Trial Design

Successful clinical trials balance scientific rigor with ease of executability. Trials designed with the best intentions of collecting as much evidence as possible are often (ironically) the ones generating the least useful data because they are too difficult to execute. Clinical trial design must take into account the time and effort required from subjects (patients), coordinators, and investigators. Protocols achieve this through what we refer to as Design for Executability (DFE). DFE optimizes trial logistics by including only what is essential, and incorporates reasonable expectations for subject commitment, site staff effort, and inclusion/exclusion criteria. A trial designed with executability in mind will lower the barriers to enrollment while also being robust enough to show statistical significance. DFE includes concepts such as protocol simplicity, subject visits that are not too burdensome, and ease of data collection and management. When planning a trial for executability, consider the ‘ask’ required of subjects and site personnel, as well as the ease of implementation at each unique study site.

Consider The ‘Ask'

First, think about your study from the perspective of subjects. For almost every participant, getting to the clinical study site is not easy; some live hours away, while others live within the same city but have to endure traffic or lengthy journeys on public transit to get there. Moreover, most subjects will either need to take time off of work or out of their free time to attend study visits. If your study asks significantly more of subjects than their standard of care option (number of visits and complexity of testing), this will decrease your enrollment rate and also negatively impact subject retention, and hence, data quality.

Next, consider your study from the perspective of research coordinators. An average coordinator is overseeing three to five actively-enrolling studies, not to mention several others in long-term follow-up. Coordinators can have tremendous influence over screening and enrollment for a study. Is your study designed with the coordinator’s ease of executability in mind? If your study is more difficult and demanding than other studies and the coordinators do not feel adequately supported, they will focus their efforts on other trials and your enrollment rate will suffer.

DFE is critical from the investigator’s standpoint as well. Does your study fit in with their standard practice? Can they consent subjects and conduct screening/baseline testing without modifying their schedules? Does your investigational product add significant time to surgical procedures? If your study design doesn’t incorporate DFE, investigators will not be as motivated to enroll subjects.

The key takeaway is that every additional ask is a tradeoff against enrollment. Trials involving frequent visits with numerous tests and procedures often result in low enrollment rates, poor subject retention, and low-quality data. Over-designed trials often arise out of a fear of futility, and include extraneous data points and overly-stringent inclusion/exclusion criteria. While in theory, more data on a more specific subject population offers more support for the safety and efficacy of a therapy, in reality, overdesign creates insurmountable challenges. DFE weighs the value of each data point against the difficulty it imposes on trial participants and sites, resulting in trial design optimized for enrollment rate, subject retention, attention devoted by site staff, and data quality.

Ease of Study Implementation

Understanding the intricacies of how various clinical sites function and accordingly designing your protocol will drastically improve the execution of your study. Each clinical site supporting your trial will have varying standard practices and capabilities, such as the availability of onsite testing, when and how it screens and consents subjects, and inter-departmental communication. Research a variety of sites before you design your protocol - including non-academic centers. You may be surprised to find that while some key opinion leaders (KOL) see patients two weeks prior to surgery and might perform post-consent screening procedures during that visit, other sites may do this six weeks in advance. If your Screening Visit window is one to three weeks prior to surgery based on KOL input, many sites will have a disappointing enrollment rate. Do your homework on sites early on and design your protocol to accommodate real-world practices, so that there are natural in-person opportunities for consenting, screening, and enrolling subjects.

Below are eight key elements to consider when designing a clinical trial protocol for executability.

Eight Key Elements of DFE:

1. Time Commitment of Subjects

How frequently does your protocol ask subjects to travel to the clinical site and what is the length of each visit? Surely one or two study visits can be eliminated from the schedule without sacrificing primary endpoint data. Consider substituting phone visits for in-person visits, or utilize mobile apps for collecting subject-reported data remotely. And always offer a stipend to cover travel costs -- this is one area not to skimp on when budgeting for your study.

2. Medical Testing Intensity

How many medical tests are required of subjects, how uncomfortable are the tests, and how often do they occur? Will research or clinical staff administer the tests? Does the research staff have working relationships with the staff in these departments? What are the logistical challenges for the subject for each test -- do they need to walk between multiple buildings or perhaps visit different locations? Minimize the frequency and complexity of tests while still proving the benefits of the therapy.

3. Coordination Complexity

How difficult is your study for the Coordinator to manage? How much time is required to locate and enter all requested data points into the EDC? Is the EDC platform for your trial well-known or will the Coordinator need to learn a new software? How many different online systems are you asking the Coordinator to utilize during the trial? By simplifying a Coordinator’s efforts, they will in turn devote more attention to your study.

4. Feedback on Executability

Did you receive feedback on the protocol design not only from the Medical Review Board but also from Study Coordinators, FCEs, and people linked more closely with trial execution? Have you checked with non-academic sites in addition to your more typical KOL sites? This is crucial for balancing scientific rigor with executability.

5. Inclusion/Exclusion Criteria

Stringent subject selection criteria will have a direct negative impact on enrollment rate. Reasonable criteria will assist with study team engagement and the trial proceeding according to schedule. Do you need every single exclusion criterion, or can some be eliminated?

6. Data Collection Intensity

View every additional data point you ask for as a hit against your enrollment rate. Items that may sound easy to capture are sometimes the most difficult to obtain. If the data point is not essential to demonstrating the safety or efficacy of the therapy, eliminate it. For inclusion/exclusion, have your protocol allow for previously-collected data to be used, as sites and subjects despise repeating medical testing.

7. Minimal O.R. Disruption

Testing a novel device is enough of a change for a surgeon and their O.R. staff to take on; if your protocol also imposes additional requirements during surgery, your study will be perceived as difficult to execute. This also applies to intraoperative data collection, as most coordinators may not have the schedule flexibility to capture data in the O.R., especially on short notice. Is additional intraoperative data truly critical to proving safety and efficacy, or can you increase executability by simply relying on the surgeon’s standard operative report?

8. Natural Screening & Enrollment Opportunities

If your protocol requires a post-consent Screening Visit, provide as large a visit window as possible and make sure this lines up with the standard of care pre-surgical visit across a variety of sites. By aligning your study design with the way sites manage standard of care patients, you provide natural opportunities for screening and enrollment.

As field clinical engineers with decades of collective study experience, our team at FCE Source knows how to make a study executable. Contact us when your protocol is in its conception stage and we’ll help you streamline it into an executable study designed for success. Contact info@fcesource.com for more information.