COVID-19 off-label uses of medicines: the role of civil liability and regulation.

Physicians can prescribe medicines for different indications than the tested and authorised ones. Such 'off-label' uses expand therapeutic options but also create uncertainties. The COVID-19 pandemic triggered new off-label uses and, despite issues being reported in the literature, these have not resulted in substantial personal injury litigation in the EU. Against this backdrop, this article argues that civil liability plays, in fact, a limited role in off-label uses. In particular, civil liability may incentivise health actors to follow and react to the development of the evidence basis for off-label uses. However, it is ultimately unable to incentivise the conduct of additional research on off-label uses. This is problematic, as off-label research is key to protecting patients and is recommended by international medical ethics. The article concludes by critically discussing proposed mechanisms to incentivise off-label research. It argues that extending civil liability for unknown risks may have undesired effects on insurability and innovation, and most regulatory proposals seem ineffective. Building on the 2014 Italian reform of off-label uses, the article proposes the establishment of a fund financed by mandatory contributions from the industry, which should be used by pharmaceutical regulators to promote off-label research and develop guidelines for prescribers.

The Profile of Use of Rituximab in Tertiary Care Hospitals of Central India.

Background: Rituximab, one of the most commonly used biologics, was once approved by the United States Food and Drug Association (US FDA) for the management of different systemic autoimmune disorders, and it is now used extensively in managing off-label indications. There is a scarcity of data regarding its utilization pattern in India. Objective: To assess rituximab usage pattern in two tertiary care hospitals of Central India. Methods: A cross-sectional, retrospective study was performed to analyze the data of patients from two tertiary care centers of Central India who had received rituximab between 2019 and 2021. The usage was categorized either for FDA-approved indications or for off-label indications. Multiple logistic regression was applied to evaluate which factors would influence the use of rituximab for an FDA-approved indication. Results: A total of 79 medical records of patients. The majority of the patients (77.2%) had received rituximab for an FDA-approved indication. The most common approved and off-label indications detected were non-Hodgkin's lymphoma and autoimmune disorders, respectively. The use of rituximab for an FDA-approved indication was associated with increased age (adjusted odds ratio [AOR] = 1.04, 95% confidence interval [CI] = 0.99-1.1), male sex: AOR = 2.55, 95% CI = 0.74-9.93, malignancy: AOR = 9.39, 95% CI = 1.46-76.12, and diabetes: AOR = 1.38, 95% CI = 0.19-13.74. Conclusions: The use of rituximab was more common for an FDA-approved indication rather than for an off-label indication. Factors such as advancing age, male sex, and malignancy were frequently associated with the FDA-approved use of rituximab.

Off-label use information in electronic drug information resources.

Objective: To compare electronic drug information resources for scope, completeness, and consistency of off-label uses information, and to group resources into tiers based on these endpoints. Methods: An evaluation study of six electronic drug information resources (Clinical Pharmacology, Lexi-Drugs, American Hospital Formulary Service Drug Information, Facts and Comparisons Off-Label, Micromedex Quick Answers, and Micromedex In-Depth Answers) was conducted. All off-label uses for the top 50 prescribed medications, by volume, were extracted from all resources and used to determine scope (i.e., whether the resource listed the use). Fifty randomly selected uses were then evaluated for completeness (i.e., whether the entry cited clinical practice guidelines, cited clinical studies, provided a dose, described statistical significance, and described clinical significance) and consistency (i.e., whether the resource provided the same dose as the majority). Results: A sample of 584 uses was generated. The largest number of listed uses was in Micromedex In-Depth Answers (67%), followed by Micromedex Quick Answers (43%), Clinical Pharmacology (34%), and Lexi-Drugs (32%). The highest scoring resources for completeness were Facts and Comparisons Off-Label (median score 4/5), Micromedex In-Depth Answers (median score 3.5/5), and Lexi-Drugs (median score 3/5). Consistency with the majority in terms of dosing was highest for Lexi-Drugs (82%), Clinical Pharmacology (62%), Micromedex In-Depth Answers (58%), and Facts and Comparisons Off-Label (50%). Conclusion: The top-tiered resources for scope were Micromedex In-Depth and Quick Answers. For completeness, the top-tiered resources were Facts and Comparisons Off-Label and Micromedex In-Depth Answers. Lexi-Drugs and Clinical Pharmacology were the most consistent in dosing.

Clinical Applications of Aspirin as a Multi-potent Drug Beyond Cardiovascular Implications: A Proof of Concept for Anesthesiologists- A Narrative Review.

