Sponsors/CROs, clinical sites and CRAs each play a critical role in ensuring data integrity and the protection of participating subjects’ rights, safety and wellbeing; however, with the increase of protocol violation findings in the past 3 years, especially those pertaining to enrollment, stirs up thought-provoking questions:
Are site investigators providing adequate training and oversight of staff involved in enrolling subjects?
Are CRAs performing to their best ability to detect protocol violations?
Are Sponsors/CROs providing sufficient guidance to ensure adequate compliance?
This article will discuss the increasing trend of protocol enrollment violations, how enrollment violations produces detrimental effects on premarket clinical trials, and how sponsors/CROs, sites and CRAs can help minimize future violations in an effort to increase subject safety and data integrity.
ENROLLMENT VIOLATIONS CITED FROM 2007 – 2009
In the past 3 years, the issuance of FDA's Bioresearch Monitoring (BIMO) warning letters for both pharmaceutical and medical device trials has been on the rise. In the year 2007, eight warning letters were issued; however in years 2008 and 2009, the number of warning letters tripled to twenty-five and twenty-six respectively 1.
Of the total number of warning letters issued, there was a drastic increase each year in the number of cited enrollment violations (see Table 1). From 2007 to 2008, the number of enrollment violations tripled which can possibly be attributed to the triple amount of warning letters issued within those two years. However, from 2008 to 2009, the number of enrollment violations nearly doubled even though there was a minimal increase of warning letters issued between the two years.
The most common violations noted over the 3 year span include:
DETRIMENTAL EFFECTS OF ENROLLMENT VIOLATIONS Enrollment violations not only reflect poorly on the sponsor, site and project team but can also potentially pose significant risks to subjects' and accuracy of study data.
Enrollment violations can potentially lead to:
Serious Adverse Events
An ineligible subject who is enrolled outside the protocol's safety parameters of inclusion/exclusion criteria can potentially encounter serious injuries, hospitalization, fatality, or other complications.
Withdrawal of Data 2 If the data integrity is affected by ineligible randomized subjects, the data from these subjects will oftentimes be removed from the primary data analysis of treatment which can further distort overall safety and efficacy results of the investigational product.
FDA Enforcement Actions3 When frequent violations are noted and noncompliance to federal regulations are evident, FDA will enforce such actions such as issuance of a warning letter or delaying approval of the investigational product's application. In addition, the application can be withdrawn especially when FDA believes the risks of the investigational product outweigh benefits and there is a major concern about the safety aspects or data integrity of the trial.
MINIMIZING STRATEGIES Initiation of the following methods by clinical sites, CRAs and sponsor/CROs can be helpful strategies in minimizing the increase and recurrence of enrollment violations.
Clinical investigators should ensure that staff are:
Qualified or trained to perform delegated roles especially those delegated to perform screening procedures, evaluations and study assessments.
Adequately trained and familiar with protocol details (including changes), study requirements and attributes of the investigational product as needed to perform their delegated roles. FN
CRAs can strategically minimize violations by:
Implementing “Detective Monitoring” Techniques My experience as a CRA has taught me to always be aware of linked violations. Oftentimes, enrollment violations are linked to a trend of other protocol violations. According to warning letters from 2007- 2009, those sites with enrollment violations were also cited for other violations.1 The 5 most common were:
Inadequate CRFs/Source document discrepancies
Deviations from protocol procedures and requirements
Informed consent issues
Drug/Device disposition/accountability issues
Poor AE documentation and SAE/ADE reporting issues
The CRA must, therefore, expect to find other violations and follow-up appropriately.
Providing Continuous Site Training Site training does not end at the Initiation visit. It continues throughout the study and, at times, up to closeout. When enrollment violations and other deviation trends are noted at the visit, research staff, especially those who are new or research-naïve, will need guidance and refresher trainings throughout the study. Additionally, Principal Investigators will need reminders of their responsibility to adequately oversee study staff and inform the sponsor/representative of all borderline enrollment issues.
Communicating proactively with sites Communication with sites should not only consist of follow-up of previous action items, status of patient recruitment or study supplies, but should also check for any enrollment issues that occurred since the last monitoring visit or site contact.
Sponsors/ CROs can implement supplementary guidance to clinical sites that focuses on compliance with enrollment. For example, the following enrollment checklist can be implemented for each subject:
SUBJECT ENROLLMENT CHECKLIST
Informed consent form is the current version and has been properly signed and dated prior to study procedures being performed
All screening/baseline tests (i.e., Lab, pregnancy, etc) have been conducted, reviewed and confirmed as within protocol parameters prior to enrollment.
Borderline Subject? YES NO
If YES, the sponsor/representative has been notified prior to enrolling the subject
ETC…
Although the implementation of these methods may not eradicate all enrollment violations, it will help minimize the rise of future violations and ensure what matters most…patient safety and data integrity.
According to a review of FDA's BIMO's Warning letters issued in 2009 (Jan-Sep) to sponsors, clinical investigators and sponsor-investigators, 15 of 19 warning letters included protocol noncompliance due to enrollment of ineligible subjects 1 . The top 5 enrollment findings (as noted in the chart below) include:
Unconfirmed or Exclusionary test results (i.e. laboratory, pregnancy, etc)
C. D. Furberg and B. D. Furberg. "What happened to the study subjects who disappeared from the analysis?," in Evaluating Clinical Research: all that glitters is not gold, 2nd Edition. (Springer Science + Business Media, LLC, New York, Harvey, 2007), p 77.
H Breslawec and N Teague, "FDA’s Enforcement Options in Clinical Trials, “Medical Device & Diagnostic Industry”, August 1996, pp 1-6.
About the Author:
Kimberly Kiner, CCRA is the President of 2K Clinical Consulting, Inc., a niche company specializing in providing monitoring and co-monitoring services to CROs and sponsor companies. She can be reached at [email protected]
