Introduction to Integrated Summaries of Efficacy and Safety
When sponsors prepare an application for the registration of pharmaceuticals for human use, a common technical document (CTD), with organization and content driven by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guidelines, must be submitted to the regulatory authorities to facilitate the review process.
This article in our Content of Integrated Summaries of Efficacy and Safety (ISE/ISS) series focuses on the structure of the common technical document (CTD) and the objectives of the ISE/ISS. The subsequent articles focus on what elements are required in the ISE/ISS and the specific requirements in FDA submissions.
The CTD must include the Summaries of Clinical Efficacy and Safety (SCE/SCS), which provide a comprehensive summary of all the safety and efficacy data gathered on a study drug across all clinical trials based on individual and pooled analyses. Their content is supported by ISE/ISS which are highly technical documents that require expertise and experience to complete and submit successfully.
About the CTD Organization
The electronic CTD (eCTD) is organized into five different modules, Module 1 being region specific and Modules 2, 3, 4, and 5 related to quality, non-clinical and clinical being common to all regions. A graphical overview is shown below:
In particular, clinical data are summarized within Module 2 and 5, following the organization below:
Module 2 – Common Technical Document Summaries
Section 2.5 – Clinical Overview
Section 2.7 – Clinical Summary
- Section 2.7.1 – Biopharmaceutic Studies and Associated Analytical Methods
- Section 2.7.2 – Clinical Pharmacology Studies
- Section 2.7.3 – Clinical Efficacy
- Section 2.7.4 – Clinical Safety
- Section 2.7.5 –Literature References
- Section 2.7.6 – Synopses of Individual Studies
Module 5 – Clinical Study Reports
Section 5.2 – Tabular Listing of All Clinical Studies
Section 5.3 – Clinical Study Reports
- Section 5.3.5 – Study reports
- Section 220.127.116.11 – Reports of analyses from more than one study (ISE/ISS)
Section 5.3.7 – Case Report Forms and Individual Patient Listings
- Section 5.4 – Literature Reference
Objectives of Integrated Summary of Efficacy (ISE) and Integrated Summary of Safety (ISS)
The ISE and ISS are the supporting basis of Module 2.7.3, the Summary of Clinical Efficacy (SCE) and Module 2.7.4, the Summary of Clinical Safety (SCS), in the eCTD. The ISE and ISS allow for:
- Discovery of trends in patient subgroups
- Improving the precision of results by integrating trials together leading to a greater population size
- Comparing of disparities and differences in trial results in benefit/risk assessment
More explicitly, the ISE provides evidence to support the dosage and administration section of the labelling, summarize effectiveness of data by subgroup, and demonstrate substantial evidence of effectiveness for each claim, while the ISS identifies risks for the product label, characterizes the overall safety profile, and evaluates rare and/or unexpected trends or safety signals.
Although New Drug Applications (NDA) and Biologics License Applications (BLA) submitted to regulatory authorities across the world mostly follow the CTD format as per ICH Guidelines, requirements differ with regards to ISE and ISS. As an example, these integrated analyses are not strictly required for NDA submissions to EMA but are one of the key elements required for submissions to FDA with specific guidance on their content. The format and content of the ISE and ISS closely follow the format and content of the SCE and SCS, respectively.
The ISE and ISS provide comprehensive and detailed integrated analyses of the cumulative relevant information coming from multiple sources, while the SCE and SCS provide a summary of the critical findings reported in the ISE and ISS. The SCE and SCS should not contain any information or data not discussed or explained in the ISE and ISS.
Referring to the picture above, the ISE and ISS are usually included in section 18.104.22.168 of Module 5 of the
CTD. In some cases, the SCE and SCS can serve as the ISE and ISS and are included in Module 2 when they are not extensive, given the space limitation of Module 2.
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) – YOU ARE HERE
- 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