Towards the end of 2016, the US Food and Drug Administration (FDA) and the Japan Pharmaceuticals and Medical Devices Agency (PMDA), will require electronic submissions of certain nonclinical data using the CDISC SEND standard format. Other regulatory agencies, including the European Medical Agency (EMA), Korean Ministry of Food and Drug Safety, and China Food and Drug Administration, are also considering the use of CDISC standards. In this blog post, I’ll discuss how the move towards using CDISC standards will facilitate review of datasets in a standard format between sponsors and CROs and standardize submission of nonclinical data to the FDA and other regulatory agencies. I’ll also mention some solutions for streamlining data preparation for CDISC-ready submissions.
What is CDISC?
The Clinical Data Exchange Standards Consortium (CDISC) is a global, multidisciplinary, non-profit organization. CDISC established standards to support the acquisition, exchange, submission and archive of nonclinical and clinical data. Since its formation in 1997, the CDISC 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.” CDISC provides data standards for the entire clinical trial process, from source to analysis/reporting and culminating in regulatory submission. This includes standards for Trial Design and Protocol Information, CRF and Subject Data, Analysis Datasets and Regulatory Submissions.
What are the new data submission guidelines for non-clinical data and what type of submissions are required to follow these guidelines?
The FDA mandate for using the CDISC SEND format for non-clinical data, depends on when a study commenced, and the type of submission. The SEND format, which goes into effect for studies started on or after December 18, 2016, is required for data contained in New Drug Applications (NDA), abbreviated new drug applications (ANDA), and certain biologics license applications (BLA). Detailed information on study and submission guidelines for the FDA, EMA and PMDA can be reviewed at CDISC and regulatory agency websites.
What are the consequences for not following CDISC electronic data submission guidelines?
Submissions that do not comply with CDISC requirements could receive a Refuse to File (RTF) for NDAs and BLAs, or Refuse to Receive (RTR) for ANDAs from the FDA. Furthermore, retroactively standardizing data can be a very complex and daunting task. Although these requirements will not impact IND submittals until December 2017, the FDA Center for Drug Evaluation and Research (CDER) strongly encourages companies to consider the implementation and use of data standards for the submission of applications. Such implementation should occur as early as possible in the product development life cycle, so that data standards are accounted for in the design, conduct, and analysis of studies.
Why are data standards important?
As outlined by the Critical Path Institute (C-PATH), CDISC specifies how to “structure data that has been collected in a dataset, not what should be collected nor how to conduct clinical assessments or protocols.” When data content, structure and quality are standardized, it enables quality research. Standardizing the management of data sets within your organization, particularly those associated with large preclinical studies, can reduce the risk of data loss in the event of personnel changes, increase productivity through collaboration enabled by standard data structuring, and allow for easy exchange and review of nonclinical and clinical trial data between pharmaceutical sponsors and CROs.
What are the CDISC data standards and how are CDISC data organized?
The CDISC foundational data standards comprise a suite of standards that support clinical research processes from planning (Protocol Representation Model, Study Design) through data collection (CDASH, Lab) and data tabulation (SDTM, SEND) to statistical analysis (AdaM). CDISC data are organized into domains. For example, some of the relevant domains for PK analysis include demographic information (DM), exposure information (EX), pharmacokinetic concentration data (PC), Laboratory (LB) and pharmacokinetic parameters (PP). Data content is structured using Study Data Tabulation Mode (SDTM), the general model for representing study tabulation data used in clinical research, which is then transported via the Operational Data Model (ODM). This approach retains data reporting consistency across the review and submission cycle.
How do the new standardization guidelines govern SEND non-clinical data submission?
Standard Exchange of Nonclinical Data (SEND) is an implementation of the CDISC Standard Data Tabulation Model (SDTM) for non-clinical studies. SEND compliance for the FDA goes into effect December 18, 2016. At the time of implementation, SEND compliance will apply to general toxicology (single- and repeat-dose) and carcinogenic studies with the goal to expand to other service areas, eg, safety pharmacology and DART/EFT. SEND provides guidance for the organization, structure, and format of standard nonclinical tabulation datasets for interchange between organizations such as sponsors and CROs and for submission to the FDA.
