Off-label Drug Use Research Articles

Situation analysis of off-label drug use in China

To introduce current literature reporting situations of the off-label drug use(OLDU) by analyzing relevant literatures published in China, this study comprehensively focused on literatures about OLDU in China in seven Chinese and English databases, then extracted and analyzed the data by different literature types. A total of 667 papers were analyzed. The number of literatures about OLDU data analyzed in hospitals was 325, and the number of clinical studies relating to OLDU was 329, in which case series and case reports were the majority(69.91%). In addition, there were 13 expert consensuses of OLDU and another 56 studies about drug use based on the real-world data characteristics and influencing factors. The number of OLDU data studies has increased year by year. Based on the existing studies, there were more western medicine reports than traditional Chinese medicines, and OLDU types were mainly for over-dosage use. The literatures from OLDU data in hospital were mostly limited to one or several tertiary hospitals in a certain area, and the OLDU types were not uniform. Clinical studies were mainly clinical control trials and case series/reports, but with contradictory reporting results. There were fewer OLDU consensus, and the recommended classification was not uniform. The characteristics and analysis of influencing factors of drug using data in real-world focused on traditional Chinese medicine injections, and the results were not the same. In the future, we shall pay more attention to and strengthen reporting and analysis of OLDU, define study objectives, and unify the content and reporting standards, so as to promote the integrated utilization of OLDU data and reflect real situations in our country.

Use of unapproved or off-label drugs in Japan for the treatment of graft-versus-host disease and post-transplant viral infection.

Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.

Off-Label Drug Use in Pediatric Out-Patient Care: A Multi-Center Observational Study

Prescribing a drug for a child is not an easy task and requires using the best available evidence as a guide, especially when a drug is used off-label. The practice of prescribing a drug for off-label use is fairly widespread worldwide. The FDA does not regulate prescribing patterns or practices of individual practitioners and, therefore, allows off-label use. The main objective of this study is to evaluate off-label prescribing among the pediatric population in the Kingdom of Saudi Arabia (KSA). This is a retrospective, simple random selection observational study of children (≤15 years) who visited pediatric clinics and had at least 1 drug prescribed over a 12-month period (January to December 2018). A total of 865 drugs (mean 1 and SD 0.24) were prescribed to 326 children. Off-label was identified in 39.4% of the drugs with a frequency of 512 (as 1 drug may belong to more than 1 off-label category). The most common reason for off-label prescribing was related to doses that were "higher or lower than the recommended use" (48.6%), and the most frequently identified drug class prescribed for off-label use was anti-infective drugs for systemic use (39.9%). The percentage of off-label drug use was found to be higher in girls and in the age group of 1 month to 2 years (P = .001) for both variables. In addition, a significant association was found between off label drug use and the total number of drugs prescribed, P < .001. The findings of this study showed a high incidence of off-label prescribing mainly related to dosing and indication. The results of this observational study support the need to establish a unified national pediatric dosing formulary guide to ensure safe drug use in pediatrics.

Stosowanie leków poza wskazaniami — przesłanki oraz refundacja

Off-label use of drugs is one of the most important elements of the work of doctors and, unfortunately, it still raises a great deal of controversy and doubt. This is because of the lack of explicit, detailed legal regulations on this. On the one hand, physicians should follow the dosage regimen and indications for use specified in the Summary of Product Characteristics (SPC), while on the other hand, for some patients, in particular regarding paediatrics and oncology, there may be a lack of therapy that would be characterized for such use as in the SPC. When prescribing off-label therapy, doctors must primarily be guided by current medical knowledge and due diligence. Despite the lack of legal regulations, several criteria can be distinguished that justify the off-label use of drugs, e.g. the need to save the patient’s life or the unsatisfactory result of the therapy recommended to date. Before prescribing a particular drug, the patient should be informed, for instance, about the risk of the unregistered use of the medicine. Only after the patient has been properly informed can informed consent for treatment be received. The doctor’s failure to satisfy these obligations can expose him to civil, criminal or disciplinary liability. Polish law also allows for therapy conducted in indications other than those arising from the SPC to be publicly financed. Although this requires compliance with the statutory requirements, this often constitutes the patient’s key opportunity to actually undergo treatment.

Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group.

Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers. Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.

