Clinical Question: As in the past, please briefly outline the scenario and state your clinical question as concisely and specifically as possible

A 59-year-old female undergoing her second round of chemotherapy.  Her oncologist discussed all of the potential chemo side effects with her prior to beginning treatment and she understands there is a medication (granulocyte colony-stimulating factor) she can take that is effective in preventing neutropenic fever. However, given their price, she is curious as to whether there are other medications, which are equally effective to act as prophylaxis for febrile neutropenia that are more cost-effective?

SEARCH QUESTION: Are biosimilar granulocyte colony-stimulating factors (i.e. filgrastim-sndz, zarxio) more cost-effective in the prophylaxis of chemotherapy induced febrile neutropenia for adults undergoing chemotherapy than granulocyte colony-stimulating factors?

PICO Question:

Identify the PICO elements – this should be a revision of whichever PICO you have already begun in a previous week

P	I	C	O
Cancer patient with Febrile Neutropenia	Granulocyte colony stimulating factor	Biosimilar Granulocyte colony stimulating factor	Cost savings
Adult cancer patient	G-CSF	Filgrastim-sndz	Cost-efficient
Chemo patient	Neulasta	Biologics	Cost benefit
Chemotherapy induced febrile neutropenic patient	Pegfilgrastim	Zarxio
Prophylaxis of febrile neutropenia in a cancer patient	Filgrastim	Biosimilar drugs

 

Search Strategy:

Outline the terms used, databases or other tools used, how many articles returned, and how you selected the final articles to base your CAT on. This will likewise be a revision and refinement of what you have already done.

PubMed

• Cost effectiveness analysis neulasta –> 45
  • Cost effectiveness analysis neulasta –> 46 (Best Match)
  • Cost effectiveness analysis neulasta –> 15 (Best Match + Last 5 Years)
• Cost effectiveness analysis febrile neutropenia prophylaxis –> 80
  • Cost effectiveness analysis febrile neutropenia prophylaxis –> 22 (Last 5 Years)
• Cost-effectiveness of prophylactic granulocyte colony-stimulating factor febrile neutropenia –> 4 (Last 5 Years)

Google Scholar

• Neulasta vs. Zarxio cost effectiveness –> 186
  • Neulasta vs. Zarxio cost effectiveness –> 155 (Since 2015)

NEJM

• Biosimilars febrile neutropenia –> 1

A large majority articles that came back directly answered the question; however, these articles addressed populations in foreign countries. While one article may reflect a broader population, outside of the United States, it was important for me to include articles that evaluated the costs for patients being treated in America. This fact made the research significantly more difficult. I, ultimately, included one article from the European G5 countries because it seemed to be a reference point and was included as citations in almost every article evaluated. It seems that given Europe’s longer history with biosimilar drugs, these results and recommendations are published and utilized as a benchmark across the globe. Although there are many similarities between these nations, as they are all developed countries, there are certainly environmental factors that play a role in healing, likelihood to come down with febrile neutropenia as well as the associated healthcare policies that impact out of pocket costs for patients. It is important to keep that point in mind when evaluating these topics but I don’t think for this particular purpose it is harmful to include this one particular article, given its significance.

In selecting articles it was challenging because many of the studies / research evaluated patients with a particular type of cancer and was hyper focused on the details associated with that particular diagnosis, which didn’t aid in answering my PICO question. Additionally, many of the articles I found were not Indexed for Medline and while they would have been useful they fell outside the realm of this assignment. A large majority of the articles were published by pharmaceutical companies working to evaluate costs of the medications they’re producing, which is why I ultimately didn’t include them.

Finally, given the question at hand is a cost-analysis; the study selection is going to be different as it relates to evaluating articles for highest levels of evidence. The articles included for the purposes of this PICO, while not systematic reviews, review literature and data that helps to yield educated findings surrounding the cost-effectiveness of prophylaxis for febrile neutropenia. While a few of the meta-analyses and systematic reviews touched upon the cost-effectiveness of these medications, the articles selected speak directly to these findings and were exponentially more useful for the purposes of this assignment. The highest levels of evidence answered my initial PICO question regarding the effectiveness of providing prophylaxis against neutropenic fever undergoing chemotherapy and the costs analysis evaluates how biologics (biosimilar drugs) compare to granulocyte-colony stimulating factor in practice.

