Abstract
Aim: Characterize the logistical challenges faced by healthcare professionals (HCPs), patients and caregivers during the chimeric antigen receptor T-cell (CAR T) treatment process for non-Hodgkin lymphoma patients.
Materials & methods: HCPs in the US and UK experienced with CAR T administration participated in interviews and completed a web-based survey.
Results: A total of 133 (80 US, 53 UK) HCPs participated. Two or more logistical challenges were identified by ≥60% of respondents across all stages of the CAR T process. Commonly reported challenges were lengthy waiting periods, administrative and payer-related barriers, limited healthcare capacity, caregiver support and (particularly in the US) patient out-of-pocket costs.
Conclusion: The CAR T treatment process presents numerous challenges, highlighting an unmet need for more convenient therapies.
Keywords: : access to care, CAR T cell therapy, clinical decision-making, logistical challenges, non-Hodgkin lymphoma
Plain Language Summary
Chimeric antigen receptor T-cell (CAR T) therapy is a new treatment for patients with non-Hodgkin lymphoma that have not responded to other types of treatment. CAR T therapy uses a person's own immune cells (T cells), which are modified in a laboratory to attack cancer cells. While CAR T therapy has the potential to be effective, there are challenges associated with the treatment process. In this study, we surveyed 133 healthcare professionals (HCPs) in the United States and United Kingdom to understand their experiences with logistical challenges involved in navigating the CAR T process. More than 60% of participants identified two or more logistical challenges at every stage of the CAR T treatment process. The most commonly reported challenges included long waiting periods, limited room at hospitals, availability of caregivers to support patients and issues related to out-of-pocket costs, travel and lodging for patients who are treated at specialized centers. In the United States, challenges related to insurance coverage and out-of-pocket costs for patients were highlighted. More than half of HCPs reported that patients' cancer getting worse while waiting to receive CAR T was a reason why patients may not proceed to treatment. While operational improvements might address some challenges in the CAR T treatment process, these findings highlight the need for more convenient, readily available and easily administered therapies for patients with non-Hodgkin lymphoma.
Plain language summary
Article highlights.
While chimeric antigen receptor T-cell (CAR T) therapy represents an advancement in the treatment of non-Hodgkin lymphoma, it is associated with a number of logistical challenges for patients, caregivers and healthcare professionals (HCPs).
We surveyed physicians, nurses and other HCPs involved in the various stages of CAR T therapy administration in the US and UK to characterize logistical challenges at each stage of the CAR T process.
Initial in-depth qualitative interviews (n = 25) of HCPs highlighted lack of caregiver support, time and administration, travel and accommodations and payer access as key themes.
In a subsequent quantitative survey of HCPs (n = 133), more than 60% of respondents identified at least two logistical challenges faced at every stage of CAR T administration.
Respondents most commonly reported challenges related to lengthy waiting periods, slow approval processes, limited capacity and availability of caregiver support.
More than half of respondents reported rapid disease progression as a common reason why eligible patients do not proceed to CAR T infusion.
The availability of caregiver support was selected as a logistical challenge present at every stage of the CAR T treatment process.
Respondents highlighted out-of-pocket costs, travel and lodging challenges throughout the CAR T process, although out-of-pocket costs and insurance-related challenges were more pronounced in the US than in the UK.
This study adds to the growing body of literature addressing the logistical challenges associated with CAR T therapy.
Infographic
Infographic:
A PDF version of this infographic is available as supplemental material.
1. Introduction
Chimeric antigen receptor T-cell (CAR T) therapy has emerged as a promising treatment option for patients with non-Hodgkin lymphoma (NHL) that is relapsed or refractory (R/R) to other therapies [1]. Four CAR T therapies are currently available for the treatment of various subtypes of R/R NHL [1], including tisagenlecleucel (Kymriah®) for R/R large B-cell lymphoma (LBCL) and R/R follicular lymphoma (FL) [2,3], axicabtagene ciloleucel (Yescarta®) for R/R LBCL and R/R FL [4,5], lisocabtagene maraleucel (Breyanzi®) for R/R LBCL and R/R FL [6], and brexucabtagene autoleucel (Tecartus®) for R/R mantle cell lymphoma [7]. The approval of these CAR T therapies was based on demonstrated efficacy and safety across these different NHL indications in clinical trials [1,4,5,8].
CAR T therapies represent a significant advancement in R/R NHL treatment. However, the fact that all treated patients incur full upfront treatment costs (often exceeding $400,000 per patient), but a fraction experience long-lasting remission, raises concerns regarding the treatment value [9–11]. In addition, the specialized management protocols require treatment to occur at certified centers, typically a large academic institution or cancer center [12]. The patient advocacy group Blood & Marrow Transplant Information Network reports that CAR T for lymphoma is offered at fewer than 150 centers of excellence in the United States (US) [13]. This further reduces the number of patients who may benefit from treatment, as patients without a treatment center near to them may need to travel and lodge near these centers. Patients and their caregivers also may incur out-of-pocket costs and work productivity loss due to these geographical constraints [10].
The CAR T treatment process entails various stages: the referral process, determination of CAR T eligibility, review and approval for CAR T treatment, leukapheresis (often followed by a waiting period as the patient's cells are being manufactured), potential treatments and procedures preceding CAR T infusion (e.g., bridging therapy and conditioning regimens) and subsequent post-infusion monitoring (with decreasing frequency if a patient experiences remission). The complexities of this process have been well documented among healthcare stakeholders [11,14–16]. Still, efforts to characterize specific challenges from the perspective of HCPs have been limited. The aim of this study was to identify and quantify the logistical challenges experienced throughout the CAR T administration process as reported by HCPs in the US and United Kingdom (UK).
2. Methods
2.1. Study design & population
This was a cross-sectional, mixed-methods study comprising two phases: an initial set of qualitative interviews and a larger quantitative survey. The participants in both research components included HCPs in the US and UK experienced in the coordination and administration of CAR T for patients with R/R NHL. Eligibility criteria for all participants included a requisite of more than 2 years of clinical experience treating patients with R/R NHL and having provided care to a minimum of three patients eligible for CAR T therapy within the past 2 years. Physicians were deemed eligible if they had experience in the referral of patients to CAR T therapy or if they worked within a CAR T therapy team supporting any part of the treatment process. Nurses, social workers and physician assistants were required to have experience in at least one aspect of the CAR T therapy process. If one reported aspect was a direct CAR T treatment administration process, such as leukapheresis, bridging therapy, or lymphodepletion, experience in a second aspect was then required to ensure respondents were familiar with the patient pathway.
