The Value of Specialty Pharmaceuticals - A Systematic Review

Objectives

Novel specialty biopharmaceuticals hold promise for patients living with complex and chronic conditions. However, high research and development costs, special handling, and other necessary enhancements to patient support programs all contribute to frequently higher prices for these products. This study sought to assess the value of specialty pharmaceuticals through an examination of the clinical, functional, and economic benefits of these treatments for the top 3 disease areas by pharmaceutical spend: rheumatoid arthritis (RA), multiple sclerosis (MS), and breast cancer (BC).

Study Design

Systematic literature review.

Methods

A systematic review of market research and cost-effectiveness articles was conducted for each disease area to assess clinical, functional, and economic outcomes associated with specialty medicine treatments versus the previous standard of care

Results

All RA clinical (American College of Rheumatology) and functional (Health Assessment Questionnaire) outcome articles were classified as positive. The median cost-effectiveness ratio was $38,900 per quality-adjusted life year (QALY). All MS clinical outcome (relapse rate) articles were positive. The MS functional outcome (Expanded Disability Status Scale) findings were less conclusive. The median cost-effectiveness ratio was $248,000 per QALY. The majority of BC articles yielded statistically inconclusive results for survival. All functional outcome (Quality of Life Questionnaire- Core 30) articles were positive. The median cost-effectiveness ratio was $51,900 per QALY.

Conclusions

Novel specialty therapies hold promise for arresting disease progression and improving quality of life for the 3 conditions associated with the highest specialty pharmaceutical spend. These findings demonstrate a strong value proposition for specialty pharmaceuticals, and suggest even greater potential individual patient benefit with consideration of patient heterogeneity.

Am J Manag Care. 2014;20(6):461-472

Specialty pharmaceuticals can offer significant benefits to patients living with complex and chronic conditions compared with previously available therapies.

• In rheumatoid arthritis patients, the introduction of biologics cost-effectively improved clinical and functional outcomes compared with traditional disease-modifying antirheumatic drugs.

• In multiple sclerosis patients, this review indicates biologic therapies are clinically effective, as all studies reviewed reported a reduction in the relapse rate. Functional studies provided neutral findings.

• In breast cancer patients, the majority of articles reviewed yielded statistically inconclusive results for survival. With respect to the functional metric, the results were strongly favorable, indicating that specialty pharmaceuticals improve quality of life.

Novel specialty pharmaceuticals—typically biological therapies which may cost tens of thousands of dollars for a course of treatment—hold great promise for patients living with complex and chronic conditions. ¹ The improved efficacy and the potential to redefine treatment modalities, however, are not without cost. High research and development costs, special handling and distribution networks, and necessary enhancements to patient support programs all contribute to the high price of specialty pharmaceuticals.² Due in part to the high and often rising cost of these products, payers increasingly demand evidence of their value.^3,4 It is predicted that by 2017 specialty pharmaceuticals will represent more than half of total pharmaceutical sales, intensifying the need to clearly understand their clinical and functional value.⁵

To holistically characterize the value of specialty pharmaceuticals, one must look beyond cost and take into account benefits. To this end, we systematically reviewed published studies involving specialty pharmaceuticals for the top 3 disease areas by pharmaceutical spending in the United States, namely rheumatoid arthritis (RA), multiple sclerosis (MS), and breast cancer (BC). For each disease area, we compared the clinical and functional efficacy of specialty pharmaceutical treatments with conventional therapies representing the previously available standard of care. To evaluate therapeutic benefits in an economic context, we also reviewed available cost-effectiveness findings for the specialty pharmaceuticals. This combined economic and clinical approach allowed us to comprehensively assess the value of specialty pharmaceuticals from both a patient and payer perspective.

METHODSDefinition of Specialty Pharmaceuticals

A variety of definitions exist for “specialty pharmaceutical.” We performed a literature search to identify a “specialty pharmaceutical” definition that was well accepted in the medical literature and would provide a reasonable framework for our review. Based on articles reviewed,^1-4,6-9 we defined specialty pharmaceuticals to be pharmaceutical treatments that: (1) are high cost (generally accepted as having prescription price exceeding $600 per month); (2) require close monitoring, including personalized or frequent adjustment of dosing; and (3) require special handling, such as careful temperature control, or restrictions on where the medication can be administered, prepared, or distributed.