Articles Chosen (3-5) for Inclusion (please copy and paste the abstract with link):

Please pay attention to whether the articles actually address your question and whether they are the highest level of evidence available. If you cannot find high quality articles, be prepared to explain the extensiveness of your search and why there aren’t any better sources available.

1. Cost-efficiency analysis

J Med Econ. 2017 Oct;20(10):1083-1093. doi: 10.1080/13696998.2017.1358173. Epub 2017 Aug 4.  Cost-efficiency analyses for the US of biosimilar filgrastim-sndz, reference filgrastim, pegfilgrastim, and pegfilgrastim with on-body injector in the prophylaxis of chemotherapy-induced (febrile) neutropenia. McBride A^1,2,3, Campbell K⁴, Bikkina M⁴, MacDonald K⁵, Abraham I^2,3,5,6,7, Balu S⁴.

Abstract
AIMS:
Guidelines recommend prophylaxis with granulocyte colony-stimulating factor for chemotherapy-induced (febrile) neutropenia (CIN/FN) based on regimen myelotoxicity and patient-related risk factors. The aim was to conduct a cost-efficiency analysis for the US of the direct acquisition and administration costs of the recently approved biosimilar filgrastim-sndz (Zarxio EP2006) with reference to filgrastim (Neupogen), pegfilgrastim (Neulasta), and a pegfilgrastim injection device (Neulasta Onpro; hereafter pegfilgrastim-injector) for CIN/FN prophylaxis.

METHODS:
A cost-efficiency analysis of the prophylaxis of one patient during one chemotherapy cycle under 1-14 days’ time horizon was conducted using the unit dose average selling price (ASP) and Current Procedural Terminology (CPT) codes for subcutaneous prophylactic injection under four scenarios: cost of medication only (COSTMED), patient self-administration (SELFADMIN), healthcare provider (HCP) initiating administration followed by self-administration (HCPSTART), and HCP providing full administration (HCPALL). Two case studies were created to illustrate real-world clinical implications. The analyses were replicated using wholesale acquisition cost (WAC).

RESULTS:
Using ASP + CPT, cost savings achieved with filgrastim-sndz relative to reference filgrastim ranged from $65 (1 day) to $916 (14 days) across all scenarios. Relative to pegfilgrastim, savings with filgrastim-sndz ranged from $834 (14 days) up to $3,666 (1 day) under the COSTMED, SELFADMIN, and HPOSTART scenarios; and from $284 (14 days) up to $3,666 (1 day) under the HPOALL scenario. Similar to the cost-savings compared to pegfilgrastim, filgrastim-sndz achieved savings relative to pegfilgrastim-injector: from $834 (14 days) to $3,666 (1 day) under the COSTMED scenario, from $859 (14 days) to $3,692 (1 day) under SELFADMIN, from $817 (14 days) to $3,649 (1 day) under HPOSTART, and from $267 (14 days) to $3,649 (1 day) under HPOALL. Cost savings of filgrastim-sndz using WAC + CPT were even greater under all scenarios.

CONCLUSIONS:
Prophylaxis with filgrastim-sndz, a biosimilar filgrastim, was associated consistently with significant cost-savings over prophylaxis with reference filgrastim, pegfilgrastim, and pegfilgrastim-injector, and this across various administration scenarios.
PMID: 28722494         DOI: 10.1080/13696998.2017.1358173

2. Retrospective Claims Analysis

J Manag Care Spec Pharm. 2018 Oct;24(10):976-984. doi: 10.18553/jmcp.2018.17447. Epub 2018 Apr 24.
Clinical Outcomes of Treatment with Filgrastim Versus a Filgrastim Biosimilar and Febrile Neutropenia-Associated Costs Among Patients with Nonmyeloid Cancer Undergoing Chemotherapy. Schwartzberg LS¹, Lal LS², Balu S³, Campbell K³, Brekke L², DeLeon A³, Elliott C², Korrer S².

Abstract

BACKGROUND:
Granulocyte colony-stimulating factors such as filgrastim are used to decrease the incidence of febrile neutropenia (FN) among patients with nonmyeloid cancers undergoing chemotherapy treatment. Although the biosimilar filgrastim-sndz has been approved in the United States since 2015, limited real-world comparisons of filgrastim-sndz versus reference filgrastim (filgrastim-ref) have been conducted.

OBJECTIVE:
To compare FN incidence and assess overall FN-related health care resource utilization and medical costs among U.S. patients with non-myeloid cancer who received filgrastim-sndz or filgrastim-ref during their first chemotherapy cycle.

