Dis Manage Health Outcomes 2004; 12 (1): 1-8 1173-8790/04/0001-0001/$31.00/0

CURRENT OPINION

© 2004 Adis Data Information BV. All rights reserved.

Adalimumab for Rheumatoid Arthritis Considerations for Reimbursement by Third-Party Payors Leo van de Putte1 and Michael B. Nichol2 1 2

Department of Rheumatology, University Hospital, Nijmegen, The Netherlands Department of Pharmaceutical Economics and Policy, School of Pharmacy, University of Southern California, Los Angeles, California, USA

Abstract

Third-party payors and national health systems require evidence that new medications for rheumatoid arthritis are cost effective. To determine cost effectiveness, one must consider the cost of a given therapy versus the long-term cost of the disease, with and without therapy. The direct and indirect costs of rheumatoid arthritis over the course of the disease, including the considerable costs related to hospitalization and disability, have been quantified. Resource utilization and treatment costs are high for patients with rheumatoid arthritis, and there is a strong link between functional disability and direct cost of care. Traditional disease-modifying antirheumatic drugs (DMARDs) [such as methotrexate and gold] have limited long-term effects in improving lives and avoiding costs for patients with rheumatoid arthritis. Tumor necrosis factor (TNF) antagonists, the newest class of rheumatoid arthritis drug therapies, significantly improve patient outcomes, including reducing the signs and symptoms of rheumatoid arthritis, improving physical function and health-related quality of life, and inhibiting radiographic damage. Failing to treat rheumatoid arthritis effectively is very costly; effective treatment includes early, aggressive therapy. As a result, the National Health Service in the UK, other societal decision-makers, and third-party payors have recommended the use of TNF antagonists, in many instances, for the treatment of rheumatoid arthritis. The TNF antagonists – infliximab, etanercept, and the most recently approved, adalimumab – address the limitations of traditional DMARDs, thus setting a new therapeutic standard for rheumatoid arthritis. Data from three key studies (Anti-TNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis, DE019 and DE011) indicate that adalimumab provides a rapid, sustainable, predictable, and significantly greater reduction in the signs and symptoms of rheumatoid arthritis than traditional DMARDs. Adalimumab yields significantly less structural joint damage as measured by the total Sharp scores and scores on its two major components: joint erosions and joint space narrowing. It also improves physical function (as measured by the Health Assessment Questionnaire Disability Index) and health utility (as measured by the Health Utilities Index Mark 3). In conclusion, rheumatoid arthritis and other musculoskeletal diseases are costly, but an upfront investment in highly effective therapies may provide long-term cost savings compared with traditional therapies. The immediate, out-of-pocket costs of TNF antagonists are greater than traditional DMARDs, but with the potential to significantly improve response rates, inhibit structural joint damage, and improve disability and health utility, TNF antagonists have the potential to be more cost effective over the long run. TNF antagonists can be valuable for patients in need and therefore appropriate for reimbursement by national health systems and third-party payors.

Third-party payors and national health systems require evidence that new medications are cost effective. Private health payors prefer that new therapies offer cost savings, as well as cost

effectiveness. Yet for chronic, disabling diseases, direct, short-term cost savings may not adequately assess the value of new medications. For example, patients with rheumatoid arthritis

