Moving from EDC to a complete eclinical trial solution

To improve returns on research and development investments, pharmaceutical and biotechnology companies are continuing to develop new products, while at the same time are attempting to shorten product development timelines.

These efforts have placed more drugs into the clinical development process, but despite the rise in R&D spending, there has not been a corresponding growth in the number of innovative drugs generated through such investments which have been registered and introduced into the market.

One key bottleneck of turning biomedical innovations into actual product has been the design and execution of critical clinical trials to prove the safety and efficacy of various innovative biomedical products while balancing regulatory pressures with a constant drive to control costs and improve quality.
Sponsors of clinical trials have attempted to create process efficiencies, to control fixed costs and expand capacity by outsourcing clinical research activities and by increasingly adopting technology.

Among the different technological solutions to be used in clinical trials, the “internet approach” offers the advantages of the combination of the desired targets in R&D processes: a) higher quality b) shorter time c) lower costs.

Technology adoption in clinical trials is progressively advancing and it will continue to do so over the next several years.

Experience-based estimations of market penetration for electronic clinical trials (eClinical trials ) approximated 20% at the end of 2005 and many pharmaceutical and biotechnology companies state expectations of performing more than 75% of their clinical trials using electronic CRF (eCRF), within the next five years.

Through the use of internet in clinical trials, the companies have the opportunity to become more competitive, as many processes have been proven to be significantly improved through the use of technology compared to manual methods.

In addition, the use of technology in clinical trials can unquestionably improve the ability to be aware of real-time information on the adverse effects of investigational drugs and devices and therefore can have a significant impact on patient safety.

Therefore technology in clinical trials is both an economical and ethical improvement over traditionally slower and more costly means of information processing with manually-based paper methods.

In addition to the economic advantages from leveraging technology, most importantly, the immediate “ability to know” can have a positive and ethical impact on the patients' protection from adverse events of investigational drugs or devices, while participating in clinical trials.

As the technology market for clinical trials advances, customers are increasingly seeking for additional and expanded functionalities that would extend well beyond just EDC.

The collection of data from the investigational centre directly into the study eCRF represents a significant advantage in terms of time from data generation to data cleaning and ultimately to database lock.

However, the conduction of a clinical trial is a complex process which involves many activities to deal with data, documents, information and communications. Therefore to limit the use of technology to the on-line data collection (eCRF) will not exploit its real benefits that can also improve the quality and performance of other project processes and tasks.

In this respect the support of technological solutions to the expertise and professionalism of the trial staff will contribute significantly to the success and quality of the study. The regular, immediate and constant update of the study progress, study documents and reported SAEs is nearly impossible in a normal paper-based study, unless a huge amount of resources have been allocated.

Investigators, CRO and Sponsor’s staff are willing to operate in a comprehensive study environment where all the appropriate information are available, constantly updated, easily accessible, always printable and securely stored. However, in order to avoid the risk of over-flooding with excess information, the system may provide the study team with automated reports and statistics summarizing and highlighting the key study process variables which help in keeping on with timelines and quality of data. Therefore technology vendors should move from the offer of a limited EDC software to the new and more complete eClinical trial solution, defined as a clinical trial in which primarily electronic processes are used to collect (acquire), access, exchange and archive data and documents required for conduction, management, analysis and reporting of the trial.

There are intangible benefits of eClinical trial that are not easily transparent and often difficult to measure, which can be the most advantageous to the sponsor and CRO clinical study team .

A preliminary self-registration of each investigators into the study web-site allows the automated generation of the centre staff list, which reports the authorized tasks of each investigators, their users’ profiles, and their accounts activation/deactivation dates. In addition, if required, the registered investigators/centres may be asked to fill in a pre-study questionnaire or complete a feasibility phase form, whose data will be immediately available to the trial coordinators for a more accurate assessment and judgement on the centre suitability to the proposed study.

During the study conduction a dynamic site management guarantees that problems with data quality captured at investigative sites, whether due to ineffective site training, poorly designed case report forms or inattentive site personnel, can be identified and resolved quickly, eliminating many errors downstream .

In eClinical trial, automated queries provide instantaneous corrective feedbacks to sites avoiding the repetition of errors and introducing an upfront quality control process, immediately when data are entered into eCRF, contributing to a significant reduction, more than 80% as according to literature reports, of the number of queries generated during data cleaning, as compared to the paper based trials.

Clinical monitors have a continuous window into site data entry practices enabling them to intervene quickly before a small issue becomes a major problem .
One of the most overlooked benefits to an eClinical trial utilizing real time data capture and reporting is that the sponsor for the first time has the ability to measure the CRO and participating sites performance online, in real time.

