Off-Label Prescription of COVID-19 Vaccines in Children: Clinical, Ethical, and Legal Issues.

The US Food and Drug Administration (FDA) approval of the biologics license application for the Pfizer-BioNTech coronavirus disease 2019 vaccine (Comirnaty) on August 23, 2021, opened the door to the off-label vaccination of children younger than the age range currently covered by either the biologics license application (16 years old and older) or the emergency use authorization (12 to 15 years old). Although prescribing medications at doses, for conditions, or in populations other than those approved by the FDA is generally legal and is common in pediatrics, the FDA, the Centers for Disease Control and Prevention, and the American Academy of Pediatrics have recommended against off-label prescription of the coronavirus disease 2019 vaccine. Several commentaries consider a case in which parents ask their child's pediatrician to prescribe the vaccine for their 11-year-old with special health care needs before approval or authorization in her age group. The first commentary considers the potential benefits and risks to the patient, as well as to the family, the provider, and society, emphasizing the unknown risks in younger patients and the need for adequate informed consent. The second commentary describes an algorithm and principles for evaluating off-label prescribing and argues that the current benefits of prescribing Comirnaty off label to children <12 do not outweigh the risks. The third commentary addresses ethical and legal issues, ultimately calling on federal agencies to remove legal barriers to making the vaccine available to children in age groups that currently lack authorization.

Webinar RedETSA: uso de emergencia de intervenciones no probadas y fuera de la investigación

El 5 de agosto de 2020, tuvo lugar la 30ma edición del programa de Webinars de RedETSA. La Dra. Carla Sáenz, Asesora Regional en Bioética de la OPS dio una presentación sobre Uso de emergencia de intervenciones no probadas y fuera del ámbito de la investigación: Orientación ética para la pandemia de COVID-19.

Hospital pharmacist challenges in evaluation of scientific evidence and its incorporation to pharmacotherapeutic protocols through therapeutic committees in COVID-19 times.

Type 2 coronavirus pandemics that is plaguing almost all the world has caused  qualitative and quantitative strains in health systems that have had to be responded to. The lack of known vaccines and effective treatments has generated the need to  use drugs with very little evidence for their incorporation into pharmacotherapeutic  protocols agreed by the clinical team. The hospital pharmacist, within the  multidisciplinary team, has been responsible for critically evaluating the alternatives and positioning them in these protocols. Finally, some ethical and legal questions  that should be considered in this scenario are analyzed in this article.

La pandemia por coronavirus tipo 2 que está azotando prácticamente todo el mundo ha provocado en los sistemas sanitarios tensiones cualitativas y cuantitativas a las  que ha habido que dar respuesta. La inexistencia de vacunas y de tratamientos  eficaces conocidos ha generado la necesidad de utilizar fármacos con muy escasa  evidencia para su incorporación en protocolos farmacoterapéuticos consensuados  por el equipo clínico. El farmacéutico de hospital, dentro del equipo multidisciplinar,  ha sido en muchas ocasiones el responsable de evaluar críticamente las alternativas para su posicionamiento en estos protocolos. Se analizan en el presente artículo algunas cuestiones éticas y legales que deben ser consideradas en este  escenario.

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

BACKGROUND: The 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. OBJECTIVES: In 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. RESULTS: The 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. CONCLUSION: There 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.

Balancing evidence and frontline experience in the early phases of the COVID-19 pandemic: current position of the Italian Society of Anti-infective Therapy (SITA) and the Italian Society of Pulmonology (SIP).

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19), which has rapidly become epidemic in Italy and other European countries. The disease spectrum ranges from asymptomatic/mildly symptomatic presentations to acute respiratory failure. At the present time the absolute number of severe cases requiring ventilator support is reaching or even surpassing the intensive care unit bed capacity in the most affected regions and countries. OBJECTIVES: To narratively summarize the available literature on the management of COVID-19 in order to combine current evidence and frontline opinions and to provide balanced answers to pressing clinical questions. SOURCES: Inductive PubMed search for publications relevant to the topic. CONTENT: The available literature and the authors' frontline-based opinion are summarized in brief narrative answers to selected clinical questions, with a conclusive statement provided for each answer. IMPLICATIONS: Many off-label antiviral and anti-inflammatory drugs are currently being administered to patients with COVID-19. Physicians must be aware that, as they are not supported by high-level evidence, these treatments may often be ethically justifiable only in those worsening patients unlikely to improve only with supportive care, and who cannot be enrolled onto randomized clinical trials. Access to well-designed randomized controlled trials should be expanded as much as possible because it is the most secure way to change for the better our approach to COVID-19 patients.

