Pragmatic decentralized clinical trials

By: Douglas Bain, Chief Technology Officer at KCR

Let’s start from definition of what we mean as “pragmatic” with some help of Merriam Webster online dictionary:

The research community has often sought improved methods for the execution of science in researching cures for human conditions. Timeframes for the development and application of new methods are often driven by budgets and the impact that such a discovery might have.

Today, we have both a critical demand to rapidly research COVID and COVID-like pathogens, and a changing environment in which to execute clinical trials. Essentially, the goal posts have moved.

We now have an urgent requirement to seek new methods of clinical trial operations that can deliver trustworthy results in less time. A novel approach to this that leverages a spectrum of methods is decentralized clinical trials.

Decentralized clinical trials have not existed for long — less than 5 years in a largely agreed form. Virtual trials were popular and are still used in many places today, but with the FDA’s backing, the preferred term is now “Decentralized Trials”. These trials are also called “Remote,” “Patient-Centered,” “Virtual” or “Direct to Patient” Clinical Trials.

The most common interpretation is that rather than having patients come to a hospital (site) in order to enroll and participate in a clinical trial, they can participate remotely (decentralized from their site). In practice, this usually means a reduced number of patient visits rather than no patient visits — the challenge of patient identification and physical screening activities often make the initial steps of a clinical trial with a patient non-transferable to a remote setting — but it is not impossible.

Considerations

For those interested in operating a decentralized trial, the following considerations were developed from personal experience and industry perspective.

❌ Large number of sites

Sites often remain active participants in a decentralized trial. Getting a large number of sites effectively informed using new, potentially foreign research methods can pose a significant challenge. Controlling a smaller number, or even a single site is far easier when launching a new study. The smaller the number of sites, the greater potential for the sites to become true partners in patient support. This reduces the risk of failure. For various reasons, you may need at-least one site per country, but distance between site and patient may not necessarily be a significant factor site selection. As research methods mature, the ease of using them with a larger number of sites may also evolve. For now — keep the number of sites low.

❌ Inadequate Support

All patients must receive strong and interactive support in a virtual setting. In a traditional clinical trial, a patient visits a hospital and meets with the study team who provides comprehensive information and assumes responsibility for the research they are supporting. In this situation, sites are more likely to help the patient feel confident and the site will likely be a positive contributor throughout the trial.

By removing these interactions in a virtual setting, study teams are more likely to see negative outcomes like dropouts, compliance issues or simply inferior patient care.

Sites may not be setup to provide adequate remote support on demand. This may lead to the development of a separate ‘super-site’ that extends these services, or to collaboration with a service organization that can supplement sites with direct-to-patient support (call center) services.

✅ Apply the right technology

If you have a lot of time and a large budget, you can make all kinds of disparate technology work, but the most common reality is that you will need to execute quickly and safely to select budget-friendly technology.

Patients need and demand simplicity; technology applications should be one single solution that services patient requirements and adequately supports the science and treatment methodology. The tech should help not hinder the research process. In practice, research activities like Consent, Data capture, video conferencing and support should all be in the same place for a patient — in a single integrated solution. Ideally, this is the same solution that the site(s) are using.

✅ Right sized Wearables

Wearables provide data; whether it’s good data or bad, reliable or representative depends on your definition of wearable data as a digital endpoint. There are many ongoing initiatives to define digital endpoints in a consistent and documented fashion, and without them, the potential for unpredicted and uncontrolled variance in statistical outcomes becomes too great. This will help determine things like if patients are fasting before taking a reading, how sleep is tracked, and how step counts are tracked on level surfaces vs. climbing stairs. Using wearables will continue to provide valuable information in a real world, decentralized research setting. Some initiatives are ongoing to support the development of digital endpoints — two are noteworthy currently;

· Mobilise-D is a 5-year, IMI-funded project that will produce validated digital mobility outcomes to monitor the daily gait of people with mobility problems, with the goal of improving follow-up and personalized care. By creating an accepted ‘gold standard’ for measuring mobility, we can effectively apply this to clinical research settings that measure levels of mobility as an outcome.

