Decentralized clinical trials (DCTs) are clinical trials in which some or all trial-related activities occur at locations other than traditional clinical trial sites, such as via a telehealth appointment or in a clinical trial participant’s home. DCTs differ from traditional site-based clinical trials in the extent to which (a) the investigator uses telehealth, (b) trial personnel work remotely, (c) trial procedures and data capture may be performed in a participant’s home, (d) the local healthcare personnel and professionals (HCPs) are engaged to conduct aspects of the clinical trial, and (e) the investigator uses digital health technologies (DHTs) in the conduct of the trial.
Whereas conducting clinical trials remotely may increase the convenience and efficiency of the process and help to improve diversity, it is imperative that sponsors (i.e., the person or entity initiating the trial and often financial supporting the trial such as a pharmaceutical or device company), investigators (i.e., the person conducting and supervising the trial), and other stakeholders are aware of regulatory considerations that may impact the design and conduct of a trial. These stakeholders must pay careful attention to both state and federal laws when designing and conducting clinical trials with decentralized elements. It remains critical that sponsors and investigators collect consistent data across trial sites, regardless of where the trial participant is located, which local HCP is involved in the visit, or which DHT is used or local HCP is collecting the trial data.
In recent years, the U.S. Food and Drug Administration (FDA) has expressed a commitment to supporting the use of DHT with the development of the Digital Health Center of Excellence, housed under the FDA’s Center for Devices and Radiological Health (CDRH). The Digital Health Center of Excellence develops new regulatory approaches for FDA regulation of digital health products and provides services to digital health stakeholders, many of which are new to the healthcare sector, as they navigate the FDA’s regulatory process. The use of DHT is paramount in the performance of DCTs, and stakeholders need to be aware of the FDA’s positions with respect to same.
In December 2023, the FDA issued a guidance document titled Digital Health Technologies for Remote Data Acquisition in Clinical Investigations (DHT Guidance). The guidance provides recommendations on the use of both hardware and/or software DHTs to acquire data remotely from participants in clinical investigations that evaluate medical products. In general, DHTs help expand the types of trial-related data that can be obtained remotely from trial participants. The use of such DHTs can improve trial recruitment, engagement, and retention by reducing the burden on the trial participant. In its guidance, the FDA provides recommendations for how DHTs should be selected and used when conducting a clinical trial to ensure that sponsors and investigators are collecting consistent data across study sites and that such data may be appropriately verified, validated, and used to support a drug or device application. This guidance enables investigators to use DHTs, such as remote patient monitoring devices, to collect trial participant data during a telehealth visit, provided that the DHT is selected and used in such a way that is consistent with the FDA’s recommendations.
In September 2024, the FDA issued another guidance document applicable to trials conducted remotely titled Conducting Clinical Trials with Decentralized Elements (DCT Final Guidance). Interestingly, the title changed from the previous draft version of the guidance, which was titled Decentralized Clinical Trials for Drugs, Biological Products, and Devices issued in May 2023 (DCT Draft Guidance). The title change illustrates the FDA’s movement away from separately classifying trials as either DCTs or hybrid DCTs and its focus on the elements of decentralization, such as telehealth visits, visits with local HCPs, or in-home visits with remote trial personnel. By implementing this title change, FDA has highlighted that a DCT is still a clinical trial and, therefore, subject to all typical laws and regulations. The title change, however, also broadens the scope of the guidance and emphasizes the FDA’s flexibility with respect to clinical trial design—an entire trial does not need to be decentralized, and a sponsor can choose when decentralized elements could be useful.
The DCT Final Guidance further reflects the FDA’s effort to modernize clinical trial design and efficiency and to reduce the burden on clinical trial participants. The FDA has expressly stated that the final guidance is only a part of a “multifaceted FDA effort.” Such efforts will likely involve new policies and additional guidance from the FDA. In fact, the FDA already simultaneously released new draft guidance titled Integrating Randomized Controlled Trials for Drug and Biological Products Into Routine Clinical Practice, regarding incorporating trial activities for drugs and biological products into routine clinical practice to expand the role of local HCPs in trial settings, as well as a new revised Part 11 electronic systems Q&A document issued in October 2024.
In addition to FDA guidance, when conducting DCTs, stakeholders must also be aware of the FDA regulations governing research in 21 C.F.R., the Department of Health and Human Services (HHS) Office of Human Research Protection (OHRP) regulations governing federally funded research in 45 C.F.R. Part 46 (also known as “the Revised Common Rule”), federal and state privacy and security laws (e.g., HIPAA), and state digital health and telehealth laws and regulations. These regulations remain applicable to DCTs.
