A Value-Based Pricing Study of Inotuzumab Ozogamicin for B-Cell Precursor Acute Lymphoblastic Leukemia (B-Cell All) in the United States

A VALUE-BASED PRICING STUDY OF INOTUZUMAB OZOGAMICIN FOR B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-CELL ALL) IN THE UNITED STATES

ZIYAN CHEN

A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN PHARMACY

UNIVERSITY OF FLORIDA

2018

To my mom

ACKNOWLEDGMENTS

Foremost, I would like to express my sincere gratitude to my advisor Dr. Diaby for the continuous support of my research, for his patience, motivation, enthusiasm, and immense knowledge. His guidance helped me in all the time of research and writing of this thesis.

Besides my advisor, I would like to thank my thesis committee: Dr. Xiao, for her encouragement and insightful comments.

Last but not the least, I would like to thank my parents for supporting me to pursue my study.

TABLE OF CONTENTS

page

ACKNOWLEDGMENTS ...... 4

LIST OF TABLES ...... 7

LIST OF FIGURES ...... 8

ABSTRACT ...... 9

CHAPTER

1 INTRODUCTION ...... 10

Background ...... 10 Research Aim ...... 12 Specific Aim 1 ...... 12 Specific Aim 2 ...... 12 Research Questions ...... 13 Significance of This Study ...... 13 Organization of This Thesis...... 13 Chapter 2 ...... 13 Chapter 3 ...... 13

2 COST-EFFECTIVENESS OF IMMUNOTHERAPY IN HEMATOLOGIC MALIGNANCIES: A SYSTEMATIC REVIEW ...... 15

Criteria for Considering Studies for This Review ...... 18 Search Strategy for Identification of Studies ...... 18 Methods of the Review ...... 19 Selecting Studies ...... 19 Data Extraction ...... 19 Quality Assessment ...... 19 Strategy for Data Synthesis ...... 20 Results...... 20 Description of Studies ...... 20 Rituximab ...... 22 Alemtuzumab ...... 24 Blinatumumab ...... 25 Daratumumab ...... 25 Brentuximab Vedotin ...... 25 Ofatumumab ...... 26 Obinutuzumab ...... 26 Discussion ...... 27 Conclusions...... 29

3 INOTUZUMAB OZOGAMICIN IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) ACUTE LYMPHOCYTIC LEUKAEMIA (ALL): ESTABLISHING A VALUE-BASED COST – PRELIMINARY RESULTS ...... 51

Methods ...... 53 Overview of the Economic Model ...... 53 Estimation of Transition Probabilities ...... 54 Medical Resource Use and Costs ...... 55 Health Utility Weights ...... 55 Discounting ...... 56 Analyzing the Cost-Effectiveness Model ...... 56 Sensitivity Analysis ...... 56 Variations in the Cost of Inotuzumab Ozogamicin for Value-Based Price ...... 57 Results...... 57 Individual Patient Data Reconstruction ...... 57 Parametric Distribution Fitting ...... 57 Equation for Transitional Probabilities ...... 58 Equations for transitions from being alive (progression or progression) to death ...58 Equations for transitions from being stable (progression-free) ...... 59 Equations for transitions from being stable to progression ...... 59 Establishing a Value-Based Cost ...... 60 Discussion ...... 60 Conclusion ...... 61

LIST OF REFERENCES ...... 64

BIOGRAPHICAL SKETCH ...... 68

LIST OF TABLES

Table page

2-1 PubMed search strategy ...... 30

2-2 Study characteristics ...... 31

2-3 Study Results ...... 38

3-1 Summary measures collected from the original publications and their corresponding estimates obtained from the reconstructed individual patient data (IPD)...... 62

LIST OF FIGURES

Figure page

2-1 Flow chart of the article selection process ...... 50

3-1 Bubble diagram of the multi-state model with 3 health states: progression-free, progression, and death...... 63

Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science in Pharmacy

A VALUE-BASED PRICING STUDY OF INOTUZUMAB OZOGAMICIN FOR B-CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA (B-CELL ALL) IN THE UNITED STATES

Ziyan Chen

May 2018

Chair: Vakaramoko Diaby Major: Pharmaceutical Sciences

The aim of this study is to establish a value-based cost range for inotuzumab ozogamicin

(InO), a new immunotherapy agent approved in 2017 by US Food and Drug Administration

(FDA) for the treatment of relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL).

This study is composed of 2 independent sub-studies. The first sub-study is to systematically review the literature and report the cost-effectiveness of immunotherapy for hematologic malignancies. The second sub-study is to prospectively identify the range of drug costs of InO from a US perspective within which it could be considered cost-effective.

The results of the first sub-study show that there is a limited number of cost-effectiveness analyses of newer immunotherapeutic agents. These findings highlight the need for more research on the value assessment of newer immunotherapeutic drugs. We will use the transition probabilities estimated earlier as input parameters to estimate the value based price for inotuzumab ozogamicin.

CHAPTER 1 INTRODUCTION

Background

B-cell Precursor Acute Lymphoblastic Leukemia (B-cell ALL) is a rapidly progressing type of blood cancer characterized by an overproduction of lymphoblasts. [1] It is the second most common type of acute leukemia in adults. [2] The National Cancer Institute (NCI) estimates that approximately 5,970 people in the United States will be diagnosed with ALL this year, out of which approximately 1,440 will die from the disease. [3] The prognosis of patients with refractory or relapsed (R/R) ALL is poor with only 30% expected to have a complete response after 1st salvage therapy and around 5% long-term survival when treated with cytotoxic chemotherapy and allogeneic stem cell transplantation. [4]

The first-line therapy for ALL involves standard and high-dose chemotherapy (dosage determined by age, ALL subtypes, and prognosis), hematopoietic stem-cell transplantation, and targeted therapy. [5] While high-dose chemotherapy improves the response rate in patients, about

60% of these patients experience relapses. [6] Immunotherapy, a subtype of targeted therapy that can target on leukemia cell surface markers and release cytotoxicity factors to the targeted cells, is purported to be an alternative treatment option for patients with B-cell ALL. [7]

Blinatumomab (Blincyto) and inotuzumab ozogamicin (Besponsa), represent two examples of recent FDA-approved drugs. [8-10]

Inotuzumab ozogamicin is a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, a cytotoxic antibiotic agent. It works in three steps: 1) the conjugate binds to

CD22 expressed on the B-lymphocyte blasts, 2) the CD22–conjugate complex is rapidly internalized, and calicheamicin is released, and 3) calicheamicin can induce apoptosis of B- lymphocyte blast by binding to the minor groove of DNA and induces double-strand cleavage.

[11] The approval of inotuzumab ozogamicin was based on the phase-3 INO-VATE ALL clinical trial. [10] In this trial, adults with relapsed and refractory B-cell ALL were randomly assigned to receive either inotuzumab ozogamicin or standard of care intensive chemotherapy

(SOC). The primary endpoints were complete remission and overall survival. The results showed a higher rate of complete remission with inotuzumab ozogamicin than with SOC, and a higher percentage of patients in the inotuzumab ozogamicin group had results below the threshold for minimal residual disease. Both progression-free and overall survival were longer with inotuzumab ozogamicin.

The price of cancer treatments is increasing significantly with the development of novel treatments, which are adopted as standards of care. Projected national costs of cancer care suggest an increase from $124.57 billion in 2010 to $173 billion in 2020 (39% increase) under the dynamic assumptions of current trends in incidence, survival, aging, and growing of the US population. [12] The novel cancer treatments impose an immense cost burden and cast doubt on whether their high prices reflect their worth. Therefore there is a critical need to comprehensively assess the value of these therapeutic options. [13]

Cost-effectiveness analysis is very commonly used to evaluate the cost and benefit of pharmaceutical products. However, for newly approved drugs, it is hard to find transparent pricing information that matches the value conferred to treatment to the money invested for its acquisition. Under these circumstances, value-based pricing frameworks can be utilized to estimate the price range based on the willingness-to-pay threshold and cost-effectiveness approaches. [14, 15]

For cancer drugs, the particular issue of drug wastage has increasingly been under scrutiny when conducting economic evaluations. Economic evaluations are often conducted

under the assumption that every milligram of a drug is effectively used. [16] However, evidence suggests that, in clinical practice, wastage of residual vial contents cause by the mismatch of vial size and individualized doing based on body-surface area or weight has the potential to significantly affect overall drug expenditure. [17] Since most of the immunotherapies for hematologic malignancies are parenteral drugs and have the potential for drug wastage, it is necessary to explicitly take into account of drug wastage in economic evaluations.

In this dissertation, we developed and used a value-based pricing framework that accounts for the impact of drug wastage. This framework was used in the context of the estimation of the value-based price range for inotuzumab ozogamicin.

Research Aim

The aim of this dissertation was to establish the value-based price of inotuzumab ozogamicin, which includes a formal assessment of the impact of drug wastage on the estimated value-based price. The following specific aims have been addressed to meet the overall aim:

Specific Aim 1

To review the literature and summarize the cost-effectiveness of immunotherapies for hematologic malignancies. This systematic review was focused on 1) current consideration of drug wastage in cancer treatment and how does it affect the cost-effectiveness of cancer drugs when involving in evaluation models; 2) economic modeling used in the economic evaluations;

3) model inputs that can be used in the value-based pricing study.

Specific Aim 2

To conduct a value-based pricing study of inotuzumab ozogamicin when compared with salvage chemotherapy and involving drug wastage. The objective of the present study was to prospectively identify the range of drug costs from a US perspective within which inotuzumab ozogamicin could be considered cost-effective.

Research Questions

The following questions are evaluated to address the overall research aims:

• What could the optimal value-based price range for inotuzumab ozogamicin be? • How does drug wastage affect the value-based price of inotuzumab ozogamicin?

