Blog #3 Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical document

Theresa Seiverd
BW706-Blog 3

Name: Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical document

Status: Final Guidance

Release Date: April 2009

Link to Guidance:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM136174.pdf

Target Audience: Industry, specifically clinicians, biostatisticians, and writers who work together to write the Integrated Summary of Efficacy (ISE) and Integrated Summary of Safety

Laws and regulations referenced:
21 CFR 314.50(c)(2)(viii)
21 CFR 314.50(d)(5)(v)
21 CFR 314.50(d)(5)(vi)(a)

Summary: There has been confusion on the part of applicants submitting a new drug application (NDA) or a biologic license application (BLA) in omitting the ISE and ISS documents from Module 5 of the Common Technical Document (CTD) because of their similarity to the Summary of Clinical Efficacy (SCE) and Summary of Clinical Safety (SCS) that are located in Module 2 of the CTD. Many applicants have argued that it is redundant to submit a separate ISE and ISS because of the similarity to the SCE and SCS. Consequently, the FDA had observed an increase in the number of NDAs without a fully comprehensive ISE and ISS that is required by US regulations.

This guidance was intended to clarify the location regarding the ISE and ISS documents in the CTD and the differences of intent between the ISE/ SCE and ISS/SCS.

Rationale: The ISE and ISS are documents that are unique to the United States. A common assumption is that the documents are summary documents that provide an overview of efficacy and safety data. However, the ISE and ISS provide a detailed integrated analysis with more tables, figures, and listings that are far more extensive and may number up to a 1000 pages. Unlike the SCE, the ISE will often explore similarities and differences among an extensive set of baseline characteristics to determine whether these factors influence outcomes. Similarly, the ISS will analyze data across multiple studies with a more in depth analysis to identify safety signals that the overall safety database may not identify. 1 Therefore, it is essential that these documents are not omitted from the CTD and have a separate location from the clinical summaries section located in Module 2 of the CTD.

Resulting recommendation: Due to the extensive length of the ISE and ISS compared to the SCE and SCS documents, the appropriate location in the CTD is Module 5, or more specifically Section 5.3.5.3, “Reports of Data from More than One Study”. The guidance does provide examples of when it is acceptable to use the same information in the ISE or ISS in the text of the SCE and SCE for both modules, or how to appropriately cross reference between Module 2 and Module 5. For instance, the text summary must be listed in both modules even though it may be the same, but it is okay to just include the tables and appendices in Module 5 and reference this information in Module 2. It is not acceptable, to include all information for the integrated