The effectiveness and value of targeted immune modulators for moderate to severe ulcerative colitis

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, California Health Care Foundation, The Donaghue Foundation, Harvard Pilgrim Health Care, and Kaiser Foundation Health Plan to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from AbbVie, Aetna, America's Health Insurance Plans, Anthem, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Boehringer-Ingelheim, Cambia Health Services, CVS, Editas, Evolve Pharmacy, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, HealthFirst, Health Partners, Humana, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Pfizer, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, uniQure, and United Healthcare. Pandey, Fazioli, and Pearson are employed by ICER. Ollendorf reports grants from ICER related to this study and reports other support from the CEA Registry Sponsors and consulting and advisory board fees from EMD Serono, Amgen, Analysis Group, Aspen Institute/University of Southern California, GalbraithWight, Cytokinetics, Sunovion, University of Colorado, the Center for Global Development, and Neurocrine, unrelated to this work. Bloudek reports grants from ICER related to this work and reports fees from AbbVie, Astellas, Akcea, Dermira, GlaxoSmithKline, Sunovion, Seattle Genetics, TerSera Therapeutics, and Incyte, unrelated to this work. Carlson reports grants from ICER related to this work.


Summary of Findings CLINICAL EFFECTIVENESS
We compared the clinical effectiveness of TIMs with the ongoing background conventional therapy (i.e., placebo arms of clinical trials) and to each other.
The Institute for Clinical and Economic Review (ICER) conducted a systematic literature review and cost-effectiveness analysis to evaluate the health and economic outcomes of these TIMs for UC. Here, we present a summary of key findings and highlights of the policy discussion with key stakeholders held at a public meeting of the California Technology Assessment Forum (CTAF) on September 24, 2020. Complete details of ICER's systematic literature search and protocol, as well as the methodology and model structure for the economic evaluation, are available in the full report at https://icer.org/ assessment/ulcerative-colitis-2020/.
The effectiveness and value of targeted immune modulators for moderate to severe ulcerative colitis Ulcerative colitis (UC) is a chronic inflammatory bowel condition affecting nearly 1 million individuals in the United States. 1,2 UC causes inflammation in the inner lining of the large intestine, including the colon and the rectum. 3 The course of the disease is characterized by phases of remission and relapsing symptoms such as frequent diarrhea, often with blood or pus; abdominal discomfort; rectal pain; fatigue; and weight loss. 4 The onset of UC usually peaks between the ages of 15 and 35 years. 5 Treatment options for moderate to severe UC are aimed at inducing clinical response or complete remission in the short-term (induction phase, 6-14 weeks) and maintaining response or remission in the longer term (maintenance phase), often with a lower dose. Treatment options depend largely on the extent of the disease and the severity of symptoms. These may include conventional systemic immune modulators such as aminosalicylates, thiopurines, and budesonide or systemic corticosteroids.
When the disease has not responded adequately to systemic immune modulators, patients are potentially eligible to receive a targeted immune modulator (TIM). TIMs may be used alone or in combination with other systemic agents, such as azathioprine, to induce population, 4,6-22 with only 1 head-to-head trial (VARSITY) of 2 active treatments, adalimumab and vedolizumab. 16 Primary efficacy endpoints were clinical response and clinical remission assessed at the end of weeks 6-14 (induction phase) and week 52-60s (maintenance phase). The trials were generally comparable, allowing the conduct of Bayesian network meta-analyses (NMAs) to obtain indirect comparative efficacy estimates. Induction and maintenance phase benefits were assessed separately for 2 patient subpopulations: (1) patients without evidence of previous TIM exposure ("biologic-naive") and (2) those with previous exposure to TIMs ("biologic-experienced").
Data for all TIMs were available in the biologic-naive population. 4,6-20 We did not identify any evidence for golimumab or infliximab in the biologic-experienced population. Our assessment of tofacitinib was limited to the biologicexperienced population based on a recent change to its label that now specifies a requirement for previous TNF inhibitor use. 23 In placebo-controlled trials, TIMs demonstrated superior rates of response, remission, or both at the end of induction and maintenance. Results from the VARSITY head-to-head trial showed that vedolizumab had a higher rate of response than adalimumab during induction in the biologic-naive and biologic-experienced populations and a higher rate of remission during maintenance in the biologic-naive population. 16 NMA results suggested inferior rates of response and remission for adalimumab compared with several other agents as well. For induction, the NMA showed adalimumab to be inferior to infliximab and vedolizumab in the biologicnaive population and inferior to ustekinimab, tofacitinib, and vedolizumab in the biologic-experienced population. In addition, rates of response and remission were higher with vedolizumab compared with golimumab and adaliumab in the biologic-naive population during maintenance. No other statistical differences among TIMs were observed.
Mortality rates and serious adverse events in available long-term RCT extensions generally showed rates similar to those observed during randomized periods. Of note, 3 TNF inhibitors (adalimumab, golimumab, and infliximab), as well as tofacitinib, carry a black box warning in their FDA labels for an increased risk of serious infections, lymphomas, and other malignancies. [24][25][26][27] Data from observational studies demonstrate slightly higher rates of serious infection for certain TIMs versus conventional therapy but no consistent differences among TIMs; long-term data are lacking for the newer TIMs.