Significance of This Study

As an aggressive type of leukemia, patients with ALL have a high unmet need and poor prognosis. Inotuzumab ozogamicin represents a breakthrough treatment compared to the current intensive and long-term chemotherapy.

This research contributes to the literature of inotuzumab ozogamicin by providing a value-based pricing framework that can be further used to support clinical and reimbursement decision-making. Also, this research addresses the issue of drug wastage in the estimation of the value-based price of inotuzumab ozogamicin.

Organization of This Thesis

This dissertation is composed of 3 chapters (excluding the introduction) that are interconnected. The second and third chapters will be presented as research manuscripts. An overview of the structure of this dissertation is presented below.

Chapter 2

Cost-effectiveness of immunotherapy in hematologic malignancies: a systematic review.

This chapter discusses and summarizes cost-effectiveness literature that assesses the value of immunotherapies for hematologic malignancies.

Chapter 3

Inotuzumab ozogamicin in patients with relapsed or refractory (r/r) acute lymphocytic leukemia (all): establishing a value-based cost. This chapter describes the estimation of the

optimal price range at which inotuzumab ozogamicin will deliver value, based on benchmark willingness to pay threshold.

CHAPTER 21 COST-EFFECTIVENESS OF IMMUNOTHERAPY IN HEMATOLOGIC MALIGNANCIES: A SYSTEMATIC REVIEW

The purpose of this study was to systematically review cost-effectiveness studies of immunotherapies in hematologic malignancies. A systematic review of cost-effectiveness studies of treatment for hematologic malignancies, focusing on immunotherapy, was carried out. Studies were identified through a literature search of PubMed, Ovid Medline, and Econlit. We included

41 studies that met inclusion criteria in this systematic review. After the examination of study characteristics, they were stratified by treatment agents. Most studies evaluated rituximab (25), followed by obinutuzumab (5), alemtuzumab (4), brentuximab vedotin (3), ofatumumab (2), daratumumab (1), and blinatumomab (1). No eligible studies were found for the other identified immunotherapy agents. Rituximab was found to be cost-effective when combined with chemotherapy compared to chemotherapy alone. However, there is a lack of evidence regarding the newer immunotherapeutic agents. Future research is needed to address the value of immunotherapy for hematologic malignancies.

Over the past decades, the field of cancer immunotherapy has witnessed an increased breadth and growth in the development of immunotherapeutic agents. [18] As a result, cancer immunotherapy has become a leading area of ongoing research. Because of the unique characteristics of hematological cancers and their close relationship with host immunity, the recent successes of cancer immunotherapies have been initially proven by the development of treatments for hematologic malignancies. [19] Rituximab, as the first anti-CD20 monoclonal antibody to treat hematologic malignancies was approved in 1997. [20] After that, the U.S. Food and Drug Administration (FDA) has granted the approval for its extended indications as well as

Paper included as per permission from author.

systemic therapy in combination with other chemotherapy agents. During the same period, newer immunotherapies for hematologic malignancies were approved at an exploding rate, which made immunotherapies accessible to patients. [18]

Immunotherapy, as a class of clinically beneficial alternatives to conventional therapies, has increased its accessibility since 2001. [21] In fact, clinical trials have demonstrated that immunotherapy agents, exhibit acceptable long-term safety, favorable 1-year or 2-year progression-free survival (PFS) and overall survival either monotherapy or in combination with other chemotherapy agents. [22-28] However, besides the fact that not all patients respond to immunotherapy, it has notably high cost.

The price of cancer treatments is increasing significantly with more expensive novel treatments adopted as standards of care. Projected national costs of cancer care suggest an increase from $124.57 billion

In 2010 to $173 billion in 2020 (39% increase) under the dynamic assumptions of current trends in incidence, survival, aging, and growing of the US population. [29] The novel cancer treatments have imposed an immense cost burden, which begs the questions as to whether their high prices reflect their worth. Therefore, there is a critical need to evaluate immunotherapeutic agents based on their overall value, accounting for financial costs, clinical outcomes, side effects, and impact on patients’ quality of life. [30] Little work has been done in hematologic cancer in this regard. Saret, Cayla J., et al. conducted a systematic review of the value of innovative treatments using data from the Tufts CEA Registry. They concluded that these novel treatments for hematologic malignancies appear to be cost-effective because their incremental cost- effectiveness ratios (ICERs) were below the threshold of $50,000/QALY or $100,000/QALY.

[31] However, Prasad and colleagues criticized this work by pointing out the facts that many

novel drugs confer marginal survival benefits at tremendous cost and the majority of the cost- effectiveness studies in this systematic review were sponsored by the product manufacturer. [32]

Additionally, their systematic review was limited to cost-utility studies and only two immunotherapies were included. In contrast to the increasing development of immunotherapies, no value assessment with a special focus on the unique aspects of cancer immunotherapies has been done, which may have resulted in a lack of understanding of the true value of these therapies. [30]

A growing issue gaining significant attention in the literature is the impact of drug wastage on the economic evaluations of immunotherapies for hematologic malignancies.

Economic evaluations are often conducted under the assumption that every milligram of a drug is effectively used. However, evidence has demonstrated that, in clinical practice, wastage of residual vial contents cause by the mismatch of vial size and individualized doing based on body-surface area or weight has the potential to significantly affect overall drug expenditure.

[33] Since most of the immunotherapies for hematologic malignancies are parenteral drugs and have the potential of drug wastage, it is necessary to explicitly take into account drug wastage in economic evaluations. A recent systematic review conducted by Goede and colleagues investigated the current trend of considering wastage in economic evaluations of new therapies for hematologic malignancies. They argued that that wastage was considered in less than one- third of publications. [34] In their study, they claimed to have included all parenteral drugs for hematologic malignancies identified from U.S. FDA approval and safety notification. (2006 to

2014) However, among the 7 drugs they included, Lenalidomide is an oral drug. Moreover, they did not include all drugs that had met the inclusion criteria. To our knowledge, there is no

investigation of drug wastage in economic evaluations with the special focus of immunotherapies for hematologic malignancies.

The primary objective of this study was to systematically summarize and examine studies that evaluated the cost-effectiveness of immunotherapies for hematologic malignancies. The secondary objective was to examine the frequency of drug wastage modeling in economic evaluations of immunotherapies for hematologic malignancies.

Criteria for Considering Studies for This Review

We first identified 12 immunotherapy agents through the U.S. Food and Drug

Administration (FDA) approvals for hematologic malignancies (Rituximab, Ofatumumab,

Nivolumab, Brentuximab vedotin, Obinutuzumab, Alemtuzumab, Daratumumab, Elotuzumab, gemtuzumab ozogamicin, Inotuzumab ozogamicin, Blinatumomab, Pembrolizumab). An economic evaluation was considered eligible for inclusion in the data extraction and quality assessment portion of this review if the study met all of the following inclusion criteria: 1) evaluate the value of identified immunotherapies for hematologic malignancies, 2) assessed and reported incremental cost-effectiveness ratios (ICERs) as a primary outcome, 3) published in

English language.

Studies were excluded if they: 1) were not cost-effectiveness or cost-utility analyses, 2) did not include a comparative evaluation of the different treatments for hematologic malignancies, 3) studied the drugs of interests for indications other than hematologic malignancies, 4) were conducted in animal subjects, 5) cannot be accessed.

The protocol of this systematic review is registered with the International prospective register of systematic reviews (PROSPERO) under the registration number CRD42018088581.

Search Strategy for Identification of Studies

The following electronic bibliographical databases were searched:

• Ovid Medline – from January 1st 2007 to December 31st 2017; • PubMed – from January 1st 2007 to December 31st 2017; • Econlit – from January 1st 2007 to December 31st 2017.

Databases were searched utilizing a search strategy that incorporated keywords comprised of the generic name and brand name of each identified agent and “cost”, “costs and cost analysis”, “cost-benefit analysis”, “cost-effectiveness analysis”, “cost-utility analysis”,

“health care costs” terms. The search strategy used for searching PubMed is provided in Table 2-

1 but was modified to reflect the indexing systems of other databases.

Methods of the Review

Selecting Studies

The selection of relevant bibliographic records was done by two independent reviewers

(ZC, VD). Bibliographic records obtained from the execution of the search strategy were first checked for duplicates removal. Then, each reviewer screened and assessed the titles and abstracts of the articles to assess their adherence to inclusion criteria. Furthermore, the full-text review of the remaining bibliographic records was conducted. The reference lists of identified studies were also searched for relevant studies manually. Inter-rater discrepancies were resolved between the two reviewers until they reached a consensus on the final results.

Data Extraction

One reviewer (ZC) extracted data into evidence tables. The other reviewer (VD) checked the table accuracy. Reviews focused on the economic modeling and wastage consideration in each study.

Quality Assessment

The methodological quality of the included studies was assessed using two quality assessment tools frequently referenced in the literature: Drummond 10-Point Checklist

(Drummond, 1987) and Evers Checklist (Evers, Goossens, Vet, Tulder, & Ament, 2005). The

use of the two checklists is recommended by the Cochrane Handbook for Systematic Reviews of

Interventions for the critique of economic evaluations (Shemilt et al., 2011). The Drummond checklist was used primarily to provide useful guidance in assessing economic evaluation, the

Evers checklist served as a supplement to the former by including aspects such as the independence of investigators.

