The introduction of chimeric antigen receptor T cell (CAR-T) therapy has been transformative in hematological malignancies. In the US, there are now 6 FDA-approved products across 5 malignancies; acute lymphoblastic leukemia, diffuse large B cell lymphoma (DLBCL), follicular lymphoma, mantle cell lymphoma, and multiple myeloma. These are highly potent treatments that are effective in patients that are highly pretreated and chemo-refractory and are likely curative in some cases. However, despite the fact that the first commercial CAR-T product (axicabtagene ciloleucel) received an FDA approval in October 2017, access to CAR-T remains challenging for myriad reasons including, but not limited to, expertise, infrastructure for apheresis and administration, manufacturing capacity, and cost. In particular, the cheapest CAR-T product is $373,000 USD. Even in a world where we have become accustomed to targeted therapies costing well over $10,000/month, these prices are extraordinarily high.

How can these astronomical sums be justified? From an innovation standpoint, the potential for outsized profit incentivizes large-scale investments in biotechnology. Since the market for these cancer treatments is relatively small, product pricing in biotechnology needs to be commensurately high to ensure an adequate return on investment and compete for venture funding. Other justifications include the high clinical unmet need, and striking efficacy as a single CAR-T infusion can result in prolonged remission or even cure, as is the case for about 30%–35% of patients with DLBCL receiving CAR-T therapy.

However, once an effective product is approved, it is difficult to ignore that product profit margins are driving a substantial proportion of the health care costs. In addition, the overall system cost of CAR-T therapy is significantly higher than the list price for the product itself given the need for apheresis, bridging therapy, lymphodepletion, hospitalization, management of acute toxicities, and longitudinal follow up; one study found a mean total healthcare expenditure ranging from $380,000 to $560,000 USD in the 3 months following CAR-T treatment for DLBCL.1

These issues naturally lend themselves to the question of how to properly assess the value of CAR-T and other cellular therapies. In most industries, market forces make this determination. However, healthcare is not a pure market, and one consequence is distorted pricing. Therefore, external value assessment is critical. For cellular therapies, it is specifically challenging for multiple reasons including, but not limited to, patient complexity; the existence of therapeutic alternatives; the potential for patients to receive CAR-T after multiple lines of prior therapy; significant variability in the cost of care delivery across the country; and incomplete knowledge of long-term toxicities of treatment. A case in point is that the fact that two separate cost-effective analyses for second-line CAR-T therapy in DLBCL came to differing conclusions regarding cost effectiveness at accepted willingness-to-pay (WTP) per quality-adjusted life year (QALY) thresholds despite good-faith attempts to account for pertinent variables and outcomes in their respective statistical models.2^,3 The reality is that these models do not fully encompass all of the nuances of real-world practice given that models generally draw from trial populations with healthier patients than their real-world counterparts and have relatively low levels of attrition after each line of therapy compared with what is observed in real patients. Furthermore, other highly relevant outcomes such as patient-reported outcomes, quality of life, and financial toxicity, which also should figure into the value calculus, are unaddressed by these analyses. The sad truth is that it is much cheaper for patients to succumb to their disease than to receive cellular therapies, with a resulting perverse incentive for payers to delay or deny needed therapy, furthering exacerbating the inequity that already exists between the wealthy and poor.

At present, a true, impartial value determination for CAR-T therapy is elusive and is further obfuscated by opaque cost structures for ancillary costs of care and complicated payer agreements. Therefore, as valuable as these cost-effectiveness analyses are, they are only rough estimates. Two of us (M.D.M. and M.D.J.) are hematologists and are charged with the responsibility to treat our patients to the best of our ability, a task that increasingly entails use of radically expensive therapies. However, we remain keenly aware of the fact that the unsustainable costs of treatment continue to perpetuate inequity both nationally and on a global level as well as contribute to the growing percentage of national gross domestic product (GDP) spent on healthcare costs.

What can be done? Ultimately, any reform to CAR-T pricing will be challenging without general drug pricing reform given that product acquisition costs are benchmarked to existing costs of therapy. As one example, the market would function better if large payers, such as Medicare, could negotiate prices; the recent passage of the Inflation Reduction Act is a small but important step toward this goal.4 Societally, is there a way to ensure ongoing investment and innovation in oncology with lower costs? Or to re-balance profits toward truly innovative therapies (such as cell therapies) and lower the costs of older therapies, perhaps by lowering barriers to generic competition? Greater transparency in pricing and clarity over the true costs would allow more robust analyses predicated on firm data. Better measurements of value that draw upon real-world evidence, such as registry or hospital administrative data, can help to reduce the uncertainty in cost-effectiveness models, where the results are highly dependent on assumptions regarding patient attrition and long-term survival. Innovative payment models such as outcomes-based payment schemes may also help, such as are currently being used in Europe, as would more streamlined access and standardized payer agreements. There is also opportunity to reduce ancillary costs; for instance, CAR-T therapy is increasingly being shifted to the outpatient setting with a significant cost savings.

There is some urgency to explore these issues further as CAR-T therapy is still a relatively recent addition to our therapeutic armamentarium; it is almost certainly a matter of time before CAR-T and/or other cellular therapies become widely used in solid tumors. Meanwhile, the development of other types of cellular and genetic therapies continues apace; in fact, three genetic therapies are available in the US for monogenic disorders (beta-thalassemia, spinal muscular atrophy, and cerebral adrenoleukodystrophy), all of which cost more than $2 million USD, a price point nearly an order of magnitude above the already high costs of CAR-T therapy. While much enthusiasm rightly surrounds these novel therapeutics, ongoing health services research is needed to better establish value and to ensure that these treatments can reach all those who may benefit.