The latest, and perhaps most promising, treatment breakthrough in oncology has been chimeric antigen receptor T-cell (CAR-T) therapies. CAR-T therapies are treatments in which a patient’s T-cells are removed from the blood and re-engineered to produce cells that are able to target and bind to cancer cells through recognition of chimeric antigen receptor (CAR) target antigens. CAR-T cells are then multiplied in the laboratory and reintroduced into the patient’s body to target and kill cancer cells, and to prevent cancer cells from returning.
CAR-T therapies have significant potential to improve health outcomes but also to increase spending on cancer treatments. The global CAR-T therapy market is currently valued at $295.1 million and is projected to grow to over $3 billion in the next decade. As of March 2018, over 300 CAR-T therapies were being investigated globally, with 65 active therapies being investigated across multiple hematologic and oncologic indications in the US. However, given the complexity of producing targeted, patient-specific treatment, these innovative technologies come with a high price tag, creating an unprecedented and significant challenge for decision makers. Regulatory agencies and payers are faced with assessing the value of a curative therapy, while simultaneously struggling to appropriately fit CAR-T therapies within the existing classification systems.
Determining the value of CAR-T therapies is critical given the high cost of treatment, which has the potential to greatly hinder market access and commercialization of these promising therapies. Across the globe, regulatory agencies and payer organizations are exploring and pioneering innovative strategies to mitigate costs and provide access to patients.
Within the last year, axicabtagene ciloleucel (Yescarta®) and tisagenlecleucel (Kymriah®) were approved and introduced for the treatment of specific hematologic cancers in the US. On October 18, 2017, axicabtagene ciloleucel became the first CAR-T therapy to market, gaining Food and Drug Administration (FDA) approval for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) and primary mediastinal large B-cell lymphoma, after 2 or more lines of systemic therapy. Tisagenlecleucel was approved ~7 months later on May 7, 2018, for the treatment of pediatric and young adult patients (up to 25 years of age) with B-cell acute lymphoblastic leukemia (B-ALL) that is refractory or in second or later relapse, and in adult patients with relapsed or refractory DLBCL after 2 or more lines of systemic therapy. Both treatments were granted fast track, priority review, and breakthrough therapy designations by the FDA.
United States: Institute for Clinical and Economic Review
Although the US has no formal health technology assessment (HTA) body in place, CAR-T therapies have been evaluated by organizations such as the Institute for Clinical and Economic Review (ICER), an independent, non-profit organization that evaluates the cost-effectiveness of emerging therapies. ICER recently reviewed CAR-T cell therapies in an evidence report released on March 23, 2018. Their analyses reviewed outcomes for tisagenlecleucel in B-ALL and non-Hodgkin’s lymphoma (NHL) and axicabtagene ciloleucel in NHL compared with outcomes in patients who received other therapies with similar FDA indications. ICER determined that both therapies provide a net health benefit compared with standard chemoimmunotherapy regimens. ICER found both therapies to be cost-effective in the long term for the specified indications at the manufacturer-determined prices (axicabtagene ciloleucel, $373,000 and tisagenlecleucel, $475,000). The cost-effectiveness of each therapy for the population assessed fell below or within commonly cited thresholds of $50,000 to $150,000 per quality-adjusted life-year (QALY) over a lifetime horizon. (Table 1). ICER determined that after accounting for price mark-ups typical of hospital-administered therapies, tisagenlecleucel’s price would remain in alignment with value even if price premiums of 102% to 194% were applied. ICER also determined axicabtagene ciloleucel’s price could be increased by up to 11% and remain in alignment with the upper threshold of cost-effectiveness ($150,000 per QALY gained) but would need to be discounted by 28% to align with the lower boundary of cost-effectiveness ($100,000 per QALY gained).
Table 1. ICER's Evaluation of CAR-T Therapy Long-Term Cost-Effectiveness
Key: B-ALL – B-cell acute lymphoblastic leukemia; DLBCL – diffuse large B-cell lymphoma;
LY – life year; QALY – quality-adjusted life-year.
United States: Centers for Medicare & Medicaid Services
In an attempt to provide access to CAR-T therapies, the Centers for Medicare & Medicaid Services (CMS) recently proposed a reimbursement scheme for the launch of tisagenlecleucel in which they drafted an outcomes-based payment agreement with Novartis. This value-based contract was designed so that tisagenlecleucel treatment was reimbursed if there was a measurable response after the first month of treatment. However, earlier this year, CMS suspended the agreement amid various concerns and probing from Congress regarding details of the arrangement. One of the major contributing factors in suspending this contract revolved around agreeing to the 1-month time frame for assessing patient outcomes, given that tisagenlecleucel may have unknown long-term consequences including adverse effects. As with any outcomes-based scheme, endpoints and time frames are critical to determining reimbursement, and in this example, an agreement could not be reached. Coding and reimbursement limitations such as these add to the challenges of commercializing CAR-T therapies.
In the European Union, both axicabtagene ciloleucel and tisagenlecleucel gained marketing authorization through the European Medicines Agency (EMA) in June 2018 for DLBCL and B-ALL, respectively. The medications were also the first to gain positive reviews through the EMA’s PRIority MEdicines (PRIME) scheme. Similar to the FDA’s breakthrough therapy designation, the PRIME scheme allows manufacturers who target an unmet need to streamline development plans and gain accelerated evaluations for marketing authorization.
