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

Many drugs are still prescribed off-label to the pediatric population. Although off-label drug use not supported by high level of evidence is potentially harmful, a comprehensive overview of the quality of the evidence pertaining off-label drug use in children is lacking. The Dutch Pediatric Formulary (DPF) provides best evidence-based dosing guidelines for drugs used in children. For each drug-indication-age group combination-together compiling one record-we scored the highest available level of evidence: labeled use, systematic review or meta-analysis, randomized controlled trial (RCT), comparative research, noncomparative research, or consensus-based expert opinions. For records based on selected guidelines, the original sources were not reviewed. These records were scored as guideline. A total of 774 drugs were analyzed comprising a total of 6,426 records. Of all off-label records (n = 2,718), 14% were supported by high quality evidence (4% meta-analysis or systematic reviews, 10% RCTs of high quality), 20% by comparative research, 14% by noncomparative research, 37% by consensus-based expert opinions, and 15% by selected guidelines. Fifty-eight percent of all records were authorized, increasing with age from 30% in preterm neonates (n = 110) up to 64% in adolescents (n = 1,630). Many have advocated that off-label use is only justified when supported by a high level of evidence. We show that this prerequisite would seriously limit available drug treatment for children as the underlying evidence is low across ages and drug classes. Our data identify the drugs and therapeutic areas for which evidence is clearly missing and could drive the global research agenda.

Pharmacogenomics decision support in the U-PGx project: Results and advice from clinical implementation across seven European countries.

BACKGROUND: The clinical implementation of pharmacogenomics (PGx) could be one of the first milestones towards realizing personalized medicine in routine care. However, its widespread adoption requires the availability of suitable clinical decision support (CDS) systems, which is often impeded by the fragmentation or absence of adequate health IT infrastructures. We report results of CDS implementation in the large-scale European research project Ubiquitous Pharmacogenomics (U-PGx), in which PGx CDS was rolled out and evaluated across more than 15 clinical sites in the Netherlands, Spain, Slovenia, Italy, Greece, United Kingdom and Austria, covering a wide variety of healthcare settings. METHODS: We evaluated the CDS implementation process through qualitative and quantitative process indicators. Quantitative indicators included statistics on generated PGx reports, median time from sampled upload until report delivery and statistics on report retrievals via the mobile-based CDS tool. Adoption of different CDS tools, uptake and usability were further investigated through a user survey among healthcare providers. Results of a risk assessment conducted prior to the implementation process were retrospectively analyzed and compared to actual encountered difficulties and their impact. RESULTS: As of March 2021, personalized PGx reports were produced from 6884 genotyped samples with a median delivery time of twenty minutes. Out of 131 invited healthcare providers, 65 completed the questionnaire (response rate: 49.6%). Overall satisfaction rates with the different CDS tools varied between 63.6% and 85.2% per tool. Delays in implementation were caused by challenges including institutional factors and complexities in the development of required tools and reference data resources, such as genotype-phenotype mappings. CONCLUSIONS: We demonstrated the feasibility of implementing a standardized PGx decision support solution in a multinational, multi-language and multi-center setting. Remaining challenges for future wide-scale roll-out include the harmonization of existing PGx information in guidelines and drug labels, the need for strategies to lower the barrier of PGx CDS adoption for healthcare institutions and providers, and easier compliance with regulatory and legal frameworks.

Best Evidence-Based Dosing Recommendations for Dexmedetomidine for Premedication and Procedural Sedation in Pediatrics: Outcome of a Risk-Benefit Analysis By the Dutch Pediatric Formulary.

BACKGROUND: Dexmedetomidine is currently off-label for use in pediatric clinical care worldwide. Nevertheless, it is frequently prescribed to pediatric patients as premedication prior to induction of anesthesia or for procedural sedation. There is ample literature on the pharmacokinetics, efficacy and safety of dexmedetomidine in this vulnerable patient population, but there is a general lack of consensus on dosing. In this project, we aimed to use the standardized workflow of the Dutch Pediatric Formulary to establish best evidence-based pediatric dosing guidelines for dexmedetomidine as premedication and for procedural sedation. METHOD: The available literature on dexmedetomidine in pediatrics was reviewed in order to address the following three questions: (1) What is the right dose? (2) What is known about efficacy? (3) What is known about safety? Relevant literature was compiled into a risk-benefit analysis document. A team of clinical experts critically appraised the analysis and the proposed dosing recommendations. RESULTS: Dexmedetomidine is most commonly administered via the intravenous or intranasal route. Clearance is age dependent, warranting higher doses in infants to reach similar exposure as in adults. Dexmedetomidine use results in satisfactory sedation at parent separation, adequate sedation and a favorable recovery profile. The safety profile is good and comparable to adults, with dose-related hemodynamic effects. CONCLUSION: Following the structured approach of the Dutch Pediatric Formulary, best evidence-based dosing recommendations were proposed for dexmedetomidine, used as premedication prior to induction of anesthesia (intranasal dose) and for procedural sedation (intranasal and intravenous dose) in pediatric patients.

Implementing pharmacogenomics decision support across seven European countries: The Ubiquitous Pharmacogenomics (U-PGx) project.

Clinical pharmacogenomics (PGx) has the potential to make pharmacotherapy safer and more effective by utilizing genetic patient data for drug dosing and selection. However, widespread adoption of PGx depends on its successful integration into routine clinical care through clinical decision support tools, which is often hampered by insufficient or fragmented infrastructures. This paper describes the setup and implementation of a unique multimodal, multilingual clinical decision support intervention consisting of digital, paper-, and mobile-based tools that are deployed across implementation sites in seven European countries participating in the Ubiquitous PGx (U-PGx) project.

Prescribing with indication: uptake of regulations in current practice and patients opinions in the Netherlands.

BACKGROUND: Since January 2012 the Dutch Medicines Act has been changed to enable medication monitoring and counselling for individual patients. Prescribers of medicines are now obliged to record the indication on the prescription of medicines mentioned in this law. OBJECTIVE: To assess patients' opinion about recording of the indication on prescription and to explore the uptake of alterations in the medicines act in clinical practice. METHODS: The study was conducted in a sample of 57 community pharmacies belonging to the Utrecht Pharmacy Practice Network for Education and Research. In total, 528 patients were interviewed in these pharmacies and automated dispensing records were obtained from 22 community pharmacies to check prescriptions for linking of diagnosis codes (indications). RESULTS: For 12.5 % of the prescriptions that required notification of the indication, a diagnosis code was mentioned. For all other medicines, 15.1 % of the prescriptions were provided with diagnosis codes. There was large variation between different drugs. Only 11.7 % of the interviewed patients were familiar with the law. The majority of patients (91.1 %) had no objections with mentioning the indication for use on the prescription. CONCLUSION: Indications are insufficiently mentioned on prescriptions while the majority of patients are generally positive about the law.