As the FDA continues to stress modernization of clinical trials, it is important to be intimately familiar with the principle elements of using computerized systems during the course of clinical trials.
In a recent statement announcing the FDA’s partnership with Duke University aimed at modernizing clinical trials, Janet Woodcock M.D.—the FDA’s deputy commissioner, chief medical officer, and leader of the Critical Path Initiative—stressed the importance of technological advances in clinical trial processes. “To ensure the safety of clinical trial participants and to improve the health of the public, the clinical research enterprise needs to evolve,” Dr. Woodcock said. “It needs to be more streamlined and efficient, and at the same time it needs to be better equipped to answer the pressing questions that confront both patients and health care professionals” 1
Since most of the data currently collected in the majority of clinical trials is recorded on paper, the FDA is looking to extend the use of technology to improve data management and possibly standardize electronic systems across the United States. To keep pace with these advances and make significant strides on the path toward modernization it is crucial to have a fundamental understanding of the critical components involved in implementing computerized systems in clinical trials. The following provides some brief detail on five of those essential elements:
Managing a secure computer system is inherently difficult because the innumerable numbers of tasks involved in clinical trials are extraordinarily complex and many of the regulations associated with those tasks are open to varied interpretations. According to FDA Director of Scientific Investigations David A. Lepay, M.D., Ph.D., computerized systems used in clinical trials are also difficult to secure due to the unique circumstances of clinical trial environments, particularly:
- Sites are highly fragmented and geographically dispersed
- Sites are not standardized
- Sites may be small and have limited resources
- Sites may be performing multiple studies for multiple sponsors
- Systems in use may serve multiple purposes
- Users may have limited experience with computerized record keeping
- Change can be frequent, rapid and haphazard
- Participants may have limited experience in regulated research2
Many of the FDA’s security recommendations may appear to be no-brainers on paper, but actual implementation of such security measures is far more difficult and complicated than it initially appears. Consider the steps necessary to restrict data to authorized personnel or the processes involved in establishing, handling and storing standard operating procedures (SOPs), for example.
Regardless of complexity, there are several key security factors that must be addressed to stay in accordance with FDA guidelines, specifically:
- Systems must be dedicated to the purpose for which they have been intended and validated and must be logically and physically isolated as necessary.
- Data at clinical sites must be restricted and monitored through the appropriate system’s software, never external applications.
- Thorough, cumulative authorized personnel records must be maintained.
- Virus prevention and detection controls should be in effect.
Conducting a clinical trial requires not only that an entity must maintain compliance with FDA record retention requirements but also that investigators are able to immediately access study records at any time. Data and documentation can be generated from all manner of sources—laboratory devices, word processing systems, spreadsheets, e-mail messages, databases, Web applications, etc. Any electronic system implemented in a clinical trial must be able to assimilate all the information and documentation from these various sources in a central, secure repository that can be readily accessed by authorized users and investigators alike. Such a system must therefore feature robust indexing, reporting and search functionalities.
FDA defines an audit trail as “…a secure, computer generated, time-stamped electronic record that allows reconstruction of the course of events relating to the creation, modification, and deletion of an electronic record.”3 The purpose of audit trails, according to 21 CFR Part 11.10(e), is to protect the authenticity, integrity and confidentiality of electronic documents.4 Electronic document management tools can make it easier to conduct regular internal audits and accurately record audit trails, ensuring compliance with the FDA’s quality requirements. Automated systems also enhance auditing control measures and control revision errors.
Many of the larger pharmaceutical companies (Bayer, Schering-Plough Corp., Novartis—the list is endless) have employed electronic systems in clinical trials because the audit trail capability of such systems facilitates the management of documentation and data in such a manner that they actually add uniformity and credibility to clinical research. Such dividends ultimately result in reduced FDA scrutiny and possibly even limit the chances of a drug company being audited at all. Audit trails in paper-based systems, on the other hand, are more difficult to validate in terms of compliance with study protocols and can possibly raise questions regarding the reliability of clinical outcomes.
