Marina Acosta Enslen

Due to the timing of the industry’s gradual shift towards more decentralized clinical trial (DCT) models, when COVID pushed trials outside of the sites, Rho was already positioned to quickly adapt and narrow its focus towards the development of technological solutions that capture efficient and high-quality data in a virtual setting.

To seize the right opportunities, we have had to remain flexible in our approach. This adaptability is the driving force behind Rho’s development of a robust Risk-based Quality Management framework (RBQM). The customized framework has allowed many sponsors to navigate and implement decentralized solutions for their clinical trials and programs. While focusing on potentially critical risks, the framework helps you identify the right monitoring strategies for your trial. Rather than spending more time and money on-site, the streamlined approach provides the most value without sacrificing data quality.

Due to the ICH E6r2 requirement of sponsors (or CRO delegates) to implement quality risk management of clinical trials, it is more important than ever to direct our attention towards highly effective technology advancements. A federally registered revision to ICH E6 (R2) makes explicit the responsibility of the sponsor to understand and actively manage the risks to quality in clinical trials using a Quality Risk Management (QRM) approach.

Based on our experience helping sponsors navigate and implement decentralized solutions for their clinical trials and programs, we believe that the best decentralized solutions are patient-centric, customized and rooted in a robust Risk-Based Quality Management (RBQM) framework. Rho’s methodology was developed in partnership with a consultant from PharmaInitiatives and is derived directly from ICH E6R2. Other tools Rho used to develop its RBQM framework included resources and tools available from Transcelerate and the Metrics Champion Consortium, now part of the WCG Avoca Group.

The following are considerations for successfully implementing effective decentralized solutions:

—A formal risk analysis is the foundation for implementing a decentralized solution. A data driven RBQM process that allows you to identify and evaluate risks early, monitor those risks and provide insights to adjust throughout your trial is essential. A robust RBQM process led by an experienced CRO will help determine the type of decentralized solution needed for your clinical trial (e.g., fully virtual or hybrid). It will also help you make decisions around the most appropriate use of monitoring strategies, including risk-based monitoring, central monitoring, off-site monitoring, and targeted source data verification (TSDV), as well as provide insight into other critical considerations for subject safety and data integrity.

—The patient must be the central focus of any decentralized solution. This includes considerations for safety, engagement, and study logistics. When clinical sites are closed and/or travel to sites is a burden to patients, it’s important to consider the following:

—Many of our sites have implemented telemedicine visits to evaluate subject safety throughout a decentralized trial. In a telemedicine visit, the clinical site staff connect with the patient via phone or web conference to assess new and/or ongoing adverse events and any changes to the patient’s medications.

—It is important not to overlook a local laboratory as an option for certain blood collections. Allowing a patient to have blood draws done at a lab closer to his or her home, can reduce patient burden. We have also partnered with a vendor that provides the patient with the ability to collect blood, urine, saliva and stool samples in their own home and send it directly to the lab for analysis.

Direct to patient (DTP) Investigational Product (IP) shipments

—We have developed strategies for the dispensation of IP, such as home delivery or use of courier services for shipment of IP directly to patients’ homes. To ensure IP maintains a specific temperature in transit, our shipping partners use a controlled temperature shipper and a temperature tracking device.

—We have implemented many types of off-site monitoring processes to meet the needs of specific decentralized clinical trials. These solutions have included customized approaches to and levels of risk-based monitoring, off-site monitoring and targeted site data verification (TSDV). The right combination of these solutions for your clinical trial will depend on the risks identified in the RBQM process, along with the status of your clinical trial or program (e.g., a new study that has not begun yet versus a study that has been on-going and needs to implement a decentralized solution partway through), and the level of access to your clinical sites.

