To conduct clinical trials efficiently and effectively from start to finish, there are a number of factors to consider. Critical steps in a trial can have huge impacts on outcomes and can affect whether or not your trial stays on track from start-up to close-out. While there seems to be agreement within the clinical research community that such factors should be taken under consideration, there is no clear consensus regarding what factors should be considered and the best practices to address these factors. This may in part be due to the diverse nature of clinical trials, which often requires a level of uniqueness in the conduct and management of each clinical trial. Nonetheless, the clinical research community as a whole can still benefit from sharing best practices. The following are a few best practices from a clinical operations perspective you may consider when conducting your next trial.
Pre-Trial Due Diligence
Prior to launching a trial, the most important factor is a true understanding of your protocol, and what it requires from a logistical standpoint. This understanding must come from a comprehensive assessment, considering the protocol from the perspective of the site, investigator, coordinator, and patient. Evaluating the protocol from the patient’s perspective is particularly important, as understanding the logistical requirements from their point of view will help with the recruitment of patients willing and able to commit to participating in the trial from start to finish.
Once your understanding of the protocol is complete, it will be easier to begin the site selection process and start considering what type of sites you will need for the trial – private practices, specialized clinics, hospitals, group practices, etc. Site distribution should also be considered. It is beneficial for sites to be geographically diverse so the trial is accessible to more patients. Consider how each region might affect the study. For example, does the population of an area fluctuate throughout the year, or does it remain steady? How might the weather within the region impact your trial?
Pre-feasibility assessments can help provide a critical snapshot of the current landscape for your trial before the trial begins. Are there sites interested and available to participate in your trial? The information received from pre-feasibility assessments can provide the baseline for developing initial assumptions regarding recruitment and enrollment. By taking a fresh look at the therapeutic market and availability, interest, and recruitment potential of sites, sponsors can get a more accurate proposal for execution of their trial. Just because a trial succeeded at that site in the past doesn’t guarantee another success
In the pre-feasibility assessments, a site’s proposed recruitment methods can be collected. This information can be used to determine which methods of recruitment would be ideal. Should social media be considered, or would the trial be better suited for more traditional methods, such as print, TV, or radio advertising? Does the patient population have a strong advocacy group, such as the Cystic Fibrosis Foundation, and is there a way to leverage a relationship with the group to help recruit patients? Proactively identifying the recruitment methods for your trial and developing study level materials to support those methods will facilitate recruitment for your trial from the start.
An initial risk assessment should also be conducted during the pretrial phase. Risks can affect each stage of the trial. By identifying and categorizing risks from the beginning, Sponsors can be aware of potential risks to begin determining whether to accept, avoid, mitigate, or transfer these risks. Consider non-protocol risks. For example, have the sponsor and CRO ever worked together? If the sponsor and CRO do not have an established working relationship, risk mitigation may be needed for each party to have a clear understanding one another’s responsibilities, expectations, needs, and temperament. Risk mitigation may also be necessary if the CRO and/or Sponsor have never worked with the vendors selected for the trial. Clarifying pathways of communication is key to managing these relationships – knowing from the start who to contact and how to communicate across project team members from the sponsor, CRO, and vendors can help avoid future confusion, delays, and unnecessary back and forth.
Finally, during the pre-trial phase training should be considered – both training of site personnel and project team members. Again, understanding the protocol is key in determining how much training is needed and the best way to deliver that training. For example, for site personnel, is the project simple enough where online training will be sufficient, or does it make sense to hold a face-to-face investigators’ meeting? Consider onsite training for more complex trials. Will site personnel need to be certified to complete specific trial procedures? If so, consider how this certification is obtained. Consideration should also be given to re-training and the training of new site personnel and project team members. Recording trainings is a best practice. By recording live trainings, site personnel and project team members can complete initial or refresher self-paced training by reviewing the recordings independently. During the pre-trial phase consideration should be given to whether clinical research associates (CRAs) will be involved in the study start-up activities. Involving CRAs in study start-up activities early on is beneficial for training purposes. CRAs can attend the kick-off meeting and take part in user acceptance trainings. This early involvement, gives CRAs a firsthand view of study decisions and the rationale behind those decisions, which aids their understanding of the study as a whole.
Though many don’t consider the pre-trial phase to be the start of a clinical trial, it is during this phase that foundational actions are taken and these actions are critical with the potential for significant implications. Clear, open, and honest communication is imperative during this time – maintaining transparency about the basis of risks, assumptions, and recommendations.
Trial Maintenance and Close Out
The two key factors to consider during trial maintenance are enrollment and data: ensuring each site is enrolling patients that meet all eligibility criteria (patient safety), and ensuring accurate data is being collected (data integrity).
Enrollment
Slow enrollment plagues most clinical trials, so almost every trial should implement proactive measures to foster enrollment because the assumption should be that enrollment will be slower than projected. Study-level materials should be developed and made available to sites from study start to facilitate enrollment for your trial. Nine times out of 10 these materials will be needed. Consider establishing site recruitment and enrollment plans with each site to clearly document the site’s enrollment plan. As CRAs follow up with sites regarding enrollment these plans facilitate discussions and provide a clear baseline for follow up. Having sites complete a pre-screening log helps depict the number of subjects that have been assessed for the trial and the reasons for ineligibility, which helps identify enrollment trends and challenges.
Bringing site personnel together to discuss enrollment and share successes, failures, challenges, and best practices can help identify enrollment trends and challenges. Conducting site recruitment calls/Visits to collect detailed information regarding sites’ recruitment and enrollment activities provides valuable information regarding enrollment activity. Reviewing the study from a macro perspective can also help. After reviewing and summarizing the detailed enrollment data collected from sites, trends can be identified. Based on the trends identified, consideration should be given to whether a protocol amendment, additional recruitment funds, site closure, etc. are warranted.
Enrollment should be monitored frequently at both the site and study level. Actual enrollment should be compared to the projected enrollment data regularly. If your trial is not meeting the projected enrollment goal, an assessment should be performed to identify why the enrollment goal is not being met. The purpose is to stay on target with your projected goal. If your actual enrollment is way behind the projected goal, the projected enrollment may need to be re-evaluated and updated. Projections are important to keep enrollment moving toward the pre-defined goal, but without regular assessment, these projections don’t mean much.
Data
Gathering clean data is among the most important steps to a successful clinical trial. Sites can be found, patients can be recruited, but if the data is inaccurate, it will not be of use to the sponsor.
Consider doing early and routine review of data – whether remotely or during a monitoring visit. Priority should be given to primary endpoint data. Identifying data quality issues early on, correcting those issues, retraining site personnel, and establishing preventative measures allows for data issues to be addressed and resolved quickly before evolving into significant problems.
Data is also a key factor to consider during trial close-out. However, the primary focus from a clinical operations perspective is data cleaning to meet the database lock milestone. CRAs should collaborate directly with data management to ensure data is monitored and cleaned on an ongoing basis. Data management should provide status trackers or reports routinely that outline the current status of CRF data review – what queries are open, what data has been SDVed, what data has been frozen, etc. Connecting CRAs directly with data management removes excess layers of communication and streamlines the database lock process.
Shanna Allen, M.P.H.,CCRA is a Clinical Team Lead at Rho with over ten years of experience in managing, leading, monitoring and coordinating domestic and global Phase I-IV clinical trials across various therapeutic areas. As a Clinical Team Lead, she has overall accountability for the execution of clinical operations activities from project initiation through closeout.