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Amgen Response to the Proposed ICER Review of Treatments for Rheumatoid Arthritis (RA) and Psoriatic Arthritis (PsA) "Open Input"

Introduction

Amgen recommends that two separate and independent reviews be performed concurrently to assess targeted treatments for RA and PsA. Though joint damage is the most impactful clinical complication associated with RA or PsA, these are clinically distinct diseases that manifest with different pathophysiology, clinical presentation, comorbidities, and dosing regimens.1 Moreover, while many therapies overlap, not all therapies are approved for both RA and PsA. Based on the currently available efficacy evidence, it is unlikely that all of these therapies will be approved for both indications (eg, IL-17s, PDE-4, JAKs). Our recommendation is for the direction of these 2 parallel analyses to reflect patient-centeredness and complexity of these diseases.

Rheumatoid Arthritis

Patient Population

The moderate to severe RA patient population being evaluated should be consistent with established practice with the biologics being used predominantly after methotrexate (MTX) inadequate response. This population will derive a different value than with MTX-naïve or biologic experienced patients. Specifically, the RA assessment should focus on patients who are inadequate responders to non-biologic disease modifying anti-rheumatic drugs (nbDMARDs-IRs). As demonstrated in numerous clinical studies evaluating therapy effectiveness in patients with moderate to severe RA, patient history (eg, disease duration or baseline disease,2 prior treatment failure3,4) and proper patient selection have a profound impact on long-term treatment effectiveness and value.

Comparators

The therapeutic comparison most relevant to moderate to severe RA patients who are nbDMARDS-IR is between the multiple biologic classes (TNFi, IL-6) and JAKi treatments. Given current RA treatment guidelines, a single nbDMARD would not be a relevant comparator in a nbDMARD-IR patient population due to previous failure with continuation causing additional disease progression and joint destruction. An alternative regimen may be a combination of MTX, hydroxychloroquine, and sulfasalazine in patients who demonstrate the ability to tolerate this multi-dose per day regimen. However, triple therapy is associated with low adherence and its use in clinical practice is rare. 5,6 It is estimated that among patients with moderate to severe RA who advance to more intense therapy, about 6% advance to triple therapy with the remaining 94% receiving targeted agents, mostly biologics.6 The low use and adherence challenges of triple therapy raise questions about the clinical relevance of triple therapy as a comparator. The most relevant baseline comparator group is clearly the tumor necrosis factor inhibitor (TNFi) class based on 18+ years of availability and widespread adoption into standard of care for progressive moderate to severe RA that has not responded to MTX. Comparison of TNFis with the non-TNFi biologics will be consistent with treatment guidelines and provide a valuable assessment in the nbDMARD-IR patients at risk for progressive structural joint damage.7

Endpoints

Along with changes in the American College of Rheumatology (ACR) response criteria and health assessment questionnaire (HAQ), radiographic progression, disease activity, work productivity, and patient reported outcomes (PROs) (such as short form 36 [SF-36]) should be considered as endpoints to reflect the multidimensional benefits of any therapeutic intervention. Further, ICER models must be extended to a time horizon of at least 20 years to account for the long-term, progressive and crippling nature of moderate to severe arthritis. ICER should be very expansive in trying to capture the lifetime effects such as cost of loss of mobility, pain, emergency care and/or hospitalization, and effects on employment that accompany chronic disability.

Modeling Approach

A sequential treatment model with at least three sequences steps is recommended in order to closely align the modelled scenarios with the realities of patient-focused care. This is especially relevant given the many available treatments and the number of key variables that affect treatment decisions such as physician practices, patient preferences, coverage options, and past and present RA treatment guidelines. The reality is that patients often end up using many of the available treatments in their lifetime, even after failing to respond to nbDMARDs. It is as important to focus on the order in which the drugs should be used whether it be as monotherapy or in combination with a nbDMARD to determine the most cost-effective treatment sequence. Relevant and defensible assumptions must be made regarding natural progression of the disease, disease progression while on therapy, and maintenance or rebound in RA outcomes for patients who initially attain response but then discontinue therapy. It is also important that the utility-estimation approach used takes into account the multidimensional aspect of RA as a disease that can cause functional impairments, disability, and pain. As noted above in the endpoints section, the model should be long term (at least 20 years) and account for the multidimensional impact of progressive and crippling arthritis over time. Great effort should be made to adapt long-term patient survey data and other real-life data that account for disease impact into the model.

Psoriatic Arthritis

Patient Population

The PsA patient population is defined by 6 disease domain manifestations with peripheral arthritis considered a major debilitating domain. The recent Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) guidelines suggest early treatment is likely of benefit.8 As such, the ICER assessment should take into consideration the treatment of eligible patients, especially those with the domain of disease of peripheral arthritis.9-12

Comparators

In evaluating the domain of peripheral arthritis, initial treatment comparators should be consistent with product labels and include the TNF inhibitors (with and without MTX), IL12-23, IL17, and, and apremilast. MTX is not FDA labeled for the treatment of PsA, but it is included in guidelines for the treatment of some PsA domains. Best supportive care, if used as a treatment, should be clearly specified. The most relevant comparison would involve sequences of TNFis and newer biologic DMARDs.