Chloroquine and Hydroxychloroquine for the Prevention or Treatment of COVID-19 in Africa: Caution for Inappropriate Off-label Use in Healthcare Settings.

The novel severe acute respiratory syndrome-coronavirus-2 pandemic has spread to Africa, where nearly all countries have reported laboratory-confirmed cases of novel coronavirus disease (COVID-19). Although there are ongoing clinical trials of repurposed and investigational antiviral and immune-based therapies, there are as yet no scientifically proven, clinically effective pharmacological treatments for COVID-19. Among the repurposed drugs, the commonly used antimalarials chloroquine (CQ) and hydroxychloroquine (HCQ) have become the focus of global scientific, media, and political attention despite a lack of randomized clinical trials supporting their efficacy. Chloroquine has been used worldwide for about 75 years and is listed by the WHO as an essential medicine to treat malaria. Hydroxychloroquine is mainly used as a therapy for autoimmune diseases. However, the efficacy and safety of CQ/HCQ for the treatment of COVID-19 remains to be defined. Indiscriminate promotion and widespread use of CQ/HCQ have led to extensive shortages, self-treatment, and fatal overdoses. Shortages and increased market prices leave all countries vulnerable to substandard and falsified medical products, and safety issues are especially concerning for Africa because of its healthcare system limitations. Much needed in Africa is a cross-continental collaborative network for coordinated production, distribution, and post-marketing surveillance aligned to low-cost distribution of any approved COVID-19 drug; this would ideally be piggybacked on existing global aid efforts. Meanwhile, African countries should strongly consider implementing prescription monitoring schemes to ensure that any off-label CQ/HCQ use is appropriate and beneficial during this pandemic.

High prevalence of off-label and unlicensed paediatric prescribing in a hospital in Indonesia during the period Aug.-Oct. 2014.

BACKGROUND: Data on off-label and unlicensed prescribing in children in Indonesia is limited. The aims of this study were to determine the prevalence of off-label and unlicensed prescribing for paediatric patients in a public hospital, Indonesia. METHOD: A retrospective cross-sectional study of 200 randomly selected paediatric patients admitted to hospital between August and October 2014, collected patient details and all drugs prescribed. Licensed drugs were classified as off-label if there was a non-compliance with the Product Information for age, weight, indication, dose, frequency and route of administration, if there was a contraindication, special precautions or not recommended for children. Unlicensed drugs were those not approved for use in Indonesia. The main outcome was the prevalence of off-label or unlicensed prescribing to infants, children and adolescents and the impact of age group on off-label prescribing. RESULTS: A total of 200 patients received 1961 medicines of which 1807/1961 (92.1%) were licensed and 154/1961 (7.9%) were unlicensed. There were 1403/1961 (71.5%) drugs prescribed off-label. More than half of the total drugs (n = 1066; 54.4%) were administered parenterally. Every patient was prescribed at least one off-label drug. Indication (n = 810; 34.6%) was the most common reason for off-label prescribing. Ranitidine was the most frequent drug prescribed off label. Darplex® (dihydroartemisinin and piperaquine), although manufactured in Indonesia, was unlicensed. There was a significant difference between age group and off-label prescribing in that children were prescribed significantly less off-label drugs (p<0.0003). CONCLUSION: This study revealed a high prevalence of off-label and unlicensed drug use in paediatric patients in this hospital, exposing them to drug treatments or regimens that had not been approved by regulatory authorities. The high incidence of invasive parenteral prescribing is of concern for paediatric patients. Incentives are needed to encourage specific drug evaluation in paediatric populations.

Retos del farmacéutico de hospital en la evaluación de la evidencia científica y su incorporación a los protocolos farmacoterapéuticos a través de las comisiones en tiempos de COVID-19 / Hospital pharmacist challenges in evaluation of scientific evidence and its incorporation to pharmacotherapeutic protocols through therapeutic committees in COVID-19 times

La pandemia por coronavirus tipo 2 que está azotando prácticamente todo el mundo ha provocado en los sistemas sanitarios tensiones cualitativas y cuantitativas a las que ha habido que dar respuesta. La inexistencia de vacunas y de tratamientos eficaces conocidos ha generado la necesidad de utilizar fármacos con muy escasa evidencia para su incorporación en protocolos farmacoterapéuticos consensuados por el equipo clínico. El farmacéutico de hospital, dentro del equipo multidisciplinar, ha sido en muchas ocasiones el responsable de evaluar críticamente las alternativas para su posicionamiento en estos protocolos. Se analizan en el presente artículo algunas cuestiones éticas y legales que deben ser consideradas en este escenario

Type 2 coronavirus pandemics that is plaguing almost all the world has caused qualitative and quantitative strains in health systems that have had to be responded to. The lack of known vaccines and effective treatments has generated the need to use drugs with very little evidence for their incorporation into pharmacotherapeutic protocols agreed by the clinical team. The hospital pharmacist, within the multidisciplinary team, has been responsible for critically evaluating the alternatives and positioning them in these protocols. Finally, some ethical and legal questions that should be considered in this scenario are analyzed in this article

Off-label use of bevacizumab in the treatment of retinal disease: ethical implications.

