Specific Requirements for Integrated Summaries of Efficacy and Safety in FDA Submissions

Data Standards

Since 2017, FDA (and Pharmaceuticals and Medical Devices Agency, PMDA) has required studies to be submitted in a standardized data structure following Clinical Data Interchange Standards Consortium (CDISC) standards to increase transparency on the handling of clinical data and interoperability, as well as facilitating the review process.

CDISC is a global, non-profit organization that develops and advances data standards supporting the acquisition, organization, analysis, exchange, submission, and archival of non-clinical and clinical data in medical research. CDISC clinical standards include the Study Data Tabulation Model (SDTM), the Analysis Data Model (ADaM) and the Data Exchange Model (refer to CDISC for details).

A compliant CDISC and documents study package will include the following elements:

• Protocol (in .pdf format)
• Statistical Analysis Plan (in .pdf format)
• Blank electronic Case Report Form, eCRF (in .pdf format)
• Clinical Study Report (in .pdf format)
• SDTM datasets containing formatted and standardized clinical data organized by clinical domain (in xpt format)
• ADaM datasets containing derived and non-derived data used as sources of all statistical analyses (in xpt format)
• SDTM annotated blank CRF providing the links between data collection fields used to capture data in the CRF and corresponding variable in the SDTM datasets
• Define.xml containing metadata describing the datasets structure
• Reviewer’s Guides providing additional context for SDTM (SDRG) and ADaM (ADRG) datasets
• Analysis-results metadata and key SAS programs (in .txt format)

Requirements for submission of SDTM and CDISC of individual studies for legacy data (started prior to Dec. 17, 2016) can vary depending on how they are used in supporting the evaluation of the drug under the targeted indication. There are also no official rules on how data supporting ISE/ISS should be integrated under CDISC standards, and therefore several integration approaches are possible:

• Integrated ADaM derived from individual study ADaM
• Integrated ADaM derived from individual study SDTM
• Integrated ADaM derived from integrated SDTM

The approach for integration is described in the Study Data Standardization Plan (SDSP). The FDA encourages sponsors to share the data integration and analysis strategy (by submitting the SDSP and the SAP) at the time of the pre-NDA meeting at the latest to confirm if the chosen approach for integration fits the requirements.

The FDA also offers a process to validate sample eCTD submissions and standardized study datasets. After processing the sample submission, FDA provides feedback, highlighting the errors found and allowing corrections to be implemented before the final submission.

No matter the approach chosen, the provision of the required elements from the CDISC standards aligned with the integration strategy remains mandatory and can become complex, costly and time critical. Nonadherence to data standards or failure to provide full traceability of the data from collection through to transformation, analysis and reporting can trigger a refusal to file and delay in the review process and marketing authorization.

Other Specific Requirements

In addition to the global CDISC standards, the FDA has also implemented different requirements for specific therapeutic areas. As an example, a product in HIV, Vaccine or NASH areas would need to comply with the specific requirements regarding potential SDTM domains and ADaM or controlled terminology.

Bioresearch Monitoring Information (BIMO)

To facilitate the planning and conduct of site inspections by the Center for Drug Evaluation and Research (CDER), summaries by clinical sites can also be provided in the initial submission package, according to the latest draft FDA guidance, consisting of the following elements:

Part 1 – Clinical study-level information including:

• List of clinical sites
• List of entities to whom the sponsor has contracted clinical study-related activities
• Protocol, protocol amendment, case report form, annotated case report form (if not already included as part of clinical study report)

Part 2 – Subject-level data listings by clinical site with information on:

• Consented subjects
• Treatment assignment
• Discontinuations
• Study population
• Inclusion and exclusion criteria
• Adverse events
• Important protocol deviations
• Efficacy endpoints
• Concomitant medications
• Safety monitoring

Part 3 – Summary-level clinical site data including information on the safety and key efficacy endpoints

While Part 1 is usually compiled from information collected by clinical operations or regulatory affairs, and therefore not part of the CDISC datasets, Part 2 and 3 can be produced by leveraging existing SDTM or ADaM datasets and existing listings programs from study or pooled analyses. Therefore, planning the inclusion of BIMO information at the same time as integrated analyses package can prove more efficient.

Learn More about Integrated Summaries

For more details on what the Integrated Summaries must include and the requirements for the electronic submission of clinical data, download the Comprehensive Guide to the Content of Integrated Summaries of Efficacy and Safety (ISE/ISS).

Series: Content of Integrated Summaries of Efficacy and Safety (ISE/ISS)

• Introduction to Integrated Summaries of Efficacy and Safety (ISE/ISS) 
• Content of the Integrated Summaries of Efficacy and Safety (ISE/ISS)
• Specific Requirements for Integrated Summaries of Efficacy and Safety(ISE/ISS) in FDA Submissions – YOU ARE HERE