Mitigating Clinical Trial Enrollment Challenges with Information and Communication

As complex as clinical trials are, one of the greatest barriers to success isn’t biomedical or regulatory, but rather the ability of sites to enroll a full panel of patients (and to keep them for the duration). Difficulty enrolling patients in a clinical trial can result in costly delays or even termination of the trial. In fact, nearly 80 percent of all trials fail to meet their original enrollment deadline¹ and 55 percent of trials are terminated for failure to achieve full enrollment.² There are many reasons clinical trial sites don’t meet their targets, but study sponsors can take steps to overcome some key barriers to enrollment.  

First, let’s look at some common reasons:

Inadequate site training

Before enrollment even begins, it’s critical that clinical trial sites thoroughly understand all protocols. Challenges at this step can cascade into more and more down the line until the study fails or is terminated, starting with not enrolling enough patients or enrolling the wrong ones.

For example, a lack of understanding of eligibility and inclusion/exclusion criteria will result in either failure to enroll patients who may have been good candidates for the study or enrolling poor candidates who then have to be bumped or, worse, remain and skew the results. Often, this stems from a lack of engagement during the investigator meeting or other missed training opportunities.

Of note, simpler misunderstandings between study sponsor and site can result in bottlenecks and delays as they try to work out confusion over who is managing certain elements of the study or providing or paying for specific supplies. A clear understanding of roles and responsibilities and a clear and open line of communication between sponsor and sites can avoid many problems.

Inaccurate enrollment projections

Even with the most carefully thought-out projections, a site could struggle to find sufficient patients to fully enroll. However, sometimes the projection itself is just wrong. According to Pratik Kalsaria, a clinical project manager with Med Institute, “Most enrollment projections in a clinical trial are based on best-case scenarios. Trial sites tend to over commit and are overly optimistic about their enrollment rates. Relying solely on these estimates leads to improper projections due to faulty enrollment forecasts–eventually creating delays and cost increases downstream. It is important to be realistic about how many patients each site can enroll each month or quarter based on the assessments conducted earlier during trial start-up – no one likes surprises.”³

Difficulty meeting inclusion/exclusion parameters

Difficulty finding the correct patients is probably the most common enrollment challenge. It’s generally not easy to find patients who can check all the boxes for inclusion without also checking some for exclusion. Even criteria such as patients needing to be on certain medications or having to wean off current treatments to join the study can disqualify what would otherwise be good candidates.

An article in Perspectives in Clinical Research explains, “This becomes more complicated in the case of rare diseases, where the relevant patient population is smaller and harder to find, or where criteria have become increasingly tight. At present, clinical trial designs are ‘complex, sophisticated and modernized’ to find the right answer for third- or fourth-line therapy for advanced clinical conditions having no treatment options or treatment-resistant/refractory cases. For example, the straightforward study design to enroll all patients with Stage II breast cancers has been replaced by specific genetic biomarkers. The inclusion criteria are more specific, stringent, and narrowed that requires intensive trial-related testing and restricts eligible participants. This may lead to longer recruitment period and eventually force protocol amendment to recruit more patients or additional study sites. It has been reported that more than 40% of the trials amend the protocol before the first subject visit, delaying the trials by 4 months.”⁴

Patients Unsure or Unwilling

Essentially, full enrollment boils down to finding and keeping enough patients. If people aren’t aware that studies exist and they may be candidates, though, they obviously won’t participate. Even if patients know about a study, they may have fears or misconceptions and no way to get the facts that might compel them to take part.

According to the National Cancer Institute, 1.6 million new cancer cases were diagnosed in 2012 alone. Nevertheless, according to a survey only 15% of cancer patients are aware of opportunities to participate in research, and out of those only 25% report participating in a trial, which amounts to 3% of all adult cancer patients.⁵ Studies are missing enrollment goals for a basic lack of communication to the necessary audience.

In the case of cancer and other serious diseases, motivation also is a critical factor. Patients are motivated to find a new, more successful treatment. Often, though, they are unwilling to give up treatment when there’s the risk they will receive a placebo during the trial and end up worse instead of better.

Another barrier to patients opting in is the daunting amount of paperwork associated with enrollment and sometimes required of them throughout the clinical trial. As this can be lengthy or complicated, a lot of clinical trials now have online systems to ease this, but the user interface may be a barrier to some patients.

Fighting against time

While it’s easy to keep track of patients for several months, it can grow more and more difficult when a clinical trial stretches on to years. People move or change contact information and don’t think to tell the study team. Life gets busy, or they lose interest in a study that seemed altruistic or promising to be part of originally but has lost its excitement over time.

Getting a site excited about a long-time or dormant study can be as difficult as keeping patients engaged. Sometimes the first investigator meeting is delayed because there are not enough sites on board, or the FDA has requested another look at the protocols. When a meeting is delayed after initial excitement about the study has been generated, sites may refocus back to their day-to-day practice or to other studies. Re-energizing them to reach enrollment goals after a delay can be a real challenge.

Avoiding Barriers to Enrollment

Given the wealth of potential challenges, it’s important to consider them realistically and early in the planning process and develop strategies to help mitigate them. The following are some actions that can be taken during planning to help prevent some challenges from arising:

•       Set realistic criteria so you’re not turning away patients who otherwise would have met the study’s needs.

•       Choose to work with experienced sites with a history of meeting enrollment goals, a skilled staff and an appropriate patient pool.