The participants included academic and community-based physicians (hematologist/oncologists), physician assistants, cell therapy coordinators/navigators, social workers, nurses and nurse practitioners working at CAR T therapy centers. Recruitment of study participants was undertaken via panel-based sampling and all participants were required to provide informed consent prior to participation.
Ethics approval for this study was obtained prior to data collection from the Western Institutional Review Board-Copernicus Group (study #1346939).
2.2. Survey development
2.2.1. Qualitative interviews
A semi-structured interview guide was created to aid the research team in carrying out the qualitative interviews. Specialists with expertise in CAR T therapy were consulted to inform development of the interview guide. Interviews were conducted via teleconference and audio recorded. At the onset of each interview, participants were briefed on the study and asked to provide verbal consent to participate. Immediately after the interview, brief notes were taken by the interviewer and uploaded into an Excel spreadsheet. All interviews were transcribed verbatim and uploaded into an open-source qualitative analysis software. Themes identified during the qualitative interviews informed the development of the quantitative survey to further investigate the logistical challenges associated with CAR T therapy administration and treatment process.
2.2.2. Quantitative survey
The quantitative survey was administered using a customized online survey platform and was divided into six main sections. The first five sections corresponded to the chronological stages in the CAR T therapy administration process: referral processes, eligibility determination, pre-infusion procedures (e.g., leukapheresis, bridging therapy, lymphodepletion), infusion and immediate post-infusion monitoring and long-term follow-up. The sixth and final section of the survey addressed other general logistical components of the CAR T therapy process.
Survey participants were asked to identify the logistical challenges encountered at each stage, to select reasons why a patient may not progress to the subsequent treatment stage (e.g., from leukapheresis to infusion), and to provide estimates for relevant measures (e.g., days between leukapheresis and infusion, duration of inpatient stay). After selecting a logistical challenge, respondents were required to indicate the degree of impact of the challenge in determining whether a patient would successfully undergo CAR T therapy using a scale of one to five, ranging from “Not at all impactful” to “Extremely impactful.” Respondents were also asked to assess how frequently the challenge affects patients, caregivers, or HCPs using a scale of one to five, ranging from “Never” to “Very often.” The full survey instrument is available in the Supplementary Material.
2.3. Statistical analysis
2.3.1. Qualitative interviews
The qualitative interviews were audio recorded, transcribed verbatim, de-identified and reviewed by interviewers for accuracy. Data were analyzed inductively using reflexive thematic analysis, in accordance with the guidelines described by Braun and Clarke [17]. The researchers first familiarized themselves with the qualitative data by reading interview transcripts and making notes of key observations. An initial codebook was developed, and labels were applied to data excerpts that were germane to the research questions. Codes were iteratively refined and themes were generated, reviewed and finalized by the researchers.
2.3.2. Quantitative survey
The analysis of quantitative survey data was descriptive. Means, medians, interquartile ranges and maximum/minimum values were calculated for continuous variables and frequencies and percentages were calculated for categorical variables. For the questions on the impact of each logistical challenge on patients successfully receiving CAR T therapy, the mean and median impact (on a scale of one to five) were calculated.
3. Results
3.1. Qualitative interviews
Twenty-five HCPs were interviewed (21 US, four UK). Twenty (80%) were physicians and five (20%) were other HCPs. Participants had been treating patients for a median of 18 years and had referred or prescribed CAR T therapy to a median of 12 patients in the past 24 months.
Analysis of interview data revealed a generally positive outlook on the efficacy and safety of CAR T therapy; however, several logistical challenges associated with the treatment process were discussed. Four key themes relating to logistical challenges in the CAR T treatment process were identified: time and administration issues, caregiver support, access to insurance and travel and accommodation challenges. Interview excerpts relating to each key theme are shown below, with further excerpts shown in Table 1.
Table 1.
Qualitative interview excerpts relating to CAR T therapy logistical challenges.
| Theme | Relevant excerpts |
|---|---|
| Caregiver support |
“I mean, if I really felt that I had a patient that really had no support whatsoever, I might be hesitant to refer them.” – UK HCP
“We always make sure that somebody has a caregiver before we proceed with CAR T…sometimes, some patients could hire a caregiver, but not everybody has the financial means to do so.” – US HCP “So, we make sure that the caregivers… we educate them, like, this is a big commitment. You've got to make sure that you're there with the patient for X amount of weeks. You can't really work. You have to be there with the patient present pretty much all the time in the same household monitoring them, interacting with them to make sure that… you know, you're looking for certain types of… the way that the patient is interacting with you. Are they speaking appropriately? Do they have chills? Do they have trouble breathing? Are they feeling hot? Are they shivering? Do they have a fever – things along those lines. Are they nauseous, for example? Are they feeling dizzy? Are they having problems with their memory or something like that, which, again, all these things could point to adverse events from CAR T.” – US HCP “We kind of monitor patients through the most acute phase of this. I know it's been very emotionally challenging to some of the caregivers who come in to visit and they find their loved one kind of just in the midst of either CRS [cytokine release syndrome] or, even more upsetting, neurotoxicity. Obviously when the patient is in the hospital, they aren't responsible for the care, but it's hard then to see it.” – US HCP |
| Time and administration |
“I think it's more consuming this one [the referral to CAR T] because you have to put all the patient file together, have to put together a letter why the patient needs this therapy and what's the expected result, outcome of this therapy. But also, everything related to the patient from financial or insurance coverages.” – US HCP
“So patient is waiting, waiting, waiting. It is not like bone marrow transplant, you go for transplant and the chances of getting a transplant is north of like 90%. On the other hand, CAR T, it's hard to get. Even if I refer eight patients in a year, very probably at best, two or three will get the CAR T. So it is logistically getting a slot is very important.” – US HCP “I mean they could be about… I mean at the moment I don't think that any patient has not been able to receive the CAR T because of the long queue. I don't think it has happened. But the infusion time can be… I mean it's just the infusion rather than the queue which is a problem, where the patient's cancer relapse while waiting for the cells.” – US HCP “In the centre where I work, we have a bottleneck with leukapheresis. If we had infinite leukapheresis capacity, I'm sure we would treat probably 50% more.” – UK HCP “…in terms of the manufacturing process, it takes sometimes between four to six weeks. That is an issue, and it would be good to sort of maybe shorten that process.” – US HCP |
