Access and Reimbursement for Adoptive T-Cell Transfer Drugs

Groundbreaking treatments involving adoptive cell transfer, such as CAR -T drugs, call for innovative commercialization strategies

The approval of the first genetically modified cell therapy in the US-Kymriah™ by Novartis-made headlines in late August of this year, receiving marketing approval in North America for the treatment of B-cell acute lymphoblastic leukemia (ALL) in children and young adults with limited treatment options. Less than two months later, Kite Pharma received approval for Yescarta™ for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Both breakthroughs are chimeric antigen receptor T-cell (CAR-T) therapies that involve adoptive cell transfer (ACT). Over the next decade, we can expect other ACT therapies to change the field of oncology dramatically, particularly in some of the more difficult-to-treat cancers. 

In parallel, biopharmaceutical manufacturers of ACT therapies will need to alter their traditional commercial models just as dramatically. First, ACT therapies are not drugs in any traditional sense; rather, they are medical procedures that require individualized, ex vivo processing and highly specialized healthcare professionals and facilities. If these first two market entrants are trendsetters, future treatments will be expensive and on a scale well beyond all other oncology treatments to date. ACT therapies will require a very different approach to pricing and market access than anything that has come before. 

A wave of innovation

The CAR-T cell therapies Kymriah and Yescarta are produced by deriving cells from the patient, reengineering them in a laboratory to recognize and kill cancer cells, and then multiplying them and infusing them back into the patient (see chart).

Investment in CAR-T drugs is strong, with more than 270 trials underway in this space. Of the approximately 40 companies developing CAR-T cell therapies, the leading players currently include Novartis, Kite Pharma (now part of Gilead Sciences), Juno Therapeutics (in association with Celgene), Bluebird Bio (also in association with Celgene), and Cellectis (in collaboration with Pfizer). According to Coherent Market Insights, the global CAR-T cell therapy market is estimated at $72 million today, with projected growth at a staggering CAGR of 46.1% between 2019 and 2028.  

Challenges for payers

Payers will be facing a number of difficulties in evaluating and covering ACT therapies-challenges that biopharma companies must actively address in their commercialization strategies. 

Limitations in assessing clinical benefit 

At the time of launch, the evidence base for ACT therapies will likely be immature and may not support conclusions on their potential long-term benefits. Indeed, many of these treatments may be approved on the basis of Phase II trials in relatively small patient samples, without long-term, real-world follow-up. It is safe to assume that payers will be unwilling to make the leap of faith on long-term benefit without some kind of

proof or guarantee. However, they are unlikely to expect data from ~10-year-long trials. Payers also want to be able to compare the efficacy of a new product with the standard of care, although, in most cases, the data on newly launched ACT therapies will likely not be robust enough for such comparisons. 

As with other immuno-oncology treatments, ACT therapies are likely to work well for a portion of patients, providing remission for a number of years. In Kymriah’s case, 83% of patients achieved complete remission or incomplete response with blood count recovery within three months of infusion. Payers (along with the entire medical community) will be eager for more insights into which subgroups of patient will benefit from the treatment. 

Classification as a medical procedure 

As mentioned, ACT therapy is typically developed though an individualized process for each patient, and treatment is provided in the hospital, similar to stem-cell transplants. 

This means that in the US, the manufacturer’s customer is the hospital system/provider, and only a small number (perhaps 10 to 15) of centers of excellence are likely to be capable of offering the treatment. Payers must negotiate contracts with these facilities and be prepared to address policy issues around access and funding, in particular for patients who do not live near one of these centers. 

In the major five European markets (France, Germany, Italy, Spain, and the UK), treatment will likely be covered by the hospital funding mechanisms, such as are in place for organ transplants. Funding is typically based on a single, fixed-price per patient to cover costs from the date of admission to a certain number of months post-transplant. There may be no existing mechanism for funding any additional, and costly, services related to ACT treatment.  

Cost

Currently, a one-time treatment with Kymriah is priced at $475,000-a price that has pierced prior-cost barriers. (In contrast, a one-year course of treatment with a programmed death cell protein 1 [PD-1] targeted antibody is priced around $180,000). Initially, even at this price, Kymriah will present payers with limited budget impact, as it is indicated only for ALL that is refractory or in second or later relapse in children and young adults (up to 25 years of age). However, the impact on payers will change if/when Kymriah is approved for other more prevalent indications and certainly when other ACT therapies enter the market. Yescarta is priced lower than Kymriah, at $373,000, but it will serve a considerably larger patient population

in which the unmet need may not be as high. 

While the downstream benefits of ACT therapy are likely to last for many years, the very high cost will be concentrated at the time of treatment. In the US, where patients tend to change medical insurers on average every two to three years, how can the cost be borne, and the benefits enjoyed, equitably? There may be a disincentive to cover such therapy if another entity yields the benefits. 