We assessed the inter-rater agreement for the reviewers’ assessments of study selection and quality assessment by calculating the agreement percentage κ (Cohen’s kappa coefficient of agreement). The interpretation of κ is as follows:

• A value of κ ≤ 0 indicates no agreement; • A value of κ between 0.01–0.20 indicates none to slight agreement; • A value of κ between 0.21–0.40 indicates fair agreement; • A value of κ between 0.41–0.60 indicates moderate agreement; • A value of κ between 0.61–0.80 indicates substantial agreement; • A value of κ between 0.81–1.00 indicates almost perfect agreement (McHugh, 2012)

Strategy for Data Synthesis

We used aggregate data and provided a narrative synthesis of the findings from the included studies. The synthesis was structured around the identified agents and specific indications, target population characteristics, type of outcomes, wastage modeling. We grouped cost-effectiveness studies per immunotherapeutic agent and summarized the results of such studies.

Results

Description of Studies

819 publications were identified via the literature search. Of these studies, 102 were citation duplicates and were therefore removed from the pool of bibliographic records. Of the

717 remaining records, 661 were excluded based on screening of study titles and abstracts, leaving 56 potentially relevant articles for full-text review. Of the 56 articles selected for full-text

review, 15 studies were excluded because the full text of the study was not available, leaving 41 relevant articles. Figure 2-1 is the Prisma diagram that shows the article selection process.

All 41 studies included in this review conducted a cost-effectiveness/cost-utility analysis and reported main outcomes as ICERs. The majority of the studies were model-based studies, expect four studies investigating rituximab related therapy and one study investigating treatment sequences for patients with follicular lymphoma (FL) were based on real-world data. Nine studies were conducted from the US (Delea, 2017; Pelligra, 2017; Hui, 2017; Longnakon, 2014;

Hayslip, 2008; Chen, 2015; Homberger, 2011; Homberger, 2008; Griffiths, 2012), followed by

UK (Babashov, 2017; Lu, 2012; Hatswell, 2017; Sinha, 2017; Prettyjohns, 2017; Ray, 2010;

Keep, 2016), multi-country (Herring, 2016; Parker, 2016; Becker, 2016; Soini, 2016; Griffiths,

2012; Blommestein, 2014), Canada (Khor, 2014; Nam, 2018; Prica, 2015; Mittmann, 2012),

Spain (Casado, 2017; Sabater, 2016; Casado, 2016), Netherlands (Blommestein, 2016; Mandrik,

2015), Finland (Soini, 2011; Soino, 2012), France (Deconinck, France), Sweden (Kasteng,2009),

Australia (Adena, 2014), Germany (Mu ̈ller, 2015), Italy (Ferrara, 2008), and New Zealand

(Scott, 2007). 76% (31) of included studies were pharmaceutical industry-funded. Studies included in this systematic review reported 45 cost-effectiveness ratios (some of the 41 studies reported multiple ratios). Most ratios concerned interventions for chronic lymphocytic leukemia

CLL (37%) and FL (29%). The majority ratios related to treatments for rituximab (68%). 85% of studies contained only one of the identified immunotherapy agents. 56% of the studies adopted a lifetime horizon with the remaining studies opted for short-term time horizons. Among the model-based studies, nine (Delea, 2017; Hui, 2017; Sinha, 2017; Nam, 2018; Homberger, 2008;

Scott, 2007; Becker, 2016; Soini, 2016; Blommestein, 2016, 25%) accounted for drug wastage in their base case analysis, two made a clear statement of no wastage assumption. The remaining

studies did not mention drug wastage. Table 2-2 summarizes the main study characteristics of the publications included in this review.

Rituximab

Six studies examined the cost-effectiveness of rituximab maintenance (RM) therapy compared with observation in patients with follicular lymphoma (FL). Hayslip et al. (2008) conducted a study to determine the incremental cost-effectiveness ratio (ICER) of receiving adjuvant rituximab after having a second remission from FL compared to observation from the perspective of US healthcare system. A similar study was conducted by Kasteng et al. (2008) from the Sweden healthcare provider perspective. Deconinck et al. (2010) conducted a study to assess the long-term costs and cost-effectiveness of RM after induction therapy versus observation from the French National Health Service perspective. In Chen et al. study, they examined the cost-effectiveness of RM or radio-immunotherapy consolidation following frontline therapy with respect to observation. The abovementioned studies showed that rituximab maintenance therapy demonstrated favorable cost-effectiveness profiles.

Two studies also compared the addition of RM to rituximab induction (RI) with RI strategy alone. Prica et al. (2015) conducted a study to evaluate the cost-effectiveness of RI with or without RM in comparison with the watch and wait (WW) strategy. Their results showed that

RI alone was the cheapest strategy compared with RI plus RM and WW, and it was associated with a slightly lower QALYs versus RI plus RM but was superior to WW. Prettyjohns et al.

(2017) conducted a similar study from the perspective of the UK National Health Service and found that the addition of rituximab maintenance marginally increased effectiveness but substantially increased cost. Both of these studies concluded that active treatment with rituximab induction was a cost-effective strategy to adopt in patients with FL.

Adena et al. (2014), Hornberger et al. (2011), Mu ̈ller et al. (2015), and Mandrik et al.

(2015) assessed the cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide

(R-FC) compared with FC in patients with chronic lymphoblastic leukemia (CLL). The results of these studies suggest that R-FC is a cost-effective option.

The addition of rituximab to standard chemotherapy has been shown to improve clinical outcomes in patients with hematologic malignancies [35, 36] Five studies were conducted to establish the cost-effectiveness of this strategy. (Nam et al., 2017; Hornberger et al., 2008;

Ferrara et al., 2008; Johnston et al., 2010; Ray et al., 2010) These studies reported favorable

ICERs associated with the addition of rituximab to standard chemotherapy compared to chemotherapy alone. Four studies also compared the cost-effectiveness of treatment combinations containing rituximab. Sabater et al. conducted a study to evaluate the cost-utility of rituximab-bendamustine (BR) treatment compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) treatment as a first-line therapy for patients with advanced FL. Rituximab-bendamustine was shown to be a dominant strategy over R-CHOP. In

Soino et al. study, the authors compared three treatment strategies for patients with relapsed and refractory FL: CHOP, R-CHOP, and R-CHOP with RM. The results of their study showed that

R-CHOP with RM was the optimal option. In Dewilde et al. study, the authors evaluated the cost-effectiveness of BR compared with R-CHOP and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone) as first-line treatment for patients with advanced indolent non-Hodgkin’s lymphoma (NHL). The ICERs for BR versus R-CVP and R-CHOP were shown to be below the willingness-to-pay thresholds considered in that study. BR was considered the most cost- effectiveness treatment option when compared with R-CHOP and R-CVP-R.

Alemtuzumab

Mittmann et al. (2012) study investigated the cost-effectiveness of alemtuzumab compared with various treatments (VI), fludarabine, cyclophosphamide (FC), and fludarabine, cyclophosphamide, rituximab (FCR) in the treatment of B-CLL patients ineligible for fludarabine therapy. The ICERs for alemtuzumab compared to the four comparators in B-CLL patients who have failed fludarabine ranged from $21,818/LYG to $52,536/LYG. The authors did not state the willingness to pay threshold, so the decision as to whether alemtuzumab is cost- effective compared active treatment lies in the hands of the decision-maker. Alemtuzumab was dominant over best supportive care (BSC) as it was less costly and more efficacious. Scott et al. conducted a similar study to compare the cost-effectiveness of alemtuzumab versus FCR for the third-line treatment of CLL. A deterministic decision analytic model was used to simulate the three treatment lines. Their results showed that alemtuzumab was cost-effective.

Kongnakon et al. (2014) evaluate the cost-effectiveness of using bendamustine versus alemtuzumab or bendamustine versus chlorambucil as a first-line therapy in patients with Binet stage B or C CLL. They developed a discrete event simulation model and used data from clinical trials to create a simulated patient population. Bendamustine dominated Alemtuzumab in that analysis.

Lu et al. (2012) conducted a study to evaluate the cost-effectiveness of alemtuzumab compared with conventional chemotherapy in patients with T-cell prolymphocytic leukemia (T-

PLL). They developed a decision-analytic model and conducted their analyses over a lifetime horizon. Their results suggest that alemtuzumab is more likely to be cost-effective if used earlier in the course of T-PLL and where it replaces the use of multiple alternative therapies.

Blinatumumab

Delea et al. (2017) conducted an economic evaluation using the Blincyto Global

Economic Model (B-GEM) and a 50-year lifetime horizon. The results of the study show that blinatumumab is cost-effective compared to SOC chemotherapy in patients with relapsed or refractory Philadelphia-chromosome-negative B-precursor acute lymphoblastic leukemia.

Daratumumab

In Pelligra et al. study, the authors evaluated the cost and health outcomes of three treatment strategies: 1) Pomalidomide plus low-dose dexamethasone (POM-d), 2) daratumumab monotherapy (DARA), and 3) carfilzomib monotherapy (CAR) over a 3-year time horizon using a decision analytic model. The authors concluded that daratumumab was dominated by the other two treatment strategies.

Brentuximab Vedotin

Three studies conducted a cost-effectiveness analysis that included Brentuximab vedotin

(BV) as monotherapy. Babashov et al. (2017) developed a decision-analytic model to simulate lifetime costs and benefits of brentuximab vedotin compared with BSC for the treatment of relapsed and refractory Hodgkin lymphoma (HL) in the post-autologous stem-cell transplantation

(ASCT) failure period in the Canadian setting. The authors reported an ICER exceeding

$100,000 per QALY gained, which is not considered cost-effective in Canada. The authors recommended furthering negotiation on pricing arrangement due to the lack of alternative treatment options in this disease area.