| Travel and accommodation |
“Yeah, I mean, some patients really don't want to do it because it's not readily available in their surrounding location, in our office, our clinic. They don't want to go the distance.” – US HCP
“Well, it can be work. I know it is an issue. I mean, you have to understand, for some folks, they don't venture out of the state on a general basis. So, travelling to the next state that will do this for them is like, for them, going to Europe in some cases because they just don't travel. That's a big deal for them. So, it can make an issue…[do many people refuse CAR T because of distance]…probably about, again, 15% overall.” – US HCP “So, if you have to drive a great distance – two, three hours to a CAR T center – that can be somewhat of a burden for patients. So, look, in the United States, you have this concentration of metropolitan cities, and then you have lots of rural areas and lots of driving time and patients that perhaps don't have the support structure to be staying at a CAR T therapy center in that city for a prolonged period of time. So, that can be an issue.” – US HCP |
| Insurance and cost |
“I mean, definitely insurance plays a big role, and we did have a couple of patients who were […] to get it, but despite us trying and case management getting involved, it never worked out because they were… I don't remember what type of insurance they had, or I think one of them was uninsured.” – US HCP
“The insurance approval goes through three steps. One is you first have to get the insurance approval to test the patient for CAR T, and once the testing is complete, then you have to wait for the insurance to approve the CAR T based on a review of the records of the patient. And then once approval is granted, then there is the third step, fairly unique to CAR T in that you have to have a single patient agreement negotiated with the insurance carrier for each and every patient independently. And that adds to delays. And from the time you see the patient to the time you can actually schedule for a CAR T, if the patient has private insurance, it can take up to six weeks or so to then schedule.” – US HCP “10–15% [of patients wouldn't be financially eligible for CAR T]…For people who are younger who have private insurance, they may have very high deductibles or limited coverage, and then they've exhausted it….It can be $10,000 or $20,000, their overall deductible. Frequently, they've met it, so it's not as big an issue, but for some people, again, every year it comes up, and it depends on the timing. The event could be just more than they can afford.” – US HCP |
CAR T: Chimeric antigen receptor T-cell.
3.1.1. Time & administration
HCPs reported time and administration-related issues as major logistical challenges during the CAR T treatment process. HCPs identified that several elements of the CAR T process required waiting, which could hamper patient outcomes.
“I think it's more consuming this one [the referral to CAR T] because you have to put all the patient file together, have to put together a letter why the patient needs this therapy and what's the expected result, outcome of this therapy. But also, everything related to the patient from financial or insurance coverages.” – US HCP
“So patient is waiting, waiting, waiting. It is not like bone marrow transplant, you go for transplant and the chances of getting a transplant is north of like 90%. On the other hand, CAR T, it's hard to get. Even if I refer eight patients in a year, very probably at best, two or three will get the CAR T. So it is logistically getting a slot is very important.” – US HCP
3.1.2. Caregiver support
HCPs indicated that having a caregiver to support the patient throughout the CAR T process and post treatment was non-negotiable, and that without this support patients would not be able to proceed with treatment.
“I mean, if I really felt that I had a patient that really had no support whatsoever, I might be hesitant to refer them.” – UK HCP
“We always make sure that somebody has a caregiver before we proceed with CAR T…sometimes, some patients could hire a caregiver, but not everybody has the financial means to do so.” – US HCP
3.1.3. Access to insurance
HCPs reported access to insurance as a logistical challenge for patients seeking CAR T therapy. Some participants mentioned having patients who could not proceed due to financial barriers, while others noted that the process of applying for coverage can be tedious and time-consuming.
“I mean, definitely insurance plays a big role, and we did have a couple of patients who were […] to get it, but despite us trying and case management getting involved, it never worked out because they were… I don't remember what type of insurance they had, or I think one of them was uninsured.” – US HCP
“The insurance approval goes through three steps. One is you first have to get the insurance approval to test the patient for CAR T, and once the testing is complete, then you have to wait for the insurance to approve the CAR T based on a review of the records of the patient. And then once approval is granted, then there is the third step, fairly unique to CAR T in that you have to have a single patient agreement negotiated with the insurance carrier for each and every patient independently. And that adds to delays. And from the time you see the patient to the time you can actually schedule for a CAR T, if the patient has private insurance, it can take up to six weeks or so to then schedule.” – US HCP
3.1.4. Travel & accommodations
Patient travel and accommodations were mentioned by many HCPs as logistical challenges in the CAR T therapy process. HCPs stated that they will not recommend a patient for CAR T therapy if the patient lives too far from the treatment center and would not be able to handle the travel. This would be decided together with the patient and their family.
“Yeah, I mean, some patients really don't want to do it because it's not readily available in their surrounding location, in our office, our clinic. They don't want to go the distance.” – US HCP
In summary, four distinct themes characterizing the logistical burden of the CAR T therapy process on several stakeholder groups (HCPs, patients, and caregivers) emerged from the qualitative interviews. These findings underscore the need for a readily available therapeutic option that can potentially alleviate these burdens. These themes and insights guided the creation of a survey which assessed the logistical challenges associated with CAR T therapy in greater detail using a quantitative approach.
3.2. Quantitative survey
3.2.1. Respondent characteristics
Of 222 respondents screened for eligibility, 133 were included in the final sample. Of these 133 HCPs, 80 (60%) were from the US and 53 (40%) were from the UK. Of the 80 US HCPs, 67 (84%) were physicians, 7 (9%) were physician assistants and 6 (8%) were nurse practitioners; additionally, 33 (41%) reported affiliation with an academic/teaching certified CAR T center, 22 (28%) with a community-based referring institution, 23 (29%) with a community-based certified CAR T center and 2 (3%) with an academic/teaching referring institution. Of the 53 UK HCPs, 43 (81%) were physicians, 7 (13.2%) were nurses, 2 (4%) were nurse practitioners and 1 (2%) was a cell therapy coordinator/navigator; additionally, 29 (55%) reported affiliation with an academic/teaching certified CAR T center, 8 (15%) with a community-based referring institution, 5 (9%) with a community-based certified CAR T center and 11 (21%) with an academic/teaching referring institution.