What are the potential benefits of SEND?
Depending on its length, a preclinical study can amass extremely large amounts of data, which can be challenging to interpret or share. Many companies and service providers are proactively implementing SEND. Although SEND is still an emerging standard, regulatory agencies, industries and software developers stand to benefit from using it. For regulatory agencies, SEND will help standardize data review and analysis and will provide consistent terminology. By providing a common framework, SEND will enable sponsors and CROs to better transfer knowledge and ultimately facilitate submissions. SEND will also foster developing new statistical and analysis tools.
Introducing Phoenix Workflow Template and Plugin Services for CDISC compliance
In addition to complying with CDISC data standards, companies must ensure that their processes and documentation continue to meet Good Laboratory Practice (GLP). To accelerate SEND and SDTM data submissions using the CDISC guidelines, Certara’s Phoenix Technology Services Group can jump start your Company’s non-compartmental (NCA) analysis and CDISC SEND/SDTM compliance requirements. Phoenix WinNonlin has a built-in template feature to set up standard data preparation, analysis and output presentation. While any work done in Phoenix can be saved as a template, creating CDISC workflow templates that are reusable across different studies with varying numbers of treatments, analytes, matrices, doses, etc., requires expertise and significant development time.
Our pre-defined Phoenix Workflow Templates and Plugins will help you optimize R&D productivity and achieve regulatory compliance. The CDISC workflow template will complete data transformation, analysis, and data preparation tasks to streamline routine analysis, maximize quality control output, and package data for submission for sparse and serial TK data sets.
Phoenix has an extendable plug-in framework which can be used to integrate the platform with both upstream and downstream systems such as LIMS, Study Protocol, Compound Management, Dosing/Treatment, Randomization, and CDISC Submission. The CDISC Submission plugin enables export of CDISC-formatted data from Phoenix to a SEND submission system. The plugin also locks the data set so that it cannot be altered but allows the user to add free form comments.
Use Case 1: Bioanalytical data received in CDISC SEND or SDTM format
The diagram below illustrates how the CDISC Template workflow is used in Phoenix when bioanalytical data are received in the specified CDISC format from a CRO or internal biostatistics/data management group. In this use case, data are received in CDISC SDTM format as separate files, or CDISC domains. To complete pharmacokinetic analysis, CDISC domains containing Pharmacokinetic Concentration Data, Demographic and Exposure Information, Pharmacokinetic parameters, and other information need to be merged together. The CDISC Data Preparer tool in Phoenix Connect provides a user-friendly interface for merging CDISC domains into an analysis-ready dataset. When non-compartmental analysis is completed using Phoenix WinNonlin, Phoenix CDISC Templates can automate the creation of PP and PC domains. The CDISC Export tools in Phoenix Connect can export PP, PC and Related Records (RELREC) domains.
Use Case 2: Converting bioanalytical data to CDISC format
The diagram below illustrates how the Phoenix CDISC Template workflow is used in Phoenix when bioanalytical data are not received in the CDISC format. In this use case, Phoenix WinNonlin analysis is completed according to normal operating procedures. Phoenix CDISC Templates take the output from WinNonlin and automate the creation of PP and PC domains. The CDISC Export tools in Phoenix Connect export PP, PC and RELREC domains.
Streamline data preparation for CDISC-ready submission!
Understanding and complying with CDISC data standards is critical to satisfying regulatory data submission requirements. Moreover, having data in a standard format facilitates easier and faster collaboration on projects and accelerates the review and approval process by regulatory agencies. Certara’s CDISC workflow templates and plugin services streamline routine data preparation for CDISC-ready submission, providing sponsors and CROs more effective knowledge transfer between databases and robust regulatory submission protocol.
Learn more about Phoenix support for CDISC data standards
My colleague, Chris Lovejoy, produced a webinar where he discussed how NCA data needs to be prepared, transformed, and formatted to be SEND-ready and how Phoenix tools can save time, reduce errors, and increase compliance. I hope that you’ll watch the webinar and let me know what you think in the comments section!