LIMITATIONS OF CLINICAL EVIDENCE
Comparative clinical effectiveness among TIMs was largely assessed indirectly through NMAs, the results of which can be susceptible to potential effect modification. The sparsity of data in the biologic-experienced population and adjustment for trial differences added additional uncertainty. Also, the lack of evidence on efficacy for some agents (e.g., infliximab and golimumab) for the biologic-experienced population, as well as limited longer-term safety data for newer therapies, poses a challenge in the interpretation and application of the data.

LONG-TERM COST-EFFECTIVENESS
We evaluated the cost-effectiveness from the U.S. health care sector perspective of the 6 TIMs and 2 biosimilars over a lifetime time horizon. We developed a Markov model with 8-week cycles and the following health states: active UC, clinical response without remission, clinical remission, postcolectomy (with and without complications), and death. Analyses were conducted in the biologic-naive and biologicexperienced populations.
All moderate to severe UC patients entered the model in an active state. At the end of induction, patients with response continued to receive the TIM (or conventional treatment) and those without response or discontinuation shifted to induction with a subsequent treatment. Outcomes and cost for subsequent treatment were represented by a "market basket" of TIMs, with data from treating patients in the biologic-experienced population. Patients without response to subsequent treatment discontinued the treatment and followed transition probabilities of conventional treatment for the remainder of the model time horizon. A proportion of patients with active UC were assumed to opt for colectomy in each cycle. 28 The model was informed by the ICER NMA of key clinical trials. The average net pricing estimates for TIMs with oral and subcutaneous modes of administration were obtained from SSR Health. For IV-administered TIMs, we used Centers for Medicare & Medicaid Services average sales prices (ASP) plus 9.5%. 29 Full details of ICER's costeffectiveness analysis and model are available at https:// icer.org/assessment/ulcerative-colitis-2020/.
The cost-effectiveness ratios for TIMs in the biologicnaive and biologic-experienced populations in nearly all scenarios were above commonly cited thresholds when compared with conventional treatment. In the biologicnaive population (Table 1), cost-effectiveness was closest to $150,000 per quality-adjusted life-year (QALY) for infliximab and its biosimilars: infliximab-dyyb and infliximab-adba ($212,000, $186,000 and $195,000 per QALY, respectively).

Policy Discussion
The CTAF is one of the independent appraisal committees convened by ICER to engage in the public deliberation of the evidence on clinical and cost-effectiveness of health care interventions. CTAF is composed of medical evidence experts (e.g., practicing clinicians and methodologists) and leaders in patient engagement and advocacy. Their deliberation includes input from clinical experts and patient representatives specific to the condition under review, as well as formal comments from manufacturers and the public. A policy roundtable concludes each meeting during which representatives from insurers and manufacturers join clinical experts and patient representatives to discuss how best to apply the findings of the evidence to clinical practice, insurance coverage, and pricing negotiations.
After deliberation, the CTAF panel members voted 12-2 that the evidence was adequate to demonstrate that vedolizumab has greater net health benefits compared with adalimumab. However, they voted unanimously that the evidence was inadequate to demonstrate a superior net health benefit for ustekinumab compared with adalimumab, and they voted 14-1 that the evidence was inadequate to distinguish the net health benefit among tofacitinib, ustekinumab, and vedolizumab.
The panel also voted on "other potential benefits" and "contextual considerations" of these treatments as part of a process intended to signal to policymakers whether there are important considerations when making judgments about long-term value for money that are not adequately captured in the analyses of clinical effectiveness and costeffectiveness. The results of these votes highlight several When compared with infliximab, all TIMs produced fewer QALYs except ustekinumab, with a cost-effectiveness ratio of approximately $2.9 million per QALY. In the biologic-experienced population (Table 2), the incremental cost-effectiveness ratio compared with conventional treatment was highest for adalimumab ($1,885,000) and lowest for tofacitinib ($495,000). When compared with adalimumab, tofacitinib resulted in lower costs and higher QALYs. Ustekinumab and vedolizumab also generated higher QALYs but at much higher cost ($996,000 and $464,000 per QALY, respectively). The equal value of lifeyears gained (evLYG) and cost per evLYG outcomes were similar to those for the QALY, given the relatively minor mortality effects. Full results from the one-way sensitivity analysis, as well as the probabilistic sensitivity analysis are available in the full report (https://icer.org/assessment/ ulcerative-colitis-2020/).