Anti-vascular endothelial growth factor (anti-VEGF) therapy has revolutionised the treatment of a variety of ophthalmic conditions and has become the first-line therapy for a range of retinal diseases. Bevacizumab, a VEGF inhibitor first approved for the treatment of colorectal cancer, has been shown to be nearly or virtually as effective and safe as other anti-VEGF therapies in the treatment of certain retinal diseases but is not approved or registered by the Food and Drug Administration or European Medicines Agency. While other anti-VEGF options are approved and registered, they are generally more expensive and less accessible. Accordingly, despite its off-label status, bevacizumab is frequently used for a variety of disabling retinal diseases. Indeed, bevacizumab is included on the World Health Organization's list of essential medicines. However, its use in some parts of the world remains restricted due to its off-label status. How, then, should healthcare authorities approach this situation? What are the ethical and societal implications of adhering to a standard and generally effective evaluation and approval system while restricting access to a potentially cost-saving therapy? In countries where its use is not restricted, how should providers approach off-label treatment with bevacizumab? By examining the evidence behind bevacizumab's efficacy and safety and evaluating the individual and societal implications of off-label use and restriction, this paper illustrates the ethical factors providers and policy makers must consider in the off-label use of bevacizumab and ultimately argues for increased access to bevacizumab in the treatment of retinal disease.

Off-label use of ketamine for treatment-resistant depression in clinical practice: European perspective.

Ketamine therapy for treatment-resistant depression in European national health systems may only be considered after attempting all evidence-based antidepressant strategies outlined in clinical guidelines. This paper seeks to explain the ethical, regulatory and procedural framework for the off-label use of ketamine for treatment-resistant depression within a public healthcare system.Declaration of interestNone.

Ethical Reasoning in Prescribing and Monitoring Psychotropic Medications.

Traditionally, schools of nursing teach legal and ethical responsibilities at the pre-licensure and advanced practice levels, with emphasis on legal duties and ethical principles. However, involving clinicians in the process of ethical reasoning, a process similar to the scientific method and nursing process, is much less common. The current article describes and demonstrates the steps in ethical reasoning in common situations faced by prescribing advanced practice RNs and psychiatric-mental health nurses. [Journal of Psychosocial Nursing and Mental Health Services, 57(1), 7-10.].

Bevacizumab for eye diseases - Legal, regulatory, and ethical overview.

Vascular endothelial growth factor (VEGF) inhibitors, ranibizumab, aflibercept, and pegaptanib are approved treatments for certain eye diseases that occurs especially in the elderly. These drugs are mostly inaccessible due to their high cost. Bevacizumab is a VEGF inhibitor, approved for cancer treatment. Being a cheaper alternative, it is extensively used off-label as an intravitreal injection for the treatment of eye diseases. In this article, we have analyzed similarities and differences between bevacizumab and ranibizumab, and potential long-term safety concerns with off-label use of bevacizumab. We also analyzed legal, regulatory, and ethical background of off-label use and provided recommendations to resolve this issue. Based on the extensive clinical data, actions taken, and recommendations provided by agencies such as the National Institute for Health and Care Excellence, International Council of Ophthalmology, United Kingdom and Thailand regulatory agency, intravitreal bevacizumab has adequate evidence for controlled licensing. Claiming better safety for ranibizumab at the expense of nonaffordability cannot be considered a positive risk-benefit scenario. Intravitreal bevacizumab is being used and will continue to be used off-label, if not regulatory controlled. Licensing will ensure the availability of intravitreal bevacizumab to the patients with eye diseases, without any legal or ethical concerns for the clinicians, and will also assist in generating long-term safety data. Safest delivery formulation and dosage form should be considered for approval. Both the regulatory agency and technical experts should join and take critical decision, which will be a big step forward to making a cost-effective drug available to the public.

Personalised medicine in paediatric oncology: Ethical practice outside the clinical trial framework?

