Specialty drug utilization and cost management have dominated managed care conferences and journals over the last few years, showing no sign of abating.

Typically, much of the focus in specialty drug trend management is on oral and self-administered drug formulations traditionally administered through a payer’s or plan sponsor’s pharmacy benefit. Unfortunately, this overlooks approximately 36% to 50%

 of specialty drug spend that is occurring under a payer or plan sponsor medical benefit, rather than pharmacy benefit. Drugs administered through the medical benefit are mostly injectable or intravenous formulations, and are typically administered in physician offices or clinics under the supervision of a trained certified professional (nurse, physician).

Medical benefit specialty drugs treat a wide range of diseases or conditions; however, specialty drugs used for cancer, anemia, neutropenia, rheumatoid arthritis, Crohn’s disease, age-related macular degeneration, and psoriasis make up much of the medical benefit specialty drug spend. An observation from a recently released white paper

 highlights plan sponsor concerns on management gaps for specialty drugs administered through the medical benefit.

“One of the biggest challenges is identifying what costs are running through the medical benefit versus the pharmacy benefit. With a high percentage of costs occurring through medical, as well as a variety of payment dispensing options, it can be difficult to achieve full transparency on overall spending and utilization.” 

—Cheryl Larson, President Midwest Business Group on Health 

A major hindrance for transparent, medical benefit specialty utilization and spend data is the use of less descriptive health care common procedure coding system (HCPCS) through a traditional CMS 1500 claims billing format. Other complexities for effectively managing medical benefit specialty drug spend include cost differences by site of service, provider reliance on dispensing drug revenues, and variable fee schedules.

It is, perhaps, not surprising that medical benefit specialty drug spend plan sponsors are frustrated about their inability to adequately recognize whether covered employees and dependents are receiving the most clinically appropriate and cost-effective drug therapies.

Current Strategies to Manage Specialty Drugs 

 identified a number of key main-payer strategies for managing specialty drugs. We will explore how these strategies are applied for medical benefit specialty drugs and their implications:

For medical benefit specialty drugs, the 4 major sites of care or service channels are physician offices; outpatient hospital clinics; home setting; and pharmacy benefit manager (PBM), specialty or retail pharmacy. Reimbursement methods vary with average sales price (ASP)-based reimbursement most commonly used for physician offices, while percentage of billed charges and average wholesale price (AWP) are most commonly used with outpatient hospital clinics, home, and PBM/specialty/retail sites of service.

While some payers and PBMs advocate the use of “white-bagging,” in which providers are required to acquire specialty drugs directly through the specialty pharmacy, this tactic undoubtedly creates friction among large numbers of providers, particularly oncologists, hematologists, and rheumatologists. The main source of friction is the revenue gleaned from drug dispensing and/or drug administration, and whether any of the revenue can be transferred into payer or plan sponsor savings.

It has been suggested,4 especially among community-based oncology practices, that white-bagging increases administrative burdens on providers, while also increasing drug waste. Several community-based oncology practices

 said the cost of drug waste ranged from $875,000 to more than $1.25 million dollars annually.

Such drug waste cost estimates, if correct, could certainly mitigate any payer or plan sponsor savings significantly. While there are some therapy exceptions, such as self-administered injectable drugs used for respiratory syncytial virus, most payers and plan sponsors have settled into not utilizing white-bagging as a primary tool for managing medical benefit specialty trend.

“One note of caution as we look to the medical benefit drug spend is the importance that needs to be placed on careful analysis prior to taking action. Some medical drug spend may actually turn out to be accomplished more cost effectively by pulling it out of the physician office. What’s more, other delivery methods may do the exact opposite of what is desired and drive up costs. A surgical approach to interventions, with good data mining, is essential.”

—Thomas A. Sondergeld, Vice President, Global Benefits & Mobility — Walgreens Boots Alliance 

	Most payers utilize ASP for medical benefit drugs where a mark-up to ASP is applied. While the potential for provider perverse incentives4 still exists, most payers and plan sponsors have adopted ASP-based reimbursement for medical benefit drugs. CMS, along with several regional and national payers, have launched pilot programs aimed at moving away from drug fee-for-service models into bundled payments, episode of care, shared savings from total cost of care, and medical homes. 

For the foreseeable future, ASP-based pricing will likely remain the prevailing model for medical benefit drug reimbursement. It should be noted that few, if any, PBM, specialty pharmacy, and retail pharmacy operations have the capacity to manage ASP-based claims.

Since the advent of the Affordable Care Act, hospitals have rapidly acquired community-based specialist practices (ie, oncology, hematology, rheumatology) and rebranded as out-patient facilities. To the angst of payers and plan sponsors, the cost for drug administration in a hospital outpatient setting6 greatly exceeds the same service provided in a community-based setting.

The most common site-of-care management tactics includes member outreach to encourage the use of lower-cost care sites and preferred sites that offer lower member out-of-pocket costs, narrowing provider networks and white bagging.

As Larson noted, plan sponsors require, and yet are not receiving, full transparency on medical benefit drug spend and utilization to accurately assess whether covered employees and dependents are receiving high-quality and cost-effective specialty drug therapy. Sondergeld also suggests a measured approach to yield the maximum benefit for plan sponsors.

To address this concern, payers or external vendors should be able to provide transparent and actionable data accurately reflecting optimal network management, while navigating the varied reimbursement models and sites of services. At a minimum, these data should be provided quarterly.

Prior authorization, usually in the form of pre-certification,

 is the most common mechanism for determining coverage for medical benefit specialty drugs. To a significantly lesser degree, claims processing edits that can be applied before or after claims payment are also utilized. The issue for providers and patients is that traditional medical benefit prior authorizations create administrative burdens for payers and providers, and can possibly delay patient treatment.

Projected national direct and indirect costs for prior authorizations ranged between $23 and $31 billion in 2006.

