Summer 2014

Bridging the gap between the hospital and alternate-site care Volume 3 • Number 3 • Summer 2014 • specialtypharmacycontinuum.com

In This Issue Operations & Mgmt

5

Zydelig approval an opportunity for SPs to show their value.

9 12

Hepatitis C: What’s a cure worth?

$2,000 cost to patients not uncommon

Can SPs Ease the Pain Of Soaring Deductibles?

Specialty market forecast: more confusion ahead.

Disease State Spotlight

16

The specialty pharmacy approach to optimizing cystic fibrosis management.

Clinical

18

Long-term survival ‘a good problem to have’ in HIV management.

21

Communication, deep product knowledge key in IVIG therapy.

Technology

22

Glowcap pill bottle bolsters medication adherence for Avella Specialty Pharmacy.

Primary Immunodeficiency Considerations for Selection of Appropriate Replacement Ig Therapies

Get Appy! New Tech a Bridge To Patient Care Philadelphia—As of January 2014, 90% of American adults own a cell phone, and 58% of adults have a smartphone, according to a study by Pew Research (http://bit.ly/1fvWYrL). In fact, as of 2011, there are more mobile phones, tablets and other wireless devices in the United States than there are people—a trend that could soon have a profound effect on the services that specialty pharmacy provides to patients.

Digging a bit deeper, mobile apps are rapidly outpacing computer use: In January 2014, mobile app usage surpassed desktop Internet access for the first time.

•

see NEW TOOLS, page 22

At AMCP annual meeting: Las Vegas—The growing move among employers to adopt high-deductible health plans is one of the major “trends that matter” to specialty pharmacy in today’s stormy health care environment, according to Myrtle Potter, a health care consultant and former Big Pharma executive who offered some tips for navigating this challenge at the 2014 Armada Specialty Pharmacy Summit.

In 2013, Ms. Potter noted, 17% of employers offered high-deductible health plans as their employees’ only option—up 31% from 2012, according to PricewaterhouseCoopers’ “Behind the Numbers 2014.” For 2014, she said, some 44% of employers were considering such a move (http://pwc.to/1eRYLxr).

High-deductible plans can pose challenges for anyone with a chronic condition, but they are particularly problematic for patients taking expensive specialty medications, with annual minimum deductibles of $1,250 per person and $2,500 per family.

The 2014 annual cap on out-of-pocket costs is $6,350 for an individual and $12,700 for a family—high for anyone, but harder to swallow if it’s front-loaded into the first month or two of each year because of costly specialty drugs.

Those steep costs can be a powerful trigger for noncompliance. In one study, high-deductible health plans were found to reduce adherence to prescription medication regimens in four of five conditions evaluated: hypertension, dyslipidemia, diabetes and depression ((Am J Managed Care 2013;19:e400-e407), Ms. Potter noted. Only in asthma/chronic obstructive pulmonary disease was there not a significant decline in adherence.

•

see CHALLENGES, page 8

One Payor’s Path to Benefit Integration San Francisco—You’ve — heard it for years: Aligning medical and pharmacy benefits will be essential to the specialty space going forward if inappropriate utilization and high cost of care are ever going to be controlled to achieve the holy grail of “right drug, right patient, right quantity, right time, right place.”

Indeed, a paper commissioned for CVS Caremark by the Milliman Group found that a channel transition strategy, shifting the adjudication of specialty drugs from the medical benefit to the pharmacy benefit where appropriate, could save nearly 20% on some of these costly medications

•

see INTEGRATION, page 14

See insert after page 4.

Now Available: Specialty Pharmacy News iPad App

New Product Cold Chain Technologies introduces KoolTemp® GTS-Rx See page 20.

4

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

Cancer Drugs Help SPs Show Their Value Oncology medications pose a number of complex issues. Whether it’s a potentially toxic adverse-event (AE) profile or a high deductible that could hinder patient compliance, these treatment challenges must be closely managed. Therefore, they are a natural fit for a specialty pharmacy.

Throw in the knowledge required to understand genetically aligned tumor types, biomarkers and drugs with very narrow, targeted indications, and “there will continue to be an increasing need for specialty pharmacies that can meet the stringent demands [of these medications],” said Lowery Whisenant, the director of pharmacy operations, McKesson Specialty Health, OncologyRx Care Advantage. Those demands, he noted, include patient education and physician and manufacturer support, “as well as the special distribution needs of these products for the near and longterm future.”

A case in point is idelalisib (Zydelig, Gilead), an oral kinase inhibitor that the FDA recently approved for the treatment of relapsing chronic lymphocytic leukemia (CLL), follicular B-cell nonHodgkin lymphoma and relapsed small lymphocytic lymphoma. Experts say that the drug is precisely the type of medication that should be—and will be—made available through a selected network of specialty pharmacies and distributors (See sidebar: “Who Got the Contract”).

The limited distribution route is due, in part, to idelalisib’s toxicity profile: Clinical studies have shown that the medication can cause potentially fatal hepatotoxicity, diarrhea and pneumonitis, which has prompted the FDA to place a boxed warning on the label.

The agency also has mandated that a Risk Evaluation and Mitigation Strategy (REMS) be in place for idelalisib (See sidebar: “FDA Approves Zydelig with Boxed Warning, REMS”). All of these factors will increase the complexity of managing patients on the new agent.

“The challenge of these drugs is that they create some common symptoms that have uncommon management algorithms,” said Jeff Sharman, MD, the medical director of hematology research for The US Oncology Network, which has participated in several of the research trials of idelalisib. Dr. Sherman cited, as an example, the severe diarrhea listed in the boxed warning for idelalisib that “may be unresponsive to some of the antimotility agents we typically use, such as Lomotil and Imodium.” To more effectively treat these severe cases, “you might

want to give the patient oral steroids or even systemic steroids intravenously,” said Dr. Sharman, who is also the director of research at Willamette Valley Cancer Institute, in Oregon.

Reaching Out to the Patient Patient education and relationships will be key to avoiding these AEs, several specialty pharmacy stakeholders pointed out. “From our perspective, education is one of the critical pieces,” said Eric Sredzinski, PharmD, the executive vice president for clinical affairs and quality assurance at Avella Specialty Pharmacy. “Uninformed patients have higher risks for lower adherence and unreported adverse events.”

Frank Scimeca, PharmD, BCOP, the director of pharmacy at Onco360, a care management company with executive offices in New York City, added that the education has to begin immediately.

“We reach out to patients before the start of therapy to educate and counsel them. We let them know about side effects, goals and expectations of therapy, how to take the medication, how

to store the medication, what really to expect on the treatment journey.”

The entire care team—pharmacists, patient navigators and nurses who manage oncology patients—must have an acute understanding of the possible AEs that accompany treatment, according to Mr. Whisenant, and they must be able to communicate this to the patient.

Before any chemotherapy regimen is started, specialty pharmacists will talk with patients and take a medical history that considers comorbidities, concurrent medications, over-the-counter products and herbals they might be taking, and whether the home caregiver situation poses any roadblocks to optimal care.

The medical history also needs to account for prior therapy. In the case of idelalisib, this is particularly important because the drug is indicated for patients with refractory disease. The pharmacist also will want to know whether rituximab (Rituxan, Genentech) has been prescribed, because idelalisib is approved for use in combination with rituximab for CLL. In addition to the one-on-one attention that will be so important with idelalisib, patients on the drug will be given written educational materials on possible toxicities and adherence. Patients also must understand what they are taking and why they are taking it. This is an ongoing

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5

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

process, Dr. Sredzinski said. “Education does not start and end with the first pill; [it] continues throughout the patient’s journey on that therapy.”

Who Got the Contract

Z

ydelig is available through a selected network of specialty pharmacies and distributors. Here is the list.

Specialty Pharmacy Navigating Financial Barriers “Beyond education and having patients understand their therapy,” Dr. Sredzinski added, “the initial challenge with idelalisib will be to ensure that the patient has access to the medication, and that means navigating the insurance requirements and finding copay assistance to [minimize] out-of-pocket expense.” To accomplish that goal, “we use copay cards, foundations and manufacturer assistance.”

The wholesale acquisition cost of a one-month supply of Zydelig in the United States is $7,200, according to a Gilead spokesperson. Although this is in line with other approved oral agents for various hematologic malignancies, this product is beyond the means of most patients without some type of financial assistance and/or insurance support.

Kirby J. Eng, RPh, the executive director of clinical oncology pharmacy solutions at Onco360, echoed the importance of helping patients meet the financial challenges posed by oncology drug therapy. “Our efforts have secured more than $4 million in financial assistance for our oncology patients last year,” he said.

Much of that support comes from drug manufacturers, according to Dr. Sharman, because the companies have realized that cost to the patient is perhaps the single most vital link in the prescribing chain.

But the mere existence of these programs does not guarantee access: Pharmacists must take a proactive stance and advocate for the financial needs of each patient to limit out-of-pocket expenses, Dr. Sharman and the other specialty pharmacy providers stressed.

A Market Force The flood of chemotherapy agents into the specialty drug channel is a trend that’s here to stay, according to Dr. Sredzinski. That trend is not surprising, he noted, given the many complex issues associated with these products, such as the aforementioned REMS requirements, the need for additional patient education and prior approval/copay navigation. Moreover, “sometimes the manufacturer asks for additional data points that not all pharmacies can manage,” he said.

Yet another challenge is the mandatory adverse drug event reporting that is required for many of these medications, Dr. Sredzinski noted. “For instance, if the patient is suffering shortness of breath, not only do we get involved and notify the providers and perform an assessment to determine whether the patient requires medical attention, but we also have to notify the manufacturer and

Avella Specialty Pharmacy

www.avella.com

(877) 546-5779

Biologics

www.biologicsinc.com

(800) 823-4506

Diplomat

www.diplomat.is

(877) 977-9118

Onco360

www.onco360.com

(877) 662-6633

mscs.mckesson.com

(800) 482-6700

www.oncologysupply.com

(800) 248-8205

www.asdhealthcare.com

(800) 746-6273

Specialty Distributor Oncology Supply

Hospital Distributor McKesson Plasma & Biologics www.mckesson.com

potentially the FDA, and not all pharmacies have the capability to do that.”

The sheer complexity of education dictates that cancer drugs are best placed in the specialty pharmacy channel—especially given the increasing numbers of oral agents entering the market that pose adherence problems

(877) 752-7626

and other challenges that specialty pharmacy providers are well positioned to meet. Indeed, about 25% to 30% of all oncology drugs in development are oral formulations (Community Oncol 2009;6:358-361), Mr. Eng pointed out.

“As such, specialty pharmacy will continue to exert its influence for oncology

drug management as oral formulations continue to augment or replace injectable or infused medications.”

The pipeline for new orals is not the only potent driver of specialty pharmacy: There are more than enough available cancer drugs to keep this distribution channel busy. In fact, “for many specialty pharmacies, oncology drugs make up about 32% of their total specialty revenues [2014 Genentech oncology trend report],” Mr. Eng said.

“We should keep in mind, however, that oncology drug management will only continue to increase in complexity largely due to innovative scientific research, an aging population that is living longer and a dizzying array of drug formulations,” he stressed. “This will create continued growth opportunities for specialized oncology pharmacy services that help optimize clinical outcomes for patients and financial outcomes for the health care system.”

—Marie Rosenthal None of the sources had any relevant financial conflicts of interest to disclose.

FDA Approves Zydelig with Boxed Warning, REMS ROCKVILLE, MD.—The FDA granted accelerated approval to idelalisib (Zydelig, Gilead) for the treatment of patients with three types of blood cancers, but the product carries a boxed warning about serious adverse events.

Idelalisib, the first approved kinase inhibitor, received traditional approval for relapsing chronic lymphocytic leukemia (CLL). Used in combination with rituximab (Rituxan, Genentech), idelalisib is indicated for patients with CLL for whom rituximab alone would not be considered appropriate due to comorbidities.

The agent was granted a Breakthrough Therapy Designation for relapsed CLL, a designation granted to drug candidates that might offer major advances in treatment over existing options.

The FDA also granted accelerated approval for the use of idelalisib for the treatment of patients with relapsed B-cell non-Hodgkin follicular lymphoma (FL) or relapsed small lymphocytic lymphoma (SLL) who have received at least two prior systemic therapies.

The product’s CLL approval was supported primarily by data from a randomized, placebo-controlled Phase III study of 220 patients with relapsed CLL who were unable to tolerate standard chemotherapy. The patients were randomized to idelalisib and rituximab or placebo and rituximab. The trial was stopped early because of a highly statistically significant benefit in progression-free survival (PFS) in the patients receiving idelalisib (10.7 vs.

5.5 months; hazard ratio, 0.18). Results from a second interim analysis continued to show a statistically significant improvement with idelalisib and rituximab over rituximab alone.

The safety and efficacy of idelalisib was established for relapsed FL and relapsed SLL in a clinical trial of 123 patients with indolent non-Hodgkin lymphomas. All participants received idelalisib, which resulted in overall response rates of 54% and 58% for FL and SLL, respectively. The median duration of response was 11.9 months in the SLL patients and was not reached in FL patients. Improvement in patient survival or disease-related symptoms has not

been established in these indications.

Signaling through the B-cell receptor has emerged as an important pathway in CLL, as well as low-grade chronic lymphomas. Every B cell makes its own B-cell receptors and signaling through this pathway is vital to the survival of both the leukemias and the lymphomas. Idelalisib interferes with this signaling pathway by targeting PI3 kinase and hormones that support B-cell survival, such as CD40 and B-cell activity factor of the tumor necrosis factor family (BAFF).

“It is not clear the relative importance of each pathway and which pathway is the most important to be inhibited, but the B-cell receptor is clearly a target,” explained Jeff Sharman, MD, the medical director of hematology research for The US Oncology Network and the director of research at Willamette Valley Cancer Institute in Oregon. Dr. Sharman’s group participated in several of the research trials that have been done on idelalisib.

The medication does have serious adverse effects. Some studies have reported that as many as 50% of participants suffered adverse reactions, according to the product label.

Therefore, the FDA mandated a boxed warning about fatal and serious toxicities, including liver toxicity, diarrhea and colitis, pneumonitis and intestinal perforation, with idelalisib. The drug was approved with a required Risk Evaluation and Mitigation Strategy (REMS).

“Most investigators have found this drug to have a reasonable balance between risk and benefit,” Dr. Sharman said.

“In the right setting, this is a very good drug and should be used. Because counseling is so important, this needs to be filled by a specialty pharmacy.” (See article, page 4.)

Common adverse reactions include diarrhea, fever, fatigue, nausea, cough, pneumonia, abdominal pain, chills and rash. Common laboratory abnormalities include neutropenia, hypertriglyceridemia, hyperglycemia and elevated liver enzymes.

Idelalisib is available as 100- and 150-mg tablets. The drug is administered twice daily.

—M.R.

6

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

Increased flexibility, higher-touch patient care offer an edge

Selling the Value of Mid-Size Specialty Pharmacy The majority of specialty pharmacy market share is owned by the four “big boys”: Express Scripts, CVS Caremark, Walgreens and Diplomat, roughly in that order.

Depending on the year and how the data are analyzed, Express Scripts has about 30% of the market, CVS about 25%, Walgreens about 10%, and Diplomat about 2%, according to industry figures.

