Kenneth A. Getz
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For two decades now, companies sponsoring clinical research have openly acknowledged that protocol design negatively impacts
clinical trial performance and may well be the single largest source of delays in getting studies completed. But the magnitude
of the problem and the challenge of re-engineering how protocols get crafted have squelched the will to attempt a fix. Investigative
sites are instead admonished for sluggish enrollment and rising dropout rates.
The real issue is that many patients no longer qualify for or simply lack the stamina to participate in the kinds of studies
being rolled out by drug development companies today. In terms of procedures and their frequency, protocols are more demanding
than ever before. That represents a growing burden to study subjects in terms of their time and comfort. It also places a
greater workload on investigative sites for fewer relative dollars.
Design Changes
Figure 1
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Key protocol design elements changed dramatically between 1999 and 2005, as was shown in a recent study conducted by the Tufts
Center for the Study of Drug Development and soon to be published in an upcoming issue of the American Journal of Therapeutics. More than 10,000 unique Phase I–IV protocols formulated by over 75 pharmaceutical and biotechnology companies across a wide
range of therapeutic areas were scrutinized.
During the six-year period, the number of unique procedures per protocol (e.g., routine physical exams, blood work, and heart
activity assessments) and their frequency increased at an annual rate of 6.5% and 8.7%, respectively. In 2005, across all
therapeutic areas and research phases, 158 procedures were conducted—an average of 4.5 times the number of unique procedures—during
the course of a clinical trial. Unique procedures were conducted on average 5.4 times during the course of a Phase I clinical
trial, 6.5 times during a Phase II trial, 4.0 times during a Phase III trial, and 3.1 times during Phase IV trials.
The Tufts study found that questionnaires and subjective study volunteer assessments were the fastest growing procedure type.
While these procedures may provide valuable information, they also require a higher level of volunteer compliance.
The typical protocol today has nearly 50 eligibility criteria. Whereas the number of exclusion criteria per protocol remained
stable over the time period measured, the number of inclusion criteria saw nearly a three-fold increase.
Performance impact
Study conduct performance on 57 individual Phase II and III protocols investigating chronic illnesses was examined and, predictably,
performance worsened virtually across the board. The study controlled for geographic speed differences. The average overall
duration of clinical trials increased 74%. Median cycle time from protocol readiness to both drug availability and last patient/last
visit increased by a similar margin, as did median elapsed time from protocol readiness to data lock.
Enrollment rates for volunteers who met the rising number of protocol eligibility criteria dropped from 75% to 59% between
the 1999–2002 and 2003–2006 time periods, while retention rates fell from 69% to 48%. Patient enrollment cycle times increased
for protocols conducted in the latter time period. The average length of case report forms grew from 55 pages to a whopping
180 pages per protocol. Consent forms also lengthened. Moreover, there were higher numbers of protocol amendments and a dramatic
rise in observed adverse events and severe adverse events. This last observation may be due in large part to changes in how
adverse events are defined and counted.
Without a doubt, clinical research professionals put a great deal of care and attention into their study protocols. Yet these
same protocols appear to lack adequate consideration for the human subjects participating in them and the investigative sites
that must administer them.
