Pandemic-Proof Clinical Study Start-Up

The fear of exposure to SARS-CoV-2 in healthcare settings has deterred people from seeking care for non-COVID-19 diseases. One solution to patient care and biomedical research disruptions is implementing remote solutions for conducting research and collecting samples.

As the COVID-19 pandemic continues to spread, its effects on the health of patients with diseases other than COVID-19 are becoming increasingly apparent. 

The fear of exposure to SARS-CoV-2 in healthcare settings has deterred people from seeking care for non-COVID-19 diseases, resulting in delays in screening, diagnosis, and treatment. For instance, a report showed a 46.4% drop in new cancer diagnoses across six common cancer types in the first wave of the pandemic.

In fact, a model developed by the National Cancer Institute predicts that there will be almost 10,000 excess breast and colorectal cancer-related deaths over the next decade in the U.S. due to delays in diagnosis and treatment. Similarly, experts predict a surge of cancer relapses to come to light, diagnosed later in the progression of the disease due to delays in surveillance, ultimately leading to a spike in cancer-related mortality.

Beyond clinical care, the pandemic has also caused severe disruptions to biomedical research, resulting in suspensions or shutdowns at many clinical trial sites. An analysis of 4,599 studies and 18,321 study sites showed a decrease in patient enrollment—about 48% of those in oncology clinical trials.

During these unprecedented circumstances, one solution to the current disruptions to patient care and biomedical research in oncology is implementing remote solutions for conducting research and collecting samples for clinical trials, such as liquid biopsy assays. Here, we discuss how the Signatera liquid biopsy assay, through the BESPOKE CRC study, can help cancer patients maintain their recommended surveillance schedule without in-person visits to their oncologist, as well as the operational changes Natera had to implement to successfully complete study start up during uncertainty.

A tumor-informed approach to monitoring patients with CRC

The BESPOKE Study of ctDNA Guided Therapy in Colorectal Cancer aims to demonstrate the impact of personalized molecular residual disease (MRD) monitoring on treatment decisions and outcomes in patients with Stage II-III colorectal cancer (CRC). The target enrollment for this observational study is approximately 1,000 subjects with Stage II-III CRC in the prospective arm, and 300 subjects previously treated for Stage II or III CRC into a retrospective control arm. The first site was activated in late April, and the first patient was enrolled in May of this year.

This study uses circulating tumor DNA (ctDNA) as a biomarker for MRD, which will be assessed using a personalized ctDNA assay, Signatera. Customized to the unique genetic signature of a patient’s cancer, Signatera starts with whole exome sequencing of the patient’s tumor to identify multiple high-quality clonal mutations to track over time. Signatera has been validated across multiple cancer types to detect MRD up to two years earlier than standard diagnostics tools, demonstrating that this "tumor-informed" approach enables highly specific and accurate MRD detection for the patient.

Key study endpoints include:

  1. Determining the percentage of patients whose adjuvant treatment regimen increased or decreased based on their MRD status post-surgery, as assessed by the Signatera test
  2. Determining the rate of recurrence, as evaluated by the same assay, at any point during surveillance, prior to identification by other methods
  3. Assessing anxiety levels and well-being in patients receiving Signatera ctDNA test results

Shifting strategies to complete study start-up amid uncertainty

The COVID-19 pandemic necessitated changes to clinical operations to ensure the safety of patients and healthcare professionals. For example, due to the reallocation of healthcare personnel to the pandemic response and physical distancing measures, oncologists have been forced to prioritize in-person visits with patients with a high-risk of relapse. However, a need remains to prevent interruptions to the surveillance schedules of low-risk patients and to accurately identify patients who can safely avoid or delay chemotherapy, which weakens the immune system. As such, the Signatera technology is ideally suited for remotely addressing both of these issues, and serves a critical unmet need during the pandemic.

Moreover, to ensure continued participation of clinical sites and patients in the BESPOKE study throughout the pandemic, we modified the study to thwart challenges due to travel restrictions and to protect immune-compromised patients. At Natera, we design clinical operations with a “patient first, provider friendly” mentality. Therefore, we could rapidly execute changes to manage study timelines during pre- and post-study start-up as outlined below:

Pre-study start-up

  • Conducted introductory calls with sites to review study design and procedures (data and sample collection), as well as to assess site feasibility.
  • Modified protocols to allow electronic informed consent (e-consent) of subjects, allowing them to read the study details at home and have a follow-up phone call with a study coordinator to review the study and discuss any questions.
  • Identified and developed relationships with CRC advocacy groups who could connect with patients, in the absence of HCPs, who could educate them about Signatera.
  • Established remote site initiation visits, enabling sites to operate despite lockdowns and travel restrictions imposed to minimize the spread of COVID-19.

Post-study start-up

  • Implemented an existing online portal to allow oncologists to order Signatera virtually.
  • Expanded our mobile phlebotomy service to ensure that every patient could be tested through an in-home blood draw. In-home services reduce travel, improve patient retention and ensure compliance, while decreasing the risk of patients dropping out of the study due to COVID-19 infection at the site.
  • Utilized electronic data capture, in addition to capabilities to remotely monitor and query the data, to avoid onsite monitoring visits, while maintaining oversight of the data in real time. An early insight from the study data was that patients were being excluded from the BESPOKE study because they were slightly delayed in testing post-surgery. With this information, we could relax the eligibility criteria and consent patients in a broader window.
  • Used electronic patient reported outcomes (ePRO) for collecting data on patient anxiety levels and wellbeing after receiving Signatera test results. Patient questionnaires are sent via email to the participant to complete at home, eliminating the risk of COVID-19 exposure at the clinical site.

Conclusion

The COVID-19 pandemic has placed tremendous, prolonged stress on the entire healthcare ecosystem, as well as cancer patients who are forced to reconcile their concern for recurrence with the reality of the limitations the pandemic has placed on their care. Remote monitoring technologies, such as Signatera, can be a life-saver in these circumstances, by providing a safe way for patients to stay on-track with surveillance and by avoiding needless chemotherapy that can further weaken their ability to fight off COVID-19 infection.

Natera’s ability to quickly pivot when initiating the BESPOKE CRC study—leveraging the blood-based feature of the Signatera assay to overcome challenges imposed by the pandemic and adapt its clinical operations for a remote scenario—may help others “pandemic proof” their clinical operations.

Alexey Aleshin, MD, MBA, is the Senior Medical Director of Oncology at Natera