 Traditional prior authorizations applied to the medical benefit may also not fit within existing provider clinical and operational workflows, as in the case of cancer drug treatment plans that frequently require the use of multiple specialty medications. Hence, a provider’s office may need to submit a prior authorization for each drug, creating incremental administrative burdens.

Approval delays on any drug in the treatment plan can delay the administration of the entire drug treatment plan for the patient. An alternative option is changing the way traditional prior authorizations are administered, by holistically assessing all of the drugs the patient is to receive for the condition, and doing so in a provider-centric fashion that minimizes administrative burdens on providers, patients, payers, and plan sponsors.

Additionally, the availability of an actively practicing physician specialist or sub-specialist (ie, oncologist, hematologist, rheumatologist, ophthalmologist) to provide peer-to-peer interventions on cases that do not conform to payer or plan sponsor coverage rules is a more effective way to build provider collaboration, while ensuring best evidence-based practices at a lower cost.

Another forward-thinking prior authorization opportunity involves ensuring that submitted medical benefit drug claim quantities are as close as possible to meeting individual patient dose requirements. Since medical benefit drug claims utilize fewer drug-specific HCPCS codes, it is usually difficult to identify whether the least-costly available commercial package size was utilized.

One way to address this is by informing providers on clinical appropriateness and approved drug quantities that are cross-walked to the most appropriate commercially available package size. This should minimize drug waste, while also identifying any potential issues of abuse.

For medical benefit specialty drugs, benefit design includes patient out-of-pocket costs and whether specialty drugs are covered exclusively under the medical benefit, or under both medical and pharmacy benefit. Ideally, payers and plan sponsors should be able to provide or receive integrated clinical and financial data for specialty drugs, regardless of benefit design. One way to strategically achieve this is to have a single source managing all prior authorizations, regardless of benefit design, triaging to the most cost-effective site of service, matching claims to authorizations, and finally, offering in close to real-time, transparent, integrated clinical and financial data.

The Value of Effective Medical Benefit Drug Management 

 expressing payer and plan sponsor insight into the value of an effective medical benefit drug management program highlights examples of best practices:

		Control of spending from a clinically-based partner with evidence-based experiences.

		Alignment of appropriate, transparent, nationally recognized, evidence-based guidelines, dose checks, and competent clinic dialogue.

		Evidence-based insights through the combination of good, measurable outcomes, and integration with the most up-to-date peer-reviewed clinical data.

		Efficiency in benefit design, provider capabilities, and identification of providers who significantly deviate from transparently developed “best practice” metrics.

		Meaningful collaborative clinical support that recognizes unique patient characteristics.

		Administered utilization management that mirrors physician, clinical, and operational workflow, while minimizing management burdens. 

Key Elements for Successful Medical Benefit Drug Management 

		Actively practicing credentialed clinicians, ideally physician specialists or subspecialists, to provide peer-to-peer interventions that incorporate the latest nationally accepted evidence- based medicine.

		Objective site-of-service management, ideally free from the revenue conflicts of drug dispensing.

		Integrating relevant clinical data with financial data that ensures concordance to evidence-based medicine, while reducing waste.

		Availability of near real-time transparent and actionable data.

		Improving the quality of care while reducing specialty drug trend.

		Prior authorization mechanism that minimizes administrative burdens while, fitting within physician clinical and operational workflows. 

Can PBMs or Specialty Pharmacies Play a Role in Medical Benefit Drug Management? 

The short answer is yes, but only with the right set of tools and the right mindset, that collaboratively working with providers is a necessary element for success.

“In this era of rapidly evolving drug therapies, inclusion of practicing subspecialists is a key element to any effective medical or drug benefit management process,” said Anthony Lam, MD, chief medical officer at PharMedQuest. “They can best identify cost-saving opportunities that do not compromise patient care, while maximizing physician buy-in through meaningful and collegial peer-to-peer interactions at the subspecialist level.”

The new presidential administration will likely have significant impact on the future of the Affordable Care Act. Clearly, what is currently needed by payers and plan sponsors is an effective prior authorization mechanism that addresses specialty spend under the medical benefit, which is also provider-friendly, and ensures that high-quality, cost-effective drug therapy measures for rare and complex diseases are being followed.

		PBMI 2016 Specialty Drug Benefit Report

		Access Market Intelligence Whitepaper, Bend the Curve, A New Era for the Management of Specialty Pharmaceuticals (accessmarketintell.com)

		Community Oncology — March/April 2005 – Dawn Holcombe

		Avalere Whitepaper — Total Cost of Cancer Care by Site of Service – March 2012

		Casolino LP, Nicholson S., Gans DN, et al.  What does it cost physician practices to interact with health insurance plans?  Health Aff (Millwood) 2009;28 (4); w533-43

Articles

Features

Specialty drug trend management typically focuses on drug formulations administered via a payer or plan sponsor pharmacy benefit, which overlooks drug spending occurring under a payer or plan sponsor medical benefit.

Medical Benefit Specialty Drug Managementâ€“A Call to Action

Fraud, waste, and abuse (FWA), especially around Schedule II drugs such as opioids, have reached epidemic levels in America. The CDC states that 5.1 million Americans abused painkillers to some degree in 2010, and the 2012 National Survey on Drug Use and Health found that 2.1 million Americans were addicted to opioid pain relievers.

The opioid abuse crisis is not limited to just users: it is also a very profitable business for prescribers and pharmacies, and can have far-reaching effects on certain patients, specifically those undergoing treatment for cancer. Nowhere is this more evident than with Medicare Part D.

From 2006 to 2014, spending on commonly abused opioids among Part D beneficiaries rose to $7.8 billion, an increase of 156%. According to the Office of the Inspector General (OIG) June 2015 data brief “Ensuring the Integrity of Medicare Part D,” in 2007, more than $1.2 billion was paid by claims with invalid prescriber identifiers—an amount that doesn’t include all other instances of FWA during that time.