Prevalence of Off-label Drug Use in Neonatal Intensive Care Unit of a Tertiary Care Teaching Hospital in India

Prevalence of Off-label Drug Use in Neonatal Intensive Care Unit of a Tertiary Care Teaching Hospital in India

Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity.

Molecular tumor heterogeneity may have important implications for the efficacy of targeted therapies in metastatic cancers. Inter-metastatic heterogeneity of sensitivity to anticancer agents has not been well explored in colorectal cancer. We established a platform for ex vivo pharmacogenomic profiling of patient-derived organoids (PDO) from resected colorectal cancer liver metastases. Drug sensitivity testing (n = 40 clinically relevant agents) and gene expression profiling were performed on 39 metastases from 22 patients. Three drug-response clusters were identified among the colorectal cancer metastases, based primarily on sensitivities to EGFR and/or MDM2 inhibition, and corresponding with RAS mutations and TP53 activity. Potentially effective therapies, including off-label use of drugs approved for other cancer types, could be nominated for eighteen patients (82%). Antimetabolites and targeted agents lacking a decisive genomic marker had stronger differential activity than most approved chemotherapies. We found limited intra-patient drug sensitivity heterogeneity between PDOs from multiple (2-5) liver metastases from each of ten patients. This was recapitulated at the gene expression level, with a highly proportional degree of transcriptomic and pharmacological variation. One PDO with a multi-drug resistance profile, including resistance to EGFR inhibition in a RAS-mutant background, showed sensitivity to MEK plus mTOR/AKT inhibition, corresponding with low-level PTEN expression. Intra-patient inter-metastatic pharmacological heterogeneity was not pronounced and ex vivo drug screening may identify novel treatment options for metastatic colorectal cancer. Variation in drug sensitivities was reflected at the transcriptomic level, suggesting potential to develop gene expression-based predictive signatures to guide experimental therapies.

English

Off-label prescribing is very common among physicians, particularly among psychiatrists and there is limited information regarding the extent of the unapproved drug use in Makkah city. The objective of this study was to assess the prevalence of off-label indications for antidepressant, antipsychotic and antiepileptic and the strength of evidence supporting use of the prescribed drug for the respective indication. A case sectional study was conducted on 15,955 prescriptions from 1 October 2018 to 6 January 2019 based on patient medication records obtained from an electronic medical record (EMRs) - health information system (HIS) from King Abdulaziz Hospital in Makkah city, Saudi Arabia. Two official databases (Micromedex and Lexicomp) were used to evaluate dual primary outcomes the determination off-label and on-label prescriptions and the level of evidence supporting the off-label indications. It showed that in 3 months there were 15,955 prescriptions concerning antipsychotics, antidepressants and antiepileptics drugs were issued to 5292 patients. Out of total 15,955 prescriptions, about 2218 (13.9%) prescriptions were off-label prescriptions for 29 drugs. The most frequently prescribed by class, were antidepressants 1025 (46.3%) followed by antipsychotics 1005 (45.3%) then antiepileptics 188 (8.5%). Off-label drugs use is common in psychiatric department and when physicians prescribed antidepressants, antipsychotics and antiepileptics for off-label indication, most of these prescribed indications were not supported by strong scientific evidences. The risks and benefits of off-label use should be carefully weighed up prior to prescribing these agents. Key words: Off-label, antipsychotics, antiepileptics, psychiatric, case sectional study.

Bioética em tempos de pandemia: Testes clínicos com Cloroquina para tratamento de COVID-19

Defendemos a necessidade de que se atue com rigor ético durante a pandemia do novo coronavírus e que não se afrouxem os padrões científicos e normativos nas pesquisas sobre possíveis medicamentos, em especial a Cloroquina, para a COVID-19. Argumentamos que, excepcionalmente, seria justificado pular algumas etapas na realização de testes clínicos ou tratamentos experimentais, mas que é inadequado fazer um uso indiscriminado de medicamentos off label para tratar pacientes enquanto os resultados das pesquisas não forem publicados em veículos de comprovada reputação científica. Para sustentar essa posição, aplicamos princípios bioéticos e da ética médica. Defendemos que políticas públicas para o uso de Cloroquina durante a pandemia não devem ser implementadas até que sejam divulgados os resultados das pesquisas realizadas pela “Coalizão COVID Brasil” e pela Solidarity da OMS (Organização Mundial da Saúde).&#x0D;

Colchicine in COVID-19: an Old Drug, New Use.

