RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE

Risks and Ethical Issues of Off-Label Drug Use Hannah de Luna Northeastern University

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE Abstract A significant percentage of medication filled in the United States every year are prescribed for off-label use. Using drugs for population or indications that were not approved by the Food and

Drug Administration (FDA) poses potential health risks to patients due to the lack of high quality clinical research. It has been found that many patients were not aware that they have been using drugs for non-FDA approved indications. Therefore, it is essential for prescribers to educate their patients about the medication's off-label status and the limited research available. This paper analyzes patients' awareness of off-label drug use, prevailing reasons why doctors prescribe drugs for off-label use, and the ethical issues surrounding it.

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE Risks and Ethical Issues of Off-Label Drug Use Introduction An average of 3.5 billion prescriptions is filled by pharmacies in the United States every

year. The majority of these prescriptions are maintenance medication, usually used by the elderly to regulate their cholesterol and blood pressure levels. As the elderly population increases, the number of prescriptions filled at retail and outpatient pharmacies is expected to increase as well. According to research conducted by David Radley, Stan Finkelstein, and Randal Stafford (2006) for the American Medical Association, 21% of the most commonly prescribed drugs were used for off-label indications. Off-label drug use occurs when physicians prescribe medication for indications, age groups, conditions, and other clinical parameters that did not receive FDA approval. For example, off-label use is commonly observed in pediatric clinics since pharmaceutical companies often do not perform clinical drug trials in pediatric patients and therefore have limited data to present to the FDA during the drug approval process. This unapproved use of medication poses health risks because their side effects have not been thoroughly studied. For this reason, physicians have a responsibility to make sure their patients are aware and understand the off-label status of the drug and its possible effects. The drug approval process takes an average of $500 million and 10 years, during which the drug company must conduct 3 phases of clinical trials in order to determine the drugs mechanism of action, its potency, and its safe and effective dosages. After sufficient research is available, the manufacturer submits a New Drug Application to the FDA. The application includes a label which indicates the conditions and populations that the manufacturer has found the drug to be suitable for, and the FDA approves the drug based upon this label. This lengthy

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE and expensive process of drug approval ensures that the new medication is safe for market release and has a low risk of endangering patients health. Prevalence of Off-Label Drug Use However, ensuring patient safety is also the prescribers responsibility. When physicians prescribe medications for off-label use, they are not relying on the results of years of controlled

and high quality clinical trials. Instead, according to Prof. Rebecca Dresser (2009) of Washington University at St. Louis, many physicians rely on experience, anecdotal reports, and opinion leaders to guide their treatment decisions, often failing to demand solid evidence for their prescribing choices. Without compelling evidence to support the use of off-label medication, the patients safety is put at risk. Therefore, physicians have a responsibility to prescribe these medications as a last resort and only when there is significant evidence supporting their therapeutic benefits. In all cases, patients should be made aware of their prescriptions off-label status and their physicians reasoning for prescribing the medication. It is assumed that when patients are prescribed medication for off-label use, it is because they have no other therapeutic options. However, this is not always the case. A patient who is using a drug for an off-label label indication may mean that they are not receiving the benefits of a more effective drug. In fact, since most off-label medication lack comprehensive research, the patient also faces the risk of experiencing adverse side effects especially if they are not within the age group that the drug has been approved for. A study conducted by French scientists on 1419 patients under 16 years old showed that off-label drug use was significantly associated with adverse drug reactions . . . particularly when it was due to an indication different than that defined in the Summary Product Characteristics (Horen, Montastruc & Lapeyre-mestre, 2002).

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE Off-Label Use for Orphan Diseases Despite these findings, the unapproved use of medication should not be made illegal because there are very legitimate reasons for physicians to prescribe them. For example,

pharmaceutical companies do not find enough incentive to invest their time and money in finding cures for orphan diseases. Additionally, although there is some research being done to develop orphan drugs, it still takes years before they are approved for release. Therefore, they often do not have cures, and doctors must use drugs that are already available to treat these rare diseases. According to Dr. Brian Liang and Tim Mackey (2010) of the California Western School of Laws Institute of Health Law Studies, up to 90% of drug use for rare conditions is off-label. However, in order to avoid worsening the patients condition, the responsibility falls upon the physician to procure sufficient evidence supporting the drugs use. Although prescribing drugs for off-label use is not illegal, it is still possible for them to be found guilty of malpractice if they do not adhere to the medical communitys standards of care. Ethical Concerns There are several ethical issues surrounding off-label drug use. Those who are in support of it believe that unapproved use can provide the best available therapy for some patients. On the other hand, those who are against off-label use are proponents of clinical trials. They believe that high quality and impartial trials must first be conducted in order to develop new treatments or investigate existing therapies. However, this is not always possible especially when considering the time and financial costs of conducting these trials. When there is existing medical evidence available, it is up to the physician to thoroughly evaluate the findings and determine whether it is appropriate for the patients condition. In cases where there is no available evidence, the