Endpoints

It is important that the relevant peripheral arthritis endpoints are considered both in the evaluation of comparative effectiveness as well as the cost effectiveness analysis. Other domain endpoints should be considered, and should follow in importance after the primary joint evaluations. In addition to clinical trial endpoints such as ACR response criteria, the HAQ, and the psoriatic arthritis response criteria (PsARC), measures of radiographic progression and PROs such as SF-3613 should be considered to reflect the multidimensional benefits of any therapeutic intervention. Further, ICER models must be extended to a time horizon of at least 20 years to account for the long-term, progressive nature of psoriatic arthritis. ICER should be very expansive in trying to capture the lifetime effects such as cost of loss of mobility, pain, emergency medical care and/or hospitalization, and effects on employment that accompany chronic disability.

Modeling Approach

Similar to RA above, modelling sequences of treatments is recommended to closely align the modelled scenarios with the realities of patient-focused care. This lends validity to the common use of more than one or two treatments or combination of therapies in a patient's lifetime. It is important that the models are informed by relevant and defensible assumptions regarding disease progression while on therapy, natural progression of the disease, and rebound in health outcomes for patients who initially attain response but go on to discontinue therapy. It is also important that the utility-estimation approach used recognizes the relative importance of inhibiting joint damage in PsA over the long term (at least 20 years).

In summary, we make the following recommendations:

  1. Two separate, independent but concurrent reviews should be performed to assess targeted treatments for RA and PsA.
  2. Focus on patients who are inadequate responders to nbDMARDs as supported by current treatment practices.
  3. The most relevant comparisons would be between sequences of TNFis and newer biologic DMARDs to align with treatment guidelines.
  4. In addition to ACR and HAQ endpoints, radiographic progression, disease activity, work productivity, healthcare resource utilization, and PROs should be considered, to realistically reflect the value of treatments over the long term (at least 20 years).
  5. Utility estimation approaches should reflect the multidimensional benefits of the treatments.

References
  1. Coates L, FitzGerald O, Helliwell P, Paul C. Psoriasis, psoriatic arthritis, and rheumatoid arthritis: Is all inflammation the same? Semin Arthritis Rheum. Advance Access published on June 2, 2016 as doi: 10.1016/j.semarthrit.2016.05.012.
  2. Weinblatt ME, Bathon JM, Kremer JM, et al. Safety and efficacy of etanercept beyond 10 years of therapy in North American patients with early and longstanding rheumatoid arthritis. Arthritis Care Res (Hoboken). 2011;63(3):373-382.
  3. Combe B, Codreanu C, Fiocco U, et al. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis. 2006;65(10):1357-1362.
  4. Hansen KE, Hildebrand JP, Genovese MC, et al. The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J Rheumatol. 2004;31(6):1098-1102.
  5. Sauer BC, Teng CC, Tang D, et al. Persistence With Conventional Triple Therapy Versus a Tumor Necrosis Factor Inhibitor and Methotrexate in U.S. Veterans With Rheumatoid Arthritis. Arthritis Care Res (Hoboken). Advance Access pubilshed on June 6, 2016 as doi: 10.1002/acr.22944.
  6. Sparks JA, Krumme AA, Shrank WH, et al. Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014. Arthritis Rheumatol. 2016;68(7):1588-1595.
  7. Singh JA, Saag KG, Bridges SL, Jr., et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken). 2016;68(1):1-25.
  8. Ritchlin CT, Kavanaugh A, Gladman DD, et al. Treatment recommendations for psoriatic arthritis. Ann Rheum Dis. 2009;68(9):1387-1394.
  9. de Wit M, Campbell W, Coates LC, et al. Let's talk about inclusion: A Report on patient research partner involvement in the GRAPPA 2015 Annual Meeting. J Rheumatol. 2016;43(5):970-973.
  10. Orbai AM, Mease PJ, de Wit M, et al. Report of the GRAPPA-OMERACT Psoriatic Arthritis Working Group from the GRAPPA 2015 Annual Meeting. J Rheumatol. 2016;43(5):965-969.
  11. Gossec L, Smolen JS, Gaujoux-Viala C, et al. European League Against Rheumatism recommendations for the management of psoriatic arthritis with pharmacological therapies. Ann Rheum Dis. 2012;71(1):4-12.
  12. Sritheran D, Leung YY. Making the next steps in psoriatic arthritis management: current status and future directions. Ther Adv Musculoskelet Dis. 2015;7(5):173-186.
  13. Orbai AM, Ogdie A. Patient-reported outcomes in psoriatic arthritis. Rheum Dis Clin North Am. 2016;42(2):265-283.