In both the US and UK, physicians had referred a median of 15 patients to CAR T therapy in the past 24 months. Nurses had worked with a median of 45 (US) and 30 (UK) patients during the CAR T therapy administration process in the past 24 months. Respondents were also highly experienced across the stages of CAR T therapy administration: 100% (n = 67) of US and 98% (n = 42) of UK physicians had experience with referrals and eligibility assessments; 75% (n = 50) of US and 51% (n = 22) of UK physicians had experience with infusion and post-infusion care; and 69% (n = 9) of US and 70% (n = 7) of UK nurses/coordinators had experience coordinating CAR T therapy logistics (Figure 1).
Figure 1.
Respondent experience with CAR T therapy, by country and profession*.
*Non-physicians included nurses, nurse practitioners, physician assistants and a cell therapy coordinator/navigator.
CAR T: Chimeric antigen receptor T cell; UK: United Kingdom; US: United States.
3.2.2. Logistical challenges along the patient journey
Two or more logistical challenges were identified by ≥60% of the US and UK respondents across all stages of CAR T administration. Specifically, 86% (US) and 92% (UK) respondents reported ≥2 referral process challenges; 81% (US) and 78% (UK) respondents reported ≥2 CAR T eligibility determination challenges; 75% (US) and 60% (UK) respondents reported ≥2 challenges with procedures before infusion; 72% (US) and 63% (UK) respondents reported ≥2 CAR T infusion and monitoring challenges; and 82% (US) and 64% (UK) respondents reported ≥2 challenges during long-term follow-up processes (Figure 2). Further findings within each stage are described in the subsequent sections.
Figure 2.
Percentage of respondents selecting 2 or more logistical challenges at each stage of CAR T therapy administration.
CAR T: Chimeric antigen receptor T cell; UK: United Kingdom; US: United States.
3.2.3. Referral process
The most commonly reported challenges impacting the decision to refer patients for CAR T therapy were: manufacturing wait time (reported by 42% of US and 60% of UK respondents), limited capacity at a CAR T therapy center (reported by 40% of US and 58% of UK respondents), lengthy referral process (reported by 45% of US and 37% of UK respondents), travel distance (reported by 36% of US and 38% of UK respondents), slow/complex processes for insurance (US) or National Health Service (NHS; UK) approvals (reported by 36% of US and 31% of UK respondents) and availability of caregiver support (reported by 36% of US and 27% of UK respondents). Additionally, 40% of US respondents reported absence of insurance as impacting the decision to refer a patient for CAR T therapy (Table 2). In terms of impact, in the US, most referral process challenges had a median impact rating of four (very impactful), with the exception of coordinating and providing bridging therapy while waiting for CAR T therapy (median impact rating: five [extremely impactful]) and lack of clarity on the eligibility criteria and/or referral process (median impact rating: three [somewhat impactful]). In the UK, all challenges had a median impact rating of three (somewhat impactful), except for the availability of caregiver support, which had a median impact rating of four (very impactful) (Table 2).
Table 2.
Challenges impacting the CAR T therapy patient referral processa.
| Challenge | US (n = 73) | UK (n = 52) | ||||
|---|---|---|---|---|---|---|
| Respondents (%)a | Median impact ratingb | Mean % of PTs not referred | Respondents (%) | Median impact rating | Mean % of PTs not referred | |
| Lengthy referral process | 45 | 4 | 16 | 37 | 3 | 22 |
| Wait time for manufacturing | 42 | 4 | 19 | 60 | 3 | 18 |
| Absence of insurance | 40 | 4 | 25 | 0 | NA | NA |
| Limited capacity at CAR T therapy center | 40 | 4 | 21 | 58 | 3 | 19 |
| Availability of caregiver support | 36 | 4 | 24 | 27 | 4 | 20 |
| Slow/complex process for insurance coverage (US) or NHS approval (UK) | 36 | 4 | 23 | 31 | 3 | 20 |
| Patient travel distance to treatment center | 36 | 4 | 20 | 38 | 3 | 17 |
| Patient out-of-pocket costs or loss of productivity/source of income | 34 | 4 | 21 | 8 | 3 | 26 |
| Coordinating and providing bridging therapy while waiting for CAR T therapy | 30 | 5 | 15 | 27 | 3 | 20 |
| Coordinating and providing leukapheresis and lymphodepletion | 27 | 4 | 20 | 25 | 3 | 20 |
| Lack of clarity over eligibility criteria and/or referral process | 22 | 3 | 25 | 25 | 3 | 23 |
| Patient preference for alternative treatment options | 19 | 4 | 17 | 40 | 3 | 21 |
Percentage of respondents who selected each factor for the question, “Thinking about your experience referring patients for CAR T, what are the main factors that impact your decision to refer a patient for CAR T?”.
For each factor selected, respondents selected the impact of the factor on whether a patient receives CAR T, where 1 = not at all impactful, 2 = slightly impactful, 3 = somewhat impactful, 4 = very impactful, 5 = very impactful.
CAR T: Chimeric antigen receptor T cell; NA: Not applicable; NHS: National Health Service; PT: Patient; UK: United Kingdom; US: United States.
Respondents in the US estimated that a mean of 25% of patients who are deemed eligible for CAR T therapy are not referred due to absence of insurance to cover treatment. Respondents in both the US and UK also reported that more than 20% of their potentially eligible patients were not referred due to lack of clarity over eligibility criteria and/or referral processes (US mean, 25%; UK mean, 23%) and availability of caregiver support (US mean, 24%; UK mean, 20%).
3.2.4. Eligibility determination
The most commonly reported challenges experienced while determining patient eligibility were: complex processes for applying for insurance approvals (US) or obtaining NHS approval (UK) (reported by 50% of US respondents and 41% of UK respondents), complex work-ups to determine clinical eligibility (reported by 44% of US and 55% of UK respondents), need for transportation/lodging (reported by 41% of US and 35% of UK respondents) and availability of caregiver support (reported by 34% of US and 41% of UK respondents). While 57% of UK respondents indicated that time required for communication between the referring center and CAR T therapy center was a challenge with determining eligibility, only 27% of US respondents selected this challenge (Table 3). In terms of impact, most eligibility determination challenges selected by HCPs had a median impact rating of four (very impactful) in the US. Exceptions were the time required for communication between a referral center and CAR T treatment center, patient loss of productivity/source of income and lack of clarity on eligibility criteria, all of which had a median impact rating of three (somewhat impactful). In the UK, slow or complex processes for obtaining NHS approval had a median impact rating of four (very impactful) while all other challenges had a median impact rating of three (somewhat impactful) (Table 3). In terms of frequency, most selected challenges during the eligibility determination process had a median frequency rating of four (often) in the US. Exceptions were the time required for communication between a referral center and CAR T treatment center, patient loss of productivity/source of income and lack of clarity on eligibility criteria, all of which had a median frequency rating of three (sometimes). In the UK, most challenges had a median frequency rating of three (sometimes), with the exception of patient loss of productivity/source of income, which had a median frequency rating of two (rarely) (Table 3).
