Ensuring Uniform Protocol Revision Usage in Multi-Site
Randomized Prospective Clinical Trials

Ensuring that the correct version of any given protocol is in use by all the centers in a large clinical trial can present challenges to any sponsor. Often, it is a time consuming and lengthy process that may require the trial be halted and subsequently restarted to ensure site-level compliance. Additionally, there may be regulatory compliance issues associated if the protocol change required relates to patient safety. Beyond the burden imposed on the sponsor or CRO in managing the process, stop-start delays can be costly in terms of lost strategic opportunity as it relates to product approval or claim generation, and thus any protocol-version change implementation process must concomitantly address burden, timeliness of resolution, and regulatory compliance.

This paper briefly describes the methodology employed by a major medical device company (Guidant Corporation, Indianapolis, IN) to affect a uniform protocol-version change throughout a 112 site, 1571 patient (at enrollment closure), randomized, prospective, international clinical trial during late 2003.

Situation

In the INTRINSIC RV study, an electronic research organization (eRO) had been retained by Guidant to provide data capture, management and reporting services. The eRO, MedNet Solutions Inc. (Minneapolis, MN), provided advanced technology solutions to affect these services, including web-based data capture and real-time data analytics.

Review of early, non-endpoint related data made available “at will” by the eRO via their implementation of the web-based system caused the Principal Scientist for the project to raise concerns with management over the protocol required settings for the implanted device and their effects on patient randomization. Further analysis indicated that a protocol amendment was required urgently in order to adequately address the issue and ensure a sufficient number of patients were available for endpoint analysis within the original total "n" projections and assumptions of the statistical analysis plan.

Methodology

A multi-layered approach to the problem was adopted – traditional center communications and leveraging of the eRO capabilities afforded by the technology. Guidant formulated an internal and external communication plan, and sought the advice and services of MedNet to facilitate smooth, comprehensive rollout and utilization of the new protocol. A simplified overview is shown in figure 1.

Figure 1. Protocol Revision Process Overview
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The eRO web-based system ensured that Investigators had a 30 day warning period that a protocol revision was to be implemented on the “go live” date of 08 Dec 03, and instructed them on the steps to take to remain in compliance, namely to attest to the IRB status and forward the required documents to the sponsor in the required timeframe.

In essence, the system performed a status validation in the background as the user for a given site logged on to either enroll new patients or update data on existing patients. In addition a “flashing banner” was employed on the electronic CRFs to continue to draw users’ attention to the upcoming required change. If a user did not come into compliance within the required timeframe, they were precluded from entering new patients into the study until they came into compliance. Figure 2 illustrates the flow process for the user of the system.

Figure 2. User Process Flow
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At each status check (i.e., at each login) before revision acknowledgment, the user would be given the opportunity to review and respond with IRB status and documentation thus -

Figure 3. Protocol Revision Status Form
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Users who failed to submit the required documentation within the requisite timeframe after acknowledgement were displayed the following advice regarding the outcome of post "go live" non-compliance.

Figure 4. Protocol Revision Documentation User Warning
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In addition, the real-time reporting capabilities provided by the eRO to the sponsor enabled daily monitoring of protocol-revision message viewing, acknowledgements, and likely compliance failures, which enabled them to focus field implementation efforts on problematic or tardy sites. The net effect of the methodology employed was that over 90% of sites began using the revised protocol within the required timeframe, and zero patients were erroneously enrolled under the provision protocol revision, as sites were precluded from doing so by the status validation checks used by the system. Delays to the research initiative were minimal post the "go live" date of 08 Dec 03 - as can be seen in the following chart, bearing in mind the downturn in enrollments over the holiday period was expected, and enrollments resumed at an increased rate in January 2004.

Figure 5. INTRINSIC RV Enrollments Over Time
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Conclusion

Protocol revisions are highly problematic in large multi-center clinical trials. Revisions in a paper-based system require a highly burdensome orchestration of multiple players and may result in significant delays to the research initiative. Use of a well-designed web-based data capture and management methodology such as that employed by MedNet Solutions and Guidant facilitates comprehensive and smooth communication and revision roll-out, and inherently precludes non-compliance.

© Timothy Pratt 2005