Forecasting drug utilization and expenditure in a metropolitan health region

Linear regression analysis was applied to aggregate sales data from the National Corporation of Swedish Pharmacies on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The method of statistical analysis was chosen since the forecasting was based on annual data without seasonal dependencies. We had previously ascertained there were no long term cyclical patterns during few years included. In addition, the resulting residuals from the regression analysis did not show any particular patterns. Consequently, applying time series models without any such patterns would give approximately the same results since the auto-correlations will be estimated to about zero.

Annual expenditures and volumes for all pharmacological groups at the 3rd ATC (Anatomical Therapeutic Chemical Classification) level [9] between 2006 and 2009 were included in the analysis. Expenditure was measured in Swedish Crowns (SEK) (1 Eur = 10.0 SEK, March 2010) and volumes in Defined Daily Doses (DDD) [9]. A linear regression model was applied to each time series of four observations 2006-2009. The crude predictions for the coming two years 2010 and 2011 were based on linear extrapolation. These were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee (Table 1, [10‐15]). The individual impact of these factors in each pharmacological group is presented in the results section. No specific adjustments were made for the ageing of the population, population growth and financial incentives for drug prescribing since these changes were already covered by the original trends.

New therapies were identified through horizon scanning. This is a systematic process to identify new medicines or new indications of existing medicines that are expected to receive marketing authorisation from the Regulatory Authority in the near future and to estimate their potential impact on patient care [16]. Information on drugs likely to be launched during the coming two years was collected from a number of sources. These included published reports and websites from regulatory agencies, the European Commission and the FDA, the UK organizations for horizon scanning (National Horizon Scanning Centre in Birmingham and National Prescribing Centre in Liverpool) and the pharmaceutical industry through pipeline information on their public websites, as well as formal face to face meetings with different pharmaceutical companies.

All the information collected was discussed and prioritized in consultation with each of the 23 medical and scientific expert groups belonging to the DTC system in the Stockholm County [10]. These expert groups cover diseases of organ systems e.g. cardiovascular, gastrointestinal and neurological disorders. Each group has members representing all major specialist clinics in the county as well as a general practitioner, a clinical pharmacologist and a pharmacist. All involved experts have to apply a strict policy for declaration of interests including contacts with the pharmaceutical industry [10]. Finally, the forecasting models were scrutinized and modified after input from joint workshops with expert groups and after final input and comments from the main authors, who have extensive clinical pharmacological and/or pharmacotherapeutic knowledge or experience. The final forecasting report for 2010-2011 was published in Swedish in March 2010.

In 2009, the total drug expenditure for the Stockholm County was 6.9 billion SEK, corresponding to 3.490 SEK or €349/inhabitant. This increased by 3.3% compared with 2008 (Figure 1). We predict that the total expenditure, including both ambulatory and hospital sales, will increase by 2.0% in 2010 and by 4.0% in 2011.

The expenditure is predicted to increase for all major therapeutic areas (Figure 2); most predominantly for antineoplastic and immunomodulating agents (ATC L) as well as drugs for the nervous system (ATC N), infectious diseases (ATC J) and blood-forming organs (ATC B).

In particular, large increases are expected for "biological" drugs, such as TNF-alpha inhibitors and monoclonal antibodies, and small molecules for targeted cancer therapy. We also estimate that expenditure will increase rapidly for some drugs used for common diseases, i.e. drugs prescribed for pain, asthma and diabetes, as well as anticoagulants. This is due to the launch of new medicines, as well as increasing overall volumes without expected savings from new patent expirations. Table 2 contains data on the changes envisaged for all therapeutic groups.

We expect the expenditures for anti-ulcer drugs to decrease by 5% in 2010 and 3% in 2011 due to patent expiries and decreasing prices for proton pump inhibitors. The impact of lower prices on the overall expenditures will to some extent be counteracted by increasing volumes, although reimbursement restrictions by TLV (Table 1) may limit such an increase [10].

Considerable increases are expected for antidiabetic agents excluding insulin (13% in 2010 and 9% in 2011) due to the increased prevalence of type 2 diabetes [17], new National Guidelines suggesting stricter targets for HbA1c, and the introduction of several new drugs (the GLP-I agonists exenatide and liraglutide, as well as the DPP-4 inhibitors sitagliptin, vildagliptin and saxagliptin) [18]. We anticipate that the safety problems observed for glitazones in patients with ischemic heart disease [19] may contribute to a more rapid introduction of the DPP-IV inhibitors for add-on therapy in patients with type 2 diabetes not controlled on traditional sulphonyl ureas and metformin. On the other hand, there are also anticipated safety problems with these drugs [20]. There is a need for new antidiabetic drugs, but their place in therapy will depend on their long-term safety and effectiveness suggesting a need for the step wise introduction of these NCEs. It is likely that the net increase for all antidiabetic agents will remain at 4% due to the moderation in sales of long-acting insulin as a result of new recommendations in national guidelines and the observational studies demonstrating a potential association between insulin glargin and the development of breast cancer [21].