United Kingdom: NICE
The National Institute for Health and Care Excellence (NICE) tested and revamped their health technology appraisal method pertaining to regenerative medicines and cell therapies. NICE utilized hypothetical data backed by the University of York to assess tisagenlecleucel as the test product for a mock appraisal of this new methodology. Based on this mock assessment, tisagenlecleucel yielded an incremental gain of 7.46 QALYs for £356,100 as a bridge to stem-cell transplant and 10.07 QALYs for £528,600 as a product with curative intent. Through this assessment, NICE concluded that their current appraisal method is suitable for regenerative and cell and gene therapies such as CAR-T therapies. However, NICE determined that there is much uncertainty and limitations encompassing the mock assessment given the lack of actual clinical study data at the time of assessment in 2016.
Both axicabtagene ciloleucel and tisagenlecleucel were submitted to NICE in 2017. In August 2018, NICE came to a decision to not recommend axicabtagene ciloleucel due to the single-arm study design and resulting lack of comparative efficacy data to best supportive care. While the review committee did not list the incremental cost-effectiveness ratio, they noted that the base case was over the £50,000 per QALY gained threshold based on the manufacturer model and over £100,000 per QALY gained after additional adjustments made by the evidence review group (ERG). The cost of axicabtagene ciloleucel was therefore considered too high for it to be considered a cost-effective use of resources and the ERG emphasized the “limitations in the data for the comparator and the immature survival data for axicabtagene ciloleucel.”
In September 2018, NICE deemed tisagenlecleucel too expensive to recommend as treatment for adults with lymphoma in its draft guidance report. NICE is however open to further discussion on its cost-effectiveness prior to publishing the final guidance report.On the heels of the EMA’s marketing authorization and NICE’s decision on axicabtagene ciloleucel, NHS England announced that it struck an agreement with Novartis to allow full access to the CAR-T therapy in England. This was the first full access agreement for CAR-T therapies in Europe and was one of the fastest funding approvals in NHS England history. Tisagenlecleucel will have a list price of £282,000 per patient.
The Canadian Agency for Drugs and Technologies in Health (CADTH) has decided to review CAR-T therapies under their process for medical devices and clinical interventions. Typically, pharmacological therapies are reviewed through the Common Drug Review (CDR) process or pan-Canadian Oncology Drug Review (pCODR). Both the CDR and pCODR processes review and evaluate drugs based on clinical, economic, and patient evidence to provide reimbursement recommendations, with the latter catering to oncology medications. The decision to assess CAR-T therapies through the medical device review, rather than through CDR or pCODR, was predicated on feedback from federal, provincial, and territorial Ministries of Health, and the Canadian Association of Provincial Cancer Agencies. The approach is consistent with ongoing assessment process development by several other HTA agencies in Canada, including the Institut national d’excellence en santé et en services sociaux in Quebec. CADTH released two summary reports in August and September, outlining their protocol for a health technology and optimal use assessment of tisagenlecleucel for B-ALL and DLBCL. Tisagenlecleucel was approved as the first CAR-T therapy to receive regulatory approval in Canada.
Australia received a marketing application for tisagenlecleucel through its Medical Service Advisory Committee (MSAC) in early 2018, pending review at time of publication. MSAC is responsible for assessing new medical devices and procedures based on relative safety, clinical effectiveness, cost-effectiveness, and total cost. New products or procedures are then recommended for or against public funding through their Medicare Benefits System. Under its MSAC application, tisagenlecleucel is being classified as a hybrid heath technology, defined as:
“The use of diagnostic testing, including genetic testing, to refine patient selection and eligibility for high-cost procedures, devices and particularly medicines, and the continued development of pharmacogenomics (also called ‘personalised medicine’)”
This deviates from most medications and oncology therapies that undergo submission to the Pharmaceutical Benefits Advisory Committee (PBAC). The PBAC’s role is to assess and recommend new medications for the country’s Pharmaceutical Benefits Scheme.
Summary and Recommendations
CAR-T therapies have sparked a shift in the global HTA assessment landscape, presenting new challenges and opportunities for manufacturers to attain market access and reimbursement for these products. The challenge of determining the value of this type of high-cost, one-time therapy is unprecedented, and is only further compounded by the uncertainty around long-term outcomes of treatment and limitations in providing such data at the time of evaluation. With the introduction of CAR-T therapies, many HTA bodies, US payers, and value assessment organizations are starting to recognize that current methodology and frameworks may not be sufficient to evaluate emerging technologies. As seen with the HTA organizations noted above, many are adapting existing and new methodologies to classify CAR-T therapies within the standard categories of “medication” or “medical procedure.” This challenge has led some countries to reevaluate and refine their evaluation processes to accommodate CAR-T therapies. Currently, CAR-T therapies are being assessed as an oncology medication, a medical procedure, or some hybrid between medical and pharmacy.
Overall, pharmaceutical manufacturers must keep a close watch over the development of CAR-T assessments and access globally. As HTA agencies continue to refine and innovate new processes for clinical and economic evaluations, manufacturers may have to prepare for new submission requirements and regulations. As part of this, manufacturers should consider evidence generation and reimbursement strategies that are flexible yet focused on each market based on their specific route of CAR-T therapy evaluation. As more countries complete their evaluation process for CAR-T therapies, the picture will become clearer.
The article should be referenced as follows:
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