Kenneth G. Faulkner, PhD

The pharmaceutical research industry has seen a recent explosion of publications and conferences focused on decentralized and digital clinical trials. If you search the terms “decentralized versus digital clinical trials,” however, the results will overwhelmingly relate to decentralized clinical studies, as if “digital trial” were not a discreet category. Decentralized and digital clinical trials are are two different things. Digital trials can be decentralized. And decentralized trials can use digital tools. But the terms describe different concepts. Let’s look at the differences.

A decentralized trial is, by definition, one that is done away from a central research facility. Patients complete their clinical trial visit at a remote location, either through virtual tools, such as video calls and patient reported electronic assessments, or by face-to-face interactions. The relevant feature is the 

While digital tools are often used in decentralized trials, digital technology is not their defining feature. Decentralized trials can use paper forms exchanged by mail or through house calls, for instance.

A digital clinical trial uses no paper during the conduct of the study. There may be paper forms associated with the patient prior to study initiation, but they would be digitized and curated as part of the study, with the source document remaining as a paper record. Any study can be digital regardless of the location where the clinical visits are performed. The defining feature is the 

What makes a clinical trial “digital”?

To conduct a digital trial, several components are required:

A digital study begins with translating the written protocol into a set of digital objects and specifications that help feed other digital systems for feasibility studies, modeling, and optimization. They include:

In a digital study, electronic study documents for review and approval generated from the digitized protocol can facilitate a digital IRB submission package and IRB approval.

Linked to the Electronic Medical Record (EMR) system at each research clinic, the eScreening application identifies potential study participants at each site based on the criteria from the digital protocol. These patient records are reviewed by the site research staff, and eligible patients are invited to participate. Artificial intelligence tools can aid the curation process.

Qualified participants are referred to an eConsent system that digitally describes the study, presents the risks, benefits, and alternatives, and then captures patient consent using digitally documents approved by the IRB. This system facilitates required updates, reconsent procedures and post-study surveillance assessments.

Interoperability is major challenge for digital trials. Every clinical trial uses an array of systems to manage both study conduct and data collection during the trial. Each of these systems produces clinical study data and associated case report forms managed in an integrated system. They include virtual visit systems, electronic clinical outcomes assessments (eCOA), medical imaging results, clinical trial management system (CTMS), electronic data capture (EDC) system, adverse event reports, and safety and monitoring systems.

The data captured from the study electronically populates a set of digital case report forms aligned to study protocol and the target EDC system, where they can be reviewed and approval. Once complete, the digital case report forms create a seamless audit trail for data monitoring and verification.

Better identification of potential patients, efficient study site workflows, and simplified study monitoring enhanced by artificial intelligence are among the benefits of digital trials that will ultimately increase access to research studies. Building a digital trial requires an initial investment. Once the foundational systems and workflows are in place, however, the return will continue for many years.

, PhD, is Senior Vice President of Clinical Trial Solutions at ConcertAI

Articles

Decentralized vs Digital Clinical Trials: There is a Difference

Virtual clinical trials are not a new concept, but recent events caused by the COVID-19 pandemic have forced us to rapidly adapt to their use in clinical trials. For many patients, limiting (or even eliminating) time in the clinic is critical to maintain patient safety. Here, we outline the options for performing clinical trials using virtual research tools and technologies, and how these changes will impact clinical research in the years to come.

First, we need to be clear on what we mean by virtual visits. For the purpose of this article we will use the following definitions and bear in mind that many researchers are now adapting hybrid models, where different elements of each can be incorporated into any one trial (Figure 1).

A virtual visit is defined as an interaction at a distance facilitated by technology. The people involved are physically separated and are only able to communicate using telephone, video, internet, or some other mode of distance communication (Figure 1).

A remote visit is defined as an interaction at a location away from the clinic or healthcare facility where the clinical research is normally performed. For a remote visit, the people involved are physically together, but they do not have access to the full range of clinic facilities, instruments, and other research staff. The most common type of remote visit would be by a home health provider traveling to a patient’s home, but it also includes a visit conducted at an alternate location different from the research clinic.

A clinic visit is defined as the traditional interaction where the patient physically goes to the research clinic and has full access to staff, facilities, and instruments needed to conduct the clinical trial assessments.

Figure 1: Hybrid virtual trials incorporate different elements of each model into any one trial (Source: ERT)

For a clinical research study, what assessments can be done virtually? The short answer is – more than you might think. While not all clinical trial endpoints can be adapted to a virtual mode, many can be adapted to a virtual setting. This is particularly important during the COVID-19 pandemic, where reducing exposure for patients as much as possible remains critical to patient safety. Even if not all assessments can be done virtually, reducing exposure time by completing assessments at home should be the goal of all clinical trials.

