Clinical Data Archiving

Abstract

In order to meet the requirements of industry guidelines and regulations, clinical data managers must ensure that data captured during a clinical trial are retained correctly. This chapter provides an overview of the regulations that must be followed and discusses approaches to satisfying the requirements. Consideration is given to proper handling of electronic data that are collected in a clinical trial. The components that constitute a clinical data archive are reviewed, and technical requirements for the correct use of open electronic data formats, such as XML (Extensible Markup Language) and SAS®, are discussed with an emphasis on ensuring long-term accessibility.

Introduction

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.

Scope

This section provides an outline to help clinical data managers develop an archiving strategy, working in conjunction with the project team and/or other appropriate department(s). Included are details of the regulatory requirements surrounding clinical data archives, a description of the components of an archive and information about data formats that can be used to support an archive. This document focuses on the components of the study archive that are the responsibility of data management.

Minimum Standards

• The clinical data archive should include a centralized table of contents.

• Accessibility of the clinical data archive electronic records should be tested following every major upgrade of the active clinical data management system.

• For paper case report form (CRF) studies, the original signed, dated, and completed CRF and original documentation of CRF corrections should be kept in the sponsor’s files or offsite archive facility.

• The clinical data archive should be retrievable within a reasonable timeframe.

• For each study, the documentation should identify the hardware and software used, as well as specific version of the software or hardware.

Best Practices

• All clinical data, metadata, administrative data, and reference data should be maintained in an industry standard, open system format, such as CDISC’s Operational Data Model (ODM).

• An electronic repository should link all study components, including the clinical data, CRF images in Portable Document Format (PDF) format, program files, validation records, and regulatory documentation.

• The audit trail should be stored in open format files in a secure system location.

• Copies of all user and system documentation for any applications used to collect or manage clinical data should be retained in the corporate library or archive facility.

• Reports describing the metadata and validation of study metadata, including data structures, edit check descriptions, and electronic data- loading specifications should be stored in the clinical data archive.

• System security reports, including user listings, access rights and the dates of authorization, should be printed and filed or scanned.

• The archive should include all program code for edit checks, functions, and sub-procedures, together with a copy of the version control information and validation documentation.

• Paper CRFs should be scanned and indexed. If an electronic data capture (EDC) system is used, all entry screens should be archived in an easily accessible format, such as a PDF file.

• Address archive responsibility for external data management providers. The sponsor should ensure that any signed contract with a vendor includes a section on archiving.

Background

The International Conference on Harmonisation Good Clinical Practice1 (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 Regulations2 (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 Food and Drug Administration’s (FDA) Guidance for Industry: Computerized Systems Used in Clinical Investigations3, 4 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 Investigations3, 4 (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 Practice1 (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.

Archive Contents

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. A summary of the types of information that should be included in a clinical data archive is provided in Table 1.

Table 1

*For data managed externally and then loaded into an in-house system for reconciliation, reviews, or other purposes, it is generally sufficient to limit the archive to actual data and any information pertaining to how the data are managed internally. When using an external vendor, the vendor is responsible for archiving any records that reflect how the data are managed in the vendor’s system. The trial sponsor is ultimately responsible for ensuring that any vendor who provides trial data works in accordance with regulatory requirements. Therefore, the sponsor should ensure that any signed contract with a vendor includes a section on archiving. The information in this section should comply with both sponsor and regulatory requirements.

Technical Requirements

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.

Table 2

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 Good Clinical Practice (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 electronic Case Report Forms (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.

Recommended Standard Operating Procedures

• Study Archiving Procedures
  
• Document Archiving Procedures