Turning clinical trials on their head

pharmafile | August 4, 2004 | Feature | |   

Increased pressure to get more products to market faster, with a close eye on the total cost of development and increased regulatory demands, are pushing pharma companies to speed up their clinical trial processes.  

The paper-based systems currently used by the majority of pharma companies, although well tried and tested, generate huge amounts of paper, involve inefficient processes and potentially cause major delays from the time of data capture to data review and analysis. In addition, a real time overview of the trial is not available to the sponsor, the study co-ordinators at the sites involved and the contract research organisation (CRO). Information that is stored locally at each site has to be retrieved and centralised, which of course takes time.

Early attempts to automate clinical trials' activities, using methods such as fax and traditional remote data entry (RDE), did not prove very successful. Use of a fax combined the electronic transmission of data with the paper-based system. Although the process of data collection was improved, data entry was either manual or optical character recognition, which was often inaccurate.  

The two main disadvantages of RDE were: the need for a computer, database and software to be located at the site, specific to any one clinical trial;  and data was susceptible to being lost or damaged until uploaded, which in itself was a not a robust process (Bleicher P, Contract Pharma, June 2004).

Web-based systems are now being used as a convenient and cost-effective tool to increase efficiency and thereby lower costs in areas such as patient recruitment and enrolment; data entry; query management; communication; project management and regulatory review (Mitchel J, You A, Lau A, et al; Paper Versus Web; A Tale of Three Trials, Applied Clinical Trials, p34-35; August 2003).

Web-based systems are designed to work with local web browsers so that no local data or additional software is required. Such systems can be used to assist in any individual clinical activity, such as electronic data capture (EDC) or interactive voice recognition system (IVRS) for randomisation; or for running a fully integrated e-clinical trial.

In this case, the activities of the various functional areas are harmonised and integrated into one overall process to enable efficient and accurate data collection, processing and reporting and project management. An additional advantage is the access to real time information over the entire clinical trial process.

Web-based systems have an impact on all areas of a clinical trial, some of which are discussed below.

Patient recruitment and enrolment

With internet access now widely available, large numbers of patients have easy access to information about specific diseases, treatments, products in development and searchable databases of clinical trials. Using the internet for patient recruitment could increase patient catchments, which may be particularly advantageous in the more researched therapeutic areas.

As with all forms of patient recruitment, advertisements used on the internet would be subject to the relevant ethical approval.

Patient eligibility can be determined on the web, in real time and without discrepancy. In paper-based systems, inclusion and exclusion criteria are sometimes not checked until after the patient has been enrolled into the study. A web-based system also provides an overview of enrolment numbers and can track site performance.

Data entry and query management

When a paper case report form (CRF) is completed by hand, administrative errors can be made, such as questions left blank or input of incorrect figures. Many such errors are detected by the clinical research associate (CRA) prior to data entry. Following the usual practise of double-entry of the data into two parallel databases, the data is compared, usually using a SAS-generated programme and any inconsistencies, omitted data or obvious errors are reported to the CRA, although incorrect interpretation of handwriting can still occur.

The data query must then be clarified by the study site before the database is 'locked' and the final data listings are produced. This process can be very time-consuming and hence costly. The use of e-CRFs allows data to be checked in real time to prevent some administrative errors: for example, systolic blood pressure must be a larger number than diastolic blood pressure.

If a higher diastolic value is input, then the system can detect the error and prompt an immediate correction. Also, the use of drop down boxes decreases the amount of typing required and lessens the chance of errors; systems to prevent submission of incomplete forms are also available.  

In a web-based system, manual data entry may not be required as the data can be electronically submitted to the database. The system can automatically check for inconsistent, illogical or missing data and send verification requests to the study sites directly. Hence the time-consuming process of phone calls, site visits, etc, by the CRA is eliminated, whilst producing a permanent electronic record of the query management.

Communication

Communication within and between the numerous teams involved in any clinical trial from study site staff, project managers, CRAs, data mangers to medical writers is vital to the success and efficiency of a trial. Web-based systems allow the members involved in the trial to have an up-to-date overview of all aspects of the study at any time.

For example, access to the latest version of documents, progress of the ethical submission, patient enrolment or data entry, study medication supply or any ongoing safety summaries. This is a real bonus and again saves time-consuming phone calls and visits and allows for a very effective and efficient working relationship between sponsor, investigator and CRO.

In addition to the communication of essential study status information and safety reporting online, communication covers the everyday use of e-mail and can be used for video conferencing for those staff involved in the clinical trial that cannot travel to attend meetings and training.

Online communication with patients involved in a clinical trial can be used – for example e-mailing reminders for study dates to ensure the patient does not miss appointments. One potential disadvantage of this system is that not all patients have internet access and for those that do, their e-mail address may change – therefore conventional communication methods may still be needed.

Data analysis

Project managers working on the more complicated types of clinical trials often commission the use of designated Core Laboratories, which have the necessary expertise to give accurate measurements of particular data types such as radiographic, electrocardiographic and echocardiographic data.

The application of web-based systems in this setting would allow the fast, secure, high fidelity transmission of such data in digital format to the Core Laboratories, where the original images could be reconstructed and stored. Data storage would be more robust than the ultimately degradable forms of paper and celluloid recording media, allowing the data to be revisited at any future time without disadvantage. Digital data transmission to the Core Laboratory would also enable the various primary clinical indices to be measured in a reproducible and accurate form.

