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The Paediatric Use Marketing Authorisation (PUMA) was introduced in the European Union to incentivise the development of off-patent medicines in children. However, there is limited data on the accessibility of PUMA products at the healthcare provider level. This study aimed to identify factors affecting real-world accessibility to PUMA products in the United Kingdom (UK). Inductive thematic analyses of the archives of the Neonatal and Paediatric Pharmacy Group (NPPG) online forum were conducted. A web-based survey was also distributed to NPPG members in September 2022 regarding the availability of PUMA products in their organisations. Thematic analysis generated five themes: authorisation, availability, affordability, appropriateness and acceptability. Restricted scope of the product’s marketing authorisation, market access variation, higher cost of PUMA products, product appropriateness and patient acceptability were reasons for continued off-label use and use of unlicensed products in clinical practice. Conclusion : Despite targeted legislative efforts to bring off-label uses in children into authorised use, this study provides evidence that authorisation alone does not equate to market availability, which in turn does not guarantee patient access. The study findings also suggest that cost pressure drives local procurement decisions and overshadows the long-standing problems associated with off-label use and manipulation of medicines in children. What is already known about this subject •  The Paediatric Use Marketing Authorisation (PUMA) was introduced in the European Union (applied to the UK at the time) to incentivise the development of off-patient medicines exclusively for use in the paediatric population. •  It is widely acknowledged that the PUMA concept has not achieved its intended goal, as evidenced by the few products authorised through this route. What this study adds •  This study shows inequalities in children's access to PUMA products in the UK. •  Determinants impeding patient access to child-appropriate paediatric medicines can be categorised into five dimensions: authorisation, availability, affordability, appropriateness, and acceptability.

Doctors in England’s NHS have been left seemingly unable to prescribe a cheap, safe, and effective drug despite its flourishing use elsewhere in Europe and the US. In the first of a two part investigation Deborah Cohen examines which agencies are responsible, whether commissioners and prescribers actually have more freedom to use intravitreal bevacizumab than might at first seem to be the case, and whether the UK’s drug marketing authorisation system really acts in the best interests of public health

Purpose Prevalence data on the off-label use (OLU) of anticancer drugs are limited despite OLU being controversial for medical, pharmaco-economic, and ethical reasons. We therefore quantified and characterized the OLU of anticancer drugs and compared OLU based on the national drug label with international treatment recommendations. Methods We prospectively collected data on patients receiving systemic anticancer therapy between October and December 2012 at hospitals affiliated with the Eastern Switzerland Oncology Network. Individual data on patient characteristics, tumor disease, and systemic treatment were collected, and each individual treatment was compared with the national drug label and international treatment guidelines. Results A total of 985 consecutive patients receiving 1,737 anticancer drug treatments were included in the study. Overall, 32.4 % of all patients received at least one off-label drug, corresponding to 27.2 % of all anticancer drugs administered. Major reasons for OLU were the lack of approval for the specific disease entity (15.7 %) and modified application of the anticancer drug (10 %). OLU that was unsupported by the current European Society for Medical Oncology (ESMO) treatment recommendations was rare (6.6 %) but higher for bevacizumab (29.6 %) due to its use in treating advanced ovarian cancer beyond the second-line setting and advanced breast cancer beyond the first-line setting and for lenalidomide (22.6 %) due to its use in treating Non-Hodgkin lymphoma. Conclusions Based on data collected on our patient cohort, OLU of anticancer drugs in a European clinical setting applies to one-third of all cancer patients. ESMO-unsupported use of chemotherapies or molecularly-targeted drugs is rare, opposing concerns that the off-label use of newer anticancer drugs is a substantial clinical problem.

