The article highlights the key points related to specific types of clinical trials.
Table of content
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to conducting clinical trials with decentralized elements. The document provides an overview of the applicable regulatory requirements, as well as additional clarifications and recommendations to be taken into consideration by the parties responsible for clinical investigations (study sponsors) in order to ensure the accuracy and reliability of the results, as well as the safety of study participants.
At the same time, provisions of the guidance are non-binding in their legal nature, nor are they intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the relevant legislation and has been agreed with the authority in advance.
Introduction
The FDA has issued the present guidance for sponsors, investigators, and other parties involved in clinical trials on the use of decentralized elements in order to provide recommendations that facilitate the inclusion of decentralized clinical trial (DCT) components, enhancing the efficiency and accessibility of these studies. DCTs allow trial-related activities to be conducted remotely, outside of traditional clinical trial sites, at locations that are more convenient for participants.
This flexibility can include telehealth visits, home-based interactions with trial personnel, and assessments by local healthcare providers (HCPs). It is important to mention that the FDA’s regulatory standards for clinical trials apply equally to those utilizing decentralized elements and traditional trials.
The 2023 Consolidated Appropriations Act mandates that the FDA issue guidance to promote and clarify the use of DCTs in drug and device development. This guidance fulfills that requirement and further references additional guidance, such as the document on Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (December 2023), to ensure compliance and efficient integration of DCT components.
Regulatory Background
First of all, the authority acknowledges that decentralized elements are already present in many clinical trials, such as remote laboratory testing at non-traditional sites. DCTs can significantly expand patient access, enabling participation from a more diverse and representative patient population.
With the advancement of digital health technologies (DHTs), trial-related data can be collected remotely, reducing the need for in-person visits and enhancing participant convenience. DCTs are particularly beneficial for populations with limited mobility or those residing far from traditional clinical trial sites, facilitating research on rare diseases and improving participant engagement.
This approach has the potential to improve recruitment, enrollment, and retention, ultimately strengthening the evidence generated from these studies. However, the FDA specifically mentions that DCTs are not universally applicable.
Trials with fully decentralized components are more suitable for investigational products (IPs) with well-established safety profiles that do not require complex administration or assessments. For IPs that need more intensive supervision or complex procedures, traditional clinical sites might still be necessary, with some follow-up activities conducted remotely.
The key to implementing a successful DCT lies in effective planning, risk assessment, and management, particularly when coordinating with multiple locations and personnel.
Recommendations for Implementing DCTs
In a decentralized clinical trial, some or all trial-related activities occur at locations other than conventional trial sites, such as participants’ homes, mobile units, or local healthcare facilities. DCTs may involve a network of locations where trial personnel and local HCPs perform various functions, such as imaging or laboratory testing.
Variability in data collection is a concern when trial activities are conducted remotely. For example, tests performed independently at home may yield different results compared to those conducted under supervision.
Video supervision or additional training can help reduce this variability. Additionally, participant choice in determining the location of assessments may introduce bias.
The trial design should carefully define which assessments must be conducted at a traditional site, which can be performed remotely, and which are left to the participant’s discretion. Consulting participants during trial design is crucial for understanding their preferences and ensuring that remote activities are feasible.
Moreover, certain statistical challenges may arise in DCTs, particularly when calculating non-inferiority margins. Sponsors should seek input from the FDA when planning these studies to address any unique challenges.
Remote Clinical Trial Visits and Trial-Related Activities
Remote visits are a cornerstone of DCTs, offering flexibility and accessibility for participants. These visits can be conducted through telehealth, at participants’ homes, or through local HCPs.
Specific considerations when planning remote visits include:
- Telehealth Visits: Sponsors should use telehealth for interactions where no in-person contact is necessary. The appropriateness of telehealth depends on the IP and the health status of the trial population. The trial protocol must specify when telehealth is suitable and when an in-person visit is required.
- In-Home Visits: Investigators should accommodate participant privacy during in-home visits by choosing convenient times and locations, ensuring that participants’ comfort is maintained, especially in shared living spaces.
- Visits by Trial Personnel or Local HCPs: In-person assessments can be performed by trial staff at participants’ homes or by local HCPs, depending on the trial protocol. Clear instructions in the protocol can help minimize variability in data collection.
Training and video supervision can also help ensure the accuracy of tests conducted independently by participants. However, variability may still occur, and the protocol should address these possibilities by specifying the circumstances under which remote or in-person visits are preferred.
Challenges and Considerations for DCT Implementation
Implementing DCTs involves several logistical challenges. Coordination among diverse locations, including participant homes, local clinics, and laboratories, requires careful planning.
Key considerations include:
- Feasibility and Design: The feasibility of conducting remote assessments must be evaluated during the trial design phase. Early engagement with the FDA can help address potential issues related to trial feasibility, design, implementation, and analysis.
- Risk Assessment and Management: DCTs necessitate ongoing risk management, particularly when coordinating across multiple sites and stakeholders. Continuous monitoring and adjustment are essential to maintaining data integrity and participant safety.
- Training and Oversight: Adequate training for both trial personnel and local HCPs is necessary to ensure consistency in protocol adherence and data collection. This training should be regularly updated as new challenges emerge.
Statistical and Analytical Considerations
Certain statistical approaches may need modification when trials are decentralized. For instance, trials utilizing an active control, such as a drug for sleep disorders, might yield different effect sizes when the control is administered remotely rather than in a traditional setting.
This can complicate the calculation of a non-inferiority margin. Sponsors should discuss their statistical plans with the FDA early in the trial planning process to address any discrepancies that could arise from decentralized data collection methods.
Ensuring statistical robustness in DCTs is essential for generating reliable and generalizable evidence.
Conclusion
In summary, decentralized clinical trials represent a promising evolution in clinical research, offering the potential for broader patient inclusion, enhanced participant convenience, and improved trial efficiencies. However, these benefits must be balanced against the challenges of maintaining data integrity, ensuring patient safety, and addressing variability in data collection.
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