Page 10, line 18/19: “This review has helped us gather evidence about the lacking of standardized validated measure to evaluate the KAP of PV and ADR reporting of any medical school students.”: Stange word option ( the lacking), maybe change it for “the absence”

Page 10, line 22/23: “The main limitation in our review is the heterogeneity of assessment measures used between different included studies, which band us from conducting a Meta-analysis.”: change word option (band us), maybe use “made a meta-analysis impossible”.

Conclusion

You argue that this review demonstrated the lack of PV knowledge among MEDICAL students, however you have only 5-6 studies on medical students however include a larger amount of studies with dental, pharmacy and nursing students.

Table 1

- It is surprising that you haven’t included any articles form 2019. I already know of a study by Katyal et al 2019, which should fit your search.

- Please elaborate on the difference between a cross-sectional study and a pilot study. I thought you only included cross-sectional studies? If not so, you missed a lot of interventional studies who also published cross-sectional results (ie pre- or post-interventional results).

Reviewer #2: Dear authors: I'm going to stick to the search strategy:

1. The databases searched are appropriate for a systematic review on medical education (MEDLINE & ERIC especially). I typically expect Embase to be included as well for the international literature. Is there a reason this was not included?

2. MedLine should be MEDLINE (in abstract, design & search strategy, and anywhere else mentioned)

3. Please list the platform used for the search of ERIC.

4. I have some concerns about the low numbers of results (~330). For instance, here is how I interpret the PubMed search based on the search description in the methods,

(knowledge OR attitude OR perception) AND medical students AND (pharmacovigilance OR adverse drug reactions reporting)

There are only ~30 results with that search in the version of PubMed that would've been used for this project. While it may have contained every relevant article, it seems far too narrow, especially when I run a more typical search that gets 3x as many:

(medical students[mh] or student*[tiab]) and (pharmacovigilance[mh] or pharmacovigilance[tiab] or pharmaco-vigilance[tiab] or Adverse Drug Reaction Reporting Systems[mh])

I don't mean to say that this is a perfect search, but that it brings in more suggests to me that there may be some missing in your analysis.

5. It's expected for systematic review searches to explicitly include controlled terms (MeSH in the case of PubMed) and more text word variations. For example, plurals (attitudes), other forms (perceive), other words (beliefs, residents, fellows). These are not called out in the methods at all.

6. I applaud the authors for their manual search.

I fear that the search undertaken wasn't comprehensive enough to support the review.

Reviewer #3: There are several issues with the methods of with this review

* Reviewers write that they the review was conducted according to PRISMA, However, PRISMA is about reporting not conducting. For example PRISMA says you must describe all resources searched, but Cochrane Collaboration MECIR lists which databases must be searched.

* The eligibility criteria of included studies was not clearly described. "studies pertaining to the evaluation of...". What types of studies? Were intervention studies going to be included?

*The description of the search is inadequate, and if this was the exact search it is not comprehensive enough to have retrieved all possible articles. Medline, CINAHL, and ERIC all have elaborate thesaurus terms which were not used in the searches. If the databases were searched at the same time, this is also not appropriate as this does not allow the use of thesaurus terms.

*The description of study selection does not provide information required by PRISMA. How many screeners? Was the screening done independently.

*Quality assessment used a reporting standard (STROBE) not an assessment of risk of bias in the methods. Giving the percentage of points received by each article according to strobe does not give me any information about the potential risk of bias across these studies as a whole.

*Figure 1, PRISMA flowchart, belongs in the results section, not the methods section

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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PLoS One. 2020 May 20;15(5):e0233393. doi: 10.1371/journal.pone.0233393.r002

Author response to Decision Letter 0

21 Mar 2020

We would like to thank the editor and the reviewers for the time and effort they spent on reviewing our manuscript entitled “Healthcare Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review", their valuable and insightful comments have improved our manuscript substantially.