Project management

Monitoring: Site monitoring is a major component and one of the most time-consuming areas in a clinical trial. The CRA and/or study monitor is required to perform source data verification, check and verify the data collected in the study and manage the data query process.

In a paper-based system this is all done on site and the CRA is often seeing data for the first time on the visits, which allows very little preparation to be done in advance. Queries raised often cannot be resolved during the visit due to time restriction and availability of the study co-ordinator. Indeed, it is not uncommon that some return visits are 'wasted' as CRAs discover that queries have not been resolved, causing further time delays in an already drawn out process.

Using real time monitoring in a web-based system allows issues to be resolved quickly, before they become major problems. In addition, many queries would already have been resolved prior to monitoring as web-based systems automatically check and request clarification on inconsistent, illogical or missing data. Thus, in internet-enabled clinical trials, monitoring is one of the areas in which the largest cost benefits and time savings can occur.  

Adverse event reporting: The web is a very useful tool for adverse event reporting, especially in the case of serious adverse events (SAEs), which must be reported to the sponsor, the review board and ethics committees within a pre-defined timescale.

Once the SAE has been entered into the database, an e-mail is automatically sent to any designated address. Normally, communication of the SAE is done by telephone or fax, so there is not a major time saving, however any increase in efficiency in SAE reporting is an advantage as it leads to improved subject safety.

Study treatment allocation and control: Following online enrolment into the study, patients can be randomised automatically and immediately. This avoids the need to request and open an envelope in the paper-based system or even the need to make a phone call to obtain the information from an IVRS more efficient than the paper-based system. If the procedure is completely automated, however, no site monitoring is required, resulting in reduced administrative work and chance of error.

The study treatment can be automatically requested from the pharmacy and an online inventory allows both the site and the pharmacy real time tracking of the treatments.

Document version control: In any clinical trial, it is essential that the study sites use the most recent version of all documents, from protocols, informed consent, patient information and CRFs.

In a paper-based system, the CRA has to spend time ensuring that all documents in use are the correct version. Use of a web-based system, however, allows automatic version control tracking so that only the latest version is available on the secure study site and therefore immediately available to all relevant parties.

There is of course an obvious training related issue, to ensure staff obtain the latest versions via the correct procedure rather than, for example, photocopying a hard-copy of a previous version.

Training: Investigators and study site staff can be trained to become more efficient at using web-based systems.  Without the need to travel to a central location, training can be done at any time, either at the study site or at home.

Online training can record that the training has been performed in a satisfactory manner; additional training is easier to organise and this may include video clips of non-standard procedures. New members of staff may be trained at their convenience without the need for additional CRA visits.

Regulatory review

Part of the pressure to go electronic, stems from government regulations affecting pharma IT systems, such as 21 CFR Part 11 and the Health Insurance, Portability and Accountability Act (HIPAA).

Part 11 regulates electronic records, while HIPAA addresses security standards for patient data. It does not force companies to use EDC, but e-trial service providers are making part 11 and security, selling points (for more information see the Bio-It World article e-Clinical trials catching on at: www.bioitworld.com/news/052302_report353.html).

Guidance documents that outline what the specific country regulations are for electronic CRF submission are available from regulatory authorities in most countries. Electronic signatures are often required and may be a real electronic signature, or simply a secure username and password, or remote access server (RAS) style electronic devices, creating single use passwords. A highly visible electronic log of all changes and amendments (and by who) to the electronic records after it has been entered into the database are essential requirements for these systems.

There are a number of potential issues which could apply to the application of any new system in a company. First is the willingness of staff to change to a new way of working and communicating, which may be particularly difficult when staff have been used to a paper-based system. Web-based systems have the advantage of not requiring any software or hardware installations, but training is still required; an issue that is fairly easily overcome.

Internet access at study sites may not be very good and this would have to be provided; again this issue can be overcome but does have a price tag associated with it.

A potential problem that springs to mind is that of security. Data needs protection against theft and loss or inaccuracies through corruption. To avoid theft of the data, a web-based clinical trial server can be isolated from other servers and be protected by a constantly monitored firewall. The server should be located in a physically secure location and no data stored locally at the study sites. A validated, robust clinical trial application with frequent backup should ensure that data do not become corrupt.

Using web-based technology

A practical example of the use of web-based technology in clinical trials is the International Verapamil SR/trandolapril study (International Verapamil SR/trandolapril study (INVEST), Clin. Cardiol. Vol. 24 (SupplV) V-17-V-23; 2001).

This study demonstrated that using web-based technology improved the efficiency, accuracy and safety in conducting clinical trials. Site training, study documentation, subject recruitment, randomisation, medication dispensing and management procedures were areas that were  simplified by using web-based systems, and that sites were able to focus primarily on medicine and science rather than trial administration.

Despite the number of advantages, the uptake of web-based clinical trials is relatively slow. One of the major issues is resistance to change from a well-understood paper-based system, by the sponsor; some people may find this difficult when their whole experience has been with paper-based systems. Study-site specific issues may also arise, such as old PCs, internet browsers and network systems, browser incompatibilities and controlled internet access – these issues are, however, easier to overcome.

The use of a web-based system is an effective way to increase efficiency and decrease error, time and cost in the clinical trial process. By increasing data quality as well as reducing the time to database lock, companies can expedite the time-to-market with reduced costs.

It may still be some time before companies are running fully integrated e-clinical trials, but there is no doubt that the majority will use web-based systems in at least some trial areas- for example, EDC or IVRS – in an attempt to reduce the cost and time to develop products.