Decentralized clinical trials and rare diseases: a Drug Information Association Innovative Design Scientific Working Group (DIA-IDSWG) perspective

A DCT design must identify and involve all stakeholders and develop study-specific communication logistics [16]. Examples of internal stakeholders include but are not limited to the clinical research team (clinicians, statisticians, clinical data scientists, project leads, etc.), regulatory affairs and legal team, and patient out-reach team (such as communication, marketing, training). Close collaboration is required among cross-functional teams to modify traditional study practices to DCT formats. An initial evaluation of internal skills and experiences will indicate what external collaboration and outsourcing are required to move forward efficiently. Depending on the study timeline and size of the company, some tasks might require outsourcing to an experienced third party.

External stakeholders including sponsors, patients and caregivers, patient advocates, clinicians, regulatory authorities, private payers, contract research organizations (CROs), DHT vendors, academic researchers, mobile or local HCPs, professional medical associations, and technology companies. The concerns and priorities of these stakeholders must be addressed during the design of the DCT study. The supervisory responsibilities of the investigators and the authority for remote site monitoring must be established. Cross-industry coalitions such as the Decentralized Trials and Research Alliance can help support reducing risk and promoting and improving the conduct of a DCT [17]. The Clinical Trials Transformation Initiative is another resource that can identify legal, regulatory, and practical barriers to conducting DCTs and identify opportunities to clarify and inform policies that affect the implementation of DCTs.

Planning begins with questions related to a broad context of a proposed DCT (Table B1 in Appendix B). Next, the core team defines the components of a DCT, administrative and research roles and responsibilities, internal and external required skills, technologies, and regulatory compliance. In rare diseases it is crucial to capture patient and caregiver perspectives during the trial design [18, 19].

A pre-trial feasibility study can evaluate the operational barriers, selected strategies, staff comfort level, and patients’ acceptance of this new approach. An example of successful modification of a centralized study to DCT is REMOTE [11] mentioned in Sect. 2, the first web-based study conducted under an IND application. It was designed to replicate previous clinic‐based trials of tolterodine extended release. The REMOTE study is remarkable in that it illustrates both the challenges and benefits of digitizing a clinical trial. Such pre-trial feasibility studies may be challenging to conduct for rare diseases due the rare number of patients, however, a feasibility study in a similar population can provide meaningful insight.

CROs and sponsors may be asked to fulfill novel roles as technology partners for patients and must be willing to adapt to the new approach [20]. Sites that embrace DCTs need new operational frameworks and additional support from Sponsors and CROs as they navigate this new research environment. It is important to review and understand site-specific telemedicine laws and mandated systems for tracking information, such as receipt and drug accountability in remote trials.

It is difficult to recruit patients with a specific rare disease in numbers large enough to produce meaningful results in a clinical trial. If these patients are scattered over a wide geographical area (even internationally), it is extraordinarily difficult to bring them to physical trial sites for specialized study interventions. The flexibility of a DCT allows for remote tasks and data collection, which reduces the responsibilities and limitations of a potential local sites, allowing for a larger trial network which can serve a greater number or participants.

The majority of DCT site operations are similar to that of traditional clinical research, but require modification that addresses new technology, internet availability, and interaction with participants. Clinical staff must be trained in these new processes. If a novel DCT is planned and/or the indication or target population is different from a previous DCT, early engagement can be simple with advanced interaction introduced gradually. A DCT can be a reasonable choice for early phase trials since internal decisions involve smaller sample sizes. This allows the study team to evaluate the study design and operational plan as they prepare for later stage pivotal trials and before submission of the DCT protocol to authorities.

