Beyond the budget impact model: A case study for glucarpidase and the real cost of managing curable toxicities

Abstract

The greatest challenge in healthcare today lies in managing limited resources to deliver high-quality care to the patients who need it the most. Payers heavily rely on budget impact models to assess the net costs or potential savings associated with adding a new intervention and to inform their formulary decision. Drugs developed for rare conditions are often prohibitively expensive due to the complex manufacturing processes and investments required to undertake clinical trials. These interventions often play a critical role in organ preservation and can be lifesaving when no alternative therapies are available. The significant cost of these treatments has to be weighed against the potential cost consequences of not using the treatment including downstream complications of an avoidable event. Over the past few decades, oncologic treatments have seen significant advancements. Despite these innovations, radiation therapy and chemotherapy remain the backbone of treatment for many types of cancers. These therapies often damage healthy cells alongside cancer cells, leading to a range of side effects that can affect multiple organ systems. While some side effects, such as those from radiation therapy, may be resolved within weeks or months after treatment ends, others may persist or emerge months to years later. Worse yet is the impact of these side effects on patients’ ability to continue with their cancer treatment regimen. Here we discuss a case of glucarpidase in managing high dose methotrexate toxicity and consideration of full impact, not only on the budget but also the patient.

Balancing the cost of care with patients' needs continues to be a major challenge in healthcare today, making budget impact consideration of paramount importance to informed decision making. A budget impact model (BIM) is a financial analysis tool designed to estimate the economic implications of introducing a new health technology such as a drug, biologic, or medical device into the existing mix of available treatment options.

Introducing a new intervention typically serves as either an alternative that may capture market share from approved treatments or a new addition where no available interventions exist. Some BIMs focus exclusively on the pharmacy budget, while others take a broader institutional perspective, accounting for the combined effects on both pharmacy and medical budgets.

Payers and health insurers heavily rely on the BIM to assess the net costs or potential savings associated with adding a new intervention and inform their formulary decision regarding access. These assessments usually compare two scenarios: one in which the new intervention is unavailable (current standard of care) and another where the intervention is adopted for the appropriate target population. Key outputs of a BIM typically include the total cost of care with and without the new intervention, as well as metrics like per-member-per-month or per-patient-per-year costs. These insights help decision-makers evaluate the financial feasibility and potential value of adopting new healthcare innovations.

A BIM is developed from the perspective of the institution or healthcare system rather than the patient or caregiver and as such does not consider impact of treatment on health-related quality of life, functional status, productivity/activity impairment. Regardless, the BIM may incorporate health outcomes, including quality of care indicators. This is particularly relevant in settings where reimbursement for a drug may be tied to performance metrics, such as specific health outcomes, readmission rates, or mortality. Drugs developed for rare conditions are often prohibitively expensive due to the complex manufacturing processes and investment required to undertake clinical trials and obtain regulatory approval. These interventions often play a critical role in organ preservation and can be lifesaving when no alternative therapies are available, providing healthcare providers with an option to use these specialized drugs. The significant cost of these treatments have to be weighed against the potential cost consequences of not using the treatment including downstream complications of an avoidable event.

Over the past few decades, oncologic treatments have seen significant advancements, including therapies that specifically target cancer cells, while also reducing undesirable side effects. Despite these innovations, radiation therapy and chemotherapy remain the backbone of treatment for many types of cancers. These therapies often damage healthy cells alongside cancer cells, leading to a range of side effects that can affect multiple organ systems. These side effects vary in severity, from mild symptoms such as nausea, vomiting, and diarrhea to more serious complications, such as organ damage—for instance, acute kidney injury (AKI) caused by high-dose methotrexate toxicity. While some side effects, such as those from radiation therapy, may be resolved within weeks or months after treatment ends, others may persist or emerge months to years later as late effects. Worse yet is the impact of these side effects on patients’ ability to continue with their cancer treatment regimen. Immunotherapies, though more targeted, are not without risks. Severe side effects can necessitate long-term use of steroids or other immunosuppressive therapies, which may carry additional adverse consequences over time.

Case study

Methotrexate is a chemotherapeutic agent often administered in high doses (>500 mg/m²) when used to treat various cancers, including osteosarcoma, acute lymphoblastic leukemia, primary CNS lymphoma, and other lymphomas. Primarily eliminated by the kidneys, methotrexate can lead to AKI and delayed elimination when administered at high doses. Although the incidence of AKI is generally low, occurring in fewer than 2% of pediatric patients, it can rise to as high as 15% in certain cancers and among older adults.^1-4 If unresolved, AKI can result in significant healthcare costs, including expenses associated with renal impairment, dialysis, chronic kidney disease (CKD), the need for transplantation, or even mortality.