Why is FWA so prevalent in Medicare Part D? The simple answer is that it is relatively easy to slip through the cracks. The same OIG report stated that Medicare plan sponsors; Health Integrity, the Medicare program integrity contractor for the Centers for Medicare & Medicaid Services (CMS) under the National Benefit Integrity Medicare Drug Integrity Contract (NBI MEDIC) charged with detecting and preventing FWA in Part D; and CMS itself, all lack adequate controls and mechanisms to address the issue.

For example, NBI MEDIC does very little to proactively seek out FWA. Instead, it relies on whistleblowers to call a toll-free phone number to report instances of FWA even though its charter states it should use data analytics to proactively find FWA. Medicare plan sponsors and CMS are also doing little in the way of data analytics, despite the proliferation of claims, clinical, and other data that are currently available.

What makes the opioid abuse issue even more complex is that plan sponsors are not required to report information on FWA, nor are there strict guidelines they can follow to remedy any situations that pop up. This lack of information makes it difficult for CMS to formulate broader action plans or hold plan sponsors accountable for protecting Part D from FWA.

All of this amounts to wasted opportunities to address FWA at all of its sources: beneficiaries, prescribers, and pharmacies. The raw data are there, but they aren’t enough. The real key is to apply advanced behavioral analytics to help uncover and address FWA while minimizing the false-positives that lead to wasted time and resources—and that ultimately interfere with the efficacy of an FWA program.

The pharmacy benefit under Part D is similar to the “any willing provider” provision under CMS: Patients can take their Part D prescriptions to any pharmacy or pharmacy benefit manager (PBM) that is willing to fulfill them. This is a tremendous benefit, especially for older Americans who may have trouble with transportation or who depend on a caretaker to fill their prescriptions.

By opening up the pool of pharmacies available, this provision makes the entire process much more convenient. Yet, when access is thus available, there is more potential for FWA, which degrades the integrity of the pharmacy benefit. In fact, some unscrupulous operators may open pharmacies in areas with heavy Part D populations specifically to take advantage of the lack of proactive oversight.

Advanced behavioral analytics can help payers and their PBMs stop these operators by identifying anomalies and patterns that are key indicators of FWA. These analytics rank suspected FWA on a numeric scale so that inspectors can focus their efforts on the situations most likely to occur while eliminating the false-positives that waste time. Given that payers and their PBMs are viewed by CMS as the frontline in identifying and preventing FWA, advanced analytics can help by lowering the costs and maintaining the integrity of the Part D benefit for everyone.

The 4 key areas in which advanced analytics can be most beneficial are member drug-seeking behavior, pharmacy FWA, overlaps in pharmacy and medical benefit payments, and compound claims.

Analytics make it easier for reviewers to find behaviors that are unusual. Rather than paging through spreadsheets, color-coded dashboards can assign scores based on risk factors. This format calls attention to the most likely cases of FWA based on pre-set thresholds, such as members who are seeing more than 10 physicians or filling prescriptions at more than 10 pharmacies. These thresholds can be set based on industry benchmarks or adjusted to the preferences of the payer or PBM.

One of the challenges of uncovering FWA among members is that the same patterns that indicate FWA could also indicate legitimate patient needs. For example, receiving opioid prescriptions from multiple providers and filling them at different pharmacies are common indicators of potential fraud.

Yet, an oncology patient who is receiving multiple prescriptions from several different specialists may have a legitimate reason for this behavior. This is where next-generation analytics bring in additional data, such as displaying the locations of prescribers and pharmacies on a map relative to the patient’s home. This makes it easier to detect FWA, especially if several prescriptions are being filled at different locations a long way from a patient’s home.

The intelligent application of analytics will help automate the process of bringing the most likely perpetrators of FWA to the surface, while minimizing the false-positives, thus ensuring that payers or PBM resources are being used most effectively to reduce costs, not alienate members in good standing.

Members aren’t the only ones committing FWA. Pharmacies have plenty of incentive, too. In this case, analytics can uncover illegal activity by establishing a benchmark of patterns over a specified time period, such as a year, then monitoring activities against that benchmark on a weekly basis. If there are significant deviations from the benchmark, those pharmacies are highlighted to determine whether action is required.

More sophisticated analytics packages can even color-code these pharmacies, based on severity, to make it easier to determine where immediate action is required, which pharmacies should be on the “watch list,” and which location may just have had an unusual week. They also enable payers and PBMs to comply with CMS monitoring of “watch lists.” Then, displaying the results on a dashboard makes it easy to spot overall trends, such as pending claims or withholding payment; pharmacies that may require corrective interventions; and pharmacies that may need an onsite visit or other more severe actions.

Some of the metrics that can be monitored include:

		average number of prescriptions per member (stratified by age)

This is an area in which expanding beyond typical claims data analysis can help prevent plan sponsors from paying twice for the same medications. In most cases, this is more of a waste issue than intentional fraud or abuse of the system. The central problem is that medical and pharmacy benefits are billed under 2 different claims platforms that do not talk to each other.

This can be a problem for patients with long-term or chronic conditions, such as arthritis or diabetes, since certain drugs might fall under either the medical or the pharmacy benefit depending on how tightly the plan sponsor coordinates the drugs in conjunction with the PBM. As a result, even though everyone involved—clinicians, pharmacies, and patients or their caregivers&mdash;acts in good faith, a medication may be double-billed.

Here is an example: A patient has a hip replacement and is prescribed a self-injectable medication to prevent blood clots. The health plan requires the patient to obtain this particular medication through a specialty pharmacy, which then sends that prescription to the patient’s home either the day he/she gets home or the following day. When the patient goes to the physician for a follow-up visit, the physician shows the patient how to inject the medication.

