Patients with Crohn s disease respond to tumor necrosis

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11: A Test-based Strategy Is More Cost Effective Than Empiric Dose Escalation for Patients With Crohn s Disease Who Lose Responsiveness to Infliximab FERNANDO S. VELAYOS,* JAMES G. KAHN, WILLIAM J. SANDBORN, and BRIAN G. FEAGAN *Division of Gastroenterology and Hepatology, Philip R. Lee Institute for Health Policy Studies and Department of Epidemiology and Biostatistics, University of California, San Francisco, California; Division of Gastroenterology and Hepatology, University of California, San Diego, California; and Robarts Research Institute, University of Western Ontario, London, Ontario, Canada BACKGROUND & AIMS: METHODS: RESULTS: CONCLUSIONS: Patients with Crohn s disease who become unresponsive to therapy with tumor necrosis factor antagonists are managed initially with either empiric dose escalation or testing-based strategies. The comparative cost effectiveness of these 2 strategies is unknown. We investigated whether a testing-based strategy is more cost effective than an empiric doseescalation strategy. A decision analytic model that simulated 2 cohorts of patients with Crohn s disease compared outcomes for the 2 strategies over a 1-year time period. The incremental costeffectiveness ratio of the empiric strategy was expressed as cost per quality-adjusted life-year (QALY) gained, compared with the testing-based strategy. We performed 1-way, probabilistic, and prespecified secondary analyses. The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). In sensitivity analyses, the incremental cost-effectiveness ratio of the empiric strategy ranged from $500,000 to more than $5 million per QALY gained. Similar rates of remission (63% vs 66%) and response (28% vs 26%) were achieved through differential use of available interventions. The testing-based strategy resulted in a higher percentage of surgeries (48% vs 34%) and lower percentage use of high-dose biological therapy (41% vs 54%). A testing-based strategy is a cost-effective alternative to the current strategy of empiric dose escalation for managing patients with Crohn s disease who have lost responsiveness to infliximab. The basis for this difference is lower cost at similar outcomes. Keywords: Anti-TNF Agent; Decision Analysis; Failed Therapy; Algorithm. Podcast interview: Also available on itunes. Patients with Crohn s disease respond to tumor necrosis factor (TNF) antagonist therapy but experience loss of response in 40% of cases. 1,2 This phenomenon has not been well studied, but proposed mechanisms include the following: (1) nonimmune pharmacokinetics resulting in low drug serum concentrations, 3 (2) development of antidrug antibodies, 4 (3) mechanistic override whereby cytokine pathways other than TNF are activated, 2 and (4) noninflammatory disease processes such as irritable bowel syndrome, bacterial overgrowth, or subtle stricture. 2,5 A common strategy for managing loss of response consists of empiric cycling through available Crohn s therapy in a prespecified sequence to address potential mechanisms for loss of response. 6 A recent position statement from the World Congress of Gastroenterology recommended the following sequence for managing this phenomenon: first increase the TNF antagonist dose (address low-drug concentration); next, switch the type of TNF antagonist (address antidrug antibodies); and, finally, change class/mechanism of biologic or proceed to surgery (address activation of non TNF-mediated pathways). 6 In an empiric strategy, no systematic attempt is made to identify the patient s mechanism for loss of response or to identify patients with symptoms resulting from causes other than inflammation. Abbreviations used in this paper: ADA, adalimumab; ATI, antibodies to infliximab; CT, computed tomography; ICER, incremental cost-effectiveness ratio; IFX, infliximab; QALY, quality-adjusted life-year; TNF, tumor necrosis factor by the AGA Institute /$

2 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 655 An alternative to the empiric strategy is to use a priori diagnostic testing to target treatment based on the most likely mechanistic cause for loss of response. Support for a testingbased strategy is based on a small retrospective study. Afif et al 5 reported differential response rates to TNF dose escalation and switching based on the presence of antibodies to infliximab (ATI), infliximab (IFX) drug concentration, and the presence of inflammation on colonoscopy/imaging in select patients with a therapeutic IFX concentration. Notable was the discovery of a subgroup of patients describing active symptoms with a therapeutic IFX concentration and without significant inflammation. Afif et al proposed a role for excluding noninflammatory causes when assessing loss of response to TNF therapy. The empiric and testing-based strategies are both practiced clinically. Whether the empiric or testing-based strategies differ with regard to outcomes or costs is unknown. It is reasonable to speculate that sensitized patients, those with disease mediated through alternative, non TNF-mediated pathways, and those with symptoms caused by another disease process, might derive greater benefit and/or incur lower costs if managed according to a testing-based strategy than an empiric management