Centralized Monitoring and Data Visualization

—Remote evaluation of clinical data (e.g., centralized monitoring) is a critical component of any decentralized solution, and it becomes more important as direct access to clinical sites and patients is reduced. Centralized monitoring is used to identify trends in the clinical data, including information pertinent to site management activities and data related to safety events. Our teams have centralized monitoring tools to identify key quality and risk indicators early and monitor them throughout the study to provide actionable and timely insights that will help manage your decentralized clinical trial.

—Technology is a key component of most decentralized solutions. At Rho, we have implemented eCOA and ePRO solutions, along with devices and wearables that capture data directly from patients. Technology solutions have the potential to significantly reduce patient burden and increase patient engagement if implemented properly. It’s important to map out a strategy early in the process, which includes robust plans for site and patient training. It’s also important to ensure that the CRO you are working with has developed strong partnerships with any technology vendors they bring to the table.

—The conditions at research sites and patient availability have rapidly shifted over the last few years. Therefore, it is even more important to have a decentralized approach that is grounded in a robust RBQM framework, which can provide data and triggers to determine when a shift in approach is necessary.

—To document potential changes to your decentralized strategy, make sure to update study plans and protocols throughout your trial or program. Study plans include the project management plan, clinical monitoring plan, and the statistical analysis and data management plans, among others. Updating plans and protocols will ensure compliance and result in reliable data that supports endpoints.

Looking forward, DCTs are here to stay. However, these decentralized solutions are not one-size-fits-all. The right solution for your trial or program should be determined and managed using a robust risk-assessment process, which will identify risks upfront and monitor them throughout to let you know when changes need to be made.

To fully realize all the advantages and benefits of a truly decentralized approach, partnering with a reliable and experienced CRO to implement and execute your decentralized solution is critical. While there are no set guidelines to define the future of clinical trials, our industry is at a unique point with boundless opportunities to craft adaptable solutions that best serve our patients.

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Industry provides endless methods in crafting solutions for patients.

How One CRO Uses RBQM in DCT Implementation

In March 2018, FDA placed ICH E6 (R2), a revision to Good Clinical Practice (GCP), in the federal registry. This regulatory update made explicit the responsibility of the sponsor to understand the risks to quality in clinical trials via the use of a Risk-Based Quality Management (RBQM) approach. Consisting of a variety of required components–including but not limited to quality risk assessments, a written Quality Risk Management Plan, and strategic, centralized data reviews–the revision underscores the importance of a robust RBQM framework to ensure clinical trial execution in compliance with GCP.

In the months since ICH E6 (R2) was adopted, a global pandemic has impacted clinical trial operations. However, even before the pandemic, many companies were still working to become compliant–and while COVID-19 has introduced its share of roadblocks to the industry, it has also prompted sponsors to intentionally embrace the adoption of a RBQM framework to new and ongoing trials.

In this article, we will examine the overall value of ICH E6 (R2) to sponsors, as well as how COVID-19 has and will continue to influence sponsors’ consideration of risk-based monitoring as a key component of clinical trial operations.

Benefits to ICH E6 (R2) and an RBQM framework

Early, targeted risk assessment tells you where you need to look and watch. In other words, to adopt a RBQM framework means to focus more on what matters most: the critical data/processes and potential risks unique to each trial. As the foundation for a targeted, risk-based approach to monitoring, RBQM helps sponsors first identify and understand their trials’ most critical risks before choosing the monitoring strategy that provides the most value.

So, what exactly does ICH E6 (R2) ask of sponsors, and what benefits does it offer in return for the time invested in making the transition? As it currently stands, ICH E6 (R2) requires sponsors to implement the following:

Quality risk assessments, starting at protocol development and ending with database lock

A written RBQM Plan and demonstration of plan execution

Strategic data reviews throughout the clinical trial

A robust RBQM framework and approach to ensure regulatory compliance

While these additional assessments and reviews may seem overwhelming at first glance, it is important to consider these requirements alongside the benefits they provide:

Improves the likelihood of a high-quality clinical trial

Ensures clinical trial execution in compliance with GCP

Focuses on data and risks critical to trial endpoints and patient safety

Provides quick access to data insights across clinical sites and patients

Potentially reduces the amount of on-site monitoring needed

In efforts to adapt the ICH E6 (R2) revision, many companies have encountered difficulty transitioning to a risk-based approach and adaptive monitoring strategy. However, the potential risks that could result from foregoing an RBQM framework far outweigh the transitional period.

