Journal of Clinical Neuroscience 21 (2014) 2083–2087
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Multiple sclerosis disease modifying medicine utilisation in Australia Samantha Hollingworth a,⇑, Kimitra Walker b, Andrew Page c, Mervyn Eadie d a
School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia School of Population Health, The University of Queensland, Herston, QLD, Australia c School of Science and Health, University of Western Sydney, Penrith, NSW, Australia d School of Medicine, The University of Queensland, Herston, QLD, Australia b
a r t i c l e
i n f o
Article history: Received 9 December 2013 Accepted 15 May 2014
Keywords: Fingolimod Glatiramer acetate Interferon Multiple sclerosis Natalizumab Prescribing Utilisation
a b s t r a c t With the introduction of new disease modifying medicines (DMM) for relapsing remitting multiple sclerosis (RRMS) in Australia, we aimed to examine trends in utilisation from 1996 to 2013. We analysed trends in use by administrative area (state/territory). Prescription data from Medicare Australia were converted to defined daily doses (DDD)/1000 population/day using population data. Overall RRMS DMM use increased progressively from 0.024 to 0.68 DDD/1000 population/day between 1996 and 2013. From 1996 to 1999 interferon b1B was the only such agent available. Interferon b1A became the most widely used RRMS DMM in 2001. Glatiramer acetate became available in 2004 and its use thereafter increased slowly. Natalizumab was introduced in 2008 with slow growth and fingolimod use grew substantially once it was subsidised in 2011. Both these medicines have accounted for the growth in total use of RRMS DMM in 2012 and 2013. Overall RRMS DMM use was higher in more southern states than in northern states. Patterns of preferred agent varied between different Australian states and territories. RRMS DMM use in Australia has grown progressively since 1996, probably related to growing medical and patient confidence in the benefits obtained from using such drugs, longer survival in MS patients (partly related to use of drug treatments), and easier recognition of MS with the wider availability of magnetic resonance imaging (MRI). The availability of fingolimod, the first DMM that can be taken by mouth, may have led RRMS patients who rejected parenteral therapy to commence treatment of their disease. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic inflammatory, primary demyelinating disease of the central nervous system and is the most common cause of continuing neurological disability in young adults in western societies [1]. In most patients, MS follows a relapsing-remitting course (relapsing remitting multiple sclerosis [RRMS]) at least in its earlier stages. In these stages there is often complete clinical recovery between attacks, but over time recovery between attacks becomes incomplete and most patients ultimately enter a secondary progressive phase [1]. In about 10% of patients, the disease runs a primary progressive course, with continuing deterioration in neurological function from the outset, without relapses and remissions [2,3]. The overall progressive nature of the disorder, the eventual debilitation, and the peak age of onset of 30–49 years, [1] result in high levels of support and medical care being required and significant loss of productivity in the workforce [4]. Half the people living with MS in Australia are unemployed [5]. ⇑ Corresponding author. Tel.: +61 7 3346 1981; fax: +61 7 3346 1999. E-mail address: [email protected] (S. Hollingworth). http://dx.doi.org/10.1016/j.jocn.2014.05.034 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
It is estimated that in 2010, in Australia, MS cost one billion dollars, with lost productivity being the largest cost component [6]. The greatest use of resources was for immunomodulating medicines, consultations and nursing [7]. MS treatment was essentially symptomatic until new disease modifying medicines (DMM) became available in Australia after 1985, including interferon b1B, interferon b1A, glatiramer acetate, natalizumab and fingolimod [8,9]. These medicines are approved for use in the relapsing-remitting phase of the disease and appear capable of favourably altering its natural history [2]. In Australia, they are publically subsidised on the Pharmaceutical Benefits Scheme (PBS) under the ‘Authority Required’ prescription mechanism [10] for patients who (i) have had at least two attacks in the preceding 2 years with partial or complete recovery and remain ambulant, and (ii) have their diagnosis confirmed by MRI of the brain or spinal cord. Until recently, public rebates were available only on MRI studies ordered by a specialist. As a result, prescriptions of these agents are generally initiated by specialists (specifically neurologists) but may be continued by general practitioners in the community. These drugs are too expensive to be routinely obtained by private prescription (i.e. where the consumer
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pays the total cost) and the PBS has mechanisms to ensure that individuals do not receive more than one such agent simultaneously [11]. We examined the patterns of utilisation of RRMS medicines between 1996 and 2013 in Australia and differences at various times in utilisation among the nation’s states and territories.