Parker et al. (2016) conducted another study, which compared BV to chemotherapy with or without radiotherapy (C/R) and C/R with intent to allogeneic hematopoietic stem cell transplantation (alloSCT). A partitioned survival model was used with a 40-year lifetime horizon. The ICER for BV versus C/R was £38,769 per QALY, and C/R with intent to alloSCT

was dominated by BV. Although the ICER of BV versus C/R was above the threshold applied in

Scotland, the authors argued that it was lower than other orphan drugs.

Hui et al. (2017) developed a Markov model using lifetime horizon to evaluate the cost- effectiveness of BV consolidation versus active surveillance plus BV as salvage. Their study demonstrated that BV consolidation was associated with an improvement of 1.07 QALYs compared with active surveillance plus BV as salvage and significantly higher health care costs

($378,832 vs $219,761), resulting in an ICER for BV consolidation compared with active surveillance of $148,664/QALY. As a result, the authors concluded that BC was unlikely to be cost-effective in the US.

Ofatumumab

Herring et al. (2016) evaluated ofatumumab plus chlorambucil (OChl) compared with chlorambucil alone. Their results showed that OChl was likely to be cost-effective. In Hatswell et al. study, the authors compared ofatumumab with BSC. The ICER reported for ofatumumab was £130,563/QALY. Even though the authors did not state the willingness to pay threshold considered and did not make a clear conclusion, the ICER apparently exceeded the £20,000 to

£30,000/QALY willingness to pay threshold used in the UK setting.

Obinutuzumab

Five studies evaluated the cost-effectiveness of obinutuzumab plus chlorambucil (GClb) versus different combinations of chemotherapy with and without rituximab.

In Sinha et al. study, they evaluated the cost-effectiveness of obinutuzumab plus chlorambucil (GClb) compared with ibrutinib using a semi-Markov model with a lifetime horizon in CLL patients who cannot receive fludarabine-based therapy. They found GClb is cost- effective based on the UK willingness to pay threshold.

In the remaining four studies (Casado, 2016; Becker, 2016; Soini, 2016; Blommestein,

2016), the authors compared GClb with chlorambucil (Clb), rituximab plus chlorambucil (RClb), bendamustine (Benda), RBenda, and Ofatumumab plus chlorambucil (OClb). They all used

Markov models with 20-year lifetime horizon, except Blommestein et al study, in which the time horizon was not stated. The results of these studies showed that GClb was more likely to be a cost-effective treatment option.

A comprehensive depiction of the results of the economic evaluations included in this review is reported in Table 2-3.

Discussion

The objective of this study was to systematically review the studies that evaluated the value of immunotherapy for hematologic malignancies. This review included cost-effectiveness studies or cost-utility studies for agents out of the 12 identified immunotherapy agents for hematologic malignancies. No relevant studies were found for nivolumab, elotuzumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, and pembrolizumab. This may be due to the fact that these drugs were approved in recent years (after 2014). We observed that a large majority of studies focused on rituximab. Treatment regimens containing rituximab appeared to be more cost-effective than other immunotherapy agents. One potential explanation for that finding could be that rituximab was one of the earliest of its kind, increasing the likelihood for its acquisition cost to be significantly less than more recent treatments. Some deficiencies of the methods applied in cost-effectiveness studies of hematologic malignancies mentioned in N Batty, et al. [37] were apparent in our study. There was a lack of published cost and quality of life data, which made some of these studies not transparent in their reporting. Other issues with the study design of some studies include short time horizon and lack of indirect cost analyses.

The findings in this review are different from those of Saret, Cayla J. et al. [31]. who reviewed the value of innovative treatments for hematologic malignancies using data from the

Tufts CEA Registry. They identified 9 treatment agents (interferon-a, alemtuzumab, bendamustine, bortezomib, dasatinib, imatinib, lenalidomide, rituximab alone or in combination, and thalidomide) and found 29 studies that met predefined inclusion criteria. They concluded that these novel treatments for hematologic malignancies appear to be cost-effective because their incremental cost-effectiveness ratios (ICER) were below the threshold of $50,000/QALY or

$100,000/QALY.

In spite of the trend of drug wastage issue in economic evaluations, we found only 25% studies included in this systematic review accounted for drug wastage in their base case analysis, which is similar to Lien et al. study. Their study showed less than one-third of reviewed articles accounted for drug wastage.

Publication bias, defined as the greater likelihood for studies with positive results to be published than those with negative results. This is quite a concern when reviewing the literature.

We found that most of the studies included in this systematic review were funded by pharmaceutical manufacturers, which in the literature has raised a debate about transparency, ethics and publication bias. Another concern is that peer-reviewed journals may be less interested in publishing intermediate results and/or negative results. Therefore, the number of CEAs in literature may not completely represent the true distribution of cost-effectiveness ratios.

Notwithstanding the limitations inherent in the systematic review design, our results remain useful to researchers that are interested in conducting further economic evaluations of newer treatments for hematological malignancies.

Conclusions

The results of this study suggest that there is a limited number of cost-effectiveness analyses of newer immunotherapeutic agents. These findings highlight the need for more research on the value assessment of newer immunotherapeutic drugs while accounting for dug wastage. The results of such studies might assist clinicians and policy decision-makers that are interested in cost-effective prescribing and informed resource allocation decision-making respectively.

Table 2-1. PubMed search strategy 1 cost*[tiab]

2 "costs and cost analysis"[mesh:noexp] 3 cost-benefit analysis*[tiab] 4 cost-benefit analysis[mesh] 5 cost-effectiveness analysis*[tiab] 6 cost-utility analysis*[tiab] 7 health care costs[mesh:noexp] 8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 9 Rituximab OR Rituxan 10 Ofatumumab OR ARZERRA 11 nivolumab OR OPDIVO 12 Brentuximab vedotin OR ADCETRIS 13 Obinutuzumab OR GAZYVA 14 Alemtuzumab OR LEMTRADA 15 Daratumumab OR DARZALEX 16 Elotuzumab OR EMPLICITI 17 Gemtuzumab ozogamicin OR Mylotarg 18 Inotuzumab ozogamicin OR BESPONSA 19 Blinatumomab OR BLINCYTOT 20 Pembrolizumab OR keytruda 21 #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15OR #16 OR #17 OR #18 OR #19 OR #20 22 #8 AND #21 23 #22 AND ("2007/01/01"[PDAT]: "2017/12/31"[PDAT])

Table 2-2. Study characteristics ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration Delea US Blinatumomab Patients with R/R A Blincyto Global Economic model Yes 1 (2017) SOC chemotherapy Ph- B-precursor comprising four health states: initial (pre- 50-year ALL response), response, refractory/relapsed, lifetime and death horizon

2 Mittmann Canada Alemtuzumab Patients with B Not stated (2012) Various Treatments cell CLL who Not stated Not stated FC have progressed FCR BSC despite fludarabine therapy 3 Herring Multi- OChl Chl Patients with A semi-Markov model comprising pre- (2016) countries CLL unsuitable progression health states and post- Lifetime Not stated for fludarabine- progression health states horizon based therapies

4 Pelligra US POM-d Patients with A Markov model comprising three health (2017) Daratumumab heavily pretreated states: progression-free, post-progression, 3-year time Assumption CAR R/R MM and death horizon made of no wastage 5 Babashov UK Brentuximab vedotin Patients with HL Two Markov models representing wo (2017) (BV) BSC after ASCT treatment options. BV model included Lifetime Not stated failure four health states: improvement or horizon remains stable, a treatment-related serious adverse event that prevents continuation of treatment, progresses, and death. BOC model included three health states: free from treatment failure, progression, and death

Table 2-2. Continued ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration 6 Parker (2016) Multi- Brentuximab vedotin Patients with R/R HL A partitioned survival model countries (BV) C/R after ASCT comprising three health states: 40-year Not stated alloSCT progression-free survival, post- lifetime progression survival, and death horizon 7 Hui (2017) US Brentuximab vedotin Patients with R/R HL A Markov model comprising HL (BV) after ASCT relapse treated with BV, HL relapse Lifetime Yes Active surveillance plus post-BV treatment, long-term durable horizon BV as salvage second remission, and death 8 Kongnakorn US Bendamustine Patients with Binet A discrete event simulation of the (2014) Alemtuzumab stage B or C CLL disease course of CLL. During the Lifetime Not stated Chlorambucil simulation, each patient was subjected horizon to the following risks: adverse events, disease progression, and death 9 Lu (2012) UK Alemtuzumab Patients with T-PLL A decision-analytic model comprising Conventional four health states: on treatment, in Lifetime Not stated chemotherapy response, in progressive disease, and horizon dead 10 Hatswell UK Ofatumumab Patients with CLL A partitioned survival analysis (2017) BSC refractory to model comprising three health states: Lifetime Not stated fudarabine and progression free, progressive disease, horizon alemtuzumab (double and death refractory) 11 Sinha (2017) UK Ibrutinib Patients with untreated A semi-Markov model comprising GClb CLL unsuitable for three health states: progression-free Lifetime Yes fludarabine survival (PFS), progression, and death horizon 12 Hayslip US RM Observation Patients aged 65-70 A transition state model comprising (2008) years in their second six health states: disease-free survivor, 5 years Not stated remission from FL undergoing salvage treatment, subsequent remissions, refractory disease, transplantation, and death