METHODS:
This was a retrospective claims analysis of patients with non-myeloid cancer who were enrolled in commercial or Medicare Advantage insurance plans from March 2015 through June 2016 and received filgrastim-sndz or filgrastim-ref during their first observed chemotherapy cycle. Patients with evidence of hematopoietic stem cell transplantation or pregnancy and those with missing demographic information were excluded. FN was defined on the basis of diagnosis codes for neutropenia and fever (N/F); neutropenia and infection (N/I); and neutropenia, infection, and fever (N/I/F). Cohorts were adjusted for differences in baseline patient characteristics using the inverse probability of treatment weighting (IPTW) method, and equivalence testing was used to compare the proportion of patients who developed FN between weighted cohorts. On the basis of the range of neutropenic fever incidence found in the PIONEER clinical trial, FN incidence was considered equivalent if 90% CIs for between-cohort differences were within ± 6%. Mean FN-related health care resource utilization and total FN-related medical costs were calculated for the overall study population.

RESULTS:
A total of 3,542 patients were included in the study (172 filgrastim-sndz; 3,370 filgrastim-ref; mean ages 62.1 years and 64.7 years, respectively). After IPTW, there were 162 patients in the filgrastim-sndz cohort and 3,297 in the filgrastim-ref cohort (mean age 64.5 years for both). FN incidence in the weighted filgrastim-sndz versus filgrastim-ref cohorts, respectively, was 1.4% versus 0.9% for N/F, 2.3% versus 1.7% for N/I, and 0.0% versus 0.3% for N/I/F; FN incidence was statistically equivalent between treatment cohorts. Among patients in either treatment cohort who developed FN, the proportion with FN-related inpatient stays during the first chemotherapy cycle ranged from 35.0% for N/I to 70.0% for N/I/F. Mean (SD) FN-related total medical costs across all patients who developed FN were $11,977 ($18,383) for N/F, $8,040 ($14,809) for N/I, and $21,733 ($30,003) for N/I/F, in 2015 U.S. dollars. For all 3 definitions of FN, the largest proportions (73.5%-93.4%) of medical costs were inpatient related.

CONCLUSIONS:

In this real-world study of patients with nonmyeloid cancers undergoing chemotherapy, the incidence of FN was statistically equivalent between individuals treated with filgrastim-sndz versus filgrastim-ref during their first chemotherapy cycle. FN-related health care resource utilization and medical costs among patients who developed FN were substantial.

DISCLOSURES:
This work was funded by Sandoz, which participated in the study design, data interpretation, writing and revision of the manuscript, and decision to submit the manuscript for publication. Balu and Campbell are employees of Sandoz, which is the manufacturer of the filgrastim biosimilars Zarzioand Zarxio. DeLeon was an employee of Sandoz at the time this study was conducted. Lal, Brekke, Elliott, and Korrer are employees of Optum, which was contracted by Sandoz to conduct this study.
PMID: 29687743         DOI: 10.18553/jmcp.2018.17447

3. Cost Analysis

Expert Rev Pharmacoecon Outcomes Res. 2018 Aug;18(4):447-454. doi: 10.1080/14737167.2018.1476142. Epub 2018 May 18.
Cost-savings for biosimilars in the United States: a theoretical framework and budget impact case study application using filgrastim. Grewal S¹, Ramsey S^1,2, Balu S³, Carlson JJ¹.

Abstract

BACKGROUND:
Biosimilars can directly reduce the cost of treating patients for whom a reference biologic is indicated by offering a highly similar, lower priced alternative. We examine factors related to biosimilar regulatory approval, uptake, pricing, and financing and the potentialimpact on drug expenditures in the U.S.

METHODS:
We developed a framework to illustrate how key factors including regulatory policies, provider and patient perception, pricing, and payer policies impact biosimilar cost-savings. Further, we developed a budget impact cost model to estimate savings from filgrastim biosimilars under various scenarios. The model uses publicly available data on disease incidence, treatment patterns, market share, and drugprices to estimate the cost-savings over a 5-year time horizon.

RESULTS:
We estimate five-year cost savings of $256 million, of which 18% ($47 million) are from reduced patient out-of-pocket costs, 34% ($86 million) are savings to commercial payers, and 48% ($123 million) are savings for Medicare. Additional scenarios demonstrate the impact of uncertain factors, including price, uptake, and financing policies.