strategy. Nevertheless, insufficient clinical data currently exist to justify the universal adoption of a testing-based strategy. To evaluate definitively the relative cost effectiveness of an empiric vs a testing-based strategy would require performance of a randomized controlled trial in which secondary nonresponders to a TNF antagonist would be assigned randomly to either of the 2 strategies, with subsequent evaluation of outcomes and costs. The design of such a complex trial requires a large commitment of scientific and monetary resources. To our knowledge, no such trial is underway. In the absence of experimental data, the results of subexperimental studies such as decision analyses can provide useful information to decision makers and inform the design of such a trial. To this end, our objective was to conduct a decision analysis comparing the cost effectiveness of a testing-based algorithm with an empiric algorithm. Methods Decision Analysis The decision analytical model simulated 2 cohorts of Crohn s patients with loss of response to IFX. The model compared the efficacy, costs, and relative cost effectiveness of a testing-based strategy with an empiric dose-escalation strategy. Quality-adjusted life-years (QALYs) and direct costs were calculated based on a 1-year time horizon. The analysis perspective was third-party payer and included treatment and health state costs, but not indirect costs (eg, time missed from work). The model included only IFX and not other TNF antagonists given that, first, IFX drug and antibody concentrations are the only commercial tests currently available in the United States, and, second, sufficient published data exist for IFX to populate the necessary efficacy and cost inputs. Data from primary or subgroup analyses from randomized clinical trials were the preferred source for transition probability estimates. Data from observational studies were used as necessary if appropriate clinical trial data were not available (Table 1). The base case was a 35-year-old man weighing 70 kg with moderate to severe active ileocolonic Crohn s disease who previously had achieved remission after standard IFX induction therapy (5 mg/kg at 0, 2, and 6 wk). During maintenance therapy (5 mg/kg every 8 wk), the patient experienced Crohn s-like symptoms (abdominal pain, increase in bowel movements). This model assumed nonbiological treatments such as thiopurines were tried previously, stool tests for Clostridium difficile were negative, and urgent/emergent surgery was not indicated. Model Overview An algorithm proposed by Afif et al 5 formed the basis for the testing-based strategy, whereas the consensus statement issued by the World Congress of Gastroenterology 6 formed the basis for the empiric strategy. The 2 strategies differ primarily in the first type of management response (Figure 1). In the testing-based strategy, all patients receive testing to detect ATI and quantify serum IFX concentration. The response to the results reflects a remedy tailored to the presumed mechanism for loss of response. In contrast, no initial diagnostic testing is performed in the empiric strategy and the response reflects a sequential and general approach to remedy potential mechanisms for loss of response. In the testing strategy, the response to those with measurable ATI is to switch to a different TNF antagonist, adalimumab (ADA), to remedy anti-ifx antibodies as the presumed mechanism for loss of response (Figure 2A). Patients without ATI and with a therapeutic drug concentration undergo further diagnostic testing with computed tomography (CT) enterography and/or colonoscopy. Those with a therapeutic IFX concentration and active inflammation on imaging/ colonoscopy change to a different class of therapy, specifically surgery, to remedy activation of non-tnf pathways as the presumed cause for loss of response (Figure 2B). Those without active inflammation continue on IFX 5 mg/kg every 8 weeks for symptoms presumed caused by some other disease process that does not clearly justify immediate surgery or change in Crohn s therapy (Figure 2C). Finally, patients without measurable ATI and a subtherapeutic IFX concentration receive an increased dose of IFX from 5 to 10 mg/kg every 8 weeks to remedy low drug concentration/nonimmune pharmacokinetic mechanisms as the presumed cause for loss of response (Figure 2D). In the empiric strategy, all patients first receive an increased dose of IFX from 5 to 10 mg/kg every 8 weeks in an attempt to remedy a potentially low drug concentration (Figure 2D). Responders who subsequently lose response or those failing to respond switch their TNF antagonist, specifically ADA 160 mg at week 0, 80 mg at week 2, and then 40 mg every 2 weeks to remedy the potential presence of antidrug antibodies. Responders who subsequently lose response receive an increase in dose to 40 mg every week. Patients who fail to respond to ADA switching or dose increase change to a different class of therapy, specifically surgery, to remedy the potential for activation of non TNF-mediated pathways. Patients who relapse after surgery are restarted on TNF antagonist therapy. Because noninflammatory causes for symptoms are not addressed specifically, patients with noninflammatory causes for symptoms would undergo surgery with symptoms attributed to activation of non-tnf pathways.