Selection of Disease Areas

eAppendix A

www.ajmc.com

We selected disease areas by first building a comprehensive list of specialty pharmaceuticals marketed in the United States and identifying the corresponding disease area(s) for each therapy. A full list of specialty pharmaceuticals appears in (available at ). We excluded orphan diseases because they typically lack a conventional therapy with which the specialty pharmaceutical can be compared. We excluded diseases for which specialty pharmaceuticals provide only acute or supportive care because our goal was to evaluate specialty pharmaceuticals in cases where they incur the highest costs—namely when used chronically.

Next, we reviewed market research reports and other materials to find the top 10 disease areas by specialty pharmaceutical spend in the United States. We initially focused our analysis on the 4 top areas in this list but ultimately excluded the disease area with the fourth-highest pharmaceutical spend—human immunodeficiency virus (HIV)—because we could find no studies comparing specialty therapies for HIV with nonspecialty therapies. Since HIV therapies were not available prior to the introduction of specialty pharmaceuticals to treat this disease, specialty pharmaceutical benefits to HIV patients have been substantial. Exclusion of HIV left 3 disease areas: rheumatoid arthritis (RA), multiple sclerosis (MS), and breast cancer (BC).

Selection of Pharmaceuticals

For each of the 3 disease areas, we included specialty pharmaceuticals if they were: (1) marketed in the United States; (2) identified as a specialty pharmaceutical per our constructed definition; and (3) specified by guidelines for treatment in the disease area at time of publication.

Selection of Metrics

For each of the 3 disease areas, we selected 1 clinical metric (eg, efficacy) and 1 functional metric (eg, quality of life). For the clinical metric, we first identified outcomes mentioned in clinical trials catalogued in the US government’s clinical trials registry for the pertinent disease area. We next searched PubMed (National Center for Biotechnology Information, US National Library of Medicine, Bethesda, Maryland) for articles that used each metric and also mentioned both a specialty pharmaceutical in that disease area and the disease area itself. We retained the clinical end point used in the greatest number articles as the end point for our literature review. We selected the functional metric using a similar process but the initial list of metrics was determined from review articles focused on functional outcomes in the disease area.^10-17 Our economic evaluation focused on analyses estimating cost-per-QALY (quality-adjusted life year), a gold standard metric in the health economics literature.¹⁸

Systematic Review

We identified original clinical and functional outcome articles for each disease area from review articles. We identified review in PubMed using the search phrase: “(disease AND metric)” and applying PubMed’s systematic review filter. To this list, we added original articles published too recently to appear in the reviews. We identified these articles from a supplemental search of PubMed that omitted the systematic review filter. We excluded original articles if they were: (1) published before January 1990; (2) not in English; (3) not an original article; (4) not relevant (ie, did not provide original outcome data associated with the relevant drugs) based on the title or abstract; or (5) not available for electronic download. Articles were likewise excluded if they: (6) did not report quantitative results; or (7) did not compare the selected specialty pharmaceuticals with nonspecialty treatments.

We identified cost-effectiveness articles from the Tufts Medical Center Cost-Effectiveness Analysis Registry,¹⁹ which contains 3488 cost-utility analyses on a wide variety of diseases and treatments. For each disease area, we searched the registry for articles evaluating pertinent specialty pharmaceuticals. Articles that did not compare a pertinent specialty drug with a conventional treatment were excluded.

Evidence Assessment

Two reviewers independently examined each clinical and functional metric article to determine if its results were positive (favorable), negative (unfavorable), or neutral. Results were deemed positive if they indicated that the specialty drug confers a statistically significant improvement relative to the alternative conventional treatment; negative if they indicated a statistically significant advantage for the conventional treatment; or neutral if they did not achieve statistical significance, regardless of the direction of the finding.

Given the heterogenous nature of the studies reviewed, a qualitative, as opposed to quantitative, assessment of the literature was necessary. Patient populations, time frames, treatment administration, and methods of measuring outcomes across studies were diverse, precluding the use of meta-analytic techniques. However, the more standardized nature of the cost-effectiveness papers allowed quantitative aggregation of results, and subsequent reporting of summary statistics.

We summarized economic results by reporting the mean, median, minimum, and maximum cost-effectiveness ratios reported by pertinent articles. Because each article can report multiple ratios (eg, for different populations, or evaluating different doses of the specialty pharmaceutical), we reported both unweighted and weighted summary statistics. For the weighted results, we assigned each ratio a weight of 1/n, where n is the number of ratios reported by that article. Doing so equalizes the statistical contribution from each article regardless of how many ratios it reports.