DCTs have been demonstrated to maintain engagement and retention, and, therefore, assist the FDA in its mission of ensuring the safety and efficacy of approved products. The FDA has emphasized the importance of increasing diversity in clinical trials, because people from racial and ethnic minorities and other diverse groups are overwhelmingly underrepresented in clinical research for a host of reasons. It is critical that participants in clinical trials represent the patients who will use the medical products. People of different ages, races, and ethnicities may react differently to certain medical products; for example, pathophysiology of disease (e.g., hypertension) may differ among racial groups, and some agents will be more effective than others in a given racial group. In the case of hypertension, results from clinical trials have shown that treatment of elevated blood pressure with antihypertensive medications and different medications may produce different effects in Black patients compared to White patients, even when controlling for other factors such as dietary factors; however, factors such as sample size and study design are important to consider when interpreting these results and so increasing access to such trials is critical to generate scientifically meaningful data. Ensuring people from diverse backgrounds join clinical trials is key to advancing health equity, and the FDA has demonstrated a commitment to expanding diversity in clinical trials.
FDA Commissioner Robert M. Califf, M.D., remarked that DCTs contribute to increasing diversity in clinical trials by enhancing convenience for trial participants, reducing burdens on caregivers, expanding geographic access, and facilitating research on rare diseases and diseases affecting populations with limited mobility.
The DCT Final Guidance specifies that sponsors engaging in outreach through local healthcare institutions (e.g., pharmacies and clinics) may facilitate recruitment of participants in areas where there are limited or no traditional clinical trial sites, which expands access to trials for more diverse groups of people and people in rural areas. DCTs have the ability to reach patient populations that are not able to participate in trials at brick-and-mortar sites due to geographic or economic constraints. For example, a trial conducted remotely with access to local HCPs or flexible virtual telehealth visits could recruit trial participants working multiple jobs, caring for children or other family members, or living in rural areas far from an academic medical center. In addition, using local HCPs may also help reduce cultural or linguistic barriers to participation by using providers who understand the needs of the local community and may help bridge the gap of justified generational mistrust in research institutions. DCTs also have the unique potential to increase enrollment in rare disease studies in which expanding broader geographic nets is imperative to locating a sufficient number of potential participants with rare diseases.
The FDA is actively working to address the issue of diversity in clinical trials. On June 26, 2024, the FDA released draft guidance regarding use of diversity action plans in the conduct of clinical research titled Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies (Diversity Plan Guidance). A plan is required for a clinical investigation of a new drug for a Phase 3 study and for other pivotal studies as appropriate. For medical devices, a plan is required to be included in the Investigational Device Exemption application. Generally, per the Diversity Plan Guidance, plans are intended to increase enrollment of participants who are “members of historically underrepresented populations in clinical studies to help improve the strength and generalizability of the evidence for the intended use population.” The FDA lists “[e]mploying clinical study decentralization when appropriate” as an example of a clinical study enrollment and retention strategy that may be included in a plan.
A sponsor’s core responsibilities remain the same for DCTs as for traditional, brick-and-mortar clinical trials; notably, sponsors remain subject to FDA regulations and guidance applicable to brick-and-mortar trials. When sponsoring a DCT, however, sponsors must also manage the overall coordination of decentralized activities. Such coordination involves managing the accounting for data from a variety of inputs, maintaining a record of the network of local HCPs (e.g., physicians, nurses, local clinical networks, pharmacists in community-based pharmacies) and other contracted services providers performing contracted activities, ensuring compliant shipping and administration of investigational products (IPs), and monitoring, including safety monitoring that accounts for the decentralized nature of the trial.
Importantly, sponsors conducting DCTs, in addition to compliance with FDA regulations and guidances, must also ensure compliance with relevant state and local requirements governing the practice of medicine via telehealth, contracting with local HCPs, and administration of IPs.
A DCT protocol should specify when a telehealth visit is appropriate and when a participant should be seen in person. If local HCPs are to be used, the use should be limited to the type of clinical care that is within the HCP’s typical scope of practice/qualifications, without the need for training or detailed knowledge related to the protocol, investigator’s brochure (i.e., the document summarizing the preclinical and clinical information about the IP), or IP. Local HCPs are not considered trial personnel or sub-investigators, so the protocol should clearly specify which activities can be performed by trial personnel versus local HCPs.
