Cell and gene therapies (CGTs) are a field of medicine that replace, manipulate, or engineer cells and/or genetic material to treat disease. Unlike traditional treatment options that may only target disease symptoms or slow progression of a disease, CGTs harness a patient’s own immune system to correct underlying disease-causing defects.
An Evolving and Growing Therapeutic Landscape
With their curative potential for patients with limited options, the global market for CGTs is rapidly growing at an annual rate of 21%, with a projected market size—by some estimates—of up to $50 billion USD by 2025. It is estimated that over 40 companies are currently developing redirected T-cells or NK cells for therapeutic use, and there are more than 800 CGT clinical trials underway. With this vast potential market footprint, it is key to thoroughly understand the clinical and financial impact of these therapies on the global healthcare system and evaluate them accordingly.
CGTs as a therapy class are not new; cancer vaccines, such as Provenge (sipuleucel-T) for prostate cancer, have been in existence for nearly a decade. However, the recent advent of treatment options, such as the CAR-T cell therapies, have sparked new excitement from patients and physicians—as well as trepidation from payers over financing of such therapies. In this article, we will review the unique aspects of evidence generation for, and clinical/economic evaluation of, CGTs in contrast to the traditional pharmaceutical market, examine the challenges and opportunities from a market access perspective, and provide strategic recommendations for achieving reimbursement in key global markets using recent case examples as a guidepost.
Challenges and strategies for commercialization of CGTs have also been covered in detail by Xcenda and our AmerisourceBergen partners, which can be found in this white paper.
What Are the Key Challenges in Reimbursement Evaluation of CGTs?
Given the robust pipeline and potential significant cost of CGTs, it is essential to recognize and unpack the current challenges stakeholders face in determining value of these innovative products. Perhaps most importantly, manufacturers must understand how payers are reacting to these new technologies. Thus, we have identified several of the key challenges for CGT evaluation, which are presented below, along with supporting data collected by Xcenda in a recent study with our proprietary research panel of US managed care professionals, the Managed Care Network. The respondent sample in the study included 46 payer decision makers representing 256 million covered lives.
Challenge #1: What is the appropriate comparator?
For many CGTs, the development of these new therapies brings the first glimmer of hope for a cure for several life-threatening or severely debilitating diseases. However, this can present difficulties in determining the correct standard-of-care comparator in a clinical or cost evaluation. For example, Spark Therapeutics’ drug Luxturna is indicated for the treatment of a specific type of retinal dystrophy which previously had no effective treatment. In such a situation, what is the appropriate comparator? How do you define “best supportive care” for a condition that leads to irreversible blindness? Such questions are difficult to tackle when developing a clinical trial program for a CGT and often involve enlisting the help of clinical key opinion leaders (KOLs) and other experts.
In the survey conducted by Xcenda, 47% of US payer respondents stated that they were not prepared to address the complexities of CGTs. These complexities may include issues such as determining the correct comparator to form the basis of clinical and economic evaluation.
Challenge #2: Clinical data uncertainty
CGTs may provide hope for a cure for cancers or rare genetic diseases, yet their regulatory approval currently may be based on limited clinical trials with small patient populations that do not provide robust data relating to magnitude and duration of benefits. Put another way, it remains to be seen if CGTs are truly a “cure” or more of a “long-term remission,” and also whether other complications of treatment may develop over time or in patient populations not included in the original trials. This clinical data uncertainty not only exposes stakeholders to clinical risk regarding efficacy and safety but also further heightens the financial risk of many stakeholders.
Payers share these concerns, with 57% of those surveyed noting that limited pivotal trial data at the time of therapy availability was a top-3 factor impacting potential coverage, and 74% stated the same regarding the lack of long-term outcomes data.
