There has been substantial growth in the volume of clinical research in recent years driven by the need for cures to life-threatening diseases and by the race to discover the next large, profitable drug and medical device. The increase in clinical research has dramatically upped the volume of clinical data and the size and complexity of clinical trials being conducted. This has compelled the FDA to perform increasing complex analyses and to ask more sophisticated questions of clinical investigators and sponsors in order to validate clinical trials data.

As a result, electronic records management systems (ERMS) are becoming more essential in this environment in order to handle the volume of data and related documents as well as to verify the quality and the integrity of the data for FDA auditors.

In addition, in the FDA regulated environment, compliance with the FDA’s 21 CFR Part 11 becomes a critical issue for organizations using electronic records management systems. This means having a 21 CFR Part 11 validated ERMS that contains full audit trials, version tracking and electronic signature capability.

Since 1963, when the investigational new drug (IND) regulations went into effect, the FDA has conducted clinical site inspections under the Bioresearch Monitoring Program (BIMO). The FDA now conducts several hundred inspections of clinical investigators annually to make sure they have complied and conformed with the established FDA regulations and to ensure that data from their clinical trials meet the highest quality standards.

Fundamental Elements of Data

According to FDA’s “Guidance for Industry - Computer Systems Used in Clinical Trials,” 1 clinical data needs to meet certain fundamental elements of quality whether recorded on paper or in electronic format. Data should be attributable, original, accurate, contemporaneous and legible.

In addition to collecting and recording clinical data, it is necessary to retain related documentation. FDA inspectors routinely compare data submitted to the agency with other related documents, such as the standard operating procedures (SOPs), medical charts and the source documents supporting the clinical data. Other related documents include drug accountability logs, pharmacy records, laboratory reports, etc.

Steven Mayo, PD, CCRA, states in his article “Surviving an FDA Inspection on Your Clinical Site,” 2 the FDA routinely focuses on the following issues during an inspection:

• Adequacy of communication with the Institutional Review Board (IRB), including the initial submission document, adverse event reporting and progress reports;

• Completeness of accountability documentation for the receipt, storage, administration and return of test article (drug, device, etc.);

• Compliance with the study protocol and documentation that each deviation/amendment received IRB and sponsor approval;

Appropriateness of the informed consent process (Was consent received from patient? Was the correct IRB-approved version used?);

• Prompt and complete reporting of adverse events to the IRB and sponsor;

• Compliance with the record retention requirements and that the investigator had immediate access to the study records during the trial; and

• Adequate monitoring of the site and communication with the sponsor.

Electronic record management systems facilitate the handling of data and documents in a way that can add credibility and consistency to the clinical research and thereby lessen FDA’s scrutiny or even the chances of an audit. When paper-based systems are used, there are more opportunities for data errors and inconsistencies to occur. In addition, paper-based systems cause more difficulty validating compliance with study protocols calling into question the efficacy of the clinical outcome.

ERMS-LIMS Integration

The challenge of managing records and documents in a fully-functioning laboratory environment in many cases is due to the fact that the concept of records management and an integrated document management application have not been part of any previous information technology planning or laboratory systems design. Furthermore, laboratory personnel may not have even considered the business and legal requirements necessary for effective document management.

Integrating electronic records management systems with automated laboratory information systems and clinical trial databases is a critical issue. Records and documents can come from laboratory devices as well as word processing, spreadsheet, database, e-mail and Web-based applications. An ERMS must integrate all of these functions into a cohesive work flow that prevents unauthorized access and logs all activity in an FDA compliant audit trail.

Section 21 CFR Part 11.10(e) requires persons who use ERMS to maintain audit trails to protect the authenticity, integrity and confidentiality of electronic documents. Electronic records management systems must provide for secure, computer-generated, time-stamped audit trails which record the date and time of operator entries and all actions that create, modify or delete electronic records.

These audit trails must be retained for a period no less than the time required for retaining electronic records (e.g., the study data and records to which they pertain) and must be available for review and copying. Users who create, modify or delete electronic records should not have the ability to modify the audit trails. Audit trails must be created incrementally, in chronological order and in a manner that does not allow new audit trail information to overwrite existing data in violation of section 21 CFR Part 11.10(e).

Additionally, rapid and reliable access to electronic records and documents is required. This requires a strong, yet flexible, indexing system and a quick and efficient search capability.

Another important ERMS feature—electronic signatures—can help a clinical investigator validate compliance with study protocols. Electronic signatures are defined within 21 CFR Part 11 as 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. See Table 1 for electronic signature requirements.

Record Management Needs of CROs

FDA-compliant medical software companies, like Green Mountain Logic (GML; Montpelier, Vt.), have focused some of their products on the records and data management needs of contract research organizations conducting Phase 1 clinical trials. John Rosenblum, GML’s president, sees a critical need for implementation of better data and records management systems in the clinical trials market. He believes that it is difficult to provide sufficient chain of custody tracking for pharmacokinetic (PK) samples with paper-based systems because they are inherently slow and error prone. Quality problems in this area have the potential to effect PK test results. Rosenblum states that processes where data is captured on paper and subsequently transferred into ERM systems have high potential for errors, especially when the data is entered by staff who do not fully understand the data’s relevance.

Errors that affect the validity of clinical trials can easily occur when the protocol and procedures are not well known or readily accessible. It is conceivable that a physician, who is treating a number of patients during different Phase 1 clinical trials, is not aware of the protocol for increasing or decreasing a dosage due to an adverse effect. The physician’s actions or lack thereof, if not in compliance with the study protocol, may have a serious effect on the data and the clinical trials results.

However, in a 21 CFR Part 11 validated ERMS, a participating Phase 1 clinical trial physician may have been prompted by the ERMS to read and sign the protocol or the SOP for that particular clinical trial. The physician’s actions would be logged as part of the audit trail and potentially flagged by the system with notification sent to the appropriate managers for review. The bottom line is that the data and related documentation captured and archived in an ERMS can help enforce process consistency and can provide the FDA with more confidence in the efficacy of the results.

According to Dr. Sandy Weinberg, an FDA compliance expert and consultant, most organizations under the scrutiny of the FDA’s BIMO are now in compliance with Good Manufacturing Practice (GMP) and Good Laboratory Practice (GLP). As a result, the FDA has shifted their focus to Good Clinical Practice (GCP).

GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analysis and reporting of clinical trials. The FDA is now asking more sophisticated questions of the clinical trials industry in order to meet GCP requirements.

This reinforces the need to have a 21 CFR Part 11 compliant electronic records management system. Dr. Weinberg states that FDA inspectors are now using a systems approach in their investigations and are looking at quality systems. As a result, a good ERMS allows the organization to respond to FDA’s questions about quality systems more quickly, effectively and thoroughly, thereby minimizing FDA inspector scrutiny. n

Notes:
1. Retrieved July 14, 2005 from http://www.fda.gov/ora/compliance_ref/bimo/ffinalcct.htm

2. Retrieved July 14, 2005 from http://www.sendemissary.com/compass.nsf/key/inspection.htm

Mark S. Ferrero, M.S., is president of P-Wave, Inc., a document management software company based in Reading, Pa. Reach Ferrero at 610-372-7890 ext. 22 or markf@p-wave.com.