Table 2-2. Continued ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration 13 Deconinck France RI plus RM Patients with R/R A Markov model comprising three health states: (2010) Observation FL progression-free survivial, progression, and 30-year No death lifetime horizon 14 Prica (2015) Canada RI with or without Patients with A Markov model comprising following health RM WW asymptomatic states:progression-free 1, RM in PF1, Lifetime Not stated strategy advanced-stage FL progressive disease 1, BR treatment, RM in horizon PF2, subsequent progression-free states, progression states leading to salvage treatment, palliation, and death 15 Prettyjohns UK RI with or without Patients with A Markov model comprising first line treatment Not stated (2017) RM advanced to fourth line treatment, relapse, and death. 40-year Watch and wait asymptomatic FL time (WW) strategy horizon 16 Kasteng Sweden RM Patients with FL in A Markov model comprising three health states: (2009) Observation remission after progression-free (PF), progressive disease (PD), Lifetime Not stated second line therapy and death horizon 17 Chen (2015) US RM Patients with FL A Markov model comprising 4 health states: RIT before first progression, first progression, Lifetime Not stated Observation second progression, and death horizon 18 Adena (2014) Australia R-FC FC Patients with both A Markov model comprising three health states: previously unprogressed, progressed, and death 15-year No untreated and R/R time CLL horizon 19 Hornberger US R-FC Patients with A Markov model comprising 3 health states: Lifetime (2011) FC previously progression-free survivial, progression, and horizon No untreated CLL death

Table 2-2. Continued ID Study first Country Interventions Study Model Type author Population Time Wastage (reference) Horizon consideration 20 Mu ̈ller (2015) Germany R-FC Patients with A Markov-model comprising three FC CLL health states: free from disease 30-year Not stated progression, progressive disease, lifetime and death horizon 21 Mandrik Netherlands R-FC FC Patients with A Markov-model comprising three (2015) naïve and R/R health states: stable or progression- Lifetime Not stated CLL free state, disease-progressed state, horizon and death 22 Casado (2017) Spain IR Patients with A partitioned survival Markov R R/R CLL model comprising three health 30-year Not stated states: pre-progression, post- lifetime progression, and dead horizon 23 Nam (2018) Canada Rituximab plus SOC Patients with A decision analytic model chemotherapy ALL comprising 4 health states: event- Lifetime Yes SOC free survival, relapsed/resistant horizon disease, cure, and death 24 Ray (2010) UK The addition of Rituximab Patients with A Markov model comprising three to: MCP, CVP, CHOP, advanced FL health states: progression-free 5-year and Not stated CHVP + IFNa versus survivial, progression, and death 10-year time chemotherapy alone horizon 25 Hornberger US CVP-R CVP Patients with A Markov model comprising three (2008) advanced FL health states: progression-free 30-year Yes survival (PFS), post-progression, lifetime and death horizon 26 Ferrara (2008) Italy R-CHOP Young patients A decision-analysis model CHOP with DLBCL comprising tree structure with six 3 years No possible therapeutic pathways

Table 2-2. Continued ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration 27 Johnston Canada R-CHOP Patients with DLBCL A patient-level simulation model (2010) CHOP 15-year Not stated time horizon 28 Sabater Spain BR Patients with advanced FL A Markov model comprising 5 (2016) R-CHOP health states: progression-free, 25-year No induction and maintenance; first lifetime relapse; second relapse; and death horizon 29 Soini (2011) Finland RCHOP-R Patients with follicular NHL A Markov model comprising RCHOP three health states: progression Lifetime No CHOP free, progressive disease, and horizon death 30 Dewilde Multi- BR Patients with advanced A patient-level simulation model (2013) countries R-CHOP indolent NHL Lifetime Not stated CVP-R horizon 31 Keep (2016) UK VR-CAP Patients with previously A Markov model comprising five R-CHOP untreated mantle cell health states: pre- and post- 20-year Not stated lymphoma unsuitable for progression from first- and lifetime haematopoietic SCT second-line treatment, and death horizon 32 Scott (2007) New Alemtuzumab Patients with CLL who were A deterministic decision analytic Zealand R-FC able to tolerate third-line model with 3 treatment lines Not stated Yes treatment with either FCR or alemtuzumab

Table 2-2. Continued ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration 33 Casado (2016) Spain GClb RClb Patients with previously A Markov model untreated CLL unsuitable comprising three health 20-year Assumption for full-dose fludarabine- states: progression-free lifetime made of no based therapy survivial, progression, and horizon wastage death

34 Becker (2016) Multi- GClb, RClb, CLb, Benda Untreated patients with A Markov model countries RBenda OClb CLL unsuitable for full- comprising three health 20-year Yes dose fludarabine-based states: progression-free lifetime therapy survival, progression, and horizon death

35 Soini (2016) Multi- Clb Patients with CLL A probabilistic Markov countries GClb OClb unsuitable for full doses model comprising three 20-year Yes RClb RBenda of fludarabine health states: progression- lifetime free, progression, and death horizon 36 Blommestein Netherlands Clb GClb Patient with newly A Markov model (2016) OClb diagnosed CLL comprising three health Not stated Yes RClb states: progression-free survival, progression, and death 37 Griffiths (2012) US CHOP or CVP Elderly patients with FL Multivariate regression CVP-R Four years Real world 38 Griffiths (2012) Multi- R-CHOP Patients with patients Multivariate survival countries CHOP with DLBCL analysis Four years Real world 39 Khor (2014) Canada R-CHOP Patients with patients Multivariate logistic CHOP with DLBCL regression model Median Real world follow-up 9.7 years

Table 2-2. Continued ID Study first Country Interventions Study Population Model Type author Time Wastage (reference) Horizon consideration 40 Blommestein Multi- RM Patients with R/R FL A Markov model comprising three (2014) countries observation who responded to health states: progression-free survival, 20-year Real world second-line after progression survival, and death lifetime chemotherapy horizon 41 Soini (2012) Finland FL treatment Patients with FL A Markov model comprising four health sequences states: between progression-free first- 25 years Real-world line treatment, progression-free second- line treatment, progression, and death You need to provide a legend explaining all the abbreviations/acronyms in this table. E.g. R-CHOP, RM etc…

Table 2-3. Study Results ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 1 Delea US The ICER for $150,000 per Performed and funded Blinatumumab is cost-effective compared to (2017) blinatumomab vs QALY gained by Amgen, Inc. SOC chemotherapy SOC was $110,108/QALY

2 Mittmann Canada The ICER for Not stated Funded by Genzyme The ICERs for alemtuzumab in B-CLL (2012) alemtuzumab vs VT Canada Inc. patients who have failed fludarabine ranged was $43,615/LYG; from $21,818/LYG to $52,536/LYG $52,536/LYG for the compared to active treatment, and was less alemtuzumab vs FC; costly and more efficacious compared to $21,818/LYG for the BSC. alemtuzumab vs FCR; and less costly and more effective vs BSC. 3 Herring Multi- The ICER for OChl $Can100,000 per Funded by OChl is likely to be cost-effective subject to (2016) countries vs. Chl was QALY gained GlaxoSmithKline. and uncertainty associated with the presence of $Can54,428/LYG Novartis any long-term overall survival benefit and the and Pharmaceuticals Canada model time horizon. $Can68,647/QALY Inc.

4 Pelligra US POM-d was $50,000 per QALY Performed and funded POM-d may be a cost-effective treatment (2017) associated with less gained by Celgene Corporation option relative to DARA or CAR in heavily cost than DARA (– pretreated patients with RRMM in the US. $8,919), similar to CAR (–$195), and with similar life- years and QALYs gained compared with DARA and CAR

Table 2-3. Continued ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 5 Babashov UK The ICER of $100,000 per No conflicts of interests Consider BV is an orphan drug, even though (2017) brentuximab vedotin QALY gained it has an ICER exceeding willingness to pay, was pricing arrangements should be negotiated, $164,248/QALY vs. and risk-sharing agreements or patient access best supportive care schemes should be explored.

6 Parker Multi- The ICER for Not stated Funded by Takeda Rituximab in addition to SOC was found to (2016) countries brentuximab vedotin Pharmaceutical be a cost-effective compared to SOC alone. was £38,769/QALY Company Limited. vs C/R. C/R with intent to alloSCT was dominated by brentuximab vedotin 7 Hui (2017) US The ICER for BV $100,000 per No conflicts of interests BV as consolidation therapy under current consolidation vs. QALY US pricing is unlikely to be cost-effective at active surveillance a willingness-to-pay threshold of $100,000 was per QALY. $148,664/QALY

8 Kongnako US Bendamustine was a $50,000, $75,000 Funded by Teva Branded Bendamustine can be considered as a cost- rn (2014) dominant treatment and $100,000per Pharmaceutical Products effective treatment providing health benefits compared with QALY gained R&D, Inc, Frazer, PA, at an acceptable cost versus chlorambucil in alemtuzumab. USA and conducted in the US. Bendamustine was collaboration with associated with an Evidera, Bethesda, MD, ICER of USA. $40,971/LYG and $50,619/QALY.

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 9 Lu (2012) UK The ICERs for £20,000 to £30,000 Partially funded by the Alemtuzumab appears more likely to be cost- alemtuzumab versus per QALY gained National Institute for effective if used earlier in the course of T- conventional Health Research (NIHR) PLL and where it replaces the use of multiple chemotherapy alternative therapies. ranged from €34,163/QALY to €95,746/QALY 10 Hatswell UK The ICERs of Not stated Funded and performed No conclusion made on the cost- (2017) ofatumumab were by GlaxoSmithKline effectiveness £130,563/QALY and £63,542/LYG vs. BSC 11 Sinha UK The ICERs were £20,000 to £30,000 No conflicts of interests An adequate discount on ibrutinib is required (2017) £75,648 /QALY for per QALY gained to make it cost-effective as per the UK ibrutinib vs. GClb thresholds.

