Dermatology: Practical and Conceptual Review | Dermatol Pract Concept. 2025;15(4):5668 1 Meta-Research Study on the Quality of Randomized Controlled Trials Evaluating Drug Therapy for Impetigo Juliana Cavaleiro Rodrigues1, Kamilla Mayr Martins Sá1, Giullia Carvalho Mangas Lopes2, Marcella Cosmo Piovesan1, Elaine Marcílio Santos2, Ana Luiza Cabrera Martimbianco2 1 School of Medicine, Universidade Metropolitana de Santos, Santos, SP, Brazil 2 Postgraduate Program in Health and Environment, Universidade Metropolitana de Santos, Santos, SP, Brazil Key words: Impetigo, Drug therapy, Randomized controlled trials, Methodological quality, Meta-research Citation: Rodrigues JC, Sá KMM, Lopes GCM, Piovesan MC, Santos EM, Martimbianco ALC. Meta-Research Study on the Quality of Randomized Controlled Trials Evaluating Drug Therapy for Impetigo. Dermatol Pract Concept. 2025;15(4):5668. DOI: https://doi. org/10.5826/dpc.1504a5668 Accepted: June 11, 2025; Published: October 2025 Copyright: ©2025 Rodrigues et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Ana Luiza Cabrera Martimbianco, Postgraduate Program of Health and Environment, Universidade Metropolitana de Santos, Santos, SP, Brazil. Avenida Conselheiro Nébias 536, Santos - SP, Brazil. Zip code 11045-002. ORCID :0000-0002-4361-4526. Email: analuizacabrera@hotmail.com Introduction: Impetigo is a common, highly contagious bacterial skin infection primarily affecting children. Treatment usually involves topical or oral antibiotics, and numerous clinical trials have been published to support these therapeutic approaches. Objectives: To evaluate the methodological quality of randomized clinical trials (RCTs) on the phar- macological treatment of impetigo in children and adolescents. Methods: This meta-research evaluated RCTs on systemic or topical pharmacological treatments for impetigo in children and adolescents. A comprehensive literature search was conducted in September 2024 across MEDLINE, Embase, CENTRAL, and LILACS databases. The methodological quality of the included RCTs was assessed using the Cochrane Risk of Bias tool. Data are presented as percent- ages. Results: Twenty-one RCTs on pharmacological treatments for impetigo were identified and assessed. The findings identified some methodological concerns: i) 53% to 57% of RCTs had an unclear risk of selection bias due to insufficient information on randomization and allocation concealment; ii) 71% were at high risk of bias for blinding of participants and personnel, while 57% had a high risk for ABSTRACT 2 Review | Dermatol Pract Concept. 2025;15(4):5668 Introduction Randomized controlled trials (RCTs) are the gold standard for generating high-quality evidence on the effects of health- care interventions. Their methodological rigor, particularly in minimizing bias, ensures more accurate and valid estimates of treatment effects. As a result, RCTs play a pivotal role in informing clinical practice and shaping healthcare policies, either directly or through their integration into systematic reviews and meta-analyses [1–3]. However, the reliability and applicability of RCT findings are highly dependent on their methodological quality. Across diverse medical fields, persistent deficiencies such as inade- quate randomization, poor allocation concealment, insuffi- cient blinding, high attrition without appropriate handling, and the absence of prospective protocol registration remain prevalent. These shortcomings introduce various sources of bias, leading to distorted effect estimates and ultimately compromising the credibility of the evidence base [1,4–6]. The evidence on pharmacological treatments is well es- tablished in the context of impetigo, a common and highly contagious superficial bacterial skin infection that predomi- nantly affects children [7,8]. Numerous RCTs have evaluated the efficacy and safety of both topical and systemic antibiot- ics for this condition. However, despite the substantial body of research, no prior study has systematically examined the methodological quality of these trials. This represents a critical gap, as deficiencies in trial design and reporting can undermine not only the validity of individual studies but also the reliability of evidence syntheses and the clini- cal guidelines derived from them. Moreover, systematically identifying recurring methodological limitations can inform improvements in the design, conduct, and reporting of future trials, ultimately contributing to more transparent, rigorous, and trustworthy research that underpins evidence-based clinical practice [1,4]. Objective This meta-research study aimed to evaluate the methodolog- ical quality of the RCTs on the pharmacological treatment of impetigo in children and adolescents. Methods This meta-research study adheres to the methodological guidance proposed