The protocol must take into account the fact that the trial is conducted with decentralized elements. It should specify how adverse events identified remotely will be evaluated, reported, and managed, and it should describe how care will be provided for adverse events that require urgent or in-person attention. The protocol should also identify how operational aspects of the DCT will be implemented, including but not limited to: (1) scheduled and unscheduled clinical trial visits (remote and in-person, as applicable), (2) activities to be performed by trial personnel versus local HCPs, (3) transmission of reports on activities performed at different locations (e.g., medical imaging, clinical laboratory tests, and procedures performed at trial participants’ home, work, or other local facility), (4) delivery of IP to study participants, if applicable, and accountability for IPs, (5) safety monitoring and management of adverse events, and (6) ensuring patient privacy during in-home and telehealth visits (e.g., by accommodating times most suitable for a participant or using convenient locations outside of a participant’s home if a participant shares their residence with others).
The sponsor must ensure that there is a physical location in which a responsible person is available to facilitate an FDA inspector’s access to all clinical trial-related records (either paper or electronic access) for participants under the investigator’s care and to facilitate interviews with trial personnel (either in-person or remotely). This location should be listed on Form FDA 1572 or must be included in the investigational device exemption (IDE) application if applicable.
When using DHTs, the sponsor must ensure that DHTs used in a DCT are available and suitable for use by all study participants. To ensure that the collection of data is consistent across sites, training should be provided to all parties (e.g., trial personnel, local HCPs, and trial participants) using software to support the conduct of DCTs. In addition, sponsor-provided DHTs should be available as an option to ensure that participants who do not have a protocol-specified DHT are not excluded from the DCT for that reason.
Sponsors should include at least the following in a data management plan (DMP) to account for multiple sources of data collection:
Sponsors must also ensure that case report forms identify the visit type (i.e., remotely or in-person), when and where the data was collected, and by whom.
When creating a trial monitoring plan, the sponsor must describe how monitoring will be implemented to assess protocol compliance and data quality and integrity, specify the frequency with which trial records and source documents will be reviewed, and note any unique aspects related to the DCT procedures.
The sponsor must also implement a safety monitoring plan to ensure the safety and welfare of trial participants in a DCT. The plan should describe how participants are expected to respond to and report adverse events, including where to seek medical assistance locally when necessary and where to receive follow-up care. The safety monitoring plan should describe the type of information that will be collected by a DHT (when used to collect data in a DCT), how that information will be used and monitored, and what action trial participants or personnel should take in response to abnormal findings or electronic alerts.
Generally, adverse events should be captured during scheduled visits with trial personnel or investigators. Local HCPs performing activities must also be instructed on how to report any concerning signs, symptoms, or clinical events. The safety monitoring plan should take the decentralized nature of the clinical trial into account and ensure that adverse events are appropriately captured and adequately addressed. The monitoring plan should prespecify if and when telehealth visits or in-person visits will be scheduled with trial personnel or local HCPs to collect safety data. Trial participants must be able to contact trial personnel to report adverse events and to have pertinent questions answered and should be able to arrange for an unscheduled visit using telehealth or an in-person visit, as appropriate.
Sponsors must comply with applicable federal, state, and international laws and regulations concerning the packing, shipping, and storage of IPs in their respective jurisdictions. The protocol should describe how the physical integrity and stability of the IP will be maintained during shipment to trial participants, including appropriate packing materials and methods (e.g., temperature control). Shipping containers should include clear instructions for handling and storing the IPs and instructions for returning unused IPs.
The protocol should describe how investigators will track and document whether and/or how local HCPs or trial participants (or their legally authorized representatives) receive IPs. The protocol should describe procedures regarding how the investigator, local HCP, or trial participant will return or dispose of unused IPs and how this will be documented.
DCT personnel should be trained on procedures and appropriate documentation for handling, packaging, shipping, and tracking IPs. A central distribution service could be used to ship the IP directly to trial participants. The investigator or delegated trial personnel must control the release of the IP by the distributor; monitor receipt and use by trial participants (or their legally authorized representatives), according to procedures described in the protocol; and monitor the return or disposal of any unused product as directed by the sponsor.
Investigators continue to be responsible for overseeing the conduct of clinical trials, including DCTs, and the supervision of individuals delegated to perform trial-related activities. The key difference for investigators between DCTs and traditional site-based trials is the extent to which the investigator and/or sub-investigators use telehealth, trial personnel work remotely, local HCPs are leveraged, and/or DHTs are utilized in the conduct of the trial.
