Practical ways CROs and sponsors can support sites and improve quality.
While a lot has changed in the past five years in clinical research, the most common findings from Food and Drug Administration (FDA) inspection of research sites remain the same.1 Issues such as protocol non-compliance, incomplete case history documentation, and inadequate investigational drug disposition records are the most frequently cited items year after year.
Implementing clinical trial technology at the site level can detect and potentially avoid frequently observed quality issues arising during the trial. Technology systems considered core to site operations include:
This paper summarizes the most common reasons for findings (often referred to as FDA Form 483 observations) during FDA inspections, and how technology deployed at the clinical trial site can help address these issues.
The FDA’s Office of Regulatory Affairs conducts inspections and documents any conditions potentially in violation of FDA’s requirements on an FDA Form 483.2 Of particular importance is FDA’s Bioresearch Monitoring (BIMO) program, which provides for the protection of human subjects by assuring the quality and integrity of data submitted to the agency for new product approvals. The FDA summarizes data on inspection findings for each fiscal year tied back to the Code of Federal Regulation referenced in the citation.
Over the past five fiscal year periods (FY 2018 to FY 2022), there were 763 findings related to bioresearch monitoring. Table 1 below summarizes the top eight reasons for inspection findings. These eight reasons for citation represent 59% of all findings over the five fiscal years; all the other findings represent less than 1.5% of the total related to inspections.
As described above, high volume clinical trial sites and site networks generally invest in three types of technology: CTMS, eReg binders, and eSource/EDC. In addition to standardizing the research process at the site, each of these technologies has the potential to address the reasons for common FDA Form 483 inspection findings related to biomedical research monitoring.
Sponsor benefits from CTMS usage are summarized in Table 2. Adopting a site CTMS can prevent and/or detect six of the eight most common observations during an FDA inspection. The two common observation items not covered by CTMS would generally be the responsibility of the study sponsor, as opposed to the site. Outside of these eight common compliance issues, site-level CTMS also can also improve patient recruitment and retention, support financial compliance and insurance versus study billing (i.e., coverage analysis), and guide study startup staffing and timelines.
As seen in Table 2, an eReg system provides benefit in five of the eight most common compliance issues found during FDA inspection. One of the three items not covered by eReg is typically a sponsor responsibility. In addition to the benefits displayed in Table 2, an eReg system also helps decrease study startup timelines by leveraging documents across trials, as well as facilitating capture of signature for eConsent.
It is generally accepted that electronic capture of data via eSource offers benefits over paper, improving timeliness and quality of data. But it may not be as well-known that eSource and EDC systems decrease risk associated with five of the eight common findings displayed in Table 2. Similar to CTMS, two of the three areas not covered are typically sponsor responsibilities. Also seen in Table 2, the benefits from CTMS, eReg, and eSource/EDC differ, providing a variety of benefits for the large proportion of sites who use all solutions in combination.
Sites invest in technology at the enterprise level for use across all studies and sponsors, including industry, government, and investigator-initiated trials (IITs). Sponsors and CROs wanting to support sites in using their own technology to drive more compliant and higher quality study delivery can help in the five ways listed below.
Providing support through the five mechanisms listed above offers a “win-win” situation for sites, sponsors, and CROs: a decrease in site burden related to technology and an improvement in sponsor and CRO efficiency, quality, and compliance in study delivery.
The reasons for quality findings related to clinical trials are well documented, and many experienced sites have chosen to purchase technology to decrease risk associated with protocol compliance, inadequate case histories, and accountability records (i.e., drug disposition), among other issues. What is not well known, is how this technology benefits sponsors and CROs. In fact, the majority of sponsors and CROs who oversee clinical trials are not at all familiar with site technology and its value.
Press releases, websites, and participation of sponsors and CROs in clinical trial workforce associations such as the Association of Clinical Research Professionals (ACRP) all point to a strong desire to decrease site burden, but there's not always a clear, actionable path for sponsors and CROs to address the problem. The five suggestions listed above—pre-qualifying software tools; calendar builds, budget setup, Medicare coverage analysis in CTMS, and offering BYOT—are practical ways sponsors and CROs can support sites and ultimately help themselves through faster startup and higher quality study delivery. Recognizing sites are already struggling to achieve workforce levels to keep pace with industry clinical trial volume, anything sponsors and CROs can do to decrease site burden will likely have a positive impact on the clinical trial industry, well beyond an individual trial.
Elisa Cascade, chief product officer, and Kate Yawman, director, product management; both with Advarra