The ATC group A also includes orphan drugs for patients suffering from rare enzyme deficiencies, e.g. Gaucher's disease. In Europe, orphan drug status can be granted when the prevalence of the disease does not exceed 5 cases per 10 000 inhabitants [22]. Since 2000, when the ad hoc legislation came into force, up to 2007, out of 528 designated orphan indications related to 400 orphan medicinal products (OMP) only 45 (44 drugs) were approved (8.5%) [22]. Access to these drugs varies greatly both between and within countries, mainly because of the high annual cost of treatment (up to € 300 000 per patient) [22]. We predicted the expenditure for orphan drugs within ATC group A to increase by 10% in 2010 and by 9% in 2011.

The expenditure for anticoagulants is likely to decrease by 9% in 2010 and increase by 17% in 2011. The decrease predicted for 2010 is explained by the patent expiry for clopidogrel in November 2009. In March 2010, the price for generic clopidogrel had fallen by 90% compared to the originator price before patent expiry. The subsequent increase in expenditure in 2011 is partly explained by the introduction of dabigatran, rivaroxaban and apixaban [23]. The clinical development of these new anticoagulants is following the well tested strategy of dose-ranging and registration studies for short-term use after major orthopaedic surgery, prior to the development for long-term use in atrial fibrillation. Phase III trials for stroke prevention in patients with atrial fibrillation (AF) are ongoing or recently presented (e.g. RE-LY, Aristotle, Rocket, Borealis and Averroes) [24, 25]. Rapid increases in drug expenditure can be anticipated if these drugs will replace warfarin for large numbers of patients [24]. A potential argument for the new more expensive anticoagulant drugs is that increasing drug expenditure may be counteracted by substantial savings in other areas of healthcare if less coagulation control is needed. However, our current opinion is that these drugs also need to be monitored due to the narrow therapeutic margin of anticoagulants, and for the purpose of monitoring compliance. Another factor contributing to the expected increase in antithrombotic drug expenditure is longer treatment periods with clopidogrel in combination with low dose acetylsalisylic acid if the European Guidelines for cardiovascular prevention proposing 12 months treatment [26] are to be adhered to. However, our National Guidelines recommend 3 to 12 months co-treatment and most patients receive shorter co-treatment periods. Lastly, the introduction of prasugrel and tigacrelor may also influence expenditure. Prasugrel has been introduced at a 50% higher price than the original clopidogrel (Plavix), and has recevied reimbursement for treatment of patients with stent thrombosis despite clopidogrel treatment only; this restriction is challenged by the company. However, we do not anticipate that prasugrel will cause major expenses during 2010-2011. Ticagrelor was shown to be superior to clopidogrel in the PLATO study [27], and will presumably be launched in 2011. Its future place in the therapeutic arsenal is so far unclear.

Expenditure for erythropoietin may be reduced due to the introduction of biosimilars but we have not forecasted any major changes in drug expenditure for this group of drugs due to the ongoing uncertainty about differences in biological activity [12]. This may change as more data becomes available about the safety and efficacy of the biosimilars in practice, as well as any significant differences in price between biosimilars and originators in hospital or ambulatory care.

The total expenditure for cardiovascular drugs has remained stable between 2002 and 2009 despite increasing volumes. This is mainly explained by patent expiries and generic availability for some high volume drugs such as simvastatin, amlodipine, enalapril and ramipril during a period when few new drugs were launched [10]. It is likely that expenditures will continue to decrease during the coming two years, mainly due to patient expiries for the angiotensin receptor blockers (ARB's).

As a result of a reimbursement review, ARB's are only reimbursed for patients intolerant to ACE-inhibitors (ACEi) since 2008 [28, 29]. This restriction resulted in a 20% decrease in the initiation of ARB while at the same time the number of patients initiated on ACE-inhibitors and calcium channel blockers increased [29]. We believe this change in reimbursement status combined with DTC educational activities and patent expiry of losartan in early 2010 will decrease the expenditure for ARB's by 23% in 2010 and 12% in 2011 (Table 2).

