As clinical trials become more globalised and complex, there is an increased need for investigators in all regions of the world, as well as for treatment-naïve patients. The industry faces demanding regulatory needs, as well as the complexities of innovative treatment combinations and adaptive trials, against the backdrop of needing to find new cost and time efficiencies. Many challenges associated with this changing landscape, including administering, planning, monitoring and controlling clinical trials, can be addressed through the effective use of a CTMS (Clinical Trial Management System). Most companies adopt such a system as a means of providing a central database for all non-clinical and some clinical data, as well as providing all the tools for entering and reporting this information. Yet it is within the effective use of a CTMS that a development “edge” can be achieved. This article will consider four different aspects of the clinical trial process that illuminate this point.
The CTMS Role in Patient Recruitment and Site Management
The definition of a successful study starts and ends with recruiting enough evaluable subjects. Yet even with the best patient recruitment web pages, a greater need yet is for well-qualified, enthusiastic, effective sites. It is difficult to argue with the assertion that picking the best sites matters more than anything else in achieving trial success.
As was recently reported in CenterWatch, ‘On any given clinical trial, half of all sites under-enroll or fail to enroll a single patient, while 30 percent of sites provide 70 percent of all evaluable subjects…’. (Advocacy groups use Internet to target patients for disease-specific Recruitment, CenterWatch Monthly, November 2010).
The critical questions then remain: How can the “30 per cent” become the majority? How might the failure rate be reduced? Worse still, sites that only enroll one subject can impose even more workload burden than those that fail to recruit at all. To make headway, there is a need for effective tools to assess a site’s suitability.
A well-designed trial management system can positively impact the success of patient recruitment and site management. It will store information gleaned from mailshots and CRA interviews, providing a first indication of who should be approached to participate. A data mining tool in the CTMS facilitates the process, allowing one to focus on those people who responded a certain way to a given question or questions – as an example, if the sites were asked “How many new asthma patients do you see each month?”, an initial screen could seek to retrieve those doctors and those sites who responded with ‘5 or more’. This list of names could then be further filtered using a geographical or specialist/key opinion leader search with the potential to narrow it down even further to those in a given city, province or country, and to those with appropriate certification or experience.
This can be a useful first step, but self-reported information can only go so far. Objective, retrospective data obtainable from a CTMS, as it is used year on year, will offer an extraordinarily rigorous method for finding the very best investigators. Examples of key metrics to consider include:
• When they were recruited before, did they hit or exceed their planned number of patients?
• Was their dropout rate lower than average?
• Did they avoid protocol deviations?
• Were they ahead of the curve in their speed of startup – in getting all the documents together, obtaining ethics approval and recruiting their first patient?
And these quality measures can be combined with other criteria, such as:
• Promptness at resolving issues
• Correct follow-up of all serious adverse events
• Performance in overall per-patient and per-site costs
Note that all of these measures are objective, avoiding the trap of evaluating a site’s suitability on the basis of personal preference, or on their availability for preliminary investigator meetings. This methodology instead relies on their proven track record.
The Advantage of CTMS Integration with Other eClinical Systems
Once the sites have been selected – using all of these intelligent assessment methods – it will be necessary to further qualify sites using on-site or telephone assessments. Their regulatory documents will need to be collated and the necessary ethics approvals obtained. A final step before enrolment can start will often be the setting up of the sites’ EDC (electronic data capture) and RTSM (randomisation and trial supply management) accounts. It is important not to activate these accounts too soon – before trial supplies are delivered and the staff are trained. A winning approach is to have the CTMS signal to the other systems that the site is ready: a combination of ‘all personnel are trained’, ‘drug supplies are available’, and ‘ethics approval is obtained’. A clinical trials management system is, after all, the primary source of site statuses; therefore, it is clearly the system to rely on.
This is just one facet of the eClinical approach, linking all critical pharmaceutical software components together. The most effective CTMS has the latest enrolment data funneled into it from all the electronic data capture tools in use; that is, the data from one or more RTSM systems and an EDC system are fed into the CTMS. This helps to avoid over-enrolment, equating to cost overruns, and also keeps the trial manager alert to failing sites and countries.
CTMS Support for Monitoring
The “100% SDV” pendulum has swung back and forth over the last two decades. A monitor may – or may not – need to visit his or her sites every month: a large Phase IIIb or Phase IV study would be a challenge to monitor that closely. This does not mean, however, that the sponsor or their CRO are free of their GCP responsibilities. Instead, there is a trend towards virtual site management, that is, a flexible combination of EDC, some site monitoring, and skilled company personnel reaching out to the site by telephone. The clinical trials management system can guide the office-based CRA or administrator by displaying which sites have not been contacted recently, which sites have recruited new patients and which ones are falling behind compared with their planned enrolment. This allows the users to know whom to contact first. The CTMS will show them the best time to call the site and their preferred method of contact.
The caller will be able to perform a variety of activities including discussing any issues the site may be having, following up on any expiring or missing documents, covering any recruitment or supplies difficulties, and dealing with inquiries concerning payments. This will be possible as the CTMS will have all of this information on one screen.
ROI with CTMS
Whenever “return on investment” for a CTMS is discussed, one consistent message is the ability of the best systems to automatically calculate and generate investigator payments. Any study involving more than a few investigative sites brings with it the headache of ensuring accurate and prompt reimbursement to the site. It would be sufficiently complicated to be paying on a patient visit by patient visit basis, together with a percentage holdback until all data are certified as ‘clean’. There is, however, an additional wrinkle in certain regions of the world in the form of multiple contracts, all paying on a visit-by-visit basis, but paying different amounts to different payees – the sub-investigators, the PI (principal investigator), the institution and even the pharmacy and the laboratory.
This represents a quantum leap in complexity, and it is the most stringent test of any clinical software system to achieve precise payments in this scenario – especially if the programme involves several dozen sites like this. The most efficient way is to have a CTMS capable of storing all the contract payment rules and updated with the exact details of each patient visit as it is recorded. This might mean an EDC link, or simply very diligent monitoring of the centre.
Reducing Time to Market with CTMS
“It does not matter what innovation or technology is being discussed, it always promises faster time-to-market!” This was the exasperated cry of a clinical executive recently. Can a clinical trials management system really make any difference?
If the most effective, i.e. ‘best’, sites are chosen, as discussed, then it will result in studies starting more rapidly, studies completing sooner and submissions filing earlier. It is clear that the best available systems can help with this.
However, shouldn’t a company use a tailored system, one exquisitely shaped for their needs? Where is the competitive advantage if a “configurable off-the-shelf system” is used?
When this question is posed, I tend to respond that it is a company’s drugs that will make it competitive. The CTMS will help with a lot of things, but it cannot fill a development pipeline. Although it may seem ideal for a company to build a system that precisely matches their processes, as regulations and departmental priorities change, so must the system. It can often be the case that home-grown systems become a heavy IT burden to maintain and keep up-to-date.
As we discussed in the previous section, software per se must not be considered as a clinical research panacea. Yet the intelligent application of a CTMS will substantially increase the chances of a successful drug programme, particularly when linked with all the other tools we have at our disposal: safety systems, EDC, and RTSM. With this approach we really can know what is going on, know where we are going and know how to do better next time.
Product Director, CTMS