3 656 VELAYOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Table 1. Model Inputs and Utility Scores Parameter Base estimate Reference Transition probabilities Proportion with mild/minimal inflammation with symptoms Initial response ADA switch (total population) Anti-IFX antibody present (17% population) Subtherapeutic IFX concentration (48% population) Therapeutic IFX concentration (35% population) 0.59 Calculated IFX increase to 10 mg/kg (total population) 0.52 Adapted from 8 Anti-IFX antibody present (17% population) Subtherapeutic IFX concentration (48% population) Therapeutic IFX concentration (35% population) 0.21 Calculated CTZ switch (total population) a NAT (total population TNF failures) a Sustained response at 1 y ADA switch b Sustained responders in remission IFX increase to 10 mg/kg b Sustained responders in remission ADA increase to 40 mg every week b Sustained responders in remission Surgery switch Sustained responders in remission IFX 5 mg/kg maintenance Restart biological for postoperative recurrence Proportion sustained responders in remission CTZ switch a Sustained responders in remission CTZ increase (1 extra dose) a Sustained responders in remission NAT out-of-class switch a Sustained responders in remission Mortality After biological therapy After surgery Costs Interventions c IFX 100-mg vial ADA kit (2 pens; 40 mg/0.8 ml) Surgery 12, Certolizumab (2 pens; 200 mg/1 ml) Natalizumab 300-mg vial Diagnostics Anti-IFX antibody/serum IFX measurement CT enterography Colonoscopy Health states Remission Minimum/mild inflammation with symptoms Response (mild symptoms) Active disease Utility scores Medical remission Surgical remission 0.86 Extrapolated 39 Mild/minimal inflammation with symptoms Response Active disease Death 0 39 NOTE. Transition probabilities, costs, and utilities were varied through a range of plausible and extreme values (0 1 for probabilities/utilities, 0- to 5-fold greater than the base case for costs). Representative low and high values are presented in Table 2. CTZ, certolizumab; NAT, natalizumab. a Alternative scenarios to base-case. b IFX use for 70-kg person: 5 mg/kg: 4 vials; 10 mg/kg: 7 vials. ADA use: induction 6 pens; 40 mg every other week-2 pens; 40 mg ew-4 pens. c Among initial responders.

4 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 657 Figure 1. Schematic overview of the decision model for managing secondary loss of response. Ab, antibody. Transition States The 1-year (52-wk) time horizon was divided into thirteen 4-week intervals to proportion quality of life and cost and to model clinically based time points for interventions, response to interventions, and initiation of new treatments. The quality-of-life utilities and costs assigned to each 4-week interval for each branch of the tree were based on the following model. All of the patients started with moderate-severe active Crohn s disease. Those responding to any change in medical therapy did so in the 4-week interval in which therapy was started and maintained the end-state (remission or response) in the following 4-week interval. Responders who lost response (active disease) did so 6 cycles (months) after initiating therapy. Nonresponders underwent surgery the cycle after initiating therapy and had active disease during these 2 cycles. After surgery, sustained responders achieved the end-state (remission or response) the cycle after surgery. Responders who lost response (recurrence) did so 6 cycles after surgery and were in response (mild disease) until recurrence, at which point they had active disease. TNF-antagonist therapy was initiated at this point given they previously had sufficiently aggressive disease to require therapy with a TNF antagonist. Patients then entered either remission, response, or stayed in active disease for the remainder of the study. The testing-based groups that had a therapeutic drug level and underwent CT enterography and/or colonoscopy experienced a 1-month delay in recommended therapy (surgery or next dose of IFX at 5 mg/kg) to account for time to schedule and complete these diagnostic tests. Patients who continued IFX 5 mg/kg with minimal/mild inflammation and progressed to surgery (because symptoms were caused by an occult stricture or required surgery for Crohn s for another reason) had active disease at interval 6 and underwent surgery at interval 7. For the purposes of this study, mortality after medication or surgery was classified as an early event, occurred in the month given, and resulted in 0 QALYs from that interval forward. Adverse side effects causing discontinuation of medical therapy were considered to not have a significant effect on QALYs in this 1-year time horizon. Other Model Assumptions/Definitions Initial response to therapy was defined as a decrease of 70 points in the Crohn s Disease Activity Index and long-term response was defined as a Crohn s Disease Activity Index score of less than 150 at 1 year. The proportion of persons in remission at 1 year was calculated by dividing the remission rate by the overall response rate (which includes persons in response only and persons in remission). Patient symptoms but minimal to mild evidence of significant inflammation on CT/colonoscopy were grouped with the response group for efficacy outcomes but the remission group for cost because their symptoms already had undergone investigation to determine no escalation or change in therapy was required. Insurance approval for diagnostic testing and medication changes was assumed to be timely and did not delay treatment. Costs for diagnostic testing, medication, or surgery were assigned to the 4-week interval in which they were performed. The quality of life associated with the group of patients with minimal to mild inflammation with symptoms was specified as

