Amgen’s Response to ICER’s Background and Draft Scoping Document: “Disease-Modifying Anti-Rheumatic Drugs for Rheumatoid Arthritis: Effectiveness and Value”

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune inflammatory condition that can lead to structural joint damage, disability, quality of life and functional impairments, as well as productivity losses both in the short and long terms.^1-8 The short and long term effects of RA are not limited to patients; they extend to the patients’ families, employers, and society as a whole. Over the last several decades, sustained investments in research and development have translated into numerous innovative treatments available to patients. Since their introduction, these biologic disease modifying anti-rheumatic drugs (bDMARDs) in particular have revolutionized the prognosis of RA, significantly altering the course of disease for those whose disease is inadequately controlled with conventional disease modifying anti-rheumatic drugs (cDMARDs).^9,10

Amgen has reviewed the ICER draft scoping document “Disease-Modifying Anti-Rheumatic Drugs for Rheumatoid Arthritis: Effectiveness and Value” and has the following recommendations:

1. The Population Must be Clearly Defined: Biologic DMARDs are generally used in patients with moderate to severe disease who have failed conventional and cheaper options. All of ICER’s analyses should therefore focus on adult patients with moderate to severe RA who have had inadequate response or intolerance to prior treatment with cDMARDs. The scoping document’s reference to ‘patients with no prior therapy’ should be clarified as ‘no prior therapy with targeted agents’.
2. The Research Question Must be Relevant and Patient-Centric: The review of targeted agents^[a] for RA must define and address a relevant research question which is the lifetime value of successful treatment with a DMARD compared with continuation of the less successful treatment using the patient’s previous DMARD regimen. Further, if the research question involves comparing failed treatment with the oldest DMARDs to any of the newer treatments, the analysis must quantify the multi-decade outcomes of patients who would have been inadequately treated for their lifetime, and experienced progressive disease.
3. The Current Treatment Paradigm Must be Accurately Modeled: As alluded to above in the definition of the research question, the demonstrated long-term therapeutic value of sequential bDMARDs needs to be accurately captured. The American College of Rheumatology (ACR) treatment guidelines recommend a treat-to-target approach with the goal of achieving low disease activity or remission using appropriate treatment sequences.¹¹ Most patients work with their physicians to rotate through regimens until they find one that achieves a state as close to remission as clinically possible. While the value delivered to patients of a sequential treatment strategy playing out over multiple decades may be challenging to quantify, ICER must make a best estimate of this value to credibly assess the full array of targeted treatments now available. Such an approach may very well involve allowing patients to switch treatments three or more times including using biologics with or without concomitant methotrexate.
4. Treatment Patterns Must be Informed by Real World Clinical Practice: In any such rotation or sequencing of regimens, real world practice and success rates must inform the probability of success and outcomes of any such switching. For example, given the progressive nature of choosing sequential RA treatments, it is not realistic to assume that patients with an inadequate response to one or two biologics will switch back to cDMARDs. It is also not realistic to assume that an “augmented conventional DMARD” such as triple therapy can be used to maintain any but a small number of highly motivated and uniquely responsive patients prior to switching to biologics. Evidence supporting the use of triple therapy is limited to studies like O’Dell et al,¹² which has been disputed and is inconsistent with the most meaningful and patient-centric treatment objective of disease remission, captured by the ACR treat-to-target goal. In O’Dell et al, the endpoint changed mid-study from clinically relevant DAS28 low disease activity to a substantially lower and statistically attainable endpoint of a small one-sided change in DAS28.¹² The related editorial raised a concern that “justification that this margin is acceptable to clinicians and patients is not provided (pg.384)”.¹³ The estimated use of triple therapy is only 6% in patients with moderate to severe RA¹⁴ and only 17% of patients starting triple therapy are adherent after a year.¹⁵ Any analysis comparing such regimens to bDMARDs which have achieved much more stringent endpoints would be methodologically suspect and largely clinically irrelevant, however economically attractive such schemes appear on paper.
5. Observational Evidence of Long Term Outcomes Must be Used to Model Beyond Trials: In order to achieve the above points, comparative clinical and economic evaluations of the treatment benefits of targeted treatments must be substantially based on real-world data using a transparent and patient-centric approach. The long-term value of RA treatment has resulted in remission, inhibition of radiographic progression, prevention of joint structural damage and disabilities, and improvement in quality of life, functioning, and productivity. ^{9-10; 16-17} Reliance only on short term clinical trials will significantly undervalue a patient’s lifetime gains in avoiding disability and deformity, as well as fail to capture the current value of multiple treatment options for patients.
6. Budget Impact Should Commence from Present Day and Reflect Market Realities: Separate from the cost-effectiveness analysis, the budget impact analysis should start from the existing state of treatment which is already being provided to patients, and model the additional costs or savings that accrue as treatment options change over time, starting in present day. In particular, the budget impact model should use existing-agent net prices and the incremental budgetary impact of introducing newer therapies as well as biosimilars. Again, this will not be easy, but it very well could be that the introduction of biosimilars begins to offset the development of newer treatments so that the net cost of managing RA begins to decrease early in the next decade.

In choosing to review targeted agents in RA, ICER has an obligation to address the most relevant questions with the appropriate data in an unbiased, objective, and patient-centric manner. RA is a particularly challenging disease area to evaluate, with many targeted treatment options, patient heterogeneity, and outcomes that play out over decades. The stakes for patients are so high given the crippling nature of the disease, and they risk lifelong consequences of pain and deformity if progression is not arrested. These effects must be captured in ICER’s evaluation to avoid undervaluing treatments for a disease where life changing treatment is now possible.

References

[a] Targeted agents include bDMARDs and targeted synthetic DMARDs (eg, tofacitinib).