December 18th 2016 was a significant date for the pharmaceutical industry and regulatory submissions. For trials which commence after this date, the FDA will no longer accept non-CDISC data submissions for new drug applications ( NDAs) , certain investigational new drug applications, abbreviated new drug applications (ANDAs) and certain biologics license applications (BLAs).
The FDA guidance Providing Regulatory Submissions In Electronic Format — Standardized Study Data (1) also notes that the requirement will include ‘all subsequent submissions, including amendments, supplements, and reports’ to the submission types.
With regard to other regulatory agencies position on CDISC, the Japanese Pharmaceuticals and Medical Devices agency ( PMDA) will now request CDISC compliant submissions after October 2016 with a certain transitional period. This will be fully mandatory by 2018. While the European Medicines Agency (EMA) is adopting a top-down approach and therefore more focused on topics such as data transparency, issues of data integration and interoperability will also form part of the EMA’s future plans.
With this in mind, any sponsor planning an NDA, BLA or other regulatory submission needs to make sure they are observing best practice with regards to CDISC. In this blog, we outline some of the key issues to bear in mind as you prepare for your data submission.
While timeline or investment reasons may mean it’s not always possible to create CDISC compliant datasets at the time the study is originally reported, it’s nevertheless important to have a plan with regard to CDISC. Planning and implementing a program of CDISC conversion work is a complex matter which for multiple studies may require a robust team of statisticians and programmers and several months of work.
In a situation where studies need to be converted from legacy formats into SDTM a precise and intelligent approach is required- the conversion process is a significant transformation effort- not just a matter of renaming variables. A gap analysis which assesses the current state of the data can ensure your project is commenced on the right footing.
MedDRA ( Medical Dictionary for Regulatory Activities) is a clinically validated international medical terminology dictionary. In the regulatory submission the MedDRA version used should be consistent across the trials. This may mean upversioning legacy studies to the latest version of MedDRA as part of a CDISC conversion project. The dictionary name and version should be documented in define.xml.
Make the most of the reviewer meeting
Proper management of the Pre-NDA Meeting with the FDA is crucial for data submission success. The objective of this meeting is to obtain guidance on certain aspects of the Sponsor’s plans for NDA submission. During the meeting, the sponsor asks for agreement related to activities that must be undertaken prior to the final submission. It’s important that during this meeting, you use the opportunity to obtain confirmation from the agency regarding your proposed course of action with your data activities:
“Does the FDA concur with the Sponsor’s plan regarding the composition and format of the clinical data submission for the XXXXXXX eCTD NDA”
Provide Robust Documentation
It may be the case that not all aspects of the standards apply to your study or submission . To avoid reviewer comments that there is incomplete information, then it’s advisable to submit supporting documentation in the form of a “Reviewer’s Guide” to explain how the data standard was implemented.
This guide is not strictly required by regulation at this point, but it has become increasingly popular to use one. The purpose is to supplement information that is not included elsewhere in the submission and ensure clarity.
Your specialist biometrics CRO will have experience in producing reviewer’s guides to supplement data submissions.
Traceability is an important topic and the FDA cite lack of traceability as one of their top CDISC issues with submissions. For clinical information, traceability means understanding where your data are located, how information is derived and from which data. It’s very much a two way process. A regulatory reviewer wants to be able to trace a clear path from the Analysis results, to the ADaM, to the SDTM and back to the CRF. When planning upfront within the trial, we need to create a clear and traceable path forwards from the CRF through the SDTM and ADaM and on to the Analysis results.
Engaging a specialist biometrics CRO that aligns data management with biostatistics for your studies can be an important strategy for submission success.
Our expert team brings strong technical understanding of both Study Data Tabulation Model (SDTM) analysis Data Model (ADaM), corresponding implementation and Reviewers’ guides, CDISC terminologies and the related regulations.
With thanks to Angelo Tinazzi, Director Clinical Data Standards and Data Submission at Cytel
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1) Providing Regulatory Submissions In Electronic Format — Standardized Study Data