We are excited to have been given the opportunity to revise our manuscript and respond to the revisions. We have gone through all comments received and appropriate changes/amendments have been made correspondingly to the paper (Highlighted) are summarized in the following:

Reviewer(s)' Comments to Author

Reviewer# 1

Comment # 1: The manuscript is technically sound, however this manuscripts aim is not consistent with the outcome of the search and the results. The authors claim to have only included MEDICAL students, however most included articles are NOT about medical students (ie pharmacy, dental or nursing). The conclusion, where you claim knowledge and perceptions about PV in MEDICAL students is insufficient, should therefore be changed.

Response: We thank the reviewer for his valuable comment. The authors meant “Healthcare students (i.e., medical, pharmacy, dental or nursing)” not “Medical students. We now have changed from “Medical students to “Healthcare students” throughout the whole manuscript.

Comment # 2: The manuscript doesn’t include a section on statistical analysis, although some descriptive statistical tests were probably done.

Response: Thank you for pointing this out. Now we have included the statistical analysis part in (Page 7, line 8-10)

Comment # 3: Introduction: Page 5, line 8: “Have the above questions adequately… “:This sentence is too complicated and doesn’t flow, please rewrite.

Response: We have rewritten the sentence to make it clear to the reader (Page 5, line 8-9).

Comment # 4: Methods: Overall: No section was dedicated to the (descriptive) statistical analysis.

Response: Now we have included the statistical analysis part in (Page 7, line 8-10). We have also changed “the disagreement” to “any disagreement” (Page 6, line 11).

Comment # 5: Methods:

Page 5, line 21: “Limits that were applied included selecting studies those published in English from inception until December 2019 …… “: Incorrect grammar. Possible to delete “those”.

Page 6, line 1: “studies that pertaining to the evaluation …..”: Incorrect grammar. Either: use “studies pertaining to” OR “studies that pertained to the ……”

Page 6, line 13: “This tool covers twenty-two criteria for Study design quality and biases in the study.“ : No need for a capital letter.

Response: Thanks for the correction (Page 6, line 12, 13) (Page 7, line 6).

Comment # 6: Methods: Page 6, line 2/3: “and where the participants are medical schools students but not healthcare professionals”: Too much information, medical students are not healthcare professionals, so choose either “medical school students’ or “not healthcare professionals”.

Response: We made the suggested change (Page 6, 14).

Comment # 7: Results: General remarks: Your aim is to analyze MEDICAL students knowledge and perceptions, you have only included the term MEDICAL STUDENT in your search, however have found studies who only include PHARMACY or DENTAL students. Please elaborate on this strange finding. Do you also think PHARMACY and DENTAL students are MEDICAL students. In this case you should clearly state this.

Response: We meant healthcare students which include MEDICAL, PHARMACY, DENTAL, and NURSING. Therefore, now we have changed it from “Medical students” to “Healthcare students” throughout the whole manuscript. To make it clear to the reader we have included the methods section the eligibility criteria (Page 5, line 12-17).

Comment # 8: Results: Page 7, line 6/12: Please add more source remarks to these lines. E.g. “Twenty studies examined the Pharmacovigilance knowledge and nine evaluated attitudes towards pharmacovigilance and thirteen studies measured the perception of pharmacovigilance”: has no sources.

Response: Change has been made (Page 8, line 3-6).

Comment # 9: Results:

Page 8, line 11/12: “Attitude towards pharmacovigilance and ADR reporting was measured using multiple-choice response options range from 2 to 5 questions”, should be “ranging”.

10: Page 8, line 15/16: and 24/1 “The attitude towards PV and ADRs from the included studies was ranging from 25% to 97%”: should be “…. studies ranged from ……”

Response: Changes has been made (Page 9, line 10, 14)

Comment # 10: Discussion: Page 9, line 11/13: ´Moreover, some studies piloted their instrument and some were face and content validated, around 50% measured the reliability, i.e., internal consistency using Cronbach’s Alpha.”: Incorrect grammar and is too long, try making it into two sentences.

Response: We made the suggested change (Page 10, line 10-11).

Comment # 11: Discussion: Page 9, line 16/19: “This variation could be attributed to the following factors: i) inconsistency in tools/measured used to evaluate KAP between the studies; ii) lacking validated KAP measures, iii) different study setting, and iv) different experience the students have during their education about PV and ADRs reporting.”: point iv) Incorrect grammar. Try “and iv) different PV and ADR reporting experiences during their education.”

