Drug Safety
Figure 1: Identification of At-risk Investigative Sites that May Require Increased Clinical Monitoring
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Using a safety-scaling model, each coloured circle represents a clinical trial site projected into 3D from a dissimilarity matrix based on important measures, such as adverse events, withdrawal rate, main laboratory parameter values/outlier rate, electrocardiogram values/ outlier rate or other incidence indicators, etc. Based upon this method, one can see in realtime that site #5,605 is an outlier site and merits additional attention.
Efficient Safety Monitoring
“What we need is: 1. a way to identify the areas of effectiveness (of possible significant results); and 2. a method for concentrating on them,” Peter Drucker.7
Ways to identify areas of effectiveness by defining some of the categories of risk factors have been discussed above. The next task, as can be inferred from Drucker, is to focus on the areas of effectiveness and carry out monitoring efficiently. In other words, improving on monitoring that has been implemented in the past.
Whereas not long ago thorough case-by-case review was the standard, the information revolution has given us a few more tools. The trick is using them for optimal effect. Such tools include:
• large databases; • data standards; •
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Optimally, independent data monitoring committee input should be sought at the protocol design stage. If there is a safety concern, the committee can often help with trial design in early interim meetings and with independent analyses that may ultimately decrease the burden on clinical trial investigators or decrease the number of patients needed in the trial.10
Additionally, committees may serve as the initial quality control for the integrity of safety data.
On the negative side, an independent committee that is poorly run or inexperienced is a high-risk proposition. Such a committee can subject the sponsor to substantial regulatory and financial risks.
Clinical site monitors are often thought of as the least efficient part of the clinical trial operations factor. The FDA’s Clinical Trials Transformation Initiative has, however, suggested that efficiencies in monitoring are possible by focusing on high-risk investigative sites.9 Additionally, because site performance and interpretation of adverse events can be so variable,11–14
creating a monitoring plan that focuses
on precisely detecting key safety and efficacy information may improve safety monitoring efficiency. By careful monitoring of at-risk investigative sites, better safety information can be obtained in a timely fashion.
On the negative side, if not properly maintained and controlled, site monitoring is a very expensive endeavour and can be prone to abuse, confusion and variability.
New models of efficient safety monitoring include:
independent data monitoring committees; and • clinical site monitors.
Large databases are a cost-efficient method for hypothesis generation in terms of patient- and compound-based risk factors. Through data mining, they lend themselves to powerful observations. As such, large databases are powerful tools when looking for a potential safety signal or looking to discount a potential safety signal.8
On the negative side,
large databases are also prone to drawing false conclusions. When compared with a clinical trial database, data integrity is low. Additionally, the less strictly the data mining is statistically guided, the more open its findings may be to misinterpretation.
Data standards as a long-term strategy can demonstrate efficiencies by creating more rapid communication and, overall, lower costs.
10
• innovative clinical trial designs; • data sharing; and •
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Independent data monitoring committees, such as DSMBs or end-point committees, are often seen as a ‘behind the wall’ regulatory requirement. Despite this, these committees can often provide tremendous efficiencies in communication and operations factors. They do, however, have to be used correctly.
On the negative side, the most promising clinical data standards proposed by the Clinical Data Interchange Standards Committee (CDISC) have not reached maturity. Additionally, the CDISC’s standards have a certain complexity, and therefore initial expense, which diminishes their efficiency advantage in the short term.
Optimally, they allow for consistent and precise generation of more analyses that produce faster communication and enhanced comprehension of safety information.
innovative safety models utilising data collected via realtime electronic data capture.
Innovative clinical trial designs, such as adaptive trial design and clinical trial simulations, are gaining increased regulatory acceptance. These models have the ability to markedly reduce the number of patients necessary to complete studies. The downside is that, because they have not yet been widely used, there is not universal acceptance of their safety conclusions, especially if the adaptative design is not safety driven.
Data sharing is gaining currency as an efficiency improvement. The basic sciences have made great strides in data sharing (e.g.
DRUG DEVELOPMENT
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