Applied Clinical Trials
Clinical research is complicated, and it?s not just the science. Take CDASH, CDISC and E2B for example. Aren?t acronyms awesome?
Clinical research is complicated, and it’s not just the science. Take CDASH, CDISC and E2B for example. Aren’t acronyms awesome?
Different data standards—and the various acronyms associated with them—can certainly contribute to the complexity of the clinical research process, even though they ultimately simplify the conduct of a trial. Often, data collected at site is not aligned with common data standards, including those established by the Clinical Data Interchange Standards Consortium (CDISC) or those established for the transmittal of electronic drug safety data by the International Conference of Harmonization (ICH). Further complicating matters, CDISC’s Clinical Data Acquisition Standards Harmonization (CDASH) and ICH’s E2B standards are not entirely consistent with one another. This makes it very challenging to standardize data between CDASH-compliant electronic data capture (EDC) systems and safety systems using the E2B format. After all, the data captured must be reconciled before it gets sent to safety systems to be processed and then reported to regulatory authorities.
Recognizing the need to improve data quality and align clinical and safety databases, CDISC is expanding its CDASH model to capture adverse event (AE) data associated with E2B standards. Within the next few months the E2B subcommittee of the CDASH committee within CDISC will issue an addendum with recommended updates to CDASH that will facilitate the ability to capture E2B data.
While offering background on these data standards, this article outlines the major changes to CDASH currently in progress and describes how the CDISC organization aims to improve data standardization.
CDISC and CDASH in a Nutshell
To get a better sense of the upcoming changes and prepare for them, it’s important to understand the objectives of CDISC overall and the CDASH standard specifically.
Formed in 1997, CDISC is a non-profit organization focused on developing and furthering the usage of standards in clinical research. Its mission is "to develop and support global, platform-independent data standards that enable information system interoperability to improve medical research and related areas of health care."1 CDISC’s standards support medical research of any type from protocol through analysis to the reporting of results. When implemented at the beginning of the research process, CDISC standards have been shown to decrease study resources needed by 60 percent overall and 70-90 percent during the start-up stages.2
A key component of CDISC’s standards for the study start-up and conduct stages of a clinical trial, CDASH was developed to standardize the underlying structure of a trial’s data and to sort that data into 16 categories called “domains,” ranging from AEs to demographics. Introduced in late 2008, the primary goal of CDASH was to find out which data fields are essential to the analysis of clinical data and collect only that data in a standard manner. CDASH provides the industry with clear definitions, Study Data Tabulation Model (SDTM) mapping (if relevant), case report form (CRF) completion instructions and additional information for each data element.
The focus of CDASH, however, is on data collection, not data reporting. As a result, in some instances, this optimal data collection method conflicts with SDTM for reporting data. In these cases, additional transformations and derivations may be needed to create the final SDTM compliant datasets. One way to think about it is that the SDTM standard is for presenting study data, while the CDASH standard is for collecting this same data using CDISC compliant specifications.
Implementing a standard data collection methodology has many benefits. The main one comes from standardizing the definitions for the data that is collected across multiple studies. CDASH defines standards to facilitate the cleaning of data and the identification of missing data. Additionally, CDASH provides value by reducing the production time associated with the design of electronic case report forms (eCRFs) and the training time for sites, leading many clinical organizations to leverage CDASH in order to facilitate eCRF reuse across multiple trials or programs.
The Benefits of E2B
Traditionally, sites conducting clinical trials collect clinical data multiple times. It is very common for clinical data to be captured in an EDC system. Data is also gathered on paper, using handwritten notes that are faxed or emailed to safety organizations and later triaged and manually entered into safety systems. The data is then evaluated and reported to regulatory authorities.
In 1997, ICH issued E2B standards to ensure that standardized data elements are included in the transmission of Individual Case Safety Reports (ICSRs) for pre and post-authorization periods, as well as for adverse drug reaction and AE reports. Last updated in 2001, these standards have been adopted by regulatory groups in the EU, US and Japan, as well as pharmaceutical industry organizations. Adopting E2B standards has allowed these groups and organizations to more easily share ICSR data with one another.
As technology has improved, so have the methods sites use to collect and deliver data to safety systems, enhancing the ability to share data in a consistent and efficient fashion. Many sponsor organizations have adopted processes that allow safety systems to automatically import electronic files in an E2B format and, thus, transmit data more quickly. The data reported using these processes is more complete and accurate because it leverages the edit checks and data validations built into an EDC system’s eCRF. Also, as a result of these process and quality improvements, safety groups direct fewer queries regarding missing or unclear data to study sites. Most important, applying E2B standards helps to significantly reduce (and in some cases eliminate) the number of discrepancies between clinical and safety databases.
Reconciling CDASH and E2B Standards
Most organizations have adopted CDASH standards to capture data within EDC systems. These organizations are also electronically submitting that data to safety systems using E2B standards. It is, therefore, very important that EDC systems gather data in accordance with both CDASH and E2B standards.
To streamline the data collection process, CDISC formed the CDASH-E2B team in 2010. The team’s primary goals are to reduce repetitive data collection processes, teach study sites how to effectively collect serious adverse event (SAE) data and, ultimately, provide safety groups with needed—and standardized—metadata that meets regulatory reporting requirements.
Prepared by the CDASH-E2B project team, the Serious Adverse Event Addendum to the CDASH update expands the current AE domain to now include the capture of data elements in an SAE form. The purpose of including the form is to facilitate the collection of comprehensive information that is relevant to the understanding of the SAE, providing an interpretable assessment for causality. Collecting data in this way also reduces the need to continually re-enter data in incomplete E2B fields.
The chart below provides an overview of the domains listed in the addendum and describes each element needed for the ICSR. Every E2B data field is matched to an SDTM or CDASH value. This creates an opportunity to not only build an eCRF with the appropriate CDASH values needed for safety systems, but also helps identify how that data is mapped to the appropriate E2B field.
For example, as indicated in the chart, a question typically asked in an eCRF is “What is the sex of the subject?” The question corresponds to the CDASH value of “SEX,” which matches the same E2B value “B.1.5” of “<patientsex>.” The above domains also show that there is a “Controlled Terminology” value, as well as basic “Completion Instructions” and standard “Implementation Instructions” to be considered by the study sites when filling out an eCRF. The abbreviation “HR” indicates that entering data in the noted field is “Highly Recommended.” Other potential values include “Recommended/Conditional” (R/C) and “Optional” (O). Generally, sponsors will determine which data fields will be included based on therapeutic area-specific data requirements, in addition to protocol and logical legal and regulatory considerations.
As demonstrated in the chart, the addendum reconciles the data sites would collect in EDC systems with the values sponsors gather in safety systems. While the addendum does not completely address all E2B fields or types of data the sponsors might want to capture, the CDASH-E2B project team’s efforts represent a strong leap forward in providing guidance on the collection of safety data.
Clearly, there is still a lot of work ahead of us. But as the new ICH E2B R3 regulations are made mandatory and the industry works to improve ICSR data collection processes, this addendum to CDASH for SAEs sets us up very nicely to accommodate new standards. In the meantime, adopting both of these important standards will prove to be worthwhile for clinical organizations of all shapes and sizes.
Written by Sean Neal. Neal is Client Services Principal at Medidata Solutions. Neal can be reached at [email protected]
2 CDISC business case, Gartner Research, http://www.cdisc.org/stuff/contentmgr/files/0/ff2953ea8dbc8e81080f0e44ba6714c7/misc/businesscasesummarywebmar09.pdf