External Infusion Pumps

CMS Pub. 100-03, (National Coverage Determinations Manual), Chapter 1, Sections 280.1, 280.14

For any item to be covered by Medicare, it must 1) be eligible for a defined Medicare benefit category, 2) be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member, and 3) meet all other applicable Medicare statutory and regulatory requirements.

The purpose of a Local Coverage Determination (LCD) is to provide information regarding “reasonable and necessary” criteria based on Social Security Act § 1862(a)(1)(A) provisions.

In addition to the “reasonable and necessary” criteria contained in this LCD there are other payment rules, which are discussed in the following documents, that must also be met prior to Medicare reimbursement:

• The LCD-related Standard Documentation Requirements Article, located at the bottom of this policy under the Related Local Coverage Documents section.
• The LCD-related Policy Article, located at the bottom of this policy under the Related Local Coverage Documents section.
• Refer to the Supplier Manual for additional information on documentation requirements.
• Refer to the DME MAC web sites for additional bulletin articles and other publications related to this LCD.

For the items addressed in this LCD, the "reasonable and necessary" criteria, based on Social Security Act § 1862(a)(1)(A) provisions, are defined by the following coverage indications, limitations and/or medical necessity.

Payment may be made for supplies that are necessary for the effective use of durable medical equipment. Such supplies include those drugs and biologicals which must be put directly into the equipment in order to achieve the therapeutic benefit of the durable medical equipment or to assure the proper functioning of the equipment. However, the coverage of such drugs or biologicals does not preclude the need for a determination that the drug or biological itself is reasonable and necessary for treatment of the illness or injury or to improve the functioning of a malformed body member.

An external infusion pump is covered for the following indications (I-V):

An infusion pump described by codes E0779, E0780, E0781, and E0791 is covered for indications I – III, V(A) – V(D), V(F), V(G), V(I) and V(J). Coverage of other pumps is addressed under indications IV, V(E), and V(H).

1. Administration of deferoxamine for the treatment of chronic iron overload.
2. Administration of chemotherapy for the treatment of primary hepatocellular carcinoma or colorectal cancer where this disease is unresectable or where the beneficiary refuses surgical excision of the tumor. Anticancer chemotherapy drugs used in these conditions are not required to meet the criteria described by indication V, situation A.
3. Administration of morphine when used in the treatment of intractable pain caused by cancer.
4. Administration of continuous subcutaneous insulin for the treatment of diabetes mellitus (Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses.) if criterion A or B is met and if criterion C or D is met:
   1. C-peptide testing requirement – must meet criterion 1 or 2 and criterion 3:
      
      1. C-peptide level is less than or equal to 110 percent of the lower limit of normal of the laboratory's measurement method.
      2. For beneficiaries with renal insufficiency and a creatinine clearance (actual or calculated from age, weight, and serum creatinine) less than or equal to 50 ml/minute, a fasting C-peptide level is less than or equal to 200 per cent of the lower limit of normal of the laboratory’s measurement method.
      3. A fasting blood sugar obtained at the same time as the C-peptide level is less than or equal to 225 mg/dl.
   2. Beta cell autoantibody test is positive.
   3. The beneficiary has completed a comprehensive diabetes education program, has been on a program of multiple daily injections of insulin (i.e., at least 3 injections per day) with frequent self-adjustments of insulin dose for at least 6 months prior to initiation of the insulin pump, and has documented frequency of glucose self-testing an average of at least 4 times per day during the 2 months prior to initiation of the insulin pump, and meets one or more of the following criteria (1 - 5) while on the multiple injection regimen:
      1. Glycosylated hemoglobin level (HbA1C) greater than 7 percent
      2. History of recurring hypoglycemia
      3. Wide fluctuations in blood glucose before mealtime
      4. Dawn phenomenon with fasting blood sugars frequently exceeding 200 mg/dL
      5. History of severe glycemic excursions
   4. The beneficiary has been on an external insulin infusion pump prior to enrollment in Medicare and has documented frequency of glucose self-testing an average of at least 4 times per day during the month prior to Medicare enrollment.
   
   If criterion A or B is not met, the pump and related accessories, supplies, and insulin will be denied as not reasonable and necessary. If criterion C or D is not met, the pump and related accessories, supplies, and insulin will be denied as not reasonable and necessary.
   
   Continued coverage of an external insulin pump and supplies requires that the beneficiary be seen and evaluated by the treating practitioner at least every 3 months. In addition, the external insulin infusion pump must be ordered and follow-up care rendered by a practitioner who manages multiple beneficiaries on continuous subcutaneous insulin infusion therapy and who works closely with a team including nurses, diabetic educators, and dieticians who are knowledgeable in the use of continuous subcutaneous insulin infusion therapy.
   
   Subcutaneous insulin is administered using ambulatory infusion pump E0784. Claims for usage of infusion pumps other than E0784 will be denied as not reasonable and necessary.
   
   The HCPCS code combination of E0784 plus E2103 is used to describe external ambulatory insulin infusion pumps that incorporate dose rate adjustment using non-adjunctive continuous glucose sensing. Coverage for this HCPCS code combination is only met if the beneficiary meets all of the coverage criteria for insulin pumps outlined in this policy and all criteria for CGMs as outlined in the Glucose Monitors LCD (L33822).
   
   For claims with dates of service on or after April 1, 2022, the HCPCS code combination of E0784 plus E2102 is used to describe external ambulatory insulin infusion pumps with integrated adjunctive continuous glucose monitor receiver functionality. Coverage for this HCPCS code combination is only met if the beneficiary meets all of the coverage criteria for insulin pumps outlined in this policy and all criteria for CGMs as outlined in the Glucose Monitors LCD (L33822).
   
   Refer to the GENERAL section below, and to the CODING GUIDELINES section in the LCD-related Policy Article for additional information regarding supplies used in conjunction with insulin infusion pumps (E0784).
   
   Claims with dates of service on or after January 01, 2017 for supply HCPCS codes A4221, A4222 and K0552, when used with an external infusion pump HCPCS code E0784 will be denied as incorrect coding.
   
   
5. Administration of other drugs if either of the following sets of criteria (1) or (2) are met:
   • Criteria set 1:
     • Parenteral administration of the drug in the home is reasonable and necessary
     • An infusion pump is necessary to safely administer the drug
     • The drug is administered by a prolonged infusion of at least 8 hours because of proven improved clinical efficacy
     • The therapeutic regimen is proven or generally accepted to have significant advantages over intermittent bolus administration regimens or infusions lasting less than 8 hours
   • Criteria set 2: 
     • Parenteral administration of the drug in the home is reasonable and necessary
     • An infusion pump is necessary to safely administer the drug
     • The drug is administered by intermittent infusion (each episode of infusion lasting less than 8 hours) which does not require the beneficiary to return to the practitioner's office prior to the beginning of each infusion
     • Systemic toxicity or adverse effects of the drug are unavoidable without infusing it at a strictly controlled rate as indicated in the Physicians Desk Reference, or the U.S. Pharmacopeia Drug Information

Coverage for the administration of other drugs, based on criteria set (1) or (2), using an external infusion pump is limited to the following situations (A) - (J):

1. Administration of the anticancer chemotherapy drugs cladribine, fluorouracil, cytarabine, bleomycin, floxuridine, doxorubicin (non-liposomal), vincristine (non-liposomal) or vinblastine by continuous infusion over at least 8 hours when the regimen is proven or generally accepted to have significant advantages over intermittent administration regimens 

