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International Clinical Trials

All the Pieces of the Puzzle

The role of the clinical research associate (CRA) has changed dramatically over the last 10 years. As sponsor companies realise the value of a good relationship with their sites, the site monitor has become a key link in the communication chain. Not only does the monitor have responsibilities for carrying out patient monitoring, but the success or failure of the study may lie with the expertise of the CRA’s involvement in day-to-day site management. Managing multiple sites across multiple trials means the CRA leads a hectic life, juggling many tasks and activities.

Ensuring that all of the sites across all of the relevant studies are progressing at the optimal rate from qualification and initiation through to closeout is a huge task. In order to make certain that patients are being treated ethically and effectively, while ensuring collection of the correct data, the CRA needs to be extremely organised.

A CRA’s time is mainly split into two components; the first and most widely acknowledged aspect is the time spent on on site visits. For each phase of the trial, the CRA is responsible for progressing the site through the study process by travelling to the site and carrying out site visits.

Conducting feasibility and qualification checks for verifying the site’s general research eligibility, as well as its ability to meet the particular study needs, requires vast amounts of time and effort on the part of the CRA before the study can even begin. Once all the essential documents have been collated and ethics committee approval has been obtained, the site can be initiated. During the site initiation phase, the CRA must discuss the protocol with the site and ensure all supplies are ready before enrolment can begin.

The study conduct phase requires the CRA to visit the site regularly, carrying out source data verification (SDV) and general data monitoring on the CRFs, or eCRFs, together with compliance activities such as drug accountability. Once all patients have completed the trial, the CRA is responsible for ensuring all data is clean, data clarification forms have been resolved, and closeout visits are ready to take place.

After every site visit, the CRA has to complete at least one report which details all the work that has been performed on site. This is a time-consuming task. After a long day travelling to and from the site, the CRA may spend an additional four to five hours compiling the reports, along with a follow-up letter for the site outlining any actions that must be undertaken.

Our recent research indicates that the work described above, which seems to warrant a full time job in its own right, is only approximately 30 to 40 per cent of the CRA’s typical workload. The remaining 60 to 70 per cent of a CRA’s time is spent on site management duties.

Site management is a very broad term, covering everything that a CRA needs to manage, track or monitor to ensure that the site runs smoothly. They are responsible for helping with the resolution of data queries and tracking any miscellaneous issues that may have surfaced during the trial; which may be as varied as the departure of the principal investigator, the flooding of the pharmacy, or the research nurse having to go on maternity leave – not to mention any protocol deviations. The CRA helps facilitate ethics submissions and monitors the approvals over time to make sure that they are resubmitted when approaching expiry. Another crucial task is verifying drug and other supplies have not expired and are in adequate quantities at the site. Finally, ensuring that the site is paid the proper amounts in a timely manner (with the payments going to the correct payees) is also included in a CRA’s to-do list. All of these are important and necessary ingredients for the successful running of the study. In general, site management is very reactive, whereby the CRA is responsible for ensuring that everything that the site needs to be successful is arranged for them. The list of tasks noted here is by no means exhaustive.



IMPROVING A CRA’S ROLE THROUGH TECHNOLOGY

Where does eClinical technology fit into these business processes? It is widely acknowledged that the use of electronic data capture (EDC) is rising dramatically. As patient data, along with visit dates and informed consent dates, are provided electronically by the site, it is an obvious benefit to the sponsor or CRO to feed that information directly into a clinical trial management system (CTMS) where it can be centrally stored, viewed and analysed for all trials. Although the monitor can perform data monitoring and SDV within EDC, all the data ultimately needs to be stored in a central repository – the CTMS. But which is the most important tool?

The answer is both. To cover the all-important site visits, a CTMS-based monitoring tool which holds patient monitoring data such as visit dates and SDV from the EDC system can prevent duplication of data entry for the CRA, while also allowing a cross-study and cross-site view of all relevant data. A monitoring tool can also provide the ability to automatically create the site visit reports and follow-up letter without the hours of manual effort that would otherwise be required. Of course, as the monitoring tool is based within the CTMS, all reports are stored centrally, accessible by the rest of the study team for review and approval, and easily transferrable to the electronic trial master file (eTMF). Furthermore, the system will be validated against 21 CFR Part 11.

So, what else does a CRA track and check when performing a site visit? There are many things, and keeping track of them all is not easy. Within the limited time available, having the ability to refer to a list of tasks ensures that nothing is missed, and that the visit is successful and productive rather than a wasted journey. Sponsor companies can drive adherence to their enterprise-wide SOPs by enforcing the standard list of tasks into the monitoring tool in the form of a visit-specific checklist. Not only can the checklist include prompts to check adverse events, which is one of the first things a CRA has to do when visiting a site, but it will also allow a monitor to view the data associated with those adverse events as recorded within the CTMS.

Having access to any site issues that have been raised during a previous site visit, or even between visits, is a must, so that those issues, including protocol deviations, can be followed up while the CRA is on site. All sites are responsible for keeping a site binder containing essential documentation up to date, and therefore a good monitoring tool should provide the CRA with a comprehensive list of documents against which to check. Having the information readily available is valuable for the CRA’s onsite activities including the important step of verifying that each patient has signed the correct informed consent form.

TAKING THE PAIN OUT OF SITE MONITORING

As CRAs do not always have internet access, a good monitoring tool should give them the ability to work online for accessing the CTMS database, as well as offline by keeping a copy of the relevant data on their laptop hard drive or through a flash drive, allowing synchronisation when internet access becomes available. With travel being such an integral part of the CRA’s life, having access to their data while on a train or plane makes it much easier for them to fulfil their responsibilities.