National Immunization Technical Advisory Groups (NITAGs) are crucial for enhancing vaccine use in immunization programs, particularly through off-label recommendations. This study sought to assess the adoption and trends of off-label vaccine recommendations made by NITAGs across low-, middle-, and high-income countries since the COVID-19 pandemic. An online survey was distributed to NITAG representatives in World Health Organization (WHO) member states, asking questions related to off-label use of vaccines including policies, procedures, legislation, and regulations for NITAGs in participants' countries. Respondents across all six WHO regions were invited to participate. Respondents from 76 countries participated in the survey (55 %) were NITAG representatives, and 45 % were immunization program managers or from the NITAG secretariat). Most respondents 52 (68 %) reported their NITAG makes off-label recommendations, 18 (24 %) indicated their NITAG does not make off-label recommendations, and 6 (8 %) were unsure of their NITAG's role. There was a noticeable shift relating to off-label vaccine recommendations observed pre, during, and post-pandemic period. Prior to 2022, 25 (48 %) respondents indicated their country recommended off-label vaccines, 11 (21 %) specified off-label recommendations were limited to emergencies as temporary or conditional expansions, and 6 (12 %) were unsure. After 2022, 30 (58 %) respondents indicated their country recommended off-label vaccines, 4 (8 %) specified off-label recommendations were limited to emergencies as temporary or conditional expansions, 18 (35 %) selected no, and 0 (0%) were unsure. While most countries make off-label recommendations, few (15 %) have policies and procedures to support implementation. Although WHO broadly provides guidance on the mandate and core functions of NITAGs, globally, they have differing mandates and operational capacities related to off-label vaccine use. These findings suggest the need for increased awareness of off-label vaccine recommendations and strengthened dialogue around implementation of off-label recommendations.

Botulinum toxin (BoNT) is a neurotoxin produced by the Clostridium botulinum bacteria. Among seven different isoforms, only BoNT-A and BoNT-B are commercially used. Currently, botulinum toxin has been indicated by the U.S. Food and Drug Administration in several disorders, among others: chronic migraine, hyperhidrosis, urinary incontinence from detrusor overactivity, or cosmetics. However, there are numerous promising reports based on off-label BTX usage, indicating its potential effectiveness in other diseases, which remains unknown to many. Among them, dermatological conditions, such as rosacea, annal fissure, Raynaud phenomenon, hypertrophic scars and keloids, and also hidradenitis suppurativa, are currently being investigated. This article aims to provide a comprehensive update on the off-label use of botulinum toxin in dermatology, based on an analysis and summary of the published literature.

Background The \"Law on Doctors of the People's Republic of China,\" which was officially implemented on March 1, 2022, emphasizes the requirements for rational drug use and the necessity for appropriate management of off-label drug use. The safety and ethical considerations related to off-label drug use are different in children than in adults. There is so far no management guideline for pediatric off-label use of drugs in China, and the applicability of foreign guidelines is limited. Establishing a localized evidence-based management guideline for pediatric off-label use of drugs to support the national legislation and clinical practice is of critical importance. Methods We established a guideline working group, including experts from a broad range of disciplines and developed recommendations following the guidance of the World Health Organization Handbook and the Chinese Medical Association. The following themes were identified by questionnaires and expert interviews to be of great concern in the management of off-label drug use in children: general principles and characteristics of management of pediatric off-label drug use; establishment of expert committees; evidence evaluation; risk–benefit assessment; informed consent; monitoring and assessment of the risk; and monitoring and patient education. Two rounds of Delphi surveys were organized to determine the final recommendations of this guideline. We graded the recommendations based on the body of evidence, referring to the evaluation tool of the Evidence-based management (EBMgt) and the Oxford Center for Evidence-Based Medicine: Level of Evidence (March 2009). Results We developed the first guideline for the management of pediatric off-label use of drugs in China. Conclusions The guideline is to offer guidance for pediatricians, pharmacists, medical managers, policymakers, and primary care physicians on how to manage off-label drug use in pediatrics and to provide recommendations for Chinese healthcare policy in the future.

