Clinical Trial Enrollment Benchmarks:
How We Compare to Industry Averages

Pre-Site Engagement

When a study is in its infancy, enrollment assumptions and expectations may go through an evolution and be impacted by the business unit, regulatory strategy, and/or medical team. During this period, it is important to engage key opinion leaders from sites to help determine
if enrollment expectations are aligned with real-world estimates. From an enrollment perspective, engaging investigators during the protocol development process can allow for potentially challenging eligibility criteria to be clarified or refined. It can also help set initial expectations with key stakeholders.

To create an accurate baseline, a study team should feel empowered to challenge initial enrollment assumptions. Without an accurate initial forecast, it’s possible that a study team will be set up for failure. For example, an inaccurate enrollment forecast combined with a site performing at maximum enrollment capacity can set up a scenario where enrollment-boosting efforts have minimal or no impact. And for a study team with limited resources, there might not be a lot of options for boosting enrollment.

Evaluating these initial assumptions can help determine:

1. How many sites are required to successfully execute the study according to the study timeline
2. Whether the study is feasible
3. Best- and worst-case enrollment scenarios

Post-Site Engagement

As clinical teams begin to engage prospective sites, teams may be presented with the first challenge to enrollment expectations. During the site qualification/feasibility/assessment process, study teams should review feedback from prospective sites to determine if enrollment expectations are in line with study assumptions.

You’ll want to consider:

• The number of individuals treated each month/year at a site against the total number of study subjects.
• The estimated screen failure rate and whether this is reasonable relative to the protocol-specific requirements.
• Whether enrollment assumptions align with the study timelines

Throughout this process, what can a study team do to ensure that enrollment forecasts are communicated to the appropriate members of the clinical team?

If your enrollment starts to drift out of alignment, take a breath and start to develop a plan for getting enrollment back on track. Developing a successful action plan is only good if you have the correct tools and resources available to determine the root cause(s) behind the issue.

Begin by breaking down some of the possible reasons for slower enrollment into different categories (i.e. site motivation, low screening numbers, protocol challenges, etc.). It could also be helpful to make a list of the potential risks if enrollment numbers don’t improve as boosting efforts may require buy-in from additional stakeholders.

While there is not a cookie-cutter template for developing action plans, there are common problems (and solutions) that can be considered when reviewing your study

High Screen Failure Rate

If you have been collecting pre-screening/screening information from your sites, this is a good place to start. Trials with a high screen failure rate can indicate a number of potential issues.

Causes: The inclusion/exclusion criteria are too restrictive; sites chosen for the study do not have the population to support enrollment expectations; the study protocol requires diagnostic information that is unavailable due to local standards of care (e.g., liver biopsy requirements for NASH studies).

Solutions: Re-evaluate the protocol and determine if any criteria can be adjusted (any changes impacting study endpoints should be discussed with the regulatory/statistical team); reconsider site selection criteria to determine if additional sites may need to be considered for the study.

Issues With the Protocol

Beyond the eligibility criteria, prospective subjects or study sites may have difficulty executing or have reservations about the requirements of a clinical study.

Causes: Challenging/difficult study assessments, collection of non-standard-of-care tests, visit or travel requirements.

Solutions: Ask whether the protocol requirements for the patient/site are reasonable/justifiable for the study. Do the challenging requirements support a primary or exploratory endpoint? What would be the impact if the information weren’t collected?

Site Interest/Motivation

Maintaining site engagement and interest throughout a trial is essential toward a clinical study’s success.

Causes for Disinterest:

• A site was chosen because of a marketing relationship, but didn’t really want to take part in the study
• Changes in team (sponsor or site personnel)
• Frustration with delays in the project
• Frustration with budgetary items
• The start of a more exciting project 
• Lack of communication with the study team
• Inconsistent communication or messages from the study team
• Poor working relationship with clinical research associate
• Very restrictive entry criteria that creates more work with no enrollment success
• Changes in priorities

Solutions:

• Re-engage communication and set-up a regular cadence for engagement
• Re-build relationships and schedule 
• Re-evaluate study budget
• Schedule investigator meeting
• Change who spearheads the communication 
• Leverage additional stakeholders to manage the relationship
• Offer incentives
• Schedule meetings with the right people at the site

Low Screening/Recruitment Numbers

Low screening numbers may not always be due to the items listed above.