2

are estimated to have three times the direct medical costs, twice the hospitalization rate, and 10 times the work disability rate of an age- and sex-matched population.[1] Furthermore, it is estimated that half of all patients with rheumatoid arthritis are unable to work after 10 years following the diagnosis.[2] Even with early and aggressive antirheumatic therapy, the prevalence of work disability among patients with rheumatoid arthritis was 44% after 10 years.[3] There is increasing evidence that the timing of effective treatment is key in rheumatoid arthritis. Modern treatment paradigms stress early, aggressive therapy since this is critical in ensuring that effective treatments are initiated when they have the best chance of making the biggest difference.[4] For example, the progression rate of joint damage is greatest in the first year of disease. Over the first 2–3 years of the disease, an already damaged joint is more likely to continue to degenerate than a previously unaffected joint is to become damaged.[5] Since evidence from published studies of observational data sets from the US, Sweden and Germany indicates a strong relationship between disability and costs of patient care,[6-9] it may be less costly and more effective in the long-term to provide early, aggressive treatment. For example, a study by Yelin and Wanke[6] in the “pre-biologics era,” using data from the University of California-San Francisco Rheumatoid Arthritis Panel Study, revealed that more than 50% of the money spent on treatment of rheumatoid arthritis pays for hospital admissions alone. Yet, these hospital admission costs are used for only 10% of the total number of patients with rheumatoid arthritis. Therefore, according to this study, at least 50% of healthcare financial resources are being spent on an overwhelming minority of patients. Through new rheumatoid arthritis management tools, such as biologic disease-modifying antirheumatic drugs (DMARDs), the possibility of saving costs on hospital admissions and joint replacement surgeries, for example, represents an opportunity to avoid some costs altogether or spread resources over a greater number of patients. But this result depends on how early therapy is initiated and the effectiveness of the DMARDs used. Conventional DMARDs do not adequately provide the needed degrees of pain relief, control of inflammation, and inhibition of joint damage in many patients with rheumatoid arthritis. They are slow-acting drugs that require months of compliance before achieving clinical effectiveness, and are poorly tolerated as long-term therapy. A meta-analysis of discontinuation rates in clinical practice indicated that the median duration of DMARD monotherapy was less than 2 years for a non-methotrexate agent.[10,11] Since guidelines advocate sustained long-term therapy,[11,12] discontinuing treatment increases the risk of relapse. © 2004 Adis Data Information BV. All rights reserved.

van de Putte & Nichol

On the other hand, tumor necrosis factor (TNF) blocking agents, a new class of DMARDs, have already been shown to be a cost-effective advance over traditional DMARDs, such as gold, in patients with long-standing, active disease.[13,14] These agents significantly improve patient outcomes, including symptoms and disease progression, disability, and quality of life.[15,16] As a result, they have been accepted for reimbursement by third-party payors. For example, in 2002, the National Health Service (NHS) in the UK, via guidance published by the National Institute for Clinical Excellence (NICE),[13] recommended that etanercept and infliximab be considered as treatment options for adults with rheumatoid arthritis who continue to have clinically active disease that has not responded adequately to at least two conventional DMARDs, including methotrexate, unless contraindicated. To make its recommendation, NICE evaluated the clinical effectiveness of etanercept and infliximab, calculated the cost effectiveness of each, and reviewed cost-utility analyses. In addition, by employing drug response rates from clinical trials and using drug costs, NICE estimated the cost implication for the use of these agents on the NHS budget and found it to be acceptable. Adalimumab is the latest TNF antagonist, and is the first and only fully human anti-TNF monoclonal antibody. Adalimumab received US FDA regulatory approval late in 2002 – for use alone, or in combination with methotrexate and other traditional DMARDs – in adults with moderately to severely active rheumatoid arthritis. In September 2003, the European Medicines Evaluation Agency (EMEA) also approved adalimumab for the treatment of adult rheumatoid arthritis in Europe. Currently, adalimumab is the only TNF antagonist indicated for use with concomitant methotrexate or as monotherapy in both the US and Europe. NICE has not yet published guidance on the use of adalimumab. However, by reviewing the clinical effectiveness and utility of adalimumab, and with consideration of the US and international prices for adalimumab, this article explores the implications of the use of adalimumab for national health systems and third-party payors. This article reviews the healthcare-related costs associated with rheumatoid arthritis, and a payor’s perspective of initiating effective treatment early in the progression of the disease. The effect of adalimumab on the disease course of rheumatoid arthritis, including quality of life and health utility, is also discussed, with a focus on the implications for third-party payor reimbursement. 1. Costs of Care and Disability Associated with Rheumatoid Arthritis Of interest to third-party payors are the costs associated with healthcare as well as the effectiveness of particular healthcare Dis Manage Health Outcomes 2004; 12 (1)