Both traditional centralized trials and DCTs must report study related safety events. Sometimes, participants must understand how to access DHT information and communicate this data and any significant health developments to the clinical staff. If the participant is cognitively impaired or has difficulty with technology, it is important to ascertain whether the caregiver will be available to manage the DHTs, connection to remote visits, etc. Participants who do not have reliable internet service may not be able to participate remotely unless the sponsor explicitly provides this. Options must be individualized, and the study team must listen carefully to the preferences and concerns of participants and caregivers. One of the advantages of using DHTs in a DCT, is that continuous monitoring of participants can flag safety issues and adverse events in real-time, allowing investigators to respond in a timely manner. This might be preferable, for example, in pediatric studies or with cognitively impaired patients who cannot communicate or recall the occurrence and details of adverse events on their own. Although early detection of peripheral problems by DHTs is not the primary goal of a DCT, there should be plans for real-time response to such events. In addition, the risk of erroneous measurements should be addressed. Finally, detection of some risk states requires advanced physical examination skills that specialized physical examination skills that are not generally shared by home health personnel. For example, cardiac auscultation by an experienced cardiologist may detect cardiac issues that are not detectable by remote technologies. Conversely, continuous cardiac and/or activity monitoring may be superior to an examination by an experienced cardiologist for detecting other cardiac issues.

As mentioned, a DCT can be fully remote or hybrid with both remote and on-site components. It can be beneficial to have the patients come to an on-site visit in DCT, especially for the baseline visit and/or the study end visit. Clinically vulnerable pediatric patients may require an initial on-site visit for a comprehensive evaluation. There is no “one size fits all” and DCT designs, and individual patient schedules should remain flexible.

In 2017 and 2018, over 1100 unique trials included the use of DHTs as compared to only eight trials in 2000 [21]. COVID-19 accelerated this shift. Stakeholders now realize the advantages of this approach, especially in the case of extremely ill patients, children, and rare disease populations. Continuous data collection using DHT in free-living environments allow the capture of a new category of objective measurement that illuminates the nature of disease progression and derives clinically meaningful endpoints that were previously impossible.

Data provided by vendors and device companies do not always translate to a specific patient population. When incorporating DHTs into a DCT, it is important to select fit-for-purpose DHTs to quantify a measurable estimator in the targeted population that is based on the study objectives and ensure comprehensive and validated evidence when using digital endpoints. A validation plan integrated into the early stages of clinical development might be necessary. Low numbers of potential participants in rare disease trials might best be saved for a pivotal study rather than a pilot study to test DHTs, but strategies can be borrowed from “drug repurposing” studies, to reduce the time, cost, and risk to deliver a drug candidate for a new indication based on previous work that may include validation of previous DHTs [22]. Similarly, devices and the accompanying novel digital endpoints can be derived and/or validated on a common disease population with similar symptoms/indications to a rare disease. For example, common chronic heart failure and heart failure due to a rare genetic mutation (e.g. LMNA related dilated cardiomyopathy [23]) both share symptoms including fatigue, exercise intolerance, and limitation of activities of daily life [24, 25]. Therefore, if physical activity measured by an actigraphy device has shown to be clinically relevant to disease progression for a common chronic heart failure, it is reasonable to generate such digital endpoints to rare cardiomyopathy.

As suggested previously [26], when deploying DHTs into clinical studies, it is crucial to incorporate patients’ voices, provide comprehensive audio-visual instructions related to DHT use, and develop a support system (e.g., 24/7 technical assistance) for patients and caregivers in case of technical difficulties.

There is a growing amount of guidance on DHT use for remote data acquisition. Examples include the ICON plc white paper for an eight-item checklist [8] and the Digital Medicine Society (DiME)’s proposal of the V3 framework (verification, analytical validation, and clinical validation). The V3 framework evaluates DHTs as fit-for-purpose for use in clinical trials. It is emerging as the gold standard, and has been adopted by the European Medicines Agency (EMA) [27]. DiME also hosts a library of digital endpoints used by registrational clinical trials [28]. A recent work was published to discuss the “bring your own device” (BYOD) option as a more user-friendly strategy to allow patients to use familiar technologies, which can ensure better compliance and unbiased measurements [29]. This is closely related to and applicable for a DCT.

