By Sarah V. Ferranti and Shine Chen Schattgen
“Decentralized” clinical trials (referred to as “DCTs”) are not novel, but nevertheless failed to gain real momentum given the regulatory and operational complexities involved. In light of COVID-19, however, it seems almost certain that the remote and virtual study activities that characterize DCTs, and a site and sponsor’s ability to flex to “meet the participant where they are” will be critical to the conduct of clinical trials going forward.
In the first half of 2020, as health care facilities prepared for capacity-exceeding patient volumes and equipment shortages, non-essential clinical care and non-COVID-related clinical trials came to a screeching halt. According to ClinicalTrials.gov, 1473 clinical trials were suspended, terminated, or withdrawn between December 1, 2019 and July 1, 2020, with a reported reason that explicitly mentioned COVID-19.
At the same time, initiation of clinical trials for COVID-19 vaccines and treatments exploded at speeds previously considered unachievable within the clinical trial industry. As of October 13, 2020, 811 COVID-19-related clinical trials had been initiated in the United States. To enable COVID-19 trials and, more recently, to restart previously paused non-COVID trials, clinical trial sponsors and sites have been forced to quickly adapt to protect participants and preserve the integrity of clinical trial data and results.
The Tufts Center for the Study of Drug Development (“TCSDD”) has reported that 40 percent of trials ongoing at the time of the outbreak of SARS-CoV-2 moved to models that included home health visits, direct-to-patient drug and supply delivery, and collection of data by portable devices. Likewise, WIRB-Copernicus Group has reported that 64% of clinical trial sites have used telemedicine “sometimes,” “often,” or “always” during the COVID-19 pandemic.
This transition effectively “decentralizes” the participant experience, moving trial-related activities away from a single site and to a participant’s home or health care providers within the participant’s local community.
What are decentralized clinical trials (“DCTs”)?
Traditional clinical trials often involve a series of onsite visits, generally at a single clinical trial site. By contrast, DCTs may be executed through use of technology, such as telehealth for conducting virtual visits, electronic systems for obtaining informed consent, or digital health technologies for collecting clinical data from participants, as well as other “remote” strategies including shipment of investigational medical products to participants’ homes or use of local health care providers to assist with trial-related functions.
Clinical trials may be fully decentralized (i.e., participants may never encounter the clinical trial site or interact directly with the investigator) or partially decentralized (also referred to as “hybrid” trials, which combine traditional clinical trial activities with innovative strategies). The U.S. Food & Drug Administration (“FDA”) established a formal working group on DCTs in 2018 and is drafting a guidance document on approaches for these trials, which is planned to be released by the end of 2020.
What are potential benefits of DCTs?
DCTs may offer benefits to clinical trial sponsors, sites, and participants, and may result in products being brought to market (and the patients who need them) more quickly. Potential benefits of DCTs include:
- Reduced barriers to and burdens of participation. DCTs may reduce barriers to participation for patients who cannot leave their homes and those not living in the geographical area of the site and reduce burdens for patients for whom participation is inconvenient (due to travel costs and time away from work and home, etc.). Patients appear to be in favor of study designs that include DCT components, with approximately three-quarters of patients finding alternative models (such as data collection at home, visits being conducted by a nurse at home, and some visits at home and some visits at the site) very or somewhat appealing. While the overall impact is to reduce barriers and burdens, for certain participants who do not have access to internet or videoconferencing or without experience utilizing such tools, DCTs may pose challenges. Sponsors and sites may need to consider whether they are able to assist such participants in overcoming those challenges.
- Improved patient engagement. Use of technology, including appointment reminders pushed to smart phones, online patient diaries, collection of data through wearable devices, and electronic access to study staff, may contribute to increased participant engagement and, consequently, retention.
- Diversity. DCTs undoubtedly will increase geographic diversity of participants, but they also may contribute to increased gender and racial diversity. According to TCSDD, women are underrepresented in clinical trials by 7% and Black or people of African descent are underrepresented by 65% (compared to levels in general consensus and disease populations). These groups may be particularly attracted to DCTs. As noted above, approximately three-quarters of patients find alternative models very appealing or somewhat appealing – broken down into demographic categories, women are more likely to find home visits from a nurse and home data collection to be “very appealing” compared to men and 40% of individuals who identify as Black find home visits from a nurse to be “very appealing” compared to 30% of the general population.
- Economically efficient. Remote and virtual visits reduce sponsor expenses being allocated toward travel, lodging, and local transportation for participants and clinical trial monitors. Initially, reduced costs in these areas may be offset by increased resources dedicated to adoption of new technologies and training of personnel, but over time it is expected that DCTs will promote overall trial efficiency.
