Cost-Effectiveness of Tafamidis Therapy for Transthyretin Amyloid Cardiomyopathy

The ongoing pandemic offers a grim reminder that even wealthy countries like the U.S. have finite healthcare resources. Society must therefore make difficult choices about what to fund and what to forego. A systematic cost-effectiveness assessment does not dictate what we ultimately decide to invest in; it simply clarifies the opportunity costs involved.¹ We believe that orphan drugs should be subjected to rigorous economic evaluation to determine whether the benefits they produce justify their high cost. This is particularly important in the case of tafamidis because increasing rates of diagnosis of transthyretin cardiomyopathy – due to the availability of an accurate noninvasive diagnostic modality – have resulted in more patients being eligible for tafamidis than initially anticipated.

Early in the lifecycle of new therapies, there is substantial uncertainty about long-term effectiveness and safety. Despite this uncertainty, timely cost-effectiveness analyses performed shortly after drug approval can help inform payers and policy makers about the value of the drug and help determine drug pricing. Investigators must therefore use all available data and make realistic assumptions to project long-term outcomes regarding the underlying disease course, the durability of the effectiveness of the therapy, and the probability of unforeseen adverse safety signals. The ATTR-ACT trial provided 30 months of follow up with tafamidis; a preliminary report of the “long-term extension” study included an additional 6 months. In our analysis, we modeled long-term survival by fitting separate Weibull curves to the observed data in the control and intervention arms of the ATTR-ACT trial and explored alternative approaches to projecting cardiovascular outcomes (Figure 1 in the manuscript). Real-world heart failure patients tend to be sicker and have more co-morbidities than patients enrolled in clinical trials, and may have worse clinical outcomes than those observed in ATTR-ACT. If so, the cost-effectiveness of tafamidis may be worse than our report suggested. Of course, these analyses should be updated as new effectiveness, safety, and cost data emerge.

As ATTR-ACT did not report a summary statistic of health-related quality-of-life, we developed an algorithm to map the publicly available heart failure-specific health status from the Kansas City Cardiomyopathy Questionnaire results to EQ-5D-derived utility weights. Key methodological details were provided in the online Supplement, and the algorithm has since been validated in other datasets (John Spertus, personal communication). The quality-adjusted life year (QALY) is an imperfect but useful metric that combines survival and quality-of-life, and remains the standard for cost-effectiveness analyses.² Tafamidis does not meet conventional cost-effectiveness thresholds even when alternative approaches are used to quantify its effectiveness: the incremental cost-effectiveness ratio relative to usual care is $627,000 per equal value of life-year gained (assuming any extension of life to have a perfect quality-of-life of 1)³ and $709,000 per life-year gained (fully accounting for improved survival but ignoring any changes in quality-of-life). No matter how the evidence is examined, the health benefits of tafamidis do not appear to justify its high price.

Orphan drugs enjoy substantial pricing power because there are few or no therapeutic competitors. As a result, discounts off the list price, if any, tend to be small. In a recent study of 50 patients receiving tafamidis, the mean (SD) cost of a 30-day supply was $23,485 ($2); the resulting annual cost of $281,820 is greater than the $225,000 list price we assumed.⁴ In fact, U.S. prices for specialty pharmaceuticals typically experience substantial year-on-year price increases during the period of market exclusivity. Should the manufacturer choose to make the discounted price of tafamidis available, we would be happy to include this in future analyses. Since tafamidis’ market exclusivity period is longer than the expected survival of patients with transthyretin amyloid cardiomyopathy, any price declines with future entry of generic competitors would not alter this initial cost-effectiveness assessment. Finally, our analysis used a healthcare sector perspective, which includes all direct healthcare costs regardless of who pays for them. Copayment assistance provided by the manufacturer reduces the cost of tafamidis for the individual patient but is unlikely to meaningfully improve the population-level cost-effectiveness of tafamidis.

The U.S. experience with tafamidis highlights the promise and pitfalls of the Orphan Drug Act, and bolsters calls for its reform.⁵ Solutions that improve the affordability of and access to novel therapies must address competing stakeholder priorities and watch for unintended consequences. But reform is urgent – and the stakes have never been higher.