2. Methods All the medicines were available under the Australian Government’s subsidised medicine formulary, the PBS. The PBS provides a broad range of Australian registered medicines to Australian citizens with two levels of patient co-payments: general (AUD$36.10, 2013) and concessional (AUD$5.90, 2013) [12]. Concessional beneficiaries are those who receive social security benefits because they hold a Pensioner card, a Health Care card, or a Commonwealth Seniors Health card. The medicines considered in this study are listed only for use in patients with diagnosed RRMS that meet the criteria mentioned above and are all priced substantially above the level of co-payment. Patients who have progression of disease despite treatment are not eligible for repeat prescriptions of subsidised medicines [2]. None of these medicines has any other subsidised therapeutic use and they are almost invariably used in the same standard dose without individual variation. A single prescription (initial plus five repeats) supplies one person for 24 weeks. The medicine cost for all the agents (except natalizumab and fingolimod) for one person with RRMS is approximately AUD$1092 per 28 day period – more than AUD$13,100 per annum. There would likely be very little prescription of these agents in public hospitals due to costs and because patients with RRMS are mostly managed on an outpatient basis. Natalizumab, a monoclonal antibody, has been available since July 2008 (under PBS Section 100 Public from August 2010) for use in approved hospitals for monthly intravenous infusion as day procedures for the treatment of RRMS. It costs AUD$2,038 for a month’s supply. Fingolimod was subsidised in 2011 and costs AUD$2,313 per month. The number of dispensed prescriptions for RRMS medicines was obtained from public domain Medicare Australia PBS statistics provided by the Australian Government Department of Health [8]. Data were collected for the period between January 1996 and December 2013 and stratified by administrative areas – state or territory – for each formulation of each medicine. The amount of medicine dispensed (as prescriptions) was standardised to utilisation using the defined daily dose (DDD) per 1000 population per day. The DDD, as established by the World Health Organization Collaborating Centre for Drug Statistics Methodology, is the assumed average maintenance dose per day (expressed in terms of the dose contained in marketed dosage forms) for a medicine used for its main indication in adults [13]. For DDD calculations we used the midyear population for each state or territory and Australia as a whole [14]. Yearly totals of DDD were summed for each administrative region and for the whole nation. The medicines in alphabetical order by generic name (with the trade name and DDD) are: fingolimod (Gilenya, 0.5 mg [Novartis, Basel, Switzerland]), glatiramer acetate (Copaxone, 20 mg [Teva Pharmaceutical Industries, Petah Tikva, Israel]), interferon b1A (Avonex, 4.3 mcg [Biogen Idec, Weston, MA, USA]), interferon b1A (Rebif, 4.3 mcg [Merck Serono, Darmstadt, Germany]), interferon b1B (Betaferon, 4 mU [Bayer HealthCare AG, Levekusen, Germany]); and natalizumab (Tysabri, 10 mg [Biogen Idec]). Interferon b1B was listed on the PBS in November 1996 followed by interferon b1A-Avonex preparations in February 1999 and interferon b1A-Rebif preparations in May 2000. Glatiramer acetate was listed in May 2004, natalizumab in July 2008 and fingolimod in September 2011.
3. Results 3.1. Utilisation use over time Overall use of RRMS DMM increased 28-fold between 1996 and 2013 (from 0.024 to 0.680 DDD/1000 population/day; Table 1). The most commonly prescribed medicine from 2001 was interferon b1A with a peak utilisation of 0.359 DDD/1000 population/day in 2010 (Fig. 1). Glatiramer acetate use reached 0.085 DDD/1000 population/day in 2010 and had about 15% share of the market in the last few years (Table 1). Interferon b1A use, as a proportion of all RRMS DMM use, decreased from about two thirds in 2003 to less than half in 2013 (Table 1). Natalizumab use has increased to 12% and fingolimod has increased to 21% of RRMS DMM use in 2013. There was a relative plateau in overall RRMS DMM use between 2005 and 2007, but use increased in 2009 and subsequently – the increase being largely accounted for by growth in use of fingolimod and natalizumab (Fig. 1). 3.2. Utilisation use by state or territory The total Australian RRMS DMM use was 0.592 DDD/1000 population/day in 2013 (Fig. 2). Tasmania had the highest utilisation with 0.845 DDD/1000 population/day in 2013 and the Northern Territory (NT) the lowest with 0.105 DDD/1000 population/day, about one eighth that of the Australian Capital Territory (ACT). In all jurisdictions, interferon b1A was the most used RRMS DMM. Interferon b1B use was low and fairly consistent across most states and territories, with higher use in Tasmania. Although there was increasing use along a general north– south gradient of states, there was a major exception in that its use in the ACT (0.733 DDD/1000 population/day) was greater than in the geographically surrounding state of New South Wales (NSW; 0.532 DDD/1000 population/day). The population in the ACT is about 5% of NSW. The use of fingolimod, relative to the other medicines, was low in the NT, Queensland and Tasmania. 3.3. Utilisation use with time in different administrative areas The introduction of each new RRMS DMM to the PBS was associated with changes in the proportion of overall use for which each agent was responsible, both nationally and in the individual states and territories. The proportions for each medicine in each administrative area for the years 2001 (before glatiramer acetate became available), 2007 and 2013 are shown in Table 2. Overall in Australia and in each administrative area, as glatiramer acetate, natalizumab and fingolimod use grew, the use of b-interferons showed a relative decline (especially after 2006). In the areas where interferon b1A initial use was higher, use declined to a fairly consistent figure of around 40–50% of overall use. Interferon b1B use declined progressively in all states and territories as use of the other medicines grew, with the decrease being greatest in the NT (from 74% to 35%). The ratio of interferon b1B to interferon b1A use was below unity in 2007 and 2013 (except for 347% in the NT in 2013, Table 3). The wide variation in ratios in the NT likely reflects the very small number of patients. In 2013 the ratio of use ranged from 49% in Tasmania to 13% in the ACT. 4. Discussion Over the period between 1996 and 1999, when interferon b1B was the only RRMS DMM available in Australia, its use in the whole country increased more than 4-fold. This growth may have mainly been a result of prescribers becoming increasingly familiar with the idea of a new type of therapy being available, and people with
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S. Hollingworth et al. / Journal of Clinical Neuroscience 21 (2014) 2083–2087 Table 1 Utilisation (DDD) and proportion of all use (%) for all relapsing-remitting multiple sclerosis medicines between 1996 and 2013 in all of Australia Year
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Interferon b1B
Interferon b1A
Glatiramer acetate
Natalizumab
Fingolimid
All RRMS
DDD
%
DDD
%
DDD
%
DDD
%
DDD
%
DDD
%
0.024 0.065 0.085 0.101 0.116 0.116 0.131 0.133 0.132 0.136 0.135 0.133 0.123 0.123 0.118 0.102 0.095 0.068
100% 100% 100% 80% 62% 44% 37% 34% 29% 26% 25% 25% 23% 22% 20% 18% 14% 11%
– – – 0.025 0.070 0.149 0.227 0.263 0.299 0.321 0.339 0.347 0.334 0.350 0.359 0.344 0.340 0.263
– – – 20% 38% 56% 63% 66% 64% 62% 63% 64% 63% 63% 62% 60% 52% 44%
– – – – – – – – 0.033 0.058 0.062 0.063 0.068 0.079 0.085 0.086 0.087 0.070
– – – – – – – – 7% 11% 11% 12% 13% 14% 15% 15% 13% 12%
– – – – – – – – – – – – 0.004 0.000 0.014 0.022 0.041 0.069
– – – – – – – – – – – – 1% 0% 2% 4% 6% 12%
– – – – – – – – – – – – – – – 0.022 0.094 0.122
– – – – – – – – – – – – – – – 4% 14% 21%
0.024 0.065 0.085 0.126 0.186 0.265 0.358 0.396 0.465 0.515 0.535 0.543 0.529 0.552 0.575 0.577 0.655 0.592
100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
DDD = defined daily dose/1000 of population/day, RRMS = relapsing-remitting multiple sclerosis.