Adalimumab for Rheumatoid Arthritis: Third-Party Reimbursement

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Table I. Annual costs (€) correlated with functional disability of patients with rheumatoid arthritis[7] HAQ DI score

Direct costs inpatient

<0.5

237

Indirect costs outpatient 286

drugs/tests

total

67

total

590

0

0.5 to <1.1

967

325

112

1404

3664

1.1 to <1.6

1438

327

121

1886

7914

1.6 to <2.1

3096

334

138

3568

13 273

2.1 to <2.6

3581

309

147

4038

13 483

>2.6

1593

325

126

2044

14 903

HAQ DI = Health Assessment Questionnaire disability index.

regimes. Therefore, the first step is to consider the cost of healthcare associated with rheumatoid arthritis.

up to a HAQ DI score of 2.6, because of the costs of hospitalization, which accounted for the majority of direct costs in this study.

Resource utilization and treatment costs are high for patients with rheumatoid arthritis in the industrialized world. Costs are much higher when lost productivity is considered and the disease is more advanced. For example, in a study evaluating patients across five countries,[17] the total costs (excluding drug costs), for patients with long-standing rheumatoid arthritis (a mean duration of disease of 11 years) and a history of having failed several traditional DMARDs were, on average, approximately $US7000 (2001 values) per patient per year, ranging from $US5174 in Australia to $US9277 in the UK. Direct non-medical costs accounted for the largest proportion of the total costs (excluding drug costs), averaging 35.5% and reaching as high as 47.7% in Canada. Direct medical costs (in-patient) averaged 27% of the total costs. These costs were consistent with those estimated from a systematic review of four European and 11 US studies that compared direct and indirect costs of rheumatoid arthritis between and within countries.[18]

This study by Kobelt et al.[7] also projected the 5-year costs of rheumatoid arthritis, taking into account the distribution of patients across the different HAQ DI categories in year 1 and the movement between categories over time. As shown in figure 1, the 5-year direct and indirect costs increased proportionally to the level of disability, while indirect costs accounted for most of the costs at the highest levels of disability.

Kobelt et al.[7] reported both direct and indirect annual costs in Sweden (Swedish Kronor [SEK], 1997 values) for six different categories of the HAQ DI score. The direct costs were also broken down into ‘inpatient,’ ‘outpatient,’ and ‘drugs/tests’. These costs are shown in table I after conversion to euros (€) using a conversion rate of 1€ = 9.15947 SEK). The results illustrated that indirect costs increased with functional disability (as measured by the HAQ DI), and direct costs increased with functional disability © 2004 Adis Data Information BV. All rights reserved.

Resource utilization studies – such as Kobelt et al.[7] and Leardini et al.[19] – also offer evidence that it is very costly not to control rheumatoid arthritis and prevent the naturally occurring progressive and disabling nature of the disease. Regarding the converse, there are, as yet, no long-term results that measure the effectiveness of rheumatoid arthritis biologics on disability levels 80 Projected 5-year costs (€ x 1000)

Other research has investigated the relationship between functional disability and direct cost of care. Three studies[6,7,19] demonstrated that the costs of rheumatoid arthritis were related to the level of disability of the patient, as measured by the Health Assessment Questionnaire (HAQ) disability index (DI). Yelin and Wanke[6] reported on total direct costs per patient in the US, which were divided into four categories on the basis of the HAQ DI score. They found that total direct costs increased with increasing functional disability measured by the HAQ DI.

Finally, the third study, by Leardini et al.,[19] investigated the costs of rheumatoid arthritis in Italy and also demonstrated that the per-patient direct and indirect costs increased substantially with decreased function, as measured by American College of Rheumatology (ACR) functional class.