by Murad et al. [9] and the relevant items of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [10] to enhance the quality and transparency of the study report. Criteria for Inclusion of Studies Randomized clinical trials (RCTs) that evaluated the effi- cacy of systemic or topical pharmacological interventions, including antimicrobial and antiseptic agents, for treating impetigo in children and adolescents, regardless of dosage, treatment duration, or route of administration. Studies were eligible if the authors identified them as “randomized clinical trials.” Studies employing quasi-randomized methods, such as allocation based on date of birth, medical record number, or alternation, were not considered due to the high risk of selection bias associated with these designs. Search Strategy A comprehensive literature search was conducted on 19 September 2024 to identify the RCTs using the follow- ing databases: Medical Literature Analysis and Retrieval System Online (MEDLINE), by PubMed; Excerpta Med- ica Database (Embase), by Elsevier; The Cochrane Cen- tral Register of Controlled Trials (CENTRAL) (by Wiley); Latin American Literature on Health Sciences and the Caribbean - LILACS (Biblioteca Virtual em Saúde - BVS) (Table S1). Selection of Studies and Data Collection Two independent reviewers screened the titles and abstracts using the Rayyan platform [11]. References that met the eligibility criteria were then selected for a more detailed analysis through full-text reading. A third author resolved disagreements between reviewers about the inclusion or ex- clusion of studies. Data extraction was conducted by two independent reviewers who collected the following informa- tion from the included RCTs: year, participants’ character- istics, intervention, comparator groups, outcomes assessed, and funding sources. blinding of outcome assessors; iii) 24% exhibited a high risk of attrition bias due to significant par- ticipant losses without justification; iv) 81% had an unclear risk of bias due to the lack of registered protocols available. Conclusions: Based on the methodological quality of the assessed RCTs, this study highlights the need for more rigorous design and reporting standards in future research on pharmacological treat- ments for impetigo to enhance the reliability and validity of the evidence, thereby supporting more informed clinical decision-making. Review | Dermatol Pract Concept. 2025;15(4):5668 3 Assessment of the Methodological Quality of the Included Studies Two reviewers independently assessed the methodological quality (risk of bias) of each included RCT, using the Co- chrane Risk of Bias (RoB) tool (version 1.0) following the recommendations of the Cochrane Handbook of System- atic Reviews of Interventions [12]. This tool is composed of seven domains that assess potential sources of bias that could affect the study’s validity, as follows: • Random sequence generation (selection bias): evaluate the method used to generate the random sequence for assigning participants to intervention or control groups. It assesses whether the process was genuinely random, helping to ensure that any systematic factors did not in- fluence group allocation. • Allocation concealment (selection bias): examines whether the allocation of participants to intervention or control groups was concealed from those assigning par- ticipants. Proper concealment prevents selection bias by ensuring the researchers cannot predict or influence the group assignment. • Blinding of participants and personnel (performance bias): assesses whether participants and personnel were blinded to the administered intervention. Blinding helps prevent performance bias, where knowledge of the intervention may influence how participants or staff behave or inter- act, potentially skewing the study results. • Blinding of outcome assessors (detection bias): evaluates whether those assessing outcomes were blinded to the in- tervention received by participants. Blinding of outcome assessors helps prevent detection bias, where knowledge of the intervention might influence outcome assessment. • Incomplete outcome data (attrition bias): analyses how incomplete outcome data (e.g., losses and withdrawals) were handled. It covers the difference in the number of participants withdrawn from each group (intervention and control) and how the losses were considered in the data analyses. • Selective reporting: assesses whether the study reported all intended outcomes. This domain identifies any selective reporting of results that could skew findings, as published studies are more likely to report analyses showing signif- icant differences between groups rather than those with non-significant differences. • Other sources of bias: examines any other potential sources of bias not covered by the previous