12 Hayslip US The ICER for Not stated Not stated Rituximab maintenance offers a clinical (2008) rituximab benefit to patients aged 65-70 years who maintenance was have a second remission from FL at a cost $19,522/QALY generally acceptable to the US healthcare system. 13 Deconinck France The ICERs for €50,000 per QALY Funded by Roche The results tend to show that rituximab (2010) Rituximab gained maintenance therapy may be a cost-effective maintenance were strategy in the management of €7612/LYG and relapsed/refractory FL. €8729/QALY vs. observation

Table 2-3.Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 14 Prica Canada RI was the cheapest $50,000 per QALY no conflict of interest RI without maintenance is the preferred (2015) strategy. It was less gained strategy: it minimizes costs per patient over a costly at $59,953 lifetime horizon versus $67,489 for the RM arm and $75,895 for the WW arm. It was also associated with a slightly lower quality-adjusted life expectancy at 6.16 quality-adjusted life years (QALYs) versus 6.28 QALYs for the RM strategy but was superior to WW (5.71 QALYs). 15 Prettyjohn UK In comparison to £20,000 per QALY No conflicts of interests Active treatment with rituximab induction is s (2017) WW, both rituximab gained a cost-effective strategy to adopt in patients strategies were found with asymptomatic follicular lymphoma to be more effective and cost saving. In comparison to RI, the addition of RM marginally increased effectiveness but substantially increased costs, resulting in an ICER of £69,406/QALY

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 16 Kasteng Sweden The ICER of €54 000 per QALY Funded by Roche AB, Rituximab maintenance treatment after (2009) rituximab gained Sweden successful induction therapy for patients with maintenance therapy relapsed/refractory follicular lymphoma in was €12,600/QALY Sweden is cost-effective compared to and €11,200/LYG observation.

17 Chen US The ICER of MR $50,000 per QALY Partial funded by MR and RIT following frontline FL therapy (2015) were $40,335 or gained Spectrum demonstrated favorable and similar cost- $37,412 per QALY effectiveness profiles gained and $40,851/QALY for RIT vs. observation

18 Adena Australia The ICER of R-FC Not sated Funded and performed Rituximab, in combination with (2014) was $42,906/QALY by Roche Products Pty chemotherapy, when used multiple times vs. FC Limited throughout the treatment algorithm, appears to be cost-effective for CLL. 19 Hornberge US The ICER of R-FC $50,000 per QALY Funded by Genentech, Within the limitations of modeling long-term r (2011) was $31,513/QALY gained Inc. outcomes, R-FC is cost-e active for vs. FC previously untreated CLL.

20 Mu ller̈ Germany The ICER for R-FC $100,000 per Funded and performed R-FC chemotherapy represents good value (2015) was € 17,979/QALY QALY gained by F.Hoffmann-LaRoche for first-line treatment of patients with CLL vs. FC Ltd., Switzerland. and compares favorably with chemotherapy alone

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 21 Mandrik Netherlands The ICER of FCR $15000 per QALY No conflicts of interests Rituximab treatment may be considered a (2015) was $8,704/QALY gained cost-effective treatment vs. FC for treatment- naï ve patients and $11,056/QALY for refractory/relapsed patients 22 Casado Spain Total ICER of IR €45,000 per QALY Funded by Gilead IR can be considered a cost-effective (2017) was €29,990/QALY gained Sciences treatment compared to R. vs. R

23 Nam Canada The ICER of adding C$100,000 per Performed by Hoffmann- Rituximab in addition to SOC was found to (2018) rituximab to SOC QALY gained La Roche Limited. be a cost-effectivecompared to SOC alone. chemotherapy was C$21,828/QALY vs. chemotherapy alone 24 Ray UK The ICER for the £30,000 per QALY Funded by F. Hoffmann- The addition of rituximab to chemotherapy in (2010) addition of rituximab gained La Roche, Ltd. advanced FL was found to be highly cost- were £7474, £8621, effective £10,732, and £8551 per QALY gained vs. MCP, CVP, CHOP, and CHVP respectively. 25 Hornberge US The ICER of CVP-R $100,000 per Funded by Genentech, The cost-effectiveness ratio of R-CVP r (2008) was $28,565/QALY QALY gained Inc. compared with CVP is projected to be cost- vs. CVP effective.

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 26 Ferrara Italy The R-CHOP was €50 000 per QALY Funded by Roche SpA. The clinical and economic benefits of adding (2008) dominant vs. CHOP gained rituximab to a CHOP chemotherapy regimen with less cost (- in young patients who present with DLBCL €717.73) and with good prognosis superior efficacy (0.18 LYG).

27 Johnston Canada The ICERs were $50,000 per QALY Founded by Genome CHOP-R was found to be a cost-effective (2010) $11,965/LYG, gained Canada/Genome BC, and alternative to CHOP, particularly for $19,144/QALY for by British Columbia individuals aged 60 years and older. younger Cancer Foundation. individuals.For older individuals, the ICERs for all health outcomes were below $10,000 per unit outcome gained.

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 28 Sabater Spain Rituximab– €30,000 per QALY Funded and proformed First-line therapy with RB in FL patients was (2016) bendamustine was gained by Mundipharma the dominant strategy for treatment with R- dominant compared Pharmaceuticals, S.L CHOP with R-CHOP, yielding 12.86 LYG(9.63 QALYs) versus 12.62 LYG(9.23 QALYs) and representing a total cost of €68,357 per patient, compared with the total cost for R- CHOP treatment (€69,528) 29 Soini Finland The ICER of €18,399 per QALY Funded and performed RCHOP-R is a potentially cost-effective (2011) RCHOP-R versus gained by Roche treatment option for the FL RCHOP were €18,147/QALY, €16,380/LYG; €14 360/QALY, €13 041/LYG for RCHOP-R versus CHOP; and €12 123/QALY, €11 049/LYG for RCHOP versus CHOP

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 30 Dewilde Multi- The ICER was £20,000–30,000 per Funded by Napp The ICERs for BR vs CHOP-R and CVP-R (2013) countries £5249/QALY for B- QALY Pharmaceuticals Limited were considerably below the thresholds R vs CHOP-R, and and Mundipharma normally regarded as cost- effective in £8092/QALY for B- International Limited. England and Wales R vs CVP-R

31 Keep UK The ICER for VR- £20,000 to £30,000 Performed and funded by VR-CAP is a cost-effective option for (2016) CAP was per QALY gained Janssen-Cilag previously untreated patients with MCL in £20,043/QALY vs. UK. R-CHOP

32 Scott New Zealand The cost per survival Not stated Funded by Bayer New Third-line treatment of eligible patients with (2007) month gained for Zealand Limited alemtuzumab was found to be $NZ15,303 alemtuzumab was less costly than FCR per patient $NZ3144 and for FCR was $NZ4101, and the cost per QALY gained was $NZ46,016 and for FCR was $NZ60,012 33 Casado Spain The ICERs for GClb Not Stated Performed and funded by Treatment with GClb versus RClb can be (2016) were €23,314/LYG Roche regarded as efficient when considered the and €24,838/QALY willingness to pay thresholds commonly used vs. RClb in Spain.

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 34 Becker Multi- GClb was cost- £30,000 per QALY Performed and funded by GClb was estimated to increase both quality- (2016) countries effective against all gained F. Hoffmann-La Roche adjusted life expectancy and treatment costs comparators in the Ltd. compared with several commonly used model, with cost per therapies, with ICERs below commonly QALY gained referenced UK thresholds. ranged between £13,747 (RBenda) and £28,686 (Benda).

35 Soini Multi- The ICERs for Clb €30,000 and Performed and funded by GClb was the most cost-effective with 93% (2016) countries varied from €50,000 per QALY ESiOR Oy probability; RClb was the second most cost- €29,334/QALY vs. gained effective (73%); and RBenda was the third GClb to most cost-effective (65%). €82,159/QALY vs. OClb. The ICERs for GClb were €20,038, €11,556, and €15,586 per QALY vs. RClb, RBenda, and OClb 36 Blommest Netherlands The ICERs for GClb € 50,000 per QALY Performed and funded by GClb appeared to be a cost-effective ein (2016) were € 21,823 and € gained Roche treatment strategy compared to RClb, OClb 11,344 per QALY and Clb. vs. Clb and RClb.

37 Griffiths US The ICER of CVP-R Not stated Not stated Adding rituximab to first-line chemotherapy (2012) was for elderly patients with FL results in higher $102,142/QALY vs. direct medical costs to Medicare and longer CHOP or CVP cumulative survival after four years

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 38 Griffiths Multi- The ICER of R- Not stated No conflicts of interests Rituximab was associated with survival (2012) countries CHOP was benefits comparable to those observed in $62,424/QALY vs. clinical trials. However, these benefits did CHOP not translate into the previously reported cost savings. 39 Khor Canada The ICER of $100,000 per LYG No conflict of interest The addition of rituximab to standard CHOP (2014) RCHOP was chemotherapy was associated with $61,984 (95% CI improvement in survival but at a higher cost, $34,087‐$135,890) and was potentially cost-effective by per LYG vs. CHOP. standard thresholds for patients<60 years old. The ICER was most favorable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60–79 years old and $110,100/LYG for patients ≥80 years old. 40 Blommest Multi- The ICER of RM Not stated Multiple sponsors Although differences in real-world and trial ein (2014) countries was ranged from population were found, using real-world data €10,591/LYG to €21 as well as results from long-term trial follow- 202/LYG and €11 up showed favorable ICERs for rituximab 245/ QALY to €23 maintenance 821/QALY vs. observation

Table 2-3. Continued. ID Study first Country Cost-effectiveness Willingness to pay Conflict of interests Authors' Conclusion author ratio threshold (reference) 41 Soini Finland The ICER for €20,000 to €30,000 Funded by Roche Oy, Sequences that included first-line rituximab (2012) RCHOPR- per QALY gained Espoo, Finland. maintenance and second-line bendamustine RCOPR/bendamusti are potentially cost-effective in the treatment ne-BSC, RCHOPR - of FL RCOPR/COP-BSC, and RCHOP- RCOPR/bendamusti ne-BSC were €9575/€8014/€5900, €9881/€8310/ €6013, and €8812/€7194/€5808, respectively, per QALY/life- year/progression-free year gained in comparison with RCHOP- RCOPR/COP-BSC

