1 INTRODUCTION

Over the last decades, an increasing number of human research, especially in case reports and case series [1], has emphasized the important role of ethical approval [2, 3]. Ethical considerations have changed from no rule to a wide consensus with strict regulations in the clinical trials and epidemiological research for tens of years [4-6]. The concept of informed consent began with a series of judicial decisions in the early 20th century, which generated the fundamental principle of patient autonomy. However, the basis of “informed consent” remained unknown until the term was first publicly recorded in the court documents for the 1957 case [7]. An institutional review board (IRB), also known as an independent ethics committee, is an administrative unit that applies research ethics by reviewing the proposed methods to ensure that they are ethical [8]. IRB is widely required by the law or regulation in jurisdictions globally [9].

In any research that involves human participants, the authors prepared for the declaration of Helsinki (DoH) [10] to present their manuscripts to an appropriate committee called IRB [11] and to take informed consent from participants to publishers. These three items came from three different parties contributed to ethical practice and protection of the patients' rights, welfare, and health. Also, patients should anticipate the purpose, benefits, risks, and other options of the test or treatment. Meanwhile, authors not only have to gain the approval to carry out the research activities under the supervision of the affiliated institution, but also need to obtain a set of ethical standards, which was developed by the World Medical Association. Those statements of ethical principles should be entirely read and applied with consideration.

However, there exists an ever-expanding issue, which is associated with the increasing number of publications. While most medical journals require confirmation of IRB approval and patient consent before publishing a manuscript, there is a lack of these requirements in journal publications [12-15] or errors related to ethical approval [16-18]. As a result, there are raising concerns about authors' reporting integrity and patients' rights [19].

Most studies on ethical approval have been published years ago. Therefore, those publications mostly focused on randomized controlled trials (RCTs), prospective observational studies, and retrospective observational studies [20], whereas few studies carried on case reports/case series as human subjects research [21]. Acknowledging that issue, we hypothesize the high-quality reporting of ethical components with a clear explanation in protocols and manuscripts of case reports/series, which are decent execution for journals and readers in recent years. It is noticed that no case report is published in the absence of consent [22]. Case reports/series are generally retrospective although can occasionally be prospective, which can also define their subject by exposure or outcome [23]. Case reports/series commonly contain demographic information about the patients, such as age, gender, and ethnicity. When more than three patients are included, the case series are considered as a systematic investigation to highly contribute to the research, therefore, submission is required to the IRB.

In response to these issues, we aimed to assess the frequency of reported ethical approval and informed consent. Furthermore, we also aimed to determine the correlation between characteristics and factors of study populations in reporting ethical statements throughout the last decade.

2 MATERIALS AND METHODS

3 RESULTS

3.1 Search results

We initially retrieved 2400 papers from the PubMed database including 1200 case reports and 1200 case series. In each cluster of case reports/series, articles were retrieved from 12 consecutive years, including 20 papers from 20 different journals each year. Following title and abstract screening, 2066 articles were eligible for full-text screening. After checking the inclusion and exclusion criteria, 480 included studies were finally selected for data extraction. Reasons for excluding the remained studies were provided in the diagram (Figure 1).

3.4 Ethical approval characteristics by year

The change in reporting ethical statements over the years was described in Figure 2. In general, although there was variability among years, only the practice of reporting DoH in case series was expressed a significant increment by years, with Mann-Kendall trend test z, τ being 2.235, 0.529, respectively, with p = 0.025.

4 DISCUSSION

Along with the increasing numbers in the case reports/series, our study found that reporting of IRB approval, DoH, and informed consent had not reached the expected intensive level.

Among 480 included articles, more than half of included studies surprisingly lacked ethical statements, most of them did not fulfill all three components of ethical approval. Meanwhile, there was a significant difference in frequency between ethical components that persisted from case reports/series. The Cochran's Q test statistically presented a significant difference between the frequency of informed consent (37.1%), IRB approval (9.2%), and DoH (2.9%).

