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.

Assessment of Drugs Approved by Public Knowledge-Based Applications (Kouchi-shinsei) During the Last Two Decades in Japan.

Public knowledge-based application ("Kouchi-shinsei" in Japanese) is unique to Japan, implemented to eliminate the off-label use of unapproved indications, dosages, and administrations because of drug lag. The guidance for public knowledge-based application was issued in 1999. This study comprehensively investigated the trends of items approved by public knowledge-based application in Japan during the last 2 decades. Prescription drugs approved from January 2000 to December 2019 were surveyed. In Japan, 1,855 drugs were approved within the target survey period. Among them, 219 (11.8%) were approved by public knowledge-based application. Considering the changes in the number of items approved by public knowledge-based application over the years, the number of items approved in 2000 was 7, reaching a maximum of 34 items in 2011, and decreased after that, 8 items were approved in 2019. The regulatory characteristics of drugs approved by public knowledge-based application and those of other drugs were compared. By public knowledge-based application, more anticancer and pediatric drugs were approved (P < 0.001), and only one drug for orphan diseases was approved (P < 0.001). In addition, the review time of public knowledge-based applications was significantly shorter than that of normal applications regardless of time point. The approval system using public knowledge-based application began in 2000, following issuance of the "Guidance for off-label use of prescription drugs." Furthermore, the approved items were mostly drugs for cancer, infectious diseases, and pediatric drugs. We anticipate the promotion of public knowledge-based application to accommodate the approval of drugs for orphan diseases.

Prospects for Enforcing Prohibitions on Off-Label Drug Promotion after United States v. Caronia: An Analysis of Litigated Cases.

CONTEXT: Food and Drug Administration (FDA) rules restrict pharmaceutical manufacturers from promoting drugs for non-FDA-approved (off-label) indications. When manufacturers violate this rule, it has in many cases led to unsafe prescribing. However, in 2012, a federal circuit court ruled in United States v. Caronia that truthful off-label promotion was protected under the First Amendment, threatening government enforcement in this area. METHODS: The authors extracted cases from the WestLawNext database that mentioned Caronia from 2012 to 2019. They collected information about plaintiff, procedural history, product and manufacturer involved, and case outcome. Cases were categorized as either "follows," "does not follow," or "distinguishes" from Caronia. The authors qualitatively reviewed the full text of each case to verify whether Caronia was given substantive discussion for perceptions of off-label promotion, application of commercial speech rights, and how courts interpreted Caronia. FINDINGS: Among 42 cases in the study cohort, 22 (52%) followed Caronia's core holding that truthful, non-misleading off-label promotion was not actionable under FDA rules. By contrast, 20 cases (48%) treated Caronia negatively, either declining to follow (9 cases) or distinguishing it (11 cases). CONCLUSIONS: Enforcement of restrictions on off-label marketing became more challenging after Caronia. This gives manufacturers greater flexibility to promote drugs for unapproved uses despite the substantial public health risks.

The Law and Practice of Off-Label Prescribing and Physician Promotion.

Prescription of medications for off-label indications is an increasingly common practice; recent events highlight such prescribing as one of the cornerstones of evolving clinical treatment. Clinicians are afforded substantial deference in prescribing practices and other treatments falling within the realm of the actual practice of medicine, including prescribing for off-label indications. Yet clinicians are not necessarily free to promote a medication for the same off-label indication they may have just prescribed for a patient. While trends in jurisprudence appear to be favoring clinicians' freedom to promote prescription medication for any use, in a majority of jurisdictions, the U.S. government can still bring considerable weight to bear on clinicians promoting off-label uses of prescription medications. We review the relevant laws and regulations pertaining to off-label prescription and promotion, as well as the possible legal consequences. The regulations pertaining to physician and pharmaceutical manufacturers regarding off-label drug use are complex. Suggestions are provided to help physicians better navigate the medical-legal landscape when prescribing or promoting medications for off-label use. Physician mindfulness to pertinent legal precedents will allow them to prescribe and promote medications with a higher level of critical reasoning to optimize care and reduce risk.

Pharmacoepidemiology of testosterone: Impact of reimbursement policy on curbing off-label prescribing.