According the FDA’s Computer Systems Used in Clinical Trials guidance, clinical data must be “attributable.”5 Linking attribution via electronic signatures insures that all separate parties involved in a trial—be they a nurse, a monitor, an outsourced function or any other source—can be attributed to any set of data for which they are responsible or with which they have worked. The FDA’s precise definition of an electronic signature is: “…a computer data compilation of any symbol or series of symbols, executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual's handwritten signature.”6
Electronic signatures, like audit trails, help insure that the documentation that comprises a drug application is reliable prior to submission. Unique electronic signatures must be attributable to all employees and interrelated sources involved with a trial. To prevent accidental or intentional damage to clinical trial documents and files, electronic signatures must even be maintained for former employees.
The crucial key to implementing electronic systems in clinical trials is the cost-efficiency of the software validation processes and the time required to validate the system. If system validation requires an exorbitant amount of time and resources it will slow a drug’s time to market, potentially costing millions of dollars daily. If the time and resources wasted during the validation process are too immense, companies and sponsors may find themselves in a worse position than before the system was implemented. Such a scenario could even put smaller drug companies out of business.
If you are considering the implementation of commercial off-the-shelf (COTS) solution for use in a clinical trial, be certain the vendor has a proven track record of rapid, efficient and thorough validation. As stated in the Computerized Systems Used in Clinical Trials guidance, “For software purchased off-the-shelf, most of the validation should have been done by the company that wrote the software.” While basic functional testing must be performed by the company implementing a COTS system, the design level validation should have already been performed by the vendor.
Section VIIIB(2) of the Computerized Systems Used in Clinical Trials guidance outlines the type of documentation that is vital in demonstrating that a software system has been validated, specifically:
- Written design specification that describes what the software is intended to do and how it is intended to do it;
- A written test plan based on the design specification, including both structural and functional analysis; and,
- Test results and an evaluation of how these results demonstrate that the predetermined design specification has been met.7
The capability of a software solution to effectively respond to these key documentation issues should be taken into consideration prior to implementing the system.
Most of the proven software solutions on the market today provide a central repository where clinical data and documentation can be securely stored and easily accessed for audit purposes. Many COTS systems now available also feature electronically recorded and managed audit trails and signatures. Regardless of a vendor’s reputation or the assorted bells and whistles your company requires in a software solution, however, the most important element to take into consideration is the overall speed and cost-effectiveness of the validation process.
Many companies resist a complete overhaul of their clinical study operations because revamping a paper-based system is costly, time consuming, training intensive and a drain on resources. However, a common denominator of each of the five system elements discussed above is that they all involve processes that can be managed by off-the-shelf software solutions. Such solutions can ease the cost and resource pains typically associated with a conversion to an electronic system.
References1 FDA press release “FDA and Duke Launch Public-Private Partnership to Modernize Clinical Trials,” retrieved December 28, 2007 from http://www.fda.gov/oc/initiatives/criticalpath/partnership.html.2 “Computerized Systems Used in Clinical Trials,” presentation by David A. Lepay, MD, PhD, retrieved January 2, 2008 from http://www.fda.gov/Cder/present/dia698/diafda1/index.htm. 3 FDA Guidance for Industry, “Computerized Systems Used in Clinical Trials,” retrieved December 31, 2007 from http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm. 4 FDA Guidance for Industry, “Part 11, Electronic Records; Electronic Signatures – Scope and Application,” retrieved January 2, 2008 from http://www.fda.gov/Cder/guidance/5667fnl.htm#P212_18341. 5 FDA Guidance for Industry, “Computerized Systems Used in Clinical Trials,” retrieved December 31, 2007 from http://www.sans.org/reading_room/whitepapers/casestudies/708.php.6 Ibid.
Read more about using electronic systems in clinical trials::
?E-solutions in Clinical Trials: Digital Dilemma,? by Michael D. Christel, R&D Directions July/August 2007
?Designing Secure IT Environments for Pharmaceutical Clinical Trial Data Systems,? Sans Institute article by Paul Drapeau.