Hybrid clinical trials allow sponsors to strategically incorporate decentralized clinical trial (DCT) elements into study designs. These trial models offer unprecedented flexibility—and sponsors are taking notice. More companies than ever are interested in hybrid trials, and the resulting growth is redefining the industry landscape.

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^{Let’s trace the expansion of hybrid clinical trials in recent years:}

• Only 20% of clinical trials used a hybrid design in 2019, according to CenterWatch.
• In 2020, the FDA recommended that sponsors incorporate DCT elements in clinical study designs when appropriate.
• Hybrid trials dramatically increased in 2021, exceeding traditional on-site trials at 59% of all clinical trials. In 2022, they’re expected to climb to 77% of all clinical trials. APAC is gearing towards decentralized and hybrid clinical trials in the years to come.
• The FDA plans to unveil protocols in 2023 to further support the use of DCT methods, inspiring confidence in these components for future clinical research.

The shift toward hybrid clinical trials is a positive development for sponsors and participants alike. We’ll explore three ways incorporating DCT elements into hybrid models improves clinical research and unlocks healthcare innovation, including:

• Driving operational efficiency
• Increasing participant engagement
• Enhancing data quality for more robust evidence

But, first, let’s review what a hybrid clinical trial entails—and how to determine whether this model could be a fit for your study.

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^{What is a Hybrid Clinical Trial?}‍

In 2011, Pfizer announced it would conduct the first fully decentralized clinical trial without the use of any physical sites. This game-changing move reconceptualized how clinical research could be carried out. As a result, forward-thinking sponsors started exploring the application of DCT methods in their studies.

But, not all decentralization is alike. DCTs exist on a spectrum between two "extremes": traditional clinical trials and fully virtual or decentralized trials. In the middle sits the hybrid trial model, which can be more or less site-centric. Depending on the specifics of the study protocol, patients may or may not need to travel to sites for enrollment, onboarding, and regular appointments.

Many sponsors will admit that they previously could not imagine any element of their trials being decentralized. Today, they are more open to DCTs. But, while full decentralization can be suitable in select circumstances, it isn’t feasible for many trials. Fortunately, all clinical trials can benefit from the adoption of some decentralized elements. Enter hybrid clinical trials.

Hybrid designs allow sponsors to incorporate components of both traditional and remote models to fit the study’s needs and goals. They can include the following components:

^{Practical Applications of Hybrid Clinical Trials}

Now that we’ve defined hybrid trials, let’s turn to practical application. We’ll explore some examples of how a hybrid approach can be applied to different:

• Therapeutic areas of study
• Desired endpoints
• Industry sectors

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Therapeutic areas

Although hybrid clinical trials are conducted across a range of therapeutic areas, they are particularly effective for studies with difficult-to-recruit patient populations or those facing impediments to frequent site visits. Certain study tasks that were historically performed at clinics can be completed by patients from the comforts of home. When face-to-face medical oversight is necessary, a combination of traditional and virtual components helps to accommodate both patients’ and sponsors’ needs and preferences.

New data shows hybrid trials are most prevalent in metabolic and central nervous system conditions. Genetic disorders, cardiovascular, and respiratory therapeutic areas are also well represented within hybrid trials.

The COVID-19 pandemic has also accelerated research centered on infectious diseases. Pharmaceutical and biopharmaceutical companies have incorporated DCT components into a hybrid trial framework to study the virus and its associated health conditions.

A recent example is RedHill Biopharma, which launched a trial during the peak of the pandemic. The company was acutely aware of the safety risks associated with requiring patients with the virus to travel to a healthcare facility and were in need of creative solutions to address this challenge.

RedHill worked with its DCT partner, ObvioHealth, to devise a five-point plan

• Dynamic recruitment of trial participants from high-risk COVID-19 hotspots.
• Study product provision options offered both at site and via shipment.
• Collection of symptomatic data via an electronic patient-reported outcomes (ePRO) app.
• Remote monitoring of study participants’ vitals with digital monitoring devices.
• On-site and home health visit options for clinical evaluation.

This strategic hybrid approach was deemed successful by the sponsor, whose preliminary Phase II data demonstrated significantly reduced hospitalizations and severe COVID-19 symptoms amongst the tested group.