Table 3.
Challenges associated with the CAR T therapy eligibility determination process.
| Challenge | US (n = 64) | UK (n = 49) | ||||
|---|---|---|---|---|---|---|
| Respondents (%)a | Median impact ratingb | Median frequency ratingc | Respondents (%) | Median impact rating | Median frequency rating | |
| Slow/complex process for insurance coverage (US) or NHS approval (UK) | 50 | 4 | 4 | 41 | 4 | 3 |
| Patient out-of-pocket costs for medical services to determine eligibility | 47 | 4 | 4 | 4 | 3 | 3 |
| Complex clinical workup to determine eligibility | 44 | 4 | 4 | 55 | 3 | 3 |
| Patient transportation/lodging if travel needed to treatment center | 41 | 4 | 4 | 35 | 3 | 3 |
| Availability of caregiver support | 34 | 4 | 4 | 41 | 3 | 3 |
| Communication time between referral center and CAR T therapy center | 27 | 3 | 3 | 57 | 3 | 3 |
| Patient productivity/income loss | 25 | 3 | 3 | 10 | 3 | 2 |
| Lack of clarity over eligibility criteria | 17 | 3 | 3 | 27 | 3 | 3 |
Percentage of respondents who selected each factor for the question, “Thinking about your experience assessing patients for CAR T eligibility, what are the main factors you and your patient experience at this stage?”.
For each factor selected, respondents selected the impact of the factor on whether a patient receives CAR T, where 1 = not at all impactful, 2 = slightly impactful, 3 = somewhat impactful, 4 = very impactful, 5 = very impactful.
For each factor selected, respondents selected the frequency with which patients have had their care impacted as a result of this factor, where 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often.
CAR T: Chimeric antigen receptor T cell; NHS: National Health Service; UK: United Kingdom; US: United States.
3.2.5. Treatments & procedures before infusion
After a patient has been deemed officially eligible for CAR T therapy, logistical challenges may emerge during the procedures (i.e., leukapheresis, bridging therapy, lymphodepletion) leading up to infusion. The most common logistical challenges faced at this stage were: waiting time for healthcare capacity (reported by 57% of US and 71% of UK respondents), communication between the referral center and CAR T therapy center to coordinate treatments (reported by 25% of US and 49% of UK respondents), availability of funding/insurance to cover pre-infusion procedures (reported by 49% of US and 24% of UK respondents) and availability of caregiver support (reported by 34% of US and 29% of UK respondents) (Table 4). In terms of impact, most challenges selected by HCPs had a median impact rating of four (very impactful) in the US. Exceptions were transportation/lodging/meals for patient travel and communications between the referring center and CAR T treatment center, both of which had a median impact rating of three (somewhat impactful). In the UK, HCPs reported that transportation/lodging/meals for patient travel, availability of funding for pre-infusion procedures and patient out-of-pocket costs all had median impact ratings of four (very impactful). Waiting time for healthcare capacity to complete pre-infusion procedures, communication between referral center and CAR T center to coordinate pre-infusion procedures, and availability of caregiver support had median frequency ratings of three (somewhat impactful) (Table 4). In terms of frequency, HCPs in both the US and UK reported that patient out-of-pocket costs or patient loss of productivity/source of income had median frequency ratings of four (often) in the procedures before infusion stage. All other challenges selected by HCPs in both regions had median impact ratings of three (sometimes) (Table 4).
Table 4.
Challenges associated with treatments and procedures before CAR T infusion.
| Challenge | US (n = 68) | UK (n = 45) | ||||
|---|---|---|---|---|---|---|
| Respondents (%)a | Median impact ratingb | Median frequency ratingc | Respondents (%) | Median impact rating | Median frequency rating | |
| Waiting time for healthcare capacity to complete pre-infusion treatments | 57 | 4 | 3 | 71 | 3 | 3 |
| Availability of funding/insurance to cover pre-infusion treatments | 49 | 4 | 3 | 24 | 4 | 3 |
| Patient out-of-pocket costs or productivity/income loss | 37 | 4 | 4 | 9 | 4 | 4 |
| Availability of caregiver support | 34 | 4 | 3 | 29 | 3 | 3 |
| Patient transportation/lodging/meals if travel needed to treatment center | 29 | 3 | 3 | 13 | 4 | 3 |
| Communication between referring center and CAR T therapy center to coordinate pre-infusion treatments | 25 | 3 | 3 | 49 | 3 | 3 |
Percentage of respondents who selected each factor for the question, “What are the main logistical factors you and your patients experience during treatment/procedures before CAR T infusion (leukapheresis, bridging therapy and lymphodepletion)?”.
For each factor selected, respondents selected the impact of the factor on whether a patient receives CAR T, where 1 = not at all impactful, 2 = slightly impactful, 3 = somewhat impactful, 4 = very impactful, 5 = very impactful.
For each factor selected, respondents selected the frequency with which patients have had their care impacted as a result of this factor, where 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often.
CAR T: chimeric antigen receptor T cell; UK: United Kingdom; US: United States.
