The cost of developing new treatments has always been rising and will continue to do so in the future. Taking into account all the work that needs to be done to gain marketing authorization, the average cost of developing a single new treatment is currently estimated at 2.6 billion USD. Adding up all the research conducted worldwide, the cost of global clinical trials is currently estimated at about 44 billion USD and is expected to reach 69 billion USD by 2026.
To curb the ever-rising cost of clinical trials, regulators and technology vendors encourage sponsors to adopt innovative solutions and specifically recommend the use of centralized monitoring (CM) to oversee clinical trials more efficiently. Nevertheless, there is still little evidence that CM can produce a significant ROI. What is the true value of CM in clinical trials then?
Implementing CM in Phase 3 Trials Represent the Most Potential Cost Savings
Among all phases of clinical research, phase 3 trials are the costliest phase of treatment development. They involve the largest number of subjects and investigational sites and require the most amount of oversight. As such, they are the type of trials for which CM holds the most cost-saving potential.
How Much Are We Talking About?
Phase 3 trials have a median cost of 19 million USD. The table below indicates the number of phase 3 trials funded by different sources according to clinicaltrial.gov. Accordingly, to this date, pharmaceutical companies have funded approximately 63% of phase 3 trials in the world and the Pharmaceutical Research and Manufacturers of America (PhRMA) member companies reported that 28.9% of pharmaceutical’s trial funding, which amounts to 23 billion USD, were spent on phase 3 trials in 2018. The exact amounts funded by universities, academic and non-profit agencies are difficult to obtain but the fact that the pharmaceutical industry finances 63% of phase 3 trials with 23 billion USD allows to estimate that the total amount spent for phase 3 clinical trials is approximately 36 billion USD per year.
Table 1. Number of Completed Phase III Trials by Source of Funding
|
Source of Funding
|
Number of Trials | Percentage of Trials |
| Industry | 13835 | 63% |
| NIH | 1801 | 9% |
| Other U.S Federal agencies | 324 | 1% |
| Universities, Hospitals, Academic and Non-Profit Agencies | 5925 | 27% |
| Total Number of Trials | 21885 |
* Clinicaltrial.gov searched on 17-Oct-2019
How Much of Phase 3 Trials Spending Go Towards Monitoring?
The monitoring of clinical trials is traditionally done by Clinical Research Associates (CRA) who act as liaison between sponsors and investigational sites. They typically visit sites on a periodic basis to ensure compliance with the protocol, regulatory requirements and GCP. Monitoring represent between 9%-14% of clinical trial expenditures. If we multiply this by the total clinical trial expenditures for phase 3 trial monitoring (36 billion USD) we can estimate that the total cost of monitoring Phase 3 trials is between 3.24 and 5.04 billion USD per year.
How Much Can Be Saved by Using Centralized Monitoring?
CM can reduce the amount of traveling and source data verification (SDV) required but it does not affect much of the other monitors’ tasks such as verifying subject’s eligibility, managing trial materials and liaising with sponsors. Assuming that CM can produce a 50% reduction in traveling and SDV, the total potential cost-savings that can be realized with CM is around 30% of monitoring cost. As such, if we consider that monitoring represents between 9%-14% of clinical trial expenditure, CM can only save between 2.6%-4.1% of total trial cost. The table below shows the work behind this estimate.