5 658 VELAYOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Figure 2. Overview of major decision branches for managing secondary loss of response. having a value between response (0.77) and remission (0.89), and assigned the QALY reported for patients with symptomatic irritable bowel (0.80). 7 At inception the virtual cohorts in both the testing and empiric groups were assumed to contain the same proportions of subjects with active inflammation and detectable ATI and a therapeutic IFX concentration. Incompletely reported rates of response to ADA switching or IFX dose escalation based on the presence or absence of IFX

6 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 659 antibody and therapeutic IFX concentration were calculated using available data. 5 The study by Afif et al 5 provided data on the rate of response to ADA switching or IFX dose escalation for subjects with a detectable IFX antibody and a subtherapeutic IFX level but did not report a response rate based on a specific target IFX level. To calculate this missing variable, we assumed the response rate for the total population reported in clinical trials consisted of a blend of response rates of subpopulations defined by positive drug antibody, subtherapeutic IFX concentration, and therapeutic IFX concentration. We then solved the equation so that the response for each subgroup multiplied by the frequency of the subgroup (both variables were reported in the study by Afif et al 5 except response to therapeutic IFX) equaled the overall response rate reported in clinical trials. For this model, the overall rate of response to IFX dose escalation was assumed to be equal to that of ADA switching reported in the Gauging Adalimumab Efficacy in Infliximab Nonresponders (GAIN) clinical trial. 8 We did not use the estimate derived from the subgroup analysis of the A Crohn s disease Clinical trial Evaluating infliximab in a New Longterm Treatment regimen in patients with fistulising Crohn s disease (ACCENT) I study 9 that reported a 90% response rate to IFX dose escalation in all-comers for 2 reasons: first, the initial response rate of 90% was mentioned in only one sentence in the discussion without identifiable corroborating data in the Results section. Second, given the reported response rates to IFX dose escalation in IFX-antibody positive patients (0.17) and subtherapeutic IFX level patients (0.86), use of this overall 90% response rate resulted in a nonplausible response rate in the therapeutic IFX group ( 100%). Assuming the overall response rate to ADA switching and IFX dose escalation to be equal, the response rate to ADA switching in the setting of a therapeutic IFX level was calculated as 59% and the response rate to IFX dose escalation was calculated as 22%. Analyses Extensive analyses of the model were performed. The primary analysis compared the QALYs, costs, and relative cost effectiveness of a testing-based strategy with an empiric doseescalation strategy in the simulated cohorts. An incremental cost-effectiveness ratio (ICER) for the empiric strategy was calculated by dividing the difference in cost associated with the testing strategy by the difference in QALYs. When the QALY estimate for the empiric strategy was greater or the cost was lower, the ICER was reported. If not, the empiric strategy was considered dominated by the testing strategy. Prespecified secondary analyses measured additional efficacy outcomes, as follows: (1) the number of patients in response/ remission at 1 year, (2) the proportion of months (4-wk cycles) spent in response/remission during the year, (3) the number of patients in remission at the end of each quarter (weeks 12, 24, 36, and 52), and (4) the number of patients in sustained remission, defined by the presence of remission at the end of more than one quarter. Other prespecified analyses included the number of patients and proportion of months spent on specific Crohn s therapies, including no therapy and surgery at 1 year and the number of patients and proportion of months receiving high- and standard-dose biological therapy. Extensive one-way sensitivity analyses determined the strength of the estimates and significant drivers of the model. Transition probabilities, costs, and utilities were varied through a range of plausible and extreme values (0 1 for probabilities 0 5 fold greater than the base case for costs) to define any threshold where important changes in effectiveness or cost might change our conclusions. Representative low and high values are presented (Table 2). Probabilistic sensitivity analyses determined uncertainty in model results, specifically incremental QALY and costs. A total of 10,000 simulations simultaneously varied multiple transition probabilities and costs used in the one-way sensitivity analyses. Prespecified alternative scenarios addressed important assumptions of the base-case or addressed limitations of the current data. These included the following: (1) reducing the rate of response to switching or dose-escalation of biological therapy if used later (after failure of other therapies) instead of earlier in the treatment algorithm; (2) reducing the rate of response to biological therapy when used in patients with mild/minimal inflammation compared with active inflammation; (3) using certolizumab instead of ADA in the model; (4) using natalizumab before surgery in the model; and (5) changing the underlying prevalence of inflammation, antidrug antibody, and therapeutic