Beyond the Label: Steering the Focus Toward Safe and Effective Prescribing

Abstract

Each year, hundreds of millions of prescription medications are dispensed to pediatric patients. 1 A significant proportion of prescriptions are used in an off-label manner, outside the specifications approved by the US Food and Drug Administration (FDA), rendering off-label prescribing a "public health issue for infants, children and adolescents, " as described by the Committee on Drugs for the American Academy of Pediatrics. 2 The committee also explicitly states that off-label use "does not imply an improper, illegal, contraindicated or investigational use. " Yet, when used in research, clinical practice, or even the lay media, the term off-label commonly carries a negative connotation. This interpretation probably reflects the sense of uncertainty in understanding the risk-benefit balance of a medication without FDA review and approval. However, prescribing according to the package insert does not necessarily translate to the safe and effective use of a medication. 3 The clinical trial data required for FDA approval often represent highly select populations in controlled settings with limited follow-up. These data may not translate well to real-world use, hence the need for postmarketing surveillance and research. Conversely, lack of pediatric labeling for a medication does not necessarily indicate a lack of evidence. It may simply mean the pharmaceutical company has not submitted an application for FDA approval to add a new indication or population.This apparent paradox gives us the opportunity to consider how we, the pediatric community of clinicians, researchers, and policymakers, think about the issue of off-label prescribing and how best to direct future efforts in medication research and policy. The Best Pharmaceuticals for Children Act prioritization process focuses on gathering expert opinion to inform research priorities related to therapeutic needs, with a primary goal of identifying drugs for pediatric clinical trials. 4 We argue that such approaches should be complemented by a structured consideration of risks and benefits informed by increasingly available data from practice. Pediatric research on off-label prescribing often focuses on the dichotomy of on-label versus off-label prescribing rates, defined mainly by age limits and occasionally indication. Understanding the extent of off-label practice is important, but it represents only a single dimension of a complex issue. This information does not necessarily determine whether the way a

Optimizing therapeutic decision‐making for off‐label medicines use: A scoping review and consensus recommendations for improving practice and research+

“…A total of 5109 publication records were screened, 31 of which were included in the analysis (Figure 1). Of these, 21 (68% of total) publications refer to 20 unique guidances providing general considerations, frameworks, and recommendations to guide decision‐making for off‐label medicines use 8,14–17,22–37 . Ten papers (32%) provided off‐label use recommendations for specific medicines or therapeutic categories but also described the types of evidence, expertise, and processes used in developing recommendations and thus were included 38–47 …”

“…Of these, 21 (68% of total) publications refer to 20 unique guidances providing general considerations, frameworks, and recommendations to guide decision-making for offlabel medicines use. 8,[14][15][16][17][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] Ten papers (32%) provided off-label use recommendations for specific medicines or therapeutic categories but also described the types of evidence, expertise, and processes used in developing recommendations and thus were included. [38][39][40][41][42][43][44][45][46][47] 3.1.2 | Thematic concepts of general guidances for off-label medicine use…”

Towards a Responsible Transition to Learning Healthcare Systems in Precision Medicine: Ethical Points to Consider

“…Drugs used in precision medicine, and the biomarkers on the basis of which these drugs are prescribed, are oftentimes relatively novel. In addition, in precision medicine, off-label prescription (i.e., prescription for indications not authorized by regulatory agencies), is even more common than in many other fields of medicine [36,37]. As a result, patients who are prescribed precision medicine interventions face different, and comparatively more unknown, risks than patients in the stereotypical contexts for which the LHS concept has originally been developed.…”

Advancing evidence-based treatment of infectious diseases in children with real-world data: Opportunities and challenges

“…Studies have found that 42%–73% of drug prescriptions in patients under 18 years were off-label, with the highest frequencies reported in neonates ( Cuzzolin and Agostino, 2016 ; Hoon et al, 2019 ; Yackey et al, 2019 ; van der Zanden et al, 2022 ). However, off-label use does not mean off-evidence nor does it imply improper or contradicted use ( COMMITTEE ON DRUGSNeville et al, 2014 ; Czaja et al, 2017 ). Highly prescribed drugs off-label may have strong evidence for safe and effective use, yet a formal application for regulatory authorization may not be sought ( Czaja et al, 2017 ).…”

“…However, off-label use does not mean off-evidence nor does it imply improper or contradicted use ( COMMITTEE ON DRUGSNeville et al, 2014 ; Czaja et al, 2017 ). Highly prescribed drugs off-label may have strong evidence for safe and effective use, yet a formal application for regulatory authorization may not be sought ( Czaja et al, 2017 ). In a recent study of the Dutch Pediatric Formulary, 42% of prescribed drug records were off-label, of which only 14% were supported by high-quality evidence and 37% by expert opinion ( van der Zanden et al, 2022 ).…”