3.2.6. Infusion & immediate post-infusion monitoring
The most commonly reported logistical challenges experienced in the infusion and immediate post-infusion monitoring stage were: availability of caregiver support (reported by 44% of US and 53% of UK respondents), waiting time for healthcare capacity (e.g., an open inpatient bed) (reported by 40% of US and 50% of UK respondents), transportation, lodging and meals for patients/caregivers (reported by 37% of US and 32% of UK respondents), and patient out-of-pocket costs (reported by 47% of US and 5% of UK respondents) (Table 5). In terms of impact, in the US, patient out-of-pocket costs, requirements for treatment centers to have medicines on-site for managing adverse events and availability of caregiver support had median impact ratings of four (very impactful). Wait time for healthcare capacity, transportation, lodging and meals for patients/caregivers and patient/caregiver productivity or income loss had median impact ratings of three (somewhat impactful). In the UK, all challenges selected by HCPs had median impact ratings of three (somewhat impactful) (Table 5). In terms of frequency, in both the US and UK, most challenges reported during the infusion and immediate post-infusion monitoring stage had median frequency ratings of three (sometimes). Requirements for treatment centers to have medicines on-site for managing adverse events had a median frequency rating of four (often) among US HCPs. Some differences also emerged between regions: patient out-of-pocket costs for treatment had a median frequency rating of four (often) in the US and two (rarely) in the UK (Table 5).
Table 5.
Challenges associated with CAR T infusion and post-infusion monitoring procedures.
| Challenge | US (n = 57) | UK (n = 38) | ||||
|---|---|---|---|---|---|---|
| Respondents (%)a | Median impact ratingb | Median frequency ratingc | Respondents (%) | Median impact rating | Median frequency rating | |
| Patient out-of-pocket costs for treatment | 47 | 4 | 4 | 5 | 3 | 2 |
| Availability of caregiver support | 44 | 4 | 3 | 53 | 3 | 3 |
| Wait time for healthcare capacity | 40 | 3 | 3 | 50 | 3 | 3 |
| Patient transportation/lodging/meals if travel needed to treatment center | 37 | 3 | 3 | 32 | 3 | 3 |
| Requirements for treatment centers to have medicines (eg, tocilizumab) on-site to manage AEs | 32 | 4 | 4 | 29 | 3 | 3 |
| Patient/caregiver productivity/income loss during infusion | 18 | 3 | 3 | 21 | 3 | 3 |
Percent of respondents who selected each factor for the question, “What are the main logistical factors you and your patients experience during CAR T infusion?”.
For each factor selected, respondents selected the impact of the factor on whether a patient receives CAR T, where 1 = not at all impactful, 2 = slightly impactful, 3 = somewhat impactful, 4 = very impactful, 5 = very impactful.
For each factor selected, respondents selected the frequency with which patients have had their care impacted as a result of this factor, where 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often.
AE: Adverse event; CAR T: Chimeric antigen receptor T cell; UK: United Kingdom; US: United States.
3.2.7. Long-term follow-up care
The most common logistical challenges reported during the long-term follow-up stage of the CAR T treatment process were: the availability of caregiver/social support (reported by 55% of US and 72% of UK respondents), transportation/lodging/meals for traveling for follow-up appointments (reported by 39% of US and 38% of UK respondents), availability of funding/insurance for long-term follow-up care (reported by 52% of US and 21% of UK respondents) and patient/caregiver work productivity/income loss (reported by 31% of US and 38% of UK respondents) (Table 6). In terms of impact, in the UK, all challenges reported by HCPs in the long-term follow-up stage had median impact ratings of three (somewhat impactful). In the US, the following challenges had median impact ratings of four (often): patient out-of-pocket costs for long-term follow-up care, availability of funding/insurance for long-term follow-up care and transportation/lodging/meals for traveling for follow-up appointments; the availability of caregiver support and patient or caregiver productivity/income loss both had median impact ratings of three (somewhat impactful) (Table 6). In terms of frequency, the availability of funding/insurance for long-term follow-up care had a median frequency rating of four (often) among US respondents; all other challenges selected by HCPs in both the US and UK had a median frequency rating of three (sometimes) (Table 6).
Table 6.
Challenges associated with long-term follow-up care after CAR T therapy.
| Challenge | US (n = 62) | UK (n = 47) | ||||
|---|---|---|---|---|---|---|
| Respondents (%)a | Median impact ratingb | Median frequency ratingc | Respondents (%) | Median impact rating | Median frequency rating | |
| Patient out-of-pocket costs for follow-up care | 55 | 4 | 3 | 15 | 3 | 3 |
| Availability of caregiver support | 55 | 3 | 3 | 72 | 3 | 3 |
| Availability of funding/insurance for follow-up care | 52 | 4 | 4 | 21 | 3 | 3 |
| Patient transportation/lodging/meals if travel needed for follow-up care | 39 | 4 | 3 | 38 | 3 | 3 |
| Patient/caregiver productivity/income loss when receiving follow-up care | 31 | 3 | 3 | 38 | 3 | 3 |
Percentage of respondents who selected each factor for the question, “What are the main logistical factors you and your patients experience during long-term follow-up after CAR T administration?”.
For each factor selected, respondents selected the impact of the factor on patients' treatment experience, where 1 = not at all impactful, 2 = slightly impactful, 3 = somewhat impactful, 4 = very impactful, 5 = very impactful.
For each factor selected, respondents selected the frequency with which patients have had their care impacted as a result of this factor, where 1 = never, 2 = rarely, 3 = sometimes, 4 = often, 5 = very often.
CAR T: Chimeric antigen receptor T cell; UK: United Kingdom; US: United States.
3.2.8. General CAR T treatment logistics
HCPs in both the US and UK estimated that the mean time between leukapheresis and infusion was 21 days (US mean, 21 days; UK mean, 22 days). They also estimated that patients spend 5 days (US mean, 5 days; UK mean, 6 days) in nearby accommodations prior to infusion, and 12 days during and immediately after infusion (US mean, 13 days; UK mean, 12 days). HCPs estimated that a mean of 21% of patients (US mean, 22%; UK mean, 20%) require intensive care admission during infusion and a mean of 24% (US mean, 25%; UK mean, 24%) were estimated to require re-admission to the hospital during the post-infusion monitoring period (Table 7).
Table 7.