Purpose of ReviewCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, is a pandemic causing havoc globally. Currently, there are no Food and Drug Administration (FDA)-approved drugs to treat COVID-19. In the absence of effective treatment, off-label drug use, in lieu of evidence from published randomized, double-blind, placebo-controlled clinical trials, is common in COVID-19. Although it is vital to treat affected patients with antiviral drugs, there is a knowledge gap regarding the use of anti-inflammatory drugs in these patients.Recent FindingsColchicine trials to combat inflammation in COVID-19 patients have not received much attention. We await the results of ongoing colchicine randomized controlled trials in COVID-19, evaluating colchicine’s efficacy in treating COVID-19.SummaryThis review gives a spotlight on colchicine’s anti-inflammatory and antiviral properties and why colchicine may help fight COVID-19. This review summarizes colchicine’s mechanism of action via the tubulin-colchicine complex. Furthermore, it discussed how colchicine interferes with several inflammatory pathways, including inhibition of neutrophil chemotaxis, adhesion, and mobilization; disruption of superoxide production, inflammasome inhibition, and tumor necrosis factor reduction; and its possible antiviral properties. In addition, colchicine dosing and pharmacokinetics, as well as drug interactions and how they relate to ongoing, colchicine in COVID-19 clinical trials, are examined.

On-Label and Off-Label Clinical Studies of FDA–Approved Ophthalmic Therapeutics

The U.S. Food and Drug Administration (FDA) regulates the commercial availability of novel therapeutics but does not restrict physician prescribing. Although the FDA approves a product for clinical use based on a risk–benefit assessment for a specific indication, physicians may legally prescribe approved agents for unapproved indications (i.e., off-label). Within ophthalmology, the use of previously approved therapeutics for off-label indications is common, including intravitreal antibiotics for endophthalmitis and bevacizumab for neovascular age-related macular degeneration. However, little is understood about the accumulation of evidence to support use of novel therapeutics for unapproved indications, which has implications for current practice and adoption of approved drugs for new uses. Prior work has demonstrated associations between off-label use and adverse events, suggesting potential gaps in evidence supporting safety. 1 Eguale T. Buckeridge D.L. Verma A. et al. Association of off-label drug use and adverse drug events in an adult population. JAMA Intern Med. 2016; 176: 55-63 Crossref PubMed Scopus (143) Google Scholar To better elucidate the clinical evidence base supporting off-label use, we characterized the frequency, accrual and quality of on-label and off-label prospective studies of novel FDA-approved ophthalmic therapeutics.

Common Drugs with Effective Off-Label Uses

The term off-label drug use (OLDU) is utilized broadly in the medical literature. It is a polarizing term since it may be related to incredible advantage or harm to patients. OLDU is defined as drug uses that not included in the indications or dosage regimens listed in the drug labeling. The main issue with off-label use is that there is insufficient information supports the use of the drug so this review aims to give brief information about some common drugs with effective and useful off-label uses based on scientific study and to encourage the researcher to provide sufficient information for the physician and health care providers about off-label uses to decrease the risk of harm to the patients. There are many drugs with various off-label uses that play an important role clinically such as using atorvastatin in chronic heart failure (CHF) due to its pleiotropic action also it can show a significant reduction in the frequency of hospitalization due to CHF exacerbation. However, that make off-label uses an important is several diseases do not have approved drugs, partly because the diseases are rare or conducting clinical trials and marketing the drug for such diseases may not be gainful.

Risk Minimization Measures in Off-Label Drug Use: A Survey of Community Pharmacists in Malaysia.

While off-label drug use is common and sometimes necessary, it also presents considerable risks. Therefore, measures intended to prevent or reduce the potential exposure to off-label risks have been recommended. However, little is known about community pharmacists' beliefs regarding these measures in Malaysia. This study examined community pharmacists' beliefs towards risk minimization measures in off-label drug use in Malaysia and assessed the relationship between perceived risk of off-label drug use and beliefs towards risk minimization measures. A cross-sectional survey was conducted among 154 pharmacists practicing in randomly selected community pharmacies in Kuala Lumpur and the State of Selangor, Malaysia. The majority agreed or strongly agreed that adverse drug events from the off-label drug should be reported to the regulatory authority (90.9%) and the off-label drug should only be used when the benefit outweighs potential risks (88.3%). Less than half (48.1%) agreed or strongly agreed that written informed consent should be obtained before dispensing off-label drugs and a majority (63.7%) agreed or strongly agreed that the informed consent process will be burdensome to healthcare professionals. Beliefs towards risk minimization measures were significantly associated with perceived risk of off-label drug use regarding efficacy (p = 0. 033), safety (p = 0.001), adverse drug rection (p = 0.001) and medication errors (p = 0.002). The community pharmacists have positive beliefs towards most of the risk minimization measures. However, beliefs towards written informed consent requirements are not encouraging. Enhancing risk perception may help influence positive beliefs towards risk minimization measures.

