Addressing Barriers to the Use of Gene Therapies and CAR-T Therapies

Despite exciting advancements in the development of gene therapies and chimeric antigen receptor T-cell (CAR-T) therapies for the treatment of hematologic disorders, there are a range of factors that may limit access to these agents. In 2 studies presented at the 2021 American Society of Hematology (ASH) Annual Meeting, Ajeet Gajra, MD, MBBS, FACP, chief medical officer at Cardinal Health Specialty Solutions and clinical professor of medicine at SUNY Upstate Medical University in Syracuse, New York, and colleagues aimed to elucidate these factors through surveys of community oncologists and hematologists in the United States.^1,2

Gene Therapies

In a study focused on potential barriers pertaining to the use of gene therapies in clinical development for the treatment of disorders including hemophilia, hemoglobinopathies, and congenital immunodeficiency syndromes, Dr Gajra and colleagues received responses from 369 physicians with an average of 19 years in practice.¹

Regarding awareness of recent data regarding gene therapies in adult hematology and oncology, many physicians indicated that they were “not very aware” (35%) or “not at all aware” (15%).

Regarding the use of gene therapies in adult hematology and oncology in the next 2 years, 53% “reported that they expect gene therapies to mostly be administered and managed by academic centers to which they will refer their patients; 27% reported that indications will be limited and unlikely to affect their practice.”¹

Respondents identified cost as the main barrier to the adoption of gene therapies into their own practices, with prohibitive costs to patients (46%) and practices and hospitals (37%) anticipated along with cost limitations by payers (49%). Additional barriers cited included long-term complications (13%) and limited data showing real-world efficacy (18%).

When asked about prescribing a gene therapy for adult hematology and oncology indications if the cost were reimbursed, many physicians indicated a moderate (39%) or high (43%) comfort level.

CAR-T Therapies

The second study focused on CAR-T therapy utilization and associated barriers. Dr Gajra and colleagues surveyed 371 community oncologists and hematologists, ofwhom 72% have referred patients for CAR-T therapy. Respondents identified chronic lymphocytic leukemia, acute myeloid leukemia, and B-cell non-Hodgkin lymphoma as the top 3 hematologic malignancies treated in their practices.²

Physicians cited a slow payer approval process (34%) and a slow intake process at the CAR-T center (23%) as the top 2 barriers affecting timely referral of patients. Patient deterioration was identified as a challenge in 40% of cases, while additional challenges related to the CAR-T center included lack of communication during the referral process and lack of clear instructions regarding follow-up care.

Perceived barriers to prescribing CAR-T therapy included lack of long-term survival data (14%), toxicity (30%), administration logistics (37%), and cost (39%). Regarding cost of CAR-T therapy, 60% of respondents indicated that the price is acceptable.

In addition to better provider support, faster approval, and more clinical trial data to facilitate prescribing of CAR-T therapies, physicians cited the need for great financial support for patients (59%), more education for prescribing physicians (53%) and patients (29%), more decision support tools (38%), and improved communication between community physicians and CAR-T centers (37%).

In a recent interview with Dr Gajra, we discussed the findings of these 2 studies as well as potential solutions to reduce the barriers identified by providers.

Regarding your findings on oncological perceptions of future gene therapy use, how accurate are the perceptions by oncologists that gene therapy will be administered by academic centers and that costs would be prohibitive to patients?

Dr Gajra: Overall, I agree with the perceptions of community oncologists reported in our research.¹

When gene therapy is approved for hematological diseases, it will most likely fall to academic centers in the beginning. The reason for this is that while the infusion itself is considered the essential portion of the therapy, the overall advancement of gene therapy requires careful training and education. Because a vast majority of patients receive hematology and oncology care in the community setting, the community providers will play a critical role in identifying and referring patients who may be candidates for gene therapy to academic centers.

For example, the proper gene therapy and patient timing must be determined by the provider at the academic center, as well as managing the post-infusion period. As a new therapy, the post-infusion period is actually 2-fold: the short-term effects (from the time of infusion to around a month after) and the long-term effects which track everything from immune response, off-target effects, and even the concern of mutagenesis or the development of cancer in later life. Additionally, long-term monitoring will need to track the efficacy of the gene therapy.

All this is to say, it makes sense why gene therapies will be administered by academic centers in the beginning, but I believe that once safety and efficacy are managed and established, they will move to community practices. In addition, I foresee some of the essential follow-up being transferred to the local community providers, with the patient making infrequent visits to the academic centers, which may even be telehealth visits now that the technology is well-established.

The cost aspect is a bit more nuanced, but the short version is that we need to look at the “value” of the therapy rather than the absolute cost itself. Even if a single dose of potentially “curative” gene therapy, say for hemophilia, costs a million dollars (hypothetically), we need to compare that cost to a lifetime of prophylactic factor replacement, morbidity of disease, and acute care utilization.

