Moulik Shah

Since the release of the first ICH E6 Good Clinical Practice guidance in 1996, outlining international standards in the design, recording, and reporting of clinical trial data, technological advances in drug development have made it possible to conduct more clinical trial activities remotely and in patients’ homes. Although a revision to this earlier guidance was released in 2016 (ICH E6 R2), there has since been increasing adoption of decentralized clinical trials, as well as more use of technology given the COVID-19 pandemic. As investigative sites conduct more decentralized and hybrid trials, data collection is increasingly falling to the patient (e.g., wearable devices, smart phones). Stakeholders have expressed concerns about the impact of this trend on protocol complexity and patient participation burden during trials. The principles and guidelines in ICH E6(R2) influence the complexity of trial protocols and, by extension, the burden of data collection, validation, and reporting on investigative site staff and patients. Although the ICH E6(R2) guidance is meant to protect the “rights, safety, and well-being of trial subjects,” it does not sufficiently address the patient’s growing role or the roles of the many vendors and third parties that have entered the market.

The ICH E6 guidance is currently being revised (ICH E6 R3), and the industry has yet to see how this new iteration will approach oversight of these emerging external stakeholders. The goal of this study is to provide insight on ICH E6 revisions that could improve clinical trial operating activity by incorporating the patient’s changing role and those of the many stakeholders, including new entrants into the pharmaceutical industry.

The Tufts Center for the Study of Drug Development (Tufts CSDD) conducted a study in collaboration with MaxisIT, a technology solutions provider.* In early 2021, Tufts CSDD examined and identified areas in the ICH E6(R2) guidance document that fall short in accommodating the role of patients/study volunteers as partners in clinical data collection. To gather in-depth perspectives on these topics, Tufts CSDD facilitated three 2-hour virtual listening sessions in March 2021 among 20 clinical operations, data management, and regulatory affairs executives. A 2-hour virtual roundtable discussion was later held in mid-June 2021 to review the results of the listening sessions, gather additional insights from listening session participants, and add new voices and perspectives to the research. A total of 26 individuals attended the roundtable. Finally, Tufts CSDD interviewed six roundtable attendees during the summer of 2021 with relevant and extensive backgrounds in clinical trial regulation and development to expand upon the findings from previous discussions.

One pervasive issue that emerged during the interviews and discussions is the increased patient and study staff burden when unfamiliar technology is utilized for a trial. Although awareness and knowledge among the general public surrounding basic technology has grown exponentially in the last 10 years, patient and study staff burden can increase when the technology is sophisticated or has an interface that is unfamiliar. As a result, patient and study staff capabilities differ by trial, site, and geographic area, so the use and type of technology should be centered around the individual patient as well as the site capabilities.

One suggestion for decreasing knowledge-based patient burden when patients are oversight partners in a trial is adhering as much as possible to existing standards of care. For example, a diabetes patient participating in a diabetes-related clinical trial will have certain familiarity and capability around medical instruments and procedures more than a “healthy participant.” Whenever possible, responsibilities placed on the patient should adhere to the existing standard of care for the given disease.

Collecting feedback from trial participants and sites is another important way to prevent burden in future trials or improve the level of burden in ongoing trials. Some sponsors have struggled to effectively collect feedback from patients due to confidentiality concerns, or simply do not have feedback mechanisms available. A few participants from larger sponsor companies discussed channels in place for some trials that collect feedback from patients and sites during the study design process, throughout the treatment duration, and following the end of the trial. Such feedback channels can potentially decrease patient burden by adhering to what the patients believe is burdensome. However, these feedback channels have not been widely implemented and it will take time for sponsors to not only establish these mechanisms but also to learn to accurately interpret and cater to the patients’ needs.

A consistent theme surrounding patient burden and data collection is to only collect data that is critical to the trial and avoid extraneous protocol data collection. Although guidance in this area has been established, further clarity surrounding the restriction of extraneous data collection in ICH E6(R3) could decrease burden for the patient and the site. Other basic guidelines that currently exist may contribute to resolving this issue, such as ICH E8, which encourages patient feedback and input into study design.

During trials in which patients collect their own data and provide oversight, monitoring professionals still must review all patient activities and data. Discussions and interviews revealed concerns about how monitoring professionals can identify relevant data; validate the data; and integrate new technology in this process. Though we have yet to see how many companies will revert to on-site monitoring after the pandemic and how many will continue with decentralized models, multiple participants stated that they think many companies will return to on-site monitoring. Some of these are smaller sponsors without the technology to continue remote monitoring. Others might have a new system that relies on CRO partners, and internal staff may not be familiar with the technology. If on-site monitoring returns, the development of a remote monitoring process that allows monitoring professionals to overcome the challenges that accompany patient-collected data and patient oversight practices could be delayed until the use of decentralized trial models is more established among both large and small sponsor organizations.

Training and technological solution standardization were proposed as resolutions for decreasing burden on both patients and study staff and was discussed extensively throughout the listening sessions, roundtable, and interviews. Although there were mixed thoughts on the effectiveness of training in patient data collection and incorporating new technology systems, most participants agreed that training helps, but it should not be the only solution when confronted with these challenges. The simplicity and clarity of processes and systems, among others, are also important factors.