Cancer genomic medicine using next‐generation sequencers has been developing. However, the number of patients who could receive genomically matched therapy is limited because off‐label use or patient‐oriented compassionate use was not permitted under National Health Insurance in Japan. To improve patient drug accessibility, we initiated a biomarker‐based basket‐type clinical trial (NCCH1901) in October 2019 under patient‐proposed healthcare services. We listed the drugs that had high medical needs but were not covered by National Healthcare Insurance. Then we included these drugs before patient proposal so that they could access off‐label drugs soon after they had the results of CGP tests. All drugs were provided free of charge by pharmaceutical companies. The objective was to administer off‐label drugs and to collect efficacy and safety data for these drugs. The primary endpoint was the response rate based on the best overall response for up to 16 weeks. As of January 31, 2022, we included 18 drug cohorts and 295 patients were treated in this study. The most common cancer was brain tumor, followed by carcinoma of endocrine organs and colorectal cancer. BRAF mutations and ERBB2 amplifications were the frequent genomic abnormalities to be enrolled. This study was one way to access off‐label drugs, and contributed significantly to providing treatment opportunities for patients in Japan. This is a progress report of a biomarker‐based basket‐type clinical trial (NCCH1901). About 300 patients were treated in this trial and patients with BRAF mutations and ERBB2 amplifications were the frequent genomic changes to be enrolled. This trial has contributed to increasing treatment opportunities for patients in Japan.

PurposeThe purpose of this international study was to investigate prescribing practices of dexmedetomidine by paediatric anaesthesiologists.MethodsWe performed an online survey on the prescription rate of dexmedetomidine, route of administration and dosage, adverse drug reactions, education on the drug and overall experience. Members of specialist paediatric anaesthesia societies of Europe (ESPA), New Zealand and Australia (SPANZA), Great Britain and Ireland (APAGBI) and the USA (SPA) were consulted. Responses were collected in July and August 2019.ResultsData from 791 responders (17% of 5171 invitees) were included in the analyses. Dexmedetomidine was prescribed by 70% of the respondents (ESPA 53%; SPANZA 69%; APAGBI 34% and SPA 96%), mostly for procedural sedation (68%), premedication (46%) and/or ICU sedation (46%). Seventy-three percent had access to local or national protocols, although lack of education was the main reason cited by 26% of the respondents not to prescribe dexmedetomidine. The main difference in dexmedetomidine use concerned the age of patients (SPA primarily < 1 year, others primarily > 1 year). The dosage varied widely ranging from 0.2–5 μg kg−1 for nasal premedication, 0.2–8 μg kg−1 for nasal procedural sedation and 0–4 μg kg−1 intravenously as adjuvant for anaesthesia. Only ESPA members (61%) had noted an adverse drug reaction, namely bradycardia.ConclusionThe majority of anaesthesiologists use dexmedetomidine in paediatrics for premedication, procedural sedation, ICU sedation and anaesthesia, despite the off-label use and sparse evidence. The large intercontinental differences in prescribing dexmedetomidine call for consensus and worldwide education on the optimal use in paediatric practice.

BackgroundPrescription drug labeling is an authoritative source of information that guides the safe and effective use of approved medications. In many instances, however, labeling may fail to be updated as new information about drug efficacy emerges in the postmarket setting. When labeling becomes outdated, it loses its value for prescribers and undermines a core part of the FDA’s mission to communicate accurate and reliable information to patients and physicians.MethodsWe compared the number of drug uses indicated on product labels to the number of uses contained in a leading drug compendium for 43 cancer drugs approved between 1999 and 2011. We defined a “well-accepted off-label use” of a drug as one that was not approved by the FDA and received a category 1 or 2A evidence grade.ResultsOf the 43 drugs reviewed in this study, 34 (79%) had at least one well-accepted off-label use. In total, 253 off-label uses were identified; 91% were well accepted, and 65% were in cancer types not previously represented on labeling. Off-patent drugs had more well-accepted off-label uses than brand-name drugs, on average (mean 13.7 vs 3.8, P =.018).ConclusionsThe labeling for many cancer drugs, particularly for older drugs, is outdated. Although FDA-approved labeling can never be fully aligned with real-world clinical practice, steps should be taken to better align the two when high-quality data exist. Such steps, if taken, will assist patients and prescribers in discerning which uses of drugs are supported by the highest quality evidence.