Abstract
Data collected from external sources can be essential to the quality of a clinical trial. This chapter reviews some of the types of external data that may be utilized within a clinical trial and discusses the best practices for handling such data. Processing steps for the validation, editing, and verification of external data are examined, and the importance of key variables is emphasized. Discussions are included concerning file and record formats, transmission of data, procedures for database updates, and archiving of external data.
Introduction
Often during the conduct of a clinical trial, much data external to the case report forms (CRFs) will be collected. If not included in the primary safety or efficacy parameters, these data can be used for subject screening, routine safety and quality-of-life monitoring, or trend analysis. To speed up this process and minimize the use of different analyzing methodologies and equipment, it is common for sponsors to refer to the use of centralized vendors. Such vendors provide electronic transfer of computerized data into the sponsor’s database, thereby offering quick results, standardized testing, and reference and calibration values applied to data collected across study sites with the potential to eliminate transcription errors and key entry of data. This chapter focuses on the structure and handling of external data most often required in clinical trials.
Scope
What follows is the data management perspective of the challenges involved in incorporating any external data into a clinical database while assuring that the quality, integrity, confidentiality, and plausibility of the clinical information is maintained. Further, processing steps that affect the data quality are identified, and a solution framework proposed.
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For information specific to the handling of laboratory data, see the chapter of Good Clinical Data Management Practices entitled “Laboratory Data Handling.”
Minimum Standards
Establish the procedures for collecting, transferring, loading, validating, and editing external data through sponsor and vendor collaboration.
Identify and involve vendors as early in the process as possible.
Identify key individuals for communication and follow through.
Provide written specifications for loading external data into the sponsor’s database. In advance of loading the data, identify and agree upon mandatory fields or critical variables.
Maintain a documentation trail.
Ensure that parties involved have written standard operating procedures and documentation to support that the SOPs have been followed.
Establish written procedures for safeguarding the blind when primary efficacy data are collected externally.
Apply quality control procedures to each stage of data handling to ensure that all data are reliable and have been processed correctly.
Best Practices
Audit external data providers on a regular basis as part of your vendor audit practice (see also the Vendor Selection and Management chapter).
Enforce a formal data clarification process for handling data discrepancies and data updates.
Validate all programs and systems used for processing clinical trial data in a clinical research environment (see also the Database Validation, Programming, and Standards chapter).
Provide vendor-specific training. A clear understanding of what is expected by both sides is critical for quality and efficient conduct of the clinical research.
Types of External Data
External data can originate from different sources, but it is a common practice for a centralized vendor to specialize and produce one or more major data types. Examples of data types include:
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Refer to CDISC for additional information.
External Data Processing Steps Affecting the Data Quality
The following areas may adversely affect the integration of external data and should be accounted for during database setup:
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When any of the efficacy parameters are collected in the external data, particular attention should be paid to safeguard the blind. For example, bone density indicators in an osteoporosis trial may be collected with a study’s lab data and could be blinded to the physicians and clinical personnel at the sponsor’s site. In case of full double-blind or full triple-blind trial, these data must only be disclosed to parties not directly involved in the trial or data safety monitoring committee. A written procedure must exist describing how this data will be handled and to whom it can be disclosed before the clinical database lock. In a similar scenario, subjects may be excluded from the efficacy analysis for loss of baseline data if any of the pre-treatment blind results are incidentally revealed to personnel directly involved in handling the subject.
Data Editing and Verification Procedures
For quality and timely processing of data, errors must be eliminated at the source or as close to the source as possible. To facilitate this goal, sponsors and vendors must work together to develop editing and verification procedures. These procedures should include:
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Definition and details of the process for resolution of discrepancies between external and CRF data should be established as part of the study setup. The process should address the issues of both sponsor and vendor or third-
party participant.
Record Formatting and File Formats
Quality and efficient integration of data demands up-front consensus between the sponsor and vendor with respect to record and file format. Areas for initial discussion include the size of data fields, clarification of numeric versus character fields, decimal granularity, use of characters such as “>” and “<”, quotation marks, commas, and other special characters. Special consideration should be paid to handling of null or missing data.
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Data management professionals should evaluate and leverage the experience of some of the existing and emerging vendor independent standards for data interchange between clinical systems, including HL7,5 ACDM’s Standards for Electronic Transfer of Laboratory Data,6 and CDISC.2
Data Transmission
Problems encountered with transmission of data from vendor to sponsor will result in data being lost or incorrectly loaded. To facilitate the transmission process in all cases, complete naming conventions and labeling information must be established. Any data transferred between the vendor and sponsor must contain sufficient information to be uniquely linked to the source of the data and corresponding project and protocol. Origin, date created, date sent, number of records, and a version-controlled file naming convention should be followed.
Public encryption mechanisms such as PGP® (Pretty Good Privacy®) are recommended for use when transferring data via the Internet. Thus, the data transfer process will ensure compliance with the regulatory guidelines and provide authenticity and confidentiality protection. Not all countries allow the use of strong encryption software. In such cases, consider the use of password-protected files such as ZIP archives or dial-up FTP transfer. Both processes will verify the integrity of the file being transferred and provide feedback in case of file corruption.
Procedures for Database Updates
The processes by which updates to subjects’ records are made are among the most vulnerable for generation of errors. Special consideration should be paid if the edit affects any of the primary key variables, and thus propagates multiple records (see also the Data Processing chapter).
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If applicable, vendors should provide the investigator site and sponsor with updated hard-copy information in addition to electronic updates.
File Storage and Archiving
Ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor. Thus, the sponsor should specify in the contract a definitive time period beyond the initial transmission of information during which the records will be maintained by the vendor for access by the sponsor and regulatory agencies. It is desirable that vendors maintain active copies of data files during the study stages that require unconstrained accessibility. After these stages, the vendor should maintain an archived version for the remainder of the retention period. When all reports have been finalized and the sponsor’s database has been locked, a study should no longer require access to the records except for auditing purposes during the record- retention period.
For additional information, see the Data Storage chapter, the Database Closure chapter, and the FDA’s Guidance for Industry: Computer Systems Used in Clinical Trials.3
Recommended Standard Operating Procedures
SOPs should be established for, but not limited to, the following:
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