The physician’s office may then mistakenly bill for the medication under the Healthcare Common Procedure Coding System as a J Code, while the specialty pharmacy correctly bills for the medication under the National Drug Code (NDC). Without analytics, the physician will likely be reimbursed for the erroneous claim.

Advanced behavioral analytics, however, can merge data from both systems, compare them, and identify both overlaps and opportunities for recovery by looking at the day span, the unit, the amount billed, and the amount paid. Advanced analytics can also help ensure physicians get paid for legitimate claims, such as when a diabetic patient goes to the physician’s office and the physician sees a dangerous spike in the glycated hemoglobin level.

Since it is urgent, the physician may give the patient an injection in the office and a prescription for an insulin pen to be filled at the local pharmacy. Although a comparison of the J Code and NDC code will show that the insulin was paid for twice, the analytics will confirm that both payments are justified in this case.

One other common area of FWA, under Part D, that advanced analytics can address is compound claims. This is accomplished by identifying spikes and bring hidden information to light so plan sponsors and their PBMs can take action to stop them. This area is very susceptible to fraud especially because, in many cases, a claim will only show 1 line of the prescription compound rather than all of the ingredients.

This limitation can give a pharmacy intent on committing FWA the opportunity to create a custom compound when there is already a less expensive option commercially available—a move that only adds to the cost&mdash;or the chance to submit a false claim for a bulk powder as 1 of the ingredients, even though it is not covered under Part D. Therefore, even though an end-stage cancer patient may be receiving a constant low dose of morphine powder rather than other, more expensive forms of the drug, the claim just shows morphine.

The sheer dollar volume and lack of proactive oversight make Medicare Part D particularly susceptible to FWA. Advanced behavioral analytics use new data sources to help health plan sponsors and their PBMs identify instances of FWA more precisely. This, in turn, allows stakeholders to use their resources wisely and take the lead to shut FWA down and make sure older Americans receive the benefits they deserve.&ensp;

Advanced behavioral analytics can differentiate patterns of fraud and abuse from instances such as oncology patients receiving multiple prescriptions from different specialists.

Behavioral Analytics: Key to Shutting Down the Medicare Part D ATM

Last year was another year in which specialty pharmaceuticals featured prominently in the FDA’s new drug approval and expanded indications list.

Below is the second installment of a summary of specialty pharmacy-related FDA approvals and expanded indications that took place in 2016. The first installment reviewed non-oncology specialty actions in 2016, while this installment reviews approvals related to oncology drugs, as well as late-breaking FDA actions that took place after the first installment was published.

Consult the respective product-prescribing monographs for complete information, including dosing regimens. New oncology molecular entities that were approved in 2016 are detailed below, and previously approved oncology drugs that received expanded indications in 2016 are listed below in Chart 1.

(venetoclax) was approved by the FDA for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test (companion diagnostic Vysis CLL FISH probe kit), who received at least 1 prior therapy. Venclexta is a BCL-2 inhibitor that was granted breakthrough therapy designation, priority review, and accelerated approval based on overall response rate.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. The recommended dosage of Venclexta is initially 20-mg once daily for 7 days, followed by a weekly ramp-up dosing schedule to the recommended daily dose of 400-mg.

Venclexta tablets should be taken orally, once daily with a meal and water. It is recommended to assess patient-specific factors for level of risk of tumor lysis syndrome (TLS), and provide prophylactic hydration and anti-hyperuricemics to patients prior to first dose of Venclexta to reduce the risk of TLS. Venclexta comes in a 10-mg, 50-mg, and 100-mg tablet for oral use. Venclexta has a starter pack that provides the first 4 weeks of medication according to the ramp-up schedule.

(melphalan) was approved for use as a high-dose conditioning treatment prior to hematopoietic progenitor (stem) cell transplantation in patients with multiple myeloma (MM), and for the palliative treatment of patients with MM for whom oral therapy is not appropriate.

Evomela is an alkylating drug that is available in a 50-mg single dose vial, as a lyophilized powder for reconstitution. The recommended dosage for Evomela for conditioning treatment is 100-mg/m2 per day administered over 30 minutes by intravenous infusion for 2 consecutive days (day -3 and day -2) prior to autologous stem cell transplantation (ASCT, day 0). The recommended dosage for palliative treatment is 16-mg/m2 administered as a single intravenous infusion over 15 to 20 minutes at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals.

(cabozantinib) was approved for the treatment of patients with advanced renal cell carcinoma (RCC) who have received prior antiangiogenic therapy. Cabometyx was granted Fast Track and Breakthrough Therapy designations by the FDA.

Cabometyx is a kinase inhibitor that is available in a 20-mg, 40-mg, and 60-mg tablet. The recommended dosage for Cabometyx is 60-mg orally once daily with a full glass (at least 8 ounces) of water. Patients are advised not to consume grapefruits, grapefruit juice, or nutritional supplements that are known to inhibit cytochrome P450 while on this medication; and should not eat at least 2 hours before, and at least 1 hour after, taking Cabometyx. Cabometyx tablets are not to be substituted with cabozantinib capsules.

Urothelial Carcinoma and Non-Small Cell Lung Cancer 

(atezolizumab) was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy, or have had disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response.

Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Furthermore, on October 18, 2016, Tecentriq was approved for the treatment of people with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy.

Patients with EGFR or ALK genomic tumor aberrations should have disease progression on an FDA-approved therapy for these aberrations prior to receiving Tecentriq. It is available in a 1200-mg/20 mL (60 mg/mL) solution in a single-dose vial. The recommended dose for Tecentriq is 1200-mg as an intravenous infusion over 60 minutes every 3 weeks. Medication should be diluted prior to intravenous infusion.

(olaratumab) was granted accelerated approval in combination with doxorubicin for the treatment of adult patients with soft tissue sarcoma with a histologic subtype for which an anthracycline-containing regimen is appropriate, and is not amenable to curative treatment with radiotherapy or surgery. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trial.