But that leaves about one-third of the market outside the footprint of the giants and in the hands of other specialty, retail and mail-order pharmacies. At recent specialty meetings, such as Armada in May and the World Congress in July, significant attention focused on the role of the mid-size specialty pharmacy and how those operators can distinguish themselves in today’s market.

“Just like when American and US Airways had to give up gates at LaGuardia to make room for Southwest and Virgin, the opportunity will continue to exist for high-quality, mid-tier specialty pharmacies,” said Michael Nameth, the CEO of Aureus Health Services, speaking at Armada.

A number of mid-tier independent specialty pharmacies have shown remarkable growth over the past several years. In September 2013, Adam Fein’s Pembroke Consulting published an analysis of the 12 fastest-growing private specialty pharmacies for 2012, and found an average three-year revenue growth rate of 352% (http://bit.ly/ XkdGcb%; Table). Topping that list was Diplomat; the other names in the leading six were Avella, BioRx, Amber Pharmacy, Onco360 and Pentech Health.

One key advantage for mid-tier specialty operations is their increased flexibility over larger operations. “We’re like a PT boat as opposed to an aircraft carrier,” Mr. Nameth said. “Just throw us overboard and give us some ammunition. We can be more nimble, respond more quickly to new referrals and triage no-go’s right away.”

Mr. Nameth also argued that the lower overhead of mid-size specialty pharmacies allows them to pursue a higher-touch patient-care model. “We can go the extra mile to assist with programs, PAs [patient assistance programs] and appeals, and making those extra couple of calls every month that certain patients need. It’s just good oldfashioned service.”

But when a manufacturer is creating a limited distribution network for its product, it is common to assume that the major players will be the first ones given access—and that’s not unreasonable, said Wesley Winn, speaking at the World Congress. Mr. Winn is the vice

president of commercial operations, supply chain and market access for Brisbane, Calif.-based Hyperion Therapeutics, an orphan-disease biopharmaceutical company.

“When I was launching a product at Genentech, we had a little more open model; we’d start with the larger specialty pharmacies, then add some other folks in,” he said. “But as a small company, I find now that we have to go in and pick two or three players that we know are going to drive the market.

Ultimately, of course, specialty pharma-

cies can’t sell for you, but you have to look at a specialty pharmacy like a dedicated sales hub that will be interacting with the customer on a daily basis.”

It is in those customer interactions that mid-size operations must try to distinguish themselves. “Especially for us in the rare space, we’re very high-touch,” Mr. Winn said. He estimated that his company has approximately 2,000 U.S. customers for its two urea-cycle disorder medications, and another 2,000 outside the United States. “We’re looking to you to provide

‘Is a national presence as important as a dominant regional presence, if the company has a very strong market share and is loved in the local marketplace?’

—Scott Friedman

Table. Fastest-Growing g Private Specialty p y Pharmacies, 2012

Year Founded

2012 Revenue, $ (millions)

3-Year Growth Rate, %

URAC Accreditation Statusa

Diplomat Specialty Pharmacy

1974

1.100

199

Yes

Avella

1995

493.5

379

Yes

BioRx

2004

156.6

181

In process

Amber Pharmacy

1997

155.6

113

In process

Onco360

2003

112.2

124

In process

Pentec Health

1982

76.9

152

No

MedPro Rx

2002

76.3

51

Yes

HealthStat Rx

2000

66.2

243

No

PharmaHealth Specialty Pharmacy

1977

50.2

401

Yes

THN Pharmacy II

2009

37.7

2.248

Full

MedExpress Pharmacy

1994

30.0

89

No

South Miami Pharmacy

2003

15.5

89

No

Average

197.6

352

Median

76.6

167

Name

For more details, visit the URAC Directory of Accredited Companies and search for “Specialty Pharmacy Accreditation.”

that service, to support that customer relationship. If all we’re getting is mail order, we’re not getting a market.”

That’s exactly what drug manufacturers should be thinking about when they make decisions about their limited distribution networks, said Aureus’ Scott Friedman at the World Congress.

“It’s assumed that these [networks] will be automatically awarded to the specialty pharmacies with national reach and the most covered lives, and often the RFP [request for proposal] is seen as just an exercise,” said Mr. Friedman, the senior vice president for specialty pharmacy, trade relations and marketing at Aureus. “But is a national presence as important as a dominant regional presence, if the company has a very strong market share and is loved in the local marketplace?”

Mr. Friedman also noted that a growing number of mid-tier players are also acquiring multiple accreditations with entities like URAC (formerly known as the Utilization Review Accreditation Commission), the Joint Commission and the Accreditation Commission for Health Care.

Aureus’ Gary Conte, the senior vice president for commercial sales, also spoke at the World Congress. He suggested that drug manufacturers establishing limited distribution networks should ask several key questions about the specialty pharmacies they plan to include: • What are the most valuable resources specialty pharmacies can provide?

• What criteria are important to you in evaluating HUB service companies for orphan drugs?

• How can outcomes data be collected and used to increase your marketing efforts?

• What can specialty pharmacies do differently to service patients and gain access to additional drug products?

• What technological advances are you looking for from specialty pharmacies?

Mr. Conte noted that mid-size players have the “no job is too small” advantage, which may be a particular plus in the rare/orphan disease market. “A lowervolume product needs more attention, which is typically more important to a smaller specialty pharmacy,” he said.

“At the end of the day, it’s about driving high patient satisfaction—because if you can’t do that, you aren’t going to be in business very long.”

—Gina Shaw None of the sources had any relevant conflicts of interest to disclose.

7

Specialty Pharmacy Continuum • Summer 2014

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8

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

CHALLENGES continued from page 1

The conditions included in the compliance study generally do not require specialty medications, Ms. Potter pointed out; it’s thus possible that the documented adherence problems might be even more pronounced when it comes to specialty medications, “particularly because few of these drugs have generic alternatives in a lower tier, and patients may have to pay $7,600 or more per year out of pocket for specialty medications,” she said.

Health Exchanges Not Immune If employer-sponsored plans are increasingly moving toward high deductibles, many plans on the new health insurance exchanges—especially at the lower bronze “metal level”—are already there. In December, HealthPocket Inc., which compares health insurance plans for consumers, found that the average annual individual deductible for a bronze plan was just over $5,000, in addition to the average premium of $295.51 a month, or $3,546 a year (http://bit.ly/1oevFqq).

“These high-deductible plans are causing a bit of a problem,” Debbie Stern, president of Rxperts, told Specialty Pharmacy Continuum. “It’s really putting a high burden on the patient to come up with all of that up front. Even if it’s just a $2,000 deductible, the patient has to pay that up front almost immediately for most specialty drugs, so the first prescription is going to cost them

almost the full out-of-pocket for the year. When these plans were designed, people were thinking of drugs that cost $200 a month, not specialty drugs that cost $2,000 a month or more.”

Here’s where good specialty pharmacies can really distinguish themselves, Ms. Potter said. “You can provide additional patient support, working proactively to help patients understand their medical plans and anticipate their financial demands.” (See sidebar for more details on these strategies.)

That’s already happening at many specialty pharmacies around the country, according to Kyle Skiermont, PharmD, the director of specialty/infusion operations at Fairview Pharmacy Services in Minneapolis. “We’re seeing a big increase in high-deductible plans, along with a rise of coinsurance,” Dr. Skiermont said. “We’re seeing both more patients with these plans, as well as higher dollar amounts they’re needing.”

Fairview has doubled its staff of patient financial advocates over the past year to help address the growing need. And it’s not just that more patients need assistance—their situations are also becoming more and more complicated, Dr. Skiermont noted.

“Where one advocate might have been able to handle many more patients in the past,” he said, “each patient we are helping is taking more time and getting more complex in [his or her] needs.”

Many of the foundations and other sources of funding for medication assis-

Average Deductible Amounts for the Four Metal Plans

tance are also getting tapped out more quickly. That, too, requires creativity.

“Some foundations recharge their funds over the year, so if you ask for a grant on behalf of your patient and it’s not there, you need to know when to go back to them,” Dr. Skiermont said. “Maybe there was no funding in March but there may be in October. It requires a lot more interaction and advocacy for our patients, multiple times a year, whereas historically we might have only needed to do that once a year.”

“We’ve been getting more and more creative around what we can do as far as payment plans,” Dr. Skiermont added. “If we know someone has a big out-of-pocket maximum that they’re going to hit in the first month, we’ll try to make arrangements to pay that over the year.”

It’s a patchwork solution that likely is

Taking the Sting Out of a $3,000 Deductible

W

hen a patient comes to Fairview Specialty Pharmacy with a prescription for Tecfidera, Humira or any other specialty drug, and has a high-deductible insurance plan that front-loads much of the expense for that medication from the patient’s pockets, that patient’s financial worries also become the problem for Aubree Dorr.

Ms. Dorr, Fairview’s specialty pharmacy liaison, supervises its staff of patient financial advocates (PFAs)— experts who know all of the options for coping with the burden of deductibles and coinsurance—and to walk patients through the often-confounding maze. “We’re generally the first ones to find out about a really high copay, due to the proactive processes we’ve employed here,” Ms. Dorr said. “We run a test claim to find out exactly what the insurance is going to charge to patient responsibility, and then we start our research process.”

PFAs may be called by a different name depending on where they are located, but at any good-sized specialty pharmacy, there probably will be at least a few of these experts who know the ins and outs of manufacturer’s coupons, Medicare Part D extensions and foundation grants. Fairview assigns its PFAs to one or two particular specialty disease states, so that they can develop thorough knowledge of each drug and therapy and their support programs.

Three Steps to Financial Support The PFAs usually follow a three-step process in finding financial support for patients who have difficulty managing their crushing pharmacy costs:

Step 1: Manufacturer’s coupons or copay/coinsurance assistance cards. “These can be the quickest and easiest go-to solutions,” Ms. Dorr said. The coupons and cards have no income criteria, and are essentially open access to anyone prescribed the applicable medication.

“There are a lot of instances I’ve seen where a copay card will cover all but $5 to $50 of the patient’s responsibility,” Ms. Dorr said. These cards generally can be renewed annually, although she noted that she has seen some cards that last through a total dollar amount of coverage. The cards typically look like standard insurance cards, and the pharmacy will put it through the billing system as a secondary claim. “If, for example, $400 comes back, we then bill it to the copay card, and [insurance] will pay all except $5 or $10 or whatever the amount is,” Ms. Dorr said.

To qualify for an even more generous option—manufacturer’s free drug programs—patients must meet certain income thresholds. These vary, but generally range

not sustainable in the long term. “In the short term, we feel we owe this to our patients. As a nonprofit, health-system– based specialty pharmacy, providing this kind of high-touch financial assistance is one of our differentiators. It’s core to our mission,” Dr. Skiermont said. “We need to continue to be innovative and make this work for our patients, but ultimately something is going to have to change. A lot of the burden is falling on specialty pharmacy, but at the same time, the providers and the pharmaceutical companies are beginning to understand the coverage issues better than they did a couple of years ago, and are helping us bring the message to the patient. The reality is that everyone’s still trying to figure this out.”

—Gina Shaw None of the sources had any relevant financial conflicts of interest.

from 250% of the federal poverty level at the very low end, to somewhere closer to 400% of the federal poverty level at the high end. If a patient qualifies, he or she will have a profile and a case manager in place at the manufacturer’s assistance hub—typically, a website that offers a variety of patient assistant tools— and the hub coordinates with the manufacturer about the source of the drug. “At that point, it takes us out of the loop,” Ms. Dorr said. “The drug comes from another pharmacy or the manufacturer directly.” But the specialty pharmacy PFA is invaluable in getting the patient through the application process for the free drug program in the first place, she noted.

Step 2: Foundations and Grants. If manufacturers’ programs don’t meet a patient’s needs, the next sources that the PFAs tap are foundations such as the Patient Access Network (PAN) Foundation, the HealthWell Foundation and CancerCare (for oncology patients only).

“Their grants open and close on an annual, quarterly or monthly basis,” Ms. Dorr said. “Every foundation and grant for every diagnosis is different. It’s almost a full-time job, just keeping up with the grants. As soon as they open up, they could be absorbed in a day, or it could take all month—it just depends on the need in the nation.”

When a grant is set to be replenished with funds, PFAs “line up”—virtually or by phone—much like avid online ticket buyers for a show. “You’ll know that, at the stroke of 8 a.m. EST on July 1, there will

9

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

Hepatitis C: What’s a Cure Worth?

Las Vegas—If you created a word cloud to represent the frequency of drugs discussed at the 2014 Armada Specialty Pharmacy Conference in April, it might look something like the one on this page.

All right, so we’re exaggerating—but not much. Sovaldi (sofosbuvir, Gilead) and its eye-popping $84,000 price tag was the hot topic in many Armada sessions.

Speaking on the evolving specialty landscape at the general session, CVS Caremark’s senior vice president for specialty pharmacy services Randy Falkenrath, MBA, presented a drug launch pricing analysis that tracked specialty pricing’s journey upward from Copaxone (glatiramer acetate, Teva), $1,000 a month when it launched in the 1990s, to Sovaldi.

“At $30,000 a month, it literally broke the chart,” Mr. Falkenrath said.

The drumbeat of outrage over the cost of Sovaldi has continued steadily since its January introduction for the treatment of hepatitis C infection. Express Scripts’ chief medical officer Steven Miller, MD, told Bloomberg that it would “break the country.” America’s Health Insurance Plans chief executive Karen Ignagni has talked about “whatever you can get away with” pricing. And in June, Congress members Henry Waxman (D-Calif.) and Diana DeGette (D-Colo.) called for a hearing on the cost implications of Sovaldi, citing new research from Georgetown University and the Kaiser Family Foundation estimating that Sovaldi will be responsible for increased Medicare Part D drug spending of as much as $6.5 billion in 2015 alone, as noted in a June 5 Health Affairs blog (http://bit.ly/1oZqYX1).

However, others have raised the point that Sovaldi is not like Tecfidera (dimethyl fumarate, Biogen Idec) at $55,000 a year or Provenge (sipuleucel-T, Dendreon) at $93,000 for one course of treatment. Solvadi is a cure for a disease that has become the leading indication for liver transplantation in the United States.

“I would just like context,” said Doug Long, the vice president of industry rela-

tions at IMS Health, in a trend session on specialty markets. “How much does a liver transplant cost? Around $300,000.

And what about the immunosuppressant drugs [required post-transplant], which cost tens of thousands of dollars per year?

What’s the cost of a third line of therapy after someone has failed twice? We need to have a discussion about investment.”

Of course, not everyone infected with hepatitis C virus (HCV) develops cirrhosis; indeed, not everyone with HCV may need treatment (approximately 15% of HCV infections will clear on their own).

So, a key part of the ongoing debate about Sovaldi (and new competitor pipeline drugs and combinations from AbbVie, Merck and Bristol-Myers Squibb) is whether or not everyone seeking hepatitis C treatment needs the antiviral agent.

Guidance Sheds Some Light A general guidance document for HCV treatment was issued by the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA), in collaboration with the International Antiviral Society-USA (IAS-USA) in March (www. hcvguidelines.org/full-report-view). The guidance will be updated on an ongoing basis; the original version makes no mention of cost, but a summer update indicates that a new section on “When and In Whom to Initiate Therapy” will begin to address cost issues. (This update was not yet released at press time.)

“The guidelines recommend daily sofosbuvir with ribavirin plus weekly pegylated interferon for 12 weeks for eligible patients,” noted Jason Lynn, the vice president of clinical services and trade

be another million dollars in this fund,” Ms. Dorr said. “For some funds, like PAN, you can apply online; for others, you have to call. Some require that the patient call as well; we do setup on the front end and open the case, and then the patient calls to give [his or her] information.”

