A Case for Resiliency in Clinical Trials
Recent major historical events – the emergence of COVID-19 and the ongoing military conflict in Ukraine – has painfully proven to the global life sciences community that unexpected disruptions are inevitable. In part one of this article series, we examined difficulties encountered in the field during the initial months of the conflict in Ukraine, including patient communication and safety, regulatory hurdles, supply chain challenges, and ethical concerns. As a community, we continue to carry these challenges forward, with many wondering if they made the right decisions in the moment.
The advent of new technologies and flexible approaches in trial management provides a unique opportunity to creatively integrate compliance, convenience, and risk management. Though no one can truly prepare and completely mitigate against the potential impacts of emergent global events, it is possible to incorporate hard-learned lessons into future responses to the ethical, medical, and methodological effects of clinical trial disruptions of this scale.
In this second installment of the article series, we seek to examine components that may offer conflict-resilient strategies in clinical trial design. Here we provide an in-depth analysis of a few key strategies to safeguard the success of clinical studies through integrated technology solutions, incorporating flexibility into protocol design, and ensuring program agility in supply chain management.
Meeting Patients Where They Are: Decentralizing Clinical Trials
A site-centric approach requires patients to attend study visits in person at the clinic. This often has a negative effect on long-term patient retention, satisfaction, and diversity, biasing patient samples towards a whiter, wealthier portion of the population who were able to meet the rigid long-term schedules of in-person clinical visits for studies. While most clinical trials don’t have the capability to be entirely virtual, there are many opportunities for using decentralized elements based on suitability for primary and secondary endpoints.1
During the COVID-19 pandemic, the landscape of the randomized controlled trial (RCT) with a site-centric approach rapidly shifted. Decentralization became a necessity with clinical trials transitioning to either hybrid or fully remote settings. In many ways not dissimilar to the pandemic, the conflict in Ukraine has placed a heavy burden on ongoing on-site trials in the region and has created gaps and stoppages for trial participants living in Ukraine. Yet, as we examine the increased enhancement and implementation of digital health technologies (DHTs), there is an opportunity for greater future trial success.2
Implementation of increased decentralized elements to clinical trial operations can have many benefits, but as is typically the case with traditional trial approaches, study visits for Ukrainian patients have largely been limited to the physical site. Many sites in Ukraine, Russia, and surrounding areas were functioning within traditional expectations, maintaining paper study documentation, and requiring all visits to be in person on-site at the clinic of record. Unfortunately, this meant that maintaining treatment protocols with patients was nearly impossible once the conflict began. Transfer of these patients, along with their records and data, to sites in neighboring countries to ensure their safety and continued care as refugees created an additional challenge.
Decentralized Clinical Trials (DCTs) leverage telemedicine, home visits, secure online data collection platforms, wearable devices, and direct delivery of study drugs and materials to patients’ homes to streamline the trial process where and when feasible.3 Decentralization of clinical trials has been shown to reduce the traditional burdens on patients by bridging their involvement through more remote, and perhaps safer, trial design.
In the case of Ukrainian patients, DCTs offer the opportunity to continue studying treatments while minimizing the inherent risks of travel through a war zone. Dr. Maksym Basarab, of the Clinic Garvis in Dnipro Ukraine, noted “Currently in Ukraine, there have been three situations, each with different considerations and recommendations for clinical trials: active war zones, frontline zones, and areas where aggression, is for now, unlikely… all three scenarios are present simultaneously and dynamically”.4 In each of these zones, patients, and physicians are making evaluations of trade-offs between access to conventional therapy, clinical trials, and most importantly, patient safety. DCTs provide physicians additional tools to continue to offer treatment to patients, even in less-than-ideal circumstances, when standard therapies are not available or when traveling to a clinical research site is an undue risk to patient and site safety.
Telehealth components of DCTs may be a way for patients to continue participation in studies, but these technologies may also provide a benefit to patients. A study assessing patient-reported outcomes (PRO) for symptom monitoring during routine cancer treatment noted a statistically significant increase in overall survival of five months in the PRO group.5 Another study of patients providing daily symptom assessments noted decreased presentation to acute care facilities when compared with patients who were not providing symptom assessments.6 Many clinical trials, of which there were over 400 in Ukraine in April 2022 could collect toxicity data from devices that patients could use from their homes.7 An example of this is pulse oximeters to identify toxicities such as pneumonitis, which ideally leads to early detection and intervention.8 Knowing that a healthcare provider has provided input on a symptom can be comforting to a patient or can convey the need for expedited intervention. Regardless, connecting the patient and provider in the most efficient manner may allow for the remaining operating healthcare systems to serve as many as possible by utilizing the resources available.
For patients around the world, clinical trials offer value. Hope is a big value driver for patients. Today, we are armed with the resources, frameworks, and technology to continue to offer hope to patients amid increasingly difficult circumstances and this may be the most patient-centric action the greater clinical trial community can implement.
Building Flexibility into Protocol
Structuring a clinical trial protocol to allow for a decentralized approach has undeniable benefits. In a DCT, the management of study medication and collection of data may never involve in-person contact between the study team and the patient, which enables a clinical study to continue even in times of significant disruption.