Direct costs Indirect costs

70 60 50 40 30 20 10 0 <0.5

0.5 < 1.1

1.1 < 1.6

1.6 < 2.1

2.1 < 2.6

>2.6

Baseline HAQ DI score (functional disability)

Fig. 1. Five-year direct and indirect costs associated with level of functional disability.[7] The HAQ DI scale ranges from 0 = no difficulty to 3 = unable to do, for several activities of daily living. HAQ DI = Health Assessment Questionnaire disability index. Dis Manage Health Outcomes 2004; 12 (1)

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van de Putte & Nichol

2. Response Rates with Adalimumab 2.1 Combination Therapy

Recent publications report studies evaluating the clinical effectiveness of adalimumab, used either alone or in combination with methotrexate. Two studies that evaluated combination therapy were the Anti-TNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis (ARMADA) study[22] and the DE019 study.[23] These trials enrolled patients with moderate to severe rheumatoid arthritis who had an inadequate response to traditional DMARDs and who remained on a stable dose of methotrexate treatment during the trials. The duration of the ARMADA study was 24 weeks, while the duration of DE019 was 52 weeks. A primary efficacy endpoint for these trials was the ACR20 response, i.e. the ACR criterion for assessing clinical response to drug therapy.[22,23] An ACR20 response is defined as at least a 20% improvement in tender joint count and swollen joint counts, plus at least a 20% improvement in three or more of the following five parameters: (i) patient’s global assesment of disease activity; (ii) physician’s global assesment of disease activity; (iii) patient’s assessment of pain; (iv) HAQ DI score; and (v) acute phase reactant laboratory measurement. In addition, both trials calculated ACR50 response rates (i.e. at least a 50% improvement in both tender and swollen joint counts and at least a 50% improvement in three or more of the previously listed five individual measures). The results for the ARMADA study[22] showed a statistically significant improvement in ACR20 with adalimumab administered in the recommended dose of 40mg every other week subcutaneously in combination with methotrexate, as compared with placebo plus methotrexate. A more rapid onset of relief was observed with adalimumab plus methotrexate compared with placebo plus methotrexate. Statistically significant differences in ACR20 response between adalimumab and placebo were evident within 1 week of treatment, which was the first evaluation point in the trial, and the efficacy was maintained through the 24 weeks of the study (figure 2). At week 24, about two-thirds (67%) of patients in the adalimumab 40mg group achieved an ACR20 © 2004 Adis Data Information BV. All rights reserved.

response, compared with approximately 15% of the placebo group, a statistically significant difference in response. Moreover, in the open-label extension of this study, 79% of patients remained on adalimumab therapy for a duration of 30 months, and these patients demonstrated sustained efficacy as measured by the Disease Activity Score (DAS) 28, ACR response (at all levels; ACR20, ACR50, and ACR70), tender joint counts (TJC) and swollen joint counts (SJC), and HAQ DI.[24] Adalimumab in combination with methotrexate was also significantly superior to placebo plus methotrexate in terms of the percentage of patients achieving the more stringent ACR50 response (figure 3) [i.e. at 24 weeks, 55% for the 40mg group versus 8% for placebo]. The results for the DE019 study,[23] another placebo-controlled, randomized trial, also found that the combination of adalimumab and methotrexate was significantly more effective than placebo combined with methotrexate in reducing the signs and symptoms of rheumatoid arthritis. At week 24, the ACR20 response rate was 63% for patients in the adalimumab 40mg every other week group, compared with 30% for those in the placebo group. The ACR50 response rate reported in this study was also significantly superior for patients receiving adalimumab compared with placebo, with nearly four times the number of responders in the adalimumab group than in the placebo group: 39% versus 10% (p ≤ 0.001). In the ARMADA study,[22] adalimumab was well-tolerated during the 24-week study, with adverse events reported at a similar rate between adalimumab-treated and placebo-treated patients. Placebo + MTX Adalimumab 20mg eow + MTX Adalimumab 40mg eow + MTX Adalimumab 80mg eow + MTX

80 70 60 Patients (%)

and costs of care. However, data on adalimumab suggest that it has the potential to provide cost effectiveness of care because of its ability to sustain reductions in rheumatoid arthritis-related levels of disability for up to 5 years.[20,21] From a payor’s perspective, if there is a long-term focus, then not treating rheumatoid arthritis effectively is costly and progressive, especially as the condition deteriorates and causes more disability and morbidity.