domains. It includes factors such as baseline data imbalance and other factors affecting the study’s validity. Blinding and incomplete outcome data were evaluated separately for each outcome, as recommended. However, since all outcomes of interest in this meta-research study were subjective (cure response, bacteriological response, adverse events, and quality of life), the lack of blinding in these domains could have potentially influenced the re- sults, which were assessed together. The judgment of risk of bias for each domain is categorized into three levels: (1) low risk of bias, when the method is adequately addressed in the study; (2) high risk of bias, when the method is inadequately addressed; (3) unclear risk of bias, when there is insufficient information to make a definitive assessment. Data Synthesis The risk of bias assessments were reported as absolute fre- quencies and proportions for each domain of the RoB tool. In addition, 95% confidence intervals (95% CI) for pro- portions were calculated using the Wilson score interval, in the binomial R® software package (version 4.5). Results Search Results The database search yielded 907 references. After remov- ing six duplicates and screening the titles and abstracts, 878 studies were excluded for not meeting the inclusion criteria. Twenty-nine studies were assessed in full text, and eight were excluded [7,13-17] because they were not randomized clini- cal trials (RCTs). Consequently, 21 studies were included in this meta-analysis [18-38] (Figure 1). Characteristics of the Included Studies The 21 randomized controlled trials (RCTs) published be- tween 1986 and 2023 included 2,876 participants diag- nosed with impetigo. The most common interventions were macrolide antibiotics, bacterial protein synthesis inhibitors, penicillins, cephalosporins, quinolones, sulfonamides, and antifungals. These interventions were compared regarding their effects via topical versus oral administration or against a placebo (Table 1). Risk of Bias Assessment The methodological quality of the included RCTs was as- sessed using the Cochrane Risk of Bias (RoB) tool following the assessment recommendations outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Figure 2 presents the overall assessment, while Table S2 pro- vides detailed judgments for each study. Only one RCT (5%, 95% CI: 0.85%–23%) was classi- fied as having low risk of bias across all domains assessed [35], while three trials (14%, 95% CI: 0.5%–35%) demon- strated low risk in six out of the seven domains of the RoB tool [26,29,30]. 4 Review | Dermatol Pract Concept. 2025;15(4):5668 Id en tif ic at io n References from electronic search (N=907) Se le ct io n Duplicates removed (N=6) References eliminated (n=872) References assessed by title/abstracts (N=901) El ig ib ili ty References assessed by full text (N=29) References excluded (N=8) In cl us io n Included studies and reports (N=21) Manual search (N=0) Figure 1. Flowchart of the study selection process. Table 1. Characteristics of the Included Studies. Study, year Intervention / Number of participants (N) Control / Number of participants (n) Outcomes of interest Funding sources Anusharani 201918 Topical 2% fusidic acid cream (N=50) Topical 2% mupirocin ointment (n = 50) • Clinical response • Adverse events No sources Barton 198819 Oral erythromycin (40 mg /kg/day) (n = 29) Oral dicloxacillin (25 mg/kg/day) (n = 30) • Bacteriological response • Adverse events Warner-Lambert Corporation Ciftci 200220 Mupirocin (Bactroban 2% ointment, 3 times/ day for 10 days) (n=25) Terbinafine (Lamisil 1% cream topically, 3 times/day, for 10 days) (n=23) • Clinical response • Bacteriological response • Adverse events NR Dagani 199221 Oral erythromycin (50 mg/kg daily) + placebo ointment (n=51) 2% mupirocin ointment in polyethylene glycol + oral placebo suspension (n=51) • Clinical response • Adverse events Beecham Pharmaceuticals Dash 202322 Topical 1% ozenoxacin cream (n=16) Topical 2% mupirocin cream (n=17) • Clinical response • Bacteriological response NR Review | Dermatol Pract Concept. 2025;15(4):5668 5 Study, year Intervention / Number of participants (N) Control / Number of participants (n) Outcomes of interest Funding sources Demidovich 199023 Oral penicillin V potassium (40 a 50mg/kg, daily for 10 days) (n=25) Oral cephalexin monohydrate (40 a 50 mg/kg, daily for 10 days) (n=23) • Clinical response • Adverse events NR Oral erythromycin (30 a 40 mg/kg, daily for 10 days) (n=25) Eells 198624 15g of 2% mupirocin in polyethylene glycol (3 times/day for 12 days) (n=18) 15 g of the vehicle alone (3 times/day for 12 days) (n=20) • Clinical response • Bacteriological response • Adverse events NR Goldfarb 198825 2% mupirocin ointment (3 times/day, for 8 days) (n=30) Oral erythromycin (40 mg/kg, daily, for 8 days) (n=32) • Clinical