The role of the Clinical Research Associate (CRA) was well-defined in the 1980s and 1990s, but as the tools with which we monitor have changed so has the role of the CRA. A CRA was once defined as an individual who supported clinical trials and periodically visited investigational sites to:
- Provide training,
- Monitor completed case report forms (CRFs),
- Source document verify (SDV) reported data,
- Collect and transmit paper CRFs,
- Review/collect essential documents,
- Perform investigational product accountability, and
- Assess the investigational site and staff for compliance with the protocol.
Perhaps the most dramatic change in the clinical trials implementation is the evolution of the electronic Case Report Form (eCRF). In-house data entry has all but disappeared and sponsors have more real-time access to data without the need of physically sending a CRA out to collect paper CRFs. Rapid access to data has been the impetus for most innovations in data management, from initially having sites send in completed triplicate CRFs, transmit forms via fax, and some optical character recognition systems. Today’s EDC systems can be very sophisticated and include point-of-entry edit checks, internal calculations, and some rudimentary logic checks.
As EDC was evolving and central data review was becoming more common, CRA visits to sites became less focused on data collection and more on query resolution, SDV, and other tasks that could only be performed onsite (e.g., review of source documents, essential documents review, and IP accountability). Remote monitoring is becoming more popular with investigational sites providing remote access to electronic medical records (EMR) and transmitting de-identified source documents. In Guidance for Industry Oversight of Clinical Investigations —A Risk-Based Approach to Monitoring (FDA 2013), the FDA encourages sponsors to develop risk-based monitoring strategies that include central review of data and remote monitoring. The guidance even describes situations in which remote monitoring of informed consent may be possible (FDA 2013).
CRAs can utilize the functionality of the EDC to become more effective monitors. The old adage of “Beware the n of 1” is especially true when it comes to reviewing aggregate data. Outliers and possible transcription errors can be more easily identified when the monitor is reviewing data from several subjects or within a subject over several timepoints. Patterns of missingness or other non-compliance is often more evident when looking at aggregate data rather than individual occurrences. Many of the monitoring activities that CRAs used to do onsite can be more efficiently accomplished remotely, such as:
- Ensuring clinically significant laboratory results and vital signs are evaluated as possible adverse events (AEs)
- Reconciling concomitant medication indications with AEs and/or medical history events
- Querying possible typographical errors
- Monitoring for protocol compliance related to missed, out-of-sequence, and out-of-window assessments
Queries can be generated and many responded to prior to onsite visits which will help optimize the CRA’s time onsite to perform tasks that cannot be done remotely. These tasks could include medical chart review, which ensures the CRF accurately represents the subject’s experience in a clinical trial.
In addition to monitoring protocol compliance, SDV, and monitoring, CRAs assist sites in inspection readiness and perform Investigational Product (IP) accountability. Just as many sponsors have embraced electronic trial master files (eTMF), it is only a matter of time before investigational sites begin to gravitate toward cloud-based virtual solutions for investigational site files (ISFs). Electronic ISFs (eISFs) will permit remote review of investigational sites’ essential documents for accuracy and completeness without requiring an onsite visit. When one reviews Section 8 of Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance (ICH 1996), the duplication of the documents maintained at the investigational site and the sponsor demonstrates the efficiencies that could be realized with a mutually accessible hosted solution. Some investigational sites maintain archival copies of Investigator Brochures and prior versions of protocols as PDF documents on DVDs so it seems the next logical step may be a shared virtual environment.
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Even on-site IP accountability may see substantial changes in processes in the near future. As refrigerator manufacturers are designing refrigerators with smart technology that include internal cameras to view contents it is not hard to imagine performing IP accountability in the comfort and convenience of your cubicle.
The most important skills of a good CRA are safe from technology: the ability to establish and leverage relationships with investigational site staff; helping to problem-solve and assist investigational sites maintain compliance; being the face of the company to the investigators; and common sense.
*Thomas M Tremblay, RN BSN, is the Director of Clinical Development at Apexigen
FDA 2013, Guidance for Industry Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring
ICH 1996, Guidance for Industry E6 Good Clinical Practice: Consolidated Guidance