To the Editor: Off-label drug use (OLDU) refers to the use of a drug outside of the age, indication, weight, dose, formulation, or route of administration indicated on the label. It is a major concern and a common practice for clinicians around the globe, especially for pediatricians, owing to the lack of pediatric-specific drug information. Research showed that US office-based physicians had ordered 41.2 million off-label orders per year for children and the trend had been increasing from 2006 to 2015. However, despite OLDU has its rationality and inevitability, it still brings challenges such as safety, ethical, and legal conflicts, thereby remaining a complex and important public health issue that urgently requires more profound changes. Recently, numerous studies have emerged in the field of OLDU; however, there is no comprehensive review describing the current state of the science. Unlike a systematic review, scoping review methods can be particularly useful when the topic has not been extensively reviewed or is of a complex or heterogeneous nature. Herein, we conducted a scoping review to map the nature and extent of existing evidence on pediatric OLDU, and further propose recommendations for future research. The study followed recommendations set out in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. The protocol was prospectively registered with the Open Science Framework (osf.io/43rhv).
We searched Medline (via PubMed), Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang Data from January 1, 2010 to September 2, 2020. The main search terms were “off-label” and “pediatric” with their synonyms [Supplementary File 1, https://links.lww.com/CM9/A941]. There were no restrictions on the type and quality of included studies. Conference abstracts were deemed eligible, provided that they contain relevant and sufficient information, and will be checked for duplicates to ensure that they have not been published as full papers. We excluded studies that focused off-label use of traditional Chinese medicine, medical devices or procedures, and those without sufficient valid information.
After eliminating duplicates, titles and abstracts were screened according to the inclusion criteria, and the reasons for exclusion were recorded. Next, full texts were reassessed for relevance again. Record screening was performed independently by two reviewers. Any disagreements were resolved by consensus with a third reviewer. We recorded information using a standardized extraction table. We summarized the studies into the following parts: trend and regional proportion of studies; types; topics; authorship composition and stakeholders; and off-label medications most commonly studied. The National Essential Medicine List 2018 of China was used to guide the classification of medications. The results were synthesized descriptively. Diagrams were created using Microsoft Excel 2016 (Microsoft, USA) and SigmaPlot 12.5 (Systat Software, USA). The search strategy identified 1203 records. After eliminating duplicates, 589 records were screened for the title and abstract, which excluded 44 records. Eventually, 545 were assessed for eligibility, resulting in a total of 514 studies that were finally included in this review [Supplementary Figure 1, https://links.lww.com/CM9/A940].
The total amount of published studies related to OLDU in children showed an increase over the past decade, especially from 2010 to 2015, and recently it stayed stable at nearly treble the level of studies in 2010. More studies originated from Asia and Europe than Africa and South America [Figure 1A]. Overall, we characterized the included articles into seven types [Figure 1B]. More than half (261/514, 50.8%) were survey research, which can be broadly divided into three categories: prescription investigations that reported on the current situation of OLDU, cognitive investigations on the views and awareness of stakeholders, and adverse drug reactions (ADRs) investigations on the correlation of ADRs and OLDU. Conference abstracts and literature reviews were the second most common type of research.
Studies included in this review have focused mainly on six topics [Figure 1C]. The predominant focus (289/514, 56.2%) was to provide an overview of the current situation of OLDU in different scenarios, such as outpatients, inpatients, primary care settings, and the general population (based on big data from national healthcare systems) through reviewing the prescription data of patients, thereby analyzing the prevalence, trend, and contributing factors of OLDU. Based on these studies, nine systematic reviews were conducted. These studies have confirmed the high prevalence and rising trend of OLDU. The second major topic was about the efficacy and safety of off-label medications (118/514, 23.0%), of which 32 were case reports/series that reported the successful experience of an off-label medication. Three cohort studies compared the clinical outcomes of patients treated with and without offlabel medication. Only one randomized controlled trial was identified, which examined enalapril vs. placebo in infants with a single ventricle. Moreover, 11 studies collected the reports of ADRs, but seven studies concluded the existence of a causal correlation between OLDU and ADRs, whereas four did not. Furthermore, nearly 9% of studies introduced policies, recommendations, or called attention to change the status of OLDU. Four of these studies were guidance documents, including two policy statements from the American Academy of Pediatrics, one from the European Academy of Paediatrics, and one expert consensus from the Chinese Medical Association.