response • Bacteriological response Beecham Laboratories and Children’s Research Foundation of Cleveland Gropper 201426 Topical ozenoxacin 1% cream (twice daily, for 5 days) (n=155) Topical retapamulin 1% ointment (twice daily, for 5 days) (n=154) • Clinical response • Bacteriological response • Adverse events Ferrer Internacional SA, Barcelona, Spain Placebo (twice daily, for 5 days) (n=156) Iovino 201127 NVC-422 topical gel 0.1% (n=43) NVC-422 topical gel 0.5% (n=45) • Clinical response • Bacteriological response • Adverse events NR NVC-422 topical gel 1,5% (n=41) Jeffrey 199028 Oral erythromycin (40 mg/kg/day, 4 times/day) + topically applied placebo (3 times/ day) (n= 30) Topical mupirocin 15g 2% (3 times/ day) + orally administered placebo (4 times/ day) (n= 24) • Clinical response • Bacteriological response United States Navy Bureau of Medicine and Surgery Clinical Investigation Program Koning 200229 Topical fusidic acid cream 2% (3 times/day, for 14 days) (n=78) Placebo (3 times/ day, for 14 days) (n=82) • Clinical response • Bacteriological response Fonds Alledaagse Ziekten of the Dutch College of General Practitioners Koning 200830 Topical retapamulin ointment 1% (twice daily for 5 days) (n=139) Topical placebo (twice daily for 5 days) (n=71) • Clinical response • Bacteriological response • Adverse events GlaxoSmithKline Kuniyuki 200531 Topical 3% Oxytetracycline- hydrochloride (n=28) Topical tetracycline and oral antibiotics (cefdinir, fosfomycin and minocycline) (n=21) • Clinical response • Bacteriological response NR Table 1. Characteristics of the Included Studies. (continued) 6 Review | Dermatol Pract Concept. 2025;15(4):5668 Regarding the randomization process, which assesses the method by which participants were assigned to ensure comparable groups, 53% (11/21, 95% CI: 32%–72%) [18-23,25,27,31,32,37,38] of the RCTs presented an un- clear risk of bias due to insufficient information provided for judgment. In contrast, 47% (10/21, 95% CI: 28%–68%) [21,24,26,28-30,33-36] clearly described the random- ization process, which was typically carried out using a computer-generated randomization code, schedule, or list of random set numbers. No study was classified as having a high risk of bias in this domain. Similar proportions were observed regarding allocation concealment, where 57% (12/21, 95% CI: 37%–76%) [18-20,22-25,27,38,31,32,37] of the RCTs had an unclear risk of bias. In comparison, 43% (9/21, 95% CI: 24%–63%) [21,26,29,30,33-35,28] had a low risk of bias, with most studies describing methods such as the use of sequentially sealed opaque envelopes to ensure proper allocation concealment. The assessment of the blinding domains evaluates whether participants and outcome assessors were aware of the inter- vention assigned to each group. This awareness can influence the results, especially when outcomes are measured subjec- tively or rely on patients’ perceptions. Among the RCTs, 71% (15/21, 95% CI: 50%–86%) [18,20,22-25,27,31-28] were classified as high risk of bias for blinding of participants and personnel, and 57% (12/21, 95% CI: 37%–76%) [18- 21,24,25,27,31,32,34,36,37] were at high risk of bias for blinding of outcome assessors. This indicates either knowl- edge of the intervention or insufficient information to assess blinding. The lack of blinding of participants and assessors Study, year Intervention / Number of participants (N) Control / Number of participants (n) Outcomes of interest Funding sources Mclinn 199032 Topical mupirocin ointment 2% (3 times/day) (n=29) Oral erythromycin (30 to 40 mg/kg/ day) (n=30) • Clinical response • Bacteriological response • Adverse events NR Mertz 198933 Topical 15g mupirocin ointment 2% (3 times/day, for 8 days) (n=28) Oral erythromycin (30 to 50 mg/kg/ day) (n=25) • Clinical response • Bacteriological response Beecham Laboratories, Bristol, Tenn Nolting 199834 Topical sulconazole nitrate 1% cream (twice daily, for 14 days) (n=32) Topical miconazole nitrate 2% cream (twice daily, for 14 days) (n=34) • Clinical response • Bacteriological response NR Oranje 200735 Topical retapamulin ointment 1% (twice daily for 5 days) (n=345) Topical sodium fusidate ointment 2% (3 times daily for 7 days) (n=172) • Clinical response • Bacteriological response GlaxoSmithKline Rosen 201836 Topical ozenoxacin cream 1% (twice daily for 5 days) (n=206) Placebo (twice daily for 5 days) (n=206) • Clinical response • Bacteriological response Ferrer Internacional, SA. Sudha 201737 Oral azithromycin (10 mg/kg/day) (n=50) Oral azithromycin (10 mg/kg/day) + Probiotic (n=50) • Clinical response No sources Tong 201038 Oral trimethoprim-sulfamethoxazole (4+20 mg/kg up to 160 + 800 mg) (n=7) Intramuscular benzathine penicillin (45 mg/ kg up to 900 mg) (n=6) • Clinical response • Bacteriological response Australian National Health and Medical Research Council, Australian National Heart Foundation, Cooperative Research Centre for Aboriginal Health, Ian Potter Foundation, and the Rio Tinto Aboriginal Foundation. Abbreviations: N: number of participants, NR: not reported, NVC-422: N, N-dichloro-2, 2-dimethyltaurine. Table 1. Characteristics of the Included Studies. (continued) Review | Dermatol Pract Concept. 