Potentially relevant citations identified and screened for retrieval n= 819 PubMed n=676 Ovid Medline n=70 CRD n=70 Econlit n=3

Duplicate Citations identified n=102 Citations Excluded because of non-adherence to inclusion criteria after title and abstract review n=661

Full text of studies retrieved for more detailed evaluation n=56

Citations Excluded because of not accessible n=15

Relevant citations for inclusion n=41

Figure 2-1. Flow chart of the article selection process

CHAPTER 32 INOTUZUMAB OZOGAMICIN IN PATIENTS WITH RELAPSED OR REFRACTORY (R/R) ACUTE LYMPHOCYTIC LEUKAEMIA (ALL): ESTABLISHING A VALUE-BASED COST – PRELIMINARY RESULTS

The INO-VATE trial showed that the use of inotuzumab ozogamicin (InO) in the treatment of patients with relapsed or refractory (R/R) acute lymphocytic leukaemia (ALL) increased median overall survival by 1 month compared to standard of care (SoC) chemotherapy

(hazard ratio, 0.77 [(97.5% CI, 0.58–1.03); P=0.04]. Although this intervention is associated with better survival outcomes than SOC, it comes with a high price tag. As a result, the value associated with this intervention remains unclear. The purpose of this study was to evaluate the value-based drug price of InO in the treatment of patients with relapsed or refractory (R/R) acute lymphocytic leukaemia (ALL), accounting for drug wastage. This study was conducted according to a U.S. Medicare perspective

A multi-state model composed of 3 health states: progression-free, progression, and death was developed and populated from multiple sources, including the INO-VATE trial, [38] to evaluate the costs and patient life expectancies associated with each treatment regimen.

Transition probabilities for the multistate model was derived after individual patient data from the progression-free (PFS) and death (OS) Kaplan-Meier curves (INO-VATE trial) were reconstructed. Drug costs, administration costs, adverse events costs, and hematopoietic stem cell transplantation (HSCT) costs were included in the model and obtained using Medicare reimbursement rates ($ US 2017) . Costs and outcomes were discounted using a 3% annually.

Sensitivity analyses and scenario analyses were conducted based on the model parameters, including drug wastage.

Paper included as per permission from author

Incremental cost-effectiveness ratios (ICERs) for InO compared with SoC were assessed within a range of cost. The individual patient data reconstruction returned reconstructed median overall survival for Inotuzumab ozgamicin (7.35 months) and SoC (5.42) (that were very close to the ones reported in the INO-VATE trial (Inotuzumab ozgamicin. The next steps in this analysis is to run the multistate model and generate the range of costs at which Inotuzumab ozogamicin and make pricing recommendations.

ALL is a rapidly progressing form of cancer of the white blood cells. Even though 80% of ALL occurs in childhood, it stands for the second most common acute leukemia in adults, with an incidence of over 6500 cases per year in the United States. [39] The treatments for pediatric ALL have gained great success, which achieved 80% overall long-tern event-free survival. [40] Despite advances in management, treatment options for adult All are limited.

Furthermore, ALL in adults is a devastating disease with much lower cure rates than 40%, regardless of HSCT undergo in patients. [41] The backbone of therapy remains multi-agent chemotherapy such as fludarabine, cytarabine and granulocyte-colony stimulating factor (G-

CSF) based combination chemotherapy (FLAG) or clofarabine-based therapy. [42] While the tolerance for toxicity of high-dose chemotherapy agents is poor and carry a particularly poor response especially in elderly patients. Immunotherapy, as a new class of therapy for oncology, hold promising treatment options for ALL with less toxicity. InO is a humanized anti-CD22 monoclonal antibody indicated for B-cell precursor ALL, which stands for 75% of ALL. The approval of InO is based on the phase-3 INO-VATE clinical trial. In this trial, adults with relapsed and refractory B-cell ALL were randomly assigned to receive either InO or SoC. The primary endpoints were complete remission and overall survival. The results showed a higher rate of complete remission with InO than with SoC, and a higher percentage of patients in the

InO group had results below the threshold for minimal residual disease. Both progression-free survival and overall survival were longer with InO.

However, the novel cancer treatments impose an immense cost burden and cast doubt on whether their high prices reflect the worth. Therefore, there is a critical need to comprehensively assess the value of these therapeutic options. [43] A cost-effectiveness analysis (CEA) is one of the most applied studies to evaluate the value of health care interventions. It can quantify the long-term value and convert it into ICERs to gauge the cost of a health intervention relative to its benefits. The objective of the present study is to prospectively identify the range of drug costs from a US perspective within which InO could be considered cost-effective.

Methods

Overview of the Economic Model

A value-based pricing study was conducted to determine the range of drug costs for which inotuzumab ozogamicin could be considered cost-effective when compared to SoC.

Patients in this study were assumed to be similar to the patients enrolled in the randomized phase

III INO-VATE trial. Patients in the SoC arm were grouped into 3 sub-groups based on individual’s characteristics to receive: 1) fludarabine, cytarabine and granulocyte colony- stimulating factor (FLAG)-based combination chemotherapy, 2) cytarabine in combination with mitoxantrone (CM), or 3) high-does cytarabine-based chemotherapy (HIDAC). This evaluation was conducted according to the US Medicare perspective.

A Markov model, consisting of 3 health states: progression-free, progression, and death

(Figure 3-1), was used to simulate the lifetime costs and utilities that patients would accrue over a 40-month time should they be treated with inotuzumab ozogamicin or SoC. The 40-month temporal framework was chosen to reflect the follow-up time of patients enrolled in the phase 3 randomized INO-VATE trial. [37] A cycle length of 28 days was used to match treatment cycles

in the INO-VATE trial. [37] As part of the modeling efforts, we assumed that the occurrence of

AEs would decrease patient quality of life through utility decrements and increase the total costs over the time horizon adopted. The primary outputs of the model included total costs, quality- adjusted life-years (QALYs), and the ICER. The model and statistical analyses were implemented in R studio.

Estimation of Transition Probabilities

The estimation of transition probabilities of the Markov model involved the following steps model for the transitions among health states was performed in two main steps: 1) individual patient data (IPD) reconstruction from published PFS and OS Kaplan-Meier (KM) curves of the INO-VATE trial and 2) survival modeling for the estimation of transition probabilities for economic evaluation.

In the first step, we used an algorithm developed by Guyot et al. [44] that transforms digitized curves, using WebPlot Digitizer (https://automeris.io/WebPlotDigitizer/), back into IPD survival data by finding numerical solutions to the inverted KM equations. This process was based on the number at risk, number of events, and censoring information from the corresponding overall survival and progression-free KM survival curves from the INO-VATE trial. The accuracy of the IPD reconstruction was then assessed by comparing the original KM statistics (number of individuals at risk, median PFS and OS, confidence intervals) to the reconstructed data.

In the second step, we fitted parametric survival distributions to the reconstructed data.

We first tested whether the proportional hazards (PH) assumption was met, to ensure that hazard ratios (HRs) obtained from the comparison of KM curves remain constant over time, [45] by plotting the corresponding log cumulative hazard plot against the log time. [46] Then, we fitted parametric distributions to the reconstructed IPD survival data and these distributions for

goodness-of-fit to the reconstructed IPD using a graphical test (Cox-Snell residual test) and analytical tests [Akaike Information Criterion (AIC)].

Medical Resource Use and Costs

According to the US Medicare perspective, only direct medical costs (2017 US dollars) such as drug acquisition costs, drug administration costs, adverse events costs, and hematopoietic stem cell transplantation (HSCT) costs were included in the model. These costs were obtained from the October 2017 ASP Drug Pricing file and 2017 Physician Fee Schedule from Center for

Medicare & Medicaid Services (CMS). [47, 48] Administration costs were calculated by multiplying the required number of times of infusions by the cost for each infusion. We modeled

AEs for both treatment arms with those have grade ≥3 and incidence ≥5%. The probabilities of

AEs occurring for patients during therapy in the model were based on the reported frequency of

AEs in the INO-VATE trial.

To model drug wastage in our base case analysis, it was assumed that patients received whole vials, i.e. there was no vial sharing. Sensitivity analysis on assumption of maximum vial sharing was conducted to investigate whether drug wastage has significant influence on the

ICER, which in turn would affect the value-based price range.

Health Utility Weights

The mean utility weights for our analysis were obtained from the INO-VATE trial. [37]

For inotuzumab ozogamicin and SoC arms, the baseline utility was 0.69 (95% CI: 0.65-0.74) and

0.67 (95% CI: 0.62-0.73) respectively. The utility for progression was 0.3 (95% CI: 0.22-0.38).

Further information regarding model parameters is available in Table 1. The utility some of them may not exactly match the health outcomes of the study cohort in the INO-VATE trial. The uncertainty surrounding utility estimates was addressed in sensitivity analyses.

Discounting

Costs and utilities were discounted using a 3%, as recommended by Sanders et al.. [49]

Analyzing the Cost-Effectiveness Model

An incremental cost-effectiveness ratio was estimated as the difference in total mean costs over the difference in total mean QALYs, with the latter consisted in mean survival times adjusted by their corresponding mean utilities.