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Desired endpoints

Hybrid trials provide greater flexibility for sponsors to achieve their study endpoints. By having access to a modular study design approach, sponsors can determine which DCT or traditional components are best suited to capture accurate outcomes—be it digitally or on-site—which in turn facilitates the delivery of accurate endpoints.

With the flexibility enabled by a modular, hybrid study design, sponsors may choose to incorporate remote outcomes capture via digital instruments (ePerfO), outcomes capture during an on-site visit (ClinRO, eClinRO), or both—all subject to, and designed to deliver on, desired endpoints.

For example, in certain cases, remote measurement of a vital sign—such as blood pressure—might be done by a healthcare practitioner (HCP) on site at the end of a required visit. But, a hybrid approach might include blood pressure readings collected directly by patients at home using digital instruments. These at-home measurements can be taken more frequently and as patients go about their daily lives, providing more real-world, real-time data. Remote data capture can also mitigate the “white-coat” effect, where the presence of a doctor can affect patients’ anxiety and, thus, alter their blood pressure readings.

Each protocol can be weighted for the benefits and risks associated with traditional versus digital outcomes and endpoints.

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Industry Sectors

In the same way that different therapeutic areas are applying different iterations of hybrid models, industry sectors appear to have a greater tendency to select certain hybrid configurations.

In consumer health, where safety risks are generally lower, not only has there been more rapid adoption of hybrid models, there has also been a greater willingness to incorporate remote elements across a greater proportion of study stages. A typical consumer health study might recruit and consent participants remotely while also incorporating ePRO and remote device use.

Digital therapeutic companies represent another interesting example of hybrid model choice. Because the products they are developing are digitized, these researchers can more easily accommodate some of the remote data collection options. For instance, they can integrate their technology directly with a DCT platform and EDC so when patients use the digital therapeutic, device usage and compliance data are captured without having to prompt the patient, facilitating a seamless patient experience.

At the other end of the spectrum, pharmaceutical companies to date have tended to adopt more site-centric approaches to their trials. But, even in these cases, there are opportunities to reduce patient burden by incorporating certain hybrid components. For example, a sponsor who seeks to test a new intravenous medication that requires on-site administration might design a study as follows:

• Site-based recruitment complemented by digital recruitment
• On-site enrollment complemented by eConsent
• On-site administration of medication with direct clinical oversight
• Patient use of ePRO to track health status between on-site visits
• On-site check-ins with physicians, sometimes including radiology
• In-app reminders of upcoming study tasks and appointments
• Virtual site team support to address questions between visits

Start-up biotech companies with limited budgets and whose therapeutics are lower risk are increasingly leaning towards the incorporation of more remote elements in their hybrid trials in order to manage budgets and timelines. More established biotechs and those working in higher risk areas are positioned more closely to pharmaceutical companies in terms of their hybrid preferences.

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^{Key Benefits of a Hybrid Clinical Trial}

Now that we’ve covered practical applications of this model, let’s circle back on the benefits of adopting a hybrid approach to clinical trials.

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Improving operational efficiency

One key advantage that hybrid clinical trials have over traditional research models is their potential for improved efficiency throughout the process. For example, at the beginning of a study, the inclusion of digital components can help to streamline patient recruitment and onboarding, providing researchers with broader and more inclusive and representative patient pools, including cohorts who may have logistical obstacles to participating in a traditional clinical trial. In other cases, where in-clinic visits are necessary, there may be a need to recruit in proximity to sites. In still other cases, it may be possible for participants to visit local laboratories for testing. The hybrid trial approach gives sponsors and study designers the flexibility to recruit in the most efficient way for a given trial.

During the data collection phase, hybrid approaches can reduce both the time and cost of outcomes collection. Certain trips to on-site facilities can be reduced in favor of televisits or at-home visits. Biomarkers can be captured using wearables or sensors. DIY kits can be used for simple tests. Less frequent visits lower the overhead associated with physical facilities and staffing.

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Driving patient engagement

Another key benefit of hybrid trials is their inherent patient centricity. After all, the principle of decentralization is to reduce patient burden. Trial sponsors can examine their protocols for trouble spots where patients might feel overly burdened and look for ways to implement decentralized components in those areas.

Historically, there has been an assumption that patient engagement happens best at sites. But, when patients have long trips to a clinic followed by long waits in waiting rooms and/or unresponsive site personnel, the opposite can be true. Recent research suggests that most patients participating in clinical research often prefer to stay close to home. For instance, if a protocol calls for a lab visit and a check-in visit within the same week, the sponsor might opt for a hybrid approach with a telehealth check-in visit to decrease the amount of travel for the patient.