50 40 30 20 10 0 0

2

4

6

8

10

12

14

16

18

20

22

24

Weeks

Fig. 2. ACR20 response in patients with rheumatoid arthritis receiving adalimumab plus methotrexate (MTX) or placebo plus MTX in the ARMADA trial. p < 0.001 versus placebo for all treatment groups at week 24 (Weinblatt ME, Keystone EC, Furst DE, et al.[22] Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody for the treatment of RA in patients taking concomitant methotrexate: The ARMADA trial. Arthritis & Rheumatism, copyright (©) 2003 American College of Rheumatology. Reproduced with permission of John Wiley & Sons, Inc.). ACR = American College of Rheumatology; ARMADA = Anti-TNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis; eow = every other week. Dis Manage Health Outcomes 2004; 12 (1)

Adalimumab for Rheumatoid Arthritis: Third-Party Reimbursement

60

Placebo + MTX Adalimumab 20mg eow + MTX Adalimumab 40mg eow + MTX Adalimumab 80mg eow + MTX

Patients (%)

50 40 30 20 10 0 0

2

4

6

8

10

12

14

16

18

20

22

24

Weeks

Fig. 3. ACR50 response in patients with rheumatoid arthritis receiving adalimumab plus methotrexate (MTX) or placebo plus MTX in the ARMADA trial. p < 0.003 for 20mg group and p < 0.001 for the 40mg and 80mg groups, all at 24 weeks (Weinblatt ME, Keystone EC, Furst DE, et al.[22] Adalimumab, a fully human anti-tumor necrosis factor α monoclonal antibody for the treatment of RA in patients taking concomitant methotrexate: The ARMADA trial. Arthritis & Rheumatism, copyright (©) 2003 American College of Rheumatology. Reproduced with permission of John Wiley & Sons, Inc.). ACR = American College of Rheumatology; ARMADA = AntiTNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis; eow = every other week.

There was a higher incidence of injection site reactions (pain, erythema, localized rash, and hemorrhage at the injection site) for adalimumab compared with placebo, but these reactions were generally mild or moderate, and most reactions resolved spontaneously. 2.2 Monotherapy

Adalimumab as monotherapy received FDA and EMEA approvals in patients with rheumatoid arthritis who are non-responsive to traditional DMARDs. In a 26-week, randomized, doubleblind, placebo-controlled trial (DE011), the use of adalimumab monotherapy 40mg given every other week was assessed in patients with active rheumatoid arthritis who had not responded to DMARDs (and were no longer taking any other DMARD).[25] Among 113 patients treated with adalimumab, 46% achieved an ACR20 response, compared with 19% treated with placebo (p < 0.01). In addition, 22% of adalimumab patients achieved an ACR50 response, compared with 8% treated with placebo (p < 0.01). Thus, these results indicate that adalimumab is effective when given alone to patients with active rheumatoid arthritis. 3. Control of Disease Progression with Adalimumab As mentioned at the beginning of this article, a large percentage of patients with rheumatoid arthritis, despite being treated actively with traditional DMARDs, progress to disabling disease that results in work disability.[3] Therefore, the ability of an antirheumatic agent to prevent disease progression is very important to health outcomes and patient well-being. © 2004 Adis Data Information BV. All rights reserved.