DDD/1000 populaon/day
Fig. 1. Individual and total relapsing-remitting multiple sclerosis drug utilisation (defined daily dose/1000 population/day between 1996 and 2013 for all of Australia. DDD = defined daily dose, Int = interferon.
0.9
Int β1A
0.8
Int β1B
0.7
Glaramer
Fingolimod 0.6
0.5
Natalizumab Total
0.4 0.3 0.2 0.1
0 NT
QLD
NSW
WA
SA
ACT
VIC
TAS
Aust
State/Territory Fig. 2. Utilisation (DDD/1000 population/ day) of the two ß interferons and glatiramer acetate, fingolimod, natalizumab and the five agents combined in Australian states and territories (by latitude of capital city) for 2013. ACT = Australian Capital Territory, Aust = Australia, DDD = defined daily dose, Int = interferon, NSW = New South Wales, NT = Northern Territory, QLD = Queensland, SA = South Australia, TAS = Tasmania, VIC = Victoria, WA = Western Australia.
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Table 2 Proportion of use (%) of selected relapsing-remitting mutiple sclerosis drugs within Australian states and territories for 2001, 2007 and 2013* Administrative area
Drug
2001
2007
2013
Northern Territory
Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod
74% 26% 0% 0% 0% 69% 31% 0% 0% 0% 41% 59% 0% 0% 0% 55% 45% 0% 0% 0% 38% 62% 0% 0% 0% 39% 61% 0% 0% 0% 37% 63% 0% 0% 0% 54% 46% 0% 0% 0% 44% 56% 0% 0% 0%
24% 68% 8% 0% 0% 37% 49% 13% 0% 0% 21% 68% 11% 0% 0% 29% 65% 9% 0% 0% 21% 65% 14% 0% 0% 11% 67% 22% 0% 0% 22% 67% 11% 0% 0% 42% 47% 10% 0% 0% 25% 64% 12% 0% 0%
35% 10% 14% 3% 37% 15% 51% 14% 9% 12% 11% 47% 11% 8% 23% 12% 41% 8% 21% 17% 9% 43% 13% 12% 23% 7% 48% 29% 2% 15% 10% 40% 11% 14% 26% 22% 46% 12% 11% 8% 11% 44% 12% 21% 21%
Queensland
New South Wales
Western Australia
South Australia
Australian Capital Territory
Victoria
Tasmania
Australia
* Natalizumab data not shown because of uncertainty about its completeness but included as part of totals so not all will add to 100% within a year.
Table 3 Ratios of Interferon b1B use to Interferon b1A use in 2001, 2007 and 2013 in Australian states and territories and Australia (in bold) (expressed as percentages) Administrative area
2001
2007
2013
Northern Territory Queensland New South Wales Western Australia South Australia Australian Capital Territory Victoria Tasmania Australia
286% 225% 71% 124% 61% 63% 58% 117% 78%
35% 76% 31% 39% 32% 16% 33% 89% 40%
347% 29% 23% 30% 20% 13% 25% 49% 26%
MS becoming aware of its existence. As more treatment options became available, total RRMS DMM use continued to increase. Use of interferon b1B, which accounted for all dispensed prescriptions of RRMS therapy before 1999, provided less than one fifth of total RRMS DMM use by 2013, despite interferon b1B use being
relatively steady from 2002 to 2007, and thereafter undergoing a slight decline. The availability of various dosage forms of interferon b1A from 1999 onwards may have slowed the growth of interferon b1B use. More recently, other DMM have been subsidised, namely glatiramer acetate, natalizumab and fingolimod, and particularly the latter two are becoming more widely used and largely account for the overall increase in use of RRMS DMM from 2008 onwards. These data are consistent with those found in Canada [15]. The use of both natalizumab and fingolimod seems sufficient to account for the overall increase in national DMM use over 2011–2013. This suggests that there was a population of people with RRMS who had previously been eligible for supply of DMM but had not taken the parenteral agents that were available to them. Some of these people with RRMS were prepared to accept an oral therapy. The increase in overall RRMS DMM use over the 15 years likely reflects the influences of several factors. Though no cure has yet been found for MS, advances in the available DMM and advances in symptomatic therapy have resulted in increased life expectancy for people with MS [2]. As a consequence, there has been an increase in disease prevalence. Also, aided by the growing availability and diagnostic capability of MRI, there has been an increasing recognition of cases of RRMS in the Australian community, further increasing the number of people eligible for treatment. Following the earlier growing prescriber awareness of the availability of RRMS DMM, there has been a subsequent growing consciousness among prescribers of the benefit to people with RRMS of using such therapies and people with RRMS have more or less simultaneously become aware of the benefit. There was generally higher use of RRMS DMM in the more southerly Australian administrative areas than in the more northerly ones, consistent with the known higher prevalence of the disease with increasing distance from the equator in both hemispheres [16–23], the reasons for which remain unclear [24]. There was, however, an exception to this relationship in the relatively high use of RRMS DMM in the ACT, compared with their use in the surrounding state of NSW – a usage pattern driven by heavy prescribing of glatiramer acetate in the ACT. There is no obvious explanation for the different patterns of preferred use of the various agents in the different jurisdictions, apart from consequences of individual neurologist preferences [23]. The differences are more noticeable in jurisdictions with fewer people and fewer neurologists where one neurologist’s different pattern of practice may have more obvious consequences for the data. Utilisation use of natalizumab through the PBS, introduced in 2008, probably was greater than appears in the data. Confidential sales figures provided by the marketing company suggest that there may be delayed reporting of its use to the Australian Government by hospital pharmacies in contrast to community pharmacies who report dispensing other RRMS DMM quickly to receive government payments. This possible discrepancy confounds the interpretation of natalizumab data from 2008 to 2013. Furthermore, natalizumab use may have been slow to increase due to concerns regarding progressive multifocal leucoencephalopathy [25]. The strength of this study is that it presents national data on all subsidised prescribing, and approximately all prescribing, of RRMS DMM over an 18 year period in Australia. This is the case because, with the high cost of these medicines, it is highly unlikely that they would be purchased privately (i.e. without government subsidy). The parenteral DMM usage patterns that prevailed in the 2005–2009 period, when total use reached an approximate plateau, may provide a baseline for interpreting the situation in the near future, as orally administered agents come into increasing use when the early experience with the first agent suggests that people with RRMS who would have rejected parenteral treatments may be prepared to accept oral ones.