CONCLUSIONS:
A variety or interrelated factors influence the development, uptake, and cost-savings for Biosimilars use in the U.S. The filgrastim case is a useful example that illustrates these factors and the potential magnitude of costs savings.
PMID: 29757040         DOI:   10.1080/14737167.2018.1476142

4. Cost-Efficiency Analysis

J Oncol Pharm Pract. 2012 Jun;18(2):171-9. doi: 10.1177/1078155211407367. Epub 2011 May 24. Comparative cost-efficiency across the European G5 countries of various regimens of filgrastim, biosimilar filgrastim, and pegfilgrastim to reduce the incidence of chemotherapy-induced febrile neutropenia. Aapro M¹, Cornes P, Abraham I.

Abstract
OBJECTIVES:
This cost-efficiency analysis of the granulocyte colony-stimulating factors (G-CSF) filgrastim (originator Neupogen® and biosimilar Zarzio®) and pegfilgrastim (Neulasta®) examined against a time horizon of 1-14 days of treatment and across the European Union G5 countries (a) when, cost-wise, using Neulasta® 6 mg versus Neupogen® or Zarzio® 300 µg may be cost-saving in reducing the incidence of chemotherapy-induced febrile neutropenia; and (b) if cost-wise, treatment with Zarzio® 300 µg yields a savings advantage over Neupogen® 300 µg.

METHODS:
Cost-efficiency analysis of the direct costs a buyer or payer would incur when purchasing or covering any of these agents for managing one patient during one cycle of chemotherapy under regimens of 1-14 days of standard filgrastim using the population-weighted average unit dose cost of each agent per their public pack cost across the European G5 countries.

RESULTS:
The cost of Neupogen® treatment ranged from €128.16 (1 day) to €1794.30 (14 days), compared to €95.46 and €1336.46 for Zarzio®, thus yielding potential cost savings from €32.70 to €457.84 for the latter. Neulasta® turns cost-saving at day 12 of Neupogen® treatment. At no point over a 14-day treatment period did Neulasta® yield a savingsadvantage over Zarzio®.

CONCLUSION:
Prophylaxis or treatment of febrile neutropenia with Zarzio® is cost-efficient under all possible treatment scenarios relative to Neupogen® and to Neulasta®. In the absence of convincing evidence that pegfilgrastim is pharmacotherapeutically superior to standard filgrastim, there is no cost-efficiency rationale to treat with Neulasta® over Zarzio®, though there may be a small window of approximately 3 days where Neulasta® is cost-efficient over Neupogen®. Regardless, our analysis shows Zarzio® to be the most cost-efficient approach to reducing the incidence of febrile neutropenia in chemotherapy-treated patients.

PMID: 21610020         DOI: 10.1177/1078155211407367

Summary of the Evidence:

Author (Date)	Level of Evidence	Sample/Setting (# of subjects/ studies, cohort definition etc. )	Outcome(s) studied	Key Findings	Limitations and Biases
McBride, A et. al (2017)	Cost – Efficiency Analysis	– Cost-efficiency analyses focused on the direct costs a buyer or payer would incur when purchasing or covering prophylaxis with any four of the following agents (filgrastim-sndz, reference filgrastim, pegfilgrastim, pegfilgrastim-injection) in one patient during one cycle of chemotherapy (days 1-14) – Studied across four defined cost scenarios that are representative of cancer care in the US (includes demographic, geographic and financial factors influencing access to and utilization of cancer services) 1. COSTMED: evaluates only the cost of the medication (pegfilgrastim-injectior – body injector device) 2. SELFADMIN: patients self-administers all medication, but pegfilgrastim-injector device is applied by clinician 3. HPOSTART: Health care provider organization administers first (gilgrastim-sndz or reference filgrastim) injection and patient self-administers subsequent injections; HPO administers pegfilgrastim and pegfilgrastim-injector 4. HPOALL: healthcare provider organization administers all treatments   – Applied these scenarios to each two distinct case studies in attempts to apply to clinical setting (43y Caucasian female with BRCA and 57y AA male with BLBCL)	Cost-effectiveness of biosimilar granulocyte colony-stimulating factors in the prophylactic treatment of chemotherapy induced febrile neutropenia compared to granulocyte colony-stimulating factors.	Done with ASP-based analyses. COSTMED: – At no point over a treatment regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a savings benefit – Filgrastim-sndz retains marginal savings of $834 at 14 days, but may save $3,666 if only 1 day of filgrastim-sndz prophylaxis is administered SELFADMIN: – Similar to COSTMED scenario – At no point over a treatment regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a savings benefit – Filgrastim-sndz retains marginal savings of $834 over pegfilgrastim and $859 over pegfilgrastim-injector at 14 days, but may save $3,666 and $3,962 respectively, if only 1 day of filgrastim-sndz prophylaxis is prescribed HPOSTART: – At no point over a prophulaxis regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a savings benefit – Filgrastim-sndz retains marginal savings of $834 over pegfilgrastim and $817 over pegfilgrastim-injector at 14 days, but may save $3,666 and $3,649 respectively, if only 1 day of filgrastim-sndz prophylaxis is given HPOALL: – At no point over a treatment regimen of up to 14 daily filgrastim-sndz injections do pegfilgrastim or pegfilgrastim-injector yield a savings benefit – Filgrastim-sndz retains marginal savings of $284 over pegfilgrastim and $267 over pegfilgrastim-injector at 14 days, but may save $3,666 and $3,649 respectively, if only 1 day of filgrastim-sndz prophylaxis is prescribed   Filgrastim-sndz is the least expensive and economically most cost-efficient method of prophylaxis for cancer patients at risk for developing febrile neutropenia due to chemotherapy – Yields a cost savings of $65 over reference filgrastim, single-administration pegfiltrastim and pegfilgrastim-injector	Cost-analyses was completed and funded by Sandoz Inc – a pharmaceutical manufacturer that formulated filgrastim-sndz, which can be problematic given they created the drug they’re analyses is showing to be most cost effective. It truly could be the case but outside research should be done to verify the data and compare results across the different GCSFs.   Several of the study authors are employees of Sandoz, Inc, which while declared still could potentiate results that favor the company for which they work.   Again, even if the research is substantiated in their data sets, additional outside research should be done and contracted to support their claims and highlight the facts their analyses provided.   The study only applied these findings to two case studies. Given the frequency for which chemotherapy febrile neutropenia occurs, additional case studies of different age groups (including children and the geriatric population) should have been incorporated to continue to prove the effectiveness of the biosimilar filgrastim-sndz.   This study did not actually apply these costs to ‘live’ patients but rather applied them to clinical settings. While they acknowledge the additional costs associated with cancer care, management and treatment, the study is limited without an actual application to a clinical setting. In that application the costs should be analyzed and the study / analysis should be redone to verify the results remain accurate.
Schwartzberg, LS et. al (2018)	Retrospective Claims Analysis	Conducted 9/1/14 – 7/31/16 using data from Optum Research Database (ORD) – a proprietary US health insurance database – Evaluated 3,542 patients based on medical claims via ICD, CPT or HCPCS codes as well as outpatient pharmacy claims including dispensed medications, quantity dispensed, dose and number of days supply – Patients greater or equal to 18 years with at least 1 claim for filgrastim-sndz or filgrastim-ref during the patient identification period in the first observed cycle of a chemotherapy treatment regimen (done during first cycle because it is the time of greatest FN risk) – Patients excluded if had evidence of radiation or surgery within 6 days after index date, any claim for hematopoietic cell transplantation during the study period, evidence of chemotherapy >30 days before first qualifying receipt of filgrastim-sndz or filgrastim-ref, evidence of pregnancy during the 6-month baseline period, or missing demographic information or had switched G-CSF drugs during the observed chemotherapy cycle – Cohort assignments were based on the first qualifying claim for G-CSF   – Demographics assessed included age, sex, geographic region, insurance type, Quan-Charlson comorbidity index score, number of colony-stimulating factor doses, length of first observed chemotherapy cycle, use of CSF prophylaxis and certain diagnoses and procedures.   – FN rarely occurs within first 5 days of chemo, use of biosimilar G-CSF was categorized as prophylactic if initiated on or before day 5 if chemo, later uses were categorized as treatment.	Real-world study evaluating the incidence of febrile neutropenia and the healthcare resource utilization and medical costs among US patients with non-myeloid cancer who received filgastrim-sndz or filgrastim-ref during their first chemotherapy cycle.	One of the first analyses done on real world patients   Historically biologics are more expensive drugs. However, recent analyses conclude that prophlaxis with filgrastim is cost-efficient in routine clinical practice relative to both filgrastim-ref and pegfilgrastim –       Widespread use of the biosimilar in place of filgrastim-ref would yield cost savings sufficient to treat thousands of additional patients on a budget neutral basis   Incidence of febrile neutropenia was statistically equivalent between individuals treated with filgrastim-sndz vs filgrastim-ref during their first chemotherapy cycle –       Availability of biosimilar filgrastim may improve patient access to G-CSF treatment and assist with prophylaxis in preventing FN   Mean FN-related medical costs among all patients with febrile neutropenia was $11,977 for neutropenia & fever, $8,040 for neutropenia & infection and $21,733 for neutropenia, infection and fever. –       Given the extremely large costs associated with an episode of febrile neutropenia, the need for biosimilar and available prophylactic treatment is cost effective in helping to prevent febrile neutropenia	This study, too, was funded by Sandoz, Inc (the company that manufactures the biosimilar G-CSF) – Sandoz was involved in study design, data interpretation, writing and revision of the manuscript and the ultimate decision to submit it for publication.   