Lipid-lowering agents are the most commonly used drugs in the population after the antiplatelet agents (i.e., mostly low-dose acetylsalicylic acid). In June 2009, the TLV decided on certain reimbursement restrictions, e.g. excluding atorvastatin 10 mg and rosuvastatin 5 mg from the reimbursement scheme [30]. This resulted in a 9% decrease in expenditures. We believe that the expenditures for lipid-lowering drugs will decrease by a further 6% in 2010, but remain stable after that since there is substantial pressure to treat to low cholesterol goals (which will require higher dosages) [31].

Few new cardiovascular drugs will be launched in 2010 and 2011. In 2010, a new antiarrythmic agent, dronedarone, will be introduced as an alternative to amiodarone for patients with atrial fibrillation. The drug has in a large trial (ATHENA) been shown to decrease morbidity and mortality compared to placebo and may, consequently, offer benefits for certain patients [32]. However, the greater tolerability of dronedarone compared to amiodarone is achieved at the expense of lesser efficacy [33], and the target population for dronedarone has not yet been defined.

This group is dominated by sex hormones for contraception and hormone therapy for climacteric symptoms. The prescribing of hormone therapy decreased substantially after publication of the randomized studies HERS and WHI in 2002 [34, 35]. We predict that the use and consequently expenditure will remain stable during the next couple of years.

The expenditure for drugs for erectile dysfunction is expected to increase by 9% annually due to increasing number of men treated. Further increases in this category of drugs are expected following the launch of the first drug for premature ejaculation (PE), dapoxetin, in 2009. This is because PE is the most common male sexual disorder, estimated to affect up to 30% of men [36]. These "lifestyle" drugs have great potential for increased expenditure since an international comparison showed that Sweden had the most rapid diffusion of sildenafil [37]. However, since then, most drugs for erectile dysfunction have been excluded from reimbursement and there is also more structured diffusion of these drugs through active professional involvement, e.g. in DTC activities [10, 38]. This has been factored into the forecast model.

Substantial increases in expenditures are expected for antiviral drugs - 9% and 10%, respectively in 2010 and 2011. We anticipate the expenditure for antiviral drugs will increase due to the continued launch of new drugs for the treatment of HIV and hepatitis B and C. The numbers of patients treated for HIV will increase due to improved survival and ongoing transmission [39]. Furthermore, the emergence of viruses resistant to current drugs is driving the need for new antiretroviral agents [40]. Examples of new drugs include darunavir, maraviroc, enfuvirtide and tifuvirtide. Increasing use of combinations of inhibitors that target different steps of the viral life cycle will also contribute to increasing expenditure.

Increased expenditure is also expected for the treatment of hepatitis. Around 500 new cases of hepatitis C (HCV) are identified in Stockholm each year. This number may increase further with the introduction of retrospective screening for transfusion-transmitted HCV infections [41]. The current treatment of chronic HCV infection consists of a combination of pegylated interferon and ribavirin. New drugs in development include HCV-specific protease inhibitors, polymerase inhibitors, immune modulators and ribavirin analogues [42]. Two of these, thymalfasin and taribavarin, have recently been launched. The management of chronic hepatitis B (HBV) has improved over the last decade with the development of new drugs such as lamivudine, adefovir and dipivoxil, in addition to interferon (IFN)-alpha therapy [43]. Many other new drugs are under development which may contribute to increasing expenditure. These have been factored into the forecast.

The expenditure for antibiotics is predicted to remain stable in 2010-2011. In June 2009, Strama (the Swedish Strategic Programme against Antibiotic Resistance) and the Swedish Institute for Infectious Disease Control (SMI) launched the seventh report on the use of antibiotics and resistance in human medicine in Sweden, Swedres 2008 [44]. The use of antibiotics in Sweden is highest among the elderly and children with prescription rates varying considerably between different regions. The proportion of children aged 0-6 years treated with at least one course of antibiotics in 2008 ranged from 38 per cent in Stockholm county to 25 percent in Västerbotten county, with a national average of 33 percent.

The use of antibiotics both in primary and secondary care seems to be changing in a desirable way, with broad spectrum antibiotics being replaced by narrow spectrum substances. Various types of penicillins have increased and the use of cephalosporins and fluoroquinolones is decreasing. This is in accordance with the guidelines on the reduction of prescription of fluoroquinolones against lower urinary tract infections in women, actively promoted by Strama and the DTCs for many years [45]. There is a certain risk that the decreasing utilization will be counteracted by a recent reform increasing patient access to primary healthcare physicians in Stockholm, so continuous activities are needed. Despite these efforts we expect that expenditure in secondary care will increase in the long run due to a continuous increase in the use of more expensive antibiotics as antimicrobial resistance develops. This will be factored into future predictions.