RESULTSCase Example Disease Areas

eAppendix B

Table 1

The literature review, along with an examination of payer materials,^2,8,9 yielded 266 specialty pharmaceuticals corresponding to 85 disease areas marketed in the United States. Exclusion of 31 orphan diseases and 22 conditions for which specialty pharmaceuticals provide only acute or supportive care yielded 32 diseases for inclusion. The specialty pharmaceuticals and disease areas we evaluated are listed in . reports the estimated spend on specialty pharmaceuticals for the top 10 disease areas, as determined from various analyst and market research reports.^20-29 The top 3 areas—RA, MS, and BC—were identified as the targets for our analyses.

Identified Pharmaceuticals

We identified 10 specialty pharmaceuticals for treatment of RA: abatacept, adalimumab, anakinra, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, and tofacitinib; 8 specialty pharmaceuticals for treatment of MS: dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, interferon beta-1b, mitoxantrone, natalizumab, and teriflunomide; and 10 specialty pharmaceuticals for treatment of BC: bevacizumab, capecitabine, eribulin mesylate, everolimus, ixabepilone, lapatinib, paclitaxel, pertuzumab, trastuzumab, and vinorelbine.

Metrics

Table 2

eAppendix C

We used the following clinical metrics: the American College of Rheumatology (ACR) score for RA, reduction in relapse for MS, and overall survival for BC. The functional metrics used were the Health Assessment Questionnaire (HAQ) for RA, the Expanded Disability Status Scale (EDSS) for MS, and the Quality of Life Questionnaire- Core 30 (QLQ-C30) for BC. lists the selected metrics for each disease area and identifies which articles reported positive, negative, or neutral findings. lists all the cost-effectiveness ratios.

Evidence AssessmentRA

Figure, Panel A

We identified 64 original articles for the RA clinical outcome (ACR score) and 21 for the RA functional outcome (HAQ) (). We classified all 64 ACR studies (19,947 subjects) and all 21 HAQ studies (11,132 subjects) as positive.

We identified 15 cost-per-QALY studies (eAppendix C). Identified studies typically compared a treatment consisting of a combined biologic and nonbiologic diseasemodifying antirheumatic drug (DMARD) with a purely nonbiologic DMARD. The study populations included patients who either had severe RA or who had previously failed treatment with tumor necrosis factor alpha (TNFα) inhibitors and were being considered for nonanti— TNF biologics.

Cost-effectiveness ratios reported by these 15 studies (N = 45), all reported in 2012 US dollars, had a mean of $47,500, a median of $38,900, and a range of $5000 to $230,000 per QALY. The results weighted so that each article makes the same statistical contribution regardless of the number of ratios reported (not shown), and were comparable.

MS

Figure, Panel B

We identified 14 articles for the MS clinical outcome (relapse rate) and 14 articles that reported the MS functional outcome (EDSS) (). We classified all 14 relapse rate studies (8258 subjects) as positive, 8 of the 14 EDSS studies as positive (4429 subjects), and the remaining 6 EDSS studies as neutral (4533 subjects).

We identified 13 cost-per-QALY studies (eAppendix C). Identified cost-effectiveness studies typically compared a specialty pharmaceutical treatment with either no treatment or to best supportive care. The study populations were comprised of either patients with active relapsingremitting or secondary progressive MS.

Cost-effectiveness ratios (N = 31), all reported in 2012 US dollars, had a mean of $642,000, a median of $248,000, and a range of $13,600 to $3,730,000 per QALY. Weighted results (not shown) did not differ substantially from these unweighted results.

BC

Figure, Panel C

We identified 20 original articles that reported BC clinical outcome (overall survival) and 5 articles that reported the QLQ-C30 functional outcome (). We classified 9 of the 20 clinical outcome articles as positive (15,421 subjects), and the other 11 as neutral (8406 subjects). We classified all 5 articles reporting the QLQ-C30 functional outcome as positive (1794 subjects).

