Decentralized Clinical Trials: Coming Virtually to a Research Facility Near You

As the pharmaceutical industry pivots and takes stock of a new post-COVID-19 normal, ensuring the safety of clinical trials is at the forefront of sponsors’ and investigators’ minds. Exploring the feasibility and utility of mobile technologies was already well underway prior to March 2020; however, a fresh look at their opportunities was captured in a paradigm shift when on Jan. 27, 2021, the U.S. Food and Drug Administration (FDA) released “FDA Guidance on Conduct of Clinical Trials of Medical Products During the COVID-19 Public Health Emergency.” In the guidance, the agency supported an expanded vision of clinical trials — one that includes alternative methods of safety assessments (e.g., phone contacts, virtual visits and alternative locations for assessments, including local labs or imaging centers) provided good clinical practices (GCPs) are assured and adhered to and risks to integrity are minimized. 

Remote patient monitoring is nothing new. Considering the power of passive data capture of activity tracking through worn sensors, medication adherence through smart‐cap bottles, data entry into mobile devices and telehealth services, and as innovative usage of technology progresses, the in-person model of healthcare may not be the gold standard in the future. 

However, shifting to a virtual clinical trial as a natural extension of in-person trials is another story, particularly when the shift happens during a global pandemic. Virtual equals complexity, given the agency’s willingness to consider remote monitoring. And, ensuring all modifications to ongoing or planned studies take into account the potential safety impacts became priority No. 1. FDA does not require investigators or subinvestigators to have direct face-to-face contact with patients. Also, there is no definition for the term “clinical trial site,” so the decision to extend to a decentralized trial might be acceptable. In question, however, are potential limitations to a single investigator’s ability to oversee a decentralized trial,¹ particularly when an opportunity to expand participants into multiple geographic regions is presented.

For trials already in process at the outbreak of COVID-19, sponsors in consultation with clinical investigators, institutional review boards and independent ethics committees were forced to determine whether participants’ safety, welfare and rights were best served by continuing per the approved protocol, whether discontinuation of participation in the trial was most appropriate or whether another alternative method of safety assessment could reasonably be made. For instance, could phone contacts or virtual visits ensure trial participant safety, as well as in-person consultations? If trials can be expanded, what are the implications of licensing when trial participation crosses state lines?

Opportunities for Drug Development 

It can take 10 years and tens of millions of dollars to bring a drug to market in the U.S. A large portion of that expense (9 percent to 14 percent) is paid to research clinics to which study participants must report on a regular basis. This means the pool of available participants must be located within easy travel proximity to the (typically urban) centers conducting the trials, resulting in fairly homogenous studies. Recruitment and retention are two additional challenges with nearly 40 percent of trials failing to meet initial recruitment targets, and 49 percent of participants dropping out prior to study completion.² A major reason for participant attrition is the time, inconvenience and effort of traveling to the clinical sites for monitoring. Yet, FDA has stated its intent for greater diversity in clinical trials, meaning an expanded pool of participants must be recruited.

As such, decentralized trials offer an ability to recruit greater numbers of participants and retain them thanks to the convenience of remote data collection. Although occasional in-person monitoring may be required (a hybrid model), by largely removing geographic barriers, increased diversity will create new opportunities for drug development. And, while the first completely randomized virtual clinical trial for an investigational new drug was announced in 2011, the current state of the industry is similar to that of biomarkers in the early 2000s,³ showing great potential. 

Of course, not every clinical trial is appropriate to be held entirely virtual (for instance, those requiring imaging or drugs with uncertain safety profiles are two that would require a hybrid model at a minimum) because at the heart of any trial is safety. And, even though emphasis on patient safety is no different between decentralized and in-person clinical trials, an argument in support of a virtual component is the ability to continuously monitor through remote sensing, enabling faster response times in cases of adverse events.

However, there remain obstacles to virtual clinical trials, namely medical licensing and drug dispensing, particularly with a direct-to-patient investigational drug product. Appropriate state licenses are required, even when monitoring is remote, meaning an investigator is required in each state where participants will receive treatment. The Clinical Trials Transformation Initiative (CTTI) also recommends, in their 2018 document “CTTI Recommendations: Decentralized Clinical Trials,” contracting with companies able to provide licensed mobile healthcare practitioner research services across states in which a trial is conducted. Additionally, due to changing state laws regarding licensing of telemedicine, enlisting legal expertise is recommended.⁴ What’s more, the integrity of the supply chain must be expressly spelled out and approved as part of the trial protocol design so that the process is clear to the investigator, internal review board and applicable regulatory agencies. All parties must understand and be capable of meeting their obligations. 