· DEEP Digital Endpoints is an initiative co-created by Kai Langel to prepare a free to license methodology that organizations can use to define and validate digital endpoints. The endpoints may not be free, but the methods applied to consider them as comparable and validated are. This is ongoing and scheduled for public discussion at Scope Europe.

✅ Foster Data Donors

Data donors are individuals that volunteer to donate their data for research purposes. This has been a minefield in the past, regarding privacy concerns and technical challenges. On both fronts, we are seeing great evolutions here. A nice example is provided by Curebase;

Here, as a patient volunteer, you can choose to share your data from any of the listed providers. The technical part is handled by a combination of Cloud providers — Curebase, Human API and the vendor. These may not tick the box of “validated digital end points,” but with initiatives mentioned earlier, they are on the way.

✅ Protocol and Organizational readiness

A decentralized clinical trial protocol is a very different from a traditional Randomized Control Trial (RCT) Protocol. In a typical decentralized trial protocol, you would use a single specialized Principle Investigator Site to provide support to patients in a decentralized setting together with a support service that provides local language support to patients (e.g. KCR).

Though the model changes, decentralized trials lend themselves to patient-facing service providers to provide a matrix solution implementation and support. Each trial involves different technical data integrations and systems components which are not for the risk averse or faint hearted, but the potential benefits are enormous.

✅ Hybrid

Although I support the principles of decentralized clinical trials, I do not see them being applicable in their entirety for many trials. However, it is possible to apply decentralized trial methods to a large proportion of trials. These will supplement traditional methods and fit within standard methods of patient care.

For example; If a patient is enrolled into a clinical trial using typical referral and screening methods at an investigator site, the patient could be provided the option to complete an eConsent, to be followed-up and supported using an app on their own smart device. This might include scheduling, remote consultations, drug dose support and adherence, biometrics capture and ePRO. All of these exist today and can be integrated into hybrid models.

✅ 2-Tier Research Model for patient inclusion

Over the last 10 years, I’ve been interested in the application of a two-tier research model. Typical randomized control trials (RCT) operate with investigators at sites interacting with referred, consented patients. This typically mandates that the patient is within geographic reach of the site.

With a 2-tier model, we introduce a local support mechanism for the patient. This local support might be a remote nurse network (e.g. MRN), or the patient’s own general practitioner. This means that the actual visits between the patient and investigator site can be minimized, therefore permitting a greater physical range between the patients and their investigator site. Historically, this has been very difficult to achieve.

What is changing is the idea of being able to provide decentralized support through technology. In this model, you can have stakeholders — including the patient — in the technology supported trial lifecycle. The tech helps glue these stakeholders, their activities and their data together. The technology needed to achieve this is not simple. Ideally, the site is a single site, and is actively involved in the configuration of the trial to suit the stakeholders. Simplicity and flexibility are often at odds when it comes to meeting all potential variances across stakeholder groups, but it is possible.

✅ Pragmatic

Pragmatic is a word used to describe a clinical trial that uses real world data to correlate treatments and outcomes. Similarly, when it comes to meeting the varying demands of clinical research operations, being a pragmatist is necessary. We must be realistic in how we capture data and work effectively with patients.

We must create means to include patients in a trial as opposed to creating operational barriers to exclude them.

When will we see Decentralized Trial (methods)?

Despite recent talk about their novelty, decentralized trial methods exist today. The question more pertains to when we will see widescale adoption of them. Many of the largest contract research organizations have indicated that they expect to see more than 50% of their trials leveraging these methods by 2025. In practice, we see decentralized methods increasingly applied steadily over time. Few R&D establishments wish to be on the bleeding edge of new technology and methods. It is up to CRO and Service providers like KCR to identify, integrate and validate these new methods before they are unleashed on critical research programs. Taking a risk-based approach when designing your program or protocol are critical.

These things will all take time, but we have a ‘reason for change’. Let’s embrace this where we can, when we can.

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