One of the main problems with ICH-GCP is that it has made randomised trials much more complex and costly than they need to be. The result has been an ever increasing cost of doing trials with reports of single phase-3 trials now costing as much as a billion US dollars. This not only prevents the development of many potential new treatments, but makes it much more difficult to properly evaluate many existing treatments and other interventions. Therefore, there is an urgent need to reduce the cost of randomised trials.
Site monitoring can make up to 40% of the cost of a randomised trial so it is not surprising that in the last few years many groups around the world have developed approaches using central statistical monitoring as an alternative to site visits. Use of these new approaches has been promoted in guidance from both the FDA and EMA. Further, the update to ICH-GCP at the end of last year also reflected this trend, updating the original text on monitoring, which stated:
“In general there is a need for on-site monitoring, before, during, and after the trial.”
With this new addendum text:
“The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The flexibility in the extent and nature of monitoring described in this section is intended to permit varied approaches that improve the effectiveness and efficiency of monitoring. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring.”
Whilst the use of centralised monitoring can greatly reduce trial costs concerns had been raised that there was a lack of reliable evidence to show that centralised monitoring was as effective as traditional site monitoring. The recently published ADAMON trial from Germany addresses this concern.
The ADAMON trial team used a cluster randomised trial design to compare the effectiveness of risk-adapted monitoring with extensive on site monitoring. The trial was conducted in 11 academic trials that were classified as either low or intermediate risk. For each trial a risk-adapted monitoring plan was developed and participating centres were randomised to either risk-adapted monitoring or extensive on site monitoring with full source data verification. At the end of the trials auditors who were blinded to the randomised allocation determined the proportion of patients with at least one critical error that could impact on either the safety or rights of the trial participants or on the reliability of the trial results.
The final analysis included a total of 156 audited sites, which included 76 extensively monitored sites with 755 audited patients and 80 risk-adapted monitored sites with 863 audited patients. The average audit duration was 2.6 hours per patient and was similar in both monitoring arms. As expected, there was a clear difference in the average number of monitoring visits per site between the randomised groups (extensive site monitoring 5.4 vs risk-adapted monitoring 2.7 visits per site). The average length of the monitoring visit was also longer in the extensively monitored group. At least one critical error was found in around 60% of the patients audited with a large variance (18-99%) across the various trials. The main analysis used an approach similar to a typical meta-analysis comparing within each trial and then overall the effect of the different monitoring strategies. The study was designed to show non-inferiority (e.g. whether risk-adapted monitoring was not inferior to extensive site monitoring). The authors concluded that there was no statistical evidence that type of monitoring makes any difference in reducing the number of major audit findings either overall or in specific error domains. The point estimates lie near zero on the logit scale, and all two-sided 95% confidence intervals clearly exclude the pre-specified tolerance limit in order to show that extensive monitoring is superior to risk-adapted monitoring. Thus, non-inferiority is shown. The paper concludes that risk-adapted monitoring is not inferior to extensive site monitoring. Other groups doing similar studies will report on these in the near future
You can read the full report of ADAMON here.