In total, 27/514 (5.1%) studies assessed the perceptions and attitudes of different populations regarding pediatric OLDU. The primary respondents were healthcare professionals (pediatricians, pharmacists, and nurses), followed by parents/caregivers. Only one study investigated the children's views. OLDU seems to be a familiar concept for the majority of pediatricians, whereas some pharmacists and nurses claimed to have gained this knowledge from their professional experience instead of education and therefore have a low level of awareness. Parents and children often report having no previous knowledge of OLDU, and they thought they should be informed by the doctors. Furthermore, pediatricians and pharmacists do concern about the efficacy and safety of off-label medicines as well as medico-legal problems. Therefore, they called to conduct more clinical trials, and develop guidelines, and workflows to better guide their work.
Among all studies, authors can be classified into six categories: pharmacist, pediatrician, pediatrician and pharmacist, multidisciplinary cooperation (more than three sources), others (not fit into a predefined category), and unreported (insufficient information). Pediatricians and pharmacists dominated the research in this field, with pharmacists (229/514, 44.6%) conducting twice as much research as pediatricians (115/514, 22.4%). In addition, 5.1% of the studies were conducted under the cooperation of pediatricians and pharmacists. Moreover, 9.5% of studies involved the participation of international organizations such as the Food and Drug Administration and the Centers for Disease Control and Prevention. Multidis-ciplinary collaboration appeared in nearly 3% of all studies. Other stakeholders such as policymakers, lawyers, pharmaceutical industries, drug agencies, ethics committees, and medical insurance divisions were also involved to varying degrees.
We summarized the top 10 most studied categories of off-label medications from 183 studies [Figure 1D]. Psycho-tropic medications appeared to be the number one medication of concern. In addition, 22 studies focused on anti-tumor agents. This was followed by antimicrobial agents, nervous system medications, and biological products such as vaccines, monoclonal antibodies, or recombinant agents. One systematic review showed that OLDU was estimated between 36% and 93.2% of all antipsychotic prescriptions, and drugs for attention deficit hyperactivity disorder and sleep disorders were commonly seen. The labels of these drugs need to be updated more often, which points to the preferred direction for future clinical trials and guidelines.
In this study, we confirmed an extensive and growing body of literature regarding OLDU in children over the past decade, which reflected the high prevalence of off-label drug orders in clinical practice, as well as sustained efforts of researchers to improve the situation. We also noted that the attention on OLDU differed across regions. This imbalance could be a result of different economies, medical conditions, policies, laws, and recognition of the concept.
Obviously, there is significant room for improvement to expand the diversity of types and designs of studies. The overwhelming majority of studies were prescription analyses. A substantial proportion of such research only revealed the phenomenon of OLDU but failed to further disclose this issue in-depth, and overlapped or repeated evidence would be a waste of sources. In addition, there were also a large number of literature reviews that have offered recommendations or appeals to help improve the situation, as well as many case reports/series that reported the potential effectiveness of a specific drug. These articles are typically a part of discussion and concern, but they cannot be directly used to guide clinical decisions. In contrast, well-conducted systematic reviews are considered level I research evidence and constitute a powerful tool for guideline development and, therefore, should be encouraged. Guidelines on OLDU have great potential for ensuring patient safety, promoting informed consent, and reducing drug disputes by translating complex scientific research findings into recommendations. In this review, we identified several influential guidance documents. Some of them resulted in more drugs with pediatric information, but it was also proved that clinicians’ awareness and compliance to such consensus were low and barriers existed for utilization. Therefore, programmatic guidance documents are urgently needed and should be assessed regularly after publication.
As for the awareness of stakeholders, several key points can be concluded. First, it is necessary to further popularize the knowledge of OLDU, especially for parents, whose understanding of OLDU would largely influence their decisions on clinical trials for their child. Second, the process of OLDU is opaque and yet to be normalized. Despite knowing the importance of informed consent, pediatricians were reported to not seek informed consent or note the use in the medical record. Third, both pediatricians and pharmacists showed concerns about medico-legal and safety issues, which indicated that it is a priority to obtain more data on pediatric medications and to incorporate them into drug labels. Furthermore, there is a need to advocate for greater involvement of stakeholders other than just healthcare professionals, with particular attention to the expectations and preferences of children themselves.
In conclusion, OLDU in pediatric practice continues to be a challenging issue worldwide. Our results provide an evidence base for researchers interested in pediatric OLDU. Further in-depthanalysisonspecific topics, populations, drug categories will contribute to the development of safer and more effective therapeutic decision making in pediatrics.
Conflicts of interest
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