Decentralized, virtual, siteless, remote-all buzzwords in the clinical trial arena that are gaining increased traction in the post-pandemic landscape. Although started during the COVID-19 pandemic as a means of patient convenience and allowing for the progress of trials irrespective of safety and travel restrictions and social distancing rules, decentralized trials seem here to stay. As per the US FDA Guidance on Decentralized Clinical Trials are technology-based human clinical trials that utilize telemedicine and mobile or local healthcare providers to gather data, which differs from the traditional design approach.
Decentralized approaches do not necessarily imply that all aspects or steps of a clinical trial are conducted remotely, it also includes those trials in which some steps such as participant recruitment, electronic consent, data collection, investigational product supply, or monitoring visits are carried out without the need for a central site. As evident there are numerous benefits to decentralized trials such as:
- Improved patient convenience by allowing patients to continue with their daily activities by decreasing or eliminating site visits.
- Increased Patient retention application as patients can track data or submit data from the comfort of their own homes.
- Greater patient diversity as it enables patients living in remote locations to participate in trials that would otherwise be inaccessible.
- Greater patient inclusivity such as those with limited mobility, lower socioeconomic backgrounds, etc.
- Reduced site maintenance and staff employment costs.
- Better patient feedback can improve the quality of trials by allowing for prompt reporting of any untoward events.
- Improved data quality and quantity by allowing for more frequent measurements causing increased robustness and comprehensiveness.
- A larger number of patients as patients can be recruited from a wider range of locations.
- Data that is more representative of the real-world scenario.
- Based on all these advantages, it is not surprising that the US FDA is embracing the idea and acceptance of decentralized trials and developing recommendations for best practices for decentralized trials.
- The US FDA has released guidance on issues related to the management and requirements of decentralized trials from the sponsors, investigators, and regulatory agency perspectives. Some of the noteworthy guidances include the following:
Conduct Decentralized Clinical Trials of Medical Products During COVID-19 Public Health Emergency-2021
This guidance explains the challenges and limitations of trial conduct during the coronavirus pandemic and addresses some steps that can be taken by sponsors to maintain trial integrity, ensure accordance with good clinical practices (GCP), and protect the safety of participants. Various decentralized methods have been recommended in this guidance such as virtual, telephonic, or local visits for safety assessments, investigational product shipping to patients’ homes or local clinics, modification of methods for efficacy endpoints such as electronic clinical outcome assessments (eCOA), and electronic patient-reported outcomes (ePRO), and remote monitoring programs for oversight of clinical trials. Certain instances of protocol deviations are done to protect the participants from immediate hazards such as telephone interviews and virtual meetings can be performed by notification to the appropriate institutional review board (IRB) and without FDA approval.
In the absence of any safety concerns, direct-to-patient shipping of products that can be self-administered is permitted through protocol deviations as well as return for disposal of any unused products. Administration of complex products or infusions can be permitted by trained, non-study personnel following an adequate risk assessment by the sponsor and submission of this assessment and mitigation strategies to the FDA.
In the absence of paper-based consent forms, informed consent can be obtained using electronic forms, photographs, or virtual interviews with the participant or their legally authorized representative. When considering the use of eCOA and ePRO to capture clinical data, it is important for the sponsors to ensure data integrity and privacy, training of personnel and participants, and data quality to ensure completeness. Furthermore, suitable technologies and tech support measures should be always available to participants. Remote site monitoring should consider factors such as secure access to trial documentation and availability of records in a cloud-based system for review. Participant visits can be done using a telemedicine platform ensuring participant privacy and adequate training of personnel on videoconferencing facilities.
CTTI Recommendations: Decentralized Clinical Trials (2018)
The Clinical Trials Transformation Initiative (CTTI) which is a public-private collaboration between the FDA and whose purpose it is to streamline the clinical trial process has developed recommendations to drive the adoption of mobile technology in clinical trials and includes the following projects: decentralized clinical trials (DCTs), novel endpoints, stakeholder perceptions, and mobile technologies. The recommendations include the use of telemedicine and novel information technology to allow for increased healthcare provider (HCP) participation in patient recruitment and retention, at-home patient care, and home use of IP. DCT recommendations include DCT approaches and protocol design, telemedicine state licensing issues, drug supply chains, mobile healthcare providers, investigator delegation and oversight, and safety monitoring.
Decentralized Clinical Trials approaches and protocol design:
The approach for DCTs can range from fully decentralized to partially decentralized (hybrid) approaches which can range from virtual approaches for all clinical trial activities to the use of telemedicine or mobile sensors for some parts of the trials and physical visits to local clinics for assessments. It is essential to include engagement and participation from all stakeholders such as patients, FDA, IRBs, investigators, contract research organizations (CROs), pharmacies, and third-party vendors to ensure scheduled meetings with regulatory bodies, decrease the frequency of protocol amendments, and develop best practices for using mobile HCPs and telemedicine by experts in the clinical trial process. Various factors such as trial-specific procedures, protocol compliance, site management, storage of source documents and electronic information, technological support, and regional differences should be tailored according to each trial protocol. Procedures and flow maps should be developed to ensure secure data maintenance and storage with appropriate systems to explain the data flow whilst ensuring compliance with regulatory guidelines.
