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.

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.

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.

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.

[Proposed model for managing drugs used for unregistered indications in Colombia]. / Propuesta de un modelo de gestión de medicamentos en indicaciones no registradas en Colombia.

The use of drugs for unregistered indications, known as "off-label" use, is a practice that creates problems of rational use and access when other options are not available. Health systems should address this situation, particularly in connection with decisions concerning coverage, while trying to minimize health risks and clearly define the roles and responsibilities of the parties involved. Colombia's Ministry of Health and Social Protection (MinSalud), together with the National University of Colombia and national experts, developed a proposal for a model for managing drugs being used for unregistered indications (off-label) and their potential reimbursement with public resources, taking into account international practices and country characteristics. The management model is non-punitive and is geared toward promoting the rational use of these drugs so that barriers to access are reduced whenever their use is supported by solid scientific evidence. The model addresses patient safeguards in the bioethical domain and the roles and responsibilities of the prescriber and government entities.

Big pharma and the problem of disease inflation.

Over the course of the past decade, critics have increasingly called attention to the corrosive influence of the pharmaceutical industry on both biomedical research and the practice of medicine. Critics describe the industry's use of ghostwriting and other unethical techniques to expand their markets as evidence that medical science is all-too-frequently subordinated to the goals of corporate profit. While we do not dispute this perspective, we argue that it is imperative to also recognize that the goals of medical science and industry profit are now tightly wed to one another. As a result, medical science now operates to expand disease definitions, lower diagnostic thresholds, and otherwise advance the goals of corporate profit through the redefinition and expansion of what it means to be ill. We suggest that this process has led to a variety of ethical problems that are not fully captured by current critiques of ghostwriting and other troubling practices by the pharmaceutical industry. In our conclusion, we call for physicians, ethicists, and other concerned observers to embrace a more fundamental critique of the relationship between biomedical science and corporate profit.

The implications of methylphenidate use by healthy medical students and doctors in South Africa.

BACKGROUND: The use of medical stimulants to sustain attention, augment memory and enhance intellectual capacity is increasing in society. The use of Methylphenidate for cognitive enhancement is a subject that has received much attention in the literature and academic circles in recent times globally. Medical doctors and medical students appear to be equally involved in the off-label use of Methylphenidate. This presents a potential harm to society and the individual as the long-term side effect profile of this medication is unknown. DISCUSSION: The implication of the use of Methylphenidate by medical students and doctors has not been fully explored. This article considers the impact of this use on the traditional role of medicine, society, the patient and suggests a way forward. We discuss the salient philosophy surrounding the use of cognitive enhancement. We query whether there are cognitive benefits to the use of Methylphenidate in healthy students and doctors and whether these benefits would outweigh the risks in taking the medication. Could these benefits lead to tangible outcomes for society and could the off label-use of Methylphenidate potentially undermine the medical profession and the treatment of patients? If cognitive benefits are proven then doctors may be coerced explicitly or implicitly to use the drug which may undermine their autonomy. The increased appeal of cognitive enhancement challenges the traditional role of medicine in society, and calls into question the role of a virtuous life as a contributing factor for achievement. In countries with vast economic disparity such as South Africa an enhancement of personal utility that can be bought may lead to greater inequities. SUMMARY: Under the status quo the distribution of methylphenidate is unjust. Regulatory governmental policy must seek to remedy this while minimising the potential for competitive advantage for the enhanced. Public debate on the use of cognitive enhancement is long overdue and must be stimulated. The use of Methylphenidate for cognitive enhancement is philosophically defendable if long-term research can prove that the risks are negligible and the outcomes tangible.

Ethics & evidence in medical debates: the case of recombinant activated factor VII.

We cannot just point to the facts to solve a medical debate. The use of evidence is itself a matter of values. What the evidence tells us to do tends to depend on what we see as important.

Off-label prescriptions: how to identify them, frame them, announce them and monitor them in practice?