2. Administration of narcotic analgesics (except meperidine) in place of morphine to a beneficiary with intractable pain caused by cancer that has not responded to an adequate oral/transdermal therapeutic regimen and/or cannot tolerate oral/transdermal narcotic analgesics

3. Administration of the following antifungal or antiviral drugs: acyclovir, foscarnet, amphotericin B, and ganciclovir

4. Administration of parenteral inotropic therapy using the drugs dobutamine (J1250), milrinone (J2260) or dopamine (J1265) for beneficiaries with American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Stage D heart failure (HF) or New York Heart Association (NYHA) Class IV HF, if a beneficiary meets all of the following criteria: 
   1. Remains symptomatic despite optimal guideline directed medical therapy (GDMT) as defined below; and,
   2. As “Bridge” therapy for patients eligible for and awaiting mechanical circulatory support (MCS)/cardiac transplantation, or as palliative care for patients not eligible for either MCS/cardiac transplantation; and,
   3. Prescribed following an evaluation by a cardiologist with training in the management of advanced heart failure; and,
   4. There has been a documented improvement in beneficiary symptoms of heart failure while on the selected inotropic drug at the time of discharge from an inpatient or skilled nursing care facility; and,
   5. An evaluation every three months by the prescribing provider or a heart failure team with oversight by a cardiologist with training in the management of advanced heart failure, which documents the beneficiary’s cardiac symptoms and the continuing response and need for therapy. The heart failure team or practitioner may have no financial relationship with the supplier.

Guideline-directed medical therapy (GDMT) is compliance with optimal medical therapy as defined by ACCF/AHA guideline–recommended therapies (primarily Class I recommendations). These include the use of diuretics, ACE inhibitors or ARB antagonists, beta-blockers, aldosterone antagonists, hydralazine & isosorbide dinitrate, and statins, as appropriate.

For an external infusion pump and related inotropic drugs covered prior to 12/01/2015, if the Medicare coverage criteria in effect on the initial date of service were met, the pump and drug(s) will continue to be covered for claims with dates of service on or after 12/01/2015 as long as the beneficiary continues to meet medical need.

5. Administration of epoprostenol (J1325) or treprostinil (J3285) for beneficiaries with pulmonary hypertension if they meet the following disease criteria:
   1. The pulmonary hypertension is not secondary to pulmonary venous hypertension (e.g., left sided atrial or ventricular disease, left sided valvular heart disease, etc.) or disorders of the respiratory system (e.g., chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea or other sleep disordered breathing, alveolar hypoventilation disorders, etc.); and
   2. The beneficiary has primary pulmonary hypertension or pulmonary hypertension, which is secondary to one of the following conditions: connective tissue disease, thromboembolic disease of the pulmonary arteries, human immunodeficiency virus (HIV) infection, cirrhosis, diet drugs, congenital left to right shunts, etc. If these conditions are present, the following criteria must be met:
      1. The pulmonary hypertension has progressed despite maximal medical and/or surgical treatment of the identified condition; and,
      2. The mean pulmonary artery pressure is greater than 25 mm Hg at rest or greater than 30 mm Hg with exertion; and,
      3. The beneficiary has significant symptoms from the pulmonary hypertension (i.e., severe dyspnea on exertion, and either fatigability, angina, or syncope); and,
      4. Treatment with oral calcium channel blocking agents has been tried and failed, or has been considered and ruled out.
      5. Epoprostenol/treprostinil is administered using ambulatory infusion pump K0455. Claims for usage of infusion pumps other than K0455 will be denied as not reasonable and necessary.
         
         
6. Gallium nitrate (J7799) is covered for the treatment of symptomatic cancer-related hypercalcemia (Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses.). In general, beneficiaries with serum calcium (corrected for albumin) less than 12 mg/dl would not be expected to be symptomatic.
   
   The recommended usage for gallium nitrate is daily for five consecutive days. Use for more than 5 days will be denied as not reasonable and necessary.
   
   More than one course of treatment for the same episode of hypercalcemia will be denied as not reasonable and necessary.
   
   
7. Ziconotide (J2278) is covered for the management of severe chronic pain in beneficiaries for whom intrathecal (IT or epidural) therapy is warranted, and who are intolerant of or refractory to other treatment, such as systemic analgesics, adjunctive therapies, or IT morphine.
   
   
8. Subcutaneous immune globulin (SCIg) (see Group 3 HCPCS codes) is covered when criteria 1-3, AND criterion 4 or 5 are met:
   1. The subcutaneous immune globulin preparation is a pooled plasma derivative which is FDA-approved; and,
   2. The SCIg is administered in the home; and,
   3. The treating practitioner has determined that administration of the SCIg in the patient's home is medically necessary and appropriate; and,
   4. The beneficiary has a primary immune deficiency disorder (Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses.); OR,
   5. The beneficiary has a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) that has responded to IVIg treatment (Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses.).

Coverage of subcutaneous immune globulin applies only to those products that are specifically labeled as subcutaneous administration products. Intravenous immune globulin products are not covered under this LCD.

If a drug and pump combination is used, other than those listed in the table in the LCD-related Policy Article, the pump and drug will be denied as not reasonable and necessary (see Coding Guidelines section of the LCD-related Policy Article).

1. 9. Infusion-based therapy (including enteral suspension) for the treatment of Parkinson’s Disease will be covered if criterion 1 and either criterion 2 or 3 are met (refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses):
      
      1. The beneficiary is diagnosed with levodopa-responsive idiopathic Parkinson’s Disease; and,
      2. The dosage and/or dosing interval of non-infusion-based Parkinson’s Disease therapy cannot be further optimized due to intolerance, dyskinesia and/or other side effects/adverse events, and the beneficiary continues to experience all of the following:
         1. Inadequate control of motor fluctuation symptoms affecting daily living (e.g., unpredictable increase in stiffness, tremor, bradykinesia); and,
         2. A minimum of 2.5 hours of “off” time per day; or
      3. The beneficiary is currently being treated with an infusion-based Parkinson’s Disease therapy and is being transitioned to a different infusion-based Parkinson’s Disease therapy.

10. Blinatumomab (J9039) is covered for adult and pediatric beneficiaries (one month or older) who meet one of the following coverage criteria:
    1. Up to nine (9) cycles for the treatment of relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL); or
    2. Up to four (4) cycles for the treatment of B-cell precursor ALL in first or second remission with minimal residual disease (MRD) greater than or equal to 0.1%; or,
    3. Up to four (4) cycles for the treatment of CD19-positive, Philadelphia chromosome-negative, B-cell precursor ALL in the consolidation phase of multiphase chemotherapy. 

(Refer to the ICD-10 code list in the LCD-related Policy Article for applicable diagnoses.)

Maximum utilization is 875 units of service (UOS), which is equivalent to 25 vials per month. Claims for more than 875 UOS (25 vials) will be denied as not reasonable and necessary. Refer to the CODING GUIDELINES section of the LCD-related Policy Article for information regarding units of service.

 
GENERAL

External infusion pumps and related drugs and supplies will be denied as not reasonable and necessary when the criteria described by indication (I), (II), (III), (IV) or (V) are not met.