Response: Thanks for the correction (Page 10, line 16-17).

Comment # 12: Discussion: Page 9, line 21/22: You mention that the previous published review investigates all healthcare students (these include medical, pharmacy, dental and nursing). This review also covers these “healthcare students” and mostly focusses on pharmacy students in the text.

Response: The previously published review hase included cross sectional and intervention studies to identify effective educational interventions that promote pharmacovigilance early in their education and career among pharmacy and medical students. However, our review was to evaluate the literature that measures the level of healthcare students’ knowledge, attitude and perception of pharmacovigilance and ADRs reporting.

The focus of this review was on healthcare students in general, however, most of the retrieved published studies were among pharmacy students.

Comment # 13: Discussion:

Response: These sentences have been corrected (Page 11, line 1-4)

Comment # 14: Discussion: Page 10, line 8/10: “In our review, students satisfaction toward PV coverage in their curriculum was vary from 21 to 85% , which indicates variation in PV integration between different medical schools, highlight the need for uniform PV educational intervention.”: it should be: “student satisfaction towards PV”, it should be: “in their curriculum varied from ….”. Also please make two sentences! Please rewrite the second part of the scentence, it doesn’t flow.

Response: Changes have been made (Page 11, line 5-7).

Comment # 15: Discussion: Page 10, line 11: There is a WHO-ISoP core curriculum for pharmacovigilance! Jurgen Backmann et all. Teaching Pharmacovigilance: the WHO-ISoP Core Elements of a Comprehensive Modular Curriculum 2014, drug safety.

Response: We thank the reviewer for suggesting adding this reference (Page 11, line 9-12).

Comment # 16: Discussion: Page 10, line 11/14: Too long and malformed sentence. Please rewrite.

Response: We have rewritten to shorten and improve the sentence (Page 11, line 13-14).

Comment # 17: Discussion:

Response: Changes have been made (Page 11, line 18, 23).

Comment # 18: Conclusion

Response: We meant the “healthcare students”, now we have corrected the wording throughout the whole manuscript.

Comment # 19: Table 1

- It is surprising that you haven’t included any articles form 2019. I already know of a study by Katyal et al 2019, which should fit your search.

Response: As per the second reviewer’s suggestion, we have searched the EMBASE and included some recent articles in table 1. We have excluded interventional studies as the focus of this review was to evaluate the students’ knowledge, attitude, and perception of PV.

Reviewer# 2

Dear authors: I'm going to stick to the search strategy

Comment # 1: The databases searched are appropriate for a systematic review on medical education (MEDLINE & ERIC especially). I typically expect Embase to be included as well for the international literature. Is there a reason this was not included?

Response: We totally agree with the reviewer, initially the Embase database was not available by our institute. However, now we have requested to access this database and updated the search results (Page 6, line 1)(Figure 1).

Comment # 2: MedLine should be MEDLINE (in abstract, design & search strategy, and anywhere else mentioned)

Response: Now we have made the correction (Page 2, line 5), (Page 5, line 21).

Comment # 3: Please list the platform used for the search of ERIC.

Response: The platform used for the search of ERIC was EBSCO (Page 6, line 3).

Comment # 4: I have some concerns about the low numbers of results (~330). For instance, here is how I interpret the PubMed search based on the search description in the methods,

(knowledge OR attitude OR perception) AND medical students AND (pharmacovigilance OR adverse drug reactions reporting)

(medical students[mh] or student*[tiab]) and (pharmacovigilance[mh] or pharmacovigilance[tiab] or pharmaco-vigilance[tiab] or Adverse Drug Reaction Reporting Systems[mh])

I don't mean to say that this is a perfect search, but that it brings in more suggests to me that there may be some missing in your analysis.

Response: Thank you for pointing this out. As per the reviewer’s suggestion, we have redone the systematic search, updated the search strategy, results, figure, and tables. Appendix 1 shows the complete search strategy used in Medline.

Comment # 5: It's expected for systematic review searches to explicitly include controlled terms (MeSH in the case of PubMed) and more text word variations. For example, plurals (attitudes), other forms (perceive), other words (beliefs, residents, fellows). These are not called out in the methods at all.