It is critical to take advantage of new opportunities that integrate technological advancement as it allows for flexible and agile solutions. Protocol design not only impacts the scientific value of a clinical trial, but also influences many operational factors that impact how well the study is conducted, so it is important to consider these innovative approaches early on.9 Here are some ways to consider how to build flexibility into a protocol:
Consider Alternative Locations
Alternative clinical site locations and home health care visits typically reduce patient and caregiver burden and risk during times of uncertainty. Home health services are a flexible and safe alternative for patients to continue their involvement in clinical trials. This, in turn, also improves study participation and retention which leads to higher recruitment rates. Overall, patients are kept safe while continuing their trial involvement.
Evaluate Visit Window Expansion
Hold conversations with clinical teams and Key Opinion Leaders (KOLs) about whether additional time can be built into visit windows and if it’s logical in certain instances. It’s important to take into consideration the therapeutic area, patient population, and the needs of the clinical team while considering this direction.
Deliver Investigator’s Product (IP) Directly to Patients’ Homes
This option may be the least utilized DCT approach but is the most ideal option when patients are unable to get to the site.6 While the regulatory regulations are not clear on how to integrate this into protocols, it is an option worth looking into.
While implementing these technologies requires some upfront costs, the financial benefits of incorporating these approaches outweigh the initial investment by improving both patient satisfaction and study outcomes.
Developing and Implementing Risk Assessments (Site Selection)
Another upstream factor in building conflict resilient trials is how and to what extent a sponsor performs risk assessments during site selection at a study startup. In lockstep with the growing regulatory trend toward risk-based management, regulatory bodies have placed greater emphasis on the need for sponsors to apply risk mitigation tactics to improve study execution.10-11 Since the COVID-19 pandemic accelerated much of the thinking around adaptation to adverse trial scenarios, with additional regulatory guidance provided around patient safety and study conduct, the framework for continuing study execution in the face of extensive disruption has improved.12 However, the conflict in Ukraine has presented a uniquely severe regional challenge, coupled with an uncertain timeline for resolution, such that trial operations in Ukraine have been pushed to the brink. This highlights the importance of employing methods for assessing and accepting risk before beginning a study.
The full suite of major risks to clinical trials have been realized in Ukraine. The shutdown of trial sites, which has created stoppages and/or inaccessibility for patients to medicinal product supply, has demanded that trial operators engage with the ways that they can both support patients and ensure ongoing investigation. This situation has placed a premium on established mechanisms for communication, starting primarily with the requirement that sponsors must actively inform their trial participants about the option to continue their treatment abroad. Especially as the European Union and other relevant authorities have worked with sponsors and their contracted partners to ensure trial continuity where and when possible, enabling ongoing participation has prompted activity in three key areas: sponsor reporting of patient transfer, performing substantial modifications or amendments to trial protocol, and transferring clinical data.13
The activities incumbent upon the sponsor in supporting patient participation within regions disrupted by conflict lay the foundation for examining these same activities in the context of risk. The key, in the scenario of a potential trial being impacted by war, is determining how to define a certain risk, and then proceed after analysis of those risks with a generated outcome. While this approach is applied to conventional risk-mitigation planning during study startup, it can also be applied to aspects of trials that would become relevant in wartime, such as the nuances of the surrounding geographic regulatory landscape.
With recent enhancements to quality management through risk-based monitoring (RBM), the International Council for Harmonisation (ICH) has provided sponsors with the flexibility to approach the identification, assessment, control, communication, and review of risks in a more streamlined fashion.9 Implementation of a Risk-Based-Monitoring (RBM) methodology strengthens a sponsor’s ability to safeguard a patient’s safety, rights, and data. Without an end-to-end suite of tools that leverage data-driven metrics for trial management capabilities from the outset, a trial that becomes jeopardized by a critically impactful world event may be in much greater peril than one that has developed and implemented these approaches to risk.
Utilizing Technology: Optimizing Data Collection and Integrity
A significant contributing factor to successful DCTs is the use of technology to improve trial management and patient experience. The best-known and often most easily implemented technology solutions include electronic data collection, patient communication, and automated supply chain management platforms that streamline patient-facing activities. However, this is barely the ‘tip of the iceberg’ in terms of technology enablement options that can improve clinical trial functionality.
Currently, trial data are often processed through manual paper workflows, and in many cases leads to discontinuity in measurements and processing of endpoint data. However, new health technologies have expanded industry capabilities by utilizing smart devices, environmental sensors, and wearables, all of which can contribute to digital endpoints. Novel digital endpoints measure biomarkers of clinical relevance.14 For example, heart rate measured simultaneously with exercise intensity, and while being collected remotely in a real-world setting, may be a great addition to a cardiac function protocol with the added bonus that these data can be passively collected and compiled even if the patient is displaced or otherwise unavailable for a site visit.