It is clear that using a CTMS-based monitoring tool is hugely beneficial for site monitoring. However, the CRA is also responsible for site management. When tracking a site’s progress, the CRA must have access to the key milestones and target dates associated with the study, including first patient in, first patient treated, last patient dates and database lock. The ability to see recruitment information, fed into the CTMS from the EDC and RTSM systems, is essential. By having a cross-site, cross-study view, CRAs and their line managers are able to compare and benchmark their own progress against others.

RESOLVING SITE QUERIES

What other CTMS data is useful for the CRA? As mentioned earlier, access to issues raised by or on behalf of the site is absolutely essential. How can the CRA resolve the site’s problems without oversight of what those problems are? This requirement stands whether the CRA is working on site, at home, on the road or in an office. By having visibility of those site issues, as well as other issues being raised by other sites, one can achieve true oversight, spot trends, and take corrective and/or preventative actions.

In the same vein, access to adverse event data across sites and studies is important for safety considerations – regardless of the CRA’s location. This is only possible via a true CTMS. It allows one to spot trends within a study drug as data can be viewed across all sites working with the drug, not just the sites on a particular study.

To help maintain that good working relationship with the site, the CRA is in regular contact by phone, email and fax. For a variety of reasons – some of which are contractual, especially in the case of CROs – these contacts must be tracked within the CTMS. Having a view of previous contacts helps the CRA understand discussions that have taken place with the site, and these contacts may form part of the company’s reporting needs.

As we have established, a CRA has to fit a lot of work into a tight timescale. Using technology to rapidly identify the sites that need their attention enables them to use their time more effectively. For example, they may want to know which sites are experiencing adverse events, or have outstanding issues so that their efforts can be appropriately targeted and prioritised. Consider a scenario where the principal investigator is chasing a payment: access to CTMS data is the only way that the CRA can determine whether that payment is due, and follow up on it. In summary, CTMS data will help answer the majority of questions coming from a site.

MANAGING CENTRALISED MONITORING

On a related topic, the terms ‘centralised monitoring’ and ‘remote monitoring’ are becoming more commonplace within the industry. A good clinical trial management system needs to enable management of this kind of monitoring through a site search facility. Such functionality provides the ability to record site contacts, and checklists (‘aides memoire’) to be linked to those contacts. Our research has found that centralised monitoring can mean a variety of things, with each visit or ‘contact’ taking one of a number of forms.

A CRA may wish to learn from sites which are performing well, and carry that knowledge over to poorer-performing sites. By using the site search to identify a list of each category, and recording the subsequent discussions in a contact report, the need for a site visit is removed. The information gathered in this way can also help re-forecast the enrolment curve.

The functionality associated with centralised monitoring can be used to help make informed decisions. For example, the site search facility can be used to identify trends such as: which studies are having the most protocol deviations; which sites are continually performing poorly; and which sites often do well? It is this type of key retrospective data that can be leveraged in later studies for site selection.

When deciding where to deploy monitoring resource, a site search facility can once again be useful. By finding sites where attention is required, such as outstanding adverse events, issues or DCFs, or high volumes of patient visits, a CRA can plan ahead for those sites. These may include making more visits or spending more time during a visit. Conversely, by locating sites where there are no new patients or patient visits, a CRA can avoid or postpone unnecessary site visits. Imagine travelling for four hours, just to get to a site where no new patients or patient visits have occurred, when there may be another site that is in a desperate need of a monitor visit.

MAKING EFFECTIVE DECISIONS

The effectiveness of decision making is enhanced by having a holistic, enterprise-wide view of sites and studies.

Where the needs of SDV and/or data monitoring are low, remote monitoring can be an effective way to save time and costs. Sponsors and CROs have the option of employing office-based CRAs who are trained to carry out ‘visits’ over the phone. They can gather data and carry out duties which are normally completed during a site visit, such as feasibility or qualification questionnaires, recruitment updates and issue resolution without having to leave the office. In some cases, this work can be carried out by call centre staff, using purpose-built, standardised checklists to help guide them through the process of gathering the relevant information. The data collected will still need to be recorded in the CTMS, but once again, that CTMS data can be used to generate ‘remote visit reports’.

This method can be used at specific phases of the study – like study start up – or may be appropriate for Phase 4 or investigator-initiated trials, where the extent of site interaction is low, and the need for patient by patient monitoring is reduced.

BENEFITS OF A CTMS

We can clearly see that the CRA can benefit significantly from CTMS access. Let us now consider the benefits for the sponsor or CRO who implement the CTMS. Having a CTMS can result in the following tangible benefits:
  • Consistent reporting techniques – all visit reports will be in the same format; all study progress data is stored in the single central repository; and reports can be accessed easily
  • Reduced cycle times for visit report review and approval, with all review comments being stored with the report itself
  • CRAs can intelligently plan to visit sites that need work – becoming more effective and efficient
  • Safety can be improved, as a CTMS can provide a central place for adverse event records across trials within the same study drug
  • Cross-study reporting of site data becomes much easier
CONCLUSION

CRAs carry out a wide range of tasks, and need access to a variety of data points at different times in the study, in order to carry out tasks effectively and efficiently. Any barriers to success must be recorded, tracked and made available to the rest of the study team, so that effective solutions can be developed in order to overcome or remove those barriers. Instead of giving the CRA one piece of the puzzle, and limiting what they can achieve, they should have access to all the data and functionality they need.

The CRA is the key player across the study life cycle of start up, conduct and close out. Why not give them everything they require?


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Liz Love is Product Manager, Clinical Trial Management Systems (CTMS), at Perceptive Informatics. In this role, Liz is a subject matter expert on CTMS. She helps define product strategy and ensures that the needs of both customers and the wider CTMS market are met when designing new features. Liz has been with Perceptive Informatics for more than nine years. Email: liz.love@perceptive.com
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