Similar to the article above, two of the authors are employees of Sandoz currently and a third was an employee of Sandoz while the study was conducted. As previously stated, while the research may be statistically significant and accurate in its reporting, having a nonbiased researcher allows the interpreter to give the study more validity in its findings.   The cohorts for filgrastim-sndz included 162 patients and the cohort for filgrastim-ref included 3,297 patients, which is not at all equivalent. While the data was eventually weighted to provide a realistic comparison, it would have been helpful to have the same number of patients in each cohort.   The study was done retrospectively so is limited by the data received from the various databases and the correctness for which individuals completed the paperwork and charting.   The study doesn’t outwardly address the cost-effectiveness of the G-CSF biosimilar in comparison to the original medication but references other studies that do and addresses the importance of incorporating the biosimilar into the larger medical treatment plan to help proactively treat febrile neutropenia.
Grewal,S et. al (2018)	Cost-Savings Model	Analytic framework – Authors use a cost calculator to evaluate cost per episode for each granulocyte colony stimulating factor product to estimate cost-savings over a 5-year time period with the incorporation of filgrastim (biosimilar G-CSF) – Estimate multiplied by number of incident eligible patients per year to calculate yearly estimate and costs then aggregated over time – Model compares two scenarios in the base case: 1.    Status Quo: current usage rates and trends continue 2.    Biosimilar growth in which the use of filgrastim biosimilars grow at 10% / year   Patient population: – 19.4% of patients of 1,617,665 likely to use G-CSF in conjunction with chemotherapy (from retrospective claims data from OptumInsight) –       Use of filgrastim at 15% based on RAND analysis using IMS data   Key data input into model to evaluate the budge impacts for health insurers and patients with the use of filgrastim – Model uses 5-year time period and outcomes include the total cost for each scenario as well as incremental cost savings for biosimilar growth	Creation of a framework to illustrate the application of filgrastim to patients with neutropenic fever and analysis of estimated cost savings for the use of filgrastim biosimilars under different scenarios.	One-way sensitivity analysis –       Most sensitive to the cost of G-CSF products, the number of patients with a nonmyeloid cancer diagnosis and the G-CSF usage rates   Presence of biosimilars in the chemotherapy / febrile neutropenia space is likely to shift the market and providers are expected to write for biosimilars now more than ever.   Cost analysis estimates a cost savings of $256 million over 5 years with the use of biosimilars – depending upon the uptake rate of biosimilars in clinical practice. –       This may be an underestimate – uptake will be dependent upon education of the biosimilars and incorporation into practice –       The changes in Medicare Part B rules allows for coverage of these biosimilars –       Changes are being made to commercial insurance practices –       Regulations are evolving given the demonstration of highly similar effects to the original ‘product’ without significant difference   Of the $256 million, 18% are from reduced patient out-of-pocket costs, 34% are savings to commercial payers and 48% are savings to Medicare.	This paper / cost-savings model was funded by Sandoz Inc.  Sandoz Inc manufactues the G-CSF biosimilars and there for there is the potential for bias in the findings.  As stated in the above, these articles may have completely factual information but should be replicated and verified by an outside source that doesn’t have financial gains associated with the findings.   Additionally they reference the financial model they created to input the data but do not go into significant depth in the article address the details of the model and any biases that might lead to skewed results.   Several of the authors had previously consulted for Sandoz, Inc the company that manufactures the biosimilars but also the company that funded the study.   Given this is a future cost-model prediction, while the data is founded on facts of historic cases and analysis is thorough it is impossible to predict if their outcome is actually true without implementing the biosimilars into clinical practice.  The authors note Europe is leading the way with this practice and pushed them to complete this cost benefit analysis to see and understand the impact it could have in the United States.
Aapro, M et al (2012)	Comparative cost-efficiency analysis	Analysis focused on the European Union G5 countries (France, Germany, Italy, Spain and UK) – Population ~314,853,411 across all 5 countries   Cost model evaluated direct costs a buyer or payer would incur when purchasing or covering any of the three agents in one patient during one chemotherapy cycle – Indirect costs were not included – Assumptions made based on historical data and input values adjusted to reflect that information   Costs of treatment with Neupogen and Zarzio (which are variable costs) were calculated when used anywhere on the 14 day chemotherapy cycle and compared to the price of one dose of Neulasta (which is a fixed cost) over the 14 day period	To analyze the cost-wise benefit of granulocyte colony-stimulating factors over 14 days of chemotherapy treatment across the EU G5 countries A. Evaluate cost-wise, using Neulasta vs. Neupogen or Zarzio may be cost-saving in reducing the incidence of chemotherapy-induced febrile neutropenia B. Evaluate if cost-wise treatment with Zarzio yields a savings advantage over Neupogen (the article has two objectives but for the purposes of this assignment, the focus is on the latter)	Cost savings associated with Zarzio (the biosimilar) over Neupogen ranged from €32.70 for 1 day to €457.84 for a 14 day regimen. –       Zarzio retains a marginal savings of €78.50 at 14 days but may save up to €1319.50 if only a single dose is given   A. Neulasta yields a cost-savings benefit if G-CSF treatment equivalent to 12 or more days of Neupogen is required to increase the ANC   B. Under any treatment regimen, Zarzio is consistently more cost-efficent than both Neulasta and Neupogen – Zarzio provides the best value (defined as quality over cost) for the prophylaxis and treatment of febrile neutropenia – the findings extend across many different cancer types   Zarzio is more cost-efficient than Neupogen across any standard filgrastim regimen – the shorter the treatment period, the higher the relative savings over Neulasta	This study was done in the EU, with a different economic market and financial model it is hard to determine if these medications will have similar impact in the United States without further study and evaluation of the biosimilars in the US. Further research must be done in the US in order to validate the findings seen in Europe.   The cost model assumes all three products have similar efficacy and safety, which has been addressed in other studies but not in this study so can be a potential limiting factor.   The analysis assumes cost is evaluated under consideration of the relative outcomes achieve (decrease in the risk of febrile neutropenia or avoidance of neutropenic events, increased quality of life, etc vs outlay of cash).