We identified 15 cost-per-QALY studies. The majority of articles (N = 13) (eAppendix C) compared trastuzumab adjuvant treatment with no trastuzumab adjuvant treatment. Study populations consisted primarily of patients with human epidermal growth factor receptor 2 (HER 2)-positive breast cancer. Cost-effectiveness ratios reported by these studies (N = 28), all reported in 2012 US dollars, had a mean of $64,100, a median of $51,900, and a range of $1660 to $406,000 per QALY.

DISCUSSION

Table 3

Although specialty biopharmaceuticals have historically been associated with rare medical conditions, they are increasingly being developed and used for the treatment of a number of chronic conditions. Consequently, spending on these medicines is projected to grow to 50% of the total pharmaceutical spend by 2017.5 To shed light on the value of specialty pharmaceuticals, this study comprehensively assessed their value for the top 3 diseases by US pharmaceutical spending level, namely RA, MS, and BC. Our assessment included clinical outcomes, functional outcomes, and cost effectiveness ().

RA

RA was one of the first diseases to see widespread use of biologic agents, starting in the late 1990s.30 Our analysis indicates that the introduction of biologics substantially and statistically improved patient clinical (ACR score) and functional (HAQ) outcomes compared with traditional DMARDs. Our study further suggests that this improvement is achieved cost-effectively. The average cost-effectiveness ratio of $47,500 per QALY is substantially more favorable than the generally accepted threshold of $100,000 per QALY.¹⁸ Recent evidence suggests that earlier treatment with biologics, when used with proper adherence and compliance, can further improve outcomes^31,32; indeed, the latest guidelines recommend earlier treatment.³³ It would be useful to analyze how any additional incurred costs resulting from earlier treatment might influence cost-effectiveness.

MS

Effective treatments for MS were not available until 1993 when interferon beta-1b was shown to treat the relapsing-remitting form of the disease.³⁴ Subsequent trials demonstrated the efficacy of interferon beta-1a, glatiramer acetate, and the successful treatment of secondary progression MS with interferon beta-1b. The importance of early intervention treatments for MS was shown in the CHAMPS³⁵ and ETOMS³⁶ trials, demonstrating that the early adoption of interferon beta-1a delayed conversion from suggestive MS to clinically definite MS.³⁴

Our analysis indicates that biologic therapies for MS are clinically effective, as all studies reviewed reported a reduction in the relapse rate. Functional findings were less conclusive, as 6 of the 14 reviewed studies found no statistically significant improvement in the EDSS. These neutral findings may be attributable to side effects that compromise quality of life and hence mitigate clinical and functional improvements.

Cost-effectiveness for specialty therapies generally exceeded (was less favorable than) the conventional $100,000 per QALY threshold. Cost-effectiveness results might have been more favorable if nonresponsive patients discontinued therapy. However, the randomized clinical trials that comprise most of the literature do not allow for discontinuation among nonresponders, so this possibility cannot generally be explored using existing data.

Functional and cost-effectiveness findings may improve in the future with the introduction of new oral therapies, such as dimethyl fumarate, fingolimod, and teriflunomide, which have been shown to be superior to previously used specialty pharmaceutical interferons. These new therapies have the potential to reduce costs and improve patient clinical and functional outcomes.

We expect that the cost-effectiveness of specialty pharmaceutical treatments for MS might also be improved by monitoring patients and discontinuing treatments among nonresponders. Such a strategy could protect most of the population’s clinical and functional gains while decreasing aggregate costs.

BC

The 1998 approval of trastuzumab, a medication specifically indicated for women with elevated HER 2 production, sparked one of the largest increases in the use of personalized medicine to date.³⁷ Previously, specialty pharmaceutical chemotherapy formulations such as paclitaxel and capecitabine improved patient survival. ³⁸ The addition of personalized medicines to chemotherapy regimens, however, conferred marked mortality improvements.³⁹

The majority of studies yielded statistically inconclusive results for survival. On the other hand, the subset of studies evaluating trastuzumab showed improved survival outcomes relative to the other studies reviewed. With respect to our functional metric, QLQ-C30, the results were favorable across all studies obtained, suggesting that specialty pharmaceuticals improve quality of life among BC patients.

The limited number of cost-effectiveness studies (N = 15) we reviewed indicate that specialty pharmaceutical BC treatments are cost-effective, with a mean of $64,000 per QALY. Limiting attention to evaluations of trastuzumab (N = 13) yielded even more favorable cost-effectiveness results (mean of $51,000 per QALY).

