A Methodological Review of Drug-Related Toxicological Studies in Saudi Arabia

This study aimed to conduct a methodological review of drug-related toxicological studies in Saudi Arabia. A systematic review and a methodological analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Medline and Embase were searched for all types of studies reporting toxicological studies in the English language published until January 10, 2022. The search was conducted using both keywords and Medical Subject Headings (MeSH) terms. The methodological analysis of included studies was assessed using the Newcastle-Ottawa Scale. A total of 3,750 studies were extracted and screened. Of these, 30 observational studies (seven cohort studies and 23 cross-sectional studies) met the inclusion criteria. The methodological scores ranged from five to seven out of 10 possible points. Twelve studies had high quality, and 18 studies had moderate quality. Eight studies focused on adverse drug reactions, eight explored poisoning, four explored drug-related hospitalizations, nine explored drug-induced toxicity, and one explored drug overdose. This research project revealed that most of the drug-related toxicological studies conducted in Saudi Arabia were observational studies of moderate quality. Future studies should focus on the quality of the design and reporting.

drugs are responsible for around 90% of poisoning deaths [8]. In 2019, 70,630 deaths from the toxic effects of drug poisoning (drug overdose) occurred in the United States [9]. Moreover, the yearly cost of drug-related morbidity and mortality due to non-optimized medication therapy was estimated to be $528.4 billion in 2016, accounting for 16% of United States healthcare spending [10].
In the last years, there has been a large increase in the publication rate of studies in the toxicology field, including studies on reporting adverse drug reactions, medication surveillance, and safety monitoring. However, information on the characteristics and methodological rigor of these studies is unclear. Therefore, in this review, we aimed to explore and evaluate drug-related toxicological studies in Saudi Arabia from a methodological perspective and to identify gaps in the knowledge.

Protocol and Registration
This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to ensure clear and comprehensive reporting [11]. In addition, this study followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines [12]. The study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO).

Types of Studies Included
All types of original study designs were included in this review.

Search Strategy
We used a comprehensive search strategy developed by an expert researcher to search electronic bibliographic databases. Medline and Excerpta Medica (Embase) databases were searched up to January 10, 2022. A combination of Medical Subject Headings (MeSH) and keywords with both English and American spellings has been used to identify relevant studies. The following search query was used: (toxic* OR drug abuse OR substance abuse OR snake bite OR poison control center OR cannabinoids OR opiate OR amphetamines OR alcohol overdose OR scorpion bite OR drug reaction OR antidote OR overdose OR organophos* OR methamphetamines OR corrosive OR pesticides OR poison*) AND (Saudi Arabia). The entire search strategy for Medline and Embase can be found in Appendices 1 and 2, respectively. Articles were downloaded into EndNote software (V.20, Clarivate, London, UK), and duplicates were removed.

Study Selection
We included original studies that reported outcomes related to drug toxicology in Saudi Arabia. We did not have any restrictions on gender or age to make our conclusion more generalizable and robust. Studies not related to the topic and deemed irrelevant were excluded. Studies that reported non-drug toxicological outcomes were excluded. Randomized trials, case-control studies, cross-sectional studies, and cohort studies were eligible for inclusion in this review, while reviews, case reports, case series, ecologic, in vitro or in vivo studies, guidelines publications, and studies written in languages other than English were excluded.

Data Extraction
The data extraction template included the author's name, title, main aim, the location where the study was carried out, sample size, study design, age, and male-to-female ratio. Data extraction was conducted by one author.

Types of Outcome Measures
The methodological characteristics included the study design, study outcomes, statistical analysis, and sample size of drug-related toxicological studies in Saudi Arabia.

Assessment of Study Quality
The Newcastle-Ottawa Scale was used to evaluate the methodological quality of sampling, selection, exposure, and outcomes of the chosen studies [13]. Using the Newcastle-Ottawa Scale (Appendix 3), each study was assessed on seven criteria divided into three categories: selection of study groups (maximum of five stars), comparability of groups (maximum of two stars), and outcome ascertainment (maximum of three stars). This scale awards a maximum of 10 stars, representing the highest methodological quality. Studies with seven to 10 stars are rated as having high quality, studies with five to six stars are rated as having moderate quality, and studies with less than five stars are rated as having low quality. The Newcastle-Ottawa Scale is still the most commonly used assessment tool in practice as reported by many publications.