We expect the expenditure for vaccines to increase by 7% annually. A number of new vaccines with major potential for controlling infectious diseases have just been licensed or are at advanced stages of development. The predicted increases are mainly attributable to the introduction of a new seven- and later 13-valent conjugate pneumococcal vaccine and the use of subsidized vaccines for the prevention of cervical cancer caused by human papilloma virus (HPV) [46, 47]. The decision by the Swedish National Board of Health and Welfare that HPV vaccination should be included in the official vaccination program for all girls aged 11-12 years is likely to increase expenditures by 33 million SEK. Completely new or significantly modified vaccines may appear in the future. For the H1N1 influenza, Sweden decided to promote vaccination for its entire population. The vaccine cost for Sweden has been estimated at 1.2 to 1.3 billion SEK and total costs (including administration costs) at around 2.5 billion SEK [48]. This corresponds to a vaccine cost of approximately 0.25 billion SEK for the Stockholm region, more than the total expenditure for analgesics in the region during a year.

Increasing expenditure (5% annually) is expected for antineoplastic and immunomodulating agents. The increase is principally confined to immunomodulating agents as we do not expect any increase in the total costs for antineoplastic drugs during 2010-2012 for the reasons outlined below. The increase is mainly due to the widening indications for TNF alpha inhibitors and other drugs already available on the market (Figure 3). Cancer therapy is characterized by multimodal treatment using surgery, radiotherapy and a rapidly increasing number of antitumour agents. Today, most agents are introduced for patients with late stage (metastatic) disease. In many cases such as for example breast cancer, the efficacy in metastatic disease translates into increased cure rates when the new drug is used in earlier stages of the disease in conjunction with surgery [49, 50]. Many drugs are under development, and both academic institutions and the pharmaceutical industry are investing in cancer research at levels previously unseen. All of these factors contribute to the predicted increase in expenditure over time, but as discussed below during the time period 2010-2012, this will be counteracted by the patent expiration of several top selling cancer drugs.

Recent advances in the knowledge of the biology of breast cancer have resulted in targeted treatments, such as the monoclonal antibody trastuzumab (targeting HER2-overexpressing cells) [51]. In 2009, trastuzumab was the top selling oncology drug in our region with total sales of 72 million SEK, corresponding to € 7.2 million. However, we predict that the sales will level off during the coming years since the drug has already reached its target population in breast cancer. This will be counterbalanced by trastuzumab recently approved in advanced HER2-overexpressing gastric cancer. However, there are a more limited number of patients.

Colorectal cancer, the third most common malignancy after cancers of the breast and prostate, was treated with surgery alone until the 1980s when the combination of 5-fluorouracil and leucovorin was introduced. During the past ten years, new agents have been introduced and life expectancy has increased from 5 to 20 months in patients with metastatic disease [52]. These improvements have, however, resulted in a dramatic increase in the costs of medical treatment. In recent years, the addition of biological agents like the monoclonal antibodies bevacizumab as well as cetuximab and panitumumab have further improved response rates [53]. None of these drugs has, however, showed activity in the adjuvant setting. Consequently, no major increase in their use in colorectal cancer is expected in the period 2010-2012. The overall use of bevacizumab is expected to increase though mainly due to other indications including advanced breast, lung and renal cancer.

Advances in molecular medicine have also provided insights into the biology of several haematological diseases such as chronic lymphatic leukemia (CLL), chronic myeloid leukemia (CML), multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) [54, 55]. This has led to new treatments like the monoclonal antibody rituximab, which has improved survival rates in patients with aggressive NHL and become an important therapeutic option in the treatment of indolent lymphoma [56]. As a result, Rituximab had the second highest expenditure of oncology drugs in the region in 2008 helped also by utilisation in rheumatoid arthritis (RA - below). We predict that sales will continue to grow, mainly due to the widening of indications in haematology (CLL), but also in rheumatoid arthritis (see below). Imatinib has become the backbone of treatment of CML for which several other drugs have also been approved or are in development. Dasatinib and nilotinib are presently approved in second line treatment of CML. If these drugs are approved in first line treatment, this will have a major impact on costs as treatment of CML takes place over many years, and can be considered almost chronic treatment. Bortezomib is indicated in MM for which there are now also several new therapeutic options including lenalidomide [54, 55]. Increase in the total drug costs for MM is to be expected.