Step 3: Specialty Pharmacy Assistance. When the first two sources of financial aid are exhausted or unavailable, some specialty pharmacies— particularly those affiliated with larger health

relations at ReCept Pharmacy, in a session on the state of HCV therapy at Armada. “For interferon-ineligible patients, daily sofosbuvir with simeprevir [Olysio, Janssen] with or without ribavirin for 12 weeks was recommended.”

But a panel for the Department of Veterans Affairs took a different stance. In April, it recommended that sofosbuvir and simeprevir be prescribed primarily for patients with advanced liver disease, including those waiting for transplants, and suggested that other HCV patients could wait. “We think these drugs should be used because they have a high clinical benefit, but not everyone needs to be treated immediately,” said Rena Fox, MD, a professor of medicine at the University of California, San Francisco School of Medicine.

Sovaldi (and its future competitors) also will play an important role in the management of people with HIV; about 40% of people with HIV are coinfected with HCV. “This drug has been revolutionary for coinfected patients,” said Michael Nameth, RPh, MBA, the CEO of Aureus Health Services, who noted that he has not seen significant resistance by payors to covering Sovaldi for this population.

“Obviously, there’s a lot of clinical preparation before a doctor decides whether or not to initiate therapy, but for those patients who come on service with us, we have been successful at getting the medications covered,” Mr. Nameth said. “Because the coinfected patient is high-risk, the health plan would want to try to get them on therapy as soon as appropriate in order to get the HCV cured. Not doing so could cause worse problems down the road.”

systems—may have their own payment plans, grants or other systems to help patients afford their medications. Fairview has its Fairview Foundation, which basically allows access to a lump sum of money for pharmacy patients whose copays have become a burden.

The pharmacy also has insurance gap assistance, with an application process and financial guidelines similar to those for manufacturer’s coupons and cards, that can offer a once-yearly write-off of 25% or more of copay costs.

The whole picture is likely to change again this fall, with a series of expected FDA approvals. Gilead’s once-daily, single-pill combination of Sovaldi with ledipasvir, which garnered breakthrough designation from the FDA, has a Prescription Drug User Fee Act (PDUFA) date of October.

“The combination had a sustained viral response of 99% after 12 weeks, with very low adverse events. Gilead is obviously thrilled with this,” Mr. Lynn said.

Furthermore, in June, AbbVie’s three-drug combination of the protease inhibitor ABT-450 with ombitasvir and dasabuvir, which posted similar sustained virologic response figures in the PEARL III trial, received both priority review status from the FDA and accelerated approval status from the European Medicines Agency. Mr. Lynn said he expects a December PDUFA date for the AbbVie combination.

What the price tags will be for either of these combinations—or for Merck’s competitor drug, still in Phase II studies and likely to have a PDUFA date in 2015, according to Mr. Lynn—remains to be seen. Moreover, none of them have been tested in head-to-head trials that might establish a clear leader.

Whatever decisions that payors and policymakers ultimately make about these new HCV therapies, several things are key, Mr. Lynn noted. “We are entering an era of shorter treatment duration, diminished injection training need and higher patient response rates. We’ll have no interferon, and probably no ribavirin, in the future. However, determining the drugs and associated regimens to use may be getting more complex, due to differences in response due to cirrhosis and genotype. With therapies that are this costly, adherence is key, and this is where specialty pharmacy can have an enormous impact through things like adherence review and use of technology, like texting, to monitor compliance.”

Added Mr Lynn, “third-party providers will cover this treatment only one time, and we have to make sure it’s sound and done right the first time.”

—Gina Shaw None of the sources reported any relevant financial conflicts of interest.

“We’re going to do all that we can to make sure patients, especially those in critical situations, get the medications they need,” Ms. Dorr said. “We bend over backward, and—knock on wood—most of the time we are able to come up with what the patient needs.”

—G.S. None of the sources reported any relevant financial conflicts of interest.

10

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

Plan enrollment, acceptance of higher-tier plans outpace forecasts

Good News for SPs on the Health Exchanges Las Vegas—With the one-year anniversary of the opening of the health insurance exchange marketplace fast approaching, how well is specialty pharmacy faring?

At the Armada Specialty Pharmacy Summit in May, Zitter Health Insights’ Mark Zitter noted that marketplace exchange enrollment has significantly beat the skeptics’ projections.

“A lot of people waited until the last minute to sign up for plans; the best estimate is now that 8.1 million have signed up,” he said. “The Congressional Budget Office projects continued substantial growth in marketplace participation.

Within two years, estimates are we’ll be at 26 million. That’s not as big as commercial, but it’s right in the middle of where managed Medicare and managed Medicaid are.” Zitter Health Insights is a health care research firm located in Livingston, N.J. Exchange enrollees, he added, are also defying predictions that they would just sign up for the cheapest plans possible—especially the healthy young adults who are essential to balancing the exchange risk pool.

“Most enrollees are willing to pay higher premiums for better coverage,” he said. “Among 18- to 34-year-olds, 15% have signed up for bronze plans, 66% silver, 10% gold and 5% platinum.”

The metal selection among young adults was fairly comparable to the cumulative population; overall, 63% of total exchange enrollees signed up for silver plans, and 15% to 17% chose gold or platinum (Figure 1).

Based on exchange enrollment, specialty pharmacies can expect that many more people who require specialty

Enrollees 4% 18-34 yo

medications will have insurance going forward, Mr. Zitter said. For example, a company analysis (Zitter Health Insights Health Insurance Marketplace Exchange Monitor, Q1 2014) found that some 53,000 people with rheumatoid arthritis in California are newly insured, as are approximately 45,000 in Texas and about 28,000 in Florida.

Big Growth in Market Share Also, early data show a greater use of specialty drugs in the exchanges, said Sheri Sellmeyer, the vice president of advisory services at Decision Resources Group, Burlington, Mass., in another Armada session on exchange plans. In January and February, approximately 1.1% of total prescriptions in exchange plans were for specialty medications compared with 0.75% in commercial health plans, a 47% difference.

On the whole, exchange members are facing more restrictions and paying more out of pocket for these drugs, said Ms. Sellmeyer, citing an analysis from Avalere, a Washington, D.C.-based health care consultancy. “Consumers in exchange plans are twice as likely to face utilization management, and greater than 70% of covered mental health and oncology medications require [utilization management].”

HIV medications had the lowest utilization management incidence, with more than half of exchange plans offering open access to these medications (Avalere Analysis: Consumers Face

15%

More Hurdles to Accessing Drugs in Exchange Plans Compared to Employer Coverage; http://bit.ly/1sZUAFn). n Formulary breadth, in terms of which products are covered, looks very comparable to commercial employer plans, according to Avalere’s Caroline Pearson, the vice president of health reform practice. “The utilization management and cost sharing are much higher, but we’re not seeing dramatically restricted formularies across the board.”

However, there are definite reports of formulary restrictions, said Marc Boutin, the executive vice president and chief operating officer for the National Health Council, which represents people with chronic diseases and disabilities. “By and large, we’re seeing a great number of challenges as to how many products are covered,” he said. “We’re seeing it in the specialty space in par-

66%

10%

5%

11%

6%

Metal selection among young adults and the cumulative population is not notably different!

All Enrollees

18%

63% Metal Level

Catastrophic

Bronze

Silver

Gold

Platinum

Figure 1. Most enrollees are willing to pay higher premiums for better coverage.

Source: U.S. Department of Health and Human Services, March 2014

ticular, but not just specialty products.

We’re also seeing it for conditions where the cost of the product itself might not be that high, but treating the overall health needs of that person may be high—for example, diabetes.”

Not Always Transparent Transparency is another big challenge for consumers in the exchanges (Figure 2). “Our analysis showed that for about 50% of the plans we looked at, the formulary data were either not available or difficult to access from a consumer perspective,” Ms. Pearson said.

“It’s almost impossible for a person to go into the marketplace and identify a plan that covers their products. That’s very hard to do anywhere, but in the exchanges in particular,” Mr. Boutin agreed. “Once you figure out if your product is there, it’s also hard to figure out what cost sharing is attached to it. With many specialty products, it’s coinsurance on the cost the company paid to purchase the product, which you don’t know.”

What is difficult under the pharmacy benefit is virtually impossible under the medical benefit. “Transparency for physician-administered drug coverage is virtually nonexistent; it’s really impossible to figure out what would be covered,” said Ms. Pearson. “The federal exchange will soon require that all health plans provide a link to their formularies, but there’s no solution to the issue of physician-administered drugs on the horizon.”

Helping consumers make informed decisions about their options regarding specialty medications on health insurance exchange plans may be a valueadded proposition for specialty pharmacies going forward—the next open enrollment period starts on Oct. 1.

11

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

Formulary not available, 38%

Very accessible, 31% Moderately accessible, 21%

Very difficult, 4%

Difficult, 7%

Figure 2. Drug formulary accessibility, by plan.a

‘Transparency for physician-administered drug coverage is virtually nonexistent; it’s really impossible to figure out what would be covered.’

—Marc Boutin ter than others in addressing issues, such as the cost of specialty tiers, exceptions and appeals. “For example, Delaware and Maryland just enacted laws that essentially eliminate the specialty tiers and minimize the huge outof-pocket costs that come with spe-

cialty products,” Mr. Boutin said. “A number of states have made progress and are trying to do the right thing, but nobody’s really hit everything.”

The burden of cost-sharing mechanisms on specialty patients will have to be addressed going forward, Mr. Boutin

said. “These mechanisms were designed to eliminate or mitigate unnecessary care, but people taking specialty products really need these drugs. To put a 30%, 50% or 70% coinsurance on products like these can add up to an insurmountable financial barrier; that’s not the way to ensure good health for these patients or for society.”

—Gina Shaw The sources reported no relevant financial conflicts of interest.

a

85 plans were included in the analysis. Numbers may not sum to 100% due to rounding.

Source: Avalere Health analysis of federal and state exchange websites and select exchange plan websites.

Specialty Products & Programs Delivered with Personalized Care

“In essence, it’s virtually impossible to make an informed decision about choosing a plan right now,” Mr. Boutin said.

“People have a hard time finding the information, and then it’s presented in multiple different formats, so you can’t compare like to like.”

A lot of attention now is being focused on the Department of Health and Human Services and the work it is doing under the Affordable Care Act, to review implementation and make recommendations for changes for 2016. “We want to make sure they make ... these plans more effective for people with chronic conditions,” Mr. Boutin said.

At the state level, some are doing bet-

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12

Specialty Pharmacy Continuum • Summer 2014

OPERATIONS & MANAGEMENT

‘Confusion’ Sums Up Specialty Market Outlook Tampa, Fla.—Shifting provider business models, increasing health care costs and changes in benefit designs, among other factors, have created unstable market dynamics. Unfortunately, clarity for payors, providers, patients and specialty pharmacy is nowhere in sight, according to experts speaking at the National Association of Specialty Pharmacy 2014 Specialty Pharmacy Expo.

“Everybody wants to manage and secure appropriate access to [specialty] drugs, but no one can define what appropriate access really means right now, much less how to achieve it,” said Lauren Barnes, the senior vice president at Avalere Health, a consulting firm in Washington, D.C. The protracted uncertainty means that answers to key questions of where and when patients receive specialty pharmaceuticals, which drugs insurers will pay for and what cost burden patients will bear, will remain elusive for years to come.

Compounding the challenge is the abrupt swelling of health insurance rolls resulting from the Affordable Care Act (ACA). “The ACA by no means caused this dilemma, because rising health care costs, including drug costs, were already big factors. But the law has dialed up the intensity of the situation,” Ms. Barnes said.

Although the ACA puts health insurance within reach of millions of previously uninsured individuals, many enrollees have found that specialty drug coverage leaves a lot to be desired, particularly in lower-cost plans. For drugs listed in tiers 3 and 4 of an insurer’s approved formulary—where many specialty drugs reside—coinsurance ranges from 10% to 50%, according to Sandy Robinson, senior vice president at Avalere Health. “That’s a huge concern for specialty pharmacy, because so many specialty drugs are in those higher, more expensive tiers,” Ms. Robinson said. Patients may not only wince when they learn of their high out-of-pocket burden for drugs that often cost thousands—even tens of thousands—annually; some may decide to cut back on the dose or even forgo the drugs entirely.

Just as high copays to see medical specialists, who typically are the ones prescribing the specialty drugs, act as a barrier to health care access, so does the inability to afford medications, Ms. Robinson added.

Patients are not the only ones who are flustered. Insurers are scratching their heads over the opacity of claims for specialty drugs that are covered under a policy’s medical benefit—that is, drugs that require a medical professional to administer them. “It’s going to take several years just to get an understanding of what we’re paying for,” admitted James R. Lang, PharmD, the vice president of pharmacy services

Table. Average Adjusted Costs for Eight Most Common Cancers Type of Cancer

Office-Managed Episodes, $

HOPD-Managed Episodes, $

Lung

32,913

32,382

Prostate

21,299

25,504

19.7

Genitourinary

8,960

19,592

118.7

Breast

30,072

33,391

11.0

Hodgkin lymphoma

39,080

42,537

8.8

Colon

45,997

46,220

0.5

Digestive

30,018

30,044

0.1

Leukemia

39,008

43,508

11.5

Any

28,177

34,973

24.1

Difference, % –1.6

HOPD, Hospital Outpatient Department Source: Avalere Health analysis of National Association of Managed Care Physicians member data.

Cost estimates adjusted for age, sex and prior history of cancer and include all care received by patient during chemotherapy.

‘There’s a lot of public pressure to lower the costs of some of these medications, but the U.S. doesn’t engage in price controls.’

—James R. Lang, PharmD for Blue Cross Blue Shield of Michigan.

For example, claims frequently fail to specify the exact drug or the dose.

“Sometimes we don’t know which drug was used, what the route of administration was, or what the quantity was,” Dr. Lang said. “It’s difficult to price claims under these circumstances, and we can’t make informed decisions if we don’t know what we’re paying for.”

Dr. Lang also observed that new specialty drugs continue to flood the market, forcing providers and insurers to evaluate the efficacy and value of the medications based on limited clinical data. “Often, we don’t have complete knowledge of the effects or side effects of these drugs because the FDA has ‘fast-tracked’ approval for some of them after determining that their ben-

efits outweigh their risks, just as they did with some drugs during the AIDS crisis,” Dr. Lang said. “The medications are coming at us fast, but with less information than we normally might have gotten.”

Hospitals Still Doctor-Shopping Another seismic shift has been the number of physicians’ practices scooped up by hospital systems, Ms. Barnes said. “There’s been an explosion in the number of doctors being employed by hospitals and an explosion in integrated delivery systems.

Very new and unexpected partners are popping up left and right. To me, that shows that lots of different stakeholders are saying ‘we need to be on the bus to avoid getting hit by the bus.’”

Among the consequences of this consolidation is that hospital administrators, more than ever, dictate what drugs physicians can prescribe, she continued. “There has been an erosion of small community practice and a shift toward more hospital-based care,” Ms. Barnes said. “The change has decreased provider autonomy by moving prescribing decisions away from individual physicians.”