•       Make sure you have realistic enrollment projections.

•       Communicate: Maximize your communication with sites early and often, and provide the tools they need to both educate patients about participating in the study, and what they need to know at every step of the way after enrolling.

•       Try to minimize delays between announcing the study, investigator meeting and when the study begins.

Remember that the two most important components of your clinical trial are your patients and the sites, and a good relationship with both is essential. While you can’t communicate directly with patients, you can provide the education and training the sites need to make them feel well-informed, comfortable with the study and fully aware of their roles and responsibilities (what will be expected of them so they are clear about what they’re agreeing to). You can also establish a rapport with patients indirectly by creating a trial plan that takes their needs and perspectives into account. Can you make the study protocols less complicated or demanding for them? If there are updates or changes they should be aware of, have a means to share that with them via the sites.

A good relationship with sites starts with choosing the right ones. Choose sites that are experienced and have strong, skilled teams. Ask them to identify how they plan to meet enrollment projections and if they have a second course of action if they struggle to do so. How will they redirect their efforts? Also look for those who have relationships with their local community or the community relevant to the study, such as of a particular demographic or health condition. Their established rapport and relationships will help them identify and enroll the right patients.

Your relationship with the sites also relies on effective communication. This starts with training, making sure you clearly and effectively communicate what will be expected of them, what the study requires and how you will support them throughout the course of the study.

Investigator Meetings Help Overcome Enrollment Challenges

There are ways you can design your investigator meetings to help mitigate enrollment challenges and address problems sites are having along the way. Array has worked with clients to produce investigator meetings at the beginning of a trial, after a short delay, or at a point when enrollment projections are critically lagging. There are some key strategies we use to address challenges at any of these points.

Investigator meetings, particularly at the introduction of a study, contain a lot of important information delivered through very text-heavy presentations. This can make it easy for the most critical details, such as inclusion and exclusion criteria, to get lost. We help clients identify this mission-critical information and get it onto a few slides as a take-home resource. By placing an icon on these slides to indicate their high priority status to investigators, they know to choose the “Save” option and have it emailed to them following the meeting. The Array platform can also hold additional resource documents, such as a glossary and patient education materials. These also can be saved and used as needed throughout the enrollment process and beyond.

It's also important that investigators interact with the content and the presenters during the meeting. This helps the speaker know what information he or she needs to stress more to the group and also helps the audience better retain the information. Polling is one way to create that interaction. Multiple choice quizzes work well as an initial way to benchmark the audience’s knowledge.  It then can serve as a way to re-poll using the intial benchmarking question to assess the knowledge transfer throughout the meeting. The greatest polling benefit, though, comes from creating case-based questions that are more relevant to the study. Create a case with statistics around a patient. Then ask, “Would this patient be relevant to your study?” By doing so, you can provide real-world perspectives on what types of patients to enroll and which wouldn’t be a fit.

A study sponsor can also gain valuable information by asking investigators open-ended questions such as how they would overcome a certain barrier to enrollment. In the case of studies that are already underway and struggling with enrollment, you can ask what difficulties they are having or how they have solved them. This lets you share helpful tips from sites that have overcome problems with sites needing help and learn where amendments or other interventions by the study sponsor may be necessary to move forward.

Polling and questions are also a tool we use to help gather information down to the site and individual level. Array asks demographic information at the beginning of meetings, such as “What’s your role in the study, experience (first trial or one of many), location, etc.?” We then share this with the speaker to help them tailor or highlight information for that group. However, we can also use this detailed demographic information following the meeting, along with the other information we gathered from each individual. Array develops detailed reports as to who struggled with the prioritized messages, who saved the slides and what problems particular regions or roles may encounter. Study sponsors know exactly who to reach out to after the meeting to make sure they have the information and resources they need to help with enrollment goals. Since many meetings take place as part of a worldwide series – in the U.S., Europe, and Asia – the actionable insights provided after one meeting helps a study sponsor determine whether and how to change subsequent meetings for maximum knowledge retention.

There will always be factors beyond anyone’s control when enrolling patients to clinical trials. Careful planning, combined with effective meetings and training, will set a clinical trial up with a clear, effective enrollment strategy that’s less likely to run into barriers.

1. Pharmaceutical Technology Enrolment Issues are the Top Factor in Clinical Trial Terminations. 2018. Dec 05, [Last accessed on 2019 Dec 05]. Available from: https://www.pharmaceutical-technology.com/comment/reasons-for-clinical-trial-termination
2. Clinical Trials Arena. Clinical Trial Delays: America's Patient Recruitment Dilemma. 2012. Jul 18, [Last accessed on 2019 Dec 05]. Available from: https://www.clinicaltrialsarena.com/analysis/featureclinical-trial-patient-recruitment/
   
3. Med Institute. 5 Reasons your Clinical Trial has Poor Patient Enrollment and Retention. June 10, 2020.
4. Perspect Clin Res. Recruitment and retention of participants in clinical studies: Critical issues and challenges.2020. Apr-Jun; 11(2): 51–53. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342339/#ref7 and https://www.picronline.org/article.asp?issn=2229-3485;year=2020;volume=11;issue=2;spage=51;epage=53;aulast=Desai
5. Reuters Pharma. 5 tips on how to facilitate clinical trial recruitment. 2014. April 8. https://www.reutersevents.com/pharma/clinical/5-tips-how-facilitate-clinical-trial-recruitment