What are the challenges in implementing DCTs?
A shift towards DCTs represents a significant change in clinical trial infrastructure. At early stages, sponsors will need to consider, in close collaboration with FDA, whether a clinical trial is suitable to be conducted with remote or virtual activities, and how offsite activities may impact participant safety, data reliability and integrity, and the ability of FDA to evaluate the safety and efficacy of an investigational medical product.
Additional challenges in implementing DCTs include:
- Participant Safety. To ensure participant safety, sponsors and sites must address (1) how data collected continuously from numerous sources will be reviewed for adverse events (“AEs”); (2) the role of participants and third parties in participant safety and AE reporting, including what third parties should do if a participant presents with a potential AE or unrelated symptom or condition; (3) how investigators will facilitate access to medical care, if needed; and (4) how investigators can fulfill regulatory and sponsor obligations regarding AE reporting. DCTs should not be implemented (especially for early phase trials where product safety has yet to be established) until appropriate procedures are in place to identify, assess, and properly report AEs.
- Investigator Delegation and Oversight. FDA regulations set minimum standards for investigators for conducting clinical trials under investigational new drug (“IND”) and investigational device exemption (“IDE”) applications. These standards, established in the context of trials at brick-and-mortar sites, apply equally to investigators conducting DCTs and place primary responsibility for protocol and regulatory compliance, protection of participants, and control of the investigational medical product on the investigator. DCTs may involve a host of different health care providers including telehealth and mobile health providers and local or mobile testing facilities (MRI, phlebotomy, etc.). Sponsors and sites will need to consider the level of involvement of such providers in research activities (versus routine care) and, relatedly, (1) whether these providers constitute additional “investigators” or “subinvestigators” for FDA regulatory purposes and (2) Institutional Review Board (“IRB”) oversight over the activities of such providers. These considerations may impact whether the sponsor or site engage and contract with such third party providers. In some cases, sites have been unwilling to engage third parties in part because site IRBs are not in a position to oversee research activities of third party providers. If investigators are delegating responsibilities to third parties (including subinvestigators), they are responsible for (1) confirming that such third parties are appropriately qualified and (2) providing adequate supervision and oversight, and, with respect to third parties other than study staff, investigators should take steps to ensure the integrity of data and records obtained from the facility.
- State Law Requirements. DCTs implicate state laws governing professional licensure, including telehealth and home health, and distribution and dispensing of drugs (including controlled substances) and devices in the states where participants are located. Sponsors and sites must ensure (1) appropriate licensure and registration to perform study activities in the relevant states and (2) that the protocol does not conflict with restrictions imposed by applicable state laws. One of the major challenges for sites is making sure that investigators are aware of these requirements and restrictions in advance. In addition to adopting policies addressing this issue, investigators and research staff need to be educated on when certain DCT activities may implicate state law (g., when the remote visit may include some aspects of treatment or standard of care), or any other action that under usual circumstances, would require a professional license. Although some states have provided flexibilities with respect to certain licensure and telehealth requirements during the COVID-19 public health emergency, these flexibilities are time-limited and may have relevant scope limitations. Sites and sponsors also should confirm whether registrations are required under federal controlled substance regulations.
- Security of participant data. DCTs involve use of electronic systems that handle participant data, including protected health information (“PHI”) under HIPAA. Sponsors and sites must consider whether technologies employed to collect, transmit, and share participant data amongst themselves and third parties are compliant with HIPAA security standards for electronic PHI, FDA’s requirements for electronic records and signatures (21 C.F.R. Part 11), and other local security requirements.
- Data Collection, Storage, and Monitoring. DCTs complicate the flow of data and the storage of records. Sponsors and sites must consider carefully (1) the flow of data, (2) how source documents and clinical trial records are stored, and (3) how clinical trial monitors will access records for source data verification and review in a secure manner. As such, many sites are working with sponsors to enter into remote monitoring contracts that protect PHI.
The unique challenges posed by COVID-19 have helped push the clinical trial industry towards innovative clinical trial models, including DCTs. Although the transition to remote and virtual activities has been reactive during this time, we expect that proactively planned DCTs will increase in the future to provide greater certainty in the event of future pandemics, improve the patient experience, and speed the drug and device development process.
Sarah V. Ferranti is a Member of the Firm in the Health Care and Life Sciences practice, in the Boston office of Epstein Becker Green.
Shine Chen Schattgen is Associate Counsel at St. Jude Children’s Research Hospital in Memphis, Tennessee.