Study Selection
A total of 3,750 studies were identified from our initial databases search (Medline and Embase). After removing duplicates (499), a total of 3,251 studies were screened based on title and abstract. Of these, 3,166 studies were not related to the scope of the review and were excluded, leaving 85 articles to be screened based on the full text. Of these, four studies were from other countries, two were case reports, and we were unable to access 49 studies, which were all excluded. Finally, a total of 30 articles were included in the present systematic review. The article selection process is shown in the flowchart (Figure 1).

FIGURE 1: PRISMA flowchart
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

General Characteristics of Included Studies
All articles were written in English and conducted in Saudi Arabia. Thirteen studies were from the Riyadh region [3,[14][15][16][17][18][19][20][21][22][23][24][25], nine were from the Makkah region [26][27][28][29][30][31][32][33][34], three studies were from the Eastern region [35][36][37], three studies were from the Qassim region [38][39][40], one study was from the Najran region [41], and one study covered entire Saudi Arabia [42]. In relation to the range of years of publication, the oldest article was from 2012, and the latest was from 2021. The sample size in the included articles ranged between eight and 5,574. The total samples were 25,720. All subjects included in the study were related to toxicology. Studies can be divided into four groups based on the age of the samples. The first group was comprised only of adolescents, the second group was comprised only of children, the third group was comprised only of neonates, and the last group included samples of different ages. Most studies included both men and women, except two studies that included only women. Out of 30 studies, four studies were aimed to explore drug-related hospitalizations [3,32,35,38], eight studies explored the adverse drug reactions [14,15,17,21,33,37,40,42], three studies explored drug-induced cardiotoxicity [16,24,27], four studies explored drug-induced nephrotoxicity [19,23,30,31], one study explored drug-induced pulmonary toxicity [26], one study explored drug-induced retinal toxicity [20], eight studies explored poisoning [18,22,25,28,29,34,39,41], and one study explored drug overdose [36]. Full details about the included studies are available in Table 1 Parental experience of potential adverse drug reactions

Quality of Included Studies
The included studies were assessed for methodological quality using the Newcastle-Ottawa Scale. Among the 30 included studies, 12 studies scored seven stars, which means they had a high quality. Eighteen studies scored five to six stars, which means a moderate quality, and none were of low quality. The detailed scoring is shown in Table 2.