Response: These search terms have been used but have not been described adequately in the methods section. Now, more description is added “Research articles were retrieved from five databases (MEDLINE and CINAHL via EBSCO, EMBASE, ERIC, and Cochrane Database of Systematic Reviews via OVID) with database-specific queries. These databases were searched using both controlled and free-text language. In terms of free-text search, the keywords included the following terms/combination of terms: (knowledge OR attitude OR perception) AND (healthcare students OR medical students OR pharmacy students OR dental) AND (pharmacovigilance OR adverse drug reactions reporting). For the controlled language search included the following exploded MeSH terms: "knowledge”, “attitude”, “perception", "Students, Medical", "Students, Pharmacy", "Students, Nursing", "Students, Dental", "Pharmacovigilance" and " Drug-Related Side Effects and Adverse Reactions” as recommended for each databases (Page 6, line 2-9). Other terms have also been used “such as beliefs or views or feelings or experience”

Comment # 6: I applaud the authors for their manual search.

Response: Thank you.

Comment # 7: I fear that the search undertaken wasn't comprehensive enough to support the review.

Response: We have redone the systematic search taking into consideration the reviewer’s suggestions above (EMBASE). Corresponding changes have been made in the manuscript as well as the figure and tables.

Reviewer# 3

There are several issues with the methods of with this review

Comment # 1: Reviewers write that they the review was conducted according to PRISMA, However, PRISMA is about reporting not conducting. For example PRISMA says you must describe all resources searched, but Cochrane Collaboration MECIR lists which databases must be searched.

Response: We thank the reviewer for pointing this out. Now we have changed the wording to “The present systematic review was reported according to PRISMA” (Page 5, line 19-21).

Comment # 2: The eligibility criteria of included studies was not clearly described. "studies pertaining to the evaluation of...". What types of studies? Were intervention studies going to be included?

Response: Now we have included the eligibility criteria (Page 5, line 12-17).

Comment # 3: The description of the search is inadequate, and if this was the exact search it is not comprehensive enough to have retrieved all possible articles. Medline, CINAHL, and ERIC all have elaborate thesaurus terms which were not used in the searches. If the databases were searched at the same time, this is also not appropriate as this does not allow the use of thesaurus terms.

Response: We thank the reviewer for this comment. Each database was searched individually with database-specific queries. We agree with the reviewer that the search terms used have not been described adequately in the methods section. Now, more description is added “Research articles were retrieved from five databases (MEDLINE and CINAHL via EBSCO, EMBASE, ERIC, and Cochrane Database of Systematic Reviews via OVID) with database-specific queries. These databases were searched using both controlled and free-text language. In terms of free-text search, the keywords included the following terms/combination of terms: (knowledge OR attitude OR perception) AND (healthcare students OR medical students OR pharmacy students OR dental) AND (pharmacovigilance OR adverse drug reactions reporting). For the controlled language search included the following exploded MeSH terms: "knowledge”, “attitude”, “perception", "Students, Medical", "Students, Pharmacy", "Students, Nursing", "Students, Dental", "Pharmacovigilance" and " Drug-Related Side Effects and Adverse Reactions” as recommended for each databases” (Page 6, line 2-11). Appendix 1 shows the complete search strategy used in Medline.

Comment # 4: The description of study selection does not provide information required by PRISMA. How many screeners? Was the screening done independently?

Response: Literature screening has been done independently. Now, we clarified it in the methods section (Page 6, line 16-18).

Comment # 5: Quality assessment used a reporting standard (STROBE) not an assessment of risk of bias in the methods. Giving the percentage of points received by each article according to strobe does not give me any information about the potential risk of bias across these studies as a whole.

Response: STROBE is one of the assessment tools used in observational studies.1 It has item £ 9 that measures the risk of bias in each included study. However, it does not give any information about the potential risk of bias across these studies as a whole.

1. Sanderson, S., Tatt, I.D. and Higgins, J., 2007. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. International journal of epidemiology, 36(3), pp.666-676.

Comment # 6: Figure 1, PRISMA flowchart, belongs in the results section, not the methods section.