Limitations

Our investigation had several limitations. First, while we identified a large number of clinical efficacy studies, fewer studies evaluated functional metrics. Furthermore, the functional studies were sometimes retrospective, rather than randomized clinical trials.

Second, because of both space and scope limitations, we limited attention to one clinical and one functional metric per disease area. Our results are still informative because we chose those metrics most commonly used in the literature. Nonetheless, complete characterization of a therapy’s effectiveness should consider a composite of many metrics.

Third, cost-effectiveness studies have not been conducted for all therapies included in our review. Cost-effectiveness is less likely to have been analyzed for more recently introduced therapies. To the extent that more recently developed specialty pharmaceutical therapies are more effective than older therapies, and assuming they are comparably priced, our assessment could be biased toward reporting less favorable cost-effectiveness findings. On the other hand, if more recently developed therapies are more expensive than older therapies, our results could be biased in the other direction.

Fourth, the cost-effectiveness analyses were not all conducted in the same country and may not all account for the same types of costs (eg, patient out-of-pocket costs). This limitation is inherent to the use of published results. Nonetheless, the collective information in multiple costeffectiveness analyses still provides useful insights and as a result, such reviews are not uncommon.^40-45

Finally, pharmaceutical indications change as new efficacy and safety evidence becomes available. In some cases, studies included in our analysis pertain to products for which the indication has changed. For example, in 2010, the FDA removed bevacizumab’s indication for BC.⁴⁶ As with any review, some aspects of the constituent data may be out of date. In any case, our results still provide a general characterization of the value of specialty pharmaceuticals, even if the quantitative results may reflect an evolution of care, including some potentially obsolete treatment options, rather than the current state of the art.

CONCLUSIONS

Our review of the 3 largest specialty pharmaceutical categories—RA, MS, and BC—suggest that these novel therapies hold great promise for arresting disease progression and improving quality of life. These findings raise the possibility that specialty pharmaceuticals for other disease areas might likewise confer substantial patient benefit.

For RA, substantial clinical and functional benefits have been documented. Results are less clear-cut for MS and BC. For MS, existing therapies benefit some patients but vary substantially. This heterogeneity suggests strategies that discontinue treatment for nonresponders, an approach that is likely to improve cost-effectiveness because it reduces costs without markedly reducing aggregate benefits. For BC, benefits vary by specialty treatment, suggesting promotion of the most effective treatments—in particular, Herceptin (for which there is a biomarker for identifying appropriate patients)—while waiting for more evidence to develop for other therapies.

In short, our review suggests that specialty pharmaceuticals for 3 important diseases confer patient benefits. Although these new therapies are more expensive than older therapies, the fact that their cost-effectiveness results can be favorable indicates that these costs must be viewed in light of the patient benefits. It is important, however, to note that achieving convincing benefits and cost-effectiveness is not always straightforward, but can instead require identifying the most effective agents and the most appropriate patients. Development of nuanced strategies to take advantage of these possibilities holds great promise for improved patient quality of life and good value for the healthcare system.Author Affiliations: Trinity Partners, LLC, Waltham, MA (MZ, JSG, FK, JS); Center for the Evaluation of Value and Risk in Health at Tufts Medical Center, Boston, MA (JTC, PJN); National Pharmaceutical Council (NPC), Washington, DC (AL, DP, RWD).

Source of Funding: This study was funded by the NPC, an industryfunded health policy research group that is not involved in lobbying or advocacy.

Author Disclosures: Mr Zalesak, Ms Greenbaum, Dr Kokkotos, and Mr Stewart report employment with Trinity Partners, LLC, which was contracted by the NPC to conduct research and analysis related to this study. Dr Cohen and Mr Neumann report receiving payment from the NPC in relation to this study. Mr Lustig and Drs Pritchard and Dubois report employment with the NPC.

Authorship Information: Concept and design (MZ, JSG, JTC, AL, PJN, DP, JS, RWD); acquisition of data (JSG, JTC, PJN, JS); analysis and interpretation of data (MZ, JSG, JTC, AL, PJN, DP, RWD); drafting of the manuscript (MZ, JSG, JTC, PJN); critical revision of the manuscript for important intellectual content (MZ, JSG, JTC, FK, AL, PJN, DP, RWD); statistical analysis (JSG, FK); obtaining funding (PJN, DP, JS, RWD); administrative, technical, or logistic support (MZ, JSG, AL); supervision (MZ, RWD).

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