Site of Care Drives Costs Consolidation is also problematic for payors because services delivered in a hospital or hospital outpatient clinic cost two to four times more than they do in a physician’s office, even if there is no medical benefit for using the hospital setting. A 2012 study by Avalere (http://bit.ly/1r18MLQ) found that chemotherapy given in a hospital outpatient department costs on average 24% more than treatment received in a physician’s office (Table), and that “care for patients treated in a physician’s office [is] less expensive regardless of the length of the chemotherapy.”

Such cost variations among treatment settings have led insurance companies to seek what they call site-of-care optimization. “Rather than denying access to a drug that’s probably medically necessary, payors are saying ‘let’s look at directing where that drug can be received, so we as a payor save money but preserve access,’” Ms. Barnes said.

“Sometimes there aren’t any options left in a community because of all the consolidation. That creates opportunities for alternate-site providers, such as pharmacies and infusion centers.”

All of the experts expect the market to remain fragmented and in flux for quite some time. “There’s a lot of public pressure to lower the costs of some of these medications, but the U.S. doesn’t engage in price controls,” Dr. Lang said.

“Other than various parts of the chain trying to manage drug use and costs and putting pressure on drug companies to lower their prices, not much will change for a while.”

A balance will not be struck anytime soon, according to Ms. Barnes. “There are too many regional dynamics, individual customer dynamics and different interests that need to be taken into account,” she said. “There will be small initiatives in different regions, and from those I hope we’ll learn enough to expand to broader populations. Until then, there’s going to be a lot of confusion.”

—Steve Frandzel The sources had no relevant financial conflicts of interest to disclose.

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14

Specialty Pharmacy Continuum • Spring 2014

OPERATIONS & MANAGEMENT

INTEGRATION continued from page 1

(Table). The paper was released in April (http://bit.ly/1i1M6XD).

“Everybody’s talking about it because they have to be,” said Debbie Stern, the president of Rxperts, in Anaheim Hills, Calif. “Just because a drug is covered under a different benefit, why should it make any difference what cost share it is or how they reimburse? You can buy Remicade [Janssen] for literally 10 different prices, and that’s just crazy. But it’s going to take time.”

The reason? The practical, on-theground realities of achieving this integration have proven challenging, to say the least, and no one knows what a pharmacy–medical benefit alignment really looks like.

At the Academy of Managed Care Pharmacy’s (AMCP) annual meeting, Ohio’s Medical Mutual—the state’s

oldest and largest health insurance company—offered an inside look at how it implemented a medical benefit management program to drive integration and trend management.

The result? A savings of some $14 million in the first year.

‘Health plans are very quick to move everything from medical to pharmacy, and I was right in that boat at first, but the numbers didn’t support [the strategy].’

—Sonny Borja-Barton, PharmD

Seeking Transparency Medical Mutual started the project with the relatively simple purpose of establishing consistency in clinical criteria across the medical and pharmacy benefits. “Within a six-month period, we realized that there was so much more that could be done,” said Sonny Borja-Barton, PharmD, the vice president of pharmacy management at Medical Mutual. “The line of sight into the medical benefit has been minimal to none in many health plans, including ours. The medical side was managed in a silo.”

So Medical Mutual officials decided to pursue a broader “close to” five-

year plan to achieve medical–pharmacy benefit alignment. They debated over buy versus build—and after an analysis, chose both, selecting pharmacy benefit managers Care Continuum to help customize and implement their strategy.

It would not be cheap. “We asked our board for a lot of money to make this happen,” Dr. Borja-Barton said. “We convinced them that we would have a 100% return on their investment within the first two years of this relationship, versus taking another six years to break even if we had done everything in-house.”

‘You have to make the case that you’re going to get a return on … investment [for claims analysis], and rally the team—because you’re talking about a lot of different departments that have their hands on the medical benefit components.’

An internal analysis quickly showed the gaps between the medical and pharmacy sides. “We take so many things for granted on the pharmacy side after years of online systems and having drugs processed real-time. We simply don’t have that on the medical side. Are most claims coming in electronically?

Yes. Are we doing anything with that information? No,” Dr. Borja-Barton said.

Their first area of focus was on medical utilization management. “Health plans are very quick to move everything from medical to pharmacy, and I was right in that boat at first, but the numbers didn’t support [the strategy],” Dr. Borja-Barton said. “In fact, we reimburse physicians less than we pay pharmacies in many cases. So with many of these drugs, it made sense to leave them where they were and instead maximize the reimbursement.”

—Debbie Stern $5 Million in Savings

Table. Cost Savings (Injectable Medications) Based on Site of Carea Site of Care

a

Allowed PMPM, $

Average Savings, %

Median Savings, %

25th Percentile 75th Percentile

1.39

12.4

3.6

0.3

17.0

Home health

1.09

19.3

5.1

0.1

18.8

Hospital outpatient

0.74

34.3

28.1

15.5

42.1

Total

3.22

19.7

9.7

3.7

23.4

A 90% shift in utilization from the medical to pharmacy benefit was assumed for the analysis.

PMPM, per member, per month. Source: Evaluation of Medical Specialty Medications: Utilization and Management Opportunities, April 18, 2014.

The Milliman Group. http://bit.ly/1i1M6XD T

Over the first eight months of the Medical Mutual initiative, utilization management in the medical benefit— primarily denials, dose adjustments and preferred products—yielded more than $5 million in savings. Then came a major overhaul to the insurance company’s claims systems, one that addressed the inherent disconnect between the lingua franca of the medical benefit— Healthcare Common Procedure Coding System (HCPCS) codes—and that of the pharmacy benefit, National Drug Codes (NDCs). “Medical people don’t know what NDCs are, and pharmacy people don’t know what HCPCS codes are,” Dr. Borja-Barton said. “We overhauled the system so that we can do anything we want at an NDC level, giving us a line of sight that really opened our eyes as to what reimbursing doctors looked like.”

At this point, all providers must give an NDC for any drug to be reimbursed

by Medical Mutual. “Capabilities we’ve always taken for granted under the pharmacy benefit, we can now do under medical,” Dr. Borja-Barton said. After a

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15

Specialty Pharmacy Continuum • Spring 2014

OPERATIONS & MANAGEMENT

two-step educational process about the shift to NDCs, providers began receiving “soft message” warnings when they submitted specialty claims without an NDC, essentially stating: “In the future, we will require an NDC on this product when submitting this medical claim.”

“Earlier this year, after more education, we stopped entirely and told providers that they couldn’t get reimbursed without an NDC no matter what,” Dr. Borja-Barton said. Claims to prior authorization reviews yielded more than $4.5 million in savings over the first eight months, primarily in dose adjustments and denials.

Next steps for 2014 include a rollout of oncology decision pathways; the vendor is still being selected. “There are a select few who go beyond the drug, and because oncology is about radiation and surgery, not just chemotherapy, we want vendors who go beyond the drug.”

12 to 24 months. And although 75% considered using an external adherence vendor “highly effective,” only 4% actually are using this strategy.

“Payors have a lack of resources to do all this work. I’ve talked to a client who is hiring three new analysts just to devote to all this claims analysis,” Ms. Stern said. “You have to make the case that you’re going to get a return on this investment, and rally the team—because you’re talking about a lot of different departments that have their hands on the medical benefit components. You

Compelling Data Experts agree that although strategies may differ, some type of action should be taken in the benefits integration arena, given the compelling data on how much variation can occur between the medical and pharmacy drug spend.

A 2010 benchmark study (http://bit. ly/1obY6tp) by the Milliman Group, for example, found that as the administration of self-injectable medications con-

tinues to move out of the physician’s office (medical benefit) and into the outpatient hospital setting (pharmacy benefit), “the unit cost of these medications can vary dramatically.”

Thus, “health plans and employers need to take a more comprehensive view of specialty drug cost management” across these care settings.

—Gina Shaw The sources had no relevant financial conflicts of interest.

for HEALTHCARE BARCODING

Bad Revenue Code = No Pay Over the next year, Dr. Borja-Barton said Medical Mutual also will start piloting utilization management edits for many high-cost specialty drugs on the medical side. “We will roll out about seven or eight specialty drugs in total,” she said. “Here again, it’s about line of sight. We have a line of sight for professional claims, but on the outpatient side, we’re talking about revenue codes, and we’ve seen a lot of examples out there where you can hide what you’re actually dispensing at an outpatient facility. If there’s no indicator on a revenue code that tells us what the drug is, we’re simply not going to reimburse you. We will continue to stop these claims until we change the behavior on how that billing occurs.”

Provider contracts, when renewed, will be updated to reflect these terms.

Progress to date represents just the tip of the iceberg. “In January, we launched an online prior authorization system with the help of Care Continuum,” Dr. Borja-Barton said. “Providers now can go through the portal to get prior authorization for drugs on the medical side. Our overall strategy is ultimately a one-stop shop. If you as a physician want to prescribe whatever that drug is, you need to go through this portal.”

“They’re doing all the right things,” Ms. Stern said of Medical Mutual. “I’ve consulted with a couple of other plans that are doing some of the same things, and I think they are right on.”

But Medical Mutual is paving a still fairly uncharted path. For example, in the 10th edition of the EMD Serono Specialty Digest, which Ms. Stern presented at the AMCP meeting, 49% of plans representing 32% of lives reported having no intention of implementing oncology pathways within the next

have to bring them together, but they may not want it that way.”

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16

Specialty Pharmacy Continuum • Summer 2014

CLINICAL

DISEASE STATE SPOTLIGHT

Cystic Fibrosis for the Specialty Pharmacist

• Complete absence of CFTR protein synthesis

contributing to the continuous cycle of infection.

Another organ that is affected by CF is the pancreas, and thus involves the endocrine and gastrointestinal systems. In CF, thick mucus obstructs the pancreatic duct, scar tissue accumulates, and over time, digestive enzyme secretion is interrupted. Because digestive enzymes do not reach the intestines, CF patients experience malabsorption and malnutrition.5 CF is one of the most common causes of irreversible pancreatic insufficiency.7 Up to 80% to 90% of CF patients require exogenous pancreatic enzymes and nutritional supplementation. Their caloric needs can reach 120% to 150% of the Recommended Dietary Allowance (RDA), or up to 5,000 calories per day. For most patients with CF, drinkable supplements and high-fat foods (eg, bacon, ice cream, cream instead of milk, additional cheese, pizza) are incorporated into the daily diet. Certain minerals (eg, calcium, iron, zinc, and sodium chloride) and fatsoluble vitamins are also supplemented.

Some patients find this very challenging and require feeding tubes (G-tube or J-tube) to allow extra calories and nutrition via supplemental foods. Longitudinal studies demonstrate that undernutrition is closely related to the decline of lung function and early infection with Pseudomonas aeruginosa.5 Furthermore, there is a positive relationship between improved weight and nutritional status and better lung function.1,5 Thus, maintaining or improving body weight is an important goal for CF patients.

The literature indicates that approximately 30% of people who have CF develop CF-related diabetes (CFRD) by their third decade of life due to pancreatic complications.8 CFRD has an insidious onset, and thus it is important to screen for it annually. CFRD is different from both type 1 and type 2 diabetes.

Similar to type 1 diabetes, the only treatment is insulin, but patients with CFRD have no dietary restrictions.8 Instead, the CF care team will titrate insulin needs to the individual patient.

• Defective protein maturation and early degradation (caused by the most common mutation, ΔF508)

Clinical Management

Mary Claire Wohletz, PharmD, CSP Minneapolis, Minnesota

Introduction Cystic fibrosis is a rare, autosomal recessive disease caused by a genetic mutation on chromosome 7. The defective gene results in abnormalities in the production and function of a protein called the cystic fibrosis transmembrane conductance regulator (CFTR) found on epithelial cells.1,2 There are more than 1,500 mutations of the CFTR gene, which are cataloged into one of the six classes of known defects1,2 (Table 1). In simplified terms, CFTR acts as a chloride and bicarbonate channel involved in salt and fluid transport. In CF, a defective CFTR results in an imbalance of sodium and chloride exchange, with resulting dehydration of the airway surface, which contributes to the harmful cascade of mucus accumulation, infection, inflammation, and destruction that characterizes CF lung disease.3,4 Although frequently thought of as only a lung disease, CF can affect multiple organ systems. The widespread presence of epithelial cells, and thus CFTR, throughout the body (lungs, pancreas, liver, kidneys, sweat ducts, and reproductive tract) helps to explain why CF is a multisystem condition and also is a progressive disease over time.1 Yet, lung disease accounts for 85% of the mortality.

Approximately 30,000 children and adults in the United States have CF. An additional 10 million more—or about one in every 31 Americans—are carriers of the defective CF gene, but do not have manifestations of the disease.5 A person

must inherit 2 defective genes for disease manifestation.

Symptoms The severity of CF symptoms and the extent of system involvement vary from

person to person. Whereas some may have multisystem, life-threatening disease involvement, others may present in adulthood with infertility. For patients who present in childhood, the most common symptoms are6: • Very salty-tasting skin • Poor growth/poor weight gain • Persistent cough and phlegm production • Frequent lung infections • Wheezing or shortness of breath • Frequent greasy, bulky stools or difficulty with bowel movements • Nasal polyps

Disease Process and Clinical Manifestations It is important to understand the disease process to have insight on the complexity of care that CF patients require.

Because much of the focus of the CF care team is on pulmonary function and weight, this section highlights the effects of the disease process on the pulmonary and pancreatic systems. The basic defect in CF results in diminished cellular water flow and the buildup of thick mucus.

In the pulmonary system, this environment facilitates bacterial, viral and fungal infections, which lead to inflammation and tissue destruction.5 Neutrophils accumulate at the site of tissue damage and neutrophil elastase is released, which destroys bacteria but also destroys epithelial cells, causing permanent damage to the lung tissue surface. Degenerating neutrophils release DNA, adding further thickening of the mucus and

Table 1. Six Classes of Defects Caused by CFTR Mutations1,2

• Disordered regulation (diminished ATP binding and hydrolysis) • Defective chloride conductance or channel gating (caused by the G551D mutation) • Diminished transcription due to promoter or splicing abnormality • Accelerated channel turnover from the cell surface ATP,, ade adenosine os e ttriphosphate; p osp ate; CFTR, C , cyst cystic c fibrosis b os s transmembrane t a s e b a e conductance co ducta ce regulator egu ato

CF has changed from a diagnosis fatal in infancy or childhood to a chronic disease of children and young adults.

With aggressive treatment, the average lifespan has increased to about 38 years nationally,1 with some CF centers achieving even higher life expectancies. As a result, adult CF centers are

being created to care for the increasingly older population. Although life expectancy has increased dramatically, management of the disease still requires a complicated daily regimen of preventive and therapeutic interventions. On a daily basis, a patient with CF may take up to 15 pills and expend at least 1 hour on secretion clearance. Patients with severe forms of the disease may ingest up to 60 pills and undergo 2.5 hours of secretion clearance treatment daily.9 Patients are often prescribed oral and IV antibiotics or antifungals to continually combat invading organisms, because aggressive treatment of pulmonary exacerbations improves the lifespan of patients with CF.5,10 Table 2 provides a summary of the organ systems affected by CF, as well as the symptoms and consequences and the therapeutic classification of the drug types used, when possible, to target the symptoms.