ICH E6(R3) should focus on data quality and patient engagement—in this case, patient engagement could mean patients have input into study design or aspects of data quality and verification. Additionally, throughout this study participants have discussed the detrimental focus on 100% SDV among sites. ICH E6(R3) should further highlight risk-based monitoring over 100% SDV, as monitoring and validating patient-collected data with 100% SDV would be difficult to carry out and would increase burden on the site and the patient.

Many participants discussed lack of system standardization across sponsors and its effect on the site’s ability to collect data and conduct trials quickly and effectively. Systems can also differ across sponsor organizations or departments within the same organization, creating confusion and additional burden for sites that have to navigate learning various systems for the same purpose. Although select vendors’ products are commonly used by most sites, there is rarely only one system that sites and patients are required to use.

Some participants in the roundtable and interviews did not see any resolution to the lack of standardization and vendor agnostic** solutions. The discussions clarified the different needs and operations across sponsors and sites, which has led to adoption of hybrid technology solutions. According to participants, implementing one system with the same capabilities across every site has not been feasible, as some level of customization is necessary for most trials. Participants expressed a need for integration and standardization of systems, however, and sponsors have not yet made the move to adopt or build centralized data platforms to improve their ability to maintain oversight and collaborate. Despite various limitations and evolving scenarios, standardization is still an important topic, and some steps can be taken to minimize the cost and time burden as well as potential risks resulted from delayed data that lack of standardization causes. One of these steps involves focusing on strategy or more efficient processes for using vendor agnostic technology when attempting to standardize systems. For example, sponsors could potentially standardize their processes so sites can more easily train for and adhere to methods across sponsors. Technology solutions should then be able to support these new methods. This process has occurred previously with GCP/ICH training, where study staff training with one sponsor can be applied to multiple sponsors across trials.

Participants did not think standardization was applicable to ICH E6, and in fact some were concerned that addressing this problem in the guidance could hinder innovation and make it more difficult for sites to operate. Standardization must occur among sponsor organizations with the focus of alleviating site burden. However, the guidance can help by implementing guidelines around topics such as third-party vendor oversight that encourage standardization of processes among sponsors, which could potentially lead to system standardization.

Leaving room for innovation in ICH E6 guidance

A common thread of conversation throughout the course of the research was maintaining simplicity and flexibility in the ICH guidance in order to be widely applicable across sites. However, a more general version of the guidance may result in variation of its interpretation among sponsors and sites. Some participants said that misinterpretation can increase burden because sites do not know what the regulator will look for during inspections. This confusion over the requirements influences the implementation of 100% SDV and other unnecessary and time-consuming tactics.

Regulators can prevent misinterpretations by providing transparency around the focus of inspections, making it easier for sites to adhere to these requirements. Additionally, industry groups and institutions can contribute to a general understanding of the guidance that will help those sites or sponsors struggling to achieve clarity in the interpretation.

The ICH E6(R3) guidance that is being developed is currently a collaborative effort with professionals from a variety of clinical trial fields incorporating their insights. This effort could contribute to a more widely interpretable document. Providing transparency on the guidance’s base principles while not being too didactic or restrictive can also leave room for innovation within the space of clinical research.

The main barriers to incorporating patients as oversight partners in clinical trials—and the acknowledgement of patients as stakeholders in the ICH E6 guidance—include the absence of technology standardization between and within sponsors and sites, protocols that overburden patients or require gathering extraneous data, and industry silos. The pharmaceutical industry is unlikely to adapt quickly to the needs of remote and hybrid trials and patients overseeing their own data collection because these barriers prevent quick turnaround. Therefore, it will take time and multiple research initiatives for the idea of patients as oversight partners to become commonly accepted and implemented throughout the industry.

ICH E6(R3), which is scheduled for release later this year, is expected to address the rapid innovations in technology and design that impact the conduct of trials. The guidance can also help encourage adaptation by considering the needs of sponsors and sites and allowing for flexibility in conducting trials. According to participants in this study, innovation is not driven by regulations. Instead, regulations create a minimum standard of quality and care in a clinical trial, and the more flexible regulations are, the more space there is for innovation among sponsors and sites.

Efforts to incorporate patients as oversight partners while addressing these potential drawbacks include training, collection of patient feedback, system standardization, vendor agnostic data platforms and maintaining an open channel of communication between the site and the patient. Although these solutions also contribute to mitigating the increase of patient and study staff burden, many sponsors have not, or state that they are not currently capable of, implementing them. Additionally, despite the higher use of digital processes and remote trial solutions during the COVID-19 pandemic, participants in this study anticipate that many sponsors will likely return to pre-pandemic standards as a result of lack of infrastructure and resources. Although patient oversight approaches have a strong place in the future of clinical trial technology, progress must be made before the industry is ready to adopt.

*This research study was funded by MaxisIT.

** In this article, vendor agnostic solutions/technology refers to a solution/technology that is generalizable, so it is interoperable among various systems.

Note: The authors would like to acknowledge Monique Garrett of PrismWorks for her contribution to this article.

Research Analyst, Tufts CSDD and School of Medicine Development, 

Professor and Associate Director, Tufts CSDD and School of Medicine Development, 

Deputy Director, Research Professor, Tufts CSDD and School of Medicine

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