When an infusion pump is covered, the drug necessitating the use of the pump and necessary supplies are also covered. When a pump has been purchased by the Medicare program, other insurer, the beneficiary, or the rental cap has been reached, the drug necessitating the use of the pump and supplies are covered as long as the coverage criteria for the pump are met.

An external infusion pump and related drugs and supplies will be denied as not reasonable and necessary in the home setting for the treatment of thromboembolic disease and/or pulmonary embolism by heparin infusion.

An infusion controller device (E1399) is not reasonable and necessary.

An IV pole (E0776) is covered only when a stationary infusion pump (E0791) is covered. It is considered not reasonable and necessary if it is billed with an ambulatory infusion pump (E0779, E0780, E0781, E0784, or K0455).

Supplies for the maintenance of a parenteral drug infusion catheter (A4221) or supplies for the maintenance for an insulin infusion pump (A4224) are covered during the period of covered use of an infusion pump. They are also covered for the weeks in between covered infusion pump use, not to exceed 4 weeks per episode.

Supplies used with an external infusion pump, A4222 and K0552 or supplies used with an insulin infusion pump (A4225) are covered during the period of covered use of an infusion pump. Allowance is based on the number of cassettes or bags (A4222) prepared or syringes (A4225, K0552) used. For intermittent infusions, no more than one cassette or bag is covered for each dose of drug. For continuous infusion, the concentration of the drug and the size of the cassette, bag, or syringe should be maximized to result in the fewest cassettes, bags, or syringes in keeping with good pharmacologic and medical practice.

Claims with dates of service on or after January 01, 2017 for supply HCPCS codes A4224 and A4225 used with an external infusion pump other than HCPCS code E0784 will be denied as incorrect coding.

Drugs and supplies that are dispensed but not used for completely unforeseen circumstances (e.g., emergency admission to hospital, drug toxicity, etc.) are covered. Suppliers are expected to anticipate changing needs for drugs (e.g., planned hospital admissions, drug level testing with possible dosage change, etc.) in their drug and supply preparation and delivery schedule.

Charges for drugs administered by a DME infusion pump may only be billed by the entity that actually dispenses the drug to the Medicare beneficiary and that entity must be permitted under all applicable federal, state, and local laws and regulations to dispense drugs. Only entities licensed in the state where they are physically located may bill for infusion drugs. Drugs and related supplies and equipment billed by a supplier who does not meet these criteria will be denied as not reasonable and necessary.

Compounded drugs NOC (J7999) billed with an external infusion pump will be denied as not reasonable and necessary. Refer to the CODING GUIDELINES section of the related Policy Article for information about J7999 coding requirements.

Claims for compounded drugs that do not use code Q9977 or J7999 will be denied as incorrect coding.

A Standard Written Order (SWO) must be communicated to the supplier before a claim is submitted. If the supplier bills for an item addressed in this policy without first receiving a completed SWO, the claim shall be denied as not reasonable and necessary.

For Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS) base items that require a Written Order Prior to Delivery (WOPD), the supplier must have received a signed SWO before the DMEPOS item is delivered to a beneficiary. If a supplier delivers a DMEPOS item without first receiving a WOPD, the claim shall be denied as not reasonable and necessary. Refer to the LCD-related Policy Article, located at the bottom of this policy under the Related Local Coverage Documents section.

For DMEPOS base items that require a WOPD, and also require separately billed associated options, accessories, and/or supplies, the supplier must have received a WOPD which lists the base item and which may list all the associated options, accessories, and/or supplies that are separately billed prior to the delivery of the items. In this scenario, if the supplier separately bills for associated options, accessories, and/or supplies without first receiving a completed and signed WOPD of the base item prior to delivery, the claim(s) shall be denied as not reasonable and necessary.

An item/service is correctly coded when it meets all the coding guidelines listed in CMS HCPCS guidelines, LCDs, LCD-related Policy Articles, or DME MAC articles. Claims that do not meet coding guidelines shall be denied as not reasonable and necessary/incorrectly coded.

Proof of delivery (POD) is a Supplier Standard and DMEPOS suppliers are required to maintain POD documentation in their files. Proof of delivery documentation must be made available to the Medicare contractor upon request. All services that do not have appropriate proof of delivery from the supplier shall be denied as not reasonable and necessary.

REFILL REQUIREMENTS

For DMEPOS items and supplies provided on a recurring basis, billing must be based on prospective, not retrospective use. For DMEPOS products that are supplied as refills to the original order, suppliers must contact the beneficiary, and document an affirmative response, prior to dispensing the refill and not automatically ship on a pre-determined basis, even if authorized by the beneficiary. This shall be done to ensure that the refilled item remains reasonable and necessary, existing supplies are expected to end, and to confirm any changes or modifications to the order. Contact with the beneficiary or designee regarding refills must take place no sooner than 30 calendar days prior to the expected end of the current supply. For delivery of refills, the supplier must deliver the DMEPOS product no sooner than 10 calendar days prior to the expected end of the current supply. This is regardless of which delivery method is utilized.

For all DMEPOS items that are provided on a recurring basis, suppliers are required to have contact with the beneficiary or caregiver/designee and document an affirmative response, prior to dispensing a new supply of items. Suppliers must not deliver refills without a refill request and an affirmative response from a beneficiary. Items delivered without a valid, documented refill request will be denied as not reasonable and necessary.

Suppliers must not dispense a quantity of supplies exceeding a beneficiary's expected utilization. Suppliers must stay attuned to changed or atypical utilization patterns on the part of their clients. Suppliers must verify with the treating practitioners that any changed or atypical utilization is warranted.

Regardless of utilization, a supplier must not dispense more than a three (3) - month quantity at a time.

DRUG WASTAGE

Claims for drugs billed to Medicare must use drug dosage formulations and/or unit dose sizes that minimize wastage. Medicare provides payment for the amount of a single use vial or other single use package of drug or biological discarded, in addition to the dose administered. (See the MODIFIERS section of the External Infusion Pumps LCD-related Policy Article.)

Clinical Background

Blinotumomab

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is an aggressive, rapidly progressive blood cancer characterized by uncontrolled proliferation of abnormal, immature B- or T-lymphocytes leading to infiltration of bone marrow and other lymphoid organs.¹ In 2021, there were an estimated 115,294 people in the United States living with ALL, and based on 2017-2021 data, the rate of new cases of ALL was 1.8 per 100,000 people per year;² B-cell ALL (B-ALL) accounts for the majority of ALL cases (88% of cases in children and 75% of cases in adults).^3,4 In addition to classification by the type of precursor cell, ALL is also characterized by cell surface protein expression (e.g., CD19 positive) and the presence or absence of genetic mutations (e.g., Philadelphia chromosome positive or negative), both of which play a role in risk stratification and treatment planning.^1,3,5-7

The typical treatment for ALL involves a multi-phasic course (i.e., induction, consolidation, maintenance) of chemotherapy with or without the addition of other targeted drugs (e.g., immunotherapy) dependent upon the presence or absence of particular molecular biomarkers.^3,8 Cure and survival rates for ALL have improved significantly over the past several decades, with a 5-year survival rate of 90% in newly diagnosed patients < 15 years of age; however, long-term survival rates are notably lower in adolescents, adults, and in relapsed disease.^1,3,5,9,10 The aim of this summary of evidence is to examine the clinical literature supporting an indication expansion of blinatumomab for the treatment of CD19-positive, Philadelphia chromosome-negative, B-ALL during the consolidation phase of multiphase therapy in adults and pediatric patients one month or older.