Targeted Therapies Research has shifted from developing drugs aimed at treating the secondary manifestations of CF to those aimed at primary prevention. Many of these drugs are designed to address the underlying cause of CF—defects in CFTR protein. Two main types of medications have been developed for this purpose: compounds that increase the function of the defective CFTR protein (eg, potentiators), or those that allow the protein to reach the cell membrane before being degraded by internal cellular components (eg, correctors).2 Ivacaftor (Kalydeco, Vertex), for example, is a CFTR potentiator indicated for the treatment of CF in patients who are age 6 years or older. Ivacaftor helps the CFTR protein function more normally as a chloride channel once it reaches the cell surface.11 This drug targets

rare mutation types; thus, few people with CF qualify for treatment with ivacaftor.11 However, ongoing research holds promise for all CF patients because there are more oral therapies on the horizon designed to target the underlying defects of mutated proteins.

Clinical Care Guidelines Because CF is a complex disease that affects many organ systems, proper care requires specialized knowledge. The best place to receive that care is at one of the more than 110 accredited CF centers nationwide. These centers of excellence meet national standards of care and are reviewed annually for accreditation. These care centers typically include a multidisciplinary group of specialists, including doctors, nurses,

17

Specialty Pharmacy Continuum • Summer 2014

CLINICAL

Table 2. Common Organ System Involvement and Related CF Drug Therapy Organ

Possible Consequences

Some Drugs Used for CF Maintenance

Lungs

• • • • • • •

Chronic pulmonary infections Sinusitis Airway obstruction Bronchiectasis Hemoptysis Pneumothorax Respiratory failure

• Inhaled bronchodilators (eg, albuterol, levalbuterol) • Inhaled antibiotics (eg, tobramycin [Tobi, Novartis], aztreonam for inhalation solution [Cayston, Gilead], colistimethate) • Inhaled mucolytics to thin mucus secretions (eg, dornase alfa inhalation solution [Pulmozyme, Genentech], hypertonic saline, acetylcysteine) • Oral antifungals • Oral antibiotics • Infused antibiotics • Oral anti-inflammatory agents (eg, daily azithromycin, ibuprofen, prednisone)

Pancreas

• • • •

Maldigestion Malnutrition Chronic pancreatitis Diabetes mellitus

• • • •

Pancreatic enzymes Proton pump inhibitors, other acid reducers Nutritional supplements, vitamins, minerals Insulin

Intestines

• Meconium ileus • Distal intestinal obstruction syndrome • Chronic obstructive portal hypertension • Esophageal varices • Malabsorption • Gastroesophageal reflux • Rectal prolapse

• Polyethylene glycol

Sweat glands

Hyponatremia Salty skin

None

Reproductive

Males: obstruction of epididymis, vas deferens, seminal vesicles; aspermia Females: viscous cervical mucus

None

Bones and joints

Arthritis, osteoporosis

Calcium supplementation

Hepatobiliary

Steatosis Cholelithiasis

Ursodiol

respiratory and physical therapists, dietitians, and social workers. This specialized team works with each patient to create an individualized plan to meet that person’s specific needs and to keep him or her as healthy as possible.6 The accredited centers strive to

Table 3. Annual Care, Screening, and Prevention Guidelines for CF12

meet nationally recognized clinical care guidelines (Table 3) that have been identified to provide optimal treatment for these challenging patients.

A multidisciplinary approach has contributed to improving the life expectancy of patients who have CF. Other key factors that have contributed to increasing survival are a better understanding of the disease with associated treatment goals, improved drug therapies, and improved nutritional support, as well as screening of newborns.

CF patients are closely monitored for

maintaining or improved lung function.

However, it should be noted that as the lung is subjected to infection, the cycle of infection, inflammation, and repair causes scarring and decreased lung function over time. This is why aggressive treatment with antibiotics—even extended use of IV antibiotics—is critical to maintaining lung function. As the pulmonologist is the primary provider of the CF care team, often when patients have involvement of other organ systems such as the sinuses, liver, or gallbladder, they will be referred to the appropriate specialists.

Lung Transplantation The final therapeutic option for CF patients with end-stage lung disease is lung transplantation.1 When transplanted, the new lungs do not have the cystic fibrosis defect and will function normally. However, the patient is subject to a new problem—immunosuppression. Patients must demonstrate a certain level of compliance with current CF therapies before they are allowed onto the transplant waiting list.1

The Patient’s Perspective

proper lung function, and this is accomplished mainly by the administration of pulmonary function tests (PFTs), as well as monitoring for any fluctuations in a patient’s weight. Indeed, at every quarterly office visit, both PFTs and weight should be measured and recorded. CF teams know to watch both measures, because a decline in weight often signals a decline in lung function. Conversely, improved weight and nutritional status, which is accomplished by increased caloric intake and consistent use of pancreatic enzymes, is correlated with

Even with the help of an experienced CF care team, most day-to-day care still falls to the patient or the patient’s parent. The care schedule is demanding, and patients must be continually motivated to follow the treatment schedule. Besides the extra attention to antiinfective therapy required, as well as the pancreatic enzymes, vitamins, and other pills that must be taken, patients must complete mechanical airway clearance (frequently by use of vest therapy) with coughing to clear their lungs of excessive mucus. Indeed, removal of airway secretions is a critical component of the management of CF. (For a case study that illustrates some of these management challenges, see sidebar.)

CF can be psychosocially a lonely disease. Because of the significant concerns for cross-contamination and new infections, the national Cystic Fibrosis Foundation highly recommends that

•

see CYSTIC FIBROSIS, page 20

• ≥4 clinic visits • ≥4 respiratory cultures • ≥2 pulmonary function tests if age 6 years or older and physically able to perform • Influenza vaccine if age 6 months or older • Fat-soluble vitamin level measurements • Oral glucose tolerance test if age 10 years or older • Test for measurement of liver enzymes in blood CF, cystic fibrosis

Table 4. Functions of Pharmacy as CF Outpatient Team Member Drug Education

Specialty Services

Drug Management Services

• • • • • •

• Financial assistance • Billing expertise (multiple payor types) • Convenient shipping • Stock and dispense all medications and vitamins needed by patient • Supply nebulizer and parts • Become educated about nebulizers and nebulizer care

• • • •

Patient and parent Adolescent patients Provider education Drug–drug interaction prevention Drug–pregnancy risk guidance Be a resource for all drugs used in CF therapy (specialty and non-specialty)

CF, cystic fibrosis

Decrease pill burden Create patient education tools Provide a drug chart Develop a medication plan with the patient • Group drug therapy administration times

18

Specialty Pharmacy Continuum • Spring 2014

CLINICAL

Long-term HIV survivors transforming care

A Good Problem To Have Specialty pharmacies that manage a significant number of patients with HIV have a “really good problem” these days: Their patients are living longer, said Anthony Luna, the executive vice president for business development at Aureus Health Services, based in Pittsburgh.

A decade or so ago, specialty pharmacy management of patients with HIV focused almost exclusively on the primary challenge of suppressing the virus itself. This is no longer the case, according to Mr. Luna, formerly the chief sales officer for AIDS Healthcare Foundation and AHF Pharmacy. Individuals with HIV taking antiretroviral therapy (ART) saw a life expectancy increase of 15 years between 2002 and 2007, according to

<13

data presented at the 7th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, in Kuala Lumpur, Malaysia.

In other words, people with HIV// AIDS are living long enough to get old.

According to the Centers for Disease Control and Prevention, individuals aged 55 and older represented almost one-fifth (19%; 217,000) of the estimated 1.1 million people living with HIV V

192

53

13-14

HIV cells.

15-19

2,240

20-24

8,054

25-29

7,484

30-34

Age, y

‘It’s incumbent on specialty pharmacies that care for people living with HIV to develop enhanced clinical programs to address their changing needs, particularly in three key areas: HIV and aging; HIV and depression; and HIV and HCV coinfection.’

—Anthony Luna

6,209

35-39

5,285

40-44

5,753

45-49

5,564

50-54

3,951

55-59

2,312

60-64

1,229

≥65 65

948

0

1

2

3

4

5

6

7

8

9

Figure. Estimated diagnosis of HIV infection, 2011.a a

Thousands

infection in the United States in 2010; of the estimated 47,500 new HIV diagnoses in 2010, 2,500 (5%) were in the 50 and older age group.

As the population of individuals with HIV ages, there will be a need to manage a whole host of comorbidities that are not necessarily part of the specialty pharmacy wheelhouse, such as cardiovascular disease, depression, osteoporosis and chronic kidney disease.

“It’s incumbent on specialty pharmacies that care for people living with HIV to develop enhanced clinical programs to address their changing needs, particularly in three key areas: HIV and aging; HIV and depression; and HIV and HCV coinfection,” Mr. Luna told attendees at the 2014 Armada Specialty Pharmacy Conference, in Las Vegas.

The long-term use of highly active ART may worsen a number of the comorbid diseases that are commonly seen in the aging population, or even increase their risk for developing some of those conditions, said Jennifer Yu, PharmD, BCACP, a lecturer at the Chi-

nese University of Hong Kong School of Pharmacy and formerly an HIV clinical pharmacist with Kaiser Permanente, in Santa Clara, Calif.

“Cardiovascular disease is one chronic [condition] that is common in HIVinfected patients,” she said. “The reason could be due to HIV itself as well as the high smoker population—40% to 70% of HIV patients smoke. Long-term side effects of HIV medications may also contribute to the risk.”

For example: • Most protease inhibitors (PIs) have been shown to cause hyperlipidemia, and older PIs can cause hyperglycemia and lipodystrophy.

• Abacavir (Ziagen, ViiV Healthcare) has been associated with increased myocardial infarction in one study.

• Efavirenz (Sustiva, Bristol-Myers Squibb) has been shown to have a negative effect on lipid profile.

Given these additional risk factors, smoking cessation counseling and risk assessment for cardiovascular disease, using Framingham scoring, should be

19

Specialty Pharmacy Continuum • Spring 2014

CLINICAL

done in individuals with HIV at a younger age than in the general population.

“If the patient develops hypertension, diabetes and/or dyslipidemia, appropriate treatment needs to be initiated with careful consideration of potential drug interactions,” Dr. Yu cautioned. “For example, certain statins—e.g., lovastatin and simvastatin—should be avoided when using all protease inhibitors.”

Renal Function a Tricky Variable Another age-related comorbid disease that frequently presents with HIV is kidney disease. Managing renal function in patients with HIV often can be a delicate dance. “Regular renal function management is important, and dose adjustment on certain HIV medications may be needed,” Dr. Yu said. “However, there are also concerns that dose adjustment may bring HIV medications into subtherapeutic levels if renal function is fluctuating. It is difficult to strike a balance between virologic response and renal function preservation.”

Of course, some HIV medications may themselves be toxic to the kidneys.

For example, tenofovir (Viread, Gilead) has been shown to cause acute renal failure and Fanconi syndrome, characterized by proteinuria and hypophosphatemia, especially in patients with underlying renal impairment. In a sort of comorbid cascade, untreated hypophosphatemia can lead to osteoporosis, which can be further worsened if patients develop bone metabolism disorder secondary to chronic kidney disease. Certain PIs, like indinavir (Crixivan, Merck) and atazanavir (Reyataz, Bristol-Myers Squibb), are also associated with crystal-induced obstruction.

“These side effects underscore the importance of the role of the specialty pharmacy in providing comprehensive consultation to patients on how to properly use these PIs,” Dr. Yu said.

Watch for Psychiatric Red Flags Specialty pharmacies should always be on the lookout for depression and other psychiatric disorders in their patients with HIV/AIDS. One HIV medication, efavirenz, has itself been linked to psychiatric problems, including depressive disorders.

“The prevalence of depression is 20% to 40% in people with HIV, and suicide mortality risk is three to five times higher than noninfected persons, despite ART availability,” Mr. Luna said. “We know that treatment for depression improves adherence to ART. The key is identifying these patients through regular patient engagement and tools like a simplified depression scale questionnaire.”

Perhaps one of the most significant challenges of contemporary HIV specialty pharmacy is the frequent incidence

of hepatitis C virus (HCV) coinfection.

About 40% of people with HIV also have HCV, and HIV infection has been associated with faster progression to liver fibrosis. “Due to the complex drug interactions between HIV and HCV medications, particularly the new HCV protease inhibitors, there is a significant opportunity for pharmacists to contribute to coinfection management,” Dr. Yu said.

“Many of these patients have moved away from very complex medication regimens with a significant pill burden, sometimes down to one pill a day,”

Mr. Luna said. “As these comorbidities arise, the specialty pharmacist has to be keenly aware of the increasing pill burden, and help the patient to manage it in order to ensure adherence.”

Specialty pharmacy’s personal, handson connection to the whole patient is particularly important given the evolving needs of people with HIV, he stressed. “We’re not just putting pills in a vial and sending them out. We have a very vested interest in getting to know our patients’ needs and trying to get them solutions, whether that’s linking

them to community support and social service agencies, informing them about local housing and food assistance programs, treating depression, or encouraging them to keep active and stressing the importance of nutrition. Our role goes beyond just medications, and addresses these patients’ needs from a complete psychosocial and wellness perspective.”

—Gina Shaw The sources reported no relevant financial conflicts of interest.

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20

Specialty Pharmacy Continuum • Summer 2014

CLINICAL

CYSTIC FIBROSIS continued from page 17

CF patients remain 6 feet away from one another. Thus, CF patients may use social media to connect and provide support for themselves.

The Specialty Pharmacist’s Role With the focus of the CF care team on the body systems and complications of the disease, but with the complexity of the medication regimen, there is a need for specialty pharmacies to be an active resource for patients, parents, and providers (Table 4, page 17). Specialty pharmacies are in a key position to employ billing experts who will help patients overcome financial barriers and also bill each drug through the appropriate channel (eg, Medicare Parts B and D, Medicaid, commercial payors). Specialty pharmacists can provide drug education, and work with patients to decrease pill burden and group drug administration times. In addition, pharmacists can be a resource for providers about drug–drug interaction or drug risks in pregnant patients.

A CF drug regimen with associated mechanical clearance may be overwhelming for many patients and parents who have children with CF. While respiratory therapists can help patients and parents understand how to use a nebulizer, how to keep the equipment clean and sterilized, and how to use a mechanical clearance device (eg, the Vest Airway Clearance System, HillRom), there are many other aspects of medication therapy that patients and parents need to be educated about. It is important that pharmacists are available to field questions from parents and older patients, and insert themselves into the care team. Besides the obvious advantage to the parent and older patient, it also shifts phone calls and associated workload from the CF center offices to the pharmacy, which helps to improve the clinic–pharmacy relationship. Furthermore, it may prevent unintended drug–drug interactions when new antibiotics are added for a CF exacerbation.

There are many other aspects of a CF specialty pharmacy program, but one that may be overlooked is the need to be a full-service pharmacy for a CF patient’s medications. Remembering that CF patients require both specialty (eg, Pulmozyme) and non-specialty medications (CF vitamins, proton pump inhibitors, various nebulizations, etc), the specialty pharmacy can be a one-stop shop for a patient’s drug therapy and can create programs to help a patient stay on track with their CF drug regimen.

Conclusion CF is a lifelong, complicated, specialty disease that requires the combined

Case Study: A Typical Day With CF F

A

case study may illustrate a typical day for an adolescent with CF..

Although parents are often the primary caregivers for CF patients, as a child reaches adolescence, education should be directed to him or her. Adolescence itself poses challenges for everyone involved, but for those who have a chronic disease such as CF, there are additional compliance challenges related to school and sports schedules and youthful decision making. It is during this time that the child should start self-management of his or her CF regimen, despite the fact that the patient does not want to have the disease and does not want to be different from his or her peers.

