Ophthalmology Trial Design in the Era of Decentralized Clinical Trials

Decentralized clinical trials (DCTs) expanded rapidly during the COVID-19 pandemic, but their utility has been somewhat questioned as companies have struggled to implement them effectively. Ophthalmology clinical trials in particular have many unique challenges and nuances that have led to slower adoption of DCT.

If done correctly, these types of trials can have an overall positive impact on ophthalmology studies. From reducing cost to lowering patient burden, a thoughtful approach can have an overall beneficial impact on the study. In many cases, companies can also consider hybrid trials, which are an alternative to purely decentralized trials, utilizing a mix of traditional and decentralized approaches.

“If a decentralized approach makes a trial more accurate, better for subjects, and less costly, then those components of DCT should be emphasized.” – David Wirta, M.D.

So when should decentralized or hybrid trials be considered for ophthalmology studies? David Wirta, M.D., Medical Director and Lead Ophthalmologist at The Eye Research Foundation in Newport Beach, California, suggests guiding principles about when DCT makes most sense. “If a decentralized approach makes a trial more accurate, better for subjects, and less costly, then those components of DCT should be emphasized. Sometimes, the end result is more of a hybrid trial.” 

Let’s explore the value, challenges, and special considerations of decentralized trials in ophthalmology.

The Value of Decentralized Trials in Ophthalmology

Accelerate enrollment

A key benefit is that DCTs are less demanding on participants than traditional clinical trials. Because there are fewer inhibitors to participating in the study, it can accelerate the time to fill enrollment requirements and enables the trial to begin sooner. Patient consent is one such example that is accelerated by a DCT approach, as outlined by Dr. Wirta:

“Remote consenting is generally a verbal process so it can be done via video. eConsent has many benefits, including that sites automatically use the most recent version of the form. We don’t have to deal with paper and storage/copying burdens, and we can have a time stamped digital format that’s always accessible. Our patients read the documents at home at their own convenience, before speaking with study staff. It makes everything much more efficient. We can just discuss with the subject, answer questions and get to signature.”

Diversify the patient population

Decentralized trials also minimize the need for participants to visit clinical sites in person, reducing both the patient burden and the need to pay for transportation. This is particularly important for ophthalmology trials, which tend to have older trial populations with more limited ability to commute. As a result, DCTs provide opportunities for patients who may have greater challenges reaching sites and cannot otherwise enroll.

Older patients, however, may not always be comfortable with the technology or devices commonly used in DCTs to collect or access study data. Dr. Wirta has some practical advice here as well:

“The investigative site has to get a good feel for each patient at the screening visit. Does the patient have the ability to operate the device as needed? Or is there a caregiver who can help? If you are depending on remote technology for a critical aspect of the study, you really need to screen for suitable candidates. In practice, I suggest that you don’t screen and randomize a patient into the study on the same day, but allow some time for the subject to return for a separate baseline/randomization visit. This way the subject can demonstrate commitment to the trial and will be more likely to complete the trial activities.

On the flip side, we often see that younger patients in our clinic do not want to use a second device. They prefer to have an app on their existing phone. But if it’s on their own phone or device, then you can have issues with broken phones, cracked screens, and so on. Also, the devices are not standardized across participants, and there are no standardized approaches for dealing with unexpected issues.”

Increase measurement frequency

However, these challenges are often offset by patient data being collected more frequently throughout the clinical study. Mobile technologies can include apps that conduct basic eye screening tests via smart phones, mobile eye clinics that meet the patient wherever they are, or other tools that can be administered by either the patient or a caregiver. By allowing data to be collected regularly and without specific site visits, data can be captured in a more routine and comprehensive manner.

“Mobile devices can be nice for questionnaires and for patient reported outcomes,” says Dr. Wirta. “There is often greater compliance via diaries and we see better adverse event symptom reporting. In that sense, it can be quite helpful to get more data from the patient.

There are tools emerging where patients take a photo of their eye using their own phone. Those types of things can be useful. But you also have to acknowledge the limitations that still exist. You can’t replicate a slit lamp eye examination at home. In order to get all of the trial endpoint data, we still need the best quality tools.”

Improve patient adherence

Clinical trial participants are much more likely to drop out of the trial if the requirements are overwhelming for what they will gain from the study. Unless the treated condition is sight-threatening, a trial should not overburden participants with extensive site visits and physically taxing requirements.

Studies can increase patient engagement and retention by incorporating research into participants’ daily routines rather than requiring regular site visits. The goal should always be to decrease the participant’s burden of travel time, travel costs, and physical requirements. Mobile ophthalmology clinics that come directly to the patient, for example, can help achieve this goal.

Reduce cost

Companies that use DCT methodologies in multiple phases see a decrease in trial costs associated with various components of the study, including administrative, data capture and site monitoring costs.[1] And considering that multiple studies estimate that the cost of phase 3 ophthalmology trials is well in excess of $30M, this is a significant amount of savings that can potentially be achieved.[2] [3] In addition, shortening the total time spent on data collection reduces costs. Trials can be completed faster by eliminating the need for participants to visit clinical sites in person.

