Specialty pharmaceuticals and the quest for better outcomes

Abstract

Over the past decade, the healthcare system has seen significant growth in the number of products, pathways, and modes of treatment administration for a number of costly conditions. Many of these products are biologic agents, classified as specialty pharmaceuticals, and are distributed through specialty pharmacies. The increasing use of these expensive medications and their growing costs raise the simple question, can payers and purchasers afford to keep doing business as usual? In addition, confusion exists as to what “outcomes” are relevant for these conditions treated using specialty medications. Available information on outcomes, treatments, and pathways from multiple sources can overload clinicians and the treatment team, making it difficult to select – and receive reimbursement for – the most appropriate regimens. This article offers an approach to understanding some of the unique challenges posed in evaluating the value of specialty pharmaceuticals.

Over the past decade, the healthcare system has seen significant growth in the number of products, pathways, and modes of administration of treatments for a number of costly conditions. Survival rates and survival time for many types of cancer have increased, some autoimmune and central nervous system diseases have benefited from newer, more-effective therapies, therapy has shifted from clinician-administered hospital-based products to self-injectable products and oral therapies, and simplifications due to fixed-dose combination products and single-tablet regimens (STRs) and long-acting versions resulted in better persistence and adherence. Information available through the Internet and other sources can overload clinicians, patients, and their families with information on treatments and pathways from clinical trial registries, published studies, manufacturers, advocacy groups, and disease societies, making it difficult to select—and receive reimbursement for—the most appropriate regimen. Ensuring that the best outcomes are obtained with specialty pharmacy therapies has become confounded by a variety of factors. Recognizing these issues may advance our understanding of how treatment with specialty therapeutics can be optimized.

Making comparisons based on clinical trials is a challenge because of the varying methods used to select patient populations, differing study designs, and considerations for other therapies that subjects may receive within the study. Despite trials being pre-reviewed by the US Food and Drug Administration (FDA) and other agencies, many lack consistent timeframes, outcomes, and comparators, with varying end-points. After products are approved, physicians can prescribe them for any conditions or patients they deem appropriate. Due to the growing costs of pharmacologic treatments, managed care organizations and other payers are moving towards formulary restrictions, step-therapy, and limiting off-label use of medications.

Where are we on the quest for better outcomes information for specialty pharmaceuticals?

Where can we find the best information related to both specialty pharmacy utilization and outcomes, and where are we on this quest?

To answer this question, let’s begin with some definitions.

Specialty pharmaceuticals

According to Douglas Long, VP of Industry Relations at IMS Health, ‘specialty pharmacy’ products are pharmaceuticals designed to treat specific, complex chronic diseases and have four or more of the following attributes shown in Table 1 1. According to IMS’ analysis shared by Long1 in October 2014, although specialty pharmaceuticals represented less than 1.5% of the prescriptions processed earlier in the year, they represent ∼30.5% of US prescription drug expenditures. The highest growth specialty pharmacy categories are currently hepatitis-C (HCV), oncology, multiple sclerosis (MS), and autoimmune conditions. Traditionally, specialty pharmacy products were covered under most plans’ medical benefit. Plans are now moving these agents to the pharmacy benefit, where products are reviewed by the Pharmacy and Therapeutics (P&T) Committee, managed by the formulary, and subject to prior authorization, with differing co-pays based on formulary tier and percentage of drug cost, and other pharmacy budget management programs.

Table 1. Attributes of specialty pharmacy products.

Specialty pharmacy products are designed to treat specific, complex chronic diseases and have four or more of the following attributes:
• Initiated only by a specialist,	• requires a cold chain for distribution,
• having few prescribers or centers,	• requires special patient training to administer,
• high expense,	• needs patient’s support to achieve adherence,
• requires reimbursement assistance,	• has a unique process for distribution,
• requires processing of pre-approval essential and competitive skill,	• importance of low inventory,
• requires special handling,	• no need to supply all pharmacies through all warehouses.