In this case study, JB is a 16-year-old boy with pancreatic insufficiency, but no CFRD. He has a history of Pseudomonas infections by sputum cultures. He presents at the clinic with worsening lung function and a weight loss of 2 lb. His maintenance therapies include: • Mechanical clearance (vest therapy) twice daily • Albuterol via nebulizer twice daily • Dornase alfa inhalation solution (Pulmozyme, Genentech) via nebulizer 2.5 mg once daily • Tobramycin inhalation solution (Tobi, Novartis) via nebulizer 300 mg twice daily, every other month • Azithromycin 250 mg orally 3 times weekly • Pantoprazole 40 mg orally daily • Pancrelipase (Creon, AbbVie) 6 capsules per meal, 3 capsules per snack • ADEKS (Axcan Pharma; a multivitamin formulation) 2 tablets orally daily • Vitamin E 400 units daily • Vitamin K 5 mg orally daily • Zinc 50 mg daily • Beta-carotene 50,000 units orally daily • Calcium/vitamin D 1 tablet orally twice daily • Ascorbic acid 500 mg orally daily The patient’s care provider notes signs of a pulmonary exacerbation and puts him on oral levofloxacin. Because JB uses your specialty pharmacy, you have a list of his therapies, and you are aware of when he takes his zinc and calcium supplements, which he stated is before bedtime. Therefore, when you counsel JB about the new antibiotic, you ask when he was planning to take it.

He responds that it is easiest for him if he takes it at night. You counsel him to move his calcium and zinc intake to the morning meal, and send him a postcard to remind him of this recommendation. This is a perfect example of how a drug interaction can be avoided in this complicated CF patient.

efforts of a multidisciplinary team of health care professionals for optimal management. With aggressive treatment, the outlook for people diagnosed with CF has improved substantially in the past 10 to 20 years.

Remarkable progress has been made in the understanding of CF, which has led to therapeutic advancements in the treatment of this disease, with more on the horizon. Because CF is a progressive disease, the care burden increases over time. Specialty pharmacy can play a key role in the care of patients who have CF by providing basic drug education to providers, patients, and parents; providing help to patients and parents with drug management; and directing specialty pharmacy services toward a CF-specific program.

This article is adapted with permission from “A Review of Cystic Fibrosis” that Dr. Wohletz authored for the 2Q 2012 issue of Specialty Pharmacy Insights, a quarterly publication of Fairview Specialty Pharmacy.

Dr. Wohletz reported no revelant financial conflicts of interest.

References 1. O’Sullivan BP, Freedman SD. Cystic fibrosis.

Lancet. 2009;373(9678):1891-1904.

2. Sloane PA, Rowe SM. Cystic fibrosis transmembrane conductance regulator protein repair as a therapeutic strategy in cystic fibrosis. Curr Opin Pulm Med. 2010:16(6):591-597.

3. Gibson R, Burns J, Ramsey B. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med. 2003;168(8):918-951.

4. Cohen-Cymberknoh M, Shoseyov D, Kerem E. Managing cystic fibrosis, strategies that increase life expectancy and improve quality of life. Am J Respir Crit Care Med. 2011;183(11):1463-1471.

5. Cystic Fibrosis Foundation. What is cystic fibrosis? http://www.cff.org/AboutCF. Accessed July 27, 2014.

6. Cystic Fibrosis Foundation. Where can people with CF get the best care? http://bit. ly/1uDlJzI. Accessed July 27, 2014.

7.

Fieker A, Philpott J, Armand M. Enzyme replacement therapy for pancreatic insufficiency: present and future. Clin Exp Gastroenterol. 2011;4:55-73.

8. Costa M, Potvin S, Berthiaume Y, et al. Diabetes: a major co-morbidity of cystic fibrosis.

Diabetes Metab. 2005;31(3 Pt 1):221-232.

9. Children’s Hospital of Colorado. New hope for cystic fibrosis. http://bit.ly/X9tSNh. Accessed July 27, 2014.

10. Flume P. Pulmonary complications of cystic fibrosis. Respir Care. 2009;54(5):618-627.

11. Ramsey BW, Davies J, McElvaney G, et al for the VX08-770-102 Study Group. A CFTR potentiator in patients with cystic fibrosis and the G551D mutation. N Engl J Med. 2011;365(18):1663-1672.

12. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation patient registry: annual data report 2010. http://bit.ly/1s13Xls. Accessed July 27, 2014.

NEW PRODUCT Cold Chain Technologies Introduces KoolTemp® GTS-Rx Shipping Solutions

C

old Chain Tec T TechechhTechnologies (CCT) introduces KoolTemp® GTS Rx, a complete line of cost-effective shipping solutions designed to meet the transport needs d of specialty pharmacies, wholesalers and mail-order pharmacies, the company announced in a press release.

GTS Rx solutions provide 2°C to 8°C overnight (up to 24 hours) and .1°C to 25°C two-day (up to 48 hours) protection in payload sizes that range from 1 to 23 liters. Available in traditional EPS (expanded polystyrene) and KoolTemp® GreenSmart-approved configurations, GTS Rx is easy to pack, uses a single refrigerant SKU across all sizes, is qualified for summer and winter use, and is available in set-up and knocked versions, according to the company.

“The last mile is that crucial step that delivers life-saving medications to the patient or provider,” stated Jamie Chasteen, sales and product development manager of Cold Chain Technologies.

“This portion of distribution is subject to several competing pressures, including cost and regulatory compliance. The GTS Rx line of pre-qualified shippers brings years of expertise, allowing last-mile distribution that is both compliant and costcompetitive. Utilizing molded containers and modular single SKU refrigerants available from multiple manufacturing locations throughout the U.S. and Europe, the GTS Rx line satisfies CFOs and quality directors alike.”

The company added that all KoolTemp GTS Rx shipping solutions have been pre-qualified in Cold Chain Laboratories’ world-class ISTA-certified and cGMPcompliant labs.

For more information, visit www.coldchaintech.com

21

Specialty Pharmacy Continuum • Summer 2014

CLINICAL

How To Optimize Effectiveness of IVIG Las Vegas—Know the full range of products and ancillary supplies, understand the patient’s clinical profile, and establish clear lines of communication with physicians and nurses to help optimize the effectiveness of IV immunoglobulin (IVIG) therapy, an infusion therapy specialist said at the 2014 Armada Specialty Pharmacy Summit.

Trudy Thedford, RPh, the director of infusion therapy for specialty pharmacy BriovaRx, in Rochester, Mich., said specialty pharmacists can play an important role in ensuring the quality and safety of this treatment by reviewing the patient’s clinical profile and, if needed, helping the physician choose the product most compatible with the patient’s underlying condition and comorbidities. Product selection can include such special considerations as a low-sucrose or glucose product for a patient with diabetes or renal insufficiency, she noted.

Physicians frequently write prescriptions that state simply: “IVIG therapy,” she pointed out. “IVIG therapy is not a generic. Pharmacists should communicate with the physician to make sure he or she understands that IVIG products are not interchangeable.”

In the past, shortages of IVIG products, which were sometimes severe, contributed to this tendency by some physicians to write prescriptions generically as “IVIG” because hospitals were forced to use whatever IVIG products were available, explained Eric M. Tichy, PharmD, BCPS, the senior clinical pharmacy specialist at Yale-New Haven Hospital in New Haven, Conn. However, he noted that the improved safety profiles of current IVIG products has increased their interchangeability and made product selection less of a concern in institutions where these newer products are available.

The Devil Is in the Details The complexity of IVIG therapy requires specialty pharmacists to create comprehensive and detailed orders to guide the infusion nurse throughout

‘You don’t want to teach a patient how to self-infuse and then have them experience an adverse reaction when they’re home alone.’

—Trudy Thedford, RPh

Choosing the Best Site of Care

I

V immune globulin (IVIG) therapy can be administered in the hospital, an infusion clinic or at home. However, patients should receive their first infusion in the hospital or in a clinic, where a higher level of support by caregivers and a crash cart are readily available in the event of an emergency.

That’s the management approach recommended by Trudy Thedford, RPh, the director of infusion therapy for specialty pharmacy BriovaRx, in Rochester, Mich. If the patient agrees, Ms. Thedford noted, the infusion nurse can administer subsequent therapy in the patient’s home.

For some patients, IVIG can be self-administered subcutaneously, with instruction provided by the infusion nurse. IVIG typically is administered every three to four weeks, whereas subcutaneous infusions generally are done weekly or biweekly. This alternative offers an attractive option for patients with poor venous access, those who wish to travel and patients who prefer not to have regular home visits by a nurse, Ms. Thedford explained. The subcutaneous method is used primarily for individuals being treated for primary immune deficiency. The subcutaneous product Hizentra (CSL Behring), for example, is approved only for primary immune deficiency, she noted.

IVIG therapy dosages for these patients are generally in the relatively low 200 to 600 mL/kg range. Patients who require higher doses usually are not candidates for subcutaneous infusion because “only so much volume can be self-infused per site,” Ms. Thedford said.

The subcutaneous method’s chief drawback is that self-infusion means less support from the infusion nurse and greater patient responsibility to order the necessary supplies and maintain the infusion schedule, although pharmacists can provide valuable support by reminding the patient when supplies may be needed. However, “the patient definitely has to be evaluated by the physician to make sure it’s an option,” she stressed.

Ms. Thedford advised pharmacists to “know the supplies and how they’re being used by the patient; don’t just rely on your intake coordinator or nurse coordinator to pick the right things.” It is the pharmacist’s responsibility, she added, to double check supplies for accuracy and appropriateness.

—S.B.

the administration process, Ms. Thedford said. These orders should detail all of the nursing services required for medication preparation; the need to flush the port, change the dressing and administer premedications or hydration; and the specific ancillary supplies to be used, including tubing size.

“Anything you expect the nurse to do should be on those orders,” she said.

The physician should sign the orders so that the pharmacist, nurse and physician all agree on and understand the approach being taken.

The key to an effective IVIG therapy management plan is determining the optimal rate of infusion, which can vary greatly from patient to patient, Ms. Thedford said. She encouraged pharmacists to communicate regularly with the infusion nurse to document patient reactions to the infusion; the need for premedications to help prevent adverse events, such as headache, fever and chills; and how well these premedications are tolerated.

“All of this needs to be discussed with the nurse to make sure therapy is going well, and no changes are needed,” she said. With thorough documentation, “as the nurse gets to know the patient, he or she will know what to expect, and if there is a substitute, that nurse will also know what to expect and exactly how to do the infusion.”

Infusion Monitoring When starting IVIG therapy, the pharmacist and infusion nurse should use the instructions in the product’s package insert as a baseline, and then adjust the rate based on the patient’s responses. If the patient experiences dizziness, flushing or other side effects, the infusion rate might need to be slowed. “The nurse and patient need to work together to find a happy medium,” Ms. Thedford said.

Managing the switch from IVIG to subcutaneous immunoglobulin (SCIG) is another key to success. One potential troublespot is when patients are started on subcutaneous self-infusion. According to Ms. Thetford, it is considered best practice for the patient to receive IVIG therapy for at least three months before switching to self-infusion SCIG. Initial monitoring is important and patients receive that with IVIG. With SCIG, in contrast, “they are on their own,” she said. “You don’t want to teach a patient how to self-infuse and then

More IVIG Tips

F

or more tips about optimizing IVIG therapy, check out our IVIG FAQ column by Jerry Siegel, PharmD. To access recent columns, scan the 2D barcodes below or insert the URLs in your browser.

Intravenous IVIG FAQ: Managing Adverse Reactions http://bit.ly/ X492Ph

Filtering of Intravenous Immunoglobulins http://bit. ly/1l7frP7

IVIG and Aseptic Meningitis http://bit. ly/1qafOv6

IVIG for Alzheimers: A Glimmer of Hope? http://bit. ly/1uzqk5G

have them experience an adverse reaction when they’re home alone.”

The infusion nurse should monitor the patient’s vital signs, look for adverse reactions and ensure that patients with renal insufficiency are not volume-depleted.

Patients who are dehydrated should receive hydration before the infusion.

Certain IVIG therapies, including the carbohydrate-stabilized products, can cause renal insufficiency, Ms. Thedford noted. Also, patients aged 65 years and older are more likely to have some renal insufficiency. “It’s something you want to keep on your radar,” she said.

—Susan Birk Ms. Thedford reported no conflicts of interest. Dr. Tichy has been a consultant for Baxter and Grifols.

22

Specialty Pharmacy Continuum • Summer 2014

TECHNOLOGY

NEW TOOLS continued from page 1

Americans now spend nearly 50% of their total Internet time with mobile apps compared with roughly 45% spent accessing the Internet from a desktop and the remaining 8.3% using mobile browsers (http://bit.ly/1mWjVxG).

Of course, most of that app time apparently involves posting Grumpy Cat memes to Facebook and playing Fruit Ninja. Still, for a tech-savvy specialty pharmacy company, the opportunity to connect with patients and providers using mobile apps and Web-based tools is significant, according to Rebecca Shanahan, Esq., the CEO of Avella Specialty Pharmacy.

“We know that 80% of physicians are using smartphones and medical apps,” Ms. Shanahan said during a session on digital tech at the World Congress on Specialty Market Access. “And 93% of doctors believe that mobile health apps can improve their patients’ health.”

The challenge is developing specialty pharmacy apps that providers and patients will actually find worthwhile and want to use. Several specialty pharmacies and drug manufacturers have taken the first steps in that endeavor by developing their own apps, including: • Accredo Plus C, a free app developed by pharmacists and nurses for all patients with hepatitis C (regardless of the pharmacy they use or the insurance they have). The app creates a customized treatment schedule and offers reminders, reports, tracking and direct emailing of results to health care providers.

• Psoriasis 360 (Janssen) includes a severity calculator and an impact questionnaire.

• Biogen’s Micro8 is a hemophilia management tool designed by a patient.

It tracks infusions and bleeds, sets up personal treatment reminders and scans barcodes to log factor easily.

• Walgreens offers a comprehensive app that allows customers to refill prescriptions by scanning barcodes, transfer prescriptions by photographing the label, receive medication reminders and chat live with a pharmacist.

Avella launched an app in January, available on the iPhone, Android and Web; so far, it has about 4,000 active accounts. “We wanted a customer-centric model, not business-centric—something the customer can use easily,” Ms. Shanahan said. “Rather than something that is designed to give us information or drive our efficiency, we think the way to be successful is to put an app in patients’ hands that they’re actually using.”

The app’s functions include a prescription tracker and refill option, label scanning, physician appointment tool and the ability to manage “family accounts”—if, for example, you want to keep an eye on

Grandma’s prescriptions. “A dashboard allows us to measure usage in real time and implement changes, responding rapidly to individual requests as well as leveraging those into other features and functionality,” Ms. Shanahan said.

So far, she added, there are about 1,000 refills per month among the 4,000 Avella app users. It’s too soon to assess its effect on adherence, but other related data lead her to be optimistic. “Prior to launching the mobile app, we had a bidirectional text-messaging program in our specialty population, focused on our less adherent patients,” she said. “It included daily reminders to take medication, reminders for lab work, and educational tips about blood pressure monitoring, motivational messaging, surveys, etc. Any indication of nonadherence triggered real-time pharmacist intervention on the phone.”