Voraxaze (glucarpidase), a carboxypeptidase enzyme, is approved to lower toxic plasma methotrexate levels (>1 micromole per liter) in adults and children with delayed methotrexate clearance due to impaired renal function. ⁵ Expert Consensus Guidelines recommend that hospitals with emergency care facilities should stock 5 vials of glucarpidase for treatment of methotrexate poisoning and the manufacturer offers a replacement policy for expired vials; however, most hospitals find the cost (Wholesale Acquisition Cost [at the time of model development] of $36,648.00 per 1000 unit vial) to be prohibitive and rely on ordering at the time of emergency. ⁶ A 2023 budget impact model by Kala et al. analyzed the economic implications of early glucarpidase use (within 60 h of high-dose methotrexate [HDMTX] infusion) compared to delayed use (after 60 h) dialysis, or supportive care alone. ⁷ Built on current clinical practice guidelines, the economic model incorporated real-world data from a Medicare claims analysis of glucarpidase-treated patients. ⁸ It evaluated cost savings associated with improved clinical outcomes, such as shorter hospital length of stay and lower ICU costs, against the pharmacy expenses of glucarpidase for two hypothetical scenarios.

The first scenario considered a hospital with 3 adult patients with delayed methotrexate (MTX) elimination due to impaired renal function and the budget impact was assessed for changing practice from not stocking and treating 1 patient late to treating 1–2 patients early with glucarpidase. The second scenario considered 5 patients with delayed MTX elimination and the budget impact was assessed for changing practice from treating 2 patients early and 1 with hemodialysis to treating 4–5 patient early. For the first scenario, the change in practice resulted in a cost savings of $74,370 and an additional cost of $952, for treating 1–2 patients early, respectively. For the second scenario, the change in practice to treating 4–5 patients early was associated with an additional cost of $29,359 and $104,681, respectively. ⁷

Since the primary goal of cancer treatment is life extension, the benefits of mitigating drug toxicities must be integral to budget impact analyses for oncology products. In addition to economic considerations, the model assessed clinical outcomes, including the proportion of patients successfully rechallenged with HDMTX. The analysis also included inpatient mortality rates and projected three-year overall survival (OS) based on estimation of patients recovering from AKI and completing HDMTX treatment. For the above scenarios change in practice with early glucarpidase treatment resulted in lower inpatient mortality and a higher 3-year OS. ⁷ Further evidence supporting timely glucarpidase use v. non-glucarpidase use in patients with HDMTX-induced AKI was recently published, ⁹ demonstrating an association between timely glucarpidase use and increased odds of renal recovery, accelerated time to renal recovery, and decreased rates of grade ≥2 transaminitis and neutropenia. Feasibility of rechallenge following recovery from HDMTX induced AKI has been reported for both pediatric (n = 20) and adult (n = 11) patients^1,10 with good tolerability and no further requirement for glucarpidase administration after HDMTX rechallenge.

The comprehensive assessment of the Voraxaze BIM underscores the importance of evaluating both economic and clinical outcomes for costly interventions addressing rare but life-threatening conditions. Notably, the model likely underestimated cost savings for several reasons:

ICU Costs: The model did not account for the higher staffing costs associated with ICU care compared to general floor dialysis. For example, the cost difference between “on-floor” dialysis (code 90935) and ICU dialysis (code 99291) is substantial ($110–$150 per session vs. $200–$250 per session). ¹¹

Consultant Costs: Expenses related to medical consultants were excluded and can range, depending on complexities, in costs from $100-$400 per visit for toxicology clinical consultants visiting patients with AKI in the ICU (codes 99251–99255). ¹¹

Opportunity Costs: Earlier discharges and reduced hospital length of stay (LOS) could potentially allow hospitals to treat additional patients, yet these savings were not captured.

Cost of Recurrent Dialysis: Removing methotrexate from the bloodstream using extracorporeal methods is inefficient, necessitating repeated dialysis sessions. Glucarpidase provides the most efficient method for methotrexate removal, reducing the need for recurrent dialysis. ¹² The estimated cost of dialysis for hospitalized patients with AKI is $42,077 (95% CI, $39,820–$44,335) including 11.5 (95% CI, 11.2–11.8) hospital days. ¹³ Annual cost of CKD is estimated to be $17,472 ¹⁴ with the average cost of kidney transplant around $442,500 excluding ongoing treatment with immunosuppressants and potential additional complications. ¹⁵

Readmission Costs: Patients requiring dialysis often face complications leading to readmissions, potentially impacting reimbursement and overall costs.

Beyond the economic benefits, glucarpidase significantly improves patient care by enabling faster recovery, continuation of HDMTX therapy, and reduced reliance on hemodialysis, minimizing potential long-term adverse consequences. When considering the value of new treatment interventions, it is important to think beyond the budget impact model as demonstrated in this case and especially when the new treatment is for a rare event with significant consequences.