Infrastructure and advanced analytics platforms are the foundation of technologies for capturing high-density data. Small pharma companies and CROs who focused on orphan drugs or rare diseases can be challenged by the data volume of these technologies. For example, raw accelerometry data, which passively collects patient movement and activities, at the sub-second level can result in millions or even billions of observations during the monitoring periods of weeks and months. Multi-modal data such as audio, image and DHT data may be collected simultaneously, continuously, and longitudinally. Such high volume and complex data require advanced analytic platforms and complex analytical methods that most pharma and CROs running classical trials do not have access to. To address this, pharma companies must allocate funds to set up advanced, flexible environments for analyzing the acquired and cleaned data in house. CROs have already begun establishing platforms for accommodating digital data and gaining experience in handling new technology and data through mergers, acquisition, and collaborations with companies from tech sectors [30, 31].

Such complex data collection may not always be feasible for DCTs targeting a common disease with high prevalence as it will increase the burden of collection and handling of large volume of the data given the large number of participants. However, a DCT targeting a rare disease may benefit from such multi-modal data, since the smaller patient population means a lower data burden and an opportunity for a holistic picture of rare disease patients. This high-volume data may be important for choosing or developing an optimal pivotal endpoint for a rare disease that may be selected adaptively during a pivotal study, averting the need for a separate natural history study to choose a pivotal endpoint [32, 33].

Analytical platforms may store data in different measurement modalities, synchronize data using multiple sensors, and require (nearly) real-time data processing with remote monitoring. This synchronization of data capture is challenging [34]. Sponsors and vendors need to coordinate these functions. For example, AiCure uses mobile apps to monitor whether patients have taken the drug and collect daily adherence data; some actigraph devices can detect compliance issue (device not worn) in real time by enabling data transfer via devices’ Bluetooth to actigraph’s cloud system. Such functionality can ensure the smooth conduct of a DCT.

Similar to a traditional clinical trial, a fit for purpose statistical analysis plan (SAP) needs to prespecify analyses required to achieve study objectives. One particularly important thing to consider is the occurrence of intercurrent events (ICEs), which are events that occur after the initiation of the study intervention that precludes the observed outcome or affects the measurement and can be more complex due to the remote data collection. These call for carefully evaluation and response [31]. For example, in DCTs with remote data collections via continuous DHTs, missing data can be more complicated given the noisy and complex data structure, and the lack of supervision in the free-living environment. The characteristic of missing data from DHTs, emerging statistical and data processing techniques to analyze and impute continuous epoch level and daily summary data are discussed in the literature, and suggestions are provided for preventing missing data from device deployment and trial design [26]. Moreover, novel statistical methods such as functional data analysis, data integration, and robust feature engineering are applicable to derive meaningful summaries from the continuously collected DHT data [35‐37].

When a novel design or methodology is applied to a clinical trials format unfamiliar to regulators, careful negotiation is needed. Because there is no widely used concrete guidance for DCTs, clinical trial sponsors and regulators should work together. The success of a DCT submission hinges on good communication with all stakeholders and fulfillment of regulatory requirements. For example, the FDA published draft guidance of Digital Health Technologies for Remote Data Acquisition in Clinical Investigations in January 2022 [4]. This guidance encourages sponsors to ensure DHT is fit-for-purpose and outlines the information to be included, such as DHT selection, description, verification/validation/usability, clinical novel endpoints, statistical analysis, risk considerations for wearable device, and record protection/retention. Innovative Science and Technology Approaches for New Drugs (ISTAND) Pilot Program can be another source of information and recommends sponsors to consider cybersecurity information available on the FDA’s website. Finally, the EMA guidance on DCTs is ongoing [38].