Sensitivity Analysis

One-way sensitivity analysis: We performed sensitivity analysis following the steps of the multi-state model survival analysis framework to evaluate the robustness of the model and to address uncertainty in the estimation of variables. Using the R packages, sensitivity analysis were conducted by repeating the base case analysis with variation in the input parameter values over their confidence intervals. As an example, scenario analysis was conducted based on the different drug acquisition costs for filgrastim and cytarabine. In the SoC arm, the FLAG regimen requires 6 doses of 2.0g/m2 of cytarabine, 5 doses of 30mg/m2 of fludarabine, and 28 doses of

5μg/kg of prophylactic granulocyte-colony stimulating factor (G-CSF per cycle of 28 days). The

CM regime requires 7 doses of 200mg/m2 cytarabine and 3 doses of 12mg/m2 of mitoxantrone.

Drug costs for HIDAC for one 12-dose cycle is based on a dose of 3g/m2 per dose or 1.5g/m2 per dose for patients ≥55 years of age. In the InO arm, drug costs were based on the following doses:

Inotuzumab ozogamicin, 1.8mg/m2 per cycle (in a fractionated schedule of 0.8mg/m2 on Day 1 of each cycle and 0.5mg/m2 on Days 8 and 15).

Probabilistic sensitivity analysis: A probabilistic sensitivity analysis (PSA) using a second-order Monte Carlo simulation was carried-out to assess the impact of the joint uncertainty around key model parameters and their impact on the ICER. We sampled from recommended distributions: gamma distribution for the cost parameters and beta distribution for

parameters bounded between 0 and 1. The choice of PSA distribution was made using standard statistical methods34 and checked using a graphical technique that determined whether the data

(parameter values) followed their assigned distributions (histograms with the superimposed assigned distributions). From the probabilistic sensitivity analyses, we developed cost acceptability curves for given “willingness-to-pay” (WTP) values.

Variations in the Cost of Inotuzumab Ozogamicin for Value-Based Price

Using the approach by Goldstein et al., [50] we ran our base case model multiple times, with only the cost of InO and analyzing the effect on the ICER. Only results that produced

ICERs below commonly accepted WTP thresholds for cost-effectiveness: $50 000 per QALY,

$100 000 per QALY, $150 000 per QALY, and $200 000 per QALY were presented. The same approach is used for wastage scenarios to assess the impact of drug wastage on the value-based price range.

Results

Individual Patient Data Reconstruction

IPD were reconstructed for each arm of treatment using R statistical software. Table 3-1 summarized median PFS and OS measures collected from the INO-VATE trial [37] and corresponding estimates from reconstructed IPD. An internal validation of the IPD reconstruction process showed agreement with target data across PFS and OS, i.e. the reconstructed median PFS and OS compare very well to the original median PFS and OS published in clinical trials.

Parametric Distribution Fitting

Parametric distributions (exponential, Weibull, Gompertz, log--normal, log-logistic, and gamma) were fitted to the reconstructed data for each treatment arm. Based on the information criteria (Akaike Information Criterion [AIC] and Bayesian Information Criterion [BIC]) and a

graphical analysis of the Cox–Snell residuals, the log-logistic model was found to be the best fit for the data. (Figure. 2)

Equation for Transitional Probabilities

Based on the general equation for transitional probabilities for the log-logistic distribution (see below), we derived our transition probabilities to death, progression-free and progression [21], and further adjusted to the cycle length: tp_s_Rx = 1 − exp⁡{[Lambda_s_Rx ∗

1 1 ( ) ( ) (_STAGE)] Gamma_s_Rx − (Lambda_s_Rx ∗ (_STAGE + 1)) Gamma_s_Rx } where tp_s_Rx is the probability of transitioning to the new state (s) under the treatment Rx, _STAGE representing previous cycle, _STAGE+1 representing the current cycle, Lambda and Gamma representing the scale and shape of the log-logistic model respectively.

Equations for transitions from being alive (progression or progression) to death

Inotuzumab ozogamicin: tp_death_InO=1- exp((Lambda_death_Ino*(_STAGE))^(1/Gamma_death_InO-

(Lambda_death_InO*(_STAGE+1))^(1/Gamma_death_Ino) where InO represents inotuzumab ozogamicin.

tp_os_InO_monthly= 1-(tp_death_InO)^(1/5) where tp_os_InO_monthly is the monthly probability of transitioning to the death state under inotuzumab ozogamicin and 5 months represents the time interval at which patients in the INO-VATE trial were seen by their doctors.

Standard of care chemotherapy: tp_death_SoC=1- exp((Lambda_death_SoC*(_STAGE))^(1/Gamma_death_SoC-

(Lambda_deathSoC*(_STAGE+1))^(1/Gamma_death_SoC) where SoC represents standard of care chemotherapy.

tp_death_SoC _monthly= 1-(tp_death_SoC)^((1/5)*) where tp_os_SoC_monthly is the monthly probability of transitioning to the death state under standard of care chemotherapy, and 5 months represents the time interval at which patients in the INO-VATE trial were seen by their doctors.

Equations for transitions from being stable (progression-free)

Inotuzumab ozogamicin: tp_stable_InO=exp((Lambda_death_Ino*(_STAGE))^(1/Gamma_death_InO-

(Lambda_death_InO*(_STAGE+1))^(1/Gamma_death_Ino) where InO represents inotuzumab ozogamicin.tp_stable_InO_monthly= 1-(tp_death_InO)^(1/3) where tp_death_InO_monthly is the monthly probability of transitioning to the death state under inotuzumab ozogamicin and 3 months represents the time interval at which patients in the INO-VATE trial were seen by their doctors.

Standard of care chemotherapy: tp_death_SoC=exp((Lambda_death_Ino*(_STAGE))^(1/Gamma_death_SoC-

(Lambda_deathSoC*(_STAGE+1))^(1/Gamma_death_SoC ) where SoC represents standard of care chemotherapy. tp_death_SoC_monthly=1-(tp_death_SoC)^((1/3)*(1/HR)) where tp_death_SoC_monthly is the monthly probability of transitioning to the death state under standard of care chemotherapy and 3 months represents the time interval at which patients in the

INO-VATE trial were seen by their doctors to assess their status.

Equations for transitions from being stable to progression

Inotuzumab ozogamicin: tp_progression_InO= tp_death_InO_monthly - tp_stable_InO_monthly

Standard of care chemotherapy: tp_progression_SoC= tp_death_SoC_monthly - tp_stable_Soc_monthly tp_progression_SoC= tp_death_SoC_monthly - tp_stable_Soc_monthly

Establishing a Value-Based Cost

We will use the transition probabilities estimated earlier as input parameters to estimate the value based price for inotuzumab ozogamicin.

Discussion

The price of cancer treatments is increasing significantly with more expensive novel treatments adopted as standards of care. On the other hand, we found that many novel drugs for hematologic malignancies confer marginal survival benefits at tremendous cost and the majority of the cost-effectiveness studies were sponsored by the product manufacture. For example, alemtuzumab for patients with B-cell lymphocytic leukemia (B-cell CLL) has been evaluated in three cost-effectiveness analyses and showed unfavorable ICER of it compared with current standard of care. [51-53] We also recognized that there is a lack of evidence regarding the newer immunotherapeutic agents and many of them, but not all, may be priced above the value-based cut point. The novel immunotherapies have imposed an immense cost burden, which begs the questions as to whether their high prices reflect their worth.

InO was approved by the U.S. FDA in 2017. However, the National Institute for Health and Care Excellence (NICE) did not recommend it for routine use based on their analysis in the

NHS, England setting. They pointed out that even though it increased the number of people who can have a stem cell transplant, which may increase survival, the INO-VAT trial evidence showed no survival benefit for people having InO compared with FLAG or CM. The ICER of

InO compared with current treatment was more than £100,000 per QALY gained, higher than acceptable for end-of-life treatment. We performed a prospective assessment to establish a value- based cost for InO in the US setting.

Our study was generated for InO only based on the INO-VATE trial and did not compare this to other potential drugs indicated for ALL. For example, blinatumomab, another

immunotherapy agent approved in recent years, has been demonstrated to be cost-effective in the economic evaluation conducted by Delea et al. [54]

We used reimbursement rates provided by Medicare, the largest public payer in the

United States, which are generally lower than reimbursement rates for private insurers. Our model was developed using data from a clinical trial, and may not fully reflect the real-world experience of a population of patients. However, the ranges used in our sensitivity analyses will likely account for any variations between populations.

In this study, we adopted a Markov model framework to demonstrate how adjustments in the HR in the INO-VATE trial would affect the cost-effectiveness of InO. This analysis provides important data to guide the development of future clinical trials in hematologic malignancies to increase the value of newly approved agents.

Conclusion

The US health care system is focusing on increasing value for patients — the health outcomes achieved per dollar spent. A crucial step to increase value is an evaluation of cost and value. Cost-effectiveness analyses can help to establish drug prices that reflect the benefit they convey to patients and the health care system. Our study provides a value-based cost for InO, and in doing so has implications for the global cost of this drug.

Table 3-1. Summary measures collected from the original publications and their corresponding estimates obtained from the reconstructed individual patient data (IPD). Median PFS Median OS Treatment(s) Original Reconstructed Original Reconstructed InO 5.00m 5.03m 7.7m 7.98m SOC 1.8m 1.8m 6.7m 7.14m

Figure 3-1. Bubble diagram of the multi-state model with 3 health states: progression-free, progression, and death.

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BIOGRAPHICAL SKETCH

Ziyan Chen is a student in the Department of Pharmaceutical Outcomes and Policy,

College of Pharmacy, University of Florida.

She received her master’s degree at the University of Southern California in 2015 from the Department of Stem Cell and Regenerative Medicine. She received her bachelor’s degree of biology at the Sun Yat-sen University in 2010.

Her current research interests are health technology assessment, cost-effectiveness analysis, cancer immunotherapy, and value-base pricing.