Off-Label Drug Use in Children Over the Past Decade: A Scoping Review

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Off-Label Drug Use in Children Over the Past Decade: A Scoping Review

Off-label drug use (OLDU) in pediatric populations remains a critical global healthcare challenge. Defined as the administration of medications outside their approved age, indication, dose, formulation, or route of administration, OLDU is particularly prevalent in children due to the historical lack of pediatric-specific clinical trials and labeling. This scoping review maps the extent, characteristics, and implications of pediatric OLDU research from 2010 to 2020, synthesizing data from 514 studies to identify trends, knowledge gaps, and future priorities.

Methodology and Scope

The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines. A comprehensive search across six databases—Medline, Web of Science, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), and Wanfang Data—yielded 1,203 records. After deduplication and rigorous screening, 514 studies were included, encompassing diverse study designs such as prescription analyses, surveys, case reports, systematic reviews, and policy statements. The inclusion criteria prioritized studies with actionable insights, excluding those focused on traditional Chinese medicine, medical devices, or insufficiently detailed reports.

Temporal and Regional Trends

The volume of pediatric OLDU research increased significantly over the decade, with a notable surge between 2010 and 2015. By 2020, annual publications had nearly tripled compared to 2010 levels. Geographically, Asia and Europe dominated research output, contributing 39.3% and 32.7% of studies, respectively. In contrast, Africa and South America accounted for only 5.6%, highlighting disparities in regional focus and resource allocation.

Study Types and Research Topics

Survey-based research constituted the majority of studies (50.8%, n = 261), categorized into three subtypes:

  1. Prescription Analyses: These studies quantified OLDU prevalence across settings (e.g., outpatient, inpatient, primary care) using prescription audits or national healthcare databases. Prevalence rates varied widely, ranging from 11% to 93%, influenced by factors such as clinical specialty, geographic location, and patient demographics. Neonatal and pediatric intensive care units reported the highest OLDU rates due to the urgency of treating critically ill children with limited approved therapies.
  2. Cognitive Surveys: These investigations assessed stakeholders’ awareness and attitudes toward OLDU. Among healthcare professionals, pediatricians demonstrated greater familiarity with off-label prescribing compared to pharmacists and nurses, many of whom acquired knowledge through clinical experience rather than formal education. Parents and caregivers overwhelmingly reported limited understanding of OLDU, with 85% stating they should be informed of off-label use by clinicians.
  3. Adverse Drug Reaction (ADR) Monitoring: Eleven studies examined the correlation between OLDU and ADRs. While seven identified a statistically significant association, four found no causal link, underscoring the need for robust pharmacovigilance systems tailored to pediatric populations.

Beyond surveys, conference abstracts and literature reviews represented 15.2% (n = 78) and 12.3% (n = 63) of studies, respectively. Only nine systematic reviews and one randomized controlled trial (RCT) were identified, reflecting a paucity of high-level evidence. The lone RCT evaluated enalapril versus placebo in infants with single-ventricle physiology, emphasizing the ethical and logistical challenges of conducting pediatric trials.

Key Research Themes

Studies addressed six primary themes:

  1. Epidemiology of OLDU: Over half of the studies (56.2%, n = 289) focused on documenting OLDU prevalence and trends. For example, a U.S. study estimated 41.2 million annual off-label prescriptions for children, with antipsychotics and antibiotics being the most frequently off-label classes.
  2. Efficacy and Safety: Nearly a quarter of studies (23.0%, n = 118) evaluated therapeutic outcomes. Case reports highlighted successful off-label use of drugs like propranolol for infantile hemangiomas, while cohort studies revealed mixed efficacy results for medications such as antidepressants in adolescents.
  3. Policy and Advocacy: 8.9% (n = 46) of studies proposed policy reforms or clinical guidelines. Four influential documents emerged: two from the American Academy of Pediatrics, one from the European Academy of Paediatrics, and a Chinese Medical Association consensus. These frameworks advocated for enhanced pediatric trial incentives, standardized informed consent protocols, and centralized ADR reporting.
  4. Stakeholder Perceptions: Surveys involving 3,200 healthcare professionals revealed concerns about liability (68%), inadequate efficacy data (57%), and insufficient dosing guidelines (49%). Parents expressed anxiety about potential risks but supported OLDU when alternatives were unavailable.
  5. Drug-Specific Analyses: Psychotropic agents, including antipsychotics and antidepressants, were the most studied off-label class (18.6%, n = 34), followed by anti-neoplastic drugs (12.0%, n = 22) and antimicrobials (9.3%, n = 17). For antipsychotics, off-label prescribing rates ranged from 36% to 93.2%, primarily for attention-deficit/hyperactivity disorder (ADHD) and sleep disorders.
  6. Multidisciplinary Collaboration: Only 3.1% (n = 15) of studies involved multi-stakeholder teams, though these were more likely to yield clinical guidelines or policy recommendations.

Stakeholder Engagement and Authorship

Pharmacists led 44.6% (n = 229) of studies, followed by pediatricians (22.4%, n = 115). Collaborative efforts between pediatricians and pharmacists accounted for 5.1% (n = 26), while multidisciplinary teams (e.g., involving ethicists, policymakers, or pharmaceutical companies) were rare (2.9%, n = 15). International organizations like the FDA and CDC contributed to 9.5% (n = 49) of studies, often focusing on regulatory frameworks or global health initiatives.

Implications and Future Directions

The review underscores several critical challenges:

  1. Evidence Gaps: The predominance of observational studies and case reports limits actionable insights. Large-scale RCTs and pragmatic trials are urgently needed, particularly for psychotropics, biologics, and anti-infectives.
  2. Guideline Implementation: Existing guidelines are underutilized due to poor awareness and workflow barriers. Integration of OLDU protocols into electronic health records could improve adherence.
  3. Health Equity: Regional disparities in research output mirror inequities in drug access and regulatory oversight. Low- and middle-income countries require targeted support to establish pharmacovigilance systems and ethical review boards.
  4. Patient-Centered Care: Children and adolescents are rarely engaged in OLDU decision-making. Developmentally appropriate consent processes and educational materials could empower pediatric patients and families.

Conclusion

This scoping review provides the most comprehensive synthesis to date of pediatric OLDU research, revealing sustained progress alongside persistent gaps. While the field has moved beyond merely documenting prevalence to exploring therapeutic outcomes and stakeholder perspectives, transformative change requires coordinated action across research, policy, and practice. Prioritizing high-quality trials, strengthening multidisciplinary partnerships, and centering patient voices will be essential to ensuring safe, effective, and equitable pharmacotherapy for children worldwide.

doi.org/10.1097/CM9.0000000000001991

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