Considerations for Decentralized Trial Design in Ophthalmology

Technology  

While the COVID-19 pandemic increased interest for DCTs, the digital infrastructure hasn’t necessarily been available or reliable. This can result in some challenges to adopting DCT. Successful studies require that sites have a combination of high-speed internet, the right mobile technologies, a digital infrastructure mature enough to handle the trial design, and of course, properly-trained personnel. Unfortunately, not all sites are equipped with such requirements. This becomes a key consideration for site selection.

One example is the need to conduct DCTs using electronic source documents. Using paper documentation in a remote study monitoring situation puts tremendous pressure on sites, as discussed by Dr. Wirta:

“Sites are already overwhelmed as it is, and adding new paper requirements complicates things even further. Coordinators need to track, manage, and upload documents regularly. It makes study conduct much more difficult.” 

“It should be done with a global aim. You want accuracy, efficiency, cost savings. That has to begin with a plan of action with the aim of making it easy for people conducting studies.”

Electronic source documents address many of these pains, but have their own issues. “If it takes too long to fill out the source documents, that’s a failure of the system. The recording should be streamlined and a minor part of the process. We can’t have a repeat of the electronic medical record (EMR) fiasco,” says Dr. Wirta.

“It should be done with a global aim. You want accuracy, efficiency, cost savings. That has to begin with a plan of action with the aim of making it easy for people conducting studies.”

Another example is eRegulatory. Sites can readily access forms specific to the study, as well as certifications, licenses, malpractice insurance, and more. “eRegulatory is much more efficient for us than dealing with paper forms,” says Dr. Wirta. “We have access to all the information and it’s always updated and readily available.”

Experience

Investigators often have limited experience with DCTs, or in understanding how to put them into practice. It’s critical to speak with investigators early and help them understand how their day-to-day work routines will be impacted. For example, investigators may be used to conducting in-person examinations of a participant’s ophthalmological condition. But a DCT may require them to read data from a wearable device or collect data via virtual conversations. The contract research organization (CRO) should help streamline the trial design and implementation process, and prepare investigators for various data collection methods.

Regulatory considerations

In the United States, many states have developed or adjusted telemedicine laws in light of COVID-19. But there are still inconsistencies in those laws. Some states don’t allow a drug to be shipped directly to a patient’s home, while others require a supervising physician to be present. It requires understanding exactly which laws apply to the trial, especially if some participants will be asked to travel across state lines to fully participate in the study.

Data verification

Throughout the course of a DCT, mobile providers and a variety of other individuals collect data that may be uploaded to different systems. Having various sources of information creates a challenge that requires rethinking the traditional way of monitoring and verifying data. “If you have a source document on a screen, how do you make a note on it for the site,” asks Dr. Wirta.

“The great thing about remote monitoring is that it truly saves time and money on travel. That’s important and helpful. But if you never see the site, how do you authenticate the data? That’s why I think a hybrid approach works better.” 

At the height of COVID-19, CROs relied on centralized and virtual monitoring of study data. This process of data monitoring requires many additional steps which have proven challenging for many clinical sites to conduct.

An experienced product development organization will take different approaches to address this, including:

• determining if there are any inconsistencies in the data collection,
• identifying red flags in the way the data are collected,
• implementing a solution to limit data collection issues.
  

CRO-Site relationships

Strong site relationships are critical for success in ophthalmology studies. For every trial, there will be different volumes and types of data that need to be collected via different methods. The CRO / product development partner should answer several key questions:

• For this site and this participant pool, what data need to be collected onsite and what data can be collected remotely?
• Are there elements of the study, such as e-Consent or eRegulatory, that are well suited and can be done remotely?
• What data be collected using a wearable device, the participant’s smartphone, or a phone call?
• Are there mobile solutions that can come to the patient directly?
• Are there any nuances to this clinical site, participant pool, or study requirements that need to be considered when establishing trial protocols?
• Is the study site equipped and trained to manage the trial?
• How do we design the protocol to make it as easy as possible on both the site and the patient?
  

An ophthalmology-dedicated product development partner with strong, established relationships with clinical sites will engage them early to help streamline the decentralization process. Ideally, these will already have a strong ongoing working relationship, helping everyone to develop a smooth and efficient study protocol.

How can you know if a decentralized or hybrid trial can help you save money and be more efficient? There is no straightforward or easy answer. However, an experienced ophthalmology development organization will understand the right balance of technological and traditional methods to utilize for each particular treatment and patient pool. At Lexitas, we work with an extensive network of ophthalmology sites and have helped sponsor-partners bring multiple new eye treatments to patients. If you’d like to chat with us about your trial requirements, please contact us.

Richard C. Zink, Ph.D. is Vice President of Biostatistics and Statistical Programming at Lexitas Pharma Services.