Foslevodopa/Foscarbidopa

The Movement Disorder Society defines parkinsonism as bradykinesia, in combination with either rest tremor, rigidity, or both.¹¹ The most common form of parkinsonism is Parkinson’s disease (PD), a slowly progressive neurodegenerative disease of adult-onset, caused by the loss of dopaminergic neurons in the substantia nigra.^12-14 In addition to motor symptoms, non-motor features, such as cognitive decline, sleep disturbances, autonomic dysfunction, pain, and/or mood changes, are also present in many individuals with PD.^11,14 Idiopathic Parkinson’s disease is heterogeneous in presentation and progression, and while the exact cause is unknown, it is thought to be multifactorial, and involve a combination of genetic susceptibility and environmental factors.^14-20

The incidence of PD increases with age, with a notable rise after 65 years of age.^17,21 In the Medicare population, age-standardized PD incidence has been estimated to be 212 per 100,000 person-years with an incidence rate of nearly 90,000 per year.²¹ Additionally, the prevalence rate of PD has increased more rapidly than other neurologic conditions.^17,22 Based on a study conducted in 2017, an estimated 1 million people in the United States live with a diagnosis of PD, with 90% of this population being eligible for Medicare.²³ The prevalence of PD in the United States is projected to increase to over 1.2 million individuals by 2030.²⁴

There is no cure for Parkinson’s disease; however, pharmacologic treatments (e.g., oral levodopa/carbidopa, dopamine agonists, amantadine) and rehabilitation therapies (i.e., physical, occupational, speech), are available to help manage symptoms and improve quality of life (QoL).¹⁴ While levodopa is the most effective drug for the management of motor symptoms related to PD, the half-life of the drug is short, resulting in fluctuations in blood levels and, over time as PD advances, motor symptom control.^25,26 Motor fluctuations are characterized by patients alternating between “on” states, when symptoms are well controlled, and “off” states, when tremor and/or rigidity reappear; the timing of these states may become unpredictable as PD advances.^14,25 Motor complications are noted in up to 50% of patients within 2-5 years of dopaminergic therapy, and in 80-100% of patients after 10 years.²⁵ Newer delivery systems and formulations of levodopa have been developed to help manage motor fluctuations in advancing PD not adequately controlled with dosage and timing adjustments of oral medications or due to adverse treatment effects, such as dyskinesia (i.e., involuntary movements).²⁷ The aim of this summary of evidence is to determine if a novel, nonsurgical, prodrug combination of foslevodopa and foscarbidopa delivered via continuous, 24-hour subcutaneous infusion by a portable external infusion pump improves motor fluctuations that have been inadequately managed with oral therapy in Medicare beneficiaries with a diagnosis of PD.

Product Description

Blinatumomab

Blinatumomab (Blincyto^®, Amgen Inc., Thousand Oaks, CA) is a bi-specific antibody targeted immunotherapy that was previously approved by the Food & Drug Administration (FDA) for the treatment of adults and pediatric patients with: (1) relapsed or refractory CD19-positive B-ALL, or (2) CD19-positive B-ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. In 2024, the FDA approved a third indication for blinatumomab for the treatment of CD19-positive Philadelphia chromosome-negative B-ALL during the consolidation phase of multiphase therapy in adults and pediatric patients one month or older.²⁸

Foslevodopa/Foscarbidopa

Foslevodopa/foscarbidopa (VYALEV^™, Abbvie, Inc., North Chicago, IL) is a subcutaneous, individually titratable, 24-hour continuous infusion of levodopa-based therapy delivered via an external infusion pump (VYAFUSER^™, Abbvie, Inc., North Chicago, IL). Foslevodopa/foscarbidopa is FDA approved for the treatment of motor fluctuations in patients with advanced Parkinson's disease. The prodrugs foslevodopa and foscarbidopa are converted to the active forms of levodopa/carbidopa after infusion.²⁹

Food & Drug Administrations (FDA) Approval

Blinatumomab

Blinatumomab first received accelerated FDA approval in December 2014 for the treatment of Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL and received regular approval for this indication in July 2017.^30,31 In March 2018, the FDA granted blinatumomab accelerated approval to treat adults and children with B-cell precursor acute lymphoblastic leukemia (ALL) who are in remission but still have MRD; full approval for this indication was received in June 2023.^32,33 Most recently, on June 14, 2024, the FDA approved blinatumomab for adult and pediatric patients one month and older with CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (Philadelphia-negative BCP ALL) in the consolidation phase of multiphase chemotherapy.³⁴

Foslevodopa/Foscarbidopa

On October 16, 2024, the FDA approved (NDA 216962) foscarbidopa/foslevodopa injection for subcutaneous use for the treatment of motor fluctuations in adults with advanced Parkinson’s disease.³⁵

Evidence Questions

The development of an assessment in support of Medicare coverage decisions is based on the same general question for almost all requests: “Is the evidence sufficient to conclude that the application of the technology under study will improve final health outcomes for Medicare patients?”

The formulation of specific questions for the assessment recognizes that the effect of an intervention can depend substantially on how it is delivered, to whom it is applied, the alternatives with which it is being compared, and the setting where it is used. In order to appraise the net health outcomes of blinatumomab and foslevodopa/foscarbidopa, the DME MACs sought to address the following questions:

Blinatumomab

1. In Medicare Beneficiaries with CD19-positive Philadelphia-chromosome negative B-Cell precursor Acute Lymphoblastic Leukemia undergoing the consolidation phase of multiphase chemotherapy, is treatment with blinatumomab compared to SOC (i.e., chemotherapy alone) associated with improved clinical outcomes (i.e., disease-free survival, overall survival, minimal residual disease status)?
2. In Medicare Beneficiaries with CD19-positive Philadelphia-chromosome negative B-Cell precursor Acute Lymphoblastic Leukemia undergoing the consolidation phase of multiphase chemotherapy, is treatment with blinatumomab compared to SOC (i.e., chemotherapy alone) associated with a similar rate and/or severity of treatment-emergent adverse events?

Foslevodopa/Foscarbidopa

1. In Medicare Beneficiaries with Parkinson’s Disease symptoms not adequately controlled by oral medication, is treatment with subcutaneous foslevodopa/foscarbidopa compared to either SOC (i.e., oral levodopa/carbidopa) or other baseline therapies [e.g., dopamine agonists, monoamine oxidase B (MAO-B) inhibitors] associated with improved clinical outcomes [e.g., motor control (improvement in number of “on” time hours, reduction in number of “off” time hours), QoL]?
2. In Medicare Beneficiaries with Parkinson’s Disease symptoms not adequately controlled by oral medication, is treatment with subcutaneous foslevodopa/foscarbidopa compared to SOC (i.e., oral levodopa/carbidopa) or other baseline therapies (e.g., dopamine agonists, MAO-B inhibitors) associated with a similar rate and/or severity of treatment emergent adverse events (e.g., dyskinesia)?