5

The ability of adalimumab to moderate structural joint damage was evaluated in the DE019 study.[23] The patients were evaluated radiographically (hands, wrists, and feet) at baseline, and at 6 months and 1 year on therapy. Key radiographic measures were the modified Sharp score, an overall measure of joint structural integrity for which large increases are indicative of disease progression and/or joint worsening; and the Sharp score’s 2 component subsets: joint erosions and joint space narrowing. The results at 1 year demonstrated significantly less structural joint damage in patients receiving the combination of adalimumab 40mg subcutaneously every other week and methotrexate, compared with the placebo plus methotrexate combination.[23] The efficacy of the adalimumab plus methotrexate combination was apparent across all of the measures of structural joint involvement, with significantly smaller decreases in total Sharp score, joint erosions, and joint space narrowing. In addition, at the 52-week evaluation, statistically significantly more patients taking adalimumab plus methotrexate had no new erosions, compared with those receiving placebo plus methotrexate (62% vs 46%). Data presented at the ACR 2003 annual conference in Orlando, Florida, USA, showed that adalimumab sustains radiographic inhibition over 2 years in patients with long-standing rheumatoid arthritis.[26] More than 90% of patients remained on adalimumab therapy through the second year, and 67% of adalimumab-treated patients showed no progression of total Sharp score at 2 years. By reducing structural joint damage, and even preventing erosive changes in a large percentage of patients over the course of 2 years of treatment, adalimumab is an antirheumatic agent with the potential to influence long-term outcomes for those with rheumatoid arthritis. 4. Effect of Adalimumab on Quality of Life and Health Utility 4.1 Rheumatoid Arthritis Disability: Health Assessment Questionnaire Disability Index

In rheumatoid arthritis, elevated HAQ disability scores correlate with poor outcomes, greater utilization of healthcare resources, and increased mortality.[27] Early, aggressive intervention in rheumatoid arthritis has been advocated as an effective means of improving long-term outcomes, including disability. In the ARMADA[22] and DE019[23] trials, the effect of adalimumab on quality of life was assessed using the HAQ DI, a typical measurement of rheumatoid arthritis disability. The HAQ DI score includes elements of functional status such as dressing, walking, and gripping. In both studies, adalimumab plus methotrexate was statistically significantly more effective than placebo Dis Manage Health Outcomes 2004; 12 (1)

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van de Putte & Nichol

Table II. Results of the ARMADA[22] and DE019[23] trials regarding the effect of adalimumab plus methotrexate (MTX) on the physical function of patients with rheumatoid arthritis

HAQ DI score (0–3 scale)b

ARMADA trial (endpoint at 24 weeks)a

DE019 (endpoint at 52 weeks)a

adalimumab 40mg eow + MTX (n = 67)

placebo + MTX (n = 62)

adalimumab 40mg eow + MTX (n = 207)

placebo + MTX (n = 200)

Baseline value (mean ± SD)

1.55 ± 0.61

1.64 ± 0.63

1.45 ± 0.63

1.48 ± 0.59

Absolute change (mean ± SD)

–0.62 ± 0.63c

–0.27 ± 0.57

–0.59 ± 0.57c

–0.25 ± 0.56

Percentage change

–40.0

–16.5

–40.7

–16.9

a

Based on the last observation carried forward to week 24 or 52.

b

The HAQ DI scale ranges from 0 = no difficulty to 3 = unable to do, for several activities of daily living.

c

p ≤ 0.001, absolute change for adalimumab vs placebo treatment, by analysis of covariance with baseline as the covariate; statistical significance was set at p ≤ 0.05.

ARMADA = Anti-TNF Research Program of the Monoclonal Antibody Adalimumab in Rheumatoid Arthritis; eow = every other week; HAQ DI = Health Assessment Questionnaire disability index.

plus methotrexate in improving HAQ DI scores at the 6-month and 1-year endpoints for the ARMADA and DE019 trials, respectively (table II). Similar statistically significant decreases in HAQ DI scores were observed in the DE011 study for patients receiving adalimumab monotherapy compared wtith placebo.[25] Goldsmith et al.[28] have suggested that a 0.22 increase or reduction from baseline in HAQ DI score represented the minimum clinically important change in patient functioning. Patients in the adalimumab groups in both studies experienced average decreases of nearly three times that magnitude (0.62 and 0.59 reductions in the ARMADA and DE019 trials, respectively), therefore, the response to adalimumab was clinically meaningful and could translate into improved abilities for patients to function. 4.2 Health Utility: Health Utilities Index

