B. Decision tree for budget scenario with drug E
12.1 Off-Label Drug Use
Drugs are given labeled indications by regulatory agencies such as the United States Food and Drug Administration and the European Medicines Agency. These indica- tions are the use of the drug for which the regulatory agencies have deemed it appro- priate based on adequate demonstration of its safety and efficacy. Most prescription drugs will be used according to these labeled indications. However, there are cases in which prescription drugs are prescribed or used outside of the approved indica- tion. This is often referred to as nonapproved or off-label use.
Off-label use may occur for two primary reasons. First, the drug may have been on the market and used for treating certain conditions for such a long time that regu- latory agencies have not retrospectively reviewed the safety and efficacy of the drug within the condition due to limited availability of clinical trials according to today’s standards. In these instances, the drug is considered beneficial by both physicians and patients perhaps based on belief, published results from real-world data, or small randomized controlled trials. A second reason that a drug may be used off label may be when a patient has exhausted all options with approved drugs without achieving effective relief. A physician may then prescribe a drug off-label for which clinical trials or published case series data are available for the indication, but the regulatory agencies have not approved such use due to need for additional trials, which the manufacture did not pursue because of perceived limited return on invest- ment, limited beneficial effect, or other reasons.
When developing a budget-impact analysis, off-label drug use may be relevant.
Perhaps the most common instance in which off-label drug use should be consid- ered is when some of the drugs used in the current treatment mix for the condition of interest are being used off label. If there is reason to believe that the treatment shares of these drugs will change when the new drug is added to the treatment mix, then they should be included in the estimates of the current and new treatment mix (Sullivan et al. 2014). The data providing their treatment shares, dosing levels, and number of pills per day should be obtained using the same data sources as used for the on-label drugs if possible.
In Box 12.1, we present an example where only off-label drugs are currently used to treat a rare condition, neuromyelitis optica, and in Box 12.2, we present several other examples of off-label use of current drugs.
1 In this chapter we make the simplifying assumption that the budget-impact analysis is based on the introduction of a new drug to the current mix of drugs for treatment of a condition. Changes in our recommended approaches to estimate the budget impacts of other types of healthcare interven- tions (i.e., vaccines, diagnostics, surgery, and devices) are discussed in Chap. 13.
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Box 12.1 Prevention of Relapses in Neuromyelitis Optica: Use of Off-Label Drugs
Neuromyelitis optica (NMO) is a rare condition that results from inflammation and demyelination of both the optic nerve and the spinal cord. It is often misdiag- nosed as multiple sclerosis, but the same drug treatments that are used for multi- ple sclerosis are not effective for NMO. Most patients have a relapsing remitting form of the disease, with each relapse associated with increasing permanent dis- ability. For example, in those with relapsing disease, up to 50% may have blind- ness or paralysis in one or both legs within 5 years (Wingerchuk 2006).
There are currently no drugs indicated for the treatment of NMO. However, many immunosuppressive drugs indicated for other conditions have been tested in case series or small trials and have been shown to be effective at reducing the frequency of relapses and slowing the increase in disability over time. In addition, intermittent plasma exchange is an alternative treatment that has been shown to be effective. If a new drug were to be indicated for the treatment of NMO, the following treatments that might be displaced by this drug would all be off label (Sellner et al. 2010):
• Azathioprine
• Prednisolone
• Rituximab
• Cyclophosphamide
• Mitoxantrone
• Mycophenolate mofetil
• Intravenous immunoglobulin
• Methotrexate
• Intermittent plasma exchange
Treatment with combinations of these drugs may also be used. Treatment shares for current drug regimens could be obtained from observational data- base studies or expert opinion. Treatment shares for a new drug approved for NMO and changes in the treatment shares for the currently used drugs could be estimated based on expert opinion.
Box 12.2 Other Examples of Off-Label Use of Drugs (Walton et al. 2008)
Drug (brand name)
Approved indication in the United States Common off-label use
Quetiapine (Seroquel)
Schizophrenia, acute treatment of manic episodes associated with bipolar I disorder (Seroquel extended release prescribing information 2013)
Bipolar disorder, maintenance Warfarin
(Coumadin)
Prophylaxis and treatment of venous thrombosis, pulmonary embolism, complications with atrial fibrillation, and cardiac valve replacement (Coumadin prescribing information 2011)
Hypertensive heart disease
12 Additional Pragmatic Topics
However, a problem may arise with estimating the administration, monitor- ing, and/or condition-related costs associated with the off-label drug.
Specifically, there may be limited data on efficacy or safety for the off-label drugs that are included in the current treatment mix as their impact may not have been examined in clinical studies. In addition, published information about the product, although available for other indications, may not give suffi- cient information to assess its administration or monitoring costs for people with the condition of interest. Thus, expert opinion might be needed to supple- ment the published and label data likely available for other indications for these off-label drugs.
Another way in which off-label use might need to be considered for the budget- impact analysis is when physicians may consider a new drug for uses other than those in the approved indication (i.e., expanded use of a new drug). In jurisdictions where such use is allowed, budget holders might be interested in obtaining estimates of this possible use, as was expressed by the authors of commentaries on the most recent International Society for Pharmacoeconomics and Outcomes Research (ISPOR) Task Force report on budget-impact analysis (Watkins and Danielson 2014; Goettsch and Enzing 2014) (see Chap. 2).
There are several problems with including off-label use for a new drug in the budget-impact analysis. First, if the analysis is being prepared by the product man- ufacturer, this might be viewed as off-label promotion and banned by the regula- tors. Second, just as we saw for the inclusion of other drugs that may be used off label, there be may be limited or no data available for the new drug in the off-label indications. The safety data from the approved indication might be transferrable to the off-label indications. However, if the drug has not been studied within the off- label indication, there will be no data on its safety, efficacy, or the relevant dosing for the off-label indications. Third, to include estimates of the budget impact of off-label use in a different condition would require consideration of this off-label indication in addition to the indicated condition. Thus, input data that are required for the approved indication, including treated population size, current treatment mix, costs, and efficacy and safety, are required in addition to input data for the other indication, which could be substantially different from the approved indica- tion. For all these reasons, off-label use of the new drug is rarely included in bud- get-impact analyses.
Escitalopram (Lexapro)
Acute and maintenance treatment of major depressive disorder and acute treatment of generalized anxiety disorder (Lexapro prescribing information 2014)
Bipolar disorder
Montelukast (Singulair)
Prophylaxis and chronic treatment of asthma, prevention of exercise-induced
bronchoconstriction, seasonal allergic rhinitis (Singulair prescribing information 1998–2012)
Chronic obstructive pulmonary disease
Celecoxib (Celebrex)
Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute pain, primary dysmenorrhea (Celebrex prescribing information 2013)
Fibromatosis
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