Response: Thank you for this suggestion (Page 6, line 21)

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PLoS One. doi: 10.1371/journal.pone.0233393.r003

Decision Letter 1

Lisa Susan Wieland

8 Apr 2020

PONE-D-20-00501R1

Healthcare Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review

PLOS ONE

Dear Dr. Alwhaibi,

We would appreciate receiving your revised manuscript by May 23 2020 11:59PM. When you are ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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Lisa Susan Wieland

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

The manuscript is improved, however some of the reviewer comments have not yet been adequately addressed. See comments here:

1) The search strategy is improved. However, if you did not have the searches developed and carried out in collaboration with a trained information specialist please add this to the limitations of the study, as you cannot be certain that there were not additional studies that you did not retrieve. Also, did you search the Cochrane Database of Systematic Reviews or was it the Cochrane Library? If you were searching for systematic reviews it was probably the Cochrane Database of Systematic Reviews but if you were searching for individual controlled trials it was probably the Cochrane Central Register of Controlled Trials. Both of these databases are in the Cochrane Library.

2) The rationale for including a ‘pilot study’ in which pre and post tests were administered and excluding studies reporting KAP measures pre- and post- some intervention is unclear. What is the difference between assessing the results of an intervention and testing the effects of usual education? This needs to be clarified. The inclusion of cross-sectional studies is clear, but the cohort studies could mean anything from a single group tested at multiple time points to a randomized controlled trial.

3) The reviewer is correct that STROBE is a reporting guideline. The authors of the article you cite say that STROBE was referred to in many of the assessment instruments because many STROBE items may have been selected because of presumed association with risk of bias. However the authors do not suggest that STROBE should be used as a risk of bias assessment tool. The authors state that ‘Just under three-quarters of all tools were proposed as being suitable for future use, including all of the critical appraisal tools and generic systematic review tools and six of the tools originally designed for use in a specific systematic review.’ Look in Tables 5-7 for the tools that meet the important criteria identified by the authors (selection of participants, measurement of variables, and control of confounding). These are the tools that the authors judge as appropriate.

A more recent and more targeted approach to risk of bias for surveys may be found in https://www.evidencepartners.com/wp-content/uploads/2017/09/Risk-of-Bias-Instrument-for-Cross-Sectional-Surveys-of-Attitudes-and-Practices.pdf. See https://www.evidencepartners.com/wp-content/uploads/2017/04/Methods-Commentary-Risk-of-Bias-in-cross-sectional-surveys-of-attitude....pdf for comments and further guidance on this tool.

For the pre-post surveys, you might have to look further for a suitable tool, or you could decide to assess the risk of bias based on either the pretest or the posttest survey if you are not interested in the effects of the education intervention. However, as I mentioned above, the inclusion of pretest/posttest pilot studies but the exclusion of other interventional studies lacks a rationale and this needs to be addressed.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

PLoS One. 2020 May 20;15(5):e0233393. doi: 10.1371/journal.pone.0233393.r004

Author response to Decision Letter 1

10 Apr 2020

We would like to thank the editor and the reviewers for the time and effort they spent on reviewing our revised manuscript entitled “Healthcare Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review"

All appropriate changes/amendments have been made correspondingly to the paper (Highlighted) are summarized in the following:

Reviewer Comments to Authors

Comment # 1: The search strategy is improved. However, if you did not have the searches developed and carried out in collaboration with a trained information specialist please add this to the limitations of the study, as you cannot be certain that there were not additional studies that you did not retrieve.

Response: Thank you for the suggestion; we have added this limitation to page 12, lines 1-2

Also, did you search the Cochrane Database of Systematic Reviews or was it the Cochrane Library? If you were searching for systematic reviews it was probably the Cochrane Database of Systematic Reviews but if you were searching for individual controlled trials it was probably the Cochrane Central Register of Controlled Trials. Both of these databases are in the Cochrane Library.

Response: We have searched the Cochrane Database of Systematic Review (Page 6, line 3).

Comment # 2: The rationale for including a ‘pilot study’ in which pre and post tests were administered and excluding studies reporting KAP measures pre- and post- some intervention is unclear. What is the difference between assessing the results of an intervention and testing the effects of usual education? This needs to be clarified.