So, how will ACT therapies fit into the existing funding structure? How will payers respond? Their approaches will be different by country and region, but we can expect that they will take a conservative approach when data packages are limited. Particularly in the Euopean Union (EU), payers can prolong their drug listing/formulary decision-making process as approvals work their way through national, regional, and then hospital-level bodies. It is not unusual for this process to take as long as two years. As an example, access decisions on the multiple myeloma drug Farydak® took around two years in both France and Italy. Ultimately, they can restrict or deny access based on the price.

Offsetting uncertainty with innovative contracting options 

Experience suggests that some payers will not cover such novel and expensive therapies based on immature evidence without a way to either share the risk or curb or delay the budget impact.  They will look for manufacturers to enter into innovative agreements such as: 

• Installment payment plans. To our knowledge, this has not yet been tried, but such an arrangement would allow payers to stagger their payments, perhaps upon completion of specific steps in the treatment process. One payment might be made, for example, when the therapy was prescribed, another when the patient was infused, and another at a certain point posttreatment when outcomes could be assessed. The final payment could even be spread out over a number of years. 

• Outcomes-based agreements. Such pay-for-performance or risk-sharing agreements are increasingly common in the EU where the single-payer system results in stable patient populations for payers. Now, the model is coming to the US. In a novel deal, Novartis has entered into an outcomes-based agreement with the US Centers for Medicare and Medicaid Services (CMS) through which the agency need only pay for Kymriah in instances in which the patient responds after a month. CMS, which has praised the arrangement, plans to publish guidance for other companies interested in exploring innovative contracts. 

• Managed-entry agreements/coverage with evidence. This is the coverage equivalent to approvals with risk evaluation and mitigation strategies (REMS). Under these agreements, the product is covered upon market entry, albeit conditional on a postmarketing assessment to revisit pricing. Usually, a registry is created to generate evidence that is later evaluated by the payer. 

• New debt instruments. In the future, it is possible that access will be funded by such means as annuity payments, bonds, credit, mortgages, and risk pooling. 

Manufacturers, start your commercial engines 

We know that, in general, payers have little appetite to accept uncertainty. A study performed by the UK’s National Institute for Health and Care Excellence (NICE) revealed that even when they had a five-year dataset (which is greater than most therapies have at launch), payers were concerned about low subject numbers and the use of a single-arm study. To secure access in this environment, manufacturers of ACT therapies will need to:

• Develop products with the payer in mind. In terms of evidence generation, payers should be considered just as important as regulators. Payer-relevant endpoints (e.g., overall survival) for a new cell therapy should be included in early-stage trials; if planned properly, these data can be mature by launch, providing outcomes data over a long period. 

• Continue following patients after trial close. Trial participants should be followed after the close of the pivotal trial via long-term follow-up to gather data on overall survival. (Novartis’s initial Kymriah patient is still alive five years post-treatment). 

• Engage treatment centers early. In the EU, new funding pathways and contracts will likely be required, and manufacturers can help ensure that they are in place and workable. And in the US, contracts must be in place between treatment centers and payers before treatment can begin. Drug manufacturers can engage with their customers to ensure that they have all that they need to support the contracts.

• Develop and share data on the burden of disease. To appreciate fully the economic benefit of ACT therapy, payers should be given data on the costs that are averted. These could include an organ transplant, other associated treatments and costs for families in missed work and stress, etc. 

• Establish launch pricing based on value. Manufacturers should take into account epidemiology data, the degree of therapeutic unmet need in the market, and the product’s clinical value in comparison to that of competitors.  

• Help payers understand which patients are the right candidates for treatment. Payers may benefit from education on the type of patients who are best suited for treatment (e.g., biomarkers) and from epidemiology data on the prevalence of specific diseases. This will help payers in their budgeting and may allay their concerns, as the number of eligible treatment candidates may be smaller than what they fear. 

• Carve out a unique target. Competition will increase in this space, and ACT therapy manufacturers should choose their trial populations with care, limiting their focus to those patients for whom the greatest payer-perceived benefit can be demonstrated. 

Think ahead

ACT therapies are so new that most payers have not yet updated their systems, policies, or budgets to accommodate them. Thus, it is impossible to know exactly how to meet their requirements, but manufacturers with ACT therapies in the pipeline should be actively exploring this. It seems clear that early manufacturers of ACT therapies need to consider unique strategies toward evidence generation, working to understand how ACT therapies will require different payer policies, and planning new types of agreements with payers that will afford access to patients. 

Jill Condello is Vice President, Strategic Services; Andrea Favaro is Senior Consultant, Pricing and Market Access; Martin Lachs is VP, Project Management, Oncology; and Rebecca Walker is Principal, Pricing and Market Access; all with ICON plc