2025;15(4):5668 7 Figure 2. Risk of bias assessment. can significantly impact the results since clinically relevant efficacy and safety outcomes were measured subjectively. With a low risk of bias, 29% (6/21, 95% CI: 14%–50%) [19,21,26,28-30] had adequate blinding of participants, and 43% (9/21, 95% CI: 24%–63%) [22,23,26,28-30,33,35,38] had adequate blinding of assessors. In these studies, the com- pared medications were identical in appearance and char- acteristics, or participants received a placebo that closely resembled the intervention, such as a placebo ointment for the oral administration group versus the topical treatment. The incomplete outcome data domain assesses how re- sults are reported, including participant losses or withdraw- als during the study, and examines the impact of these losses on the final analysis. Among the included RCTs, 76% (16/21, 95% CI: 55%–89%) [18,19,21-23,25-27,29,31,32,34-38] were considered to have a low risk of bias, as they reported losses of less than 20% of participants and provided appro- priate justifications. In contrast, 24% (5/21, 95% CI: 11%– 45%) [20,24,28,30,33] had a high risk of bias due to losses exceeding 20% and lacking justification. The selective reporting domain revealed that 81% (17/21, 95% CI: 60%–92%) [18-29,31-34,37] of the studies had an unclear risk of bias, as most did not provide a regis- tered protocol, making it impossible to assess the differences between reported and unreported outcomes and results. No other source of bias was identified in the evaluated RCTs. Discussion This meta-research evaluated the methodological quality and risk of bias in randomized clinical trials (RCTs) concern- ing pharmacological treatments for impetigo in children and adolescents. Impetigo, a highly contagious skin infection, is a common condition requiring effective treatment options, yet evidence supporting various interventions remains uncer- tain. This study aimed to assess the reliability and applica- bility of current RCTs, mapping the methodological flaws to clinical practice and providing recommendations for future research. The results revealed that a significant proportion of the included RCTs exhibited unclear or high risks of bias, particularly in domains related to randomization, blinding, and handling of incomplete outcome data. A significant proportion of the included studies presented an unclear or high risk of bias regarding the randomization process, with 53%–57% of studies lacking sufficient details. Randomization is critical to ensuring that participants are allocated to treatment groups without bias, guaranteeing comparability. Inadequate or poorly described randomiza- tion methods can lead to selection bias, potentially affecting the generalizability of the results and distorting the perceived treatment effect. Rigorous randomization procedures are es- sential to ensuring baseline comparability and to reducing the risk of bias [1,5,39]. Most studies had a high risk of bias concerning the blinding of participants and outcome assessors. This lack of blinding can introduce performance and detection biases. When par- ticipants or researchers know the treatment allocation, it may influence participant behavior and the interpretation of out- comes. For example, participants aware of receiving a pla- cebo might report subjective outcomes differently from those receiving the active treatment. Similarly, unblinded assessors may unintentionally assess outcomes in a biased manner. Such biases can lead to overestimations or underestimations of treatment effects, affecting the reliability of study results [6]. 8 Review | Dermatol Pract Concept. 2025;15(4):5668 1.0 was made because it includes a dedicated domain for selective reporting, a critical issue not explicitly assessed in RoB 2.0. Selective reporting bias is a significant concern in clinical research, occurring when pre-specified outcomes are omitted, reported incompletely, or presented selectively, leading to biased effect estimates with overestimation of ben- efits and underestimation of harms. The decision also reflects growing concerns in the literature regarding the complexity and operational challenges associated with RoB 2.0, which has demonstrated lower inter-rater reliability and consider- able implementation challenges, even when applied by expe- rienced systematic reviewers [44–46]. The methodological shortcomings identified in this meta-research