Lartruvo is a platelet-derived growth factor receptor alpha (PDGFR-α) blocking antibody. The recommended dose of Lartruvo is 15-mg/kg administered as an intravenous infusion over 60 minutes on days 1 and 8 of each 21-day cycle until disease progression or unacceptable toxicity. For the first 8 cycles, Lartruvo is to be administered with doxorubicin. Lartruvo is available in a 500-mg/50mL (10-mg/mL) solution in a single dose vial.

(rucaparib) was approved as a monotherapy for the treatment of women with deleterious BRCA mutation (germline and/or somatic) associated advanced ovarian cancer treated with 2 or more chemotherapies. Patients should be selected for therapy based on an FDA-approved companion diagnostic, such as FoundationFocus CDxBRCA.

This indication was granted accelerated approval based on objective response rate and duration of response. Rubraca is a poly (ADP-ribose) polymerase inhibitor that is available in a 200-mg and 300-mg tablet. The recommended dosage is 600-mg orally twice daily, with or without food. Treatment should be continued until disease progression or unacceptable toxicity. For adverse reactions, consider interruption of treatment or dose reduction.

 (dronabinol) was approved for the treatment of adults with anorexia associated with weight loss in patients with AIDS; and nausea and vomiting (N/V) associated with cancer chemotherapy in patients who have failed to respond adequately to conventional antiemetic treatments.

Syndros is an orally active cannabinoid that has complex effects on the central nervous system, including central sympathomimetic activity. Syndros is available in a 5-mg/ml oral solution. For patients with anorexia associated with weight loss from AIDS, the recommended starting dosage is 2.1-mg orally, twice daily, 1 hour before lunch and dinner.

For patients with N/V associated with chemotherapy who have failed conventional antiemetics, the recommended starting dosage is 4.2-mg/m2, administered 1 to 3 hours prior to chemotherapy, then every 2 to 4 hours after chemotherapy, for a total of 4 to 6 doses per day.

The first dose should be given on an empty stomach at least 30 minutes prior to eating; subsequent doses can be taken without regard to meals. The calibrated oral dosing syringe included in the product packaging should always be used to measure the dose. Syndros should be taken with a full glass of water (6 to 8 ounces).

extended-release injection, formerly APF530, was approved in combination with other antiemetics in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide combination chemotherapy regimens. Sustol is a serotonin-3 (5-HT3) receptor antagonist available in an extended-release 10-mg/0.4ml single-dose, pre-filled syringe.

The recommended dosage in adults is 10-mg administered as a single subcutaneous injection at least 30 minutes before the start of emetogenic chemotherapy on day 1. Sustol should not be administered more frequently than once every 7 days, and use of Sustol with successive emetogenic chemotherapy cycles for more than 6 months is not recommended.

Additional Late-Breaking Specialty FDA Actions 

(ranibizumab) received an expanded dosage form approval for 0.5-mg prefilled syringe (PFS) to treat people with wet age-related macular degeneration and macular edema after retinal vein occlusion (RVO). The Lucentis PFS is the first syringe prefilled with an anti-vascular endothelial growth factor (VEGF) medicine approved to treat 2 eye conditions.

Lucentis is a VEGF inhibitor that was initially approved in June 2010 for the treatment of macular edema following RVO. It was approved in 2012 for the treatment of diabetic macular edema, and in 2015 for the treatment of diabetic retinopathy. Lucentis is available in 2 dosage strengths: 10-mg/mL (Lucentis 0.5-mg) and 6-mg/mL (Lucentis 0.3-mg) in single-use glass vials and 10-mg/mL PFS solution designed to provide 0.05-mL for intravitreal injection.

(etanercept) received an expanded indication for the treatment of pediatric patients (ages 4 to 17) with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy. Enbrel is a tumor necrosis factor blocker that was initially approved in November 1998.

Enbrel is also indicated for the treatment of adult PsO, rheumatoid arthritis, polyarticular juvenile idiopathic arthritis in patients aged 2 years or older, psoriatic arthritis, and ankylosing spondylitis. Enbrel is available in a 25-mg/0.5 mL single-dose prefilled syringe and in a 50-mg/mL solution in a single-dose prefilled syringe or in a single-dose prefilled SureClick Autoinjector. It is also available in a 25-mg lyophilized powder in a multiple-dose vial for reconstitution. The recommended dosage for pediatric PsO is 0.8-mg/kg weekly, with a maximum of 50-mg per week subcutaneously.

(maraviroc) received an expanded indication for the treatment of only CCR5-tropic HIV-1 infection, in patients age 2 years and older weighing at least 10 kg, in combination with other antiretroviral agents. Selzentry is not recommended in patients with dual/mixed- or CXCR4-tropic HIV-1. Selzentry is a CCR5 co-receptor antagonist that was initially approved in August 2007 for HIV in adults.

It is available in a 25-mg, 75-mg, 150-mg, and 300-mg tablet; and a 20-mg per mL oral solution. The recommended dose of Selzentry, in pediatric patients 2 years and older and weighing at least 10 kg, is based on body weight and concomitant medications and given twice daily, with or without food. Dosage should not exceed the recommended adult dose.

(tenofovir alafenamide) was approved for the treatment of chronic hepatitis B virus infection in adults with compensated liver disease. Vemlidy is a hepatitis B virus (HBV) nucleoside analog reverse transcriptase inhibitor that comes with a boxed warning of lactic acidosis/severe hepatomegaly with steatosis and post treatment severe acute exacerbation of HBV.

Prior to initiation of Vemlidy, patients should be tested for HIV infection. Vemlidy alone should not be used in patients with HIV infection. Vemlidy is available in a 25-mg oral tablet, and the recommended dosage is 25-mg once daily with food.

