Database Lock & Data Archive
Closing or locking a study database is fundamental to preventing inadvertent or unauthorized changes once the final analysis and reporting of the data have begun. Although important in open-label studies, database closure is even more critical to preserve the integrity randomized trials after the blind has been broken. Therefore, any clinical trial must have a well defined process for closing its database and clear change-control procedures for re-opening the database, if necessary.
Database lock must be documented with proof that edit access was removed at a definitive point in time. To decrease the need to unlock the database after this point, a well defined and organized procedure must be followed to ensure that all data have been processed, that the quality level has been assessed, and that relevant study personnel have been notified or have approved the database lock. Items to consider in preparation for the database closure include whether the following steps and tasks have occurred:
- All data have been received and processed.
- All queries have been resolved.
- External data (e.g., electronic laboratory data) are complete and reconciled with the study database.
If a separate database exists for adverse event database, it is reconciled with the main study database.
- The coding list has been reviewed for completeness and consistency.
- Final review of logic and consistency check output has taken place.
- Final review for obvious anomalies has taken place.
- A quality audit of the data and the corresponding documentation of the error rate have both occurred.
- All documentation is updated and stored according to standard operation procedures.
Once these steps are complete, a documented approval process with sign-off by relevant study personnel (e.g., data management, biostatistics, monitoring representative, clinical/scientific representative) should take place. As soon as the necessary approvals have been obtained, edit access to the database should be removed, and the date of the removal should be documented.
Errors Found After Database Closure
If errors are found after database lock, the steps to handle and document these errors should be carefully considered. Foremost, the errors’ potential effect on the analysis of safety and efficacy should be evaluated. However, not all errors found must be corrected in the database itself. Errors may also be documented in the statistical or clinical report. Although some companies choose to change all errors found, others may only change those that have a major impact on the safety/efficacy analysis. What is of primary importance is that a company implements a predefined process to determine how such errors will be handled and documented.
If the database is unlocked after initial lock, the process for doing so must be carefully controlled and documented. Procedures should include notification of the project team, a clear definition of the change(s) being made, and the date of the change. Re-locking the database should follow the same process for notification/approval as the initial lock.
Clinical data archiving includes planning, implementing and maintaining a repository of documents and/or electronic records containing clinical information, supporting documentation, and any interpretations from a clinical trial.
The ICH GCP requirements stipulate that data collected in a clinical trial must be maintained for a period of two years, following either the last regulatory submission or a decision to discontinue development of a compound, biologic, or medical device. To meet this requirement, as well as to ensure that the sponsor is able to answer questions related to clinical trial data that may emerge many years after the trial is conducted, it is important to archive clinical data, as well as the accompanying trial processing documentation. Historically, the most common mechanism for long-term clinical data storage has been to extract the final data from the clinical data management system into SAS® datasets. The extracted SAS® datasets are still an important component of the clinical data archive; however, with the increasing importance of electronic regulatory submissions in recent years, requirements for clinical data archives are changing. As a result, clinical records that are part of an electronic submission must now comply with the 21 Code of Federal Regulations (CFR) Part 11 ruling, which was originally published in 1997. Part 11 defines specific requirements with respect to authentication and auditing of electronic records. In addition, the FDA Guidance for Industry: Computerized Systems Used in Clinical Investigations defines requirements for data archiving. This guidance was published in 1999 and updated in 2007. To fully meet the requirements of these regulations and guidelines, a comprehensive archiving strategy is needed.
Regulations and Guidance
The tenets of 21 CFR Part 11 include no specific requirements for data retention or data archiving capabilities. However, the FDA has made it clear that the intent of the guidance is to supplement the predicate rules and ICH GCP requirements for those cases where electronic records are either directly or indirectly part of an electronic submission. Guidance documents with specific mention of archive and record retention requirements include:
- Guidance for Industry: Computerized Systems Used in Clinical Investigations (CSUCI) published by the FDA in 1999 and updated in May 2007. This document describes requirements surrounding the need to preserve the systems environment in which electronic records are captured and managed.
- ICH Good Clinical Practice (Section 5 Sponsor requirements) provides information about record retention requirements. Regulatory guidance is being actively developed in the area of electronic records handling. Before finalizing your clinical data archive design, it is necessary to consult with the regulatory affairs specialists within your organization to ensure your design approach is consistent with the organization’s regulatory policies. (Please also see Guidance for Data Retention for Subjects that Withdraw)
To successfully reconstruct a clinical trial, an auditor must be able to view not only the clinical data, but also the manner in which the data are obtained and managed. The types of information that should be included in a clinical data archive is:
- Clinical data, external data, database metadata, coding dictionaries, lab ref ranges, audit trail, listings, discrepancy logs, queries, program code, CRF images, DMP, study validation documentation, clinical documents/memos
Designing a clinical data archive for long-term accessibility presents a challenge in the face of proprietary applications, tools, and platforms. This design should include input from all team members to ensure that the archive will meet department, corporate and regulatory requirements. A well-designed clinical study archive can facilitate compliance with the long-term data access requirements of the regulations for both paper based and electronic clinical trials. For this reason, the ideal clinical data archive should be based on standards and open systems. The open formats that are typically used for clinical study archives are described in Table 2. No single format is ideal in all circumstances. Due to the fact that a study archive will usually include many different types of information, it will most likely include multiple formats. The format chosen for each type of information should be based on the likely future use of the information. Long-term data access requirements suggest that the choice of data format is limited to ASCII based formats, or formats based on an open standard, such as SAS® Transport files. The choice may be further influenced by the format used in the original data management or data collection system.
Archives for Clinical Sites
The CFR predicate rules and the ICH GCP guidelines specify that a copy of clinical data must be retained at the investigator site throughout the records retention period. For paper based studies, this can be achieved by keeping a copy of the paper records at the site. For EDC studies it is important to have a strategy in place for ensuring that these guidelines are met appropriately. Many EDC vendors will provide PDF files for all of the eCRFs collected from the site during the trial. The Clinical Data Manager (CDM) may provide assistance and/or coordination with this procedure. If your company builds EDC studies in-house, the data manager will be responsible for ensuring the quality of the PDF outputs prior to sending the files back to the clinical sites. Also Trail Master file recommendations for essential documents in the (ICH) E6, Guideline for GCP and the European Commission Recommendations for Trial Master File.