Discussion
To the best of our knowledge, this is the first study to evaluate toxicological studies in Saudi Arabia from a methodological perspective. The findings of this study show that all studies published within the last 10 years were primarily observational in nature (seven cohort studies and 23 cross-sectional studies). According to the Newcastle-Ottawa Scale, 12 studies had high quality, and 18 studies had moderate quality.
Administratively, Saudi Arabia is divided into 13 regions. The majority of the studies were conducted in Riyadh (43.3%) and Makkah (30%) regions. This could be attributed to the fact that those two regions have better and more healthcare facilities, the most prominent universities, and an increased population than other regions in Saudi Arabia, which might facilitate more research to be conducted.
The term "methodological quality" relates to all parts of a study, including design, conduct, analysis, and reporting of results that impact the study's capability to answer the question addressed adequately [43]. Limitations in any part of the study's design, conduct, analysis, and reporting of results contribute to the "risk of bias" or lower methodological quality. Furthermore, research data that produce negative results are not always reported, resulting in publication bias [43]. However, given the nature of the specialty (toxicology), most of the studies are expected to be reporting events or medication misuse of safety.
Most of the studies included in this review (86.66%) gathered their data from local health institute databases and/or patient interviews. Using administrative databases/registries for observational studies has several advantages, including considerable sample size. These registries can boost the study's validity, reduce standard error, improve precision in identifying any effect, and be highly representative of the general population [44]. When compared to research using alternative data sources, the pre-existing and continual accumulation of patient information in an administrative database/registry, whose primary goal is to record health information, saves time, money, and human resources in the data collection process. On the other hand, administrative databases/registries for identifying cases and exposures have limitations. Significant disparities in diagnosis may compromise the validity of the study results if there is misclassification or changes in disease coding over time. The coding accuracy varies depending on the conditions, databases, and registries [45].
In this review, all the studies included were observational in nature. This could be attributed to the objectives of this study, as drug-related toxicity studies are usually conducted for monitoring the drugs, and in most cases, these studies are usually cross-sectional or post-marketing cohort studies [46]. In addition, another reason that could be attributed to these findings is the low volume and rate of published randomized clinical trials in Saudi Arabia. Furthermore, observational studies have the advantage of being usually more inexpensive, relatively rapid, and more accessible than randomized controlled trials.
The main strength of observational studies over randomized controlled trials is their more excellent proximity to "real-life situations," as randomized controlled trials have stricter inclusion criteria and strict protocols that may not reflect clinical practice, especially when investigating safety or toxicology-related outcomes. However, it is important to highlight that observational studies have more significant variability of medical interventions and patient populations that are more representative of clinical practice. They can be used to investigate rare outcomes and uncover unusual adverse effects [47]. Hence, the previously mentioned advantages might be the reason for conducting observational studies, as shown in our methodological review [48].
Toxicologists should carefully select the titles, abstracts, and keywords of their studies to ensure access and retrieval in literature reviews of the research and provide study protocol in sufficient detail to allow reviewers to assess methodological quality. This, in turn, recommends that future researchers should be trained properly in choosing study design, sample size, appropriate statistical analysis, and proper reporting to ensure high-quality research that would help policymakers to make the right decision. Furthermore, improving the knowledge of the physicians with respect to drug-related problems as well as education of the community regarding the risk of medication misuse could help in the improvement of patient safety. Future studies should also focus on highlighting gender variation in toxicological outcomes.
This study has several notable strengths. It is the first study to evaluate toxicological studies in Saudi Arabia from a methodological perspective, including a comprehensive literature search in two relevant databases (Embase and Medline) and proper screening of studies that meet the eligibility criteria. The review's conformance with established guidelines for systematic literature reviews is an additional strength of this review (i.e., PRISMA statement). In addition, we used the Newcastle-Ottawa Scale, which is a widely used and endorsed tool by the Cochrane Collaboration. The study protocol was registered with PROSPERO to provide openness and allow replication or modifications in the future.
Most of the information in toxicology-related databases is not available to the general public. Other considerations include confidential data that would not be exchangeable. Furthermore, the lack of MeSH terms to categorize toxicology makes retrieving toxicological data from search engines challenging [43]. This limited and difficult access could be a reason behind the lack of national data.
However, there are certain limitations to this study. First, this methodological review has a limitation in that we only searched publications in two relevant databases (Embase and Medline), which means we may not have included all prospective toxicological studies. However, Embase and Medline are considered the largest medical databases and they include most of the studies in the literature; therefore, we assume that we have not missed important studies in the literature. Even though this review was intended to cover a broad spectrum of literature, it is limited to current publications from the last 10 years. This was attributed to time constrain.

Conclusions
The present paper systematically evaluated the methodological quality of the studies related to toxicology published in Saudi Arabia during the last 10 years. All the studies included in this review were crosssectional and cohort studies. Based on the score stratification approach we used to categorize research based on their final ratings, most of the studies in our review demonstrated moderate methodological strength.
(3) Non-respondents: (a) Comparability between respondent and non-respondent characteristics is established, and the response rate is satisfactory. * (b) The response rate is unsatisfactory, or the comparability between respondents and non-respondents is unsatisfactory.
(c) No description of the response rate or the characteristics of the responders and the non-responders.
(4) Ascertainment of the exposure (risk factor): (a) Validated measurement tool. ** (b) Non-validated measurement tool, but the tool is available or described. * (2) Statistical test: (a) The statistical test used to analyze the data is clearly described and appropriate, and the measurement of the association is presented, including confidence intervals and the probability level (p-value). * (b) The statistical test is not appropriate, not described, or incomplete.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.