drug concentration in the underlying study population. The earlier-described analyses were stratified to evaluate the subgroups we speculated would have better outcomes and lower cost with the testing-based strategy: sensitized patients (antidrug antibody positive, active inflammation), those with disease mediated through alternative non-tnf inflammatory pathways (therapeutic drug concentration, active inflammation), and those with symptoms caused by another disease process (therapeutic drug concentration, minimal/mild inflammation). Outcomes stratified based on subgroups with and those without inflammation also were performed. Post hoc sensitivity analyses explored questions generated by the results. We first assessed the effect of excluding functional symptoms in all patients (regardless of the testing or empiric dose-escalation arm) with up-front testing using CT enterography/colonoscopy and continuing IFX at 5 mg/kg in those with no evidence of significant inflammation. We also varied the cost of IFX to 5 and 10 times the base case to account for potential additional costs associated with facility fees. Results Comparative Effectiveness and Costs The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). Thus, the testing strategy dominated the empiric strategy (numerically higher QALY and lower costs) (Table 2). Secondary Analyses At week 52, the proportion of patients in response and remission was similar in both groups (Figure 3A); however, this was achieved differently. Compared with the empiric group, patients in the testing group underwent more surgery (48% vs 34%, respectively; not shown in Figure 3) and had substantially lower use of high-dose biological therapy (41% vs 54%, respectively) (Figure 3B). In addition, more patients in the testing

7 660 VELAYOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Table 2. Results of Base-Case Analysis and One-Way Sensitivity Analyses for Transition Probabilities, Costs, and Utilities Testing strategy Empiric strategy Parameter (base-case value) Value QALY Cost, $ QALY Cost, $ QALY Cost, $ Cost/ QALY Base case , , Dominated Initial response ADA switch Total population (0.52) , , Dominated , , $3,274,500 IFX Ab (0.92) , , Dominated , , Dominated Subtherapeutic IFX (0.33) , , Dominated , , Dominated Therapeutic IFX (0.59) , , Dominated , , $6,290,000 Initial response IFX 10 mg/kg Total population (0.52) , , Dominated , , $709,625 IFX Ab (0.17) , , Dominated , , $2,550,500 Subtherapeutic IFX (0.86) , , $5,073, , , Dominated Therapeutic IFX (0.22) , , Dominated , , $794,714 Sustained response ADA switch (0.37) , , Dominated , , $930,200 IFX increase 10 mg/kg (0.62) , , Dominated , , $5,419,000 ADA increase ew (0.75) , , Dominated , , Dominated Surgery (0.62) , , $719, , , Dominated Maintain IFX 5 mg/kg (0.86) , , $4,985, , , Dominated Restart biological (0.69) , , $1,685,333 Mortality , , Dominated ADA (0.001) , , Dominated , , Dominated IFX (0.001) , , Dominated , , Dominated Surgery (0.001) , , Dominated , , $503,545 Cost Ab/drug level (225) , , Dominated Colonoscopy (838) , , Dominated CT enterography (849) , , Dominated ADA 2 pens ( ) , , ,757 Dominated IFX unit dose (756.02) , , ,011 Dominated Surgery (12,261) 61, , , $1,531,000 Medical remission (17) , , Dominated Surgical remission (17) , , Dominated Mild/minimum inflammation (17) , , Dominated Response (152) , , Dominated Active disease (374) , , Dominated Ab, antibody. strategy were managed without biological therapy (34% vs 27%, respectively). At the end of 1 year, the time, defined by the proportion of months (4-week intervals), spent in response, remission, and active disease also was similar between the 2 groups (Figure 3C). Compared with the empiric group, the testing group spent fewer months receiving high-dose biological therapy (39% vs 53%, respectively), more months in surgical remission (18% vs 10%, respectively; not shown in Figure 3), and more months without biological therapy (34% vs 19%, respectively) (Figure 3D). When analyzed by quarter, the proportion of patients in remission at the end of each quarter was similar and increased with time (Figure 3E). Sustained remission, defined by being in

8 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 661 Figure 3. Secondary analyses. Proportion of patients in (A) remission, response, and active disease, and (B) medication dose at week 52. Proportion of time spent in (C) remission, response, and active disease, and (D) dose of medication over 52 weeks. (E) Proportion of patients in remission at the end of each quarter. (F) Proportion of patients in remission at the end of more than 1 quarter. remission at the end of multiple quarters, was more prevalent in the testing group (Figure 3F). One-Way and Probabilistic Sensitivity Analyses One-way sensitivity analyses identified values for some parameters for which the empiric strategy was better than the testing strategy with regard to QALYs, although the differences typically were small (Table 2). Nevertheless, the testing strategy was superior with regard to cost in almost every circumstance. Even in situations in which the empiric strategy was not dominated by the testing strategy and thus an incremental cost-efficiency ratio was calculated, the estimates ranged between $500,000 to more than $5 million per QALY gained, well in excess of the $50,000 to $100,000 per QALY considered to be a reasonable cost-effectiveness threshold. 10 A notable observation from the one-way sensitivity analyses was that the empiric strategy was less expensive when the cost of surgery was tested at 5-fold more than the base case. Reducing the utility state of the mild/minimal inflammation with symptoms group to that of remission (0.77) resulted in only marginally greater QALYs in the empiric group (0.799 vs 0.800). By using the 90% response rate to dose-doubling of IFX in all-comers with loss of response as reported in a post hoc analysis of the ACCENT I study resulted in greater QALYs for the empiric group (0.801 vs 0.809) with a cost-per-qaly of $709,625 (Table 2). Increasing the cost of drug testing to more than 25-fold ($5700) resulted in the testing strategy no longer being less expensive than the empiric strategy ($37,267 vs $37,266, respectively). Probabilistic sensitivity analysis of the base case showed that 68.9% of results were within quadrant 4 (testing strategy was