S. Hollingworth et al. / Journal of Clinical Neuroscience 21 (2014) 2083–2087
Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements The data used in this study were obtained from Medicare Australia administered by the Australian Government Department of Health and Ageing. No funding was received for this study beyond existing salaries. No ethics approval was required for this study as all the data was available in the public domain and no individual receiving the therapies was identified at any stage. References [1] Ropper AH, Samuels MA. Multiple sclerosis and allied demyelinating diseases. Adams and Victor’s principles of neurology. 9th ed. USA: McGraw-Hill Companies Inc.; 2009. p. 874–96. [2] Taylor I, Macdonell R, Coleman J. Treatment of multiple sclerosis with newer immune-modulating drugs. Aust Prescr 2002;25:32–5. [3] Poser CM. The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994;36:S180–93. [4] Simmons RD, Tribe KL, McDonald EA. Living with multiple sclerosis: longitudinal changes in employment and the importance of symptom management. J Neurol 2010;257:926–36. [5] Access Economics. Acting positively: strategic implications of the economic costs of MS in Australia. Report by Access Economics Pty Limited for Multiple Sclerosis Australia. Canberra: Access Economics Pty Ltd, 2005. [6] Palmer AJ, Colman S, O’Leary B, et al. The economic impact of multiple sclerosis in Australia in 2010. Mult Scler 2013;19:1640–6. [7] Taylor B, McDonald E, Fantino B, et al. The cost of multiple sclerosis in Australia. J Clin Neurosci 2007;14:532–9. [8] Medicare Australia. Pharmaceutical Benefits Schedule Item Reports, ; 2014 [accessed 01.05.14]. [9] Pender MP. Recent progress in the diagnosis and treatment of multiple sclerosis. J Clin Neurosci 1999;6:367–72.
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[10] MIMS Australia. MIMS Australia. St Leaonards, Australia: UBM Medica Australia; 2009/2010. [11] Department of Health. Section 100 – Highly Specialised Drugs Program, ; 2014 [accessed 01.05.14]. [12] Department of Health. About the PBS, ; 2014 [accessed 01.05.14]. [13] Zivadinov R, Iona L, Monti-Bragadin L. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A metaanalysis study. Neuroepidemiology 2003;22:65–74. [14] Australian Bureau of Statistics. Population by Age and Sex, Australian States and Territories. Cat. No. 3201.0: Australian Bureau of Statistics, 2013. [15] Rotstein DL, Mamdani M, O’Connor PW. Increasing use of disease modifying drugs for MS in Canada. Can J Neurol Sci 2010;37:383–8. [16] McCall MG, Brereton TL, Dawson A, et al. Frequency of multiple sclerosis in three Australian cities–Perth, Newcastle, and Hobart. J Neurol Neurosurg Psychiatry 1968;31:1–9. [17] Hammond SR, McLeod JG, Millingen KS, et al. The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart. Brain 1988;111:1–25. [18] Sutherland J, Tyrer J, Eadie M. The prevalence of multiple sclerosis in Australia. Brain 1962;85:149–64. [19] Sutherland JM, Tyrer JH, Eadie MJ, et al. The prevalence of multiple sclerosis in Queensland, Australia. A field survey. Acta Neurol Scand 1966;42: 57–67. [20] Miller DH, Hammond SR, McLeod JG, et al. Multiple sclerosis in Australia and New Zealand: are the determinants genetic or environmental? J Neurol Neurosurg Psychiatry 1990;53:903–5. [21] Alla S, Mason DF. Multiple sclerosis in New Zealand. J Clin Neurosci 2014;21:1288–91. [22] Hollingworth S, Walker K, Page A, et al. Pharmacoepidemiology and the Australian regional prevalence of multiple sclerosis. Mult Scler 2013;19: 1712–6. [23] Palmer AJ, Hitchens PL, Simpson S Jr, et al. A novel method for calculating prevalence of multiple sclerosis in Australia. Mult Scler 2013;19: 1704–11. [24] van der Mei IA, Ponsonby AL, Blizzard L, et al. Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation. Neuroepidemiology 2001;20:168–74. [25] Chaudhuri A. Lessons for clinical trials from natalizumab in multiple sclerosis. BMJ 2006;332:416–9.