When considering virtual assessments, the FDA has provided guidance on alternative data collection procedures, including the following general considerations (Figure 2):

Preserving patient safety and privacy should be the primary goal

Data quality and integrity should be maintained, including minimizing missing data and ensuring that the data which can be collected are sufficient to address the associated research question

Sponsors need to ensure appropriate training for personnel and trial participants regarding any changes to procedures.

Let’s look at some of the common assessment types and how virtual solutions may be used to keep both patients and site staff safe while still maintaining privacy and data integrity.

Typically, a patient reported outcome (PRO) is captured directly from the patient, preferably using an electronic questionnaire (ePRO). Under normal circumstances, it is not uncommon for patient reported assessments to be completed at the study site using an electronic device provided to the patient during the clinic visit. Under the conditions of a virtual visit, the patient may not have access to the questionnaire or the technology/device used to capture the information, so an alternate collection method is required.

For assessments which are already configured to be completed at home (using paper forms, electronic devices, or a web browser), there is no problem converting to a virtual model. The patient can continue to submit the information as per protocol using their established method of collection. For paper assessments, checking compliance is problematic as form receipt can be delayed by weeks or months which can jeopardize safety and efficacy. This is a primary reason for use of electronic data collection methods, as compliance can be actively monitored as results are transmitted from the patient directly to the study database.

If the study was not configured with electronic devices available for home use, the sponsor can provide them to the patient so that the assessment can be completed as it was done in the clinic. These should be configured consistent with the site device, but have electronic audit trails to capture when and where the data were entered. It is also important to provide appropriate training in the use of these devices for the patients.

An alternative to providing a device for in-home use is to have the site staff virtually capture patient reported information by telephone or video call. Even if the assessment was not designed to be captured by interview, many questionnaires can be adapted to interview mode with the investigator entering responses on behalf of the patient, and to somehow indicate in the audit trail that the data was captured by site staff as opposed to directly entered by the patient. It is important that the interviewer have proper training on how to conduct an interview to avoid adding bias to the assessments. There is also a chance that the interviewer could make a mistake when entering data. To guard against this, it is helpful to use screen sharing software so that the patient can read along during the interview, improving their understanding of the assessment questions and verifying that the proper responses were entered by the investigator.

Figure 2: When considering virtual assessments, the FDA has provided guidance on alternative data collection procedures (Source: ERT)

A Clinician Reported Outcome (ClinRO) is an observation captured by a trained investigator based on a patient’s observable behaviors, signs or symptoms. For example, the investigator may be able to see that a patient is experiencing pain, has tremors, or is acting confused. A ClinRO is designed to capture this information in a systematic way, preferably using an electronic capture method (eClinRO).

Because these assessments are completed directly by a clinician, they are already designed to be used in interview mode. However, the ability to extend a ClinRO to a virtual setting will depend on suitability of a virtual communication tool to monitor the desired behaviors. In most cases, video interaction will be critical, as telephone communication will limit observational abilities. With proper training, virtual ClinRO assessment can be done successfully provided that the targeted behaviors can be viewed on video. If video is not considered sufficient for clinical observations, then these aspects of the ClinRO will need to be skipped or evaluated remotely, for example, by a healthcare professional in the patient’s home.

It is important to note that some ClinROs (and some PROs as well) include critical measures of patient safety. For example, assessing suicide risk is a required safety evaluation for many drug classes, particularly those treatments which cross the blood-brain barrier. When evaluated in the presence of a clinician, immediate intervention is possible for any patients presenting with increased suicide risk. However in virtual visit situations, immediate intervention may not be available, so additional precautions (e.g., immediate notification of the managing physician) should be considered for obtaining assistance for patients identified at increased risk. 

Assessing performance related outcomes usually requires a patient to attempt certain tasks followed by an assessment (typically by a clinician) of how well the task was completed. Depending on the type of assessment, these outcomes may be evaluated virtually. For example, range of motion assessments might be possible through the use of video communication. However, other more complicated performance assessments may not be practical in a virtual setting.

The FDA recommends that sponsors should assess whether evaluation of a performance outcome can be done accurately in a virtual setting. If only some aspects of the assessment can be collected virtually, sponsors must document and report which aspects of the assessment cannot be accomplished. For more complex performance assessments, a remote (off site) visit may be required but only if safety and privacy can be preserved.

