Issue 21 / 16 June 2014

LEADING doctors have backed a new national framework for off-label prescribing which recommends obtaining written patient consent and closely monitoring treatment outcomes.

Developed by the Council of Australian Therapeutic Advisory Groups (CATAG), the framework provides guiding principles for hospital-based doctors to get through the ethical minefield of prescribing drugs for indications not approved by the Therapeutic Goods Administration, or involving non-approved patient groups or routes of administration. (1)

Professor Madlen Gazarian, co-chair of the expert advisory group that wrote the document, told MJA InSight the framework asked prescribers, drug and therapeutics committees and consumers to more rigorously evaluate the benefits and harms of off-label medicines before starting treatment.

“For example, we are asking doctors to see if there is a clearly demonstrated benefit of a new medication over an older one before deciding to prescribe the newer drug off-label. We don’t believe this question is being systematically asked at the moment”, she said.
In a letter published in the MJA, Professor Gazarian and coauthor Steve Morris, chair of CATAG, wrote that there were seven overarching guiding principles, including a core principle of systematic evaluation of the evidence base and risk–benefit ratio for proposed off-label uses. (2)

They wrote that applying the principles in routine practice would help address clinical, safety and ethical concerns. “CATAG anticipates undertaking future work to support wider implementation of the guiding principles.”

Professor Gazarian told MJA InSight the framework included a series of questions for doctors to determine what kind of off-label use may be appropriate — “routine use”, “exceptional/individual use”, “conditional use, with evidence development” or “research or investigational use”.

For example, based on current evidence, valproate for migraine would be considered “routine use”, while rituximab for chronic, refractory immune thrombocytopenic purpura in adults would be considered appropriate only for “exceptional/individual use”.

If a proposed off-label use does not fall into one of the four categories, its use is “not recommended”.

Controversially, Professor Gazarian said using proton pump inhibitors in infants to treat gastro-oesophageal reflux would fall into the “not recommended” category, as “currently available evidence indicates they are not effective in this age group and their longer-term safety is unknown … the overall harm–benefit ratio may be unfavourable”. (3)

In all but “routine” off-label uses of medicine, the framework says written informed patient consent should be obtained.

However, Professor Gazarian said CATAG was concerned about “creating paperwork without adding benefit”. They therefore recommended hospitals develop a generic information leaflet and consent form for prescribers when discussing off-label medicines, and the creation of education and training tools.

CATAG also said further work was needed to build an off-label use of medicines registry to improve pharmacovigilance and a centralised evidence-evaluation process for selected types of off-label uses.

The principles have been applauded by two experts who recently wrote about potential pitfalls of off-label prescribing in the MJA.

In an MJA editorial Professor Ian Hickie, of Sydney’s Brain and Mind Research Institute, raised public and professional concerns about medications not indicated for common mental health conditions often being prescribed. (4)

In a separate MJA editorial, Professor Paul Seale, professor of pharmacology at the University of Sydney, discussed the need to fully inform patients when prescribing off-label. (5)

Professor Hickie told MJA InSight he strongly supported the push for a registry for off-label uses of medicines.

“There are a whole lot of areas of medicine where large-scale studies are never going to be done but there are good reasons for considering use of medicines — particularly geriatrics, paediatrics, complex patients”, Professor Hickie said.

“In these areas, we should be using new e-health-based systems to monitor patient experiences, not just adverse events.”

Professor Mark Nelson, chair of the discipline of general practice at Tasmania’s Menzies Research Institute, said the recommendations to obtain consent and monitor outcomes when prescribing medicines off-label applied to general practice as well as hospitals.

“A typical example would be using paracetamol for osteoarthritis. You might give the patient paracetamol for a week and record their arthritis on a pain scale and then take them off it for a week to see if there’s any difference”, he said. “We should be doing n = 1 trials like this all the time as part of our clinical management of patients.”


1. CATAG 2013; Guiding principles for the quality use of off-label medicines
2. MJA 2014; 200: 637
3. Pediat 2011; 127: 925-935
4. MJA 2014; 200: 65-66
5. MJA 2014; 200: 65


Should patients give written consent to off-label prescribing of drugs?
  • No - verbal consent is sufficient (39%, 22 Votes)
  • Yes - in all cases (33%, 19 Votes)
  • Yes - if evidence is in doubt (28%, 16 Votes)

Total Voters: 57

Loading ... Loading ...

3 thoughts on “Off-label guide welcomed

  1. Stephen Hartwig says:

    This will contributing to creating a medical society that is drowning in paperwork. Getting consent will likely inhibit the sensible use of “routine” off-label medication use (eg metoclopromide for acute migraine).

  2. Sue Ieraci says:

    This discussion appears to confuse “Off-label” with ”against best practice”. As mentioned by Stephen Hartwig,  prochlorperazine (Stemetil) and the other phenothiazines are evidence-based as IV treatment for migraine – cheap and safe as a one-off IV dose, with appropriate cautions for side-effects). When we began using this in EDs, it was ”off label” because there was no incentive for any manufacturer to go through the long and expensive process for getting approval for another use. Not only will there be a nightmare of paperwork, but quite likely a limitation of the use of cheap and effective drugs. If patients have to consent for any treatment, it sould be for non-evidence-based use of medications, not non-registered uses. TAG approval is not the same as evidence-based.

  3. Madlen Gazarian says:

    We thank Sue Ieraci and Stephen Hartwig for their comments and would like to provide a few clarifications in reply:  1) The CATAG guidance clearly acknowledges that not all off-label prescribing is the same & that some uses are “evidence-based” & may even represent “best practice”;  2) It also acknowledges that current approaches to decision-making about off-label uses are highly variable;  3) The CATAG framework provides a structured process for systematic evaluation of the evidence base & more rigorous assessments of potential harms & benefits of proposed off-label uses before initiating treatment;   4) Following this process, if a proposed use is considered “evidence-based” (meeting criteria for “routine use”), then the usual process for consent to treatment is sufficient & there is NO requirement for “written” consent;   5) These recommendations were developed with extensive national consultation, including with consumers and national medical indemnity bodies, who provided important input to the recommendations for appropriate patient information & consent processes and ethical oversight of off-label prescribing. The full CATAG guidance provides further details.

Leave a Reply

Your email address will not be published.