Similarly, if there is an effective gene therapy for sickle cell disease that can obviate the need for acute care and hospitalization for vaso-occlusive crises and transfusions for other medication and chelation, and can alter the natural history by preventing sickle cell-associated cardiac, hepatic, renal, and joint damage as well as avoid strokes, then a very high one-time cost may be justifiable. However, we need products with excellent long-term efficacy and minimal risk of long-term side effects.

Your abstract says, “Future work should focus on enhancing education of gene therapy products to community providers as well as identifying support programs that lessen the burden of cost.”¹ What are some examples of actions that would support these goals?

Dr Gajra: Because more than 50% of the care for oncological and hematological diseases take place in a community setting, it is important to address these issues ASAP.²

For the knowledge gap, one action would be clear guidance from academic centers to community oncologists. Education is critical from 2 angles: The first is appropriate identification of eligible patients for these therapies, as well as the timing constraints for patients to be referred and receive these therapies. The second is education regarding what happens after the infusion, especially if the patient cannot continue to make trips to the academic center. Community oncologists will need a firm understanding of how to monitor for both loss of efficacy as well as emerging complications.

In terms of identifying support programs, manufacturers can not only provide guidance on what types of patients are eligible, but in many cases can also offer patient-directed support in terms of transportation, housing, and lodging for patients who may need to travel to academic centers to lessen the burden of cost.

According to your findings on CAR-T therapies, the top 2 barriers to timely referral are a slow approval process by payers and a slow intake process at the CAR-T center.² What are potential solutions to these barriers?

Dr Gajra: We witnessed data for the use of CAR-T in first relapse in large B-cell lymphoma at ASH 2021, a very exciting development that will likely move CAR-T to an earlier line of therapy. As oncologists and hematologists get more comfortable prescribing this kind of therapy, how the healthcare community addresses these barriers will be key to CAR-T therapy access, especially for the large percentage of patients treated in community settings.

I see a 3-fold approach to the lag in the intake process:

Intake programs should expect more CAR-T patients as acceptance and usage continue to grow, and they should put care coordination in place. Some studies show that CAR-T may soon outperform stem cell transplant, so these intake teams may want to examine whether their stem cell transplant teams can work with CAR-T patients as well.
Plan for more certified locations. As CAR-T grows as a therapy choice, it is logical to assume there will be more treatment locations for these therapies. More locations should provide a greater number of choices for patients to receive these treatments, reducing the demand on current intake centers.
Referral timing needs to start earlier. Especially as the demand grows, community oncologists and hematologists must be preemptive with their referral instead of waiting until the patient is ready for treatment.

The payer issue is a bit more complex, because the healthcare community can only control a small amount if this. I recommend both providers and manufacturers look into third-party services or offerings that can essentially collect and obtain a benefits investigation and prior authorization through automation in order to decrease the payer approval time, irrespective of who the payer is.

What should be done about cost as a barrier to prescribing CAR-T therapy?

Dr Gajra: The cost barrier is particularly interesting because some of it based on perception. While there is an initial high cost of these therapies, if it leads to long-term remissions and downstream reductions in acute care, the cost may ultimately be lower.

The reality is that we need more studies that look at the overall cost benefit of these therapies in order to demonstrate the utility and value of CAR-T in the real-world setting. These cost analyses will also facilitate and demonstrate the sticker shock issue.

In some cases, we are already seeing significant progress in how payers are addressing the cost of these therapies as they become more accepted.

A final note is how value-based care may address this barrier in the future. Some manufacturers of CAR-T products are trying innovative payment strategies where, essentially, the cost of therapy is reimbursed back under “value-based contracts” if the patient does not respond adequately to therapy. In these scenarios, it is important to clearly define the desired outcome and the time, such as complete remission at 4 weeks, 6 weeks, and so on.

Regarding both studies, what are the most important remaining needs in terms of research or otherwise?

Dr Gajra: I see these needs as the “4 Es:”

We need education regarding CAR-T and gene therapies to community providers and caregivers and patients. Many patient advocacy groups and cancer foundations are already taking this on and advancing education.
We must eliminate the easily modifiable barriers like streamlining prior authorization, intake process, and demonstrating the value of novel therapies.
Expertisein the area of CAR-T and gene therapy is critical. This is why a lot of the responsibilities go to academic centers when novel therapies are introduced to the healthcare world, specifically for safety precautions and monitoring.
The fourth and perhaps most important is the need for evidence generation or research in 2 areas:
Clinical trials: the more safety and efficacy data we have, the better off we are when introducing these new therapies.
Real-world evidence: Even if the therapy worked great in a trial setting, we must understand how it works in the real world in order to demonstrate value through cost-benefit analysis and how it is applicable to real-world patients.

Are there any further points you would like to mention about these topics?

Dr Gajra: I expect we will see a focus on the outpatient administration of CAR-T with appropriate remote monitoring to simplify the process, remove patient access barriers, and potentially reduce the cost burden as the therapy becomes safer and more effective.

Disclosures: Each study author is employed by Cardinal Health, and Dr Gajra is an equity holder in the company.

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