Telemedicine state licensing to conducting Decentralized Clinical Trials:
This section is related to the license requirements in states as well as for DCTs conducted across states. It is essential for sponsors to understand telemedicine state laws and be aware of the legal landscape for state laws.
ü Drug supply chain: It is essential to understand state and federal regulations relating to IP delivery and direct-to-patient shipping. It may be beneficial to collaborate with experts and vendors that are well-versed in these requirements and maintain a standard operating procedure (SOP) for all activities related to IP accountability and distribution.
Mobile healthcare providers (HCP) of Decentralized Clinical Trials:
Mobile HCPs (nurses, physicians, phlebotomists) form an integral part of DCTs by replacing visits to investigative sites with home visits. It is necessary that personnel are trained and qualified on trial-specific procedures to protect the safety of trial participants.
Investigator delegation and oversight to perform Decentralized Clinical Trials:
This should be performed according to the same rigor and standards as traditional trials. Mobile or local HCPs should perform their duties according to FDA regulations and should be appropriately listed in FDA Form 1572 (Statement of the Investigator) for their responsibilities.
Safety monitoring under conducting Decentralized Clinical Trials:
Remote safety monitoring should be more rigorous or to the same level as traditional trials with suitable record-keeping measures in place for trial participants to report to investigators and clinicians. Appropriate plans should be specified in the protocol for safety monitoring and communication escalation for participants, trial personnel, third-party vendors, and investigators.
Digital Health Technologies for Remote Data Acquisition in Decentralized Clinical Trials Investigations (2022)
Remote data acquisition in DCTs is achieved through digital health technology (DHT) that uses computing platforms, connectivity, software, and/or sensors for healthcare and related uses. This guideline provides recommendations for the following topics:
Selection of DHTs for Decentralized Clinical Trials:
Various factors such as the clinical investigation population (age, technical aptitude, education, language), design and operation of DHT (design, power needs, operational specifications such as data storage, environmental factors), and use of the participants’ own DHT such as continuous glucose monitor, mobile phone, tablet, etc.) should be considered in selecting an appropriate tool to use. The sponsor should describe the DHT in detail in the submission and clearly state that it is fit for purpose for its use.
Verification and validation of DHTs:
This step is required to ensure that the DHT is fit-for-purpose for remote data acquisition and that the parameters that it is measuring remain accurate and precise over time in the proposed participant population. Validation testing is done at the benchtop level and then in human volunteers and should be performed on sensor-based DHTs, DHT software, and general-purpose computing platforms for interoperability and usability applications.
Use of DHTs to collect data for Decentralized Clinical Trials endpoints:
A precise definition of the endpoint including the type of data collected and frequency of collection should be defined. In the case of established clinical endpoints validation should be done to prove reliability whereas for novel endpoints it is necessary for the sponsor to show clinical relevance and that it describes disease severity and how it is related to other endpoints used to measure effectiveness.
Identification and management of risks associated with DHTs:
The risks associated with the use of DHTs can include clinical risks such as injury and privacy risks, especially for DHTs that are run on general-purpose platforms. It is necessary to provide appropriate cleaning instructions and evaluate cybersecurity risks for the protection of data privacy. Like any other clinical trial, DCTs using DHT require informed consent from participants. The informed consent form should explain unforeseeable risks associated with the DHT, the type of information to be collected and how the information will be used, data access and sharing information, and measures taken to protect participants’ safety and data.
Sponsor’s role to conduct Decentralized Clinical Trials:
Ensure adequate training of trial personnel and development of technical assistance, risk management, and safety monitoring plans, and ensure that the data is downloaded from the DHT to a secure repository.
Investigator’s role to conduct Decentralized Clinical Trials:
Ensure that the participants understand the data to be collected from the DHT and safety and privacy features as well as that they are trained on the appropriate use of the DHT according to the trial protocol.
Therefore, the widespread uptake and employment of decentralization in trials have led to several published guidelines to ensure that these aspects are used in the best way possible to realize their full suite of benefits. These guidances are expected to help sponsors, CROs, and regulatory agencies understand what is required of virtual clinical trials without jeopardizing patient safety or data integrity.
1) Guidance for Industry (fda.gov)
2) CTTI Recommendations: Decentralized Clinical Trials (ctti-clinicaltrials.org)
3) Conduct of Clinical Trials of Medical Products During COVID-19 Public Health Emergency (fda.gov)