(nusinersen) was approved for the treatment of spinal muscular atrophy in pediatric and adult patients. Spinraza is a survival motor neuron-2 (SMN2)-directed antisense oligonucleotide that is administered intrathecally. Spinraza received fast track designation, priority review and orphan drug designation by the FDA. Also, the sponsor is receiving a rare pediatric disease priority review voucher for prevention and treatment issued by the FDA.

The recommended dosage of Spinraza is 12-mg (5 mL) per administration. Initial treatment with Spinraza includes 4 loading doses; the first 3 loading doses should be administered at 14-day intervals; the 4th loading dose should be administered 30 days after the 3rd dose; a maintenance dose should be administered once every 4 months thereafter. Spinraza is supplied as a 12-mg/5 mL (2.4 mg/mL) solution in a single-dose, preservative-free glass vial.

(antihemophilic factor [recombinant] pegylated) received an expanded indication for hemophilia A (congenital factor VIII deficiency) treatment in pediatric patients under age 12 for on-demand treatment, control of bleeding episodes, and routine prophylaxis to reduce the frequency of bleeding episodes. Adynovate was also approved at that time for use in surgical settings for both adult and pediatric patients.

Adynovate was initially approved in November 2015 for the treatment of hemophilia A in adolescent and adult patients (12 years and older). Adynovate is not indicated for the treatment of von Willebrand disease. Adynovate is available as a lyophilized powder for reconstitution in single-use vials containing approximately 250, 500, 1000, or 2000 IU of factor VIII potency.

The dosage and duration of treatment depends on the severity of factor VIII deficiency, the location and extent of the bleed, and the patient’s clinical condition. Careful monitoring of replacement therapy is necessary in cases of serious or life-threatening bleeding episodes.

Venclexta Prescribing Information, Abbvie Inc., April 2016. Available at: http://www.rxabbvie.com/pdf/venclexta.pdf 

FDA approves new drug for chronic lymphocytic leukemia in patients with a specific chromosomal abnormality, US FDA, April 11, 2016. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm495253.htm Accessed: May 2, 2016

Clinical Insights

A comprehensive review of new oncology molecular entities and previously approved oncology drugs that received expanded indications in 2016, as well as drugs approved in the final days of the year.

Specialty Drugs Year in Review Part II: Oncology Drugs and Late-breaking FDA Actions

In recent years, there have been major advancements in the development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS), with promising new treatments soon. Despite this, there are still many unmet needs in the treatment of MS.

Existing treatments for MS may reduce relapse rates and slow disease progression, but responses to these treatments are often suboptimal, produce variable responses in patients, and, if successful, are only preventative and not restorative. Currently, there are no FDA-approved treatment options for progressive forms of MS.

This article will review MS treatments currently in phase 3 trials, and how they may address some of the unmet needs of patients.

Siponimod is an oral drug in the same class as the FDA-approved DMT fingolimod (Gilenya), a sphingosine-1-phosphate (S1P) modulator. Like fingolimod, siponimod binds S1P receptors on the surface of lymphocytes. These receptors play a key role in the immune system, and regulate the movement of lymphocytes from lymph tissue into circulation.

By binding to these receptors, S1P modulators ultimately cause receptor down-regulation, resulting in lymphocytes remaining in the lymph tissue.

As a second-generation S1P modulator, siponimod targets S1P receptors 1 and 5, while sparing receptors 2, 3, and 4.

The goal of this specificity is to improve upon the side effect profile of fingolimod (a first-generation S1P modulator).

The efficacy and safety of various siponimod doses was evaluated in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 2 BOLD trial. In this double-blind trial, patients were assigned to 1 of 2 cohorts.

In the first cohort, 188 patients were randomized (1:1:1:1) to receive once-daily siponimod 0.5-mg, 2-mg, 10-mg, or placebo for 6 months. In the second cohort, 109 patients were randomized (4:4:1) to receive once-daily siponimod 1.25-mg, 0.5-mg, or placebo for 3 months.

The primary endpoint was percent reduction in monthly number of combined active lesions, as determined by MRI at 3 months for the 5 different doses.

Despite limited sample size and duration in this trial, siponimod demonstrated dose-dependent reduction of combined active lesions ranging from 35% (0.25-mg) to 82% (10-mg).

The most common adverse events were headache, upper respiratory tract infection, nasopharyngitis, increase in liver transaminases, lymphopenia, and heart rate reduction. Currently there is an ongoing phase 3 trial of siponimod in patients with progressive MS.

Like siponimod, ponesimod is an oral investigational drug in the S1P modulator class. Ponesimod is a second-generation S1P modulator that targets S1P receptor 1 with some effect on receptors 3 and 5, but no effect on receptors 2 and 4.

In trials, ponesimod has been found to have less pharmacokinetic variability then fingolimod and a shorter half-life (approximately 32 hours compared with approximately 8 days with fingolimod). Ponesimod’s pharmacological effects are rapidly reversible, with lymphocyte counts returning to normal range within 96 hours.

In comparison, lymphocyte counts return to normal within 1 to 2 months after therapy with fingolimod. The results of a double-blind, placebo-controlled phase 2 trial evaluating the efficacy and safety of ponesimod in RRMS were published in early 2016. In that trial, 464 patients were randomized to receive once-daily ponesimod at a dose of 10-, 20-, or 40-mg or placebo (1:1:1:1) for 24 weeks.

The primary endpoint was the cumulative number of new lesions, as detected on MRI per patient recorded every month from weeks 12 to 24. Secondary endpoints were the annualized relapse rate (ARR) and the time to first confirmed relapse. The cumulative number of new lesions was significantly lowered in a dose-dependent manner in the ponesimod 10-mg (by 43%), 20-mg (by 83%), and 40-mg (by 77%) groups compared with placebo.