Response: The reason for excluding interventional studies was because we are not evaluating the impact of educational material on knowledge, attitude, and perceptions. The reason for including pilot studies, because these studies are usually conducted to evaluate the validity, readability, and reliability of the instruments used in the survey usually among 20-30 participants (Results from the pilot subjects are not included in the study). For example, Limaye et al. study was pilot-tested to a sample of 30 pharmacy students (Pilot subjects (i.e., 30) were not part of the final study that was conducted among 352 students).

The inclusion of cross-sectional studies is clear, but the cohort studies could mean anything from a single group tested at multiple time points to a randomized controlled trial.

Response: We totally agree with the reviewer, therefore we have removed cohort study from the inclusion criteria.

Comment # 3: The reviewer is correct that STROBE is a reporting guideline. The authors of the article you cite say that STROBE was referred to in many of the assessment instruments because many STROBE items may have been selected because of presumed association with risk of bias. However the authors do not suggest that STROBE should be used as a risk of bias assessment tool. The authors state that ‘Just under three-quarters of all tools were proposed as being suitable for future use, including all of the critical appraisal tools and generic systematic review tools and six of the tools originally designed for use in a specific systematic review.’ Look in Tables 5-7 for the tools that meet the important criteria identified by the authors (selection of participants, measurement of variables, and control of confounding). These are the tools that the authors judge as appropriate.

See https://www.evidencepartners.com/wp-content/uploads/2017/04/Methods-Commentary-Risk-of-Bias-in-cross-sectional-surveys-of-attitude....pdf for comments and further guidance on this tool.

Response: We thank the reviewer for the detailed explanation about this important point and for providing the reference. Now, we have incorporated under the quality assessment the five items risk of bias in cross-sectional surveys of attitudes and practice (Page 7, lines 7-8) (Page 8, lines 15-16).

Reference: Agarwald, A., G. Guyatt, and J. Busse. "Methods commentary: Risk of bias in cross-sectional surveys of attitudes and practices." (2019).

Response: Response to this comment was hopefully explained in response to the second comment.

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PLoS One. doi: 10.1371/journal.pone.0233393.r005

Decision Letter 2

Lisa Susan Wieland

5 May 2020

Healthcare Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review

PONE-D-20-00501R2

Dear Dr. Alwhaibi,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication.

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With kind regards,

Lisa Susan Wieland

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0233393.r006

Acceptance letter

Lisa Susan Wieland

7 May 2020

PONE-D-20-00501R2

Healthcare Students' Knowledge, Attitude and Perception of Pharmacovigilance: A Systematic Review

Dear Dr. Alwhaibi:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE.

With kind regards,

PLOS ONE Editorial Office Staff

on behalf of

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Academic Editor

PLOS ONE

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Appendix. Search strategy used in MEDLINE.

(DOCX)

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S2 Appendix. PRISMA 2009 checklist.

(DOCX)

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S3 Appendix. Questions used to measures knowledge, attitude, and perceptions of medical students in the included studies.

(DOCX)

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Data Availability Statement

All data generated or analysed during this study are included in this published article.

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Healthcare students' knowledge, attitude and perception of pharmacovigilance: A systematic review

Monira Alwhaibi

Noha A Al Aloola

Roles

Abstract

Objective

Methods

Primary and secondary outcome measures

Results

Conclusions

Introduction

Methods

Eligibility criteria

Search strategy

Study selection

Fig 1. PRISMA flow diagram.

Data extraction and quality assessment

Statistical analysis

Patient and public involvement

Results

Selection process

General characteristics of included studies

Table 1. Characteristics of included studies that measures knowledge, attitude, and perceptions of medical students.

Quality assessment

Main findings

Pharmacovigilance knowledge

Pharmacovigilance attitude

Pharmacovigilance perception

Discussion

Conclusions

Supporting information

Data Availability

Funding Statement

References

Decision Letter 0

Lisa Susan Wieland

Roles

Author response to Decision Letter 0

Decision Letter 1

Lisa Susan Wieland

Roles

Author response to Decision Letter 1

Decision Letter 2

Lisa Susan Wieland

Roles

Acceptance letter

Lisa Susan Wieland

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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