have important implications for both clinical practice and future research. For clinicians, the variability and potential biases in the current evidence base emphasize the need for cautious interpretation of studies on impetigo treatments. Evidence derived from trials with a high risk of bias may not accurately represent the true efficacy and safety of pharmacological interventions, potentially leading to sub- optimal treatment decisions. For researchers, these findings highlight the urgent need to strengthen methodological rigor in future RCTs. Key areas for improvement include robust randomization procedures, proper allocation concealment, adequate blinding, and appropriate handling of incomplete outcome data. Equally important is the commitment to transparency through prospective protocol registration and adherence to standardized reporting guidelines. In this context, future RCTs should comply with the SPIRIT checklist for comprehensive and transparent pro- tocol development [47,48] and the CONSORT statement to ensure complete and accurate reporting of trial findings [49], and they should incorporate the Cochrane Risk of Bias tool to guide risk of bias assessment and improve internal validity [12]. These practices are essential to enhancing the credibility, reproducibility, and utility of clinical research on impetigo. Ultimately, improving the methodological quality of trials will support more reliable evidence synthesis, inform guideline development, and guide decision-making about which treatments should be prioritized, recommended, or funded in clinical practice. Conclusion This meta-research study evaluated the methodological qual- ity of 21 RCTs on pharmacological treatments for impetigo. The findings identified critical areas of concern: i) 53% to 57% of RCTs had an unclear risk of selection bias due to insufficient information on randomization and allocation concealment; ii) 71% were at high risk of bias for blinding of participants and personnel, while 57% had a high risk of blinding of outcome assessors; iii) 24% exhibited a high risk Over 70% of the RCTs were classified as having a low risk of bias regarding participant losses or withdrawals during study follow-up. Incomplete outcome data can com- promise the validity of the results and introduce bias if not adequately managed. It is crucial that future studies employ rigorous methods for dealing with missing data and that they provide transparent reporting to allow for accurate assess- ments of treatment efficacy [39]. Finally, regarding selective reporting bias, 81% of the evaluated RCTs were classified as having unclear risk of bias, mainly due to the lack of prospective protocol registration. The absence of a publicly available protocol compromises the ability to verify whether predefined outcomes were al- tered, selectively reported, or omitted, which may distort study conclusions by overestimating benefits or underesti- mating harms. This issue is particularly critical in impetigo clinical trials, in which outcomes are largely subjective and prone to bias. Mandatory prospective registration of clini- cal trials in international registries such as ClinicalTrials.gov and the WHO ICTRP should be strictly enforced to mitigate this bias. This practice is widely recognized as an essential safeguard for research integrity, as it increases transparency, reduces reporting bias, and ensures that all prespecified re- sults are publicly accessible for verification [40-42]. The methodological weaknesses identified in the included RCTs are consistent with patterns observed in dermatology research. A meta-research study [42] assessed dermatologi- cal RCTs included in Cochrane reviews and reported a high prevalence of unclear risk of bias, particularly for allocation concealment (79%) and random sequence generation (64%), which closely reflects the findings of our study. Similarly, an- other recent meta-research study [43] evaluating systematic reviews of RCTs on vesiculobullous skin diseases found that over half (55.5%) of the reviews were rated as critically low quality according to the AMSTAR-2 tool assessment. This reinforces that the methodological limitations observed in impetigo trials are not isolated but are part of a wide- spread challenge. This meta-research study has some limitations that should be acknowledged. First, although a comprehensive literature search was conducted, the possibility of missing relevant studies cannot be entirely excluded. Second, the risk of bias assessment depended on the quality and complete- ness of the reports provided by the original studies. Third, the wide confidence intervals observed in some risk of bias domains reflect the uncertainty associated with the relatively small number of included trials. 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