Some types of performance outcomes require special equipment, including cognitive assessments, mobility evaluations, and others. In the case where special equipment is required, it may be possible to provide the equipment to the patient at their home so the test can be performed - potentially with the support of a clinician participating virtually. However, it is important to determine if the performance outcomes measured outside of the clinic are both safe and provide a valid result compared to what would be performed in the clinic.

Clinical outcomes such as laboratory tests and diagnostic procedures usually require specialized technology, supplies, and training for sample or data collection. This would include assessments such as blood/urine tests, cardiac tests (ECG, Stress Test), lung function tests (Spirometry), and medical imaging (Radiology) examinations. 

For these types of tests, virtual assessment requires that that the technology required to perform the test can be a) sent to the patient and b) safely and properly operated by the patient. For medical imaging assessments, virtual visits are not practical – though there may be other options (discussed below). For more routine assessments, such laboratory tests, remote methods may be the best option. For example, if a blood sample is required, the sample could be collected by a licensed and trained technician either at a patient’s home, or at a remote laboratory. Note that in the case of a home health visit, the assessment would be considered “remote” even though it is done at the patient’s home, as physical contact is required.

Advances in technology have improved virtual access for some assessments such as 6-lead ECG for cardiac safety and spirometry for basic lung function (Figure 3). The equipment can be sent directly to the patient and then supported by virtual training and data collection. This is particularly important during times of isolation or quarantine, where patient safety monitoring is critical but the patient cannot travel to a clinic or remote testing site.

Figure 3: With the KardiaMobile6L, clinical trial patients administer their own ECG/EKG testing from the comfort of home (Source: ERT)

As mentioned above, there are certain cases where virtual assessment is not possible, such as medical imaging and other advanced laboratory assessments. Very often these assessments are associated with critical safety and/or primary study endpoints, so not collecting the information could have negative impacts to study outcomes. While there are mobile facilities for some imaging procedures, this is not a practical option for at home examinations. Instead, these tests will have to be done either at the research clinic or at remote facilities with the proper equipment and trained staff.

When identifying remote facilities, it is essential that the facility and the staff are properly qualified for performing assessments consistent with the study protocol. Most remote facilities are not familiar with the special regulatory and research requirements associated with clinical research, so proper training and pre-qualification is essential to make sure tests can be done according to the study protocol.

Although the pandemic has become the worst global healthcare crisis of the past century, the adoption of virtual tools into clinical trials is a change whose time has come. While not all clinical trial assessments can be done virtually, there are many that can be adapted for virtual use. The use of virtual assessments requires new technologies, a clear audit trail of data capture modality, additional training, and careful consideration of the potential impact on study outcomes. However with proper planning, virtual visits can be successfully used for clinical trials while maintaining patient safety and study integrity. The additional advantages for patient convenience assure us that virtual visits will be a major part of clinical research going forward.

is the Vice President, eCOA Science, for ERT.

While not all clinical trial assessments can be done virtually, there are many that can be adapted for virtual use. 

What Clinical Trial Assessments Can Be Done Virtually?

	The 21st Century Cures Act was enacted in 2016 to both accelerate medical product development, and it expresses the need to include both patient experience and patient perspective in the drug development process. In accordance with the Act as well as the Prescription Drug User Fee Act, the FDA is currently developing four new methodological Patient-Focused Drug Development (PFDD) guidance documents for industry that incorporate patient experience data into drug development. The key concepts of each guidance-and their current status-are summarized below.

	Although the updated guidance documents are still in development, researchers should start planning now to incorporate the basic features outlined in the draft guidances and discussion documents, as these concepts will likely be required in future research programs.

		Guidance 1: Whom do you get input from, and why? How do you collect the information?					

		Guidance 2: What do you ask, and why? How do you ask non-leading questions that are well-understood by a wide range of patients and others?					

		Guidance 3: How do you decide what to measure in a clinical trial and select or develop fit-for-purpose clinical outcome assessments (COAs)?					

				Status: Public meeting held October 2018; 

		Guidance 4: Once you have a COA measurement tool and a way to collect data using it, what is an appropriate clinical trial endpoint?					

				Status: Public meeting held December 2019; 

	Guidance 1: collecting comprehensive and representative input 

	Guidance 1 lays the foundation for the Patient-Focused Drug Development series by defining patient experience data and outlining whom to get patient experience data from and how to collect, analyze and report the information obtained. Key points include:

	Includes the “experiences, perspectives, needs, and priorities of patients related to:

		the symptoms of their condition and its natural history

		the impact of their condition on their daily function and quality of life

		input on which outcomes are important to them

		patient preferences for outcomes and treatments

		the relative importance of any of these issues as defined by patients.”