Literature Analysis

Clinical Literature Analysis

Blinatumomab

A multicenter, phase 3 randomized controlled trial (RCT) by Hogan, et al.,³⁶ including 255 pediatric and adult patients (1 to 30 years of age) with low-risk first-relapse Philadelphia-chromosome negative B-ALL, analyzed the effect of consolidation treatment with blinatumomab and chemotherapy (n = 127; median age: 11; 59.8% male) compared to chemotherapy alone (n = 128; median age: 10; 59.4% male) after reinduction on disease free survival (DFS; defined as the time from randomization to relapse, second malignancy, or death), overall survival (OS) and adverse events (AEs). The overall 4-year DFS rate was 55.2% ± 3.6%; there was no statistically significant difference in the overall 4-year DFS rate between the blinatumomab (61.2% ± 5.0%) and the chemotherapy groups [49.5% ± 5.2%; p = 0.089; HR (95% CI): 0.76 (0.51-1.14)]. The OS rate for the cohort was 84.9% ± 2.7%, and there was no statistically significant difference in OS between the blinatumomab (90.4% ± 3.0%) and chemotherapy groups [79.6% ± 4.3%; p = 0.11; HR (95% CI): 0.65 (0.32-1.30)]. Adverse events occurred in 105 patients (89%; 103 ≥ Grade 3) in the chemotherapy group and 117 participants (97%; 104 ≥ Grade 3) in the blinatumomab group. The limitations of this study include the unclear blinding of participants/assessors and the potential for indirectness of the results in relation to the typical Medicare beneficiary (due to the primarily pediatric patient population).

A multicenter, phase 3 RCT by Brown, et al,.³⁷ including 208 pediatric and adult patients (1 to 30 years) with high- or intermediate-risk first-relapse Philadelphia-chromosome negative B-ALL, analyzed the effect of consolidation treatment with blinatumomab and chemotherapy (n = 105; median age: 9; 57% male; 65.7% high-risk) compared to chemotherapy alone (n = 103; median age: 9; 54% male; 67% high-risk) after reinduction on DFS [defined as the time from randomization to late treatment failure (≥ 5% marrow blasts after first course of randomized therapy), relapse, second malignancy, or death], OS, minimal residual disease (MRD) status, and the rate/severity of AEs. Randomization was terminated early at the recommendation of the data and safety monitoring committee due to the loss of clinical equipoise between the randomized treatments; thus, of 214 patients randomized (out of a planned enrollment of 220 patients), 6 patients were excluded due to enrollment after the interim analysis cutoff date. The DFS rate was 54.4% for the blinatumomab group compared to 39% for the chemotherapy group, which was not statistically significant, but favored blinatumomab [p = 0.03; significance set at p = 0.025; HR: 0.70 (95% CI: 0.47-1.03)]. There was a statistically significant difference in the 2-year OS rate in the blinatumomab group (71.3%) compared to the chemotherapy group (58.4%), in favor of blinatumomab [p = 0.02; HR: 0.62 (95% CI: 0.39-0.98)]. A total of 81.4% of AEs in the blinatumomab group and 92.8% in the chemotherapy group were Grade 3 or above; the most common Grade 3 or above AE was cytopenia for the blinatumomab group and cytopenia, febrile neutropenia, increased alanine aminotransferase, mucositis, and sepsis for the chemotherapy group. The study was limited by the recommended early termination of randomization which led to the primary endpoint being underpowered, the unclear blinding of participants/assessors, and the potential for indirectness of the results in relation to the typical Medicare beneficiary (due to the primarily pediatric patient population).

A multicenter, phase 3 RCT by Locatelli, et al.,³⁸ including 108 pediatric patients (age > 28 days and < 18 years) with high-risk, first-relapse Philadelphia-chromosome negative B-ALL, analyzed the effect of consolidation treatment with blinatumomab and chemotherapy (n = 54; median age: 6; 55.6 % male) compared to chemotherapy alone (n = 54; median age: 5; 40.7% male) after reinduction on event-free survival (defined as relapse, death, second malignancy, or failure to achieve complete remission), OS, MRD remission (defined as < 0.001 blast cells within 29 days of treatment initiation), and AEs. Enrollment was terminated early based on a pre-specified stopping rule after a planned interim analysis at 50% of the event-free survival events found benefit of blinatumomab; all patients enrolled at the time of enrollment termination were included in the analysis (108 out of the planned enrollment of 202 patients). Event-free survival was significantly longer with blinatumomab compared to chemotherapy alone [HR: 0.33 (95% CI: 0.18-0.61); p < 0.001] with a 24-month event-free survival rate of 66.2% (95% CI: 50.1%-78.2%) for the blinatumomab group and 27.1% (95% CI: 13.2%-43.0%) for the chemotherapy group. The median OS was 19.5 months; there were fewer deaths in the blinatumomab group (n = 8) than in the chemotherapy alone group [n = 16; HR: 0.43 (95% CI: 0.18-1.01)]. MRD remission was achieved by more patients in the blinatumomab group with an absolute percent difference of 35.6% (95% CI: 15.6%-52.5%) between the treatment groups. The cumulative incidence rate of relapse at 24 months was lower in the blinatumomab group compared to the chemotherapy alone group [24.9% (95% CI: 13.2%-38.5%) versus 70.8% (95% CI: 50.7%-83.9%), respectively; HR: 0.24 (95% CI: 0.13-0.46)]. Serious AE occurrence rates were similar in the treatment groups (blinatumomab: 24.1%; chemotherapy: 23.1%). This study was limited by the evaluation of a single course of blinatumomab during consolidation therapy, the unclear blinding of participants/assessors, and the potential for indirectness of the results in relation to the typical Medicare beneficiary (due to the primarily pediatric patient population).

An international, phase 3 RCT by Litzow, et al.,³⁹ including 224 adult patients (30 to 70 years of age) with Philadelphia-chromosome negative B-ALL who were MRD negative after induction and intensification chemotherapy, analyzed the effect of blinatumomab plus chemotherapy (4 rounds of chemotherapy with 2 rounds of blinatumomab before and after; n = 112; median age: 51.5; 51% female) compared to standard chemotherapy alone (4 rounds of chemotherapy; n = 112; median age: 50; 50% female) in the consolidation phase of therapy on OS, relapse-free survival and AEs. After a median 43-month follow-up period, the data and safety monitoring committee recommended that the third efficacy interim analysis data be released, which comprised 60% of the planned overall survival events. The 3-year OS was 85% for the blinatumomab group compared to 68% for the chemotherapy group [HR: 0.41 (95% CI: 0.23-0.73); p = 0.002, which crossed the p = 0.007 efficacy stopping point]. The 3-year relapse-free survival was 80% in the blinatumomab group and 64% in the chemotherapy group [HR: 0.53 (95% CI: 0.32-0.87)]. In a multivariate analysis, both the results for 3-year relapse-free survival (HR: 0.57; 95% CI: 0.33-0.98) and overall survival (HR: 0.44; 95% CI: 0.23-0.81) favored blinatumomab compared to chemotherapy. Patients treated with blinatumomab had significantly more ≥ Grade 3 neurologic or psychiatric adverse events compared to patients in the chemotherapy only group (23% vs 5%; p < 0.001), but other treatment-related nonhematologic adverse events of ≥ Grade 3 occurred in similar numbers (p = 0.87). This study was limited by the unclear blinding of participants/assessors.