Causes:

• Lack of study visibility across a site
• Enrollment may be seasonal due to the study condition
• Challenges with study vendors lead to disinterest/apathy among site staff
• Alternate treatment options are more effective, particularly in placebo-controlled trials

Solutions:

Increasing study awareness can be evaluated from two angles: 1) Increasing visibility among site personnel, and 2) Increasing study awareness with prospective subjects.

1. Increasing Visibility Among Site Personnel
   • Create a brief study overview that can be shared with more members at a site in order to ensure more personnel are aware of the study
   • Engage site members involved in screening/scheduling
   • Add additional investigators
   • Utilize internal site meetings (i.e. tumor boards)
   • Set up a referral system with other physicians
2. Increasing Study Awareness With Prospective Subjects**
   • Check to see if the disease is under-reported in the site’s database
   • Broaden search criteria beyond those with a known diagnosis, as needed
   • Review, revamp and create recruitment material
   • Consider recruitment options (radio/TV/Facebook/web ads)
   • Develop flair (pens/buttons/stickers)
   • Develop study educational material
   • Evaluate where/how educational material is shared
   • Incorporate visit stipends

**Ensure that any recruitment material developed receives the appropriate sponsor, institutional, and IRB review/approval prior to implementation**

Competing Trials

Trials can be difficult to enroll in if a site has competing priorities.

Causes: While the site selection process should incorporate questions related to potential competing trials/priorities, there is a possibility that enrollment may be impacted by a competing study. This could be internal (your study competes for enrollment against another study with the same sponsor), external (similar study from a different sponsor), and/or global (i.e., timely trials pulled resources from everywhere else).

Solutions: Work with the site to develop an unbiased/ethical enrollment approach. Consider the timing of enrollment for all trials and re-evaluate enrollment expectations.

At the end of the day, there may be problems that cannot be fixed, and more drastic action plans will need to be considered. This could include adding/reallocating resources or even shortening/stopping the clinical study. When considering these actions, evaluate any budget/resource implications and overall risk to the clinical study. Taking these items into consideration will be important when/if you need to justify the implementation of your action plans (both with stakeholders and impacted sites).

Implementing an action plan requires buy-in from all team members. And prior to implementing an action plan, you may need to defend or justify your reasoning for the change with key leaders. Consider the following:

• Will the proposed changes require an increase in resources?
• Will the proposed changes require an increase in the study budget?
• Will the proposed changes require an increase in efficiency?

Many trials have limited funds and/or resources, so it is important to ensure that these items can be reallocated appropriately, or additional funds/resources can be secured. This is where all of your homework and research into the root cause will come into play. 

In order to get buy-in from leadership, it is important to show your work! As you look to communicate these changes, consider demonstrating how a change could impact the overall study timeline. For example, decreasing the overall study timeline by even a month can have a dramatic impact on the overall study budget.

In addition to being prepared to justify why an action plan is needed, you should also be able to demonstrate metrics that can be used to gauge the success of a plan. Developing metrics is necessary because you may need to determine when or if you need to pivot to Plan B or Plan C. As you determine your metrics, consider how long an action plan will take to develop. For example, implementing a change to the study protocol may take longer than increasing a site budget. To complete this roll-out, you may need to collaborate and meet more frequently as a study team. As such, it could be helpful to develop a separate meeting cadence to review progress and communicate these results with stakeholders. 

Finally, because not all plans take the same amount of time to implement, it could be worth developing parallel paths in order to allow your team to be nimble throughout this process. After appropriate buy-in is obtained and an action plan is finalized, it is time to communicate the plan to the study sites and begin the roll-out.