 

Conclusion(s):
McBride, A et al conclude the biosimilar Filgrastim-sndz is the least expensive and economically most cost-efficient method of prophylaxis for cancer patients at risk for developing febrile neutropenia due to chemotherapy. The use of Filgrastim-sndz yields a cost savings of $65 over reference filgrastim, single-administration pegfiltrastim and pegfilgrastim-injector.

Schwartzberg, LS et al created a study in the US that is one of the first to include a real patient population in their evaluation and analysis. Their research concludes the variable costs associated with an episode of febrile neutropenia highlight the need for a biosimilar drug to prophylactically treat febrile neutropenia and these biosimilars are cost-effective in helping to prevent neutropenic episodes. Additionally, the availability of biosimilar filgrastim may improve patient access to G-CSF treatment.

Grewal, S et. al formulated a cost-savings model that analyzed the effectiveness of biosimilars in preventing febrile neutropenia and estimate a cost savings of $256 million over 5 years with the incorporation of biosimilars into clinical practice.

Aapro, M et al used a cost-efficacy analysis to conclude that Zarzio provides the best value for the prophylaxis and treatment of febrile neutropenia under any treatment regimen. The authors found that Zarzio is consistently more cost-efficient than both Neulasta and Neupogen and the findings are equivalent across many different cancer types.

Across all of the articles selected for the purposes of this assignment, the conclusions were overwhelmingly similar that the use of biosimilars is cost effective in the prophylactic treatment and prevention of febrile neutropenia. While the various analyses focused on slightly different aspects in their comparisons, the overarching evidence and data finds that the use of the biosimilars helps to improve access to medication essential for positive outcomes and cost savings.

