By Lucy Clark, Statistics Manager, and Barbara Arch, Senior Statistician.
The United States Food and Drug Administration (FDA) recently (September 2024) published a finalized guidance document on Conducting Clinical Trials with Decentralized Elements. [1] This document is aimed at sponsors, investigators, and other interested parties. Two of our expert statisticians at Phastar have summarized the key takeaways from the FDA’s guidance, offering their insights on how it could shape the future of clinical trials. Their expert analysis highlights the potential impact of decentralized elements on trial design, execution, and patient outcomes.
Background
The FDA defines a decentralized trial (DCT) as any clinical trial where trial-related activities occur at locations other than traditional clinical trial sites. This could include:
- Within participants’ homes
- Local healthcare facilities
- Mobile research units
- Local clinical laboratories.
Many trials already have some decentralized elements. But with advances in digital health technologies, and the desire to make clinical trials more accessible, other decentralized elements could include:
- Taking of consent
- Storage, preparation and administration of treatment
- Follow-up assessments e.g. blood tests, physical examinations
- Follow-up visits
- Outcome data collection.
Advantages of Clinical Trials with Decentralized Elements
One of the key goals of any clinical trial is to produce results that are generalizable to the broader population of participants under investigation, whilst ensuring the safety and welfare of the participants. By increasing convenience to participants, it is hoped this may bring about increased trial recruitment, engagement and retention and lead to more representative patient populations being included in trials. DCTs can also facilitate research into rare diseases and populations with limited mobility who have difficulty attending traditional clinical trial visits. There are also other advantages to be seen such as reducing the burden on caregivers and site staff and making trials run more efficiently.
The FDA guidance provides recommendations on how to implement decentralized elements in clinical trials, key elements of which are highlighted in this review. They emphasise that the guidance is not mandatory.
FDA Recommendations for Implementing DCTs
1. Design and Conduct
Standardization of trial related activities is more difficult when conducted remotely. A key aim of the design should be to limit undue variability in the treatment administration, assessments and data collection.
The protocol should contain specific instructions for performing decentralized activities, and where applicable, training or video supervision could be provided. The protocol should also specify which visits and assessments are to be conducted remotely, and which are down to participant choice.
Sample size calculations for a DCT that are based on data collected from traditional clinical trials may need to factor in potential additional variability. For example, trials designed using effect sizes that have been determined from traditional clinical trials, may not see the same effect size for an active control assessed remotely. This could present challenges in calculating a non-inferiority margin for example and sponsors should consult with the relevant FDA review division when planning such a trial.
2. Remote Clinical Trial Visits and Clinical Trial-Related Activities
The following should be considered at the planning stage:
- Whether remote rather than in-person visits are appropriate for the investigational product (IP) being studied and the medical condition of the trial population e.g. IPs with a high-risk safety profile.
- Privacy. This should be ensured for remote visits, by accommodating times most suitable for participants, and/or providing the possibility of using convenient locations outside of participants’ homes.
- Whether to send trained trial personnel or local healthcare professionals (HCPs) to participants’ homes or other preferred locations.
- Recording the source of the data i.e. where a visit was conducted, when and by whom.
- How care will be provided for adverse events (AEs) that require urgent or in-person management. This should be clearly described within the protocol.
3. Digital Health Technologies (DHTs)
Sponsors should ensure that DHTs are available and suitable for use by all trial participants and that level of access to digital technology shouldn’t be a factor in determining eligibility for a trial. Further information on this topic can be found in other FDA Guidance [1].
4. Role and Responsibilities
Sponsor responsibilities are the same for all trials regardless of whether there are DCT elements. The recommendations outline several key areas particular to DCTs:
- Decentralized elements should be properly co-ordinated, with clear records of all contracted service providers, their roles and assigned activities, ensuring they are appropriately qualified.
- Great efforts should be made to recruit a clinical trial population that reflects the intended patient population for the product being studied.
- A data management plan should be in place to document data origin and data flow from all sources, and the methods of data collection.
- The trial protocol should include a comprehensive description of the operational aspects of how the DCT elements are to be implemented.
- Compliance with local laws, regulations and licensing requirements.
- The monitoring plan should be risk based, and describe:
- How protocol compliance and data integrity will be monitored
- Frequency of monitoring
- Unique aspects related to decentralized elements.
Investigators are responsible for the conduct of trials and for protecting the rights, safety, and welfare of subjects under their care. Recommendations particular to DCTs:
- Additional training, coordination and standard operating procedures may be required to ensure consistent implementation of the trial protocol.
- Delegation of some trial-related activities may be required, and oversight should be put in place to ensure consistent implementation of these activities.
- Investigators should only enrol as many trial participants as they can appropriately manage.
- Investigators should review data from outsourced activities, assessing for accuracy, completeness and compliance with the protocol.
5.FDA Oversight
A physical location must be provided, where a responsible person is available to facilitate the FDA inspectors’ access to trial-related records and interviews with trial personnel, enabling the same oversight that normally applies for other clinical trials.
