LABORATORY INFORMATICS g
by China’s National Medical Products Administration (NMPA), in its Clinical Trial Data Management Technology Guide (July 2016). They are now requested by the European Innovative Medicines Initiative (IMI).
In its industry guidance on electronic submissions (Providing Regulatory Submissions in Electronic Format – Standardised Study Data – Guidance for Industry), released in 2014, the FDA outlined its requirements for statutory electronic submissions, including the use of defined CDISC standards for study data and controlled terminology. ‘CDISC has generated a suite of standards categories, underpinned by a set of core foundational standards,’ Trimm noted. ‘These support clinical and non-clinical research processes from end to end, and take data formats back to first principles, focusing on defining data standards, and including models, domains and specifications for data representation,’ stated Trimm ‘In parallel with the foundational standards are CDISC data exchange standards that enable the sharing of structured data across different information platforms and computer systems. Therapeutic area (TA) standards then
offer extensions to the foundational standards, and further refine and lay out standards for defining how data relating to specified disease areas is structured and communicated,’ Trimm continued. Most recently, Certara announced the
availability of PK Submit, a technology solution for automating the creation of pharmacokinetic (PK) CDISC domains during Non-Compartmental Analysis (NCA).
The generation of domains associated with PK analysis represents a unique challenge for electronic drug submissions, Trimm noted. ‘There are challenges associated with documenting record exclusions and comments in these domains, as well as generating the Relrec and Pooldef domains that explain how they were generated. Allowing the pharmacokinetic concentrations (PC) and pharmacokinetic parameters (PP) domains to be generated contemporaneously by a PK scientist, at the time of performing an NCA from a single source, is the best way to solve these problems. ‘PK Submit is integrated with software
associated with generating the data for these domains (Phoenix WinNonlin) and supports the automatic generation of a complete electronic PK regulatory submission package, including all necessary CDISC domains, during
14 Scientific Computing World December 2019/January 2020
the normal process of setting up and executing an analysis by a PK scientist who is not a CDISC expert,’ Trimm added.
Making use of standards Does FDA’s requirement for CDISC mean that drug submissions will become wholly digital with no need for human-readable data? ‘There always has been, and still is a human-readable component to a drug submission, but the requirement for submission in a standardised electronic format not only ensures equivalence in data type and form, but in control terminology, so everything is coded in the same way,’ Trimm stated. ‘These are the two elements that you need if you are going to be able to mine your data.’ So how do companies start to build
CDISC standards into their data collection, collation and formatting for submission? For companies making regulatory submissions in the US or Japan, where CDISC electronic submissions are now mandatory, one of the primary challenges is creating the right domains into which the different types of data will fit. ‘While this can be done manually, it’s hugely time consuming, and there are software packages that can streamline the process. This is one area in which Certara is engaged: creating software solutions that don’t require a lot of knowledge about the domains themselves. Because becoming an expert in electronic submissions is almost a profession in itself. Understanding all the data models,
the control terminologies – which may be updated every few months – and the most up-to-date implementation guidelines, is complex,’ notes Trimm. ‘While ideally the requirement for
electronic submissions in standardised formats should be set into the experimental mindset, in reality the data collected can be converted into the right format downstream. The tricky part is ensuring that you collect the necessary data that’s going to be required to create the domains,’ Trimm added. While electronic laboratory notebooks (ELNs) for capturing experimental workflows and processes are now relatively standard in modern labs, organisations must still consider recording the necessary data in a way that will allow it to be converted electronically, Trimm suggested. There’s no avoiding the fact that
generating an electronic submission for FDA is expensive. ‘Companies may commonly employ outside consultants that will take data and start the process of conversion,’ notes Trimm, but this can be a lengthy undertaking if the data hasn’t been captured in an easily convertible format. ‘On top of all the expense, it can add a lot of time to the creation of a regulatory submission, effectively eating away at the length of time you may have left to market your drug with patent protection,’ Trimm continued. Get your data in the right state early on, and the process can be much shorter. ‘What commonly occurs
FDA REQUIREMENTS
FDA requirements now span CDISC controlled terminology, the set of CDISC-developed or CDISC-adopted standard expressions (values) used with data items in CDISC-defined datasets. FDA-mandated CDISC standards also include SDTM (study data tabulation model), for submission of clinical studies as part of an NDA submission. SDTM provides a standard for organising and formatting data to streamline processes in collection, management, analysis and reporting. Non-clinical data for IND submissions must be formatted as Send (standard for the exchange of nonclinical data), an implementation of the SDTM standard for nonclinical studies. Send specifies
a way to collect and present nonclinical data in a consistent format. For SDTM, FDA requests that
applicants provide the data in a format that is ready for analysis; these datasets are called Analysis Data Model (ADaM) datasets, and they define dataset and metadata standards to support how clinical trial statistics are generated, analysed and reviewed. Define-XML, another FDA-required standard, is a data exchange standard for transmitting metadata, and which informs regulators which datasets, variables, controlled terms and metadata were used in studies. Japan’s PMDA requires STDM, ADaM, Define-XML and analysis results metadata (ARM, for Define-XML).
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