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Review
Multiple sclerosis disease modifying medicine utilisation in Australia Samantha Hollingworth a,⇑, Kimitra Walker b, Andrew Page c, Mervyn Eadie d a
School of Pharmacy, The University of Queensland, 20 Cornwall Street, Woolloongabba, QLD 4102, Australia School of Population Health, The University of Queensland, Herston, QLD, Australia c School of Science and Health, University of Western Sydney, Penrith, NSW, Australia d School of Medicine, The University of Queensland, Herston, QLD, Australia b
a r t i c l e
i n f o
Article history: Received 9 December 2013 Accepted 15 May 2014
Keywords: Fingolimod Glatiramer acetate Interferon Multiple sclerosis Natalizumab Prescribing Utilisation
a b s t r a c t With the introduction of new disease modifying medicines (DMM) for relapsing remitting multiple sclerosis (RRMS) in Australia, we aimed to examine trends in utilisation from 1996 to 2013. We analysed trends in use by administrative area (state/territory). Prescription data from Medicare Australia were converted to defined daily doses (DDD)/1000 population/day using population data. Overall RRMS DMM use increased progressively from 0.024 to 0.68 DDD/1000 population/day between 1996 and 2013. From 1996 to 1999 interferon b1B was the only such agent available. Interferon b1A became the most widely used RRMS DMM in 2001. Glatiramer acetate became available in 2004 and its use thereafter increased slowly. Natalizumab was introduced in 2008 with slow growth and fingolimod use grew substantially once it was subsidised in 2011. Both these medicines have accounted for the growth in total use of RRMS DMM in 2012 and 2013. Overall RRMS DMM use was higher in more southern states than in northern states. Patterns of preferred agent varied between different Australian states and territories. RRMS DMM use in Australia has grown progressively since 1996, probably related to growing medical and patient confidence in the benefits obtained from using such drugs, longer survival in MS patients (partly related to use of drug treatments), and easier recognition of MS with the wider availability of magnetic resonance imaging (MRI). The availability of fingolimod, the first DMM that can be taken by mouth, may have led RRMS patients who rejected parenteral therapy to commence treatment of their disease. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Multiple sclerosis (MS) is a chronic inflammatory, primary demyelinating disease of the central nervous system and is the most common cause of continuing neurological disability in young adults in western societies [1]. In most patients, MS follows a relapsing-remitting course (relapsing remitting multiple sclerosis [RRMS]) at least in its earlier stages. In these stages there is often complete clinical recovery between attacks, but over time recovery between attacks becomes incomplete and most patients ultimately enter a secondary progressive phase [1]. In about 10% of patients, the disease runs a primary progressive course, with continuing deterioration in neurological function from the outset, without relapses and remissions [2,3]. The overall progressive nature of the disorder, the eventual debilitation, and the peak age of onset of 30–49 years, [1] result in high levels of support and medical care being required and significant loss of productivity in the workforce [4]. Half the people living with MS in Australia are unemployed [5]. ⇑ Corresponding author. Tel.: +61 7 3346 1981; fax: +61 7 3346 1999. E-mail address: [email protected] (S. Hollingworth). http://dx.doi.org/10.1016/j.jocn.2014.05.034 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
It is estimated that in 2010, in Australia, MS cost one billion dollars, with lost productivity being the largest cost component [6]. The greatest use of resources was for immunomodulating medicines, consultations and nursing [7]. MS treatment was essentially symptomatic until new disease modifying medicines (DMM) became available in Australia after 1985, including interferon b1B, interferon b1A, glatiramer acetate, natalizumab and fingolimod [8,9]. These medicines are approved for use in the relapsing-remitting phase of the disease and appear capable of favourably altering its natural history [2]. In Australia, they are publically subsidised on the Pharmaceutical Benefits Scheme (PBS) under the ‘Authority Required’ prescription mechanism [10] for patients who (i) have had at least two attacks in the preceding 2 years with partial or complete recovery and remain ambulant, and (ii) have their diagnosis confirmed by MRI of the brain or spinal cord. Until recently, public rebates were available only on MRI studies ordered by a specialist. As a result, prescriptions of these agents are generally initiated by specialists (specifically neurologists) but may be continued by general practitioners in the community. These drugs are too expensive to be routinely obtained by private prescription (i.e. where the consumer
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pays the total cost) and the PBS has mechanisms to ensure that individuals do not receive more than one such agent simultaneously [11]. We examined the patterns of utilisation of RRMS medicines between 1996 and 2013 in Australia and differences at various times in utilisation among the nation’s states and territories.