Rationale and Design of ORCHID: A Randomized Placebo-controlled Clinical Trial of Hydroxychloroquine for Adults Hospitalized with COVID-19.

The ORCHID (Outcomes Related to COVID-19 treated with Hydroxychloroquine among In-patients with symptomatic Disease) trial is a multicenter, blinded, randomized trial of hydroxychloroquine versus placebo for the treatment of adults hospitalized with coronavirus disease (COVID-19). This document provides the rationale and background for the trial and highlights key design features. We discuss five novel challenges to the design and conduct of a large, multicenter, randomized trial during a pandemic, including 1) widespread, off-label use of the study drug before the availability of safety and efficacy data; 2) the need to adapt traditional procedures for documentation of informed consent during an infectious pandemic; 3) developing a flexible and robust Bayesian analysis incorporating significant uncertainty about the disease, outcomes, and treatment; 4) obtaining indistinguishable drug and placebo without delaying enrollment; and 5) rapidly obtaining administrative and regulatory approvals. Our goals in describing how the ORCHID trial progressed from study conception to enrollment of the first patient in 15 days are to inform the development of other high-quality, multicenter trials targeting COVID-19. We describe lessons learned to improve the efficiency of future clinical trials, particularly in the setting of pandemics. The ORCHID trial will provide high-quality, clinically relevant data on the safety and efficacy of hydroxychloroquine for the treatment of COVID-19 among hospitalized adults.Clinical trial registered with www.clinicaltrials.gov (NCT04332991).

A review on the treatment and control of ectoparasite infestations in equids.

Ectoparasites infestations are a growing concern to horse owners and equine veterinarians alike. Ectoparasites cause significant health and welfare issues and can potentially can serve as vectors for a variety of pathogens. The prevalence of ectoparasites increases around the world, and especially in horses information on the successful prevention and treatment of ectoparasite infestations in scarce and in many instances anecdotal. This poses a challenge to the equine veterinarian and off-label use of drugs can lead to detrimental effects in horses. In this review we describe the current available evidence for the prevention and treatment of ectoparasite infestations in horses. Only a very limited number of products is approved for the use in horses and fortunately many of the other products that are used in an off-label manner appear to be safe in horses. Future research in this area should aim at providing PK/PD modelling data to assure appropriate and safe dose regimen to prevent and treat ectoparasite infestations in horses.

COVID-19 and off label use of drugs: an ethical viewpoint

BackgroundThe COVID-19 outbreak is rapidly spread over the world and kills infected patients. There is no proven medication for its treatment, so, all of the medications used for treatment are considered to be off-label. Off-label uses are not under regulation in the outbreak because there is no specific regulation for this condition.ObjectivesIn this short communication we aim at describing two ways of off-label use as clinical practice or investigational use. Further, we will describe the third way of off-label use, we named it pseudo-research and then we will state the most possible ethical challenges of off-label use for better perceptions and responsibility.ResultsThe WHO considers off-label uses as country-specific. All international regulatory bodies consider off-label prescription as the physician’s responsibility and legal by necessitating some requirements. There is no international guideline for regulating investigational off-label uses as clinical practice.ConclusionThere are different types of approaches, none of them is comprehensive and conclusive. Furthermore, respecting the four ethical principles necessitates codification and strict regulation of off-label uses either as clinical practice or investigational. Besides, compilation of a special guideline based on ethical principles especially non-maleficence and autonomy for investigational off-label uses in disasters is highly recommended.

Safety of Anticancer Agents Used in Children: A Focus on Their Off-Label Use Through Data From the Spontaneous Reporting System.

