By Deb Borfitz
March 1, 2010 | A two-year-old question could get answered this year when the Clinical Trials Transformation Initiative (CTTI) publishes a position paper on how best to improve trial monitoring. “The document will be the stance of the public-private partnership’s thinking on the matter that could lead to new FDA monitoring guidance, says Mark Behm, compliance advice and assurance regional director at AstraZeneca and member of a CTTI monitoring work stream.
The last significant guidance on monitoring practices was updated by the FDA in 1998, says Behm. In the interim, clinical research has grown into a more complex, multi-national enterprise routinely aided by external service providers and technologies like electronic data capture (EDC) and e-diaries. It has also, from time to time, attracted negative media attention and a sizable up-tick in regulatory enforcement activity, turning FDA inspections and Warning Letters into key shapers of industry thinking about what is and isn’t permissible in regards to monitoring.
Ideas about how to modernize the monitoring function were explored by the Pharmaceutical Research and Manufacturers of America (PhRMA) in November 2007 and “picked up steam” in mid-2008 with a public workshop, hosted and initiated by the FDA, says Behm. Shortly thereafter, CTTI launched one of its first priorities: production of a position paper about the appropriateness of novel monitoring approaches over the traditional practice of visiting sites every four to eight weeks. CTTI includes representatives from the FDA, government, industry, academia, and patient advocacy groups collectively working to update the clinical trials enterprise.
Much of the dialogue has centered on “risk-based” monitoring that loosely connects level of oversight to clinical trial phase, says Behm. “There’s a general understanding that early phase trials need more intensive monitoring and when reaching phase IV you can really consider more novel and potentially less exhaustive efforts while not compromising quality or safety. The big question is whether or not opportunities exist in phase III or IIIb to apply a more customized [risk-based] approach.”
Risk-based monitoring generally leads to fewer, more targeted monitoring visits in large outcome trials involving hundreds of sites and thousands of subjects and has been more often used by academia or trials supported by the National Institutes of Health, says Behm. Remote monitoring has also been seen as a highly desirable trend in the modernization process. Statistical or so-called “central monitoring” is frequently part of the monitoring debate and as applied may trigger additional visits to sites identified as outliers by a statistical review of study data trends. The latter technique has on occasion proven capable of detecting data integrity failures.
A soon-to-be released PhRMA white paper on acceptable trial monitoring concludes that a variety of approaches is acceptable and may be used in combination within a particular study. The document notes that centralized monitoring practices—i.e. electronically checking for missing or invalid data and making a comparative assessment of adverse event reporting rates—as well as occasional site “audits” by peer physicians have not been categorically cited as inadequate by the FDA.
“At AstraZeneca, we look at what trial design means from a monitoring perspective and apply those principles to the monitoring plan,” says Behm. That results in the removal of non-mandatory or unnecessary procedures from the study protocol, which in turn results in more efficient monitoring. Last year, AstraZeneca conducted a small pilot with one institution that involved review of data via data transfer from an electronic medical record (EMR). The latter technique is hoped to gain widespread use but needs continued government leadership to overcome hurdles like interoperability and privacy.
The FDA holds sponsors responsible for monitoring investigators’ conduct, including keeping accurate patient case histories or ensuring substantiated information is entered on case report forms. “Ultimately, FDA incentives could further motivate sites to ‘do things the right way the first time’ and thus help alleviate monitoring requirements,” says Behm. “Investigators are key to ensuring data quality. Therefore, discussions about improvements in monitoring need to be coupled with ensuring that the obligations of investigators are fulfilled, especially in regards to data quality.”
The consensus of CTTI stakeholders as well as sites attending last fall’s Site Solutions Summit in Clearwater Beach, FL was that face-to-face interactions with study monitors could never be done away with, says Behm. But they might get augmented or, for certain tasks, replaced by utilities such as remote EMR monitoring or videoconferencing for communications with time-pressed investigators and potentially—in conjunction with document-sharing technology—for pre-study visits or site initiations.