For sponsors still weighing the necessity of adopting a RBQM approach, it is important to recognize that the decision to skip proactive, risk-based monitoring brings a risk to safety, data integrity, and even primary endpoints, any of which could drastically impact trials if not monitored appropriately.

Likewise, clinical trials characteristically produce massive amounts of data for study staff to sift through. However, if they have not proactively identified key data and processes that could bring potential risk, they run the danger of getting “lost in the weeds” and overlooking risk factors that later breached tolerance limits and resulted in issues that had some level of impact on the study and its results.

Employing the expertise of a CRO is an option for sponsors to help alleviate the work and time commitment required to adopt a RBQM process on their own. At Rho, we consider a robust RBQM framework to include dedicated quality risk managers, RBQM templates to assist with creating the plans required by ICH E6 (R2), a strategic approach to data review, among other components.

COVID-19, ICH E6 (R2) and a risk-based future

The global pandemic is a major risk in and of itself, and it has certainly revealed the extent of its negative impact on a variety of industries, resulting in closures, layoffs and more. When observed through a clinical research lens, COVID-19 is the type of risk that should be accounted for proactively–ideally via an RBQM approach. However, the reality is the shocking and surprising onset of the pandemic did not provide the clinical research industry–or any industry–the foresight to prepare for every single roadblock presented by a pandemic of this scale.

For many ongoing clinical trials, when the pandemic hit, sites stopped seeing patients in-person, encountered issues with enrollment, along with other delays. This required sponsors to pause and identify what risks COVID-19 could bring about to potentially impact the future of the trial. Arguably, this situation has forced sponsors to look at their trials through an RBQM lens and adopt this process or encounter the risk of halting their trials altogether.

On the other hand, those in the planning phase have the privilege of incorporating pandemic-related mitigations into their programs up front.

During this stage, an early adoption of RBQM provides the opportunity to proactively determine what can be monitored centrally or conducted remotely via on off-site visit or very limited on-site visits to safeguard patient and staff health and safety.

Overall, ICH E6 (R2) underscores the sponsor’s responsibility to evaluate and implement risk-based monitoring into their clinical trials, before, during and even after the era of COVID-19. We consider a risk-based future to consist of the following:

Site monitoring visits conducted based on tracking and managing risk at the site

Initial set of visits may be pre-planned but then visits are driven by findings–leading to a variable frequency of visits across the study and between sites

More findings or more severe findings leads to more visits and vice versa

Visit types (off- or on-site) driven by number, severity, and type of findings

It is important to note that the possibility of more on-site visits will likely be delayed as we continue to adapt and recover from the impacts of COVID-19. However, decentralized clinical trials provide a viable solution for this setback, as long as they are patient-centric, customized and rooted in a robust RBQM framework, per the ICH E6 (R2) guidance.

Arguably, the global pandemic has redefined our understanding of a “traditional” clinical trial, as more sponsors are implementing decentralized clinical trials to keep studies active during this time. Despite this shift, many organizations have still been slow to adopt ICH E6 (R2) and make the necessary updates. Future updates to ICH E6 (R2) will likely be driven by this need for more frequent adoption of the revisions, as well as pave the way for an easier industry-wide transition to a risk-based monitoring approach.

Associate Director, Clinical Management, Rho

COVID-19 pandemic forces compliancy within organizations following FDA’s 2018 revision of Good Clinical Practice in federal registry. 

Marina Acosta Enslen

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How One CRO Uses RBQM in DCT Implementation

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