9 662 VELAYOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Figure 4. Base-case probabilistic sensitivity analysis plot of incremental costs ($) vs QALY for testing vs empiric dose-escalation strategy for managing secondary loss of response. both less costly and more effective) (Figure 4). For the 31.1% of results within quadrant 3 (testing strategy was less costly, but the empiric strategy was more effective), none satisfied the $50,000 or $100,000/QALY reasonable cost-effectiveness threshold (diagonal lines) to support the empiric strategy as a more cost-effective strategy. None of the results of the probabilistic sensitivity analysis were in quadrants 1 or 2 (testing strategy was more costly). Alternative Scenarios The empiric strategy was sensitive to reducing the rate of response to switching or dose escalation of biological therapy if used later (after failure of other therapies) instead of earlier in the treatment algorithm, with a greater reduction in QALYs compared with the treatment strategy (Table 3). Reducing the rate of response to biological therapy when used in patients with mild/minimal inflammation compared with active inflammation reduced QALYs slightly, as did application of both scenarios simultaneously. Switching to certolizumab instead of ADA, which included use of only one extra dose of certolizumab for dose escalation as was evaluated in the open-label Pegylated Antibody Fragment Evaluation in Crohn s Disease: Safety and Efficacy (PRECISE) 4 trial resulted in lower QALYs for the testing strategy compared with the empiric strategy (0.800 vs 0.802, respectively) and a lower cost ($28,970 vs $34,282, respectively) (Table 3). Switching first to natalizumab instead of surgery as the non-tnf strategy resulted in only marginally higher QALYs for the testing strategy compared with the empiric strategy (0.800 vs 0.799, respectively), but a lower cost ($36,863 vs $41,043, respectively). Changing the prevalence of inflammation, positive drug antibody, and therapeutic drug concentration in the underlying population did not change the overall conclusions, although some differences were noted at the extremes of values tested Table 3. Results of Alternative Scenarios Testing strategy Empiric strategy Scenario Value QALY Cost, $ QALY Cost, $ QALY Cost, $ Cost/ QALY Base case , , Dominated Reduction in response to biologic for each failure , , Dominated of prior therapy (absolute percentage points) , , Dominated , , Dominated Reduction in response to biologic for the mild/minimal subgroup (absolute percentage points) , , Dominated , , Dominated , , Dominated Reduction in both , , Dominated , , Dominated , , Dominated Switch certolizumab instead of ADA , , ,656,000 Switch natalizumab before surgery , , Dominated Change rate of inflammation (base case, 0.78) , , Dominated , , Dominated Change rate drug Ab (base case, 0.17) , , $2,997, , , Dominated Change rate of therapeutic drug (base case, 0.35) , , Dominated , , ,486 Dominated Ab, antibody.

10 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 663 (Table 3). Of note was the greater QALY for the empiric strategy when the underlying prevalence of ATI was 0% (0.799 vs 0.801, respectively). The ICER was $2,997,500 per QALY. Most, but not all, of the subgroups we speculated would benefit with a testing strategy had both greater QALYs and lower cost. Sensitized patients (antidrug antibody positive, active inflammation) had greater QALYs (0.808 vs 0.794, respectively) and lower costs ($36,877 vs $39,364, respectively) with the testing strategy. Surgery rates were similar and the testing group received fewer months of high-dose biological therapy (Figure 5A). Patients with disease mediated through non-tnf pathways (therapeutic drug concentration with active inflammation) had lower QALYs (0.784 vs 0.789, respectively) and lower costs ($22,525 vs $36,788, respectively; ICER, $2,852,600/ QALY) with the testing strategy. Per protocol, all patients in the testing group underwent surgery and as a result spent more months off biological therapy (Figure 5B). Patients with symptoms caused by another disease process (therapeutic drug concentration, mild/minimal inflammation) had greater QALYs (0.795 vs 0.789, respectively) and lower costs ($21,293 vs $36,788, respectively) with the testing strategy. As expected, fewer patients in the testing group underwent surgery and none received high-dose biological therapy (Figure 4C). Overall, patients with active inflammation, regardless of subgroup, had identical QALYs (0.800 vs 0.800, respectively) and lower costs ($31,964 vs $37,268, respectively) with the testing strategy; surgery was more common (Figure 4D). Patients with mild/ minimal inflammation had marginally greater QALYs (0.803 vs 0.800, respectively) at a lower cost ($31,535 vs $37,258, respectively); surgery was less common (Figure 4E). Post Hoc Analyses Excluding functional symptoms first in all