Foslevodopa/Foscarbidopa

Outcome Measures

Objective

Parkinson’s KinetiGraph or Personal KinetiGraph (PKG): A wrist-worn device which takes accelerometry readings every 2 minutes for 6-10 days; these readings are converted into median bradykinesia and dyskinesia scores by an algorithm, which are then reported as a median and interquartile range (IQR), due to their non-normal distribution.^40,41 Lower scores indicate better motor symptoms, with some research suggesting that bradykinesia and dyskinesia can be considered adequately treated with scores of < 25 and < 9, respectively.^40,42 A PKG was used by Soileau 2022.⁴³

Subjective (Patient-reported)

EuroQol 5-Dimension Questionnaire (EQ-5D-5L): Consists of a visual analogue scale (VAS) for health and 5 descriptive statistics on mobility, self-care, usual activities, pain/discomfort, and anxiety/depression which are rated from 1 “no problems” to 5 “extreme problems.”⁴⁴ Data can be presented as descriptive, (i.e., the number of participants reporting each level), as the standard VAS, or as a summary index, which applies a formula to apply a weight to each of the descriptive values (0 = worst health and 1 = perfect health). Soileau 2022⁴³ reported the summary index while Aldred 2023⁴⁵ reported both the VAS and the summary index.

Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS): Consists of 4 sections which assess non-motor experiences of daily living (Part I), motor experiences of daily living (Part II), a motor examination (Part III), and motor complication (Part IV). Part I and Part II are reported by the patient, and use a rating scale of “0” no problems present to “4” severe problems are present.⁴⁶ Part I includes assessment of cognitive impairment, mood, hallucinations/psychosis, sleep, bowel/urinary problems, and fatigue while Part II assesses activities of daily living (i.e., speech, eating, dressing, tremor, walking, hygiene). Parts III and IV are assessed by the investigator and use a rating scale of “0” no problems/asymptomatic to “4” a severe presentation of the symptom. Part III includes an overall movement examination, including speech, gait, hands, posture, tremor, etc. Part IV is an assessment of the impact and amount of time a patient experiences dyskinesias, motor fluctuations, and dystonia. Soileau 2022⁴³ utilized Part II while Aldred 2023⁴⁵ utilized Parts I-IV.

“On”/”Off” time: A way to differentiate between periods of time where motor symptoms are improved after treatment with medication (“On” time) and periods where motor symptoms are not adequately controlled (“Off” time), either due to lack of effect of medication or wearing off of a dose of medication.²⁵ Both Soileau 2022⁴³ and Aldred 2023⁴⁵ assessed “On”/”Off” time through a daily patient diary.^47,48

Parkinson’s Disease Questionnaire (PDQ-39): A 39-item survey for quality of life which assesses domains of mobility, activities of daily living (ADLs), emotional well-being, stigma, cognition, communication, and bodily discomfort; the scores of each domain are converted into a score from “0” no problems to “100” the worst/maximum level of the problem and higher scores equal worse QoL.^49,50 This questionnaire was used by Soileau 2022⁴³ and Aldred 2023.⁴⁵

Parkinson’s Disease Sleep Scale-2 (PDSS-2): A 15-item survey which assesses sleep quality on a 5-point scale ranging from “Very often” to “Never”; a patient’s total score ranges from 0 to 60, and higher scores indicate worse sleep quality.⁵¹ This survey was used by Soileau 2022⁴³ and Aldred 2023.⁴⁵

Literature Analysis

A 12-week, phase 3, double-blind, randomized controlled trial (RCT) by Soileau, et al.⁴³ analyzed the effect of continuous subcutaneous infusion (CSCI) of foslevodopa/foscarbidopa with oral placebo compared to subcutaneous placebo with oral levodopa/carbidopa in patients with Parkinson's Disease whose motor fluctuations were inadequately controlled by their current therapy. A total of 145 patients were randomized and 141 patients were included in the full and safety analyses (CSCI group: n = 74, mean age 66.3 years; control group: n = 67, mean age 66.6 years). Both "on" time without troublesome dyskinesia and “off” time were significantly improved from baseline in the CSCI group compared to the oral treatment group [“on” time: difference (least squares means of odds ratio (SE); 95% CI): 1.75 hours (0.65; 0.46-3.05); p = 0.0083; “off” time: difference (SE; 95% CI): -1.79 hours (0.63; -3.03 to -0.54); p = 0.0054]. While the difference in the change from baseline in the MDS-UPDRS part II score between the two treatment groups did not reach significance, the results favored the CSCI group [difference (SE; 95% CI): -1.58 (1.05; 3.65 to 0.48); p = 0.13]. Additionally, morning akinesia was reported by a smaller proportion of patients in the CSCI group (17%) compared to the oral treatment group (63%), and "on" time without dyskinesia was increased by 25% in the CSCI group compared to 7% in the oral treatment group [difference (SE; 95% CI): 1.81 hours (0.68; 0.46-3.16)]. The remainder of secondary outcome measures were reported without significance calculations; however, most favored CSCI compared to oral treatment: PDSS-2 score [difference (SE; 95% CI): -5.40 (1.32; -8.03 to -2.78)], PDQ-39 score [difference (SE; 95% CI): -4.10 (2.04; -8.14 to 0.05)], EQ-5D-5L score [difference (SE; 95% CI): 0.049 (0.025; -0.001 to 0.100)], and median PKG dyskinesia score [difference (SE; 95% CI): -2.73 (1.96; -6.61 to 1.15). The CSCI treatment group experienced an increase in the median PKG bradykinesia score compared to the oral treatment group [difference (SE; 95% CI): 1.72 (0.72; 0.03-3.15)]. Adverse events (AE) were reported in 85% of CSCI patients compared to 63% of oral treatment patients; 52 AEs in the CSCI group were considered related to the study drug vs 15 events in the oral treatment group. Most AEs were mild to moderate in severity. The CSCI group, compared to the oral treatment group, had a higher incidence of infusion site adverse events (72% vs 12%), including erythema (27% vs 1%), pain (26% vs 1%), cellulitis (19% vs 0), and edema (12% vs 0); hallucinations or psychosis (15% vs 3%) were also reported more frequently in patients in the CSCI group compared to the oral treatment group. The AE profile was noted to be similar to known adverse effects of levodopa-containing medications, as well as other subcutaneously delivered medications. This study was limited by the shorter duration of follow-up and use of patient reported outcome measures (which can be subject to response and recall bias).

