Benefit‐Risk Assessment of Off‐Label Drug Use in Children: The Bravo Framework

Zanden, Tjitske M van der; Mooij, Miriam G.; Vet, Nienke J.; Neubert, Antje; Rascher, Wolfgang; Lagler, Florian B.; Male, Christoph; Grytli, Helene Hartvedt; Halvorsen, Thomas; Hoog, Matthijs de

doi:10.1002/cpt.2336

Cited by 31 publications

(28 citation statements)

References 66 publications

(130 reference statements)

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“…To reduce the risk for therapy failure and toxicity related to off‐label use, the Benefit and Risk Assessment for Off‐label (BRAvO) use decision tool was recently developed to assess and balance benefits and risks of off‐label drug use in children 47 . This may help physicians and guideline committees to address information gaps in daily practice.…”

Section: Discussionmentioning

confidence: 99%

Off‐Label, but on‐Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

Zanden

Smeets

Hoop-Sommen

et al. 2022

Clin Pharma and Therapeutics

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This study shows that the level of evidence for off-label pediatric pharmacotherapy is low: for only 14% of off-label records, high quality studies are available. Thirty-seven percent of offlabel records are not supported by any clinical studies at all. HOW MIGHT THIS CHANGE CLINICAL PHARMA COLOGY OR TRANSLATIONAL SCIENCE? Performing high quality randomized controlled trials for the > 2,000 off-label record is a very long pathway to close this information gap. Alternatively, modeling and simulation may be valuable approaches to strengthen the evidence base for offlabel use of drugs, especially in younger age groups.

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Section: Discussionmentioning

confidence: 99%

Off‐Label, but on‐Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

Zanden

Smeets

Hoop-Sommen

et al. 2022

Clin Pharma and Therapeutics

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“…The added value of PK studies was recently highlighted by a published framework for conducting benefit‐risk assessments of off‐label drugs in children 15 . Using paediatric PK studies, extrapolation approaches are increasingly used in drug development programmes in both the United States and European Union 28 .…”

Section: Discussionmentioning

confidence: 99%

Guiding future paediatric drug studies based on existing pharmacokinetic and efficacy data: Cardiovascular drugs as a proof of concept

Smeets,

Raaijmakers,

van der Zanden

et al. 2023

Brit J Clinical Pharma

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IntroductionOff‐label drug use in the paediatric population is common, and the lack of high‐quality efficacy studies poses patients at risk for failing pharmacotherapy. Next to efficacy studies, pharmacokinetic (PK) studies are increasingly used to inform paediatric dose selection. As resources for paediatric trials are limited, we aimed to summarize existing PK and efficacy studies to identify knowledge gaps in available evidence supporting paediatric dosing recommendations, thereby taking paediatric cardiovascular drugs as proof of concept.MethodsFor each cardiovascular drug, paediatric indication and prespecified age group, together comprising one record, the authorized state was assessed. Next, for off‐label records, the highest level of evidence was scored. High‐quality efficacy studies were defined as meta‐analysis or randomized controlled trials. Other comparative research, noncomparative research or consensus‐based expert opinions were considered low quality. The level of evidence for PK studies was scored per drug and per age group, but regardless of indication.ResultsA total of 58 drugs included 417 records, of which 279 (67%) were off‐label. Of all off‐label records, the majority (81%) were not supported by high‐quality efficacy studies, but for 140 of these records (62%) high‐quality PK studies were available.ConclusionWe demonstrated that for the majority of off‐label cardiovascular drugs, only low‐quality efficacy studies were available. However, high‐quality PK studies were frequently available. Combining these PK data with extrapolation of efficacy data from adults may help to close the current information gap and prioritize the drugs for which clinical studies and safety data are urgently needed.

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“…However, many other routes of administration are being explored in clinical practice and it seems to be a molecule with a great potential in many clinical situations. Data obtained from experimental animals and adult population have encouraged its off-label use [ 57 ] also in pediatric and neonatal patients. Consequently, numerous studies have been published about this subject in recent years, but the degree of evidence is moderate, being mostly retrospective observational studies.…”

Section: New Pharmacological Treatments: Dexmedetomidinementioning

confidence: 99%

Dexmedetomidine: An Alternative to Pain Treatment in Neonatology

et al. 2023

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Infants might be exposed to pain during their admissions in the neonatal intensive care unit [NICU], both from their underlying conditions and several invasive procedures required during their stay. Considering the particularities of this population, recognition and adequate management of pain continues to be a challenge for neonatologists and investigators. Diverse therapies are available for treatment, including non-pharmacological pain management measures and pharmacological agents (sucrose, opioids, midazolam, acetaminophen, topical agents…) and research continues. In recent years one of the most promising drugs for analgesia has been dexmedetomidine, an alpha-2 adrenergic receptor agonist. It has shown a promising efficacy and safety profile as it produces anxiolysis, sedation and analgesia without respiratory depression. Moreover, studies have shown a neuroprotective role in animal models which could be beneficial to neonatal population, especially in preterm newborns. Side effects of this therapy are mainly cardiovascular, but in most studies published, those were not severe and did not require specific therapeutic measures for their resolution. The main objective of this article is to summarize the existing literature on neonatal pain management strategies available and review the efficacy of dexmedetomidine as a new therapy with increasing use in the NICU.

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Benefit‐Risk Assessment of Off‐Label Drug Use in Children: The Bravo Framework

Cited by 31 publications

References 66 publications

Off‐Label, but on‐Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

Off‐Label, but on‐Evidence? A Review of the Level of Evidence for Pediatric Pharmacotherapy

Guiding future paediatric drug studies based on existing pharmacokinetic and efficacy data: Cardiovascular drugs as a proof of concept

Dexmedetomidine: An Alternative to Pain Treatment in Neonatology

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