patients with up-front testing using CTE/colonoscopy and continuing IFX at 5 mg/kg in those without evidence of significant inflammation resulted in an equivalent QALY for the testing strategy (0.799 vs 0.799, respectively) at a lower cost ($30,440 vs $35,062, respectively). Increasing the cost of IFX to more than 10 times the base-case to account for potential additional facility fee costs, thus costing $30,240 per infusion for 5 mg/kg every 8 weeks, $52,920 for 10 mg/kg, resulted in greater cost for both strategies ($153,108 vs $192,747, respectively) but an even greater difference in cost savings for the testing strategy. Discussion This decision analysis compared the cost effectiveness of a testing-based algorithm with an empiric algorithm for management of loss of response to IFX. Our results support the hypothesis that a testing-based strategy is a more cost-effective alternative than the currently advocated strategy of empiric dose escalation. The basis for this difference is lower cost at similar outcomes. To be specific, the lower cost observed for the testing strategy was achieved in 2 ways: (1) less use of high-dose biological therapy, which essentially doubles the cost of therapy, and (2) greater time spent off medication, which occurs in the testing strategy in the postoperative state. These findings were anticipated in the testing-based strategy whereby patients with a therapeutic drug level and inflammation were referred for early surgery (and received no medications in the postoperative state), and those with minimal/mild inflammation were maintained on IFX at 5 mg/kg and alternative causes for symptoms were addressed. The finding of comparable efficacy appears robust and consistent based on multiple outcomes including QALYs, number of patients in response/remission at 1 year, proportion of months spent in response/remission during the year, and number of patients in remission at each quarter. The data for the alternative scenarios that incorporated use of certolizumab or natalizumab led to similar conclusions; comparable efficacy was achieved with testing at a lower cost. Although our model showed a large cost difference in favor of the testing-based strategy, no greater efficacy was observed in comparison with empiric dose escalation. The model indicates that such a difference would be detectable if the efficacy estimates for TNF-antagonist therapy were reduced in patients who failed other combinations, and if the efficacy estimates were reduced in those with mild/minimal inflammation. Reduced efficacy of re-treatment with a second TNF-antagonist therapy after failure of the initial agent has been well described. 11,12 The phenomenon of Crohn s patients having symptoms that mimic active disease without objective evidence of inflammation also is well documented. 5,13 Although this phenomenon is poorly understood, the therapeutic index of TNF antagonists in this patient population is likely to be low even though symptoms may improve with therapy. 14,15 However, precise estimates of the value of treating these patient groups are lacking in the literature. Our primary model was defined a priori and does not reflect all possible permutations of managing loss of response. This decision was based on balancing 2 considerations: (1) the strength of data available, and (2) what would be considered generally accepted current medical practice. For example, patients failing IFX were dose intensified from 5 to 10 mg/kg every 8 weeks rather than shortening the dosing interval because data evaluating this latter strategy are quite limited. 16 Also, we did not evaluate use of a third anti-tnf antagonist after failure of 2 others. Although this practice commonly is used, 17 it is not recommended in guidelines for managing loss of response to TNF therapy, likely because the therapeutic index is perceived to be poor. 6 We used ADA rather than certolizumab in the base case for switching because data from a 52-week, double-blinded, randomized trial were available for ADA, 8 whereas the initial response data for certolizumab were derived from an open-label, run-in period of a 26-week randomized controlled trial. 18 When patients failed 2 TNF antagonists, the first out-of-tnf class option evaluated was surgery rather than natalizumab based on our opinion that, at this time, most clinicians will opt for surgery over prolonged natalizumab therapy for limited ileocolic disease. This situation may evolve as a result of serologic testing that accurately can predict the risk of John Cunningham virus carriage. 19 However, we addressed these alternative scenarios in secondary analyses, specifically switching to certolizumab for loss of response to IFX and switching to natalizumab before surgery for failure of medical therapy. The overall results were similar to the base case. At this time, the base-case analysis supports that notion that the testing-based strategy is more cost effective than the empiric strategy owing to lower cost. It does not support the hypothesis of superior efficacy, although the alternative scenarios and what

11 664 VELAYOS ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 6 Figure 5. Selected subgroup analyses based on drug antibody, drug concentration, or inflammation. Rates of surgery and proportion of time spent in response, remission, and dose of medication over 52 weeks presented. (A) Anti-drug Ab positive, active inflammation; (B) therapeutic drug concentration, active inflammation; (C) therapeutic drug concentration, minimal/ mild inflammation; (D) all groups with active inflammation; (E) all groups with mild/minimal inflammation. Ab, antibody.