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE responsibility falls upon the medical community to work together in order to compile information concerning the off-label use of existing medication. Communication between physicians, manufacturers, and the FDA must remain open to determine the adverse effects of already-available medication in certain populations and to develop new treatments which improve upon existing drugs. Another ethical question involves the use of off-label medication for non-serious diseases. In cases where it is medically necessary, there is a compelling reason for patients to

take a drug off-label after carefully weighing the possible risks and benefits. However, for drugs that are only meant to improve the patient's appearance or lifestyle, it is more difficult to justify the health risks involved. Should doctors encourage the off-label use of drugs in situations like this? For example, the anticonvulsant drug Topamax is sometimes prescribed along with the stimulant phentermine to suppress appetite and cause weight loss in patients. This drug combination was placed before the FDA for approval in 2010 under the trade name Qnexa. However, approval was denied when the FDA found that the drug caused cardiovascular disorders in patients and the risk of birth defects in pregnant women (Pollack, 2012). Regardless of the drugs failure to achieve approval, this drug combination is still widely prescribed by obesity specialists throughout the country. In cases like this, physicians have a greater responsibility to inform their patients that the drugs are being prescribed for off-label use and to provide evidence supporting their decision to prescribe it. More importantly, they should ensure that patients are aware of the health risks involved. It is then up to the patients discretion whether the benefits of the medication outweigh the possible side effects. Unfortunately, a 2006 study conducted by the Mayo Clinic revealed that half of the nations population was not aware

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE

that drugs could be prescribed for off-label use (Wittich, Burkle & Lanier, 2012). Since one-fifth of prescription drugs filled in pharmacies are for unapproved use, this finding suggests that an astonishingly large percentage of patients have benefited from off-label drug use without knowing that it was prescribed off-label. Suggested Solutions and Counter Arguments To address this discrepancy and to minimize the risk to patient safety, off-label drugs must only be used when appropriate for the patients condition and as a last resort. When the indication is inconsistent with the FDA-approved label, then there must be credible and comprehensive evidence supporting the drugs use for that patient. According to Prof. Dresser, there is a hierarchy of scientific evidence that determines its quality, citing that randomized controlled trials and cohort studies are high-quality evidence while expert opinion is low quality. Relying on controlled trials is beneficial for physicians as well since it develops new standards of practice within the medical community. As more doctors use the drug for unapproved indications, more information is gathered about its effects. If the manufacturer is made aware of these developments and finds the incentive to perform clinical trials, it may push for further research to be done, and for the new indication to be submitted for FDA approval. Regardless of the amount of evidence supporting the drugs off-label benefits, physicians have a responsibility to inform patients that the drug has not been approved for the indication. According to the Mayo Clinic, two arguments are often voiced by those who oppose any routine requirement for disclosure : (1) disclosure may unduly frighten patients and (2) the extensive burden placed on physicians to constantly review and

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE communicate medication risk and benefit information may divert attention away from other more important patient care issues (Wittich, Burkle & Lanier, 2012). However, patients should be made aware of the risks that accompany the potential benefits of their medication. If they find any compelling reasons to be frightened by its side effects, then it is a legitimate reason to decline that particular course of therapy. Furthermore, it is the doctors obligation to be informed about the most current findings regarding the medication. Doing so does not take his or her attention away from other issues, but improves the quality of patient care.

NOTE: This paper is appropriate for my professional portfolio since it employs a unique tone that is directed towards scholars in the field. It illustrates that I can understand and utilize peer-reviewed scholarly articles to support my stance towards an issue.

RISKS AND ETHICAL ISSUES OF OFF-LABEL DRUG USE References Dresser, R., & Frader, J. (2009). Off-label prescribing: A call for heightened professional and government oversight. The journal of law, medicine, & ethics, doi: 10.1111/j.1748720X.2009.00408.x Horen, B., Montastruc, J., & Lapeyre-mestre, M. (2002). Adverse drug reactions and off-label drug use in paediatric outpatients. British journal of clinical pharmacology , doi: 10.1046/j.1365-2125.2002.t01-3-01689.x Liang, B., & Mackey, T. (2010, Jan 15). Reforming off-label promotion to enhance orphan disease treatment. Retrieved from http://www.sciencemag.org/content/327/5963/273.full Pollack, A. (2012, Feb 16). U.S. to review diet treatment once rejected . Retrieved from http://www.nytimes.com/2012/02/17/business/diet-treatment-already-in-use-to-get-fdareview.html?pagewanted=all&_r=1& Radley, D., Finkelstein, S., & Stafford, R. (2006). Off-label prescribing among office-based physicians. Archives of internal medicine, doi: 10.1001/archinte.166.9.1021 Wittich, C., Burkle, C., & Lanier, W. (2012). Ten common questions (and their answers) about off-label drug use. Mayo clinic proceedings, Retrieved from http://download.journals.elsevierhealth.com/pdfs/ journals/00256196/PIIS0025619612006830.pdf