Specialty pharmacies

Because of the high prices and the special requirements for distribution, most specialty pharmacy products are handled by specialty pharmacies (SPs), most of which are privately held and do not report earnings. The largest independent SPs in the US include: Diplomat Specialty Pharmacy, Avella (The Apothecary Shops), Axium Healthcare Pharmacy, BioRx, Amber Pharmacy, Onco360, and Medpro2. In 2012, the fastest-growing SPs had a 3-year growth rate of 166%, an average revenue of $141.1 million, a median revenue of $69.3 million and median growth rate of 152%2. Recognizing the growth of this channel, it’s not surprising that the major pharmacy retail players and PBMs have focused on this channel with Express Scripts, CVS Caremark, and Walgreens, accounting for 63% of revenues from pharmacy-dispensed specialty drugs, and the next three largest players had a combined share of ∼5%3. Like most businesses, SPs need to employ the right people, tools, and systems to communicate and co-ordinate care between the physicians, insurers (payers), and, most importantly, the patients.

Outcomes

Conceptually, outcomes research simultaneously assesses multiple disease-related components. The International Society of Pharmacoeconomic Outcomes Research (ISPOR) advocates the ECHO model4:

• Economic outcomes: Direct and indirect costs compared to consequences of medical treatment alternatives, typically expressed as ratios of cost to consequence (e.g. cost-minimization, cost-effectiveness, cost-utility, and cost-benefit ratios).

• Clinical outcomes: Medical events that occur as a result of disease or treatment (e.g. stroke, disability, hospitalization).

• Humanistic Outcomes: Patient self-assessment of the impact of disease or treatment on their lives and well-being (e.g. satisfaction, quality-of-life) and can be assessed from the perspective of the patient or the caregiver.

• Patient-reported outcomes (PROs)4 are reported directly by the patient and may be used to describe a patient’s condition and response to treatment. These include global impressions, functional status, well-being, symptoms, health-related quality-of-life, treatment satisfaction, and treatment adherence.

In terms of communicating outcomes, some PubMed searches conducted for this article were revealing. The National Center for Biotechnology Information (NCBI) databases identified 22 different periodicals based on the search term ‘outcomes’; however, a few of these titles have ceased publication, and some of them are/were not related to healthcare. To see how prevalent the discussion of outcomes is in today’s medical literature, searches were conducted for ‘outcomes’ or ‘outcome’ in the title. This search identified 4.6-times more articles published in 2014 than in 2001 (22 488 vs 4895 articles, respectively). Only a small number of these articles are about specialty products. However, the use of words in a title are a simple indicator and, if applied consistently, can provide some insight. Unfortunately, titles can be misleading. For example, in 2014, the Journal of Medical Economics published only three articles with ‘outcomes’ in the title, less than half of 2013’s seven articles.

Recognizing the need to standardize outcomes research communications, researchers focusing on these areas formally formed ISPOR in 1995. Through task forces and special interest groups, ISPOR members have developed and disseminated good research practices on use of pharmacoeconomic/health economic information in healthcare decision-making5; defining, reporting, and interpreting non-randomized studies of treatment effects6; improving causal inferences using secondary data sources7; and identifying quality improvement of cost-effectiveness research8. A search of the database on ISPOR conference presentations for two disease states commonly associated with specialty medications revealed five abstracts related to MS and six related to hepatitis C were listed in 2005 compared with 65 for MS and 68 for hepatitis C in 2014—more than an 11-fold increase. These ISPOR presentations were accepted abstracts classified according to the disease specified on the submission.

Independent comparative effectiveness studies of specialty pharmacy products can be expensive to conduct. Consider a comparative study in HCV. At the end of 2014, the most common regimen of sofosbuvir (Solvadi)9, at $84 000 for 12 weeks of therapy and simeprevir (Olysio)10, with a cost of $76 000 for 12 weeks of therapy, would cost more than $160 000 in drug costs per patient. Adding in an estimated $25 000 per patient in site and investigator fees, the cost per patient would be $185 000. A study comparing a new agent with 200 patients using sofosbuvir/simeprevir regimen would cost in excess of $37 million for these two competitive agents. Added to that are the costs for IRB approvals, investigator fees, data entry, and monitoring costs in a traditional study, along with the time to identify sites, train investigators, field, and complete the study. With the high costs of comparative studies, it seems unlikely that we will see a comprehensive comparative study funded by industry.