12 June 2013 TESTING FOR LOSS OF RESPONSE TO INFLIXIMAB 665 is known clinically suggests that additional data may help to address this question more definitively. We propose this question should be investigated within the framework of a prospective comparative effectiveness trial. Such a trial would serve to confirm the main finding of this study, that a testing-based strategy is less expensive than an empiric strategy for managing loss of response. It also would provide more precise estimates for data we have highlighted as lacking or limited. These include the lack of data on the efficacy of biological therapy in the minimal/mild inflammation subgroup, the lack of data on the efficacy of biological therapy after failing standard and highdose biological therapy, as well the paucity of data on efficacy of TNF switching and IFX dose escalation in the setting of the various drug antibody and drug level subgroups, the latter estimates being generated from only one observational study. 5 These data are highly relevant to clinical decision making. Our study had several limitations. First, the time horizon for the model was only 1 year. We modeled the data using best available data from randomized controlled trials, which, for the most part, are restricted to 1-year of follow-up evaluation. Longer-term data are highly relevant and essential for understanding the long-term impact of a test vs empiric strategy but do not exist at this time. Second, disease processes are more complex and dynamic than can be represented in any model. However, we believe our conclusions are valid for the clinical scenario of a patient with limited ileocolonic disease who is symptomatic after an initial response to IFX. Furthermore, the results can be generalized to a variable degree to more complex clinical circumstance. Third, our analysis was restricted to IFX loss of response because assays for other biologics currently are unavailable. However, such technologies are likely to evolve and similar modeling exercises should be developed to assess their role in clinical practice. Fourth, we used imaging and colonoscopy to assess disease activity as outlined in the strategy by Afif et al. 5 Noninvasive markers of inflammation, including C-reactive protein and fecal markers, might be reasonable alternatives but need additional study. Increased C-reactive protein correlates with moderate-severe clinical activity and active disease at colonoscopy 20 but does not correlate with inflammation limited to the small-bowel wall. 21 Finally, a key assumption in our model was that the presence of drug antibody, drug concentration, and inflammation accurately categorizes the mechanism for loss of response and the proposed interventions represent the best approach to remedy a given mechanism. Although this assumption is reasonable based on the available data from clinical trials and biological principles, no randomized controlled trials have addressed these questions specifically. Nascent efforts are underway to study this complex topic of therapeutic drug monitoring and loss of response to biological therapy. At least 2 trials targeting and modifying IFX dosing based on drug concentration are underway or planned. The Trough Level Adapted Infliximab Treatment (TAXIT) trial prospectively has randomized 275 patients with CD and UC to dosing based on IFX trough levels (3 7 mg/ml) or dosing and optimization based on clinical symptoms. 22 The Tailored Treatment With Infliximab for Active Crohn s Disease (TAILORIX) randomized trial seeks to investigate whether sustained steroidfree remission and mucosal healing at 1 year can be achieved using IFX trough level measurements and adjustment of dosing based on these levels in comparison with standard of care IFX treatment. 23 We propose that a prospective study using drug and antibody monitoring in the management of loss of response is needed. In fact, there is a great need for understanding both pharmacokinetics and pharmacodynamic relationships of TNF antagonists and mechanisms of treatment failure. A recent review highlighted the current state of the art on this topic and gaps in current knowledge. 24 This decision analysis had several strengths. First, even with the earlier-described caveats, it provided a novel and clinically relevant analysis of 2 currently practiced algorithms and provides a framework for mechanistically profiling patients based on the most likely cause for loss of response and then targeting therapy to that mechanism. Second, it provided an initial basis for modeling complex processes not formally addressed in studies of Crohn s disease. These include accounting for the presence and differential response to TNF therapy based on antibody/drug concentration, reduced efficacy for failure of prior therapy, and accounting for the presence and response to biological therapy for symptomatic patients with minimal/mild inflammation, a population well documented to exist in the Crohn s disease population but rarely addressed specifically in studies. Finally, this study identified critical variables and drivers of efficacy that can serve for planning future studies comparing a testing-based strategy vs an empiric strategy for loss of response. In summary, this study has indicated that a testing-based strategy is a more cost-effective alternative than empiric dose escalation. The basis for this difference is a lower cost for similar outcomes realized at different rates of available interventions, notably avoiding the use of inappropriate biological therapy in patients who are unlikely to benefit. References 1. Gisbert JP, Panés J. Loss of response and requirement of IFX dose intensification in Crohn s disease: a review. Am J Gastroenterol 2009;104: Ben-Horin S, Chowers Y. Review article: loss of response to anti-tnf treatments in Crohn s disease. Aliment Pharmacol Ther 2011;33: Maser EA, Villela R, Silverberg MS, et al. Association of trough serum IFX to clinical outcome after scheduled maintenance treatment for Crohn s disease. 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Aliment Pharmacol Ther 2010;32: Gregor JC, McDonald JW, Klar N, et al. An evaluation of utility measurement in Crohn s disease. Inflamm Bowel Dis 1997;3: Reprint requests Address requests for reprints to: Fernando Velayos, MD, Division of Gastroenterology and Hepatology, University of California San Francisco, 2330 Post Street, Suite 610, San Francisco, California fernando.velayos@ucsf.edu; fax: (415) Conflicts of interest These authors disclose the following: Fernando Velayos is an advisor for Janssen Pharmaceuticals and UCB Pharma, Inc; and William Sandborn and Brian Feagan are advisors or consultants for Abbott Laboratories, Elan Pharmaceuticals, Janssen Pharmaceuticals, Prometheus Laboratories, and UCB Pharma, Inc. The remaining authors disclose no conflicts. Funding Supported by an investigator-initiated research grant from Prometheus Laboratories. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.