The ARR was reduced with ponesimod therapy compared to placebo (by 37% with 10-mg, 21% with 20-mg, and 52% with 40-mg), and the time to first relapse was also increased. Ponesimod was well tolerated at doses below 40-mg, with the most common adverse events including anxiety, dizziness, dyspnea, increased liver enzymes, influenza, insomnia, and peripheral edema.

Despite receptor selectivity, ponesimod was also associated with reduced heart rate after the first dose, as with other S1P modulators. In phase 1 trials, it was found that titrating up to the higher doses reduced this adverse event.

Currently, there is an ongoing phase 3 trial (OPTIMUM) comparing ponesimod to teriflunomide for RRMS that is expected to conclude in 2018.

 Further trials will be needed to confirm the efficacy and safety profile of ponesimod.

Like siponimod and ponesimod, ozanimod is another S1P receptor modulator that selectively targets S1P receptor subtypes 1 and 5.

At the annual American Academy of Neurology meeting in 2015, the phase 2 portion of the RADIANCE trial was presented.

The RADIANCE phase 2 trial was a 24-week, double-blind, randomized controlled trial in 258 patients who received once-daily ozanimod 0.5-mg, 1-mg, or placebo (1:1:1). The primary endpoint was cumulative number of lesions on monthly MRI, and secondary endpoints were ARR and number of new lesions. With both doses of ozanimod, the cumulative number of lesions from weeks 12 to 24 was found to be reduced by 86% compared with placebo.

The cumulative number of new lesions was reduced by 84% for the 0.5-mg group and 91% for the 1 mg group from weeks 12 to 24, while the ARR was reduced by 31% and 53%, respectively. The medication was well tolerated, with a high rate of trial completion (> 96%) across treatment groups.

The most common adverse events in the treatment groups versus the placebo group were nasopharyngitis, headache, and urinary tract infection. Effects on cardiac conduction with the first dose of ozanimod were negligible.

The phase 3 portion of the RADIANCE trial, which will evaluate ozanimod compared with interferon beta-1a in patients with progressive MS, is expected to conclude in 2017. Another phase 3 trial, SUNBEAM, will also compare ozanimod to interferon beta-1a in patients with relapsing MS. That trial will also conclude in 2017.

Laquinimod is a quinolone-3-carboxamide currently undergoing phase 3 trials for the treatment of MS. The mechanism of action of laquinimod is not fully understood, but is believed to help reduce the number of pro-inflammatory immune cells by interfering with the expression of pro-inflammatory genes.

In two phase 3 trials, laquinimod produced contradictory results. In the 24-month, double-blind, randomized, placebo-controlled ALLEGRO trial, laquinimod at a dose of 0.6-mg was found to modestly reduce annual ARR by 23% compared with placebo in patients with RRMS.

Laquinimod was also associated with a reduced mean cumulative number of lesions compared with placebo (P <0.001), as well as a reduction in disability progression. However, conflicting results were found in the 24-month, double-blind, randomized, placebo-controlled BRAVO trial comparing once-daily 0.6 mg laquinimod to placebo and to once-weekly 30 mcg Avonex.

There was not a significant difference found in the ARR between laquinimod and placebo, with ARR being reduced by only 18%. Laquinimod did produce positive results, however, with certain MRI parameters, including percent brain volume change (significantly reduced compared with placebo, P < 0.001). In both trials, laquinimod was well tolerated, with the most common adverse events including abdominal pain, back pain, cough, and elevated liver enzymes (reversible after discontinuation).

Despite the results from the BRAVO trial, laquinimod is still being studied in phase 2 and phase 3 trials. In the two phase 3 trials CONCERTO and ARPEGGIO, the higher dose treatment groups of laquinimod (1.2-mg and 1.5-mg) had to be discontinued due to cardiovascular events in 8 patients. Both trials will continue with the 0.6-mg treatment groups.

Further trials are required to establish the safety and efficacy of this drug.

Masitinib is a tyrosine kinase inhibitor (TKI), the first of its class to be evaluated in the use of MS. Masitinib blocks tyrosine kinase, an enzyme that plays a role in signaling the division, growth, and proliferation of immune cells. This blockade occurs by binding to epidermal growth factor receptor (EGFR), a receptor on the surface of most cells.

As a selective TKI, mast cells are the main target of this drug.

Oral masitinib was studied for the treatment of progressive forms of MS in a randomized, placebo-controlled phase 2 trial. Masitinib was dosed at 3- to 6-mg/kg/day for at least 12 months of therapy, with dose increases made if inadequate response and no toxicity.

The primary endpoint was a change in the multiple sclerosis functional composite (MSFC) score compared with baseline. Thirty-five patients were included in this trial, with 27 receiving masitinib and 8 receiving placebo. Although there was more improvement in the MSFC results in the masitinib treatment arm, it was not a significant improvement compared to the placebo treatment group, which had, overall, worsening MSFC scores.

This improvement was seen as early as 3 months, and was sustained through month 18. Masitinib was well-tolerated, with the most common adverse events including asthenia, rash, nausea, edema, and diarrhea. Those adverse events are consistent with other TKIs.

The frequency of adverse events was similar to placebo, but masitinib was associated with more severe adverse events.

Currently, a phase 3 trial is underway to further evaluate the efficacy and safety of masitinib in progressive forms of MS.

At this time, ocrelizumab is on the FDA fast track for approval for the treatment of RRMS and PPMS.

If approved, ocrelizumab will be the first treatment approved for PPMS. Ocrelizumab is a monoclonal antibody specific for CD20 B cells, which play an important role in pro-inflammatory processes and the creation of autoantibodies.

Ocrelizumab was studied in three phase 3 trials: OPERA I, OPERA II, and ORATORIO. OPERA I and II were 2 identical randomized, double-blind, 96-week-long, parallel phase 3 trials evaluating the safety and efficacy of ocrelizumab compared with interferon-beta-1a in patients with relapsing forms of MS.