The National Cancer Institute (NCI), ISPOR, and other organizations are providing standards for how these outcomes should be evaluated. These standards may facilitate meta-analysis and other cross-treatment comparisons. However, coverage decisions need to be made today. It takes time for manufacturers and regulatory agencies to adopt standards, as well as time for study results to become available through the peer review and publishing process. Although they may yield information for new products, those outcomes studies approved before standards are finalized often fail to meet the new standards.

Perspective can be extremely important when analyzing outcomes and value. For instance, an oncology therapy that prolongs life might have a positive effect on extending life, but it may come at the cost of reduced quality-of-life for the patient and the patient’s family, and may be expensive for the patient as well in terms of cost sharing. According to the Association for Value-Based Cancer Care (AVBCC)11, outcomes research in oncology should be interpreted with caution, understanding what outcomes the specific stakeholder is looking for, how they can be measured, and how to achieve these outcomes. The AVBCC recommendations are based on what can be measured and what oncologists think are important to measure. Ultimately, the value lies in patients’ outcomes, based on the treatment received, the quality-of-care, and the quality-of-life. The value of these outcomes may not be public knowledge and may not be tracked, even though we have increasingly better information systems. The AVBCC points out that therapies with significant side-effects may actually lower quality-of-life while extending it. This leads many to question whether life extension is necessarily a positive outcome.

The AVBCC’s attempts to assign values to different therapies identified some divergent incentives. For example, while administrative services improve outcomes in terms of patient compliance with oral therapies, these services are time-consuming, costly, and currently not reimbursed. Part of the solution to providing these administrative services will inevitably come through cognitive technologies that deliver highly integrated patient engagement platforms to assist in medical and pharmacy benefit support. These artificial intelligence platforms use a natural language understanding (NLU) interface to build scalable and personalized relationships with patients (e.g. www.engagedmedia.com). Re-defining the current expensive human resource-heavy specialty pharmacy “high-touch” model, using a smartphone infused with NLU (e.g. www.nextit.com) and fully integrated into an overall specialty pharmacy service offering can put the patient in charge of their own health and empower the patient in their journey towards better adherence and outcomes with higher reach and frequency at a fraction of what the current “high-touch”model costs12.

The healthcare industry also has different ways of defining quality. Managed care organizations (MCOs) receive payment for quality, which for MCOs generally means payment for Healthcare Effectiveness Data and Information Set (HEDIS) measures13. These HEDIS measures are markers of quality, but not actual outcomes. MCOs have enough data, or enough collected information, to determine outcomes—they just need the proper incentives.

Now that we’ve defined specialty pharmacy products, the specialty pharmacies, outcomes, and some of the challenges, how does it all fit together? Let’s consider some examples from the categories seeing the most growth in the specialty pharmacy space.

Oncology

Recently, the head of pharmacy from a major health plan described his comprehensive and complex experience with stage I testicular cancer in the early 1970s. His treatment began with an orchiectomy. One week after this initial surgery, his right-side abdominal lymph channel was removed through a sternum-to-groin incision, as the node runs along the backbone. Next, he received 6 weeks of cobalt radiation to the abdomen and groin, followed by 2 full years of chemotherapy with vincristine every 10 days. He also was hospitalized every 4 weeks to receive cyclophosphamide (Cytoxan) and actinomycin D and had annual follow-up examinations for 10 years. This complex regimen makes it hard to understand or evaluate the outcomes associated with any of the individual therapies, and resulted in a bit of a shock when years later he was diagnosed and treated for prostate cancer. More than 40 years after his treatment, this highly educated pharmacist patient has severe vincristine-induced peripheral neuropathy and serious complications from the initial abdominal surgery (requiring a foot of scarred colon to be removed 4 years ago)—well outside the initial 10-year follow-up.