Challenge #3: How to evaluate costs for a “cure”
As CGTs enter the marketplace, many stakeholders may naturally default to their traditional models for pharmaceutical product evaluation. However, multi-step production and unique administration profiles of CGTs, along with the lack of robust clinical data, can complicate the evaluation of CGTs by HTA authorities, payers, and clinicians alike. And, given the high price tag of many of these therapies (Kymriah [tisagenlecleucel] for treatment of relapsed/refractory B-cell acute lymphoblastic leukemia [R/R B-cell ALL] was the first CAR-T therapy to enter the US market in August 2017 with a cost of $475,000), stakeholders are understandably concerned by the prospect of evaluating and paying for these therapies. Furthermore, CGTs can require multiple types of providers and sites of care for collection, processing, administration of therapy, and patient follow-up, each with their own reimbursement considerations.
The Xcenda survey found agreement from payers in the complexity of the reimbursement situation, with a majority of the payer respondents (63%) stating that their organization would need a separate process for evaluating coverage of CGTs.
Challenge #4: Are stakeholders paying for a product or a process?
CGTs disrupt the traditional, linear commercialization process, as their use of living cells and genetic material make the patient part of the supply chain rather than simply the end user of the product. In many ways, CGTs could be considered a therapeutic “process” rather than a “product.” Thus, existing paradigms for coding, coverage, and reimbursement do not always adequately describe all of the processes involved in creating and administering a CGT.
Perhaps unsurprisingly, most payer representatives surveyed (57%) reported that their organizations had not evaluated a special financing mechanism to pay for CGTs; however, 28% indicated they were in the process of doing so. For these latter organizations, several commented that they were looking at annuity-based models, outcomes-based contracts, and shared-risk pools with other payer organizations.
Learning From the Present: Case Examples From Recent Events
Government Policies Case: Yescarta, Regenerative Medicines Policies, and Medicaid Coding
Innovations in therapeutic options inevitably lead to the need to evolve how government policies handle approval and coverage of these treatments. Two clear examples of this occurred in the approval of Yescarta in October 2017. First, it is notable that the United States’ FDA approved Yescarta a month ahead of schedule. In considering evaluation of the treatment, the FDA assigned multiple priority review designations, including “breakthrough therapy” and “orphan drug” statuses, which helped to accelerate the review process. Consequentially, the need to apply so many special designations to Yescarta also spotlighted the need for regenerative medicines—such as CAR-T cell therapies—to have their own policy detailing how these designations should be applied and how exactly these high-need therapies should be evaluated in order to support their continued development and approval.
But, just as policies can be used to improve access to therapies, the case of Yescarta demonstrates how antiquated policies can hinder product access. Despite the ahead-of-schedule FDA approval of Yescarta, patient uptake has been rather slow. Many physicians have been pointing the finger at Medicare, stating that its lack of a suitable payment model or proper coding procedures has led to many patients dying before they can receive the therapy. Making matters worse, Medicare’s coding is only updated on an annual basis, meaning that 2018 may be more than halfway over before more widespread access is granted to Yescarta. Such a system failure is indicative of the fact that innovative therapies can sometimes break the mold in terms of policies, and negative effects may be seen if flexible policies are not in place or potential hurdles are not addressed.
Evaluation Case: Strimvelis NICE HST Assessment and Consideration of Patient and Provider Voices
Strimvelis is a CGT developed to treat an ultra-rare condition known as adenosine deaminase deficiency, which can lead to metabolic defects and severe combined immunodeficiency. For many patients, the disease can be fatal in early childhood. Given the rarity of the disease and the pediatric population affected, the drug was able to be assessed by NICE through the Highly Specialised Technologies (HST) evaluation committee. HST evaluation allowed for additional flexibilities such as higher cost-effectiveness thresholds and lower discounting rates.
But perhaps just as important in the evaluation process was the inclusion of clinical experts and patient experts. The evaluation committee was left with many questions from the clinical trials for Strimvelis, as a small patient population lends itself to small clinical trials and lots of potential uncertainty in extrapolating the results. But, in this evaluation process, KOL providers were able to have significant and meaningful input into the clinical and economic evaluation process. Furthermore, patient experts (caregivers, advocates) were able to help the evaluation committee better understand the patient and societal burden of illness for such a rare disease. Thus, all of these factors were critical for the ultimately positive evaluation of Strimvelis in England.