In studies where on-site check-ins are not necessary or less frequent, in-app chat features and frequent check-ins from a virtual research team provide accessible ways for patients to ask questions. This approach can also help in identifying and resolving adverse events more quickly than would be possible within a traditional model. Finding productive, "hybrid" ways to build trust and rapport with participants humanizes the trial process. When participants feel supported, whether face to face or remotely, they’re more likely to consistently comply with the study protocol.

Stronger participant relationships directly impact patient engagement and retention—starting in the recruitment phase all the way through to study close-out.

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Enhancing data quality for more robust evidence

In addition to the potential for greater efficiency and engagement, hybrid trials can also help deliver stronger, more robust evidence for clinical trial sponsors. Hybrid trials can do this through:

• Larger, more diverse sample sizes, which allow for more robust data and better randomization for analysis, leading to more reliable results.
• Early trendspotting via digital data dashboards, allowing for quick detection of incomplete tasks and possible adverse events. This allows study teams to intervene in a timely manner to drive up compliance and retention.
• The ability to implement digital data capture methods—such as sensors/wearables and image/video/audio capture—that collect more objective data.
• More direct data entry translating to fewer errors.

These benefits build more robust evidence packages that allow sponsors to bring treatments to market more quickly, without compromising the quality or integrity of their research.

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^{Mitigating Challenges in Hybrid Clinical Trials}

While there are many advantages to hybrid clinical trials, there are also some challenges to consider. Proactive planning allows sponsors to anticipate and manage potential complications in a hybrid clinical study. Proper study design is key to resolving issues such as:

• Regulatory concerns: The U.S. FDA has promoted the use of decentralized methods in trial design; but, in other countries, regulatory bodies are not always as accepting. DCT adoption rates in Europe and APAC have been slower, and much of this is due to unclear guidance from government agencies. This doesn’t mean hybrid trials can’t be successfully conducted in regions outside of the U.S. But, it does require an in-depth understanding of each country’s regulations and, in many cases, can be aided by direct conversations with regulatory bodies who are still low on the DCT learning curve. Specific country regulations will dictate how to design protocols and which elements are safe to decentralize.
• Trial complexity: It is important to note that complex hybrid clinical trials with multiple data sources from CROs, physical sites, televisits, and remote data collection, if poorly coordinated, run the risk of operational, logistical, and communication nightmares. When data is siloed or not properly integrated and when communication between parties is not fluid, trial progress can be inhibited. Fortunately, decentralized clinical trial platforms can mitigate many of these issues, bringing all aspects of a trial into one unified and interoperable hub. This type of platform can support most if not all aspects of a hybrid trial design, streamlining workflows for all stakeholders.
• Tech issues: In any trial where technology is implemented, problems can arise. Clunky interfaces for both study teams and patients can cause friction, leading to inefficient workflows and participant drop-off. Teams should stress-test their technology to improve reliability, accessibility, and systems integration.
• Patient confusion: Another important consideration for smooth trial execution is the way in which the patient relationship is managed. In traditional site-based trials, the patient is managed at site. In fully virtual clinical trials, the patient is managed by a remote support team. In hybrid trials, either can be the case. But, when patients have too many interlocuters for a trial, this can increase burden for them. If they don’t know who to reach out to, if they have multiple sign-ons, and if they don’t feel responsible to one party, they are more likely to lapse. Whether the site or the virtual site team is responsible for the patient, it is essential that all communication be closely synchronized and, ideally, that the patient has a single point of contact, so he or she feels looked after.

One means of managing these challenges is to partner with an experienced virtual research organization (VRO) like ObvioHealth. A VRO can support your team at every stage of a hybrid trial, from study design to implementation of DCT modules and final regulatory submission.

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Final thoughts on hybrid clinical trials

Hybrid clinical trials vary in their degree of decentralization. Some incorporate only one or a few decentralized elements; others are close to fully remote. It’s important to consider the area of therapeutic research, desired endpoints, and unique needs of your industry and protocol to create the optimal hybrid study design.

When appropriately implemented, a hybrid model can promote greater efficiency, drive participant engagement, and improve trial outcomes. The result: Less time to take a treatment from conception to market—and better care for the people who need it.