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Since the movement of evidence-based medicine in the mid-1980s, pharmacoeconomics has gained more and more popularity. In the past decade,

pharmacoeconomic studies have been on the rise as third party payers faced budgetary issues due to the rapid growth of healthcare costs.[49] Crohn's disease is associated with a

substantial financial burden to both patients and society at large. The financial burden is further increased when costly biological therapies became available for CD patients as alternative medical therapies. Due to the high costs and lack of sufficient safety data and clinical evidence, biological therapies have been fraught with controversies and critics.[32] Several pharmacoeconomic studies from the past ten years were identified after searching PubMed with the following key words: economic evaluation, cost benefit analysis, Crohn's disease, biological therapy, and anti-tumor necrosis factor. Study setting and the main results of these studies are summarized in Table 2.4. Most of these investigations made great effort

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to demonstrate the cost effectiveness of biological therapies, mostly infliximab, among CD patients, and provided important information.

First, medical treatments with biological therapies, both infliximab (Remicade®) and adalimumab (Humira®), are associated with a very high incremental cost compared with the treatments with non biological therapy. In 2001, Arseneau et al. used Markov modeling to assess the cost-utility of infliximab by comparing infliximab combined with 6-

mercaptopurine (6MP) and metronidazole (Met). The incremental cost-effectiveness ratio (ICER) ranged from $355,450 to $377,000 per quality-adjusted life-years (QALY) while infliximab was administered in combination therapies or as mono therapy. The findings of this early study indicated that infliximab interventions are more costly than other

interventions that are already pricey, such as bone marrow transplant and peritoneal dialysis. Because clinical efficacy data were scarce, the ICERs were likely over estimated.[50] In 2003, the Health Technology Assessment program in UK reported that the cost per QALY in the treatment of chronic active Crohn's disease was £6700 ($10,953 in 2003 U.S. dollar) for a single-dose treatment, £10,400 (or $17,002) for episodic re-treatment, £84,400 (or $13,798) for maintenance treatment, and £102,000–£123,000 (or $166,750-$201,080) for initial treatment of fistulising disease.[51] Since the economic model was based on information submitted by the manufacturer and effectiveness data were obtained from randomized clinical trials (RCTs), the above results are likely downward biased.[51] Jaisson-Hot et al. compared the cost utility between infliximab and surgery among patients with severe Crohn's disease. The ICERs varied from €63,700 (episodic re-infusions) to €762,245 (maintenance therapy).[52] In a more recent study, Lindsay et al. evaluated the cost-effectiveness of maintenance treatment with infliximab among patients with active luminal and fistulising

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disease. Compared to standard care in 2008, the incremental cost per QALY gained was £26,128 ($48,397 in U.S. dollar) for luminal CD, and £29,752 ($55,110) for fistulising CD.[53] Similar results were obtained in Bodger's investigation, which compared infliximab treatment for one year with standard care. From a Markov simulation, the ICER was £19,050 per QALY gained.[54] In summary, the cost-effectiveness ratio of infliximab treatment to standard care was around $50,000 per QALY gained among patients with severe CD disease, and this cost-effectiveness ratio could be even higher among patients with mild to moderate Crohn's disease. According to the unofficial cost-effectiveness threshold of $50,000 per QALY gained in the U.S., infliximab treatments do not appear to be cost-effective.

Head-to-head comparisons of adalimumab with infliximab have suggested that adalimumab is more cost-effective than infliximab, but still not cost-effective in comparison to the cost-effectiveness threshold. Kaplan et al. compared the cost-effectiveness of

adalimumab as rescue therapy with high dose infliximab among patients who failed to respond to low dose infliximab. The cost per patient was $35,908 per QALY for patients receiving a dose escalation of infliximab, and $23,782 per QALY for patients receiving adalimumab. Even though adalimumab showed favorable cost-effectiveness, the costs of adalimumab were still considerably high.[55] In a recent study by Yu et al., adalimumab was only marginally more cost-effective than infliximab.[35] Compared with standard care, the incremental cost per QALY gained was £16,064 ($25,148 in 2009 US dollar) in severe CD patients, and £33,731($52,806) in patients with moderate-to-severe disease.[15]

Second, most analyses were conducted from the perspective of a third-party payer or healthcare system. In principle, the societal perspective is generally considered most

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encompasses all costs and health effects of an intervention regardless of who incurs the costs and who obtains the effects in the entire society.[56] However, there are many technical obstacles in accruing the effects and costs from all members in society, and in assessing the effects and costs quantitatively when conducting studies from a societal perspective. For example, indirect costs, such as productivity loss, are usually difficult to measure monetarily. More importantly, the perspective of economic evaluation should reflect the viewpoint of the key audience (e.g. healthcare decision makers) who are primarily intended to inform. The payer's perspective, either from a third-party payer or from national healthcare service, is common in economic studies conducted in the U.S. and abroad despite the differences in healthcare systems.[35, 50, 55] Compared to a broad societal perspective, a more narrow perspective can not only ease the determination of relevant healthcare services and costs, but also provide measureable values for decision makers. In this dissertation, I intend to inform the decision-makers who are responsible for budgeting health benefit plans in the third-party payers in the private sector of US healthcare system. It is not my intention, however, to inform the budget administrator of each individual health benefit plan. Instead, all health plans will be considered together as a single payer. The analyses in my dissertation will be based on the perspective of this joint single payer, which provides health benefits to all commercially insured non-elderly Americans.