2. Methods All the medicines were available under the Australian Government’s subsidised medicine formulary, the PBS. The PBS provides a broad range of Australian registered medicines to Australian citizens with two levels of patient co-payments: general (AUD$36.10, 2013) and concessional (AUD$5.90, 2013) [12]. Concessional beneficiaries are those who receive social security benefits because they hold a Pensioner card, a Health Care card, or a Commonwealth Seniors Health card. The medicines considered in this study are listed only for use in patients with diagnosed RRMS that meet the criteria mentioned above and are all priced substantially above the level of co-payment. Patients who have progression of disease despite treatment are not eligible for repeat prescriptions of subsidised medicines [2]. None of these medicines has any other subsidised therapeutic use and they are almost invariably used in the same standard dose without individual variation. A single prescription (initial plus five repeats) supplies one person for 24 weeks. The medicine cost for all the agents (except natalizumab and fingolimod) for one person with RRMS is approximately AUD$1092 per 28 day period – more than AUD$13,100 per annum. There would likely be very little prescription of these agents in public hospitals due to costs and because patients with RRMS are mostly managed on an outpatient basis. Natalizumab, a monoclonal antibody, has been available since July 2008 (under PBS Section 100 Public from August 2010) for use in approved hospitals for monthly intravenous infusion as day procedures for the treatment of RRMS. It costs AUD$2,038 for a month’s supply. Fingolimod was subsidised in 2011 and costs AUD$2,313 per month. The number of dispensed prescriptions for RRMS medicines was obtained from public domain Medicare Australia PBS statistics provided by the Australian Government Department of Health [8]. Data were collected for the period between January 1996 and December 2013 and stratified by administrative areas – state or territory – for each formulation of each medicine. The amount of medicine dispensed (as prescriptions) was standardised to utilisation using the defined daily dose (DDD) per 1000 population per day. The DDD, as established by the World Health Organization Collaborating Centre for Drug Statistics Methodology, is the assumed average maintenance dose per day (expressed in terms of the dose contained in marketed dosage forms) for a medicine used for its main indication in adults [13]. For DDD calculations we used the midyear population for each state or territory and Australia as a whole [14]. Yearly totals of DDD were summed for each administrative region and for the whole nation. The medicines in alphabetical order by generic name (with the trade name and DDD) are: fingolimod (Gilenya, 0.5 mg [Novartis, Basel, Switzerland]), glatiramer acetate (Copaxone, 20 mg [Teva Pharmaceutical Industries, Petah Tikva, Israel]), interferon b1A (Avonex, 4.3 mcg [Biogen Idec, Weston, MA, USA]), interferon b1A (Rebif, 4.3 mcg [Merck Serono, Darmstadt, Germany]), interferon b1B (Betaferon, 4 mU [Bayer HealthCare AG, Levekusen, Germany]); and natalizumab (Tysabri, 10 mg [Biogen Idec]). Interferon b1B was listed on the PBS in November 1996 followed by interferon b1A-Avonex preparations in February 1999 and interferon b1A-Rebif preparations in May 2000. Glatiramer acetate was listed in May 2004, natalizumab in July 2008 and fingolimod in September 2011.
3. Results 3.1. Utilisation use over time Overall use of RRMS DMM increased 28-fold between 1996 and 2013 (from 0.024 to 0.680 DDD/1000 population/day; Table 1). The most commonly prescribed medicine from 2001 was interferon b1A with a peak utilisation of 0.359 DDD/1000 population/day in 2010 (Fig. 1). Glatiramer acetate use reached 0.085 DDD/1000 population/day in 2010 and had about 15% share of the market in the last few years (Table 1). Interferon b1A use, as a proportion of all RRMS DMM use, decreased from about two thirds in 2003 to less than half in 2013 (Table 1). Natalizumab use has increased to 12% and fingolimod has increased to 21% of RRMS DMM use in 2013. There was a relative plateau in overall RRMS DMM use between 2005 and 2007, but use increased in 2009 and subsequently – the increase being largely accounted for by growth in use of fingolimod and natalizumab (Fig. 1). 3.2. Utilisation use by state or territory The total Australian RRMS DMM use was 0.592 DDD/1000 population/day in 2013 (Fig. 2). Tasmania had the highest utilisation with 0.845 DDD/1000 population/day in 2013 and the Northern Territory (NT) the lowest with 0.105 DDD/1000 population/day, about one eighth that of the Australian Capital Territory (ACT). In all jurisdictions, interferon b1A was the most used RRMS DMM. Interferon b1B use was low and fairly consistent across most states and territories, with higher use in Tasmania. Although there was increasing use along a general north– south gradient of states, there was a major exception in that its use in the ACT (0.733 DDD/1000 population/day) was greater than in the geographically surrounding state of New South Wales (NSW; 0.532 DDD/1000 population/day). The population in the ACT is about 5% of NSW. The use of fingolimod, relative to the other medicines, was low in the NT, Queensland and Tasmania. 3.3. Utilisation use with time in different administrative areas The introduction of each new RRMS DMM to the PBS was associated with changes in the proportion of overall use for which each agent was responsible, both nationally and in the individual states and territories. The proportions for each medicine in each administrative area for the years 2001 (before glatiramer acetate became available), 2007 and 2013 are shown in Table 2. Overall in Australia and in each administrative area, as glatiramer acetate, natalizumab and fingolimod use grew, the use of b-interferons showed a relative decline (especially after 2006). In the areas where interferon b1A initial use was higher, use declined to a fairly consistent figure of around 40–50% of overall use. Interferon b1B use declined progressively in all states and territories as use of the other medicines grew, with the decrease being greatest in the NT (from 74% to 35%). The ratio of interferon b1B to interferon b1A use was below unity in 2007 and 2013 (except for 347% in the NT in 2013, Table 3). The wide variation in ratios in the NT likely reflects the very small number of patients. In 2013 the ratio of use ranged from 49% in Tasmania to 13% in the ACT. 4. Discussion Over the period between 1996 and 1999, when interferon b1B was the only RRMS DMM available in Australia, its use in the whole country increased more than 4-fold. This growth may have mainly been a result of prescribers becoming increasingly familiar with the idea of a new type of therapy being available, and people with
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S. Hollingworth et al. / Journal of Clinical Neuroscience 21 (2014) 2083–2087 Table 1 Utilisation (DDD) and proportion of all use (%) for all relapsing-remitting multiple sclerosis medicines between 1996 and 2013 in all of Australia Year
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Interferon b1B
Interferon b1A
Glatiramer acetate
Natalizumab
Fingolimid
All RRMS
DDD
%
DDD
%
DDD
%
DDD
%
DDD
%
DDD
%
0.024 0.065 0.085 0.101 0.116 0.116 0.131 0.133 0.132 0.136 0.135 0.133 0.123 0.123 0.118 0.102 0.095 0.068
100% 100% 100% 80% 62% 44% 37% 34% 29% 26% 25% 25% 23% 22% 20% 18% 14% 11%
– – – 0.025 0.070 0.149 0.227 0.263 0.299 0.321 0.339 0.347 0.334 0.350 0.359 0.344 0.340 0.263
– – – 20% 38% 56% 63% 66% 64% 62% 63% 64% 63% 63% 62% 60% 52% 44%
– – – – – – – – 0.033 0.058 0.062 0.063 0.068 0.079 0.085 0.086 0.087 0.070
– – – – – – – – 7% 11% 11% 12% 13% 14% 15% 15% 13% 12%
– – – – – – – – – – – – 0.004 0.000 0.014 0.022 0.041 0.069
– – – – – – – – – – – – 1% 0% 2% 4% 6% 12%
– – – – – – – – – – – – – – – 0.022 0.094 0.122
– – – – – – – – – – – – – – – 4% 14% 21%
0.024 0.065 0.085 0.126 0.186 0.265 0.358 0.396 0.465 0.515 0.535 0.543 0.529 0.552 0.575 0.577 0.655 0.592
100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
DDD = defined daily dose/1000 of population/day, RRMS = relapsing-remitting multiple sclerosis.