Wearables

So, how can data be collected in a virtual clinical trial? The easy answer could be wearables. Their ability to capture vitals such as heart rate and blood pressure and their capability to track and record adverse events, sleep and movement makes them already useful tools in assessing diseases such as depression, progression of multiple sclerosis and heart disease. And, although there are noted differences in accuracy and fidelity between clinical and consumer‐grade devices, gaps are closing rapidly.

The opportunities for data collection and their utility are seemingly endless. With appropriate consideration of fit-for-purpose and verification, wearables transmitting data both actively and passively can early identify safety issues that would affect dosing and/or discontinuation of drug candidates from certain trials. Wearables can also enable faster and more objective data collection.

Of course, like any technology, wearables are not infallible. Very real concerns are software and hardware failures, lapses in tracking due to Internet outages or just a simple loss of battery life. If not provided to trial participants, wearables may introduce economic bias. There may also be differences in Health Insurance Portability and Accountability Act (HIPAA) requirements depending on whether the technology is provided as part of the trial or if data is delivered from participant-owned technology.

Data Integrity, Sharing and Patient Protections

As with any clinical trial, patients’ understanding of how their data will be collected, stored, used (and reused) and shared is paramount. And, that task becomes more complicated when the trial is conducted virtually. Investigators need to minimize the amount of data collected, limit who has access and develop accountability into the clinical trial design, all of which needs to be conveyed to participants. Open communication about what will happen to their data helps participants build trust in the process.  

The term “data” includes all data, including what is captured in the background of another activity, termed paradata. Paradata may include time stamps, geolocation, digital health technology settings and other information having little to do with the clinical trial. Specific informed consent for paradata is necessary, as is ensuring all data, passive, para and otherwise is de-identified. New federal and industry policies for mixed uses and data sources, as well as participant informed consent on data collection, are recommended.¹

The question of data accuracy is also paramount for investigators. For instance, by what mechanisms can investigators ensure the virtual data being collected is that which was intended? Are patients using the device correctly? Is the data really from the intended patient? How is this verified?

Source data, audit trails, the data originator and what constitutes a final result all are currently under debate. And this is compounded by differing rules regarding data consent, ownership, sharing, usage, privacy and security — particularly with varying laws by geography. In the U.S., HIPAA laws require consent for data collection and sharing, although data collected by personal devices, provided it is de-identified, can be shared in aggregate with less explicit information about who will ultimately have access. Of interesting note is that neither “clinical trial” nor “virtual clinical trial” is defined as part of HIPAA, although the act does discuss research requirements.¹ Ensuring data protection is further complemented by what is known as the Common Rule, the short name for the Federal Policy for the Protection of Human Subjects, which is a standard of ethics that governs biomedical behavioral research involving human subjects.  

In the European Union (EU), the General Data Protection Regulation (GDPR) requires clear definitions of data use, consent and sharing regardless of how it is collected. Within the U.S., California’s Consumer Privacy Act has a much stricter interpretation of data than HIPAA, aligned more closely to the EU’s GDPR, including a higher bar for data de-identification.¹  While an internationally harmonized approach would seemingly be of great benefit, this is such a new area of study that any meaningful outcome is likely a long way into the future.

In terms of clinical trial data collection, protections under HIPAA are less clear when a commercial or personal mobile device is used for data collection; however, the Federal Trade Commission has authority to ensure vendors are held liable for data breaches. Devices given to study participants are more likely to be covered under HIPAA. The CTTI recommends understanding applicable privacy laws by state and other jurisdictions, including those outside of the U.S., in which data will be collected. Experienced IT vendors can provide insights into telemedicine best practices. 

Decisions on data collection, mapping, storage and sharing need to be made early and discussed in clinical trial pre-meetings with FDA. In addition to data storage and consent, training and troubleshooting for all parties from participants to investigators must be articulated.

Adverse Events Reporting

An imperative consideration for virtual clinical trials is safety monitoring. Participants must be clear about steps that should be taken when an adverse event is suspected. Where do they go? Who do they contact? Likewise, guidelines for the appropriate response plans and monitoring must be established for investigators, including communication up the chain for other participants, personnel, third-party vendors and other applicable parties. Safety monitoring can be aided by digital technologies, but given the criticality of identifying an adverse event and the necessity of follow-on actions, remote monitoring should never be a sole substitute for human interaction and intervention. All parties must know what to do in the event technology goes down.

As always, all of this information should be mapped out in standard operating procedures. GCPs are the lifeblood of clinical trials and will be reviewed and assessed by FDA. It is critical for all accountable parties to be identified, to map out the supply chain, and to understand proper storage and handling of drug products. It also must be articulated how participants will take part, how their data will be collected, used and shared, and affirmed that they understand by giving informed consent. 

Decentralized clinical trials have the potential to change our understanding of diseases and the way healthcare is practiced. But out of sight does not mean out of mind. Ensuring virtual clinical trials have the same diligent protocol design and monitoring as in-person clinical trials can literally open the world of possibilities.