OBJECTIVES: To estimate the impact on testosterone prescribing over 3 years following the 2015 tightening of Pharmaceutical Benefits Scheme (PBS) criteria. DESIGN: Analysis of testosterone prescribing data from PBS and private (non-PBS) sources between 2012 and 2018 covering 2015 change in PBS prescribing criteria. MAIN OUTCOME MEASURES: New and total PBS testosterone prescriptions estimating usage by quarter analyzed by product type, patient age-group, indication and prescriber type. Total national testosterone prescriptions (private plus PBS) was verified from an independent data supplier (IQVIA). RESULTS: PBS usage peaked in 2014 declining by 30% in 2017-8 with PBS prescribing covering a fall from 97.6% by usage in 2014 to 74% in 2017-18 of all testosterone prescribing. The tighter 2015 PBS restrictions sustained the selective reduction in GP initiation of prescriptions for middle-aged men without pathological hypogonadism whereas specialist initiations and prescription for adult hypogonadism or pediatric/prepubertal indications were largely unaffected. CONCLUSIONS: The tightening of PBS criteria from 1 April 2015 to curb off-label prescribing remained effective and selective over 3 years yet total national testosterone prescribing continued with little change, reflecting a shift to private prescriptions. The continuation of off-label testosterone prescribing for unproven indications suggests that long-term androgen dependence is created in men without pathological hypogonadism who commence testosterone. This highlights the need to avoid prescribing testosterone to men without pathological hypogonadism in the absence of sound evidence of efficacy and safety, the latter including the little unrecognized risks of long-term androgen dependency when trying to quit.

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.

Off-label use of bevacizumab for wet age-related macular degeneration in Europe.

PURPOSE: To analyse current off-label use of bevacizumab for wet age-related macular degeneration (AMD) in Europe. METHODS: The study was conducted as a combined survey and literature review. It included the 22 most populous countries in Europe. In each country, ophthalmologists with particular knowledge about off-label treatment responded to a questionnaire. RESULTS: Answers were obtained from twenty European countries. The off-label use of bevacizumab for wet AMD greatly differed between nations; the bevacizumab proportion varied from non-existent (0%) to very high (97%). There were also large disparities within single countries (e.g. 0-80%), which were attributable to differences in regional decision-making. Both governmental institutions and national ophthalmological societies expressed highly diverging opinions on the use of off-label treatment. Intravitreal administration of bevacizumab had been a matter of legal dispute in several countries. The question about responsibility for off-label therapy mainly remained unanswered. CONCLUSIONS: There was a highly varying utilization of bevacizumab between European countries. Despite an intention of a consistent approach to medical regulations, Europe has not yet reached a professional or political consensus on the ophthalmic off-label use of bevacizumab.

Governing off-label vaccine use: An environmental scan of the Global National Immunization Technical Advisory Group Network.

BACKGROUND: National Regulatory Authorities approve the indications for vaccine use in the product information. Occasionally, National Immunization Technical Advisory Groups (NITAGs) make off-label recommendations for use in different age groups, populations, and dosing schedules from the product information. We sought to determine the rationale, policies and procedures for NITAG off-label recommendations. METHODS: We conducted an environmental scan of Global NITAG Network members, immunization program managers and regulators in 38 high-, middle- and low-income countries. Participants completed an online survey regarding policies, procedures, and legislation governing development of off-label recommendations. A sub-sample of respondents met for a focus group and interviews which were analyzed qualitatively. RESULTS: Thirty-four people responded from 26/38 (68%) countries surveyed; 76% of respondents were NITAG members or immunization program managers. Recommendations for off-label vaccine use were made in 14/26 (54%) countries; the NITAG made those recommendations in 8/14 (57%) countries. Reasons for off-label vaccine recommendations included response to disease outbreaks or vaccine shortages. Only one country had standard operating procedures for developing off-label recommendations while 6/14 (43%) countries had policies for implementing off-label recommendations. Nine respondents from 8 countries agreed to participate in a focus group (n = 6) or individual interviews (n = 3). Barriers to off-label recommendations included legal concerns, lack of standard definition for off-label use, and manufacturer reluctance to update product information. Facilitators included confidence in the decision-making process, and transparency of open communication among stakeholders. CONCLUSIONS: Best practice guidelines are needed that define off-label use and outline a transparent, evidence-based approach to develop off-label recommendations.

Beyond the law: Misoprostol and medical abortion in Dar es Salaam, Tanzania.