DDD/1000 populaon/day
Fig. 1. Individual and total relapsing-remitting multiple sclerosis drug utilisation (defined daily dose/1000 population/day between 1996 and 2013 for all of Australia. DDD = defined daily dose, Int = interferon.
0.9
Int β1A
0.8
Int β1B
0.7
Glaramer
Fingolimod 0.6
0.5
Natalizumab Total
0.4 0.3 0.2 0.1
0 NT
QLD
NSW
WA
SA
ACT
VIC
TAS
Aust
State/Territory Fig. 2. Utilisation (DDD/1000 population/ day) of the two ß interferons and glatiramer acetate, fingolimod, natalizumab and the five agents combined in Australian states and territories (by latitude of capital city) for 2013. ACT = Australian Capital Territory, Aust = Australia, DDD = defined daily dose, Int = interferon, NSW = New South Wales, NT = Northern Territory, QLD = Queensland, SA = South Australia, TAS = Tasmania, VIC = Victoria, WA = Western Australia.
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Table 2 Proportion of use (%) of selected relapsing-remitting mutiple sclerosis drugs within Australian states and territories for 2001, 2007 and 2013* Administrative area
Drug
2001
2007
2013
Northern Territory
Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod Interferon b1B Interferon b1A Glatiramer acetate Natalizumab Fingolimod
74% 26% 0% 0% 0% 69% 31% 0% 0% 0% 41% 59% 0% 0% 0% 55% 45% 0% 0% 0% 38% 62% 0% 0% 0% 39% 61% 0% 0% 0% 37% 63% 0% 0% 0% 54% 46% 0% 0% 0% 44% 56% 0% 0% 0%
24% 68% 8% 0% 0% 37% 49% 13% 0% 0% 21% 68% 11% 0% 0% 29% 65% 9% 0% 0% 21% 65% 14% 0% 0% 11% 67% 22% 0% 0% 22% 67% 11% 0% 0% 42% 47% 10% 0% 0% 25% 64% 12% 0% 0%
35% 10% 14% 3% 37% 15% 51% 14% 9% 12% 11% 47% 11% 8% 23% 12% 41% 8% 21% 17% 9% 43% 13% 12% 23% 7% 48% 29% 2% 15% 10% 40% 11% 14% 26% 22% 46% 12% 11% 8% 11% 44% 12% 21% 21%
Queensland
New South Wales
Western Australia
South Australia
Australian Capital Territory
Victoria
Tasmania
Australia
* Natalizumab data not shown because of uncertainty about its completeness but included as part of totals so not all will add to 100% within a year.
Table 3 Ratios of Interferon b1B use to Interferon b1A use in 2001, 2007 and 2013 in Australian states and territories and Australia (in bold) (expressed as percentages) Administrative area
2001
2007
2013
Northern Territory Queensland New South Wales Western Australia South Australia Australian Capital Territory Victoria Tasmania Australia
286% 225% 71% 124% 61% 63% 58% 117% 78%
35% 76% 31% 39% 32% 16% 33% 89% 40%
347% 29% 23% 30% 20% 13% 25% 49% 26%
MS becoming aware of its existence. As more treatment options became available, total RRMS DMM use continued to increase. Use of interferon b1B, which accounted for all dispensed prescriptions of RRMS therapy before 1999, provided less than one fifth of total RRMS DMM use by 2013, despite interferon b1B use being
relatively steady from 2002 to 2007, and thereafter undergoing a slight decline. The availability of various dosage forms of interferon b1A from 1999 onwards may have slowed the growth of interferon b1B use. More recently, other DMM have been subsidised, namely glatiramer acetate, natalizumab and fingolimod, and particularly the latter two are becoming more widely used and largely account for the overall increase in use of RRMS DMM from 2008 onwards. These data are consistent with those found in Canada [15]. The use of both natalizumab and fingolimod seems sufficient to account for the overall increase in national DMM use over 2011–2013. This suggests that there was a population of people with RRMS who had previously been eligible for supply of DMM but had not taken the parenteral agents that were available to them. Some of these people with RRMS were prepared to accept an oral therapy. The increase in overall RRMS DMM use over the 15 years likely reflects the influences of several factors. Though no cure has yet been found for MS, advances in the available DMM and advances in symptomatic therapy have resulted in increased life expectancy for people with MS [2]. As a consequence, there has been an increase in disease prevalence. Also, aided by the growing availability and diagnostic capability of MRI, there has been an increasing recognition of cases of RRMS in the Australian community, further increasing the number of people eligible for treatment. Following the earlier growing prescriber awareness of the availability of RRMS DMM, there has been a subsequent growing consciousness among prescribers of the benefit to people with RRMS of using such therapies and people with RRMS have more or less simultaneously become aware of the benefit. There was generally higher use of RRMS DMM in the more southerly Australian administrative areas than in the more northerly ones, consistent with the known higher prevalence of the disease with increasing distance from the equator in both hemispheres [16–23], the reasons for which remain unclear [24]. There was, however, an exception to this relationship in the relatively high use of RRMS DMM in the ACT, compared with their use in the surrounding state of NSW – a usage pattern driven by heavy prescribing of glatiramer acetate in the ACT. There is no obvious explanation for the different patterns of preferred use of the various agents in the different jurisdictions, apart from consequences of individual neurologist preferences [23]. The differences are more noticeable in jurisdictions with fewer people and fewer neurologists where one neurologist’s different pattern of practice may have more obvious consequences for the data. Utilisation use of natalizumab through the PBS, introduced in 2008, probably was greater than appears in the data. Confidential sales figures provided by the marketing company suggest that there may be delayed reporting of its use to the Australian Government by hospital pharmacies in contrast to community pharmacies who report dispensing other RRMS DMM quickly to receive government payments. This possible discrepancy confounds the interpretation of natalizumab data from 2008 to 2013. Furthermore, natalizumab use may have been slow to increase due to concerns regarding progressive multifocal leucoencephalopathy [25]. The strength of this study is that it presents national data on all subsidised prescribing, and approximately all prescribing, of RRMS DMM over an 18 year period in Australia. This is the case because, with the high cost of these medicines, it is highly unlikely that they would be purchased privately (i.e. without government subsidy). The parenteral DMM usage patterns that prevailed in the 2005–2009 period, when total use reached an approximate plateau, may provide a baseline for interpreting the situation in the near future, as orally administered agents come into increasing use when the early experience with the first agent suggests that people with RRMS who would have rejected parenteral treatments may be prepared to accept oral ones.