Pricing Case: Luxturna Comes to Market With a Price Below Expectations From Payers
Luxturna, as previously mentioned, is the first-ever therapy that effectively treats a rare type of retinal dystrophy. The preservation of sight is nearly priceless from the patient perspective, thus leading industry prognosticators to expect a price tag of $1 million USD or higher for the drug once it was approved.
To payers’ and the public’s delight, Luxturna came to market below expectations with a price tag of $425,000 per eye, or $850,000 total. Payers expressed their surprise over the price, with Steve Miller, MD, Chief Medical Officer of Express Scripts (a pharmacy benefits manager in the US), even calling the drug cost “wildly expensive but…what I’d call [responsible].” Spark Therapeutics is also exploring the idea of having payers pay for the drug in installments rather than a lump sum, which may help spread out the cost over time. This situation is one clear example of when payers are willing to pay for true innovation when manufacturers are willing to work together on pricing and innovative payment arrangements.
Reimbursement Case Example: Kymriah and Outcomes-based Payment Agreements With CMS
Kymriah provides us with an example of how the high cost of CGTs may necessitate a closer look at innovative payment agreements and similar mechanisms to improve patient access and affordability. Since the treatment offers a potential cure for an aggressive form of cancer and is individually made for each patient, many stakeholders may feel that the price is justifiable. However, all payers have to work within limited financial resources and have to consider the substantial budget impact of a therapy like Kymriah. Thus, in an effort to confront the realities of financing such a therapy, the manufacturer of Kymriah, Novartis, entered into an innovative outcomes-based payment agreement with the Centers for Medicare & Medicaid Services (CMS) to address the high price of treatment. Under the deal, CMS will only pay Novartis if there is a response by the end of the first month of treatment. It is important to note that some legislators are questioning the arrangement; in mid-September, 9 Democratic members of the US House of Representatives wrote a letter to CMS Administrator Seema Verma asking for additional information on the deal. Their questions included how the 1-month time frame was selected and the number of Medicare and Medicaid patients who might receive the therapy.
However, this hasn’t stopped the deal from paving the way for consideration of more alternative payment models for Kymriah and other high-cost, high-value therapies. For example, Dr. Miller of Express Scripts recently said that value-based contracting would be an effective way to ensure that payers and patients aren’t “on the hook” if such expensive therapies are less than effective.
Recommendations for Manufacturers
Pharmaceutical manufacturers face significant challenges in commercializing CGTs. First, we have seen through examples that a proper understanding of the local market’s government policies and reimbursement structure is an important component of patient access, as demonstrated in the Yescarta example. Thus, it may be advisable to develop a reimbursement and coding strategy at least 2 to 3 years prior to launch to better anticipate challenges and make plans to mitigate them. In order to optimize the likelihood of achieving reimbursement, it is essential to demonstrate that the incremental benefit afforded by a CGT aligns with the added cost incurred by patients and payers.
For many of these rare and orphan disease states, payer education is key. In the case of Strimvelis, helping the HST evaluation committee understand the burden of disease and having clinical KOL input into the clinical and economic evaluation process was an important component of the eventual positive decision by NICE. It should also be noted that an appropriate and “reasonable” pricing strategy, as demonstrated in the Luxturna example, can bring payers to the table in a position to collaborate rather than look for a reason to say no to reimbursement. Finally, as seen in the Kymriah example, innovative reimbursement arrangement and outcomes-based agreements may be more important than ever when considering CGTs, and manufacturers should be prepared to discuss these types of agreements as part of a market access strategy.
The new innovations coming to market in the CGT class present exciting opportunities for patients and manufacturers alike. Despite the high price tag—with a well-thought-out approach to clinical development, pricing, evaluation, and reimbursement—market access may be achievable across the globe for these therapies.