CAR T therapy logistical aspects and caregiver considerations.
| Estimated logistical factors | US | UK | ||
|---|---|---|---|---|
| n | Mean (Median, IQR) | n | Mean (Median, IQR) | |
| Average number of days between leukapheresis and infusion | 50 | 21 (17, 11–28) | 30 | 22 (23, 13–30) |
| Nights spent in lodging before infusion | 44 | 5 (3, 2–5) | 29 | 6 (4, 2–5) |
| Nights spend in lodging during/immediately after infusion | 44 | 13 (7, 6–20) | 29 | 12 (9, 5–14) |
| Caregiver: days spent with patient for support before infusion | 43 | 6 (3, 2–7) | 27 | 8 (5, 2–6) |
| Caregiver: days spent with patient for support after infusion | 43 | 14 (10, 4–20) | 27 | 14 (14, 6–20) |
| n | Mean % (Median %) | n | Mean % (Median %) | |
|---|---|---|---|---|
| Percentage of patients requiring admission to ICU during infusion | 51 | 22 (15) | 36 | 20 (19) |
| Percentage of patients requiring readmission to the hospital post-infusion | 54 | 25 (20) | 35 | 24 (25) |
| Percentage of patients with an informal/unpaid caregiver | 60 | 67 (75) | 37 | 67 (75) |
| For patients without a caregiver: a | ||||
| Hired, paid out of pocket | 39 | 23 (20) | 25 | 16 (15) |
| Hired, funded by insurance (US) or NHS (UK) | 37 | 18 (20) | 28 | 30 (30) |
| Hired, funded by charity/social services | 37 | 17 (15) | 26 | 19 (16) |
| Hired, funded by manufacturer | 33 | 13 (10) | 22 | 12 (10) |
| No caregiver support | 31 | 22 (10) | 24 | 31 (18) |
| Percentage of caregivers impacted by CAR T therapy in the following ways: | ||||
| Disruption of daily activities | 58 | 49 (40) | 32 | 45 (40) |
| Negative impact on quality of life or mental health | 54 | 33 (30) | 31 | 33 (28) |
| Loss of productivity and source of income | 51 | 38 (30) | 30 | 32 (30) |
Percentages in this category add up to over 100%, as respondents could have selected more than one source of caregiver support.
CAR T: Chimeric antigen receptor T-cell; ICU: Intensive care unit; IQR: Interquartile range; NHS: National Health Service; UK: United Kingdom; US: United States.
Across the US and UK, the mean estimated percentage of patients having an informal/unpaid caregiver (e.g., family member or friend) to support them during treatment was 67%. When asked to consider patients without an informal/unpaid caregiver, HCPs estimated that about one-quarter (US mean, 22%; UK mean, 31%) remained without any caregiver support while others secured a hired caregiver funded by insurance, the NHS, the CAR T manufacturer, or paid out-of-pocket. Respondents also reported that the CAR T therapy process impacts caregivers by disrupting daily activities, negatively impacting their quality of life/mental health and causing lost productivity and income (Table 7).
3.2.9. Estimated proportion of patients impacted by CAR T challenges
3.2.9.1. Patient drop-off between CAR T referral & leukapheresis
On average, HCPs estimated that 32% of patients in the US and 27% of patients in the UK who are initially referred for CAR T therapy do not proceed to leukapheresis. Reasons for not proceeding to leukapheresis included rapid disease progression (reported by 58% of US and 74% of UK respondents), a work-up showing clinical ineligibility (reported by 39% of US and 67% of UK respondents) and insurance (US) or NHS (UK) applications not being approved (reported by 34% of US and 31% of UK respondents) (Table 8).
Table 8.
Percentage of respondents reporting reasons that eligible CAR T therapy patients do not proceed to leukapheresis or infusion.
| Reason for not proceeding | Do not proceed to leukapheresis (%) | Do not proceed to infusion (%) | ||
|---|---|---|---|---|
| US (n = 59) | UK (n = 42) | US (n = 44) | UK (n = 31) | |
| Rapid disease progression | 58 | 74 | 57 | 68 |
| Work-up shows clinical ineligibility | 39 | 67 | NA | NA |
| Insurance coverage/NHS application not approved | 34 | 31 | 34 | NA |
| High OOP costs for treatment | 34 | 14 | 32 | 13 |
| Travel distance to treating center | 19 | 12 | 20 | 10 |
| Unavailable caregiver support | 15 | 5 | 14 | 16 |
| Patient preference for alternative options | 14 | 26 | 0 | 29 |
| Concerns about work productivity/income loss | 7 | 2 | 7 | 6 |
| CAR T manufacturing failure | NA | NA | 34 | 48 |
| Long wait time for manufacturing | NA | NA | 14 | 29 |
CAR T: Chimeric antigen receptor T-cell; NA: Not applicable; NHS: National Health Service; OOP: Out-of-pocket; UK: United Kingdom; US: United States.
3.2.9.2. Patient drop-off between leukapheresis & infusion
On average, an estimated 19% of US patients and 20% of UK patients who undergo leukapheresis do not proceed to infusion. Reasons for not proceeding to infusion included rapid disease progression (reported by 57% of US and 68% of UK respondents), CAR T manufacturing failure (reported by 34% of US and 48% of UK respondents) and long wait time for manufacturing (reported by 14% of US and 29% of UK respondents) (Table 8).
In summary, based on the estimated proportion of patients not proceeding to leukapheresis or infusion, an estimated 45% of patients referred to CAR T in the US and 42% in the UK do not make it to CAR T infusion due to several logistical challenges including rapid disease progression, manufacturing failure, wait time for manufacturing and access to insurance.
4. Discussion
CAR T therapy has the potential to provide durable response and survival benefits for patients with R/R NHL. However, the treatment administration process is lengthy and resource-intensive, presenting numerous logistical challenges. In this mixed-methods study, we surveyed HCPs in the US and UK to characterize the challenges that arise during the CAR T therapy process – from initial referral to post-infusion care. The most commonly reported barriers centered around prolonged waiting periods (e.g., manufacturing time, awaiting healthcare capacity, slow approvals), travel and accommodations for patients, the availability of caregiver support and – particularly in the US – out-of-pocket costs. Several challenges were reported to be very impactful on patients, caregivers, or HCPs during the CAR T treatment process.
Little previous research has quantified the logistical barriers experienced by patients, caregivers and HCPs during the administration of CAR T therapy. Still, our findings are largely consistent with those of previous studies and suggest that lengthy and complex processes may limit the benefits of CAR T therapy. Gajra et al. (2020) surveyed US community hematologists/oncologists, finding that more than half of respondents felt that the logistics of CAR T therapy administration and follow-up were cumbersome. Further, 27% identified slow approval processes as a challenge [16]. Similarly, 36% of US and 31% of UK participants in this study felt that slow approval processes would impact their decision to refer a patient for CAR T therapy. These treatment delays may be compounded by long manufacturing times – 42% of US and 60% of UK respondents in our study reported that wait time for manufacturing would impact their decision to refer a patient.