Misoprostol has during the past few years become an important obstetric drug used for different purposes both within and outside hospitals in Tanzania. In this paper, we analyze how misoprostol is perceived, accessed and used off-label as an abortion drug in the city and region of Dar es Salaam. The study took place in Dar es Salaam's three districts from July to November 2015, and had a qualitative explorative approach. We carried out in-depth interviews (42) with the following main categories of informants: women having undergone medical abortion (15), health care workers with experiences from post abortion care (16) and drug vendors (11). Focus group discussions (10) were carried out with young women. A client simulation study was carried out in 64 drugstores across Dar es Salaam assessing the availability of misoprostol and the advice given concerning its use. In addition, shorter qualitative interviews were carried out with representatives of NGOs and public agencies working with sexual and reproductive health issues (17). Our findings reveal that in Dar es Salaam, misoprostol is well known, available and accessed for abortion purposes through drugstores and health providers. Women tend to prefer misoprostol over other abortion methods since it allows for a private, low-cost, safer and less uncomfortable abortion experience. But, while misoprostol facilitates women's agency in the process of seeking abortion, a series of obstacles shaped by a restrictive abortion law and an unregulated pharmaceutical market hinder its safe use. Central obstacles are profit-seeking providers, suboptimal user instructions and poor provider follow-up. In the discussion of the material we draw upon Van der Geest, Hardon and Whyte's concept of the 'social life of pharmaceuticals' and indicate the ways in which misoprostol acts as an agent of change in the social relations connected to abortion.

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

Contrasting evidence to reimbursement reality for off-label use (OLU) of drug treatments in cancer care: rationale and design of the CEIT-OLU project.

Background: Off-label use (OLU) of a drug reflects a perceived unmet medical need, which is common in oncology. Cancer drugs are often highly expensive and their reimbursement is a challenge for many healthcare systems. OLU is frequently regulated by reimbursement restrictions. For evidence-based healthcare, treatment ought to be reimbursed if there is sufficient clinical evidence for treatment benefit independently of patient factors not related to the treatment indication. However, little is known about the reality of OLU reimbursement and its association with the underlying clinical evidence. Here, we aim to investigate the relationship of reimbursement decisions with the underlying clinical evidence. Methods/ design: We will extract patient characteristics and details on treatment and reimbursement of cancer drugs from over 3000 patients treated in three Swiss hospitals. We will systematically search for clinical trial evidence on benefits associated with OLU in the most common indications. We will describe the prevalence of OLU in Switzerland and its reimbursement in cancer care, and use multivariable logistic regression techniques to investigate the association of approval/rejection of a reimbursement requests to the evidence on treatment effects and to further factors, including type of drug, molecular predictive markers and the health insurer. Discussion: Our study will provide a systematic overview and assessment of OLU and its reimbursement reality in Switzerland. We may provide a better understanding of the access to cancer care that is regulated by health insurers and we hope to identify factors that determine the level of evidence-based cancer care in a highly diverse western healthcare system.

Pediatric drug development in China: Reforms and challenges.

In China, child and adolescent pediatricians often face challenges in treating children with the appropriate medications. Within the last 8 years, the Chinese government has already initiated a series of policies to promote development of age-appropriate medicines for children. In this study,we introduced the current status of pediatric drugs, obstacles for pediatric drugs development and regulatory reforms in China. The lack of label information in drugs for children, inadequacy of age-appropriate dosage forms and strengths, and shortage of pediatric drugs are some of the problems commonly faced. There exists neither mandatory requirements nor enough financial drivers for development of pediatric medicines. Though some progress in terms of pediatric drugs development as well as distribution have been made by Chinese government over past years, further efforts are necessary to improve availability of pediatric medications.

Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals.

BACKGROUND: A previous analysis of 113 National Comprehensive Cancer Network® (NCCN®) recommendations reported that NCCN frequently recommends beyond Food and Drug Administration (FDA)-approved indications (44 off-label recommendations) and claimed that the evidence for these recommendations was weak. METHODS: In order to determine the strength of the evidence, we carried out an in-depth re-analysis of the 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). RESULTS: Of the 44 off-label recommendations, 14 were later approved by the FDA and/or are supported by randomized controlled trial (RCT) data. In addition, 13 recommendations were either very minor extrapolations from the FDA label (n = 8) or were actually on-label (n = 5). Of the 17 remaining extrapolations, 8 were for mechanism-based agents applied in rare cancers or subsets with few available treatment options (median response rate = 43%), 7 were based on non-RCT data showing significant efficacy (>50% response rates), and 2 were later removed from the NCCN Guidelines because newer therapies with better activity and/or safety became available. CONCLUSION: Off-label drug use is a frequent component of care for patients with cancer in the United States. Our findings indicate that when the NCCN recommends beyond the FDA-approved indications, the strength of the evidence supporting such recommendations is robust, with a significant subset of these drugs later becoming FDA approved or supported by RCT. Recommendations without RCT data are often for mechanism-based drugs with high response rates in rare cancers or subsets without effective therapies.

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.