One particular concern arises in the flow of data collected from a DCT. DCT patients who experience medical issues that require intervention might contact the pharmaceutical company or the sponsor sometimes before the clinicians and/or investigators, due to the commonly used automated data transfer set-up. The pharmaceutical company or the sponsor will then have to share the patients’ requests with the clinicians and/or investigators. This is problematic because regulatory requirements (such as Health Insurance Portability and Accountability Act, a.k.a. HIPPA) require data to be anonymized to sponsors, which means that the clinicians and/or investigators will not be able to know which patient it is. Therefore, it is crucial to emphasize the data flow in the study protocol to make sure patients can contact the institutions directly to avoid raising any ethical or regulatory red flags.

The regulations differ between countries. For example, sponsors must follow national data privacy regulations, such as HIPPA in the US, General Data Protection Regulation in EU and Act on the Protection of Personal Information in Japan. As of December 2022, Japanese regulations to promote DCTs are under discussion. Topics include regulation of the remote consent and data reliability in DCTs, direct shipment of investigational medical product (IMP) to participants, and site personnel resources for visiting participant homes [39]. In Denmark, the investigator delivers IMPs directly to the participants [40]. In each instance, the DCT sponsors should document all logistics in the protocol and be sure of compliance with each regulatory agency [41].

As for DCTs targeting rare diseases, there is yet any detailed regulatory guidance. However, it is critical to think about the challenges (such as the concern about data flow and discrepancy in regulatory requirements on novel technologies between countries/regions, mentioned above) in rare disease clinical trials and investigate novel approaches that have been already offered by regulatory bodies for rare disease domains. The key consideration should be how such novel approaches can be adopted to DCTs. One has a better chance of submission and expedited review if studies are tied to the suggestions of regulatory bodies.

DCTs are more than just convenience for trial participants. Participating in research in a hybrid or completely remote manner allows a participant to spend precious minutes and their limited energy with loved ones or participating in life activities that have no connection to illness. The parent-child bond often suffers from the stress of repeatedly cajoling a child into going to the hospital or allowing strangers to do medical procedures to gather information. It is no little gift to allow parent and child to do as much as possible in the comfort of their own home. This reflects the ethical principle of beneficence, which charges researchers who are in the quest for valid scientific data to “do good” whenever possible.

As stated earlier, there may be trial participants for whom remote participation is not suitable, either due to poor internet service or lack of comfort with technology. Sending a physician to the patient’s home to perform tests that are conventionally done on a clinical site is an immediate quality of life improvement. Patients’ and caregivers’ preferences should be prioritized, and relevant questions include: Have the patient and caregiver demonstrated the ability to participate remotely? What degree of remote participation is consistent with optimal care quality? Hybrid DCTs, with potential individualization, involve active listening by the clinicians involved in study intake, considering the patients’ and caregivers’ preferences as well as the medical issues, and no compromise regarding quality of care. To fully encompass this extension of beneficence, DCT technology must be highly reliable and remote support (as well as on-site support) must be available in the event of technological failures.

DCTs allow people to participate in trials who would not have been able to manage a rigorous onsite schedule. And because of the nature of any given rare disease, eligible participants are geographically scattered. Hybrid or completely decentralized trials allow meaningful research to be done, by pulling together cohorts of participants who are not tied to a centralized physical site. This is in service to the principle of justice – supporting greater access to opportunities to participate in research and buttressing the diversity of the research participant population. As discussed above, certain components of care can be delivered at higher quality at a tertiary center. Most obviously, the trial participant may need to return to the trial center for high technology diagnostic or therapeutic interventions, and these will likely be built into hybrid trial designs when necessary. We have also alluded to a more subtle point: DCTs must incorporate in-person physical examination by experts when remote examination is not possible or feasible. This hybrid model will ensure high quality of care.

Finally, there is a psychological component embedded in learning to monitor your child’s (or your own health) for meaningful data. This personal management of care in the furthering of science – can be empowering. Active participation is the embodiment of autonomy, that is to say– those in a DCT are literally carrying out some of the research procedures themselves. DCT participants are reaffirming their consent to participate with every action they take, and their autonomous actions reinforces the reality of “partnership in research.”