Summary of EMA’s Recommendation Paper on Decentralized Clinical Trial Elements

General considerations

The paper focuses on three major areas: patient safety, patient and investigator inclusion, and evaluating DCT risks and benefits. Trial participants' rights, safety, dignity, and well-being should come first, and decentralization in clinical trials should not increase participant safety, rights, and well-being risks. While this concept is not new, the paper emphasizes that early participant and investigator involvement in clinical trial design increases the scientific value and boosts trial trust, recruitment, and adherence. Moreover, patients' perspectives on living with a condition may influence the selection of decentralized elements, such as the feasibility of videoconference appointments, the use of digital tools, the measurement of meaningful endpoints, and the selection of the right population. A risk-benefit assessment should consider decentralized elements that may affect scientific validity, data integrity, benefit-risk ratio, or trial participant rights. Decentralized trials should follow general medical rules to protect patients, especially when away from traditional patient care centers. A responsible investigator with a trial population-specific medical background should assess each patient's risk profile, including anamnestic, physical, and laboratory or imaging data.

A focus on DCT oversight

Study oversight includes delegating study tasks, vendor quality agreements, and establishing effective lines of communication. When parts of the clinical trial are conducted off-site, and additional service providers like home nurses or technology providers are involved, the sponsor, investigator, and any other parties must clearly define their roles and responsibilities before the trial begins. Additionally, when trial participants visit the clinical trial site less often, alternative methods of clinical monitoring of their health status and data collection may need to be deployed. Decentralization introduces unique risks to participant rights, safety, dignity, and results, necessitating oversight requirements for investigators and sponsors. Hence, the study's plans and procedures should show that the sponsor and investigator fully control their responsibilities, such as data processing, communication flow, and trial participants' rights, safety, dignity, well-being, and data reliability.

When sponsors outsource to vendors, all tasks must be documented in a quality agreement with the vendor. Suppose the sponsor selects a service provider, and the investigator is not involved in the contractual arrangement. In that case, the sponsor-investigator contract should document the contractual arrangements with the service provider for tasks under the investigator’s responsibility, and the investigator should be able to request additional information, require changes to the agreement or service, and have the option to reject a service provider’s trial-specific medical care tasks. The sponsor should also ensure that the contracted service provider is qualified and experienced in delegated trial tasks.

Effective lines of communication should be established, documented, and shared with all relevant parties, including trial participants, investigators, sponsors, and service providers. All parties should have access to the clinical trial information they need at any time, and an emergency communication plan allows all relevant parties to act quickly, and trial participants should receive contact information for acute cases, device failures, home visit questions, and more. Processes to recognize duplicate AE reports must be established since data tends to reside in multiple sources when deploying multiple DCT vendors. Digital tools, like wearables, increase data frequency, and hinders the investigators' time; hence, a clear process should be in place to handle constantly emerging data, and the investigator's review frequency should depend on the data's relevance to trial participant safety and efficacy. Risk-based safety data review should consider the IMP safety profile, indication, and known risks.

Investigational medicinal product home delivery

IMP home delivery was another topic reflected in the paper and included four main areas: authorization, responsibility, delivery, and dispensation and administration. Suppose the site investigator or delegated healthcare professional does not dispense the IMP to the trial participant. In that case, the vendors delivering it should be authorized and qualified to distribute or dispense medicinal products, and transportation steps should be minimized, per good distribution practices (GDP).

The investigator is ultimately responsible for the participant and must document the treatment decision before delivering IMP to trial participants' homes. Delivery to the participant's home or another suitable address is allowed as long as regulatory requirements are met, risks of exposure to conditions that could affect product quality and integrity are minimized, and the GDP guidelines for medicinal products for human use are considered.

The investigator site pharmacy, a delegated pharmacy, or a depot can deliver the IMP. The sponsor should manage the process and contracts, and the clinical trial protocol or Investigational Brochure (IB) should describe IMP delivery to trial participants. Only the trial participant (or a representative) or a clinical trial healthcare professional should receive the IMP if applicable. Sponsors need to establish IMP delivery and receipt procedures, and if the pharmacies and labeling requirements are met, and national regulations allow, local pharmacies could dispense the IMP to trial participants instead of delivering it to their homes.

If an IMP needs medical supervision, shipping directly to the trial participant may not be appropriate. Suppose IMP must be shipped directly to the trial participant. In that case, clear instructions for storage and administration should be given to the participant; trial participants should be instructed in IMP preparation and administration if the protocol requires it, must be provided via a leaflet with easy-to-understand instructions. Visiting nurses can also be delegated to administer IMP, and either the investigator or delegees should regularly check in with participants to ensure they are taking the IMP correctly. Additionally, IMP accountability and trial participant treatment compliance procedures should be established, as safety regulations require the IMP to be returned and accounted for from trial participants' homes for destruction.

Clinical operational considerations

Sponsors should consider clinical trial suitability, patient risk, training, and patient monitoring when implementing DCTs. The investigator should determine if the trial participant's home is suitable for trial-related procedures and evaluate personal/social circumstances that may preclude home visits. Inclusion/exclusion criteria should include home adequacy for critical trial procedures, and the informed consent should explain home trial procedures. Only qualified and trained individuals should perform trial-related procedures at home. For instance, if a healthcare professional collects biological samples at home, the professional should be qualified, trained, and authorized to collect, document, and ship sample collections and ensure proper sample handling and storage throughout the process. Participants who perform trial-related tasks at home should be trained and considered for any additional burden, including digital data collection, and the sponsor and/or investigator should ensure that the delegated person(s) receives proper guidance and training for home tasks. The investigator (or delegee) should monitor trial participant compliance given the decrease in face-to-face visits/meetings with the investigator and/or delegated staff. Trial participants should be able to visit the investigator in person and have a direct line of communication if they need help with a trial-related task or data collection. During home visits, the trial participant or any delegated person should report and manage adverse events, and if a trial participant cannot or will not use their mobile device, the sponsor should offer alternatives.

Remote informed consent

The EMA paper elaborates on the importance of informed consent procedures if done remotely. Face-to-face communication between the potential trial participant, the investigator, or a qualified person is essential for informed consent, and if this discussion is done in a digital/virtual meeting, it is recommended that this takes place in real-time where the parties can both see and communicate with each other via audio and video. Remote face-to-face contact should allow for questions, and the investigator should make every effort to verify the participant's identity if they don't know them. The participant should also have the right to ask for proof of the investigator's identity if they haven't met before. If trial participants and investigators prefer on-site informed consent interviews, the sponsor should allow them to be conducted in person. The investigator should evaluate participant-related factors affecting decentralized elements of the clinical trial during the informed consent interview (such as the patient's ability to use technology), and the method should be reliable and confidential. Informed consent interviews should use encrypted communication channels to protect confidential information. While providing patient information via brochures and leaflets is helpful, the sponsor should also consider that electronic methods may unintentionally discriminate against participants who cannot or prefer not to use them and should have alternatives, such as paper or physical media, and trial participants should be able to store and retrieve the information provided to them easily and at any time.

Moe Alsumidaie, MBA, MSF, is a thought leader and expert in the application of business analytics toward clinical trials, and Editorial Advisory Board member for and regular contributor to Applied Clinical Trials.