Following the COVID-19 outbreak, which caused unprecedented disruption to the running of clinical trials, there has been an increasing interest in facilitating virtual clinical trials. A recent review highlighted the potential of virtual or remote clinical trials as a viable option for enhancing efficiency in drug development, and in offering diverse patient populations easier and attractive means to participate in clinical trials.
Participation in randomised controlled trials
Recent research has estimated that the pre-approval cost of developing a new drug is around $2.6 billion, with most of the cost attributable to clinical trial operations that include patient identification, selection, trial monitoring, patient travel reimbursement, and data collection and validation. According to a recent report from the Centre for Information and Study on Clinical Research Participation (CISCRP), although most Americans appreciate the importance of clinical trials, less than 5% of them are willing to participate in them. Moreover, even among those who enrol in trials, the dropout rate in a typical trial is as high as 30%.
During the 2019 coronavirus outbreak, measures taken to mitigate the spread of the virus necessitated trial authorities to consider unprecedented measures. The rapid evolution of digital technologies means there are now opportunities to develop more remote clinical trials, and to improve their external validity, integrity and generalizability.
Establishing validity, reliability and integrity of remote clinical trial measurements
Identifying digital biomarkers and their associated clinical outcomes typically involves large amounts of longitudinal and continuous measurements, and there is usually a lack of standardisation, especially in the choice of words used to describe novel concepts. Whereas, continuously transmitting data directly to investigators and sponsors may help in the identification of safety signals in real time, the reliability and validity of such data needs to be ascertained in advance to ensure maximal protection of patient health and wellbeing. Therefore, to ensure validity, accuracy and reliability of the data collected in remote clinical trials, the computer system, hardware and software used needs to be effectively validated prior to implementation.
Traditional psychometric techniques may be used to assess the validity and reliability of a novel digital endpoint, including its ability to quantify the clinical and pathological condition of interest. However, given the magnitude and heterogeneity of the data generated by digital technologies, traditional psychometric approaches may need to be complemented with other analytical tools.
When data is captured remotely in clinical trials for decision making relating to the risks of a certain drug, one important consideration is the ascertainment and authentication of the identity of the patient from whom the data belongs. To this end, artificial intelligence and other digital technologies can be used for biometric authentication and identity verification.
The FDA highlights general principles that can be considered for software validation to facilitate efficient data collection in remote clinical trials. When the measures are obtained using patient-reported outcome (PRO) instruments, the FDA provides guidelines for establishing the acceptability of different formats, data collection methods and administration modes. Moreover, the FDA recently issued guidelines on the use of electronic health record data in clinical investigation, which provides requirements for inspection, record keeping and record retention.
Regulatory, confidentiality and data integrity considerations in remote clinical trials
Certain aspects of the implementation of virtual clinical trials, such as the increased use of electronic collection and the sharing and storage of data, can present an increased risk of detrimental impact on trial participants. For example, accidental disclosure of location and other personal data may put patients at risk. This review also highlights additional complexities that arise when the trial involves international transfer of health data. Due to differences in guidelines between the EU and US specifically, this requires a further assurance of adequate protection of individual privacy. In a recent study by Rosa et al. the researchers proposed a set of best practices, which include developing a policy on the use of technologies such as social media, email and related platforms; effective training of research staff as well as study participants; use of Health Insurance Portability and Accountability Act (HIPAA)-compliant technology; and confirmation of participant identity and whereabouts.
For electronic PRO instruments, the FDA guidelines requires sponsors to establish appropriate system and security controls, as well as cyber-security plans that ensure data integrity during network attacks and software updates. Moreover, this review stresses that as technology becomes ubiquitous, the vulnerability of trial data to nefarious activities in the context of virtual trials should be recognized as a matter of public health importance that warrants continued attention by policymakers and regulatory authorities.
In summary, this review outlines the guidelines that are needed to facilitate the increasing shift to remote clinical trials in order to protect study participants and trial data, as well as requirements for tool and algorithm validation, and the handling, storage and analysis of large volumes of complex data that is generated by the emerging technologies. Moreover, whether the impetus is to accelerate personal medicine, increase trial participation or to deal with a pandemic outbreak, hybrid or fully virtual trials are likely to represent the modernization of randomised clinical trials, and may be the driver to accelerate the development of the drugs of the future.
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