We need better evidence as a basis for off-label prescriptions

The practice of off-label prescription poses a significant issue for the advocates of evidence-based medicine, given that this area is particularly poorly served by data. Broadly speaking, off-label prescriptions fall into two classes, secondary therapeutic uses or ancillary patient populations outside regulatory approval. In some cases, it represents as high a proportion as 97% of the overall use of the product (Factor VIIa); slightly less enormous proportions apply for BMP-2 and modafinil. Paediatrics, oncology and psychiatric care are core areas of high off-label use in the 40% to 60% range.

We should be concerned about this issue because adverse events, and serious adverse events, are particularly common with off-label medication, having been reported at a level of 150% of on-label comparators. Another study from France in paediatric care showed that there were over three times as many adverse events associated with off-label medication as with ‘on-label’ alternatives. A second problem is that there is little or no good scientific evidence available for over 70% of off-label uses. And thirdly, as we said previously, that safety in one indication or patient group does not guarantee adequate safety in all; the balance of safety and efficacy needs to be borne in mind before an off-label prescription can be validly written. However, the right to prescribe in an off-label fashion, according to patient needs, goes to the heart of the doctor’s obligation to act in accordance with the patient’s best interests, and in some areas where there is no formally approved product, there may be no alternative. Off-label medication should clearly not be proscribed, but should it be more transparent?

The All-Trials movement is especially concerned about the ‘Hidden Trial’ data behind many existing medicines, where information is distorted and negative trial results kept from public scrutiny. The behaviour of the pharmaceutical industry, but also some academic investigators, are intensely criticised for this practice. In the case of off-label medicine, the issue is somewhat different, in that prescriptions are based on inadequate, sparse, or even non-existent evidence, but then the issue is compounded as outcomes from these individual cases are not written down: the knowledge is not collated, even if the information is orally available.

Statistics show that the hazards of off-label prescription to patients can be great, and despite potential benefits, efficacy is far from assured; under these conditions, the ethical imperative for recording outcomes is unarguable, if future prescribers are not to act in ignorance of the paths trodden before them. So far, we have not heard the opinion of the All-Trials movement on the issue of off-label medicine, and in particular the proposal for the outcome from all off-label prescriptions to be written down, in order to inform subsequent generations of prescribers and their patients.

Ben Goldacre describes in ‘Bad Pharma’ a simple clinical trial conducted in a doctor’s surgery to compare the outcomes from two seemingly similar statins for the treatment of high blood cholesterol levels. Particular emphasis is placed on the simplicity of the trial and the measurement of the results, so that minimal additional effort is required by the prescriber. Similar procedures should be put in place for off-label prescriptions, so that patients can report the efficacy and safety of their treatment, prescribers can collate this information and databases can be constructed for future analysis. We must recognise that individual case reports of this nature cannot compare with the rigidity and statistical power of properly conducted placebo controlled trials. But when assembled in their multitudes, individual reports become armies of information; they do acquire significant power, and they can act as gateways for proper, formal investigation.

Manufacturers who charge the same price for the sale of both ‘on-label’ and off-label products have a definite role in this process; but given the panoply of different uses, different patient groups and other ways in which prescriptions can be categorised as off-label, we should impose certain hurdles, and only above a certain frequency, for manufacturers to become involved. Properly conducted trials cost money, lots of money; even if it is not clear who would pay for recording the results of individual examples of off-label use, beyond a certain scale, manufacturers should step in to conduct this analysis.  Patients, and indeed our wider healthcare systems demand nothing less. But the information gathering must start in the doctor’s surgery, since that is where the off-label prescription decisions are first made.

It is in the prescriber’s mind to use a drug that has been examined and approved for one purpose for another purpose, and yet the essential scientific nature of this enquiry is somehow lost in translation. Two arguments are posed against this precept, the first being that some off-label prescriptions are near enough to on-label, or otherwise so widely used that there is no dispute about their medical and scientific basis. There may be rare examples of this, but we should not read too much into them.  A recent study looked at 363 articles in New England Journal of Medicine, in particular looking at medical reversals, situations in which new studies contradict current practice. The study only found a minority (38%) of current practices were affirmed by this analysis, with 40% (146) of these practices shown to be ineffective, and a further 22% where the evidence was inconclusive. This tells us the danger of accepting arguments about ‘standard of care’ without formal proof, and of course leaves unaddressed the majority of off-label prescription for which there is little or no scientific support.

The second argument used against the equivalence of off-label prescription and scientific enquiry is a legal one. Somehow, legal obstacles are placed in the way of the definition of this experiment as a ‘trial’; somehow, we have accepted the idea of off-label medicine as so much the right of the prescriber to prescribe, of ‘Doctor knows best’, that it is legally construed as ‘not a trial’. Yet, even if evidence exists in support of a particular example of off-label use, and even if (a big question) the prescriber is fully familiar with the scientific landscape, it has by definition not met the rigid hurdles of regulatory review that patients expect: the balance of safety and efficacy, of risk and reward, has not been made — the very best we can say is that the ‘trial’ is to be ‘confirmatory’.

Suddenly we are confronted with an essential conundrum: how can we pursue evidence-based medicine while ignoring the outcome from such hypothesis-driven forms of behaviour?  It is time for the All-Trials movement to shine a light on this somewhat dimly lit corner of medical practice, so that future generations can be enlightened by present day practice.