Scientific Poster Sample

Prospective data collection of off-label use of rituximab in Australian public hospitals
Kate O’Connor1, Jane Donnelly2, Chris Liddle1,3
1Westmead Hospital, 2Council of Australian Therapeutic Advisory Groups, 3The University of Sydney

Rituximab is a chimeric, anti-CD20 monoclonal antibody registered  for the treatment of B-cell malignancies and refractory rheumatoid arthritis in Australia. In addition to these approved indications, there   is anecdotal evidence that a significant proportion are is being used off-label for the management of a variety of diseases.
Aims
To provide a snapshot of the extent of off-label rituximab use;
To	describe	off-label	indications	for	which	rituximab	is	being prescribed; and
To understand the cost burden of off-label rituximab prescription.
Methods
An online survey tool prospectively collected data of off-label rituximab prescription for a six months period from April 2012 to October 2012. All Australian hospitals were contacted and provided a survey link via the State and Territory Therapeutic Advisory Groups.

Individual hospitals entered data to the survey. Data recorded included clinical indication, dosing schedule, previous therapy and efficacy assessment. For each of the clinical indications reported a literature search was conducted to assess the available level of evidence for rituximab use.
Table 1: Levels of evidence

Level	Evidence	
Level 1*	Systematic review of randomized trials	
Level 2*	Randomized trial or observational study with dramatic effect	
Level 3*	Non-randomized controlled cohort/follow up study	
Level 4*	Case-series or case-control studies or historically controlled studies	
Level 5*	Mechanism-base reasoning	

*Level may be downgraded due to study quality, inconsistencies between studies or if the effect is very small. Level may be upgraded if there is a large effect.
Modified from: OCEBM Levels of evidence Working Group. "The Oxford 2011 Levels of Evidence".Oxford Centre for Evidence-Based Medicine. http://www.cebm.net/index.aspx?o=565 3

Ethics approval was granted by The University of Sydney Human Research and Ethics Committee.
Results
Table 2: Subject and hospital demographics

Characteristics	Approvals (n=364)	
Median age (range)	46 (1-89) years	
Sex	Female: 211 (58%)
Male: 153 (42%)	
Previous rituximab	Yes: 131 (36%)
No: 218 (60%)
Not recorded: 15 (4%)	
Previous disease targeting therapy	No: 45 (12%)
Yes: 279 (77%)
Unknown: 40 (11%)	
Hospital size	> 500 beds: 227 (62%)
250-500 beds: 135 (37%)
< 250 beds: 2 (1%)	
Acknowledgements
CATAG thanks the individual hospitals who participated in the study.
This work was supported by NPS MedicineWise, an independent organisation funded by the Australian Government Department of Health and Ageing. CATAG receives administrative support from the NSW Therapeutic Advisory Group.

Further information:
O'Connor, K. and Liddle, C. (2013), Prospective data collection of off-label use of rituximab in Australian public hospitals. Internal Medicine Journal, 43: 863–870. doi: 10.1111/imj.12206

Table 3: Most commonly reported clinical conditions instigating off- label rituximab prescribing and level of evidence for use, n= 353

Condition	Number of cases	Level of Evidence	
Idiopathic thrombocytopenia purpura	23	3	
Autoimmune haemolytic anaemia	11	4	
Acquired haemophilia	10	4	
Systemic lupus erythematosus	27	4	
Rheumatoid arthritis	6	1	
Vasculitides	42		
Granulomatosis with polyangiitis	22	1	
ANCA vasculitis	7	1, 4	
Neuromyelitis optica	15	4	
Antibody-mediated rejection
transplant (lung, cardiac, renal)	18	3	
PTLD liver, renal or cardiac	10	3	
Lymphoma unspecified	25	*	
Polymyositis/Dermatomyositis/ Myositis	14	4	
Myasthenia gravis	11	4	
GN / Nephrotic syndrome	12	*	
ANCA = Anti-Neutrophil Cytoplasmic Autoantibody; PTLD= post-transplant lymphoproliferative disease GN= glomerulonephritis

Level 1 evidence of efficacy existed only for rheumatoid arthritis and granulomatosis with polyangiitis.	Level 4	evidence was available to support the use of rituximab for 40% of the indications due to the lack of sufficiently powered clinical trials or the rarity of the conditions.
Many of the listed conditions are extremely rare and a high level of evidence leading to a registered indication is unlikely to arise.

Graph 1: Reported dosing schedules (n = 348)

Number of   cases

Figure 1 demonstrates the variation in dose  regimens  for rituximab off-label prescribing. This likely reflects the lack of evidence-based guidance for an effective and safe dose for a particular condition.

Conclusions
The audit highlighted the extensive and heterogeneous nature of medical conditions for which rituximab is considered a therapeutic option	for		all	ages.	Given	the		paucity	of		evidence	for	many rituximab-treated	conditions,		standardised		consistent		drug approval	mechanisms	with		requirements	for		monitoring			and reporting of outcomes is recommended so that future decision- making may be informed by collated data analysis.
Council   of Australian Therapeutic Advisory Groups , CATAG  Secretariat, PO BOX 766, Darlinghurst NSW 2010.
Email: catag@stvincents.com.au