A non-randomized, open-label, phase 3 trial by Aldred, et al.⁴⁵ assessed the safety and efficacy of 24-hour CSCI of foslevodopa/foscarbidopa over 12-months in patients with Parkinson's disease whose motor fluctuations were inadequately controlled by their current treatment regimen. A total of 244 patients were enrolled in this study [mean age: 63.9 (51.2% ≥ 65 years)]. For safety, 230/244 patients experienced at least one AE and 224 (91.8%) of these AEs were considered related to the study drug. Most AEs were mild or moderate in severity and resolved. The most common AEs were associated with the infusion site [erythema (n = 127; 52%), nodules (n = 70; 28.7%), cellulitis (n = 56; 23%), edema (n = 47; 19.3%), pain (n = 38; 15.6%), reaction (n = 30; 12.3%), and abscess (n = 27; 11.1%)], hallucination (n = 42; 17.2%), fall (n = 41; 16.8%), anxiety (n = 29; 11.9%), and dizziness (n = 25; 10.2%). The most common serious adverse events were infusion site cellulitis (n = 10; 4.1%), infusion site abscess (n = 8; 3.3%), and hallucination (n = 7; 2.9%). It was noted that the adverse event profile was similar to other subcutaneous therapies. For efficacy, there was a significant change from baseline, at 52 weeks, in normalized "off" time [mean (SD) change: -3.5 (3.1) hours; p ≤ 0.001; average reduction: 59%], normalized "on" without troublesome dyskinesia [includes both time without dyskinesia and with non-troublesome dyskinesia; mean (SD) change: 3.8 (3.3) hours; p ≤ 0.001; average increase: 41%], and normalized "on" time without dyskinesia [mean (SD) change: 3.9 (4.2) hours; p ≤ 0.001; average increase: 58%]. Morning akinesia was reported in 77.7% of patients at baseline, which decreased to 27.8% of patients at week 52. Finally, there was a significant improvement (all p ≤ 0.001) in the PDSS-2, PDQ-39, EQ-5D-5L (VAS and summary index), and the MDS-UPDRS part II and IV (but not part III, which includes bradykinesia and tremor) at week 52 compared to baseline. This study was limited by the lack of randomization, lack of an active comparator, lack of blinding, and loss of > 40% participants over the course of the 52-week study.

Evidence Based Guidelines

Blinatumomab

National Comprehensive Cancer Network® (NCCN ®) Clinical Practice Guidelines^52,53

The NCCN Clinical Practice Guidelines include a category 2A recommendation for use of blinatumomab as a treatment option during the consolidation phase in adults and pediatric patients with CD19-positive Philadelphia chromosome-negative B-ALL. Category 2A is “based upon lower-level evidence, there is uniform NCCN consensus (≥ 85% support of the Panel) that the intervention is appropriate.” Per the NCCN Referencing Guidelines, “NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.”

Foslevodopa/Foscarbidopa

National Institute for Clinical Excellence (NICE). Foslevodopa–foscarbidopa for treating advanced Parkinson’s with motor symptoms: NICE guidance [ta934]. https://www.nice.org.uk/guidance/ta934. Updated November 29, 2023 (Accessed January 8, 2025)⁵⁴

The NICE Guidelines include the following recommendations for foslevodopa/foscarbidopa (in relevant part):

1.1 Foslevodopa–foscarbidopa is recommended as an option for treating advanced levodopa-responsive Parkinson's in adults whose symptoms include severe motor fluctuations and hyperkinesia or dyskinesia, when available medicines are not working well enough, only if:

• they cannot have apomorphine or deep brain stimulation, or these treatments no longer control symptoms, and
• the company provides foslevodopa–foscarbidopa according to the commercial arrangement.

1.2 This recommendation is not intended to affect treatment with foslevodopa–foscarbidopa that was started in the [National Health Service] NHS before this guidance was published. People having treatment outside this recommendation may continue without change to the funding arrangements in place for them before this guidance was published, until they and their NHS clinician consider it appropriate to stop.

Professional Society Recommendations/Health Technology Assessments

Foslevodopa/Foscarbidopa

Foslevodopa-Foscarbidopa (Vyalev): CADTH Reimbursement Review. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; September 2023.⁵⁵

The Canadian Agency for Drugs and Technologies in Health (CADTH) conducted a review and appraisal of sponsor-submitted evidence regarding the beneficial and harmful effects of the subcutaneous infusion of foslevodopa (240 mg/mL) and foscarbidopa (12 mg/mL) solution for the treatment of motor fluctuations in patients with advanced PD. The review focused on comparing foslevodopa/foscarbidopa to relevant comparators and identifying gaps in the current evidence. Clinical evidence reviewed included the pivotal phase III RCT (M15-736), the long-term extension study, one indirect treatment comparison, and two additional studies (M15-741 and M15-737).

The review concluded that foslevodopa/foscarbidopa demonstrated a clinically meaningful improvement in “on” time without troublesome dyskinesia and “off” time compared with oral LD-CD therapy at 12 weeks in patients with advanced PD based on the pivotal M15-736 trial. Analyses of morning akinesia, HRQoL, bradykinesia, and sleep symptoms also favored foslevodopa/foscarbidopa, however these results were inconclusive due to failure of a prior outcome in the statistical testing hierarchy. Results did not show a difference in motor experiences of daily living. The pivotal study results were overall generalizable. The safety and effectiveness of foslevodopa-foscarbidopa relative to comparators other than oral LD-CD could not be determined based on the evidence submitted. There were no direct comparisons with levodopa/carbidopa intestinal gel (LCIG), and the indirect comparison was inconclusive. There were also no comparisons between foslevodopa/foscarbidopa and DBS. Overall, the safety profile of foslevodopa/foscarbidopa was similar to oral LD-CD therapy. Infusion-site reactions and infections were more frequent with foslevodopa/foscarbidopa but most were not serious. No new serious safety concerns were identified in the longer-term safety studies.

Reimbursement recommendations from CDATH are outlined below.

Foslevodopa-Foscarbidopa (Vyalev): CADTH Reimbursement Recommendation. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; July 2023.⁵⁶

The Canadian Agency for Drugs and Technologies in Health (CADTH) makes the following reimbursement recommendations (in relevant part) for Vyalev:

“CADTH recommends that Vyalev should be reimbursed by public drug plans for the treatment of motor fluctuations in patients with advanced levodopa-responsive Parkinson disease (PD) who do not have satisfactory control of severe, debilitating motor fluctuations and hyperkinesia or dyskinesia despite optimized treatment with available combinations of medicinal products for PD if certain [reimbursement] conditions [specified below] are met.”

“Vyalev should only be covered to treat patients with advanced PD who have unpredictable changes in movement symptoms and severe limitations in being able to perform daily activities while receiving optimized oral therapy. Patients should have previously shown improvement in their symptoms when they received levodopa treatment and should not have severe psychosis or severe dementia. Patients or caregivers should be able to understand how to use the drug infusion system correctly.”

“Vyalev should only be reimbursed if prescribed by neurologists who are specialized in managing movement disorders or with expertise in managing advanced PD.”

Reimbursement Conditions for Initiation:

“1. In patients with advanced levodopa-responsive PD only if all of the following criteria are met:

1.1. have not been able to achieve satisfactory control of severe, debilitating motor fluctuations and hyperkinesia or dyskinesia despite optimized treatment with available combinations of PD treatments, including maximally tolerated doses of levodopa in combination with carbidopa, a COMT inhibitor, a dopamine agonist, a MAO-B inhibitor, and amantadine, if not contraindicated

1.2. have severe disability associated with at least 25% of the waking day in the off state and/or ongoing, bothersome levodopa-induced dyskinesias, despite having tried frequent dosing of levodopa (at least 5 doses per day)

1.3. have received an adequate trial of maximally tolerated doses of levodopa, with previously demonstrated clinical response

1.4. the patient does not have severe psychosis or severe dementia

1.5. patient or caregiver are able to demonstrate correct understanding and use of the delivery system.”

Reimbursement Conditions for Renewal:

2. “Eligibility for foslevodopa-foscarbidopa should be based on the criteria used by each of the public drug plans for the renewal of LCIG in patients with advanced PD.”

“The patient should continue to benefit from treatment for renewal of foslevodopa-foscarbidopa reimbursement. It is expected that clinicians will continue to monitor their patients and discontinue foslevodopa-foscarbidopa if the patient is no longer benefiting from treatment.”

