Contributed Commentary by Steven Benham, Formedix  

November 19, 2021 | The Clinical Data Interchange Standards Consortium (CDISC) was created in 1997 to improve medical research through data standardization. Before this date, there was no standardized way to submit clinical trial data and metadata, which increased the time regulatory authorities needed for reviewing data. Through a collaboration between CDISC and the US Food and Drug Administration (FDA), in 2000 the CDISC standards were created to improve data accessibility, interoperability and reusability, aiming to increase the efficiency of regulatory review and thereby reduce the time taken to bring potentially life-saving drugs to market.   

CDISC standards are now required for clinical trial submissions by the FDA and Japanese Pharmaceutical and Medical Devices Agency (PDMA), and are helping regulatory bodies across the globe understand and process clinical data more easily.  

Although CDISC standards are clearly helping to expedite the review of submissions, many organizations are completing this compliance step at the end of a clinical trial. The data rework involved in this process requires significant time and resources, particularly as metadata is often held in disparate systems and the evolving standards tend to be implemented manually.  

This article discusses how all-in-one, clinical metadata repositories (CMDRs) can be used to embed CDISC standards into the study’s design, build and submission. Organizations are now able to unlock the full potential of CDISC standards by controlling, organizing and reusing metadata assets to increase quality and consistency across studies. When submission-ready metadata is created from the start, rework is eliminated and new treatments can be brought to market faster. 

CDISC Data Standards: So Much More Than A Submission Requirement 

Although organizations now need to comply with CDISC data standards for submission to the FDA and PDMA, adoption throughout the trial process has been slow. This is partly due to the challenges of processing disparate metadata. The problem is exacerbated as standards evolve, requiring close monitoring of the regulatory landscape and often manual updates that can affect other metadata and trial data.   

CDISC standards were never intended as a final step before regulatory submission. The drive behind their development was to deliver faster and more cost-effective trials. But to do this, they must be embedded as a strategic tool throughout the end-to-end trial. When CDISC data standards are integrated within the design and build of studies, submission-ready data is collected from the outset. Rework is no longer required and metadata can be reused, delivering significant time and efficiency savings. 

 To provide the full range of benefits throughout the trial lifecycle, CDISC standards contain both regulatory requirements and integrative tools. The outputs of the data tabulation and data analysis stages need to meet regulatory standards, and refer to the standardization of the structure and format of submittable data, including:  

• Standard for Exchange of Nonclinical Data (SEND) – the content and structure of non-clinical data collected in a clinical trial, structured for submission. 
• Study Data Tabulation Model (SDTM) – the content and structure of the data collected in a clinical trial, structured for submission.
• Analysis Data Model (ADaM) – the content and structure of the analysis datasets generated from SDTM data, and the associated metadata. 
• Define XML – the metadata format used to describe the content and structure of the SEND, SDTM and ADaM datasets. 
• NCI Terminology – the consistent language used to make all terms in collected data clear.  

Meanwhile, the integrative elements of CDISC standards can be used by trial designers to define studies in common terms that reflect the end goal of creating submittable metadata. The models and standards used for the planning and data collection stages will determine the formats for the latter stages, and can be used to create the case report forms (CRFs) to collect standardized, submittable data.  

The Many Challenges Of CDISC Standards Compliance 

Compliance with CDISC standards can be a straightforward process. But without the necessary tools in place, significant issues can be encountered. Simply locating metadata can be difficult since many organizations operate in siloes with disparate folders, systems and formats that are not readily accessible to those that need them. And when metadata isn’t standardized, electronic data capture (EDC) systems and CRFs need to be recreated afresh each time. What’s more, pre-approved metadata can’t be easily reused, so delays are common. Moreover, inconsistencies and errors inevitably arise through manual data entry – all of which must be fixed at submission stages.  

In a dynamic drug development organization, metadata must evolve and shift with the changing regulatory landscape. When metadata is not centrally controlled, updates can be prone to error, and it can be difficult to see the history of changes and their approval. This leads to prolonged decision-making and an unstable change control process. Added to this, since CDISC standards are constantly evolving, experts are often required to monitor the regulatory landscape and filter these changes through systems, which is costly and time-consuming.   

Additionally, when data validation is carried out at the end of the study, quality issues can’t be detected as the data is gathered, which can lead to wasted time and resources. The lack of real-time, validated data also means that in-trial decision-making based on early indications is restricted. 

All-In-One CMDRs: Taking The Pressure Out Of CDISC Standards Compliance 

Next-generation, all-in-one CMDRs remove compliance challenges by providing a single-source-of-truth for all trial metadata, held in one central storage system. CDISC standards can be built into the CMDR so compliance can be managed throughout the design and build of a trial, right through to the creation of submission-ready data. Since CDISC standards are built into a trial from the outset and are standardized across every trial, pre-approved metadata can be re-used to increase trial data consistency and quality, and save time.  

A single source of pre-defined metadata allows owners to approve usage and determine change control procedures. CMDRs can contain pre-defined lifecycle states, determining how metadata is used and how and when it can be changed. Any change requests, including regulatory updates, can be managed and recorded through the CMDR. Plus, the impact of potential changes can be scrutinized before implementation, particularly when they may affect other metadata or trial designs.  

Some CMDRs also provide the ability to view and interrogate electronic CRFs (eCRFs) from validated metadata before EDC system creation. This gives an early view of how the CRF looks and offers the opportunity to change the outputs of the system before the lengthier process of EDC creation begins. What’s more, multiple EDC systems can be created directly from certain CMDRs. Not only does this give flexibility, but it also saves considerable time and reduces the transcription errors that comes from translating briefs between systems.  

By gathering data that already complies with the CDISC data standards, early indications can be more easily observed, such as adverse events or evidence that the drug is not working, for example. By stopping ineffective branches of a trial and rerouting drugs to cohorts with encouraging results, trial managers can save considerable time and money, and accelerate drug development. 

Embrace CDISC Standards Now For Long-term Benefits 

CDISC standards are a necessary and evolving part of regulatory submission, designed to increase process efficiency and eliminate the rework that can lead to submission delays and inaccuracies. But, to realize the benefits, organizations must embrace the standards as a strategic tool, embedding them into every element of a trial’s design and execution, and creating robust, internal organizational standards. 

CDISC-aware CMDRs provide the structure for this strategic approach to drive collaboration, visibility, streamlining and governance. Not only do they ensure compliance from the trial outset, but also create the environment to drive faster, more accurate and cost-effective clinical trials. 

Steven Benham has been with Formedix for over 4 years. Starting originally as a Solutions Consultant, he worked to author and present Formedix training courses for SEND, SDTM, Define-XML, ODM-XML, and Dataset-XML. He has also been involved in a number of clinical data programming projects helping to deliver in Interim Analysis (IA) SDTM and FDA SDTM clinical submissions. He is now the Professional Services Manager and currently oversees all Formedix clients. He can be reached at stevenbenham@formedix.com.