Patients were randomized (1:1) to receive intravenously infused ocrelizumab 600-mg monthly or subcutaneous interferon-beta-1a 44 mcg three times per week. The primary endpoint was number of patients achieving no evidence of disease activity (NEDA), defined as no relapses, disability progression, or new or enlarging lesions.

At 96 weeks, 47.9% ocrelizumab patients achieved NEDA versus 29.2% interferon patients in OPERA I (P < 0.0001). In OPERA II, 47.5% of ocrelizumab patients achieved NEDA vs. 25.1% of interferon patients (P< 0.001).20 In the double-blind, placebo-controlled, randomized ORATORIO trial, ocrelizumab was assessed in 732 patients with PPMS.

Patients were randomized (2:1) to receive ocrelizumab 600-mg (two doses of 300-mg two weeks apart) every 24 weeks or placebo for 120 weeks. The primary endpoint was the time to onset of confirmed disability progression (CDP) sustained for 12 weeks, as determined by an increase in the Expanded Disability Status Scale.

Ocrelizumab was found to significantly reduce the relative risk of 12-week CDP compared with placebo. Relative risk was reduced by 24% (P = 0.0321). In addition, ocrelizumab reduced the 24-week CDP by 25%, and the timed 25-foot walk test progression rate by 29% compared with placebo. Adverse events were similar in both groups.

The most common adverse events associated with ocrelizumab were infusion-related reactions and infections, most of which were mild to moderate.

With these results, ocrelizumab is the only late-stage pipeline medication with strong evidence of efficacy in primary progressive MS. The approval of ocrelizumab is highly anticipated, and the medication is expected to do well in the market.

There are several compounds in the late-stage pipeline for MS with promising clinical trial data, many of them in the S1P modulator class. Additionally, there are dozens of drugs in preclinical stages with a variety of targeted pathways. In the coming years, providers will likely have more medication options for the treatment of RRMS, as well as a much-needed treatment option for PPMS. It is important for providers and specialty pharmacists to be informed about pipeline medications, in order to provide accurate and up-to-date information to patients with MS.&ensp;

		Goodin DS, Frohman EM, Garmany GP Jr., et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. 

		Pan S, et al. Discovery of BAF312 (siponimod), a potent and selective S1P receptor modulator. 

		Selmaj K, Li DK, Hartung HP, et al. Siponimod for patients with relapsing-remitting multiple sclerosis (BOLD): an adaptive, dose-ranging, randomised, phase 2 study. 

		Brossard P, Derendorf H, Xu J, et al. Pharmacokinetics and pharmacodynamics of ponesimod, a selective S1P1 receptormodulator, in the first-in-human study. 

		Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing-remitting multiple sclerosis: a randomised phase II trial. 

		Oral ponesimod versus teriflunomide in relapsing multiple sclerosis (OPTIMUM). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02425644?term=ponesimod&rank=4. Published.  Published April 21, 2015. Accessed November 16, 2016.

		Multiple sclerosis drug candidate shows new promise. Science Daily. www.sciencedaily.com/releases/2014/09/140919092755.htm. Published September 19, 2014. Accessed November 16, 2016.

		Cohen JA, Arnold DL, Comi G, et al. Phase 2 results of the RADIANCE trial: a randomized, double-blind, placebo-controlled trial of oral RPC1063 in relapsing multiple sclerosis (LB1.1) 

		Moore C. Celgene to acquire Receptos, advancing leadership in immune&shy;inflammatory diseases such as MS and IBD. 

. http://multiplesclerosisnewstoday.com/2015/07/17/celgene-acquire-receptos-advancing-leadership-immune-inflammatory-diseases-ms-ibd/. Published July 17, 2015.  Accessed November 25, 2016.

		Efficacy and safety study of RPC1063 in relapsing multiple sclerosis (Radiance Study). ClinicalTrials.gov www.clinicaltrials.gov/ct2/show/NCT02047734?no_unk=Y&cond=multiple+sclerosis&phase=2&lup_s=12%2F01%2F2014&lup_e=09%2F29%2F2015&rank=55. Published April 14, 2015.  Accessed November 25, 2016.

		Kieseier, Bernd C. Defining a Role for Laquinimod in Multiple Sclerosis. 

New Product Pipeline

Current stage 3 trials for multiple sclerosis medications may address several unmet needs in the patient population.

Late-Stage Pipeline Review for Multiple Sclerosis Treatments

In December 2016, QuintilesIMS reported that US spending on prescription medications will reach upwards of $675 billion by 2021.

The pricing pressure on manufacturers is expected to grow along with the demand that specialty therapies, in particular, demonstrate positive outcomes in real-world conditions, as the shift from fee-for-service to value-based care accelerates, regardless of future shifts in health care policy.

To date, value-based contracts among pharmaceutical manufacturers and payers have not achieved the adoption and success levels necessary to drive significant systemic change, because many of these agreements cover only one drug, and/or rely on simple volumetric math as the arbiter of contractual conditions and payment.

Specialty pharmacies that offer effective medication therapy management and support are best suited to serve as arbiters of the next generation of value-based contracts.

January/February 2017

Medical Benefit Specialty Drug Managementâ€“A Call to Action

Behavioral Analytics: Key to Shutting Down the Medicare Part D ATM

Specialty Drugs Year in Review Part II: Oncology Drugs and Late-breaking FDA Actions

Late-Stage Pipeline Review for Multiple Sclerosis Treatments

Value-based Contracting 2.0: Is Specialty Pharmacy Ready for its Shot at the Spotlight?

HHS Guidance Requires Specialty Pharmacies to Scrutinize Patient Cost-Sharing and Incentive Programs

Should Specialty Look at Mobile Health?

Tweeting This Out: Build a Wall Around DIR Fees and Make Specialty Pharmacy Great Again

Specialty Pharmacyâ€™s Role in the Changing Face of Health Care