Abstract
A colleague in private practice commented recently that despite his best efforts he is finding it increasingly frustrating to treat patients optimally. Specifically, in many instances he has to resort to off-label use of medications. This is a growing concern as shown by a recent study in which more than half of the psychiatrists routinely prescribed psychotropic medications off-label (1). In Australia, medications are licensed by the Therapeutic Goods Administration (TGA) for a specific set of indications following application by the manufacturer. Prescribing ‘off-label’ refers to the use of a medication outside such indications. There are a number of ways in which this can occur: a drug may be deemed to be prescribed off-label if the dose exceeds that specified by the manufacturer; the prescription is for an indication that has not got TGA approval; the medication is administered to a patient that falls outside a specified group by virtue of age or diagnosis; or the method of administration is altered.
A complication for clinicians is that a medication may have a strong evidence base for its use for a specific condition, be recommended in guidelines and licensed for use internationally, but not in Australia and New Zealand. The use of this medication for this particular condition would still be regarded as “off-label”.
Off-label prescription is particularly problematic in psychiatry where accurate and definitive diagnoses are often difficult and the optimal treatment option is seldom self-evident. For example, in complex cases or where there is already polypharmacy an additional medication is unchartered territory. This is important because the prescription of a drug off-label carries with it potential risks, and it is often difficult to determine the precise benefits or risks of such treatment. For example, if a patient suffers from an adverse event whilst on a medication that has been prescribed off-label, the responsibility, and indeed liability, rests with the prescriber and in turn, their employer unless it can be shown that administration of the drug was in the best interest of the patient. Thus, off-label prescribing increases the professional responsibility of the doctor. In such cases it is wise to carefully document your rationale for the prescription, and if possible, consult with a colleague about what action to take. This is because doctors may sometimes have to justify why they have not acted in accordance with the manufacturers guidelines. In reality, in most cases, it is possible to argue that there is widespread use of a particular drug for a ‘specific off-label indication’ and that there is evidence of benefit to patients with such off-label use. In fact, some off-label uses have been adopted by prescribing guidelines and are essentially regarded as the norm. Such well-established use is also referred to as ‘near label’.
But why is it that doctors are put in this invidious position in the first place? In some instances psychiatrists themselves are to blame as they are simply not aware that they are prescribing off-label (2). Defending this in part, this is not particularly surprising, given the fact that the evidence base for most medications is vast and ever changing and it is difficult for most clinicians to remain up to date. Further, in psychiatry it is often difficult to establish the ‘boundaries of evidence’ and there is perhaps greater scope for innovation and trialing new applications. However, off-label prescribing also arises because pharmaceutical companies almost always obtain an initial license for a relatively narrow indication predicated upon diagnoses within DSM. This is because they have to first demonstrate efficacy and to ensure success they begin by testing the drug in well-controlled adult populations for which patients are easier to recruit and participants can give informed consent. Consequently, the patients in these clinical trials are usually not ‘real world’ and rarely include those that are elderly, young or pregnant. Then once a license for a specific indication is achieved, companies will usually attempt to expand the scope of the indication and extend the clinical use of the medication across a broader range of disorders. A good example of this trend of ‘migration’ across disorders is the administration pattern of atypical antipsychotics, which were initially used for the treatment of schizophrenia but have gradually seen increasing uptake in bipolar disorder and now major depression. Finally, the manufacturer may not have sought TGA approval for a specific indication, especially when the drug is off patent, despite a strong evidence base for its use.
In psychiatry, many medications are prescribed at doses higher than those recommended, or for ‘conditions’ that are beyond those for which the drug is indicated. This is a particularly common problem for populations such as children and adolescents, and the elderly, because of the paucity of studies conducted in these age groups.
Clearly this is an unsatisfactory state of affairs for all concerned but especially psychiatrists who are unnecessarily burdened with a heavy responsibility whilst attempting to best serve their patients. To this end real-world recommendations are needed in which the potential usage of drugs can be incorporated with the empirical evidence that informs clinical practice. This would allow safer and arguably more cost-effective off-label usage. At present, it is hard to quantify off-label use and determine its effectiveness. A better understanding of off-label use would provide a means for gathering accurate real world data that could then meaningfully inform clinical practice. At the same time better monitoring of prescribing patterns may help identify ‘at risk’ uses of medications that are unsupported by evidence or collective experience.
This is a big undertaking that is long overdue, but one of those rare initiatives that would benefit all parties concerned.