As with all the pivotal trials of adalimumab, the DE011 monotherapy study (see section 2.2) directly measured the impact of adalimumab on health utility.[29] A key focus of the study was the effect of adalimumab on the Health Utilities Index Mark 3 (HUI3), which measures the state of health of a patient from a societal perspective (i.e. utility, on a scale of 1 [perfect health] to 0 [death]). Scores less than zero are perceived as worse than death (i.e. the patient would rather die than undergo treatment). For this measure, a difference of at least 0.03 is considered to be clinically meaningful. Enrolled patients had a mean baseline HUI3 of 0.265 which indicated that they were in very poor health.[29] In fact, they compared unfavorably with patients in the ACR’s lowest functional class (Class IV), which typically has an HUI3 score of 0.33. At week 26, patients who were treated with adalimumab 40mg every

© 2004 Adis Data Information BV. All rights reserved.

other week (improved 0.088 points more than placebo-treated patients, about three times the minimum clinically important difference.[29] The DE011 monotherapy study confirms the previous findings with adalimumab in combination with methotrexate, i.e. that adding adalimumab to the therapeutic antirheumatic regimen significantly improves patient functioning and well-being, and does so to a level that might be seen as worthwhile by patients. The DE019[23] trial also evaluated the effect of adalimumab plus methotrexate on disability and utility. The study evaluated the relationship between a high-level ACR response achieved while taking adalimumab and health utility measured in HUI3 and the Short-Form-36 (SF-36), which includes physical function, bodily pain, vitality, mental health, and four other domains. The analysis indicated that the levels of HUI3 and SF-36 improvement were dependent on the levels of ACR response achieved. Patients with a higher ACR response (ACR50 or above) experienced a significantly greater improvement in health-related quality of life compared with patients with an ACR20 response. For instance, there was more than twice the improvement in physical function in patients achieving an ACR50 (or better) response, compared with those achieving an ACR20 response. Nearly the same magnitude of greater improvement was seen in the other measures when those with an ACR50 (or better) response were compared with those with an ACR20 response. These results suggest that sustained high-response levels with adalimumab therapy could lead to a reduction in rheumatoid arthritis-related disability and its associated costs, both direct and indirect.

Dis Manage Health Outcomes 2004; 12 (1)

Adalimumab for Rheumatoid Arthritis: Third-Party Reimbursement

5. Other Tumor Necrosis Factor Antagonists Compared With Adalimumab Another way to consider adalimumab from a third-party payor perspective is to compare it with the other available TNF antagonists, which have been found to be cost effective. Unfortunately, there are no direct comparisons between adalimumab and the other TNF antagonists in controlled clinical trials of rheumatoid arthritis, this type of comparison can be approximate at best. The primary results to compare include the efficacy rates, since efficacy (along with safety) influences how long a patient stays on therapy and the likelihood of a patient achieving a satisfactory response. As mentioned in section 2.1, the DE019[23] and ARMADA[22] trials reported that adalimumab in combination with methotrexate resulted in ACR20 response rates at 24 weeks of 63% and 67%, respectively and ACR50 response rates of 39% and 55%, respectively. In the data reviewed by NICE,[13] ACR20 response rates at 6 months were 59% for etanercept monotherapy and 71% for etanercept plus methotrexate at a dose of 25mg twice weekly (versus 11% for placebo and 27% for placebo plus methotrexate), while ACR50 response rates were 40% (monotherapy) and 39% (etanercept plus methotrexate) [with 5% for placebo and 3% for placebo plus methotrexate]. For infliximab, at its licensed dose of 3 mg/kg every 8 weeks, ACR20 response rates at week 54 were 43% (and 17% for placebo plus methotrexate), and ACR50 response rates at 102 weeks were 21% (versus 6% for placebo plus methotrexate). The NICE Technology Appraisal Guidance Report[13] mentioned that etanercept and infliximab improve joint structure damage scores. Adalimumab also improves joint structure damage scores.[23,26] These results, therefore, suggest that adalimumab is likely to have at least comparable efficacy to these other agents. Regarding safety, etanercept, infliximab and adalimumab appear to have similar safety profiles, with injection site reaction being the most common reported adverse event for both etanercept and adalimumab.[30] There were several adverse events that occurred more frequently in infliximab-treated patients compared with placebo plus methotrexate, including upper respiratory tract infections, sinusitis, pharyngitis, headache, and infusion reactions.[30] In terms of improvements in rheumatoid arthritis-related disability, adalimumab appears as effective as other TNF antagonists. For example, the NICE guidance report[13] indicates that etanercept treatment resulted in improvements in HAQ DI scores that ranged from 23% to 32%, compared with –6% to 6% for placebo. With infliximab, the median HAQ scores improved by 13% but did not change significantly with placebo plus methotrexate. The ARMADA study indicated a 40% improvement in HAQ DI for © 2004 Adis Data Information BV. All rights reserved.