Table 2. Monitoring Activities and Centralized Monitoring Potential Cost Savings
| Monitoring Activity | FTE |
% of monitoring cost (X) |
% of trial cost (assuming monitoring represent 14% of trial cost) (Y) = X * 0.14 |
Potential cost savings attributable to CM (Z) |
Potential monitoring cost savings attributable to CM (X * Z) |
Potential trial cost savings attributable to CM (Y * Z) |
| Travelling | 0.2 | 50.0% | 7.0% | 50.0% | 25.0% | 3.5% |
| Performing Source Data Verification | 0.1 | 6.3% | 0.9% | 50.0% | 3.1% | 0.4% |
| Verifying Subject`s Eligibility | 0.1 | 6.3% | 0.9% | 0.0% | 0.0% | 0.0% |
| Performing Source Data Review | 0.1 | 6.3% | 0.9% | 0.0% | 0.0% | 0.0% |
| Preparing monitoring report and liaising with sponsor | 0.2 | 12.5% | 1.8% | 10.0% | 1.3% | 0.2% |
| Off-site monitoring activities | 0.2 | 12.5% | 1.8% | 0.0% | 0.0% | 0.0% |
| Managing IP and trial materials. | 0.1 | 6.3% | 0.9% | 0.0% | 0.0% | 0.0% |
| Total potential trial cost savings attributable to CM | 29.4% | 4.1% |
The fact that CM can only produce small cost savings needs to be taken into consideration when bringing in new technology to implement CM because technology has its own costs. Namely, technology requires validation, training and user’s licenses. A CM process also requires its own quality and risk management plans which needs to be written and approved by stakeholders. Furthermore, CM requires some analytic expertise that may necessitate new talent. As such, CM has many hidden costs. On the other hand, CM can bring benefits that are hard to translate into monetary value.
Intangible Benefits of Centralized Monitoring
CM is used to identify points of concern that orient the clinical operations so they can focus on truly important things and prevent wasting time on no-value-added activities. Also, key performance indicators (KPIs) related to individual sites represent very valuable intangible assets for sponsors and CROs. For instance, being able to identify sites that have high enrolment rates and low discontinuation rates has a significant impact on projects' timelines and budgets.
The information generated through CM can elevate the level of control over a trial which can translate into faster database lock and better quality of regulatory submissions. This in turn has an impact on the time to marketing approval and product launch. Improving timelines is important because in some cases, delaying a product's entrance into a new market for even a few months can mean millions lost. However, delays do not mean millions lost for all projects as not all trials lead to marketing approval and not all marketing approval lead to blockbuster treatments.
Confusion Around Centralized Monitoring
There is still a lot of confusion that surrounds the concept of risk-based monitoring (RBM) and CM. This fact has motivated the release of a RBM Guidance Q&A by the FDA’s in March 2019. Still, there is a lot of delusion regarding the potential of CM. Although CM can produce some cost savings, one of the most efficient way to reduce trial costs is actually to reduce management complexity. Using complex technologies that requires niche expertise and extra resources goes against this notion. One should consider simple solutions first. For instance, programming effective edit checks that prevent anomalous data from being entered is much simpler and more efficient than using customized algorithms to detect statistical data anomalies after erroneous data have been entered. Also, computing KPIs and visualizing data can easily be done using free open-source softwares such as R and Excel.
Hypersensitivity to Risks
It is easy to become excessively risk averse when trying to mitigate risks but addressing every single risk factor regardless of their relative importance adds significant costs, goes against the spirit of RBM and may provide no more value than performing 100% SDV. Sponsors must actually elevate their risk-tolerance thresholds to perform RBM efficiently. Specifically, sponsor must remember that random data errors have little impact on study conclusions and that fixing them is a no-value-added activity (i.e.: a waste of time).
Ensuring subject safety, data quality and trial integrity is fine but identifying scientific misconduct perpetrated by investigators is not part of sponsor’s GCP responsibilities. The truth is that scientific misconduct and fraud are very rare in the clinical research realm. Despite a handful of prominent cases, most research professionals are highly competent people with reputations to protect. RBM involves trust and trying to identify fraudulent investigators in a RBM framework is simply contradictory.
Conclusion
When choosing to implement CM, sponsors should not expect to save more than 5% of their overall trial cost. Sponsors should also be aware that cost savings can be quickly cancelled out by the direct, indirect, and hidden costs of adopting new technology. Indeed, there is a real risk of making a change that adds to the cost of research and brings no net benefit. Still, if CM can be implemented without incurring additional cost, it stands to save the industry up to $ 1.8 billion USD per year and make research more efficient than ever.