Assessing the value of some of specialty pharmacy products is a challenge which is exacerbated by the growing number of treatments for the same condition. According to Burt Zweigenhaft, the former CEO of Onco360, a company that offers oncology pharmacy solutions, multiple Food and Drug Administration (FDA) products have been approved for treatment, with several protocols or ‘pathways’ approved by the National Comprehensive Cancer Network (NCCN) regarding their use14. Yet little agreement exists as to which is the preferred regimen for a given diagnosis and stage for a given patient. Therapy for some conditions can be targeted based on genetic markers, like human epidermal growth factor receptor 2 (HER2). The monoclonal antibodies trastuzumab (Herceptin)15 and pertuzumab (Perjeta)16 target HER2 and are effective only in cancers where HER2 is over-expressed—and, fortunately, we can test for this marker today.

Hopefully, the coming years will see more available genetic tests for therapies targeting specific tumors, and this will be transformational. Without guidance from predictive markers, decisions about therapy selections from among the available drug arsenal have to rely on today’s variable evidence. The oncology category has been subject to limited formulary scrutiny from managed care payers; however, as the costs and options increase, the responsibility of managed care payers to provide oversight also increases. Zweigenhaft suggests that roughly 30% of what’s being done in today’s oncology market is done in ‘evidence free zones’, which lack credible evidence or information that industry experts consider to support what actually works.

At a recent AVBCC meeting’s survivorship session11, a woman who had lost her husband to cancer reported he had received 75 positron emission tomography (PET) scans in his last 2 years of life. At an average cost of $530017, his 75 scans cost the system $397 500, and did not include opportunity costs to the patient, the patient’s family, the clinician, the system, or even the PET machine. Can the 75th scan be as valuable as the first one?11. This broken system needs to be modified to only pay for value-based care.

There are many cases where managed care is driving down reimbursement collectively, forcing providers or patients to buy alternate types of drugs based on cost and advocating value-based care and benefits. Can we avoid this? Blue Cross Blue Shield (BCBS) of Michigan, for example, as well as other plans, increased the payments for generic chemotherapy drugs, so the payment for a small vial of generic 5-fluorouracil, for example, is small, but the overall treatment involves a much bigger reimbursement. What this means is that many plans are moving away from the ‘buy-and-bill’ model for drugs to a model that bundles payments. There is a great need for more data and outcomes related to the use of diagnostic tests in association with specific oncology agents. The problem for health plans is that scant evidence exists that would help them understand the outcomes and make coverage decisions.

The prior authorization (PA) process provides another challenge to better outcomes. Designed to control expenditures by restricting use to specific patients, PAs seem like a good idea and are used by many managed care plans. Unfortunately, the PA process can be involved for the physicians and their staff, adding expenses to clinicians and time to the process. The AVBCC advocates moving away from PAs to using pathways11.

Study design and research on medical outcomes in cancer has come a long way. Recent advances, such as the introduction of oral and self-injectable agents, have allowed a shift from research being conducted primarily in hospitals to other areas, with community-based physicians playing a more active role. This shift away from the hospital has also resulted in managed care shifting more of the cost-sharing burden to members in the US. Lee Goldberg, Director, Syndicated Research, at Zitter Health Insights, provided data18 from the semi-annual Managed Care Biologics and Injectables Index of about 100 commercial payers19. The most recent survey identified significantly more plans relying on four-tier designs in plan year 2014 than the previous benefit period, increasing from 25% in 2011 to 39% in 2014. Although still not the majority design across all payers, this change exposes more patients to coinsurance19.