Following the Mediator crisis and the passage of the Health and Safety Law of December 2011, off-label prescriptions are a real concern shared by all those involved in healthcare system. Off-label, in the strictest sense of the term, is defined as all prescriptions that do not correspond to the summary of product characteristics (SPC), particularly those that fail to comply with the indications and dosage regimens defined by the marketing authorization (MA) for clear safety reasons. There are various rasons for off-label prescriptions, both conscious and unconscious. They are intended to respond to unmet medical needs, the needs of poorly studied populations or not studied at all in trials, but in relation to whom it is reasonable to extrapolate that MA would be given (common-sense prescriptions) and, additionally, to urgent public health needs (such as baclofen, pregnant women, and HIV drugs). All these prescriptions would deserve to be studied for a potential MA. However, there are off-label prescriptions that need to be restricted or even penalized in the case of compassionate prescriptions or unjustified prescriptions or prescriptions not based on any scientific grounds. Off-label prescriptions are not easy to track down because if the prescriber has to write "off-label" on his prescription, then clearly, in practice, he will only do so in exceptional cases. Neither the pharmacists who dispense the drug nor the Social Security that reimburses it, have access to the diagnosis (or targeted indication). Thus, in order to identify the off-label prescription, we must be able to cross reference the available databases (such as pharmacovigilance database, medicalized information system program [programme de médicalisation des systèmes d'information, PMSI], hospital drug formularies, general sample of beneficiaries [échantillon généraliste de bénéficiaires, EGB] or national inter-regional Health Insurance Information System [système national d'informations inter-régions d'Assurance maladie, SNIIRAM], sales data, and data from market surveys). The shared computerized patient file may resolve this problem. The temporary use recommendation (TUR) proposed by the Drug Safety Law will only partially deal with this problem for recently marketed molecules. This temporary and exceptional mechanism will authorize a recognized off-label prescription, which may be reimbursed and monitored for 3 years. These TURs will only concern a small portion of "off-label" drugs having yet a positive risk/benefit ratio (conditional MA) but this is far from matching with majority of off-label prescriptions. As such, and in order to improve the use of drugs, it is important to propose a control system for all "off-label" prescriptions with a dedicated committee: the "off-label" committee which would determine the frame of the "off-label" prescriptions.

Pharmacotherapy for sarcoidosis: an example of an off-label procedure.

Sarcoidosis is a granulomatous multiorgan diseases with an unknown etiology, with the predominant lung involvement. Immunosuppressive agents such as corticosteroids, methotrexate, azathioprinum, ciclosporinum A, chlorambucil, cyclophosphamide, hydroxychlorochinum, indomethacin, pentoxyfillinum, thalidomide, leflunomidum, and adalimumab, or infliximab have been used in its treatment. It should be emphasized that the Summary of Products Characteristics (SPC) of these drugs does not specifically recommend their use in the therapy for sarcoidosis. That makes the application of the drugs in sarcoidosis an off-label use, which is not formally accepted by the authorities but is supported by medical bibliography or recommendations given by scientific bodies. Thus the off-label drugs raise legal, but also ethical and medical problems. The dosing regimen and the required duration of therapy for sarcoidosis are missing. In effect the therapy usually follows the recommendations from the American and European Respiratory Societies (ATS/ERS), based on the long-term medical research. The American Food and Drug Administration recognizes the existence of the off-label use. European legislations do not precisely specify the rules for the admissibility of the off-label use. The doctrine of law assumes that the off-label use constitutes a medical experiment. Therefore, the commencement of therapy with such drugs requires patients' informed consent, which must be kept along with other medical records. Insufficient knowledge of the legal regulations may result in civil and professional liability of a physician supervising the therapy of a sarcoidosis patient, especially in case of adverse effects.

Ethical issues in new drug prescribing.

We use the format of a hypothetical case study to review issues related to pharmaceutical product approval and physician prescribing practices. In this case, a new FDA-approved drug is recommended for a patient who subsequently experiences an adverse event that may or may not be related to the prescription. This case raises a number of ethical and legal considerations physicians routinely face when deciding whether to recommend such drugs for their patients. Despite the need for ongoing observation by the regulatory apparatus, physicians should be cognizant of the limitations of the drug approval system and the post-approval prescription drug surveillance system. We discuss physicians' ethical obligations when faced with a newly approved drug, including seeking out independent sources of learning, reporting adverse effects, and notifying patients about limitations in available knowledge about therapeutic recommendations.

Off-label prescribing of medications for pain: maintaining optimal care at an intersection of law, public policy, and ethics.

For more than 60 years, regulations limited marketing of medications for off-label uses to very low levels. Some key policy changes in the late 1990s ushered in an era of deregulation of off-label marketing. Policy changes included revised United States federal law as well as modifications of Food and Drug Administration (FDA) regulations. Subsequent investigations documented an explosion in scope off-label prescribing. Attempts to limit off-label advertising by manufacturers were vigorously challenged in the courts. Other modalities are needed to maintain a clinical care environment that places the patients' best interests first. In many circumstances, an off-label medication may be in the patient's best interests; however, where there is a lower level of clinical justification, the informed consent of the patient and shared decision making of the patient is essential to optimize outcome.

Off-label prescribing in older patients.

The practice of off-label prescribing, i.e. prescribing drugs either for unregistered/unapproved therapeutic indications and age groups or using unregistered/unapproved doses or methods of administration, is common in older patients. This may be due to the poor representation of this group in pre-marketing clinical trials assessing therapeutic efficacy and safety of novel therapies or merely to the fact that trials in a particular indication have not been undertaken. Off-label prescribing should not be viewed as scientifically or ethically unsound when there are good clinical data to support a particular therapeutic indication. However, a number of steps should be followed in order to ensure therapeutic efficacy, reducing, at the same time, the risk of adverse drug reactions and/or medical litigation. This article discusses the current epidemiology and trends in off-label prescribing in older patients, the scientific and ethical justification of this practice, medico-legal implications, and proposed strategies for risk mitigation.