Realizing that previous reviews did not have sufficient attention on ethical approval in case reports/series, we investigated the studies working on RCTs only or a mixture of study designs. In detail, Schroter et al. [28] previously reported among five famous medical journals, namely Annals of Internal Medicine, BMJ, JAMA, Lancet, and The New England Journal of Medicine, stated that ethical approval and informed consent were not mentioned in 31% and 47% of 350 included articles, respectively. Meanwhile, a lack of reporting in both ethical approval and informed consent was presented in 88 (27%) manuscripts. The ethical practice outcome of Schroter's study was slightly higher than our results, which could be explained by the inclusion criteria, which were all types of study designs. Because the other study designs were frequently reported as a better ethical practice than case reports/series [29]. The study of Myles and Tan [29] investigated reporting ethical approval and informed consent of four anesthesia journals, in a wide range of study designs (1189 studies). A similar outcome to our study was presented when the authors pointed out that case reports/series were the least designed to include IRB approval and consent. IRB approval in case reports/series was obtained in only 2% meanwhile RCTs and mechanistic studies had more than 90% for each. Similar to the informed consent, case reports/series only have 3%, compared to RCTs and mechanistic studies with 97% and 83%, respectively. To support the earlier results, another study [30] working on more than 500 articles from 54 issues of the four surgery journals reported similar statistics to our study that reports (67%) did not include any statement on human subject protection. Only 74 reports (14%) mentioned both ethical approval and informed consent. Dingemann et al. [31] also reported the lowest rate, only 1.4% reporting ethical approval, and 1% informed consent was observed in 142 case reports. Moreover, corresponding to the significant difference between ethical components' recurrence in our study, two studies [32, 33] also reported that rates of IRB approval and informed consent in medical journals have improved better than DoH over the two previous decades. In a silver lining, our recent study [34] on only RCTs ethical approval showed that among 927 included trials, only 1.5% of these are lacking the ethical statements. Yet, nearly two-third (63%) of clinical trials did not completely report the investigated components (informed consent, IRB approval, and DoH).

In short, previous studies and our study have pointed out some features in common: ethical approval practice in case reports/series is not well mentioned as RCTs and the other research types meanwhile DoH is the least component that was documented in reports. Besides, limited studies have worked on the characteristics and factors of study populations, thus we could not compare to our study. However, in our study, the characteristics and factors of study populations and reporting ethical approval also presented a minor correlation as expected.

There were plenty of reasons for not seeking ethical approval in case reports/series, some studies [15, 35] demonstrated that ignorance, perceptions of cost, perceptions of certain research being exempt, impossibility to take consent (i.e., because of incompetence or age, emergency), no apparent and intelligible universal consensus. A further important question clearly concerns why the frequency of DoH is not high, in comparison with the two other components. The answer may come from the direct protection of the human subject's role of informed consent and IRB approval [22, 29], which are considered the major components. Moreover, the DoH is a set of ethical principles that serves as a guiding framework rather than a specific, detailed criteria checklist [36]. There also remains a considerable controversy about the DoH [37], along with the complicated and demanding protocols, which makes for some inevitable missing report of this component. Nevertheless, DoH itself has widely changed to update the variety of research forms and it still has a definite value when paying awareness of the need to facilitate research and the need to protect vulnerable patients [38]. In addition, IRB approval and DoH, the articles that included both adults and children/infants were significantly higher than those that included solely adults or children/infants. We believe that this is a remarkable point for the population when researchers want to conduct reports or trials: the younger the population, the more thoughtfulness of ethical approval should be made to reach the best treatment condition for the patients and the quality of the study.

Unlike the DoH, the issue of informed consent in case reports and case series has been a concern for a long time, to balance the right of patient confidentiality and the benefits to medicine and society at large coming from sharing their stories. In 1995, an international committee of 12 biomedical journal editors finalized guidelines for publishing case reports with the principle that patient privacy should take precedence over the need for clinicians to contribute knowledge and experience [39]. Since the 1995 consensus, more detailed and specific consensus on informed consent in case reports and case series have been developed over time, namely the guidelines of the Committee on Publication Ethics in 2013 [40] and the consensus of the International Committee of Medical Journal Editors in 2019 [41] with the same principle. Even though the informed consent report has been raised by time, only 38.5% of articles reported informed consent from 2006 to 2017 shown the fact that patient consent might not be taken adequately enough. The importance of obtaining patient consent if not taken seriously enough may over time cause the patient to feel violated or exploited by the doctor [42].

In addition to obtaining the consent of each patient, the publication of a case report or a series of cases may also require the approval of an IRB. In general, there are some differences in ethical considerations between case report and case series. For the case report study, there are many reasons resulting in the perforation of informed consent in ethical consideration, presented with the higher report rate compared to IRB approval in case report in our study (37.1% and 9.2%). Foremostly, most institutions do not consider case report to constitute research, leading to IRB approval is usually not required or mandatory [43]. Another reason is that even with local IRB approval, patient consent is still essential as a review criterion in many journals [40]. In contrast, IRB approval appears to be almost a mandatory requirement at many institutions before initiating research, resulting in roughly equal rate of IRB approval and informed consent (44.8% and 40.2%). However, for whatever reason, IRB approval cannot be a substitute for patient consent. Approval from an ethics committee should not overcome a patient's refusal to provide consent and whenever possible, individual patient consent should be obtained, even for retrospective research. For that reason, using an IRB as an option to waive the requirement for patient consent is another issue that needs to be concerned in research practice. Interestingly, our results found that among IRB approval studies, informed consent was only reported in 52.3% case series, compared to 90.9% in case report. That raises the question of whether IRB is a convenient form of avoiding the need for authors to obtain patient consent.

