The FDA has recently published a new version of the Technical Conformance Guide (TCG) with updates that impact regulatory data submissions.
Technical Rejection Criteria
Presenting the Technical Rejection Criteria is one of the introduced TCG updates. These criteria, to be applicable following a 30-day notice from the FDA, define several new requirements for data submissions.
One of these requirements includes the addition of TS (Trial Summary) domain for any study submitted in eCTD modules 4 and 5. TS domain provides an overview summary of the submitted trial in terms of number of participants, length of trial, blinding scheme, control type and more. The domain, in practice, demonstrates an overall summary of the trial according to predefined domain parameters.
The other requirement included in Technical Rejection Criteria, relates to the addition of SDTM Demographics (DM) dataset and define.xml for module 4 submissions, together with ADaM Subject-Level Analysis Dataset (ADSL) dataset for module 5 submissions.
DM domain and ADSL domains hold attributes for subjects participating in the study (i.e. subject number, date of birth, race, reference start and end dates, etc.), while the define.xml provides metadata attributes for the submitted study such as domains, variables, codes and dictionaries used. The FDA Technical Rejection Criteria requirements are expected to clarify the configuration of each individualized submitted study and support the review process. From the sponsor’s side, this will necessitate building compliant individualized TS, DM, ADSL domains together with the define.xml.
Supported Therapeutic Areas
Therapeutic Area (TA) relate to disease specific clinical data standards developed by CDISC, the FDA and additional stakeholders. Up to date, more than 20 Therapeutic Area User Guides (TAUG) have been published in various clinical fields such as Alzheimer’s disease, Parkinson’s disease, Diabetes, COPD and more. The guides include the domains and datasets that should be used when collecting data, what variables should be used to represent data items, definitions of SUPP variables and data relations across domains together with examples of annotated CRFs.
The TCG has defined additional Therapeutic Areas that are currently supported by the FDA. Those include Diabetic Kidney Disease, Ebola, Kidney Transplant, Malaria and Rheumatoid Arthritis. Supported therapeutic area guides may be used by sponsors for data standardization and submissions, but are not binding as long as they are not included in the SDTM Implementation Guide.
SDTM DS Domain
The TCG indicates that the variable DSSCAT in Disposition (DS) domain, in addition to EPOCH, may be used to distinguish between records for cases of more than one disposition event per patient. This, for example, will allow differentiating between disposition events related to the treatment and those related to the study. Using DSSCAT is more descriptive, offers a wide range of verbatim and allows more flexibility in choosing phrases that distinguish between records, in relation to the EPOCH variable.
As a means for defining how to best group observations in SEND, VISITDY variable may help to create consistency across different observations and domains and enables grouping for further calculations and analysis. The TCG supports this option by defining that VISITDY variable in SEND datasets can be used for grouping postmortem findings in Macroscopic Findings (MA), Microscopic Findings (MI), and Organ Measurements (OM) domains according to the grace day VISITDY value that appears in the Disposition (DS) domain. In addition VISITDY variable may also be added to life findings domains such as Laboratory Results (LB) and ECG (EG).
Another update for the SEND standardization process relates to the variable MISTRESC (Character Result/Finding in Standard Format) in Microscopic Findings (MI) domain. For this variable, non-neoplastic findings, in cases where controlled terminology is not required, should be standardized according to the base pathological process. The advantage in such mapping is that it allows cross-study and inter-study standardization and consistency, which is not always readily standardized, for this type of pre-clinical data.
Continuous monitoring of updates in the FDA Technical Conformance Guide publications is essential for understanding FDA expectations and conforming to new standards. Professional understanding and proper implementation of new standard issues supports regulatory submissions compliance and contributes to an appropriate submission process.