To the best of our knowledge, aspirin (ASA) is known as a commonly used medication worldwide. Although the cardiovascular aspects of ASA are well-established, recently, it has been identified that ASA can yield multiple extra-cardiovascular therapeutic potencies in facing neurodegenerative disorders, various cancers, inflammatory responses, and the COVID-19 pandemic. In this review, we aimed to highlight the proven role of ASA administration in the variety of non-cardiovascular diseases, particularly in the field of anesthesiology.

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.

Off-label uses of the Pipeline embolization device: a review of the literature.

The Pipeline embolization device (PED) is the most widely used flow diverter in endovascular neurosurgery. In 2011, the device received FDA approval for the treatment of large and giant aneurysms in the internal carotid artery extending from the petrous to the superior hypophyseal segments. However, as popularity of the device grew and neurosurgeons gained more experience, its use has extended to several other indications. Some of these off-label uses include previously treated aneurysms, acutely ruptured aneurysms, small aneurysms, distal circulation aneurysms, posterior circulation aneurysms, fusiform aneurysms, dissecting aneurysms, pseudoaneurysms, and even carotid-cavernous fistulas. The authors present a literature review of the safety and efficacy of the PED in these off-label uses.

Second-generation antipsychotic use in borderline personality disorder: What are we targeting?

INTRODUCTION: Borderline personality disorder (BPD) is a personality disorder plagued with high rates of psychotropic polypharmacy. Estimates show that second-generation antipsychotics (SGAs) are used in most of these patients; however, they are being prescribed off label. METHODS: A literature review was conducted via PubMed in search for studies evaluating SGA use in BPD. RESULTS: There are available data investigating 8 of 11 SGAs and their use in BPD. Of N = 269 potential articles, N = 34 evaluating the use of SGAs in BPD were included. DISCUSSION: Strong evidence supporting SGAs in BPD is lacking. Potential target symptoms in which a SGA may be useful include depression, anxiety, anger, impulsivity, and paranoia/dissociative behavior.

Clinical use and control of the dispensing of thalidomide in Brasilia-Federal District, Brazil, from 2001 to 2012 / Uso clínico e controle sobre a dispensação de talidomida em Brasília-DF, Brasil, de 2001 a 2012

The use of thalidomide was never discontinued in Brazil where it is prescribed for leprosy type 2 reaction. Babies with birth defects compatible with the thalidomide embryopathy phenotype were born after 1965, an indication that control on drug dispensing and use failed in the country. The article reports data on thalidomide dispensing and clinical uses in the Federal District in 2011/12, when new rules were put into effect, and data on drug dispensing and use obtained ten years earlier. It was found that the number of patients making use of thalidomide declined from 819 in 2001 to 369 in 2011/12. Leprosy accounted for over 70% of prescriptions in both time periods analyzed in this study. In the same time interval, however, use for lupus erythematosus decreased from 13.7 to 4.9%, while that for multiple myeloma increased from 2.9 to 20.3% of all prescriptions. Thalidomide prescription for the remaining approved indications was far less frequent, and so was the use for off label indications that accounted for <1% of prescriptions in 2001 and 2011/12. Registration of prescribing doctors, patients and dispensing units at the state department of health, apparently rendered this control more effective and reliable.

O uso da talidomida nunca foi interrompido no Brasil, sendo prescrita para tratar a reação tipo 2 da hanseníase. Crianças com defeitos congênitos compatíveis com o fenótipo da embriopatia causada pela talidomida nasceram após 1965, evidenciando que o controle do uso e da dispensação do medicamento falhou no país. O artigo relata dados sobre a dispensação e usos clínicos da talidomida no Distrito Federal em 2011/12, quando a nova regulamentação passou a vigorar, e dados sobre a dispensação e uso do medicamento 10 anos antes. Os resultados mostraram que o número de pacientes que usaram talidomida decresceu de 819 em 2001 para 369 em 2011/12. A hanseníase foi a indicação clínica para mais de 70% das prescrições nos períodos analisados no estudo. No mesmo período, entretanto, o uso para lupus eritematoso reduziu de 13,7 para 4,9%, enquanto o uso para mieloma múltiplo cresceu de 2.9 para 20,3% de todas as prescrições. A prescrição de talidomida para as outras indicações aprovadas foi muito menor, enquanto para indicações não aprovadas correspondeu a < 1% das prescrições em 2001 e 2011/12. O cadastro dos prescritores, pacientes e unidades dispensadoras na secretaria estadual de saúde, aparentemente tornou esse controle mais eficiente e confiável.