With information management tools, every site contact report, document collected, monitoring visit report, patients’ enrollment, delay in eCRF forms compilation, queries solved and outstanding, and other study quality metrics are available 24/7 from virtually anywhere in the world through an Internet connection.

The centralized e-randomization procedure will prevent the incorrect enrolment of patients not fulfilling all the inclusion and exclusion criteria. Therefore less patients are needed to reach the calculated sample size required for the per-protocol analysis. Ultimately this will ensure reduced study timelines and costs. In addition, a perspective patient’s visits calendar can be automatically generated and timely reminders, as telephone sms, could be sent to both the investigator and/or patient, few days before the scheduled visit.

Assigning the randomization code and the appropriate “Trial Drug Kit”, the software may automatically update the “Drug Distribution Process” and activate, if the case, the order of new supplies to investigational sites. The study drug expiry date can also be tracked and automated alerts may be generated in due time, in order to notify the study team as well as the drug supply center, on the need to replace the supplies which are approaching their expiry date. Finally the study drug accountability will be facilitated and simplified, since part of the information has been already processed and recorded.

Real time tracking of patient enrollment can help control trial size.

The continuous evaluation of screening results will help to determine whether protocol modifications may be required, such as inclusion/exclusion criteria, allowing a better anticipation of the recruitment period completion.

Earlier access to better information allows to take an informed look at the next stages of the development program .

In an eClinical trial environment, monitors review data in house between site visits. This ongoing review facilitates interaction/communication with site personnel and leads to dynamic site management . Because ongoing data review is being performed, CRAs can visit sites less frequently saving on travel expenses as well .
When visits are scheduled, actual monitoring time is used more efficiently and customized per site. More time is available for source data verification, and the list of all checked eCRF fields will help data manager in the cleaning process and queries generation. Surprises at the eClinical sites are virtually eliminated, and reducing CRA travel improves staff retention and productivity.

Documents in a clinical trial, mainly if multicentre, represent a significant workload which requires dedicated staff to collect, copy, distribute and file them. By regulation the study files must be kept in fire-proof storage rooms or cabinets, whose access must be controlled and permitted only to the authorized team personnel. Paper file documents consultation is possible only by physical extraction and only at the office location. On the contrary the eTMF and eISF must be accessed by the authorized CRO study team as well as by the Sponsor, wherever they are. All digitalized documents are securely stored and their upload and download is protected by encrypted transmission. The paper format of each document is immediately available, at any desired time, by a simple click.

Moreover, documents management metrics (i.e. time to … or number of documents received and filed, documents still missing, etc) must be used as performance indicators for both CRAs and Investigators.

The SAEs transmission which is usually done by the investigator, via fax, can be made electronically and integrated into the eClinical trial system with the benefit of an automated filling in of the same data that can be derived from the eCRF, limiting the need of a new data entry and subsequent reconciliation of data between safety database and the study database. A new eSAEs Form submission can be immediately notified to multiple receivers and, if required, its data automatically uploaded into a safety database, E2B compliant, for additional processing and distribution.

With eClinical trial, a study team can share a common information set at a single web-based place, and the Sponsor, CRO and sites can base decisions on accessible, real time, accurate information.

However in order to realize the Internet’s full potential of efficiency and quality improvement, there is a need for:

• a more comprehensive appreciation of the complexity of clinical trial activities where only an integrated e-Clinical solution can manage all the study related processes
• a commitment to data quality and regulatory requirements
• universal attention to the development of standards (ICH/CDISC/HL7)

Eventually the CRO and Sponsor must understand the value and benefits of the adoption of technologies in clinical trials, and must be prepared to enforce effective new workflow in order to avoid the improper addition of technology costs onto paper instead of logically eliminating redundancy and increase efficiency.

Because the use of technology in this industry is relatively new, as compared to others, the specific functionalities of individual technology applications have advanced as single point solutions rather than an overall product suite, existing under a single application, architecture and corporate offering.

As the demand for multiple applications increases, the sponsors of clinical research will move from the challenges encountered with information collected and residing in several disparate applications to one that houses multiple applications under a single software architecture .

This would represent a simplified but comprehensive approach to the workflow process of clinical trials itself and would also yield contracting advantages to sponsors, by being able to deal with only one vendor for a variety of necessary software applications.

In conclusion, only a complete eClinical trial solution can contribute to the performance of successful trials, with quality data and shorter timelines, at reduced costs.