Infectious disease: human immunodeficiency virus (HIV)

The US Department of Health and Human Services (DHHS) Guidelines advocate initiate antiretroviral therapy (ART) in patients with HIV to: reduce HIV-associated morbidity, prolong the duration and quality of survival, restore and preserve immunologic function, maximally and durably suppress plasma HIV viral load and prevent HIV transmission20. The DHHS guidelines also say that strict adherence to ART is key to sustained HIV suppression, reduced risk of drug resistance, improved overall health, quality-of-life, and survival, as well as decreased risk of HIV transmission21.

Recognizing the complex nature of HIV therapy, companies like Gilead Sciences (Foster City, CA) have long advocated and promoted single-tablet regimens (STRs). Gilead launched a fixed-dose STR combination antiretroviral (efavirenz/emtricitabine/tenofovir disoproxil fumarate)22 a decade ago. Nachega et al.23 conducted a meta-analysis of co-formulation studies and concluded that the lower pill burden in STRs was associated with both better adherence and virological suppression. This same study found that adherence, but not virological suppression, was slightly better with once- vs twice-daily regimens.

Hepatitis C (HCV)

Gilead has also used the STR in its approach to HCV. They recently received approval for a STR co-formulating sofosbuvir and ledipasvir (Harvoni)24. Gilead has priced this STR combination at $94 500 for 12 weeks of treatment24. This is up from $84 000 for 12 weeks of sofosbuvir, but is in line with the combined price of sofosbuvir, ribavirin, and interferon. The Harvoni STR costs less than today’s most common FDA-approved 12-week regimen of sofosbuvir and simeprevir, which is $160 000 per patient25. Gilead estimates that half of people with genotype 1 of HCV will require just 8 weeks of treatment, which will reduce the cost of treatment to $63 000. Both sofosbuvir-based regimens are interferon-sparing and avoid many of the toxicities and complications associated with interferon, which have been demonstrated to increase costs and absenteeism26. As reported in this journal, earlier treatment may also save significant costs that result from advanced stages of HCV27.

The Hepatitis C Impact Monitor28, a Zitter survey of how specialty therapies are evaluated, revealed that, when new HCV therapies enter the market, payers will evaluate them first on the basis of clinical efficacy (sustained virological response [SVR] rate, reported by 32% of those surveyed), followed by cost (17%), side-effect profile (13%), regimen duration (11%), and other factors. However, with the clinical efficacy of the new regimens creeping above 95% SVR at week 12 (SVR12) for many patients, manufacturers’ arguments may quickly need to shift the cost to differentiate their products with insurers and other payers.

Multiple sclerosis (MS)

The shift to oral therapies has also reached Multiple Sclerosis (MS) treatments. For years, the standard for MS were injectable therapies29, referred to as ABCR [Avonex (interferon beta-1a), Betaseron (interferon beta-1b), Copaxone (glatiramer acetate) or Rebif (interferon beta-1a)] therapy. Most of ABCR therapy has already been handled through specialty pharmacy. Beginning with the approval of Gilenya (fingolimod) in 2010, the MS market saw the launch of new oral agents including Aubagio (teriflunomide), approved in 2012, and Tecfidera (dimethyl fumarate), approved in 2013. Despite this apparent shift toward orals, a couple of recently approved agents were not orals: Plegridy (peginterferon beta-1a) is a subcutaneous injectable formulation where attached polyethylene glycol extended the biologic effects in the body for longer periods of time (two weeks), and Lemtrada (alemtuzumab), an intravenous infusion which, after a loading dose, has even fewer administrations throughout the year.

Although there has been a shift towards the oral agents in MS, and many believe these newer dosage forms will have higher compliance and better outcomes, this has yet to be proven outside of the clinical trial setting.