Raising the concern of ethical issues for case reports/series in the last decade, we also investigate two specific types which are considered as case reports/series: letters to the editor [44] and image cases. In these types, patients' information is also published directly for worldwide learning and discussion, sometimes their faces, injured areas on their bodies, their identities, family genealogy, and the likes are also published without permission. The common feature of these two types is short length. Unlike other normal case reports/series, letters to the editor and case images are often presented in very few pages with some brief information about the case. Some image cases contain only images and a few explanatory sentences. Although there is no relation between these two types and ethical practice, also there is no consensus or protocol to guide how to present ethical approval in these types, we assume that those types need ethical practice and we predict that these types are in high rate of missing ethical approval.

One of the limitations is that we used PubMed as only data source. Although this is one of the biggest research databases, taking other databases would be better for the quality of the study outcome. Besides, in the study process, we detected some reports on physically or mentally incapable of giving consent to patients that the legally allowed representative session of DoH did not recount. This issue could partially help to explain why several reports neglected the DoH. Like DoH, IRB approval had several similar limitations that they did not get a final consensus. Taking the case of some countries and areas, it is not compulsory for reports with the number of objects less than [45], therefore, authors easily omit this ethical component. However, IRB approval seemed to try hard to improve its quality (invite the third party) [19] and accessibility (shorten time on IRB, explain clearly the items) [46]. Our study also found a special situation in reports of forensic science which impossible to fetch ethical approval. Otherwise, the definition of case series is needed to operate when it exists in many definitions [47, 48], which will make authors and researchers confused to defining their types of publication. Further work is needed to determine the extent to which our results reflected the ethical issues. There are also considerable differences among countries [30], especially between the developing and developed countries [15, 49, 50] notwithstanding a clear protocol or consensus in journals as well as continents.

Our study focused on case reports/series because of their enormous numbers in publications. To protect the rights and safety of patients as well as the quality of research, our aspiration is not only limited to reports but also the other research types, the more researchers and editors pay attention to ethical approvals in case reports/series, the more concerns should be paid on other clinical trial's research. Accordingly, authors must observe the ethical approach, defined by the consensus, guidelines, and journal demands. In this situation, editors should play a gatekeeper role to ensure patients' rights and benefits, sustain human research's integrity, and gain public trust [51]. With the awareness of an ethical issue of every level of the research area, researchers can be best supported to avoid making errors. There must be some recommendations to prevent unethical research from being published [12] to establish and maintain the attitude and regularity in ethical practices. Furthermore, there is a necessity for a detailed and accessible consensus in the community of researchers and journal editors, including each ethical component and all types of study, particularly in reports and trials. Another limitation of this study is paper selection due to massive publication without proper categories to focus on any specific area. Hence, in an effort to control for the journal confounder, we set the additional criteria that 20 articles per year of each study design, not only were randomly selected but also must come from completely different journals. Finally, while this study focused on the trend and progress of ethics at the time of conducting this study, the authors aimed to raise the awareness of other authors and editors on the mentioned ethical approvals when conducting and approving clinical research. This study reflected a short period of time while further studies will be needed for real-time and up-to-date publications worldwide.

5 CONCLUSIONS

Our study found an infrequent using the ethical practices in case reports/series, which is significantly lower than other study designs. More than half of included papers in our study lack of the ethical statements (DoH, IRB, and informed consent) whereas the correlation between characteristics and factors of the study population was not noticeable. Accordingly, the awareness of ethical approval in human research should be taken into consideration. There must be an imperative need to improve the situation, which comes from participants involved in medical research.

AUTHOR CONTRIBUTIONS

Linh Tran: Conceptualization; data curation; validation; visualization; writing—original draft; writing—review and editing. Vuong Thanh Huan: Conceptualization; data curation; validation; visualization; writing—original draft; writing—review and editing. Luu Lam Thang Tai: Methodology; investigation; data analysis and curation; writing—review and editing. Adnan Safi: Data curation; methodology; validation. Moustafa ElBadry Ahmed: Methodology; investigation. Mohamed Osman Algazar: Methodology; investigation. Sedighe Karimzadeh: Investigation. Nguyen Vinh Khang: Methodology. Nguyen Hai Nam: Investigation; methodology. Zaheer Ahmad Qureshi: Validation. Nguyen Lam Vuong: Data curation. Le Huu Nhat Minh: Methodology. Nguyen Tien Huy: Conceptualization; visualization; validation; writing—review and editing; supervision.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflict of interest.

ETHICS STATEMENT

Not applicable.

INFORMED CONSENT

Not applicable.