LIMITATIONS OF LONG-TERM COST-EFFECTIVENESS
The primary limitations of our cost-effectiveness analysis included restricted data availability, a paucity of information on treatment sequencing or switching, and our need to base outcomes for conventional treatment solely on the results from the placebo arms of the trials. As previously noted, the model is based on treatment benefit inputs obtained from the NMA and, as such, is subject to the limitations previously described.   • Patients eligible for TIMs include those with moderate to severe UC whose disease has had an inadequate response to conventional systemic therapy. Patient eligibility criteria should be flexible given that clinical trials used tools (e.g., Mayo Score for disease severity) that are not routinely used in clinical practice. Inadequate response to conventional systemic therapy is the facet of clinical criteria that insurers may choose to define by specifying particular types of systemic therapies, number of attempts, or duration. This approach is reasonable as long as there is a valid citation or reference for the specifications given. Measurement of therapy "failure" in clinical trials is based on the Mayo Score, but as noted, this should not be used as a criterion within insurance coverage. • Given the lack of biomarkers and other predictors of TIM treatment success in UC, it is not unreasonable to use step therapy in this case to manage the costs of treatment.
Step therapy among agents for UC appears to meet criteria for reasonable step therapy. • Switching: Consideration of required switching policies of TIM therapy for patients who are stable on a current treatment should be limited to switches from an originator to a biosimilar agent.
factors that the panel recognized could be influential when making decisions about the value of these treatments (Table 3 and Table 4). The culminating vote of the CTAF panel on "long-term value for money" was intended to reflect the members' integration of all elements of value. The panel only voted on infliximab and its 2 biosimilars, infliximab-dyyb and infliximab-adba, because for all the other TIMs the results in the base-case economic analysis and other scenarios greatly exceeded commonly cited cost-effectiveness thresholds. In this final vote, a majority of the panel judged the longterm value for money of infliximab and its biosimilars as "intermediate." The policy roundtable discussion explored how best to translate the evidence and broader perspectives discussed into clinical practice and into pricing and insurance coverage policies. The full set of policy recommendations can be found in the final evidence report; however, several key policy recommendations are as follows: • The significantly lower prices seen for infliximab and its biosimilars highlight the important potential for improved value with broader availability and uptake of biosimilar treatment options. All stakeholders should collaborate to ensure that TIM biosimilars have an increasing and comprehensive role in the UC treatment landscape. • The "bundled rebate" approach to price negotiation and formulary development should be replaced with an indication and value-based pricing approach.
Are any of the following contextual considerations important in assessing the long-term value for money of TIMs?
These interventions are intended for the care of individuals with a condition of, particularly high severity in terms of impact on length of life and/or quality of life.

12/15
These interventions are intended for the care of individuals with a condition that represents a particularly high lifetime burden of illness.

13/15
These interventions are the first to offer any improvement for patients with this condition.

0/15
Compared with conventional therapy, there is significant uncertainty about the long-term risk of serious side effects of these interventions.

13/15
Compared with conventional therapy, there is significant uncertainty about the magnitude or durability of the long-term benefits of these interventions.

12/15
There are additional contextual considerations that should have an important role in judgments of the value of these interventions.

TIM = targeted immune modulator.
Votes on "Contextual Considerations" Important in Assessing Long-Term Value for Money   TABLE 4 Does treating patients with TIMs offer one or more of the following potential "other benefits" compared with conventional therapy?
These interventions offer reduced complexity that will significantly improve patient outcomes.

2/15
These interventions will significantly reduce caregiver or broader family burden.

9/15
These interventions offer a novel mechanism of action or approach that will allow successful treatment of many patients for whom other available treatments have failed.

13/15
These interventions will have a significant impact on improving patients' ability to return to work and/or their overall productivity.

12/15
There are other important benefits or disadvantages that should have an important role in judgments of the value of these interventions.

TIM = targeted immune modulator.
Votes on "Other Benefits" that May Not Be Adequately Captured in the Base-Case Cost-Effectiveness Model