Clinical Bottom Line:

In the United States, the FDA approved biosimilar medications to treat febrile neutropenia within the past 10 years. Given this fact, the data is extremely limited and calls for cost analyses to outline the potential for savings with the incorporation of the biosimilars into clinical practice (given the lack of patient use to date). I would weight the evidence from Aapro M et al most heavily when applying the data to clinical practice. Although this research was done in Europe and focuses on a different population with different financial practices, febrile neutropenia does not change across populations and it is consistently caused by chemotherapy. These European countries have the most data and are leading the way with the use of biosimilars in treating febrile neutropenia and therefore offer the most substantive findings allowing for US researchers and practitioners to apply this information into clinical practice. Additionally, the other three articles selected mention Europe as the leader of this practice and reference the point that it was the European work that spurred their research. Additionally, this is the only article that isn’t funded by or involed with Sandoz, Inc, the company, which manufactures Zarzio allowing the authors to provide a truly unbiased analysis.

After the Aapro et al article, I would weigh the McBride et al and the Grewal et al equally with one another, as they are financial analyses that evaluate the incorporation of biosimilars into clinical practice in comparing them to G-CSFs. While each of these articles take different approaches to evaluating the data and set up different ‘scenarios’ the results are the same that using the biosimilar medication provides a cost effective savings. Both of these articles did present with substantive biases in that researchers that work for Sandoz, Inc or are funded by the company itself fund the studies. However, given the newness of the biosimilars there is going to be limited research on cost analysis without the company first providing substantive details and research first so it is fitting that in these instances there is some involvement from the company that formulated the biosimilar G-CSF.

I would weigh the Schwartzberg LS et al article last because it doesn’t directly answer the question at hand. It provides substantive data and a real world scenario with patients that had actually received the Zarzio; however, it focuses more on the incidence of febrile neutropenia and the resource utilization over medical costs. While it does address the associated medical costs the results and data dial into the rate at which febrile neutropenia occurs during the patients first chemotherapy cycle. I decided to include the article because it does reference other studies that address costs and incorporates that information into their findings to yield results that support the other findings. This article is one of the first of its kind to retrospectively study real patient populations in the United States, which is why it was essential for it to be included in the research.

The incorporation of biosimilar G-CSFs is extremely beneficial to patients undergoing chemotherapy. As is the case with many illnesses the medical costs associated with treatment are tremendous and can bankrupt patients. The incorporation of biosimilar G-CSFs into clinical practice has the opportunity to provide life saving care to patients whose insurance may not have previously covered treatment for febrile neutropenia or governmental support to those that did but required additional assistance. With the evolution of medicine, regulations and clinical practice has begun to shift. Grewal et al addresses the shifting regulations from a governmental perspective and highlights the fact that biosimilars are beginning to be covered by Medicare Part B, providing ease of access to patient populations who previously may not have been eligible for such treatment. Given the large US population with Medicare, the new of the coverage allowances yield broader and greater coverage for people, no matter their insurance and the magnitude of that impact is enormous.

Costs should never be a concern for a patient undergoing chemotherapy. These patients are already fighting for their lives, they should not have to be on the phone fighting to get approval for medications and these changes allow for the use of biosimilar medications in clinical practice, which provide significant cost savings to G-CSFs. The inclusion of biosimilar G-CSFs into clinical practice allows for a broader population to be treated and provides life saving treatment at a lower cost. As a future provider, and someone that is interested in pursuing a career in hematology/oncology, biosimilars provide a clinically sound alternative at a lower cost and are equally as efficacious as standard G-CSFs and it is something that I would incorporate into standard practice to treat and prophylax febrile neutropenia.

While the evidence retrieve was substantive and able to answer my question, it would be beneficial to further research this question with greater patient populations. The Schwarzberg study addressed the real world clinical scenario but didn’t address it on a large scale. As biosimilar G-CSFs become more commonplace, this research should continue to ensure that it is truly cost-effective to utilize these medications in comparison to the standard G-CSFs. Additionally, the research should be funded and completed by a third party source to limit biases. As more research is done, studies at higher levels of evidence should be completed. The data should be systematically reviewed and analyzed to support the conclusions drawn here today and ensure it is applicable across all patients with the potential for febrile neutropenia following chemotherapy treatment.