How Sponsors and Sites Work Together to Improve Protocol Compliance
Sponsor study team members and research sites each play a critical role in clinical trial executions. Especially as trials continue to increase in complexity, sites and sponsors can adopt strategies to avoid quality concerns and minimize cause for Food and Drug Administration (FDA) warning letters and inspections requiring additional time and resources.
What are Site Inspection Findings?
Sites working with an investigational new drug (IND) are often subject to an FDA site inspection. Through the inspection, any potential violations of the FDA’s requirements are documented in a Form FDA 483 as observations, also called findings or citations.
What are Site Deviations, Findings, and Failures?
Deviations, findings, and failures represent different instances when study conduct and processes don’t go to plan. Some deviations are less consequential, and both site staff and study team members can identify and document necessary action to intervene. For example, a common deviation occurs when a patient has to reschedule a procedure outside of a visit window, or a routine training has not been completed on time by a site staff member due to an extended leave.
Findings are more significant deviations the FDA has identified and reported. While a study may continue after a citation is issued, resources must be allocated to develop a corrective and preventative action (CAPA) plan to address the issue.
A site inspection failure can occur when there are broader concerns leading to an overall assessment. An example of this would be the inspected site did not meet regulatory standards. Both inspection findings and inspection failures could reduce the quality of the trial data, with inspection failures being most disruptive. These may result in reputational harm, elimination of subject data from evaluation, and ultimately could jeopardize regulatory approval. Despite the consequences, the FDA has reported a failure rate of 36% in clinical trial site inspections over the past five years. Advarra analysis of the FDA Inspection Observation Datasets from 2018 – 2022 shows the following causes make up 44% of all findings:
Failure to Follow Investigational Plan (21 CFR 312.60)
Citations for failure to follow the investigational plan contribute to over half of the failures recorded since 2018. Errors such as protocol non-adherence, missing protocol amendments, or lack of institutional review board (IRB) required review all fall within this code.
Inadequate and Inaccurate Records (21 CFR 312.62(b))
Categorized within the investigational plan regulations, there is a specific emphasis on accurate and complete documentation of all trial activities. Failures such as an incomplete subject record, missing investigator CV, failure to provide delegation of authority log, and more fall within this code.
So, how can sponsor, contract research organization (CRO), and site teams better collaborate to improve quality and efficiency in their studies?
Provide Visit Guidance and Calculators to Sites
A Tufts Center for the Study of Drug Development (CSDD) study found the mean number of deviations and substantial protocol amendments has increased across all trial phases. As a result, sites find themselves forced to navigate constantly evolving directions for conducting study visits and procedures on top of the increasing protocol complexity mentioned above.
To limit the risk of mistakes, sponsors and CRO teams should invest in support tools for sites offering additional guidance on upcoming visits and procedures like:
- Adequate visit guidance, including step-by-step overviews of upcoming procedures
- Video refreshers on the specific drug mechanism of action
- Protocol text search so the site can rapidly find answers to questions
Visit calculators providing a date range for subsequent clinical visits also help ensure visits are conducted on time and with the required windows.
Over 80% of site respondents in our recent survey said additional study tools and guidance like the ones mentioned above are very or extremely helpful.
Provide Access to Ongoing Trial Training
Site staff turnover continues to disrupt trials and put strain on the remaining site team and new staff getting up to speed. In addition, many research trials are conducted over the course of many years. Recognizing the combination of challenges sites face, study teams should provide easy access to study-specific training beyond initial activation and investigator meetings. This enables higher levels of training compliance over the course of study conduct, as well as the necessary understanding of trial activities to perform the right task at the right time. In addition, providing CROs and sponsors visibility to site training compliance allows them to provide additional support and mitigate risk if necessary.
One top pharmaceutical company leveraged Advarra’s Longboat intuitive workflow technology to execute these strategies and reduced protocol deviations across their sites by 20%.
Centralize Access to Critical Resources and Documents
In addition to study guidance, it’s essential for each stakeholder to be aware of and have access to the timeliest information and documentation for a trial. But in today’s day and age, we’re all overloaded with notifications and alerts. Since we all rely on email or other communication channels, it’s easy to understand how a document could be overlooked or misplaced.
Tools designed to centralize access and monitor document versions are essential to reducing inspection findings. Documents should be well named and always up to date on the current version. Centralizing resources and documentation reduces the risk of errors, contributing to improved compliance and quality.