After a patient has been successfully referred and deemed eligible, further delays may arise that diminish the potential benefits of CAR T therapy. Respondents in this study estimated that manufacturing time (i.e., time between leukapheresis and infusion) was 21 days and more than half of respondents felt that rapid disease progression while awaiting treatment was a reason why patients do not proceed with treatment. Nearly two-thirds of respondents in Gajra et al. had also encountered the challenge of patients' disease becoming worse before treatment could be administered [16]. Another survey evaluating physician preferences for attributes of different CAR T therapies found that physicians preferred to avoid long wait times and were willing to accept increases in adverse event risks to gain reductions in time spent waiting for an infusion [18]. Further, the required inpatient stay associated with CAR T therapy administration may pose a challenge; we found that waiting time for healthcare capacity was a frequently noted logistical challenge during CAR T therapy pre-infusion and infusion procedures.
Cost and reimbursement challenges have also been at the center of the conversation, as the high cost of CAR T therapy raises affordability concerns for patients, payers and healthcare systems globally. While drug acquisition is the largest component of the cost, other elements of care such as facility and procedure costs can increase healthcare expenditures [10]. Indeed, absence of insurance coverage to cover treatment costs was noted by 40% of US respondents in our study as “very impactful” in the decision to refer a patient and 49% selected availability of funds or insurance to cover pre-infusion procedures such as leukapheresis and bridging therapy as a challenge. The high costs of treatment may be compounded by travel and lodging expenses as well as loss of work productivity or income. Total annual national costs associated with traveling for CAR T therapy have been estimated to be between $14.7 and $21.1 million [12]. Respondents in our study also frequently noted cost, travel and lodging challenges throughout the treatment process, although cost-related barriers were more often experienced and noted as impactful by US than UK participants.
Presence of a caregiver during CAR T therapy is essential, although caregivers of patients undergoing treatment report numerous psychological and logistical burdens associated with CAR T therapy [19]. This topic also emerged as a key theme from our initial qualitative interviews and survey respondents in both the US and UK frequently selected the availability of caregiver support as a logistical challenge throughout the CAR T therapy process. They also reported that caregivers were affected by disruptions to daily activities, loss of work productivity/income and diminished quality of life or mental health. The unique challenges presented by CAR T therapy necessitate further research into the caregiver experience to inform more holistic and patient-centered service models.
Some of the logistical challenges associated with CAR T therapy may be alleviated through enhancing patient services, streamlining operational processes, adopting readily available treatment alternatives and considering outpatient administrations [10,20,21]. Additionally, bridging therapies can help control the disease during the manufacturing period [22,23]. More convenient and readily available treatment alternatives such as T-cell–directed bispecific antibodies (eg, epcoritamab, glofitamab) may also address some of the logistical challenges associated with CAR T therapy.
Our findings should be interpreted considering some limitations. The panel-based sampling nature of recruitment limits the generalizability of these results to the broader HCP populations in the US and UK. We also did not directly solicit the perspectives of patients, caregivers, payers, or other stakeholders and their views on the logistical challenges of CAR T therapy may differ from that of HCPs. Still, we aimed to gain broad healthcare perspectives by surveying physicians, nurses, physician assistants, coordinators and other HCPs in the US and UK. In addition, the potential for recall bias cannot be ruled out as responses were based on HCP recollection of their experiences. Further, although four CAR T products are currently available for the treatment of R/R NHL, this study did not examine differences in the logistical challenges across different CAR T products. Overall, our study adds to the small but growing body of literature addressing the logistical challenges of implementing CAR T therapy in real-world clinical practice.
5. Conclusion
These study findings characterize the logistical burdens and challenges associated with the stages of the CAR T therapy process from the perspective of HCPs in the US and UK. Reported challenges include lengthy waiting periods, complex administrative hurdles, limited treatment center capacity, travel and lodging for patients, the availability of caregiver support and – particularly in the US – patient out-of-pocket costs. While operational improvements might address some of the logistical barriers, these findings highlight the need for more convenient, readily available and easily administered therapies for patients with NHL.
Supplementary Material
Acknowledgments
Writing and editorial support were provided by Peloton Advantage, LLC, an OPEN Health company and funded by Genmab. Genmab A/S and AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing and approval of this article. All authors had access to relevant data and participated in the drafting, review and approval of this article. No honoraria or payments were made for authorship.
Funding Statement
Genmab A/S and AbbVie funded this study and participated in the study design, research, analysis, data collection, interpretation of data, reviewing and approval of this article.
Supplemental material
Supplemental data for this article can be accessed at https://doi.org/10.1080/14796694.2024.2393566
Author contributions
A Sureda: Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, Mundipharma: Consultancy; Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Honoraria; Takeda, BMS, Novartis, Janssen, Amgen, Bluebird, Sanofi, Kite: Membership on an Entity's Board of Directors or Advisory Committees; Takeda, BMS, Roche: Travel Expenses; Takeda: Research Funding; Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite: Speakers Bureau. K Johnston: Broadstreet HEOR and Memorial University School of Pharmacy, Newfoundland, Canada: Current Employment. S El Adam, E Griffin and J Baker: Broadstreet HEOR: Current Employment. S Yang: Genmab: Former Employment. A Wang: AbbVie: Current Employment. A Chhibber and Alex Mutebi: Genmab: stockholder and current employment.
Author roles
Study design: All authors. Study investigator: A Sureda, S El Adam, K Johnston, E Griffin. Enrolled subjects: S El Adam, K Johnston, E Griffin, J Baker. Collection and assembly of data: S El Adam, K Johnston, E Griffin, J Baker. Data analysis: S El Adam, K Johnston, E Griffin, J Baker. Data interpretation: All authors. Manuscript preparation: All authors. Manuscript review and revisions: All authors. Final approval of manuscript: All authors.
Ethical conduct of research
Ethics approval for this study was obtained prior to data collection from the Western Institutional Review Board-Copernicus Group (study #1346939). All participants in both the interview and survey components of the study were required to provide written informed consent prior to participation. Participants acknowledged that the results of the study may be published, interview transcripts could be used for research/publications and that all identifying information would be kept confidential.
Data availability statement
De-identified individual participant data collected during the study will not be available upon request for further analyses by external independent researchers.
References
Papers of special note have been highlighted as: • of interest; •• of considerable interest
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
De-identified individual participant data collected during the study will not be available upon request for further analyses by external independent researchers.