BackgroundAmong factors influencing the higher risk of developing unknown or rare adverse drug reactions (ADRs) among children and adolescents, there is the frequent off-label use of drugs that seems to be very common in pediatric oncological patients. Our study aim to collect and evaluate data on the safety profile of antineoplastic drugs and their off-label use in the pediatrics population using real life data.MethodsWe retrieved Individual Case Safety Reports (ICSRs) with an anticancer agent as suspected drug among those reported through the Campania spontaneous reporting system from 1 January 2013 to 30 September 2019. We classified ICSRs into four off-label categories: “age,” “route of administration,” “weight,” and “therapeutic indication.” We defined an ICSR as an off-label case if it met at least one of the aforementioned categories for at least one of the reported suspected antineoplastic drugs.ResultsA total of 18 ICSRs (7.6%) out of 236 were classified as off-label cases. The median age of patients was 13 years (interquartile range, IQR: 6–16), with 94.4% of cases occurring in male patients. In the classification of the off-label category, 16 ICSRs were categorized according to the “therapeutic indication” and two for the “age.” No case was categorized for the off-label categories “route of administration” and “weight.” The two off-label cases categorized as “age” were both related to the use of brentuximab vedotin for Hodgkin’s lymphoma in patients aged 16 years. Twenty-nine ADRs (1.6 suspected adverse drug reactions per ICSR) were identified among off-label cases. Among ADRs, those reported more than one were diarrhea (N = 3), neutropenia (N = 3), nausea (N = 2), pyrexia (N = 2), and vomit (N = 2).ConclusionsOur findings showed a low number of ICSRs classified as off-label. The majority of off-label ICSRs were categorized for the “therapeutic indication.” This low number of off-label ICSRs might be largely due to the underreporting phenomenon, which is a major limit in pharmacovigilance. Therefore, we believe that spreading pharmacovigilance knowledge and awareness might improve this aspect.

PIH50 FACTORS AND PATTERNS OF OFF-LABEL PRESCRIBING IN CHILDREN WITH ATTENTION DEFICIT HYPERACTIVITY DISORDER (ADHD) IN US. OUTPATIENT SETTINGS OVER A TEN-YEAR PERIOD

Attention-deficit/hyperactivity disorder (ADHD) affected approximately 4% to 12% of children worldwide. Although numerous ADHD medications approved by the FDA, off-label prescribing is quite common. However, the risk and benefit of off-label drug use remain controversial especially for children. The study aimed to investigate the factors and patterns of off label prescribing in Children with ADHD.

Importance of Inclusion of Pregnant and Breastfeeding Women in COVID-19 Therapeutic Trials.

Investigators are employing unprecedented innovation in the design of clinical trials to rapidly and rigorously assess potentially promising therapies for coronavirus disease 2019 (COVID-19); this is in stark contrast to the continued near-universal regressive practice of exclusion of pregnant and breastfeeding women from these trials. The few trials that allow their inclusion focus on postexposure prophylaxis or outpatient treatment of milder disease, limiting the options available to pregnant women with severe COVID-19 to compassionate use of remdesivir, or off-label drug use of hydroxychloroquine or other therapies. These restrictions were put in place despite experience with these drugs in pregnant women. In this Viewpoint, we call attention to the need and urgency to engage pregnant women in COVID-19 treatment trials now in order to develop data-driven recommendations regarding the risks and benefits of therapies in this unique but not uncommon population.

Protected Health Information filter (Philter): accurately and securely de-identifying free-text clinical notes

There is a great and growing need to ascertain what exactly is the state of a patient, in terms of disease progression, actual care practices, pathology, adverse events, and much more, beyond the paucity of data available in structured medical record data. Ascertaining these harder-to-reach data elements is now critical for the accurate phenotyping of complex traits, detection of adverse outcomes, efficacy of off-label drug use, and longitudinal patient surveillance. Clinical notes often contain the most detailed and relevant digital information about individual patients, the nuances of their diseases, the treatment strategies selected by physicians, and the resulting outcomes. However, notes remain largely unused for research because they contain Protected Health Information (PHI), which is synonymous with individually identifying data. Previous clinical note de-identification approaches have been rigid and still too inaccurate to see any substantial real-world use, primarily because they have been trained with too small medical text corpora. To build a new de-identification tool, we created the largest manually annotated clinical note corpus for PHI and develop a customizable open-source de-identification software called Philter (“Protected Health Information filter”). Here we describe the design and evaluation of Philter, and show how it offers substantial real-world improvements over prior methods.