7

adalimumab-treated patients versus 17% for placebo-treated patients.[22] The NICE Report also commented on the difference in administration of etanercept and infliximab, and the implications on use of rheumatology services and costs. For example, it stated that infliximab requires day-care facilities because it is given by intravenous infusion, while etanercept requires reconstitution prior to being given subcutaneously twice weekly. In contrast, adalimumab has a more favorable regimen of ready-to-use subcutaneous injections self-administered by the patient every other week. In addition, based on cost-effective analyses by Bansback and colleagues[31,32] at the University of Sheffield in the UK (who investigated the available trial data and current indications for adalimumab), adalimumab is more cost effective than infliximab and at least as cost-effective as etanercept. Moreover, because more trial data are available for adalimumab, the results for adalimumab can be interpreted with greater certainty than for the results for etanercept.[31,32] 6. Conclusion For decades there has been frustration because traditional DMARDs improved the symptoms of rheumatoid arthritis, but allowed the disease to progress toward joint destruction and disability. Traditional DMARDs have helped some patients but for many others have been difficult to tolerate or have not provided sustained efficacy, thus contributing to suboptimal efficacy results and discontinuation of therapy. The introduction of biologic treatments (such as TNF antagonists) brings new hope and new treatment options to patients with rheumatoid arthritis. The most recent TNF antagonist to be introduced to the market, adalimumab, in combination with methotrexate, provides significant clinical response, improves quality of life, and inhibits disease progression in patients with rheumatoid arthritis. Furthermore, adalimumab given as monotherapy provides significant effectiveness and improvement in HAQ DI and health utility scores for patients with rheumatoid arthritis who are not responsive to DMARDs. Adalimumab has at least comparable efficacy to other TNF antagonists such as etanercept and infliximab. In addition, a cost-effectiveness analysis suggests that adalimumab is more cost effective than infliximab and at least as cost-effective as etanercept. While rheumatoid arthritis and other musculoskeletal diseases are costly, an investment in anti-TNF therapies in those patients not adequately responsive to traditional DMARDs (such as methotrexate) may provide long-term cost savings. The immediate, outof-pocket costs associated with these new treatments are greater Dis Manage Health Outcomes 2004; 12 (1)

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van de Putte & Nichol

than that of traditional DMARDs, but since they have the potential to significantly improve response rates, reduce structural joint damage, and improve disability and health utility, these drugs can be more cost effective over the long run. TNF antagonists, including adalimumab, are a valuable addition to the treatment options available for patients with rheumatoid arthritis and appropriate for reimbursement by national health systems and third-party payors. Acknowledgements We are paid consultants of Abbott Laboratories. In addition, we wish to thank Michael Nissen of the Biomedical Publishing Group of Abbott Laboratories for his editorial contributions to this article.

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About the Author: Dr Levinus (Leo) van de Putte studied medicine at the State University Leiden, The Netherlands, and was appointed professor of Internal Medicine and Rheumatology at the Medical Faculty and University Hospital, Nijmegen, The Netherlands, in 1977. Professor van de Putte is a former president and honorary member of the European League Against Rheumatism (EULAR). His research interests, reflected in numerous publications, include: clinical and experimental rheumatology, immunology, clinical pharmacology and health care. Correspondence and offprints: Dr Leo van de Putte, Department of Rheumatology, University Hospital, PO Box 9101, Nijmegen, The Netherlands 6500 HB. E-mail: [email protected] Dis Manage Health Outcomes 2004; 12 (1)