Modern paediatric oncology practice has rapidly evolved from a fatal condition at diagnosis in the 1940s to modern survival rates of over 80%. With the advent of the 'omics' era and modern diagnostics platforms, we can now determine many of the molecular driving mechanisms of malignancy. Current molecular diagnostics trials PRISM and AIM/MNP, open in Australia, allow accurate diagnosis and determination of the molecular drivers of many cancers leading to new targeted opportunities for treatment. Unfortunately, clinical trial support, development and drug access for children has lagged behind. This is leaving clinicians and their institutions with increasingly difficult medical and ethical decisions, further complicating an already demanding profession.

Controversies in off-label prescriptions in dermatology: the perspective of the patient, the physician, and the pharmaceutical companies.

The term "off-label drug use" involves the prescription of medications for unapproved indications or in unapproved dosage, dosage form, or route of administration. Off-label medications are common in the management of dermatologic diseases. In the recent years, new indications for botulinum toxin, biologics, spironolactone, topical calcineurin, and topical vitamin D analogues emerged, and these drugs are being used off-label to treat a variety of conditions. The high cost and long time required for the approval discourage pharmaceutical companies from developing studies and pursuing the approval by regulatory agencies. Patients and physicians may have a different perspective regarding the off-label use of medications. The ethical discussion is based on the different opinions concerning the need for informed consent by the patient and how this could be applicable in the clinical practice.

Patterns and predictors of off-label prescription of psychiatric drugs.

Off-label prescribing of psychiatric drugs is common, despite lacking strong scientific evidence of efficacy and potentially increasing risk for adverse events. The goal of this study was to characterize prevalence of off-label prescriptions of psychiatric drugs and examine patient and clinician predictors of off-label use. This manuscript presents a retrospective, cross-sectional study using data from the 2012 and 2013 National Ambulatory Medical Care Surveys (NAMCS). The study examined all adult outpatient visits to psychiatric practices for chronic care management with a single listed visit diagnosis in which at least one psychiatric drug was prescribed. The main outcome measure was off-label prescribing of at least one psychiatric drug, defined as prescription for a condition for which it has not been approved for use by the FDA. Among our sample representative of 1.85 billion outpatient visits, 18.5 million (1.3%) visits were to psychiatrists for chronic care management in which at least one psychiatric drug was prescribed. Overall, the rate of off-label use was 12.9% (95% CI: 12.2-15.7). The most common off-label uses were for manic-depressive psychosis treated with citalopram and primary insomnia treated with trazodone. Several patient and clinician characteristics were positively associated with off-label prescribing, including seeing a psychiatrist (OR: 1.06, 95% CI, 1.01-1.12; p = 0.03) instead of another type of clinician, the office visit taking place in the Western region of the country (OR: 1.09, 95% CI, 1.01-1.17; p = 0.02), and the patient having 3 or more chronic conditions (OR: 1.12, 95% CI, 1.02-1.14; p = 0.003). In contrast, having Medicare coverage (OR: 0.93, 95% CI, 0.84-0.97; p = 0.04) and receiving payment assistance from a medical charity (OR: 0.91, 95% CI, 0.88-0.96; p = 0.03) instead of private insurance were negatively associated with off-label prescribing. These results suggest that certain classes of psychiatric medications are being commonly prescribed to treat conditions for which they have not been determined by the FDA to be clinically efficacious and/or safe.

[Ethical and legal problems arising from off-label use of medical devices and some solution recommendations]. / Tibbi cihazlarin endikasyon disi (off-label) kullanimindan kaynaklanan etik ve yasal sorunlar ve çözüm önerileri.

The off-label use of medical devices is becoming increasingly widespread. Though the off-label use of drugs has been controlled with the establishment of legal and ethical rules, similar regulations have not been implemented for medical devices. Legal gaps in this field, and the broad initiative granted to physicians have led to the emergence of problems in practice, and physicians are vulnerable to potential criminal sanctions that may emerge as a consequence of these off-label applications. Since the off-label use of medical devices cannot rely on scientifically proven, evidence-based information, evaluation of the risks creates critically important ethical problems that may have serious deleterious effects, despite the good intent of a physician tying to be helpful. During the process of obtaining informed consent from the patient for the off-label use of a device, the physician has crucial responsibilities. The ethical responsibilities of physicians particularly increase in vulnerable patient groups that should be protected from harm. In addition to the physician, the family members who make decisions on behalf of the patient also assume some responsibilities. The development of ethical norms and guidelines enforced by legal regulations concerning this issue, an effective role for ethics committees in the decision-making process, and collaboration between patients, scientists, nongovernmental organizations, medical device companies, specialists in the field of medical ethics, and legal authorities will be important in solving this problem.