Moving the bar(rier) forward: the benefits of de-risking cytokine release syndrome

By SAMANTHA McCLENAHAN

Every breakthrough in cancer treatment brings hope, but it also comes with a staggering price, raising a critical question: how do we balance groundbreaking advances with the financial reality that could limit access for many patients? 

Developing new cancer medications involves extensive research, clinical trials, and regulatory approvals; a lengthy process that requires substantial financial investment. Within clinical trials, this includes maintaining stringent safety protocols and managing a variety of adverse events, from mild reactions requiring little to no care to extremely severe events with hefty hospital stays and life-saving medical intervention. Take Cytokine Release Syndrome (CRS), for example. CRS is a common adverse event associated with chimeric antigen receptor (CAR) T cell therapy and other immunotherapies that presents across this spectrum with flu-like symptoms in mild cases of CRS to organ damage, and even death, in severe cases. The median cost of treating CRS following cancer-target immunotherapy is over half a million dollars in the United States. Tackling that large price tag – in addition to another $500,000 for CAR-T cell therapies – and reducing associated risks are necessary to break down barriers to care for many patients – especially those who are uninsured or with limited resources hindering the ability to travel, miss work, or secure a caregiver.

Unlocking Cost Efficiency in Clinical Trials with Digital Health Technologies

Integration of digital health technologies (DHTs) including telehealth, wearables such as smart watches, remote patient monitoring, and mobile applications in oncology care and clinical trials has shown immense value in improving patient outcomes, despite the slow uptake within the field. General benefits during clinical trials are captured through: 

1. Reducing clinical visits and shortening trial length – Remote patient monitoring and virtual consultations minimize the need for physical visits, accelerating trial timelines. 
2. Enhancing recruitment, diversity, and participant completion – Targeted outreach supported by big data analytics and machine learning algorithms helps to effectively identify and engage with eligible candidates, leading to faster recruitment and lower dropout rates. Digital technologies also overcome traditional barriers to participation, such as location, transportation, language barriers, and information access.  for a broader representation of patient demographics and more generalized findings and improved healthcare equity. 
3. Increasing availability of evidentiary and safety requirements – Continuous data collection and monitoring in the setting most comfortable to patients – extending beyond clinical walls. This provides a pool of data to support clinical endpoints and enhances patient safety by enabling early detection of adverse events. 

While the exact cost of these digital interventions varies by study, there is significant evidence that cost-saving measures are emerging.

A plethora of digital technologies have been explored to enhance recruitment and enrollment with mixed-cost benefits across technologies. However, the expected net present value of employing digital endpoints is encouraging, ranging from $2.2 million to $3.3 million for phase 2 studies up to $27 million to $48 million for phase 3 studies with up to seven times the return on the investment for utilizing digital endpoints. 

How can this momentum translate to overcoming clinical trial costs associated with a potentially severe adverse event like CRS? 

Upping the game – the future of safe outpatient administration for immunotherapies

Patient safety is paramount, such that the extreme risk of CRS necessitates special safety considerations. Investigational immunotherapies with a risk of CRS are often required to be administered in an inpatient clinical setting, placing a high burden on trial participants and substantially increasing trial costs. Furthermore, highly specialized healthcare teams with expertise in CRS and related toxicities must be in place, limiting the locations of these studies to specialized sites with available resources.  With so few sites available, many patients can’t partake in clinical studies despite otherwise meeting inclusion criteria. 

The diverse clinical presentation of CRS complicates matters further. Initial and progressing symptoms of CRS may develop differently among patients, making it difficult to know which participants are likely to experience severe cases of CRS. 

Adding multiple dosing strategies, various disease states, and prophylactic treatment confounds the uncertainty, particularly for investigational immunotherapies. 

This begs to question – can these investigational studies be safely moved to an outpatient setting allowing for decentralized trials? The answer – maybe. Several facilities, including Mayo Clinic, Memorial Sloan Kettering Cancer Center, and University of Chicago Medicine Comprehensive Cancer Center offer FDA-approved CAR-T cell therapy in an outpatient setting, utilizing remote patient monitoring and clinic visits. The Phase 2 TRANSCEND study, a clinical trial evaluating Breyanzi (liso-cel) for adult patients with relapsed or refractory follicular lymphoma, treated patients in the inpatient and outpatient setting, supporting accelerated approval by the FDA. These practices are establishing safe pathways forward with reliance on prior clinical trial data and prior clinical experience. When it comes to new CAR-T therapies, a group of hematology experts convened by the American Society for Transplantation and Cellular Therapy expressed that the inpatient setting allows for the safest transition of CAR-T from the bench to the bedside. Bispecific antibodies, with more favorable safety profiles, required touchpoints and off-the-shelf capabilities, are likely to be more amenable. How this extends to truly novel cancer-targeted therapies is debatable and highlights the unmet need for mitigating risk of CRS. 

The pathway forward – reducing the risk of CRS with DHTs

Reducing the risk of CRS and related severe adverse events to safely move these studies to an outpatient setting is key to increasing access and promoting equity with these life-saving therapies. We are at the forefront of this reality with vast advancements in DHTs and supporting infrastructure.  

Deploying sensor-based, continuous monitoring devices and supporting DHTs, such as mobile apps for connecting to health records, inputting patient-reported outcomes, and offering critical care-related information, can reduce patient and caregiver burden by reducing the physical and mental load – such as remembering to collect the required vital signs checks, the weight of monitoring for early symptoms associated with severe adverse events, and the risk of experiencing CRS –  while ensuring the safety of the patient. Sensor-based technologies, like TempTraq and Current Health wearable device, offer the ability to detect potential adverse events in advance of standard of care, providing valuable time to seek care and allowing for earlier intervention, which may prevent CRS progression. 

All of this to say, reaping the full benefits of DHTs to mitigate the potential complications of CRS necessitates continued innovation. Developing risk prediction tools for CRS is key to determining which participants are good candidates for administration in an outpatient setting, which cases of CRS will progress without intervention, and predicting which participants will develop severe CRS before CRS is clinically detectable. While several laboratory markers are being explored for predicting CRS prior to the administration of immunotherapy and after the diagnosis of CRS, identifying a digital signal for risk prediction of severe CRS will be a game changer.  

Hitting the bottom line – where everyone reaps the benefits

Clinical trials are currently unsustainable, with rising costs crippling the drug development process. Patients are left to foot the bill or are without access to critical therapies, and innovative, life-saving solutions are not being administered. In severe events like CRS, the incorporation of DHTs to overcome these hurdles offers tremendous value and opportunities that have yet to be fully captured.

The ability to safely administer high-risk immunotherapies in an outpatient setting will improve patient access and equity. De-risking CRS through initiatives like the pre-competitive collaboration hosted by the Digital Health Measurement Collaborative Community (DATAcc) by the Digital Medicine Society (DiMe) is driving this reality. The project, through combining the expertise and experience of a diverse, multi-stakeholder group, will define the common elements of digital measurement of CRS and advance the development of a CRS risk prediction tool to mitigate the costs and the risk of CRS associated with cancer-targeted immunotherapies. 

This is the pathway forward – for CRS and any clinical research with serious adverse events.

Samantha McClenahan, Ph.D. is a Program Manager at the Digital Medicine Society (DiMe)