Data

So, where do electronic medical/health records (EMRs/EHRs) fit in? Excluding systems used only for billing, in the US, only 34.8% of office-based physicians used EMRs in 2007. Recognizing the need for better data, legislative mandates have more than doubled the percentage to 71.8% in 201230. Many non-office based clinicians are affiliated with hospitals where EMR adoption is lower; only 59% of non-federal acute care hospitals having adopted at least a basic EHR system with clinician notes in 201331. Adoption of EMRs/EHRs in the US faces challenges posed by: a diverse patient population; numerous payers, from regional and national commercial payers systems to Medicare; 50 states with different Medicaid programs, and the various combination of managed care payers across all sectors. Each payer has their own treatment pathways, algorithms, formularies and copay tiers, which all impact therapy selection, compliance and ultimately outcomes. EMRs take additional clinician time for data entry and the University of California-Davis found a 25–33% drop in physician productivity in the initial implementation phases of the EMR32. It’s been reported that, in a pre-EMR world, pediatricians averaged close to 40 patient visits per day, implementation of EMRs dropped that number to ∼25—a 38% reduction! Considering the shortage of physicians33, it may be even more challenging for people to receive care. So, while data from EMRs may ultimately help provide better care, the extra burden of using EMRs coupled with the physician shortage may lead to fewer patients being treated and worse outcomes.

In specialty pharmacy-oriented areas, such as oncology and virology, EMRs offer the promise of integrated guidelines and directed care. Integrating these EMR systems into the specialty pharmacies presents additional challenges—especially if we seek to limit the impact of workflow and redundant data entry. Today, we have more than 320 operational EMRs throughout the US34, and we also have numerous different SP systems—each system and SP requiring their own interface.

On the journey for better information, Gilead Sciences recently sponsored a real-world patient study through Trio Health (La Jolla, CA) for hepatitis-C (HCV). A retrospective study presented at the November American Association for the Study of Liver Diseases (AASLD) Conference focused on patients that started therapy between December 1, 2013 and March 31, 201435. Trio Health has integrated outcomes into its specialty pharmacy technology platform to allow manufacturers to collect real-time patient data along with pro-actively managing real-world patients. Since going online in November 2013, the Trio Health platform has gathered information on more than 20 000 patients with HCV, spanning all combinations of the available agents. While in development, the Trio team determined that they needed to capture information desired by clinicians (hepatologists), yet not commonly available in databases. By adding in genotype, prior treatment, patient severity, and other baseline characteristics including virologic response rates, Trio’s efforts makes them poised to revolutionize our knowledge about HCV—using real-world data. The information presented in November included outcomes on over 1000 patients that were treated with up to 12 weeks of therapy. Trio presented outcomes of those patients that exceed 12 weeks of therapy at the European Association for the Study of the Liver (EASL) focusing on HCV genotype 3 patients. Trio also demonstrated that gathering and maintaining data on real-world patients can be cost-effective36.

The AVBCC (www.avbcconline.org), ISPOR (www.ISPOR.ORG), the International Health Economics Association (www.healtheconomics.org), and the Society for Medical Decision Making (www.SMDM.org) provide education and tools to help assess outcomes. The National Association of Specialty Pharmacy (www.NASPnet.org), the Academy of Managed Care Pharmacy (www.AMCP.org), and a variety of country-specific organizations explore the impact of specialty and other products on payers and their members. Disease-specific organizations focus on providing support materials to help people afflicted with their specific conditions. Individual users must assess the credibility and accuracy of information they find in publications, on the Internet, and organizational websites to make sure they are on the right path in the quest for better outcomes.

Conclusion

On this quest, a lot of differences were noted in the specialty pharmacy world, from manufacturing and distribution; to communications between the pharmacies, the patients and the healthcare team, and the wealth of data becoming available through clinical trials, EMR systems, specialty pharmacy-based data collection, and patients. Obviously products that offer the promise of a cure are game changers—but can we afford to keep doing business as usual?

Transparency

Declaration of funding

There was no funding for this manuscript.

Declaration of financial/other relationships

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgments

I would like to thank all of the people who provided time and input to the development of this editorial–many of them are mentioned throughout the text. In addition, I'd like to recognize Stanton Mehr of SM Health Communications and Robert W Baran, RPh, PharmD, for their help reviewing and editing this paper.