The rapid increase in expenditure due to new drugs is counteracted by savings due to the introduction of generics for many oncology drugs. The patent recently expired for bikalutamide leading to a rapid price decrease. Over the next two years, patent expiries are expected for several of the best selling oncology drugs including aromatase inhibitors, docetaxel and temozolamide, resulting in the expected moderation in growth in 2010 and 2011. This moderation in growth though is dependant on the rapid uptake of generics at low prices building on previous examples [10]. It is also likely that current resource constraints may increase the need for prioritization of the utilisation of new oncology drugs with only limited improvements in survival in most new cancer drugs compared to current treatments and their high prices. This issue is currently a major focus among health technology assessment units, and in the evaluation of the actual benefit of new cancer drugs [57].

Expenditure has increased rapidly for the treatment of rheumatoid arthritis (RA) due to the introduction of anti-tumor necrosis factor (TNF)-alpha and anti-interleukin (IL)-1 agents (infliximab, adalimumab, etanercept and anakinra). Further increases are expected since the indications have widened and they are increasingly used in patients with inflammatory bowel disease and psoriasis. This considerable widening of indications for TNF-alpha blockers has not though resulted in any price reductions in Sweden. New drugs are also being introduced for the treatment of rheumatoid arthritis patients not responding to conventional treatments, which may also contribute to increasing expenditures. Such drugs include the anti-CD20 monoclonal antibody rituximab, which inhibits B-cell activity, the T-cell activation inhibitor abatacept, and other interleukin inhibitors [58].

We predict the expenditure to decrease for antipsychotics and antidepressants, while it will increase for other CNS acting drugs (Figure 4).

The expenditure on analgesics has increased by 5-13% annually the past years due both to increased volumes and increased prescribing of more expensive products such as tramadol and oxycodon. This development is likely to continue despite efforts from the DTC to moderate their use since they are not considered to provide any advantages over other recommended drugs. New formulations of fentanyl may also contribute to increased expenditures as well as the new fixed combination of naloxone and oxycodon. Some savings will be achieved through patent expiry and the introduction of generics to sumatriptan. This may, however, partly be counteracted by increased utilization of triptans. Other drugs for the treatment of migraine are under development, and it is likely that the first agonist acting on vascular calcitonin-gene related peptide (CGRP) receptors, telcagepant, will be introduced on the market in 2011 [59].

We predict expenditure for antiepileptic drugs to increase by 5% annually, mainly due to increased utilization of lamotrigine and pregabalin for nonepileptic conditions. These include various psychiatric disorders and pain syndromes [60]. Price competition is weak for these drugs since it has been decided nationally that they can not be substituted in pharmacies unlike other generic drugs [10]. Evidence for their benefit in these conditions varies though and further studies are needed to be able to fully determine their place in management. In the USA, the FDA approved pregabalin for treatment of fibromyalgia in June 2007 and the manufacturer filed for the same indication in Europe. However, EMA didn't approve an extension of indication for pregabalin to include the treatment of fibromyalgia [61].

We predict that increase in the expenditure for antipsychotic drugs will moderate over the next two years (Figure 4). This is mainly due to patent expiry and generic competition for risperidone. In 2011, we also expect generics to be introduced for the top-selling drug in the group, olanzapine. Further savings are unlikely though due to the commercial pressures to prescribe the single sourced antipsychotics quetiapine and aripiprazole.

The substantial decrease in expenditure for antidepressants in 2009 is explained by the patent expiry for, and subsequent introduction of generics to venlafaxine (Figure 4). With total sales of 58 million SEK in 2008, venlafaxine accounted for the largest proportion of anti-depressant expenditure in the region. The sales are expected to remain stable over the coming years.

The expenditure for ADHD-medications is expected to increase by 33% annually. The increases are expected both for children and adults. Sweden had earlier a low utilization of these drugs compared to other western European countries, mainly due to strict governmental regulations against the prescription of ADHD medications [62]. Changes in the legislation may partly explain the increasing utilization and also that the disease and the drugs have been heavily discussed in media.

The increasing expenditure for ophthalmic preparations has mainly been attributed to the introduction of the vascular endothelial growth factor A (VEGF-A) antagonist ranibizumab to treat neovascular age-related macular degeneration [63]. Studies are ongoing with ranibizumab and other agents for the management of diabetic retinopathy and a widening of the indication is likely to occur in 2011.