		Define the target population:  Obtain information from the specific population you wish to include in your study. This should compare to the inclusion/exclusion criteria in your protocol.

		Determine who will be providing patient experience data: FDA generally recommends that the patient self-report their experience, unless they cannot reliably do so (e.g. young children, cognitively impaired individuals).  In such cases a clinician or caregiver can report on patient experience data that is observable.

		Determine the study design and research setting: e.g. study type (clinical trial, observational, survey), sampling method, representativeness of the study population, and sample size required.

		Determine the methods for collecting and analyzing patient experience data: qualitative, quantitative, and mixed methods (both qualitative and quantitative).

		Operationalize and standardize data collection and data management:  Considerations include locating patients, sampling strategy, and collecting and managing data.

				Documents (includes medical records, scientific publications)

				Social Media and Identifiable Patient Communities

				Digital Health Technology (includes wearables such as accelerometers, heartrate trackers, etc.)     

	For full methods on collecting and analyzing COAs, the guidance document refers to the FDA Guidance for Industry “Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling.”

	Guidance 2: methods to identify what is important to patients

	Guidance 2 further expands on the methods to collect representative patient experience data, especially how to identify what matters most to patients in terms of disease burden and treatment and informs COA development and selection. Key points include:

Literature reviews and consultation with subject matter experts should be used to develop research questions and select the appropriate methods, listed below.

				One-on-One Interviews: semi-structured, structured, unstructured interviews

				Focus Groups: 5-10 participants per group 

	Note: “FDA does not have a single recommended interview mode for eliciting patient input”

		Approaches to Asking the Right Questions: Critical for obtaining unbiased patient input					

				Spontaneous responses are ideal, but sometimes participants will need to be prompted

				Avoid leading questions by using a semi-structured interview guide to facilitate discussion, do not suggest an answer, do not assume you know what the subject is feeling or thinking, do not imply that you prefer participant to respond a certain way

Collection of quantifiable data and application of statistics to summarize patient experience data

				Survey administration: self-administered or interviewer-administered

	Note: “Using survey instruments in a clinical trial for screening and/or exit visits may add greater depth to understanding the burden of disease and treatment”

		Considerations for Developing a Survey					

				Survey instructions and items should be well understood by participants, translated and culturally adapted, tested through interviews of target population to make sure the survey is interpreted as intended, and tested for usability if administered electronically

				Avoid poorly defined terms, double-barreled questions, double negatives, or leading questions

This includes research that uses both qualitative and quantitative methods.  

	Note: “FDA encourages researchers to consider the goals and objectives of using a mixed-methods approach and how the results from both qualitative and quantitative research components are intended to be used together.”

	When selecting methods, special populations (children, cognitively impaired, rare diseases) should be taken into consideration.  For example, factors such as limited attention span of children, use of caregivers for patients who are unable to self-report, remote assessment for rare diseases where patients are geographically diverse should be considered when developing surveys and data collection methods.

	Finally, Guidance 2 discusses considerations for using social media. Different social media communities appeal to different segments of the population and therefore a variety of social media communities should be used to obtain the most generalized information.  Other considerations include whether the participant is anonymous, and limitations with ability to verify patient characteristics such as identity and diagnosis.

	Guidance 3 (discussion document): selecting, developing or modifying fit-for purpose clinical outcome assessments

	After identifying what is most important to patients as outlined in Guidance 1 and 2, Guidance 3 outlines how to select, develop or modify a “fit-for purpose” COA that captures patient experience data. Currently, only the discussion document for Guidance 3 is available. This discussion document provides guidance on all four COA types: Patient-Reported Outcome (PRO), Clinician Reported Outcome (ClinRO), Observer-Reported Outcome (ObsRO) and Performance Outcome measures (PerfOs) including mobile health technologies. The discussion document aligns closely with the FDA Guidance “Patient Reported Outcome Measures: Use in Medical Product Development to Support Labeling.”

	Roadmap to COA selection: What to consider when selecting or developing/modifying a COA:

: When requesting review and advice on COAs for use in medical product development programs, the following should be submitted to the FDA:

The four new methodological Patient-Focused Drug Development guidance documents the FDA is currently developing for the industry that incorporate patient experience data into drug development, summarized.

Kenneth G. Faulkner, PhD

Articles

Decentralized vs Digital Clinical Trials: There is a Difference

What Clinical Trial Assessments Can Be Done Virtually?

FDA Patient-Focused Drug Development Guidance Update: Incorporating Patient Experience Data in Clinical Trials