While digital health technologies can have a profound positive impact on our ability to quickly and easily collect large amounts of data with little patient or clinical team effort involved, they can also open new avenues of risk to data security and data integrity.15 Evidence that suggests utilizing blockchain technology to support key clinical trial activities such as electronic consent and the exchange of information collected through digital health technologies can improve data inviolability and traceability, and even improve patient retention. Utilizing blockchain implementations to collect, store and share clinical trial data offers many enticing benefits to clinical researchers. It can support stacking data structures for collection and tracking of metadata, offers ‘privacy by design,’ and enables secure cloud data sharing, but the blockchain is still a new concept for the life sciences and medical communities and will require the support of established third-party vendors to implement. 8, 15, 16
In summary, adding wearables or digital technology to clinical studies allows digital data to be collected automatically and enables continuous and longitudinal health monitoring. This will reduce the need for clinic visits and promote continued patient participation.15 During times of crises, when patients are unable or unwilling to visit their clinical site, digital health technologies can ensure that data are still collected and protected. Implementing these solutions as a key part of a protocol will allow greater flexibility for research teams in meeting their regulatory and reporting requirements but will require special consideration to ensure data security.
The conflict in Ukraine offers an example of unique circumstances for patients and clinical trial operations where both could see benefits from further adoption of DCTs. The infrastructure that underpins DCTs is ubiquitous in the United States and most of Europe. For example, devices utilized for DCTs may need to factor in redundancy in terms of storage capacity to mitigate against the potential for dysfunction within traditional data transmission methods. Those implementing DCTs in Ukraine and surrounding regions need to plan for risks and contingencies.
Supply and Manufacturing: Challenges and Opportunities
By standard regulation, a drug product, whether approved or investigational, is clearly defined, (i.e., single-use or multiple doses) for a given dose strength and product configuration, (i.e., a single-use vial containing x mg/mL of [compound y]). Deviations from dosing based on the defined configuration without prior Health Authority approval carry significant clinical ramifications. This is important to ensure that all patients in a clinical trial receive the same Investigational Medicinal Product (IMP) so that clinical outcomes can be equivalently measured.
When conflicts such as the war in Ukraine arise, supplies of IMPs are put at risk, which in turn risks the continuity of the clinical trials in which these IMPs are used. With supply chains severed by the Russian aggression towards Ukraine, added flexibility into how these specifically defined IMPs can be utilized had to be considered. Consider that an IMP was defined as “single use,” but had excess Drug Product (DP) included in the dosage form to ensure adequate DP was present for standard dosing. Could that “single-use” dosage form, in extenuating circumstances, be used to treat more than one patient? This was assuming all proper measures to ensure patient safety were taken.
Faced with constrained (or severed) supply chains of a given IMP, some flexibility had to be considered in order to safeguard the continued ethical treatment of patients who had enrolled in the clinical trial prior to the conflict. Recognizing these constraints, and utilizing the precedents set during the COVID-19 pandemic, newer flexibility in guidelines regarding IMPs have been introduced.
Following the lead from Austria and other European countries, guidelines have been established that allow for patients within clinical trials to be transferred to other EU countries. The requirement being that the trial must have already been established in the country of the transfer. Provisions are made for the language requirements on the Informed Consent Form (ICF) and drug product label (i.e., these do not necessarily need to be relabeled in Ukrainian, but in a language that the patient can understand.) If the ICF is not in a language that is understood by the patient, both the patient and translator need to sign the form. A mechanism has been established to submit a substantial amendment to the CTA, presumably also covering required chemistry, manufacturing, and controls (CMC) changes, that are necessary due to the conflict in Ukraine. One requirement of this mechanism is to clearly call out that the changes are being made due to the war, and that these requested changes may not be bundled with other changes unrelated to the war. While it is not clear which specific CMC changes are available to be made due to the conflict, precedent from the COVID-19 pandemic has indicated that flexibility regarding supply chain and shipping conditions will be considered.
One final point for consideration is that while sponsors will have the best intentions to protect the safety and integrity of the care of the patients in the study, they must always make it abundantly clear that the safety of the patient will not be compromised to preserve the trial, even in extenuating circumstances such as wartime.
Concluding Remarks
Incorporating technologies and flexible approaches in response to or in preparation for a major global disruption is certainly not the solution to preserve all data integrity, patient and staff safety, and regulatory boundaries. But it is a strong step in the right direction and allows our industry to evaluate tools and technology that enable more conflict-resilient trials even before future conflicts arise. We are seeing more of what is possible in clinical trial design.
COVID-19 taught us to reimagine clinical operations and lean into current tools and adopt new technology, and we too see the same lesson with how clinical trials are impacted by the war in Ukraine. These lessons are certainly not the last, but they are significant enough to impact future clinical trial design and operations to come.
As advisors, thought leaders, and service members of the clinical study community, it is our responsibility to thoughtfully consider solutions and risk mitigation efforts to provide our clients with appropriate support. We will be releasing our third installment of this article series in 2023 on clinical trial risk mitigation in crisis and conflict.
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To inquire how Halloran may help your organization’s clinical trials during disruption or to plan for conflict-resilient clinical trials, please contact us.
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