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Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements The data used in this study were obtained from Medicare Australia administered by the Australian Government Department of Health and Ageing. No funding was received for this study beyond existing salaries. No ethics approval was required for this study as all the data was available in the public domain and no individual receiving the therapies was identified at any stage. References [1] Ropper AH, Samuels MA. Multiple sclerosis and allied demyelinating diseases. Adams and Victor’s principles of neurology. 9th ed. USA: McGraw-Hill Companies Inc.; 2009. p. 874–96. [2] Taylor I, Macdonell R, Coleman J. Treatment of multiple sclerosis with newer immune-modulating drugs. Aust Prescr 2002;25:32–5. [3] Poser CM. The epidemiology of multiple sclerosis: a general overview. Ann Neurol 1994;36:S180–93. [4] Simmons RD, Tribe KL, McDonald EA. Living with multiple sclerosis: longitudinal changes in employment and the importance of symptom management. J Neurol 2010;257:926–36. [5] Access Economics. Acting positively: strategic implications of the economic costs of MS in Australia. Report by Access Economics Pty Limited for Multiple Sclerosis Australia. Canberra: Access Economics Pty Ltd, 2005. [6] Palmer AJ, Colman S, O’Leary B, et al. The economic impact of multiple sclerosis in Australia in 2010. Mult Scler 2013;19:1640–6. [7] Taylor B, McDonald E, Fantino B, et al. The cost of multiple sclerosis in Australia. J Clin Neurosci 2007;14:532–9. [8] Medicare Australia. Pharmaceutical Benefits Schedule Item Reports, ; 2014 [accessed 01.05.14]. [9] Pender MP. Recent progress in the diagnosis and treatment of multiple sclerosis. J Clin Neurosci 1999;6:367–72.
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[10] MIMS Australia. MIMS Australia. St Leaonards, Australia: UBM Medica Australia; 2009/2010. [11] Department of Health. Section 100 – Highly Specialised Drugs Program, ; 2014 [accessed 01.05.14]. [12] Department of Health. About the PBS, ; 2014 [accessed 01.05.14]. [13] Zivadinov R, Iona L, Monti-Bragadin L. The use of standardized incidence and prevalence rates in epidemiological studies on multiple sclerosis. A metaanalysis study. Neuroepidemiology 2003;22:65–74. [14] Australian Bureau of Statistics. Population by Age and Sex, Australian States and Territories. Cat. No. 3201.0: Australian Bureau of Statistics, 2013. [15] Rotstein DL, Mamdani M, O’Connor PW. Increasing use of disease modifying drugs for MS in Canada. Can J Neurol Sci 2010;37:383–8. [16] McCall MG, Brereton TL, Dawson A, et al. Frequency of multiple sclerosis in three Australian cities–Perth, Newcastle, and Hobart. J Neurol Neurosurg Psychiatry 1968;31:1–9. [17] Hammond SR, McLeod JG, Millingen KS, et al. The epidemiology of multiple sclerosis in three Australian cities: Perth, Newcastle and Hobart. Brain 1988;111:1–25. [18] Sutherland J, Tyrer J, Eadie M. The prevalence of multiple sclerosis in Australia. Brain 1962;85:149–64. [19] Sutherland JM, Tyrer JH, Eadie MJ, et al. The prevalence of multiple sclerosis in Queensland, Australia. A field survey. Acta Neurol Scand 1966;42: 57–67. [20] Miller DH, Hammond SR, McLeod JG, et al. Multiple sclerosis in Australia and New Zealand: are the determinants genetic or environmental? J Neurol Neurosurg Psychiatry 1990;53:903–5. [21] Alla S, Mason DF. Multiple sclerosis in New Zealand. J Clin Neurosci 2014;21:1288–91. [22] Hollingworth S, Walker K, Page A, et al. Pharmacoepidemiology and the Australian regional prevalence of multiple sclerosis. Mult Scler 2013;19: 1712–6. [23] Palmer AJ, Hitchens PL, Simpson S Jr, et al. A novel method for calculating prevalence of multiple sclerosis in Australia. Mult Scler 2013;19: 1704–11. [24] van der Mei IA, Ponsonby AL, Blizzard L, et al. Regional variation in multiple sclerosis prevalence in Australia and its association with ambient ultraviolet radiation. Neuroepidemiology 2001;20:168–74. [25] Chaudhuri A. Lessons for clinical trials from natalizumab in multiple sclerosis. BMJ 2006;332:416–9.
