CAR T-Cell Therapy: The Sticker Price Is Just for Openers

The cost of a dose of medicine is generally thought to include just the pills or the fluid in the vial, but CMS has proposed a different way to handle payment for chimeric antigen receptor (CAR) T-cell therapy, one that the medical and manufacturing community thinks is unworkable. Although these agents' prices reach close to $500,000, they still reflect just the reengineered white blood cells, not all the ancillary elements of care, speakers testified at a recent hearing on CMS pricing policy.

The price of axicabtagene ciloleucel (axi-cel; Yescarta) does not include leukapheresis—the process of separating a patient’s white blood cells prior to reengineering them in a manufacturing plant—or the cost of dose preparation, a representative of the drug's manufacturer, Kite Pharma, explained at the May 16 hearing. In fact, hospitalization following infusion, provider fees along many steps of the treatment journey, and costs of aftercare—including treatment of cytokine release syndrome, which is potentially fatal but also a sign that the modified T cells are taking effect—are not a part of the well-publicized $395,380 wholesale acquisition cost (WAC, or manufacturer's price) of a single axi-cel treatment.

Although costs of those elements of care were not meant to be part of the WAC, CMS has written the temporary payment codes for CAR T-cell therapies as though they were, according to the manufacturer representatives, physicians, and patient advocates who testified. They have requested that the temporary Q code for axi-cel be rewritten to leave out leukapheresis and dose preparation.

Those elements of care are not performed in the manufacturing facility; therefore, the current wording suggests that providers and manufacturers must negotiate among themselves who gets paid what, when, and how, based on a single CMS payment. According to the testimony, the reality is that the $395,380 WAC is intended as payment for the manufacturer, and the physicians and medical facilities would bill CMS separately for their services (Figure).

Figure. Multiple Steps in Different Locations are Required for CAR T-cell Preparation

CAR T-cell candidates are the “sickest of the sick,” and the amount of time they spend in the hospital could add substantial amounts to the overall cost of care; therefore, those costs of care cannot be handled as a fixed cost, speakers said.Further, they said, the care of CAR T-cell—eligible patients involves numerous medical entities and providers. According to those who testified, CMS’ wording of Q codes for CAR T-cell therapy resembles an attempt at bundling care that would amount to a compliance nightmare for administrators. “Our system is not set up to separate those kinds of things,” said Aaron D. Chrisman, MHA, MBA, director of stem cell transplant and cellular therapy administration at University of Chicago Medicine in Illinois.

Speakers also testified that treatment centers are holding back on introducing CAR T-cell therapies because the payment issues have not been sorted out.

The hearing concerned proposed Healthcare Common Procedure Coding System payment codes for axi-cel and tisagenlecleucel (Kymriah), a Novartis product. Axi-cel and tisagenlecleucel are approved for the treatment of relapsed or refractory large B-cell lymphoma in adults. Tisagenlecleucel is also approved for B-cell precursor acute lymphoblastic leukemia (ALL) in patients up to 25 years of age.

Current wording for code Q2041 for axi-cel indicates that the infusion of “up to 200 million autologous anti-CD 19 CAR T cells” and leukapheresis and dose-preparation procedures will be treated as a single unit of care under CMS payment policy. Kite Pharma has requested that the payment code be simplified to “axicabtagene ciloleucel, up to 200 million autologous anti-CD 19 CAR T cells, per infusion.”

The manufacturing process for axi-cel takes 17 days. At the time of infusion, the patient is hospitalized up to 14 days for monitoring and treatment of inevitable side effects, Chrisman said. Novartis has a similar process for tisagenlecleucel, which carries a WAC of $475,000.

Opponents of the current Q code wording have contended that it appears to be based on a payment system devised for the simpler treatment regimen associated with sipuleucel-T (Provenge), an infusion-based immunotherapy for prostate cancer. In the case of sipuleucel-T, blood cells are removed from patients and processed in a laboratory, but each infusion can be accomplished in a single office patients and clinicians confidence in these panels’ analytical and clinical validity.”

The first breakthrough-designated NGS-based diagnostic test, F1CDx (FoundationOne CDx), was approved in November 2017. The powerful diagnostic tool can detect mutations in 324 genes and 2 genomic signatures in any solid tumor type. In March, CMS followed up with a national coverage determination in favor of NGS panel testing, expanding coverage to FDA-approved tests for patients with relapsed, refractory, or stage III cancers in addition to stage IV cancers.

Large-panel NGS tests will make it “easier and less expensive to screen patients for tumor mutations with a single test and then efficiently match them with available clinical trials,” Gottlieb said. He predicted that the information gained through this process will illuminate pathways to more effective therapies and stimulate the development of new agents. “This will increase the productivity of drug development, as drugs can then be targeted at common biomarkers across numerous tumor types.”

Gottlieb said that the FDA is striving to make NGS guidelines and current and future regulations “as nimble and sophisticated as the science driving these technologies so that clinicians and patients have access to them as soon as possible, while still providing patients with the reasonable assurance of safety and effectiveness they expect.”

The first set of guidelines addresses the design, development, and analytical validation of NGS-based panels, which can be used when diagnosing individuals with suspected genetic diseases. “For oncology, germline cancer predisposition contributes to about 5% to 10% of observed cancers. For cancer predisposition syndromes, such as Lynch syndrome, interventions like colonoscopies may be able to improve expected survival by sharply decreasing the rates of colorectal cancer,” Gottlieb noted.

These recommendations also explain what the FDA would look for in a premarket submission to assess a prospective test’s analytical and clinical validity, as well as its accuracy in detecting the presence or absence of a particular genomic change, leading to what Gottlieb said would be consensus standards for future NGS-based tests. The second set of guidelines recognizes the availability of public human genetic variant databases, which could help to confirm the clinical utility of in vitro diagnostic (IVD) tests, particularly during premarket review. These FDA-recognized databases could serve as sources of existing evidence for the claims, such as of the clinical significance of a germline or somatic mutation, that developers of IVD tests make in the review process.

An additional piece of draft guidance explains a process that oncology trial sponsors can use to establish the risk level associated with an investigational IVD to be used in a trial of an investigational cancer drug or biological product. ²

According to the guidelines, investigational IVDs are categorized as a significant risk, nonsignificant risk, or exempt from review. If a device is determined to be a significant risk, meaning that it could pose a serious risk to the health or safety of a patient, an investigational device exemption may be needed. The level of risk may disqualify a study for streamlined submission.

“This guidance reduces burdens on sponsors and on FDA staff by outlining circumstances under which sponsors may be able to include information about an investigational IVD into the investigational new drug application submission to the FDA center responsible for the therapeutic product,” Gottlieb said.

With these new policies, the FDA hopes to provide test developers with a more efficient path to market by means of efficient and accurate testing. They will encourage the innovation and adaptation of tools that can increase the productivity research and patient care.

References

1. FDA finalizes guidances to accelerate the development of reliable, beneficial next generation sequencing-based tests [news release]. Silver Spring, MD: FDA; April 12, 2018. 2018. www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm604462.htm. Accessed April 12, 2018.
2. Investigational in vitro diagnostics in oncology trials: streamlined submission process for study risk determination guidance for industry. FDA website. www.fda.gov/downloads/Drugs/GuidanceCompliance- RegulatoryInformation/Guidances/UCM604441.pdf. Published 2018. Accessed May 17, 2018.