Information for this article was contributed by Emily Cantrell, a Senior Project Manager at Rho with extensive experience managing clinical trials in a number of therapeutic areas.
Strong working relationships between clinical trials sites and the CRO managing the study are critical to successfully executing a clinical trial. This article shares five common challenges to establishing and maintaining these relationships as well as some tips for avoiding these common pitfalls.
Challenges in the feasibility process
CROs often conduct a feasibility study as part of the proposal process between the CRO and the sponsor. CROs typically get about two weeks (at most) to complete the entire proposal, which means that sites end up with only a few days to complete the feasibility questionnaire.
Site personnel are some of the busiest people I know. Three days is simply not enough time for site personnel to provide a thorough, quantitative response to the feasibility questionnaire, leading to answers based more on gut feel than a careful review of their patient database with consideration to the specific requirements of the trial.
It is also common for substantial changes to be made to the protocol between feasibility and study start-up. Even when sites provide an accurate, objective estimate of potential enrollment during feasibility, changes to things like inclusion/exclusion criteria can significantly change their ability to enroll the predicted number of patients. Other changes that occur between feasibility and study start-up, such as site personnel turnover and changes to the competitive landscape, can also impact a site’s ability to meet their predicted recruitment levels.
Here are a few suggestions to consider when conducting feasibility:
Leverage your investigator database: Keep track of previous responses from sites and avoid asking the same question to the same site multiple times. Follow up throughout the trial and update your database with comparisons of expected and actual recruitment data.
Ask higher quality questions: Rather than asking lots of generic questions to lots of sites focus on sending a smaller number of sites detailed, focused questions. Some questions I’ve found useful include “which inclusion/exclusion criteria will be most challenging for you?” and “what could we change that would allow you to enroll more patients?”
Close the loop: Make sure you follow up with sites that were not selected. Study start-up is a busy time, but this is important for relationship building.
One piece of the puzzle: Feasibility data is important, but it shouldn’t be the only source of information you are using to make enrollment predictions for your study. Talk to experts who have worked on similar studies, look at publications of trials in the same indication, and analyze the data you’ve collected in your own investigator database.
Be transparent: Be upfront with sites and sponsors about enrollment predictions. Make sure everyone understands the underlying assumptions that were made, so you get feedback if those assumptions change.
Ignoring site feedback
It is important to listen to site feedback about your trial, and to do so before the trial starts. Taking a ‘wait and see’ approach to acceptable protocol changes can result in costly and time consuming protocol amendments once the study has started. According to Tufts CSDD, 70% of protocols have at least one amendment, and the average cost of an amendment is $500,000. Two common areas of feedback are inclusion/exclusion criteria and deviation from site operating procedures. The inclusion/exclusion criteria will significantly impact how many patients a site can enroll and how quickly they’ll be able to do so. If you ignore their feedback and it keeps them from enrolling patients, they may quickly lose interest in your study.
The most important take-away here is to get feedback from investigators and other experts as early in the protocol development process as possible, asking specifically about inclusion/exclusion criteria and deviation from routine site operating procedures.
Finally, don’t leave questions unanswered. Even if a change will not be made, close the loop with the site that provided the feedback.
Protocol is too complex
As protocol complexity increases, so does the burden to sites and patients. Additionally, overly complex protocols reduce the pool of qualified investigators. According to a 2012 Tufts CSDD report, the average protocol has 170 procedures, 13 end points, and required trial participants to make 11 visits over 175 days. Sometimes this complexity is warranted or even required, but simplify where you can. What do you do when you must have an extremely complex protocol? Don’t skimp on training and site visits. Despite the trend towards doing more and more of this remotely, sometimes it makes sense to go “old school” and spend more time in person at the Investigator Meeting and Site Initiation Visits. Move away from trainings that are predominantly lecture format and incorporate more breakout sessions and hands-on training.
Expectations around site budgets
When sponsors and sites don’t see eye to eye on site budgets, you can be stuck with significant time delays and may not get the sites you really want. Why is there a gap in expectations? One major factor is that healthcare costs are rising significantly faster than nominal inflation. Sponsors and CROs who made their budget estimates based on studies conducted only a few years ago may be disappointed to learn that many sites will be unwilling to do the study for that same amount. This can even be true when the site participated in the previous study. To make matters worse, budget negotiations often start late in the study start-up process. Some helpful tips:
Discuss budgets during the feasibility process to help set expectations (this can be tricky because the budget can change if the protocol changes)
Remember that as your protocol changes, so will your site budget
Don’t rely solely on old site budgets to forecast project costs
Problems with enrollment and retention
If you can’t get patients interested in your study, you won’t be able to meet enrollment goals and you are likely to run into patient retention problems. One reason patients may not be interested is that their condition isn’t severe or is well controlled with an existing approved treatment. In these cases, make sure site staff are prepared to explain the benefits of participating in the study. Burdensome procedures can be especially hard on patient retention. Here are a few suggestions to mitigate the risk of patient disinterest:
Make sure the project team and all site staff understand the importance of the trial
Provide tools for site staff to use when explaining the trial to prospective subjects
Utilize centralized recruitment support
Spend time during monitoring visits discussing issues and brainstorming solutions
Think about the trial from the patient point of view to understand what may impact their interest and retention