6.Informed Consent and Institutional Review Board (IRB) Oversight
It is acceptable for informed consent to be obtained remotely (electronically or on paper) from trial participants at remote locations provided regulatory requirements are met. Some important things to consider to protect participants are:
- That they are clearly informed of whom to contact if they have any questions or in the event of a research-related injury.
- Where consent is obtained from an in-person visit to a participant’s home, this may only be carried out by individuals with detailed knowledge of the protocol and appropriate training to be able to address any questions or concerns the subject may have. It is therefore not considered appropriate for local HCPs to perform this task.
The FDA recommends the use of a central IRB in DCTs which will aid with efficient review of the protocol and other trial-related documents.
The consent form itself should adequately describe whether local HCPs will be used, which trial activities will take place at participants’ homes and who will have access to their protected health information.
7. Investigational products (IPs) in DCTs
A DCT may not be an appropriate setting for some IPs – particularly those with a high-risk safety profile, where in-person supervision is required to ensure correct administration and/or the safety of participants. It may be possible to decentralize by using local healthcare facilities, or through trial personnel coming to a participants’ home or through a telehealth visit, but the risks should be carefully considered. The same considerations should be made whether the IP is a drug, biological product, or medical device.
8.Packaging and shipping of Investigational products
If a DCT involves direct distribution of IPs to trial participants or local healthcare facilities, then some additional processes will need to be in place: ensuring the IPs physical integrity and stability is maintained during transport and at destination; tracking of all IPs; and ensuring the safe return of unused IPs.
9.Safety monitoring of DCTs
Protecting the safety and welfare of participants is key. The safety monitoring plan for a DCT should take the decentralized elements into account and ensure all AEs and medication errors are captured. It should describe how local HCPs and participants can report such findings, and how they are expected to respond to an AE and where to seek medical care locally. Participants should have clear instructions on how they are able to contact trial personal to discuss any questions or concerns and arrange unscheduled visits.
10. Electronic systems used when conducting DCTs
Electronic systems can be used to perform and manage DCT operations including:
- Taking informed consent
- Capturing and storing reports from remote trial personnel, local HCPs, local clinical laboratory facilities
- Capturing data via electronic case report forms (eCRFs)
- Scheduling trial visits and other trial activities
- Tracking shipment of IP
- Serving as a communication tool between trial personal and participants
Training should be provided to all parties.
Key Takeaways on FDA Guidance on DCTs
The release of this guidance is timely and thought provoking. With more novel ways of recruiting and retaining patients needed, as well as ways to try and facilitate research into diseases with unmet needs. The guidance is a recommendation of what should be done rather than what must be done.
Some areas that we feel are not covered by the recommendations, but would also be of benefit, are a recommendation to run feasibility studies where possible, and having patient and public involvement (PPI) in the design stage. A feasibility study would enable decentralized elements to be tested out on a smaller scale. PPI would be beneficial to understanding how potential participants may feel for example about administering their own treatment and follow-up visits within their homes or local health care facilities. A hybrid approach may be the way to go where participants get the choice.
DCTs do not come without their challenges. As discussed in the guidance, this type of design may not be suitable for all types of trials and medical products and significantly more upfront planning is required. More thought needs to go into the design stage, working through the logistics, feasibility and appropriateness of each decentralized element. Monitoring could present some challenges, and having plans in place to manage and mitigate risk to data integrity is essential.
The guidance recommends that early discussions be held with the relevant FDA review division to review specific challenges related to the feasibility, design, implementation and analysis of a DCT.
Having decentralized elements may introduce greater variability in treatment administration, outcome assessments and data collection to name but a few, so consideration should be given to this in terms of sample size/power calculations, and analysis methods with potentially a need for larger sample sizes and sensitivity analyses to assess the impact of this variability on the outcomes.
There is also ultimately more that can ‘go wrong’ with a DCT with participants and local HCPs carrying out aspects of the trials traditionally performed by site staff and Investigators. Therefore, additional guidance will be required in the protocol and other trial-related documents such as the data and safety monitoring plans, to ensure participants and local HCPs are clear on what is required of them. More upfront training will be required and support for participants and local HCPs throughout the duration of the study and to ensure consistent implementation. All of this comes with additional cost implications which may counter savings made from not having traditional site-visits.
The FDA guidance provides a useful starting point to aid discussions around incorporating decentralized elements into clinical trials, something which we believe great consideration should be given to, as despite the obvious challenges, there is also much to be gained.
Explore how decentralized clinical trials can drive innovation in clinical development. Speak to our Phastar experts to learn how we can help design and run trials that incorporate decentralized elements, facilitating increased patient access, engagement, and data integrity.
References
- US Food and Drug Administration, 2021. Digital health technologies for remote data acquisition in clinical investigations. Rockville, MD: Digital Health Technologies for Remote Data Acquisition in Clinical Investigations.