While many economic studies have evaluated the cost-effectiveness of biological therapies in different patient groups using various analytic methods, (e.g. Markov modeling), and different data source, there are several important limitations that are worthy of comment: 1. The effectiveness of medical interventions with biologics in CUA or CEA was assessed

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therapies was likely over-stated because patients enrolled in clinical trials are generally healthier. Also the assessment based on small samples in clinical trials can hardly be generalized to the CD patient population. Given the short follow-up time in clinical trials (6 months to 1 year), the long-term benefits or risks of biological therapies can not be evaluated accurately. It is interesting to note that the difference in utility values, the denominator of the incremental cost-effectiveness ratio, was small in several studies. For example, Yu et al. reported that utility indices for treatment with infliximab and

adalimumab were 0.865 vs 0.851 respectively.[35] The small difference in these utility indices can increase the magnitude of the incremental cost-effectiveness ratio. This is a controversial issue with methodology of CUA or CEA.[56] If credible long-term effectiveness data are not available, CUA and CEA are not the ideal approach for evaluating the novel drug therapies.

2. Cost data are not up to date, or are not based on real-world data. Several studies

approximated the costs by using cost information, such as wholesale acquisition costs in Redbook® (Thomson Reuters, Ann Arbor, MI), and average costs published in other studies. Only a few studies used patient level data to calculate direct medical costs. Bodger et al. used data from the UK to derive total cost.[54] Yu et al. used patient level data in the US to estimate total costs, but patients were limited to the enrollees in the Medicare program.[35]

3. Selection bias and publication bias are threats to validity of the study results because of the influence from the sponsor in pharmaceutical industry. Most economic evaluation studies have been funded by the pharmaceutical companies, who are required to submit economic data about medical products to regulatory agencies in European countries for

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market authorization. In the U.S., it is not mandatory for pharmaceutical companies to include the economic evaluation data as part of submission dossier. Thus, pharmaceutical companies have not incentive to conduct large scale economic studies, or publish those studies if the findings are not favorable to their products. Unsurprisingly, results in the literature unanimously favor therapies manufactured by sponsoring company, and against competing products. Due to this conflict of interest, economic studies purely designed as marketing tools by the pharmaceutical companies may not provide valid information to the public.

Because of a lack of data regarding the effectiveness of biological therapies among patients with Crohn's disease, we strive to evaluate costs associated with these biological therapies and, more broadly, the total medical costs of patients with Crohn's disease. Unlike existing studies in the literature, our research will use current patient level data from a large pharmacy and medical claims database to estimate costs from the perspective of third-party payers. With no conflict of interest to declare, we do not assume any proposition during the research.

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Table 2.4 Summary of Pharmacoeconomic Studies Related to Crohn’s Disease

Study Setting Perspective /

Time Horizon Findings Limitations

Arseneau, 2001

CUA: inf vs. 6MP/met

Markov modeling of 3 treatments Efficacy data: literature review Cost data: hospital billing

Third party payer, 1 year

ICER (3 tx vs. 6MP/met): Tx 1 (inf+6MP/met): $355,450 Tx 2 (inf): $360,900

Tx 3 (6MP/met+inf): 377,000

Efficacy data were scarce back in 2001; hypothetic interventions (eg. 3 infusions of infliximab).

Clark, 2003

Health Technology Assessment by NICE, revised from the company model in submission

UK NHS Cost: £1,800 per dose

CE: £6,700 for single dose, £10,400 for episodic retreatment, £84,400 for maintenance. (per QALY) Fistulizing CD, more costly

Strictly limit infliximab to severe patients, not for episodic

treatment in UK setting

Jaisson- Hot, 2004

CUA: infliximab vs. surgery Markov modeling

Efficacy data: literature+expert Cost data: literature

Payer, lifelong (2- month cycle) ICER: (2 tx vs surgery): Tx 1 (relapse): €63,700 Tx 2 (maintain): €762,245 No patient-level data; Kaplan, 2007

CEA: inf vs ada (rescue therapy) Decision tree modeling

Efficacy data: clinical trials Cost data: literature, Redbook

Payer, 1 year ICER: inf (5mg--> 10mg) vs ada

$332,032/QALY

Not real-world data; only the sub- cohort lost response to 5mg/kg infliximab

Lindsay, 2008

CEA: inf vs standard care Markov modeling

Data source: literature

UK NHS, 5 years ICER (inf vs standard care):

Severe luminal CD: £26,128 Fistulizing: £29,752

Sponsor funded, not based on patient data.

ada = adalimumab, inf = infliximab, TNF = tumor necrosis factor, WAC=wholesale acquisition cost, QALY=quality-adjusted life year

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(Continued)

Table 2.4 Summary of Pharmacoeconomic Studies Related to Crohn's Disease

Study Setting Perspective /

Time Horizon Findings Limitations

Loftus, 2009

CEA: ada vs standard of care Efficacy data: clinical trials Cost data: literatures

UK NHS, 1 year ICER (ada vs standard of care):

Severe CD: £16,064/QALY

Moderate-to-severe:£33,731/QALY

Abbott funded, not real world patient data, strong assumptions (perfect adherence, etc)

Bodger, 2009

CEA: inf / ada vs standard care Markov cohort analysis Efficacy data: clinical trials Cost data: UK patient-level data

UK NHS, 1 year ICER (ada /inf vs Standard care):

Inf (1yr, 2 yr): £19,050, £21,300 Ada (1yr, 2yr): £7,190, £10,310

Rigorous assumptions for

Markov model, source of efficacy data

Yu, 2009 CUA: ada vs inf (maintenance)

Efficacy Data: clinical trials (CHARM and ACCENT I) Cost Data: WAC, Medicare

Payer, 1 year 1-year remission: 47.2% vs 37.1%

TNF cost: $17,176 vs $18,214 Total cost: $34,193 vs $39,045 QALY: 0.865 vs 0.851

Pharma (Abbott) sponsored, Small sample from clinical trials, Short time frame

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