Conclusion

Blinatumomab

Blinatumomab is a bi-specific antibody targeted immunotherapy that has received approval from the FDA for the treatment of CD19-positive Philadelphia chromosome-negative B-ALL during the consolidation phase of multiphase therapy in adults and pediatric patients one month or older. The aim of this summary of evidence was to determine if the use of blinatumomab is associated with improved health outcomes (i.e., disease-free survival, overall survival, minimal residual disease status, treatment-emergent AEs) in this patient population. An analysis of four (4) RCTs revealed that, statistically, blinatumomab may be as or more effective in improving the rates of DFS and OS in pediatric and adult patients with Philadelphia chromosome-negative B-ALL compared to chemotherapy alone during the consolidation phase, with similar rates and/or severities of treatment-emergent AEs. Blinatumomab may also be more effective than chemotherapy alone during the consolidation phase for the rate of MRD remission achievement in pediatric patients with high-risk first relapse with Philadelphia chromosome-negative B-ALL compared to chemotherapy alone. Notably, regardless of the presence of a statistical difference, the differential treatment effect of blinatumomab compared to chemotherapy alone on DFS, OS and MRD status was > 10% in favor of blinatumomab in all included studies. Additionally, a national clinical practice guideline recommends for the use of blinatumomab as a treatment option during the consolidation phase in pediatric and adult patients with CD19-positive Philadelphia chromosome-negative B-ALL.

Based on a review of the best currently available literature, there is consistent evidence to support that blinatumomab may be an effective therapeutic option for Medicare beneficiaries with a diagnosis of CD19-positive Philadelphia chromosome-negative B-ALL during the consolidation phase. Therefore, the criteria for blinatumomab in the External Infusion Pumps Local Coverage Determination will be expanded to allow coverage for up to four (4) cycles for adult and pediatric beneficiaries one month and older with CD19-positive Philadelphia chromosome-negative B-cell precursor ALL in the consolidation phase of multiphase chemotherapy. Additionally, the existing blinatumomab criteria, for adult and pediatric beneficiaries with (1) relapsed or refractory B-cell precursor ALL, or (2) B-cell precursor ALL in first or second remission with MRD greater than or equal to 0.1%, will be updated with the age qualifier of “one month and older” to be consistent with the clinical literature and FDA prescribing information for these indications.

Foslevodopa/Foscarbidopa

Parkinson’s disease is a slowly progressive neurodegenerative disease of adult-onset caused by the loss of dopaminergic neurons leading to motor and non-motor symptoms. Levodopa is the most effective drug for the management of motor symptoms related to PD; however, the half-life of the drug is short, resulting in fluctuations in blood levels and motor symptom control. A novel prodrug of levodopa (foslevodopa/foscarbidopa) has been developed to be delivered by 24-hour continuous subcutaneous infusion and has been FDA approved for the treatment of motor fluctuations not adequately controlled by oral medications in patients with advanced Parkinson's disease. The aim of this summary of evidence was to determine if the use of foslevodopa/foscarbidopa was associated with improved health outcomes (e.g., motor control, QoL, treatment-emergent AEs). An analysis of the literature revealed that there were statistical and clinically meaningful⁴⁷ improvements in the number of “on” time hours without troublesome dyskinesia (24% to 30% increase compared to baseline; 20% differential treatment effect in favor of CSCI compared to control) and the number of “off”­ time hours (42% to 43% decrease compared to baseline; 27% differential treatment effect in favor of CSCI compared to control) with continuous subcutaneous infusion of foslevodopa/foscarbidopa compared with oral levodopa with or without concomitant therapies. Treatment with foslevodopa/foscarbidopa also resulted in an at least 50% reduction in the number of patients reporting morning akinesia. Quality of life (measured by the EQ-5D-5L and PDQ-39), motor experiences of daily living (measured by the MDS-UPDRS part II), and non-motor symptoms (measured by the PDSS-2) were also improved. The reported AE profile for foslevodopa/foscarbidopa was consistent with other levodopa-containing medications and/or other subcutaneous therapies, and most AEs were mild to moderate in severity.

Based on a review of the best available literature, there is sufficient evidence to support that continuous subcutaneous infusion of foslevodopa/foscarbidopa may improve health outcomes in individuals with a diagnosis of Parkinson’s disease whose motor control symptoms are not adequately controlled with their baseline treatment regimen (e.g., oral levodopa/carbidopa, dopamine agonists, MAO-B inhibitors). Therefore, the External Infusion Pumps LCD (L33794) will be updated to allow coverage for infusion-based therapy for the treatment of Parkinson’s Disease, such as continuous subcutaneous infusion of foslevodopa/foscarbidopa, for Medicare beneficiaries with levodopa-responsive idiopathic Parkinson’s Disease when non-infusion-based Parkinson’s Disease therapy dosage and/or dosing interval cannot be further optimized due to intolerance, dyskinesia and/or other side effects/adverse events, and the beneficiary continues to experience inadequate control of motor fluctuation symptoms affecting daily living (e.g., unpredictable increase in stiffness, tremor, bradykinesia), as well as a minimum of 2.5 hours of “off” time per day.

DOCUMENTATION REQUIREMENTS

Section 1833(e) of the Social Security Act precludes payment to any provider of services unless "there has been furnished such information as may be necessary in order to determine the amounts due such provider." It is expected that the beneficiary's medical records will reflect the need for the care provided. The beneficiary's medical records include the treating practitioner's office records, hospital records, nursing home records, home health agency records, records from other healthcare professionals and test reports. This documentation must be available upon request.

GENERAL DOCUMENTATION REQUIREMENTS

In order to justify payment for DMEPOS items, suppliers must meet the following requirements:

• SWO
• Medical Record Information (including continued need/use if applicable)
• Correct Coding
• Proof of Delivery

Refer to the LCD-related Standard Documentation Requirements article, located at the bottom of this policy under the Related Local Coverage Documents section for additional information regarding these requirements.

Refer to the Supplier Manual for additional information on documentation requirements.

Refer to the DME MAC web sites for additional bulletin articles and other publications related to this LCD.

POLICY SPECIFIC DOCUMENTATION REQUIREMENTS

Items covered in this LCD have additional policy-specific requirements that must be met to justify Medicare reimbursement.

Refer to the LCD-related Policy article, located at the bottom of this policy under the Related Local Coverage Documents section for additional information.

MISCELLANEOUS

APPENDICES

American College of Cardiology Foundation/American Heart Association (ACCF/AHA) Stage D heart failure (HF) patients have advanced structural heart disease and marked symptoms of heart failure at rest despite maximal medical therapy, and require specialized interventions. J Am Coll Cardiol. 2001;38(7):2101-2113.

New York Heart Association (NYHA) Heart Failure Symptom Class IV patients are unable to carry on any physical activity without discomfort resulting from symptoms of heart failure such as dyspnea, or have symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. The Criteria Committee of the New York Heart Association. (1994).

Nomenclature and Criteria for Diagnosis of Diseases of the Heart and Great Vessels. (9th ed.). Boston: Little, Brown & Co. pp. 253–256.

Bridge Therapy: For purposes of this policy, bridge therapy is not time-circumscribed.

UTILIZATION GUIDELINES

Refer to Coverage Indications, Limitations and/or Medical Necessity

N/A

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