Investigators may be required to perform additional training, coordination, and implement additional standard operating procedures (specific to telehealth, remote data capture, and use of DHTs) to ensure consistent implementation of processes and procedures utilized in DCTs. FDA guidance specifically notes that investigators must ensure that remote clinical trial visits conducted via telehealth comply with laws governing telehealth in the relevant U.S. states or territories and other countries, as applicable. Notably, the regulation of telehealth is largely at the state level, thus, investigators will need to be aware of and comply with all applicable individual state telehealth laws and regulations.
Investigators are responsible for the conduct of the DCT and the oversight of individuals delegated to perform trial-related activities, including ensuring that these delegated activities and/or tasks are conducted according to the investigational plan, applicable regulations, and relevant laws. When delegating trial-related activities to local HCPs, investigators should put in place quality control measures to help reduce variability, including a regular review of participant data entered by local HCPs, to assess consistency and completeness of required procedures.
Investigators should engage only local HCPs to conduct clinical care that is within the HCPs’ typical scope of practice and without the need for training related to the protocol or IP and utilize only as many local HCPs as can reasonably be overseen. When delegating trial-related activities to local HCPs, investigators should put in place quality control measures to help reduce variability, including a regular review of participant data entered by local HCPs, to assess consistency and completeness of required procedures. If local HCPs submit trial-related data to investigators by uploading forms or documents via secure data transfer, investigators or other trial personnel are responsible for entering these trial-related data into the electronic case report form (eCRF).
Note, investigators do not need to maintain a log of local HCPs who perform trial-related activities; however, investigators should ensure that reports from local HCPs include the name of the local HCP and the date the activities are performed as part of preparing and maintaining adequate case histories.
Investigators may obtain electronic informed consent from trial participants at their remote locations provided that all applicable regulatory requirements regarding informed consent are met. To ensure that the process of obtaining informed consent is adequate and appropriate, the investigator should use a central institutional review board (IRB). Obtaining informed consent is an investigator responsibility that can be delegated only to an individual with detailed knowledge of the protocol and training and credentials to address questions or concerns participants may have about the trial. The FDA does not consider obtaining informed consent an appropriate activity for a local HCP to perform because local HCPs are not considered trial personnel. Significantly, individual states may have telehealth consent regulations. In addition to complying with FDA regulations, investigators should ensure that the DCT consent and consent process comply with applicable state telehealth consent regulations.
Trial participants must be able to contact trial personnel (i.e., not the local HCP) to report adverse events, to have pertinent questions answered, and to arrange for an unscheduled visit using telehealth or an in-person visit, as appropriate.
Some trial protocols will include designated clinical laboratory facilities to perform protocol activities (e.g., phlebotomy or x-rays). Other protocols may permit the use of a variety of clinical laboratory facilities close to the trial participant. Use of a local clinical laboratory facility is generally appropriate for routine clinical tests that are well-standardized. Designated clinical laboratory facilities should be used for tests that are specialized or specific to the trial.
If appropriate, specimens from participants may be collected by remote trial personnel, local HCPs, local clinical laboratory facilities, or participants using home collection kits and sent to designated clinical laboratory facilities for processing. Investigators must maintain a record of laboratories used or added.
An investigator must administer IP only to participants under the investigator’s personal supervision or under the supervision of a sub-investigator responsible to the investigator. The nature of the IP should be considered when determining whether administration outside of a clinical trial site in a DCT is appropriate. Investigators should take steps to help ensure that participants have access to an appropriate level of local care, depending on the safety profile of the IP.
The investigator or delegated trial personnel must control the release of the IP by the distributor; track and monitor receipt and use by trial participants (or their legally authorized representatives), according to procedures described in the protocol; and monitor the return or disposal of any unused product as directed by the study sponsor. Investigators must comply with applicable federal, state, and international laws and regulations that address shipping IPs in their respective jurisdictions.
As noted above, the regulation of telehealth is largely at the individual state level. Thus, sponsors and investigators must be aware of individual state telehealth-specific practice standards and regulatory requirements, such as establishing a patient relationship, patient identity verification, informed consent, disclosure/notice requirements, and entity registration. Sponsors (and investigators) must ensure that remote clinical trial visits conducted via telehealth comply with applicable laws governing telehealth, including applicable state laws. Certain states consider clinical research the practice of medicine, which means all telehealth practice standards will apply. Additionally, even if a state does not include the conduct of research within its statutory definition of the practice of medicine, when a protocol includes standard of care activities in addition to investigational procedures, telehealth practice standards will apply.
Importantly, providers (including investigators) must be licensed in the state in which the trial participant is located at the time of the clinical trial interaction (unless an applicable exception applies, e.g., bordering state exception). Certain states (e.g., Florida) have special telehealth licenses that may be utilized.
Whether an investigator must be licensed in the state in which they are delegated to perform trial-related activities depends on state law and whether licensure is a key component of providing meaningful oversight over the individuals providing trial-related activities. The general rule is that clinicians must be licensed in the state in which a patient is located at the time of a clinical consultation. Best practice is that the principal investigator (or, at a minimum, a sub-investigator) is licensed in each state in which a clinical trial participant is located. If a research nurse is conducting clinical elements of a protocol, the research nurse should also be licensed in the state in which the clinical trial participant is located. Clinical trial agreements (CTAs) often require licensure representations as part of the contracting process as a way for sponsors to ensure compliance.
If licensure is required, there are a number of pathways available to securing such licensure: (1) traditional licensure, (2) a telehealth special purpose license or registration offered by certain states for physicians (i.e., an abbreviated licensure pathway), or (3) an Interstate Medical Licensure Compact (IMLC). There is also a Nurse Licensure Compact and a PA Licensure Compact that physician assistants may utilize.
The IMLC is an agreement among participating U.S. states and territories to work together to significantly streamline the licensing process for physicians who want to practice in multiple states. It offers a voluntary, expedited pathway to licensure for physicians who qualify. In order to qualify for compact participation, physicians must hold a full, unrestricted medical license in a compact member state that can serve as a state of principal license.
There exist significant variances across the 50 states and Washington, DC, with respect to allowable telehealth modalities (e.g., real-time audio-video, interactive audio, and store-and-forward technologies), as well as the extent to which states have favorable language in their statutes, regulations, or board of medicine guidance. Note that all clinical practice via telehealth (whether treatment, diagnosis, or prescribing) must comply with the applicable standard of care, which is typically equivalent to that for in-person services.
Many states do not require an in-person examination to establish a physician-patient relationship and instead allow a relationship to be established via an alternative modality such as an audio-only call (i.e., phone call) or audio-video call (e.g., Zoom call). Additionally, there are states that require one modality to create the relationship but allow another modality to be used for treating (including prescribing), thereafter. In these cases, states often require either an in-person or audio-video examination to establish the relationship and then will allow follow-up visits to be conducted via another modality, such as audio-only or store-and-forward. Certain states require all patients to be seen in-person before telehealth can be used.
In a number of states, the telehealth clinician must verify the identity of the individual before engaging in telehealth.
Many states have telehealth informed consent requirements. These exist in addition to the clinical trial informed consent requirements under the common rule or 21 C.F.R. Part 50.
A number of states have special telehealth disclosure or notice requirements (e.g., sharing the physician’s credentials, contact info, how to file a complaint with the medical board).
Some states have implemented “telemedicine business registrations” requiring an entity to register with the applicable state agency if such entity is practicing telehealth in the state.
Investigators may engage local HCPs directly. As such, CTA contracting and budgeting should contemplate the pass-through costs associated with the use of local HCPs and the time and effort required for principal investigator oversight of such individuals.
Care associated with participant injury and attention for adverse events is typically provided by a brick-and-mortar site in a non-DCT trial. Care may be provided at the closest place a study participant can receive clinical care, which will not necessarily be the site with which the principal investigator is affiliated. As such, CTAs should contemplate pass-through costs being made to any clinical facility (including local HCPs) that provide care to a study participant for study-related adverse events or injuries.
Confidential information related to a trial is typically shared only with a brick-and-mortar site and the study sponsor. Local HCPs and local facilities providing care to study participants (as may be true for care associated with injuries or adverse events) may have a need to receive study related confidential information. The applicable CTA (and applicable informed consent and HIPAA authorization) should account for the need to share such confidential information and receive information from local clinical facilities and local HCPs as needed for adverse event reporting.
Certain trial-related procedures may be considered standard of care when conducted in a brick-and-mortar setting and would be covered by a trial participant’s insurer as a result. The same care may not be covered if it is provided by a local HCP via telehealth because the care may not be covered when provided via telehealth. The CTA budget and analysis thereof will need to account for such services.
While conducting research remotely using telehealth, DHTs, and local HCPs can increase the efficiency and diversity of clinical trials and should be sought to be utilized by sponsors of DCTs, sponsors, investigators, and other stakeholders involved with the design and conduct of a DCT must be aware of federal, state, and international regulatory considerations impacting these cross-jurisdictional activities. In addition, although the FDA is actively encouraging the use of decentralized elements through its DCT Final Guidance and DHT Guidance, it is critical that stakeholders are aware of the FDA’s guidance documents and recommended considerations when designing and conducting the trial to ensure the trial is generating sufficient data to support a new drug or new device application.