The text-messaging program improved adherence by 29% in the nonadherent cohort, Ms. Shanahan noted. (Patients who already were adherent remained at the same high adherence levels, whereas new patients had an adherence rate of 94.5%.) But others are skeptical of just how much mobile apps and similar technology can really affect adherence.

Apps Not a Cure-All “Adherence requires real engagement,” said Thomas Morrow, MD, the chief medical officer for the virtual health assistant company NextIT, who spent eight years as the medical director for Genentech and writes Managed Care’s “Tomorrow’s Medicine” column. “That means a conversation. If so many of us are using apps, why haven’t we seen a huge jump in [medication] adherence? From everything I read, [usage is] still at around 50%. I spent an entire year looking at adherence ... at Genentech, and no matter

what the disease state, it’s virtually ubiquitous—people aren’t taking their drugs.”

During his own presentation on digital trends at the World Congress, Dr. Morrow played a short video imagining life with NextIT’s “virtual health assistant”—call her Sarah. A middle-aged man with diabetes calls out to Sarah (installed on his phone) to set his playlist for his morning run and asks her to remind him about weighing himself and taking his blood glucose readings at certain times.

Sarah pipes up to alert him that it’s been a year since his last eye and foot check, and asks if he’d like her to contact the doctor’s office to set up an appointment.

He would, and she does.

“This is actually possible right now,” he said. “Using natural language software, we can deploy virtual health assistants [VHAs] to help make decisions, enhance information exchange and enable patient self-management.” VHAs, he added, represent “automated hovering” that can’t be done with live clinicians. “We’re expecting 40,000 too few primary care doctors in the next 10 years, 6,000 too few oncologists and so on. VHAs can help to compensate for that [shortfall].”

If you’ve ever read the Tumblr feed “S***thatSiriSays,” or just had an incredibly frustrating encounter with the disembodied voice on your iPhone (or Android, for that matter, thanks to the Google Now feature), you may find this hard to believe. But a growing body of research indicates that Dr. Morrow may be right.

In 2008, researchers from Boston University School of Medicine and Northeastern University completed a pilot study using a “virtual discharge advocate” named Louise, which they explain is a “hospital bedside patient education system that engages with patients about their post-discharge self-care plans.”

The Pill Bottle That Nudges You “Hey, you. Over there. By the bed. It’s time to take your medication.”

That’s not your medication management app or a virtual health assistant. It’s another hightech adherence tool, the GlowCap (Vitality, Inc.). Inside the wireless prescription bottle, a chip monitors when the bottle is opened and sends alerts via mobile broadband. Outside the bottle, a nightlight-style plug-in as well as the bottle cap issue regular reminders.

The wireless prescription bottle first flashes orange at the time you’re supposed to take your medication; after an hour of flashing, it starts playing a ringtone as well as flashing. After the second hour, if you still haven’t opened the bottle, you get an automated phone call, email or text message reminding you that you’ve missed a dose. The system also compiles adherence data for pharmacists and other clinicians to track.

It may sound like a cross between a Furby, an alarm clock and your motherin-law, but so far the technology seems to be effective. Avella is partnering with Novartis to offer GlowCap for all the company’s oral oncology medications. A pilot study found a 50% increase in medication adherence at month 4 of therapy for patients taking nilotinib (Tasigna, Novartis) in conjunction with the GlowCap compared with the control group, reported Rebecca Shanahan, Esq., the CEO of Avella Specialty Pharmacy. “We’ve seen that it can improve adherence,” she said. “What we’re waiting to find out is if there will also be [a resultant] cost savings and positive health outcomes.”

—G.S.

Patients using a tablet computer with a continuously updated display of medication-taking activities improved their adherence rate by as much as 26 percentage points.

Photo courtesey of Carnegie Mellon University.

In the study, 74% of patients preferred receiving their discharge instructions from the virtual nurse rather than a real one. Some of their comments: “She kept asking if I was tired, if I wanted to take a break. She cared about me.” “I’ve had problems with other hospitals. I wasn’t given the quality time this lady gave me.”

“VHAs are trained to know the clinical boundaries, handle adverse events, operate within medical-legal boundaries, and get smarter over time,” Dr. Morrow said.

A Trickle of Data Until we all have our very own personal health coaches embedded in our smartphones, there does seem to be some evidence that apps can help with medication adherence.

So far, most commonly used medication adherence apps (both those put out by pharmacies like Avella, Accredo and Walgreens, as well as general apps like MyMedSchedule and MyMeds) have not been tested in a rigorous trial setting. But in April, researchers at Carnegie Mellon University reported on a 10-month study of drug monitoring systems, and found that adherence improved with ready access to a digital display of their medication-taking record (http://bit. ly/1oLVjHk). k In the study of 12 older adults in a Pittsburgh apartment for seniors, patients who got feedback from a tablet computer with a continuously updated display of medication-taking activities (see photo above) improved their adherence rate from 95% to 98%, improved the promptness of pill taking from 75% to 91% and increased the accuracy of what they took from 95% to 99%.

In general, Ms. Shanahan said, apps and other high-tech adherence tools should be designed to solve multiple challenges for patients without overwhelming them.

“Keep it simple at first; you can add functionality as patients identify what they need,” she stressed. “If I had one of the diseases treated by these drugs, I would want to work with the guy who shows up at 4 a.m. when I need him. If your specialty pharmacy can leverage these [digital] tools to do that, you win.”

—Gina Shaw The sources had no relevant financial conflicts of interest to disclose.

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AUGUST 2014 Distributed by

REPORT Primary Immunodeficiency Considerations for Selection of Appropriate Replacement Ig Therapies Introduction Primary immunodeficiencies (PIs) comprise more than 200 rare genetic disorders marked by absent or abnormal function in one or more areas of the immune system.1,2 Reported to affect 1 in 4,000 to 1 in 10,000 individuals in the United States,1 PIs are characterized by infections that can be recurring, persistent, debilitating, and chronic (Figure 1).

Approximately 60% to 70% of all PIs are related to defective B lymphocyte antibody production (Table 1).2

Diagnosis Although some PIs may not be recognized until early adulthood, many serious types are diagnosed during the first year of life when protective maternal immunoglobulin (Ig) levels decline.1 The diagnosis of B-cell PI includes a history of recurrent infection and low IgG concentrations (<2 standard deviations below the mean).1,2 Selected clinical signs of PI are provided in Table 2.1-3 Impaired antibody responses to vaccines, protein antigens, or polysaccharide antigens also are observed and are an element of the diagnostic evaluation.

Figure 1. Recurrent infection may suggest presence of primary immunodeficiency.

Program developed by Medical Insights Group and provided as an educational resource by CSL Behring LLC

REPORT Treatment With Immunoglobulin History Ig therapy is used to prevent recurrent infections in individuals with PI via antibody replacement.1,4 The use of Ig products derived from human plasma dates to the early 1950s. Early products were administered intramuscularly. However, due to an inability to deliver sufficient doses and the occurrence of significant local and systemic adverse effects (AEs), these products now are obsolete.1,4 In the 1960s, highly purified intravenous (IV) products became available for Ig replacement therapy. Since then, more stringent donor selection and testing, enhanced fractionation techniques, and progressively sophisticated viral inactivation safeguards have assured production of highly purified Ig preparations from pooled human plasma.

generally requires IV dosing of at least 300 to 600 mg/kg per month. However, clinical signs and symptoms should guide Ig replacement therapy,1 as some patients do better clinically with higher trough levels.4,6,7

Table 2. Signs of PI ≥4 new ear infections within 1 y ≥2 serious sinus infections within 1 y ≥2 mo on antibiotics with minimal effect ≥2 pneumonias within 1 y Failure to gain weight or abnormal growth in infancy

Products Comprised almost exclusively of IgG antibodies, Ig products also include subclasses of Ig similar to those found in human plasma, such as small amounts of IgA and trace amounts of IgM. Currently, 11 brands of Ig products are available in the United States (Table 3) 5,6 ; 4 of these are indicated for subcutaneous (SC) infusion, including 1 approved exclusively for SC administration.

Recurrent deep skin or organ abscesses Persistent thrush or fungal skin infection IV antibiotics required to clear infections ≥2 deep-seated infections Family history of PI disease

Dosing Ig therapy replaces antibodies and must be administered at regular intervals (usually monthly when given intravenously). The dose varies by individual patient but should aim to achieve IgG trough levels of at least 500 mg/dL. This

IV, intravenous; PI, primary immunodeficiency Based on references 1-3.

Table 1. Common B Lymphocyte Immunodeficiencies Immunodeficiency

Features

Agammaglobulinemia

• <1% of normal B-cell count • BTK gene mutation on X chromosome

CVID

• • • • • •

Hyper-IgM syndrome

• Rare, defective Ig CSR • Low levels of IgG and IgA, elevated IgM • X-linked CD40L deficiency

Selective Ig isotype deficiencies

• Recurrent sinopulmonary infections • May progress to CVID

Most common symptomatic PI disease Occurs mostly in adults Low levels of ≥1 Ig isotype Heterogeneous presentation Family history in 10% of cases Complications include autoimmune disorders, GI disease, malignancies

BTK, Bruton’s tyrosine kinase; CSR, class-switch recombination; CVID, common variable immunodeficiency; GI, gastrointestinal; Ig, immunoglobulin; PI, primary immunodeficiency Based on reference 2.

2

REPORT Available formulations contain comparable amounts of IgG; can require premedication.4 Therefore, IVIg should be adminishowever, pharmaceutical differences may affect the choice of tered slowly and titrated upward as tolerated. Serious AEs may product for a specific patient. include renal failure, anaphylaxis, and thromboembolic disorFor example: ders.4 Risk factors for serious AEs include • Some products may contain different advanced age, preexisting diabetes, carconcentrations of IgA, which is inapprodiovascular risk factors, and rapid infusion priate for certain patients. of high-dose Ig.4 The transition from IV • Some products may contain sucrose, to SC administration which is associated with an increased Subcutaneous risk for renal failure. is associated with Administration of Ig • Patients with thromboembolic risk fewer missed school should avoid high-osmolality products.

The first SCIg product available for • Low-concentration products that clinical use as replacement therapy was or work days, and require a high volume may be inapproapproved in 2006.8 SCIg formulations do several studies have priate in patients sensitive to fluid overnot require venous access and, because load due to cardiac or renal impairment. they are associated with reduced risk for shown that homesystemic IARs, can be given without coadbased SCIg can ministration of corticosteroids or antihistaIn the past, national shortages of IVIg have mines.4,9 The most common adverse events forced pharmacists to find suitable alternabe less costly than tives for patients at risk for the AEs assoare local infusion-site reactions.10 In addiIVIg therapy given ciated with product substitution. Although tion, SCIg products can be self-adminisin an institutional significant shortages have not been an issue tered, a convenience that may be attractive for a number of years, increased incidence of to many individuals interested in home11,12 setting. systemic infusion-associated reactions (IARs) based therapy and that reduces the need remains a concern when switching products. for an infusion nurse to visit the home.4,9,11 The transition from IV to SC adminisTolerability tration is associated with fewer missed school or work days, and several studies have shown that In general, Ig replacement therapy is tolerated well by home-based SCIg can be less costly than IVIg therapy given patients with PI.4,6 With IV administration, systemic IARs can in an institutional setting.11,12 Patient-reported health-related include headache, fever, myalgia, chills, rash, or rigors and

Table 3. Immunoglobulin Products Available in the United States Brand Name

Protein Amount/ Concentration

Route of Administration

Manufacturer

Bivigam 10%

100 mg/mL

IV

Biotest Pharma

Carimune NF

3, 6, 12 g

IV

CSL Behring

Flebogamma 5%

50 mg/mL

IV

Grifols

Gammagard liquid 10%

100 mg/mL

IV/SC

Baxter

Gammagard S/D

2.5, 5, 10 g

IV

Baxter

Gammaked 10%

100 mg/mL

IV/SC

Kedrion Biopharma

Gammaplex 5%

50 mg/mL

IV

Bio Products

Gamunex-C 10%

100 mg/mL

IV/SC

Grifols

Hizentra 20%

200 mg/mL

SC

CSL Behring

Octagam 5%

50 mg/mL

IV

Octapharma

Privigen 10%

100 mg/mL

IV

CSL Behring

IV, intravenous; SC, subcutaneous Based on references 5 and 6.

3

REPORT occur immediately after administration and can be extremely quality-of-life (QoL) scores also improve after the switch high (2,000 mg/dL). The IARs (eg, headache, fatigue, myalfrom IV to SC 8,13 and even more so with home-based gias, nausea) are attributed, in part, to high peak values.4,8 administration.14,15 Appropriate candidates for home therapy need to be The high initial serum levels drop rapidly, as IVIg moves into selected carefully.8 According to a recent single-payor crossthe lymphatic system. Alternatively, SCIg is reported to result in much lower peak levels as it is distributed over time from sectional survey, 54% of home-based Ig therapy now is delivthe SC space into the bloodstream.6,18 The sustained delivery ered via the SC route and 46% by IV.16 Of note, recent reviews and a meta-analysis of clinical trials comparing IVIg and SCIg of Ig from the SC space also is associated with higher trough administration showed that home-based SCIg was tolerated levels between treatments (compared with IV administration) better by adult and pediatric patients and and a more stable steady-state level of associated with greater dose flexibility Ig in circulation.6,11,18 When integrated (through options to balance number of over time, SCIg achieves a smoother, injections, injection volume, and number more consistent serum Ig concentration When integrated of treatment days), which contributes to profile. Maintaining steady-state levels over time, SCIg better overall compliance.11,17 between infusions is important for prevention of infections and for symptom Of the 4 SCIg formulations approved achieves a management.4,8,11 In a 2002 Immune for use, 3 are available as 10% concensmoother, more trates that can be administered by IV or Deficiency Foundation treatment expeconsistent serum SC, and the fourth is a 20% formulation rience and preference survey, 42% of designed specifically for SC administrapatients with PI reported that they usuIg concentration tion. The latter facilitates administration of ally could feel when their IVIg dose was profile. Maintaining a therapeutic dose via a smaller infusion wearing off, and another 26% indicated volume or with less frequent infusions they sometimes can feel the wear-off.20 A steady-state levels compared with 10% formulations.18 The pooled analysis of IVIg trials has shown between infusions higher risk for infection during IVIg ther20% formulation is stabilized with proline, apy,11 particularly in the week before the a naturally occurring amino acid present is important for 18 in food and human plasma. Proline prenext IVIg dose.21 prevention of vents Ig aggregation during storage and IVIg is generally infused monthly, lowers viscosity for ease of infusion.18 whereas SCIg is administered weekly infections and (10% or 20% formulations); additionOther SCIg formulations use glycine for for symptom ally, the 20% formulation is approved Ig stabilization. for biweekly (every 2 weeks) administraEfficacy, safety, and tolerability for the management.4,8,11 tion, offering greater dose flexibility for 20% formulation was confirmed in 2 propatients. Clinical studies have shown that spective Phase III trials in patients who weekly SCIg is equivalent to monthly IVIg switched from stable IVIg therapy to SCIg in reducing serious bacterial infections in patients with PI.4,11 for 40 and 60 weeks, respectively, and in 2 recently published extension trials that evaluated continuous weekly therapy for With expanding use of home-based SCIg administration,22 18,19 84 and 148 weeks, respectively. the efficacy, safety, and convenience of SCIg therapy across patient populations has been evaluated through retrospecPharmacokinetics tive studies. In the pediatric population (ages 6-18 years), SC administration achieved greater mean serum Ig levels than Different pharmacokinetic profiles have been characterized IV administration.23 In older patients, including those on oral for IVIg and SCIg. With IV administration, peak serum levels anticoagulation therapy, home-based SCIg therapy was well tolerated over 13 months and achieved steady-state Ig levels of 1,074 mg/dL.24 In a recent retrospective chart review, Patient A received IVIg at a dose of 30 g every 4 weeks; switching obese patients with PI from IV to SC (16% or 20% her new dose of SCIg should be 10.27 g/week. formulations) Ig replacement therapy confirmed greater mean Ig serum concentrations in the SC group. 25 The current recommendations for dosing are to multiply the current IVIg dose by 1.37 (for 10% products) or 1.53 (for the 20% product) and divide by the number of weeks between infusions (Figure 2).8 Most clinical trials report the incidence of serious systemic effects with SCIg to be 1% to 3%.8 This low rate is attributed to slower shift into the intravascular space and lower peak concentration of IgG compared with IV administration.

Figure 2. Calculation of SCIg dose.

Patients may receive SCIg in the abdomen, thigh, upper IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin arm, or lower back.8 Generally administered with an infusion Based on reference 8. pump, dosing is usually 20 to 30 mL per site per week. Multiple infusion sites may be used simultaneously.5,8

30 Ă&#x2014; 1.37 4

4

= 10.27

REPORT Best Practices and Emerging Strategies To Improve Ig Dosing Flexibility

hyaluronan levels and skin permeability to normal in approximately 48 hours.

The human genome encodes 6 hyaluronidase genes (HYAL1, HYAL2, HYAL3, HYAL4, PH-20/SPAM1, and HYALP1), A number of strategies have been employed to improve Ig which are expressed variably across key organ systems and dosing flexibility and patient empowerment, including the use stages of development.28 Recombinant human hyaluronidase of 20% formulations, infusion at multiple sites, rapid SC push (5 to 20 mL administered over 5 to 20 minutes per site as tolis derived from the testicular isoform (PH-20), which normally erated),25,26 use of SC pumps,4 and more frequent dosing.27 is expressed predominately in spermatozoa. PH-20 hyaluronidase activity plays a critical role in reproductive biology by In a study comparing rapid push with pump infusion, mean promoting initial oocyte fertilization, 29 serum IgG levels obtained were not significantly different (1,164 mg/dL for SC push whereas other isoforms are involved in vs 1,048 mg/dL for pump infusion).25 preimplantation embryo development30 “Monitoring of local Efforts to increase the volume of Ig and cervical ripening in anticipation of administered via pretreatment of the SC labor and delivery.31 effects on skin, space with recombinant human hyaluronThe hyaluronan subunits liberated by potential development idase (rHuPH20) also have been evaluhyaluronidase activity can activate inflamated in the investigational setting.27 SC matory responses associated with innate of antibodies (in immune system detection of bacterial tissue is composed of a complex matrix particular, blocking infections (bacterial hyaluronidase activof scaffolding molecules including collaity is believed to play a role in pathogen gen and hyaluronan, a high-molecularantibodies to invasiveness and survival).28 The conweight polymer that behaves as a thick rHuPH20), effects on gel-like substance, limiting the dispersion sequences of these inflammatory profertility, and possible of fluids within the SC space.4,27 Hyalurocesses in immunodeficient patients receiving repeat injections remain to be nan turnover, which is fairly rapid in skin, immunologic effects determined. occurs due to the enzyme hyaluronidase, of the hyaluronidase Animal-derived hyaluronidase has been which digests hyaluronan into progresavailable since the 1950s for acute use sively smaller subunits. SC administration fragments are some in ophthalmology 32 and plastic surgery 33 of exogenous hyaluronidase accelerates aspects that will hyaluronan degradation, disrupting the and to decrease damage from extravaSC architecture and allowing SC infusion sation following IV therapy.34 However, require ongoing of larger volumes against lower resistive these animal preparations are intended review.” pressure.27 Following SC administration, for a single course of therapy. The recent 27 development of rHuPH20 has been evaluhyaluronidase is cleared from the skin —Jolles ated for repeat SC administration in select and normal hyaluronan synthesis returns

Table 4. Comparison of IVIg and SCIg IVIg

SCIg SCIg (10%)

SCIg (20%)

Premedication requirements

Frequent

Infrequent

Infrequent

Venous access required

Yes

No

No

Storage

≤25°C

≤25°C

≤25°C

Dosing interval

q3-4wk

Weekly

Weekly or q2wk

Dose/h

30 g

6.4-8 g/site/treatment

Peak-to-trough variation

Large

Low

IVIg, intravenous immunoglobulin; SCIg, subcutaneous immunoglobulin Based on references 4, 18, and 27.

Note: At press time, SCIg (10%) + recombinant human hyaluronidase is currently not approved for use in the United States.

5

REPORT data are insufficient to assess the effect on human fertility and chronic conditions, including PI.35,36 In animal models, peak potential for AEs with conception. To date, the combination is serum levels and peak-to-trough transitions following SCIg not approved in the United States, and data in older and obese administration with recombinant hyaluronidase pretreatment patient populations are not available. were greater than those observed with SCIg alone, but less Patient preference for sequential treatment with hyaluronithan the transition seen with IV administration.37 The increased dase and SCIg after switching from IVIg was studied recently.39 peak plasma levels are related to enhanced permeability and faster Ig access from the SC to the plasma compartments.

Of the survey respondents, 43.1% indicated that they disliked A recently completed clinical trial in PI the complexity of sequential infusions compared measured IgG serum levels with recombinant hyaluronidase followed and infection outcomes observed during

by SCIg and 26% said they disliked the prior IV-based Ig therapy to rates seen changes to their physical appearance. with SCIg plus rHuPH20 pretreatment.35 The implications of these concerns for Of the survey long-term compliance and overall QoL In this study, patients stabilized on 10% respondents, among patients managed with this option IVIg for at least 3 months were converted remain to be determined. A direct comto sequential treatment with recombi43.1% indicated parison between conventional SCIg and nant hyaluronidase followed by SCIg for that they disliked sequential recombinant hyaluronidase fol14 to 18 months. Consistent with other lowed by SCIg therapy in PI has not been SC administration studies, Ig levels were the complexity of reported. similar for the combined hyaluronidase sequential infusions plus SCIg versus the IVIg groups (10.7 and 10.4 g/L, respectively) and infection with recombinant Considerations in IV or SC rates were low. Although no serious study Administration hyaluronidase drug-related AEs were reported, 13 of the 83 patients developed antibodies against Although both IVIg and SCIg can provide followed by SCIg hyaluronidase.35 To date, these antibodan effective and safe method for delivering and 26% said they Ig therapy, each has unique administration ies have not been characterized as being disliked the changes considerations (Table 4).4,18,27 neutralizing, and no temporal correlations with any AEs have been reported. A PI to their physical Conclusion expert has commented that â&#x20AC;&#x153;monitoring appearance.39 of local effects on skin, potential developFor patients having difficulty with IVIg ment of antibodies (in particular, blocking therapy for immunodeficiency disorantibodies to rHuPH20), effects on fertilders (clinical tolerability or scheduling ity, and possible immunologic effects of challenges, etc), SCIg offers an attracthe hyaluronidase fragments are some tive home-based treatment option that aspects that will require ongoing review.â&#x20AC;?27 is able to achieve similar serum levels as IV-based therapy, with fewer side effects, additional administration options, and Given the small number of participants exposed to repeat greater overall patient satisfaction. To overcome the large voltreatment with recombinant hyaluronidase, it is unclear what umes that need to be administered when using 10% SCIg effect these antibodies may have on the activity of naturally products, sequential hyaluronidase SCIg combination therapy occurring hyaluronidase in other organ systems (ie, reprohas been researched, and although not currently approved in ductive potential, vitreous structure, skeletal tissues).28 These the United States, could be a future treatment alternative in concerns are reflected in the recent European approval of the selected patient populations. The combination has been evalcombined recombinant hyaluronidaseâ&#x20AC;&#x201C;10% SCIg therapy, uated in a limited number of patients to date, and data about which is restricted to use in individuals older than 18 years long-term safety will be essential. The current availability of a of age and is contraindicated in women who are pregnant or 20% formulation for low-volume SCIg therapy further improves planning to become pregnant, due to the uncertain reproducsteady-state Ig levels and minimizes Ig level wear-off effects tive effect of recombinant PH-20 in both males and females.38 between treatments,4 with more infusion options and empowAdditional recommendations outline that men and women of reproductive potential should be counseled that long-term erment for improved home-based therapy and overall QoL.18

The availability of a 20% formulation for low-volume SCIg therapy further improves steady-state Ig levels and minimizes Ig level wear-off effects between treatments,4 with more infusion options and empowerment for improved home-based therapy and overall QoL.18

6

REPORT References 1.

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Wasserman RL. Progress in gammaglobulin therapy for immunodeficiency: from subcutaneous to intravenous infusions and back again. J Clin Immunol. 2012;32(6):1153-1164.

Wickersham RM, ed. Drug Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2014. http://online.factsandcomparisons. com. Accessed June 19, 2014.

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10. Hagan JB, Fasano MB, Spector S, Wasserman RL, Melamed I, Rojavin MA, Zenker O, Orange JS. Efficacy and safety of a new 20% immunoglobulin preparation for subcutaneous administration, IgPro20, in patients with primary immunodeficiency. J Clin Immunol. 2010;30(5):734-745.

11. Abolhassani H, Sadaghiani MS, Aghamohammadi A, Ochs HD, Rezaei N. Home-based subcutaneous immunoglobulin versus hospital-based intravenous immunoglobulin in treatment of primary antibody deficiencies: systematic review and meta analysis. J Clin Immunol. 2012;32(6):1180-1192.

12. Gerth WC, Betschel SD, Zbrozek AS. Implications to payers of switch from hospital-based intravenous immunoglobulin to homebased subcutaneous immunoglobulin therapy in patients with primary and secondary immunodeficiencies in Canada. Allergy Asthma Clin Immunol. 2014;10(1):23.

13. Gardulf A, Bjorvell H, Gustafson R, Hammarstrom L, Smith CI. The life situations of patients with primary antibody deficiency untreated or treated with subcutaneous gammaglobulin infusions.

Clin Exp Immunol. 1993;92(2):200-204.

14. Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. Bio Drugs.

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15. Gardulf A, Nicolay U. Replacement IgG therapy and self-therapy at home improve the health-related quality of life in patients with

primary antibody deficiencies. Curr Opin Allergy Clin Immunol.

2006;6(6):434-442.

16. Huang F, Feuille E, Cunningham-Rundles C. Home care use of intravenous and subcutaneous immunoglobulin for primary immunodeficiency in the United States. J Clin Immunol. 2013; 33(1):49-54.

17. Moore ML, Quinn JM. Subcutaneous immunoglobulin replacement therapy for primary antibody deficiency: advancements into the 21st century. Ann Allergy Asthma Immunol. 2008;101(2):114-121.

18. Jolles S, Sleasman JW. Subcutaneous immunoglobulin replacement therapy with Hizentra, the first 20% SCIG preparation: a practical approach. Adv Ther. 2011;28(7):521-533.

19. Jolles S, Borte M, Nelson RP Jr, et al. Long-term efficacy, safety, and tolerability of Hizentra for treatment of primary immunodeficiency disease. Clin Immunol. 2014;150(2):161-169.

20. Immune Deficiency Foundation. Treatment Experiences and Preferences of Patients with Primary Immune Deficiency Diseases: First National Survey. http://primaryimmune.org/wp-content/ uploads/2011/04/Treatment-Experiences-and-Preferences-ofPatients-with-Primary-Immune-Deficiency-Disease-First-NationalSurvey-2002.pdf. Published June 20, 2003. Accessed June 19, 2014.

21. Bexton M, Baggish JS, Rojavin MA, Berger M, Zenker O. Increased frequency of infections at the end of the IVIG dosing cycle: effect characterization from three phase III studies. Poster presented at: American Academy of Allergy, Asthma and Immunology (AAAAI) Annual Meeting; March 2-6, 2012; Orlando, FL. 22. Chapel H, Gardulf A. Subcutaneous immunoglobulin replacement therapy: the European experience. Curr Opin Allergy Clin Immunol.

2013;13(6):623-629.

23. Bezrodnik L, Gómez Raccio A, Belardinelli G, et al. Comparative study of subcutaneous versus intravenous IgG replacement therapy in pediatric patients with primary immunodeficiency diseases: a multicenter study in Argentina. J Clin Immunol.

2013;33(7):1216-1222.

24. Stein MR, Koterba A, Rodden L, Berger M. Safety and efficacy of home-based subcutaneous immunoglobulin G in elderly patients with primary immunodeficiency diseases. Postgrad Med. 2011;123(5):186-193.

25. Shapiro RS. Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis. Ann Allergy Asthma Immunol. 2013;111(1):51-55.

26. Shapiro R. Subcutaneous immunoglobulin therapy by rapid push is preferred to infusion by pump: a retrospective analysis. J Clin Immunol. 2010;30(2):301-307.

27. Jolles S. Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency. Immunotargets and Ther. 2013;2: 125-133.

28. Jiang D, Liang J, Noble PW. Hyaluronan as an immune regulator in human diseases. Physiol Rev. 2011;91(1):221-264.

29. Martin-Deleon PA. Germ-cell hyaluronidases: their roles in sperm function. Int J Androl. 2011;34(5 Pt 2):e306-e318.

30. Marei WF, Salavati M, Fouladi-Nashta AA. Critical role of hyaluronidase-2 during preimplantation embryo development.

Mol Hum Reprod. 2013;19(9):590-599.

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32. Kuppermann BD, Thomas EL, de Smet MD, Grillone LR. Safety results of two phase III trials of an intravitreous injection of highly purified ovine hyaluronidase (Vitrase) for the management of vitreous hemorrhage. Am J Ophthalmol. 2005;140(4):585-597.

33. Bailey SH, Fagien S, Rohrich RJ. Changing role of hyaluronidase in plastic surgery. Plast Reconstr Surg. 2014;133(2):127e-132e.

34. Hanrahan K. Hyaluronidase for treatment of intravenous extravasations: implementation of an evidence-based guideline in a pediatric population. J Spec Pediatr Nurs. 2013;18(3):253-262.

35. Wasserman RL, Melamed I, Stein MR, et al. Recombinant human hyaluronidase-facilitated subcutaneous infusion of human immunoglobulins for primary immunodeficiency. J Allergy Clin Immunol. 2012;130(4):951-957.

36. Dychter SS, Harrigan R, Bahn JD, et al. Tolerability and pharmacokinetic properties of ondansetron administered subcutaneously with recombinant human hyaluronidase in minipigs and healthy volunteers. Clin Ther. 2014;36(2):211-224.

37. Bookbinder LH, Hofer A, Haller MF, et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics.

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38. HyQvia [Summary of Product Characteristics]. Vienna, Austria: Baxter Innovations GmbH. www.hyqvia.de/pdf/epar-productinformation.pdf. Accessed June 19, 2014.

39. Ito D. Patient preferences for recombinant human hyaluronidase (rHuPH20)-facilitated subcutaneous (SC) infusion of immunoglobulin G (IGHy) in adult patients with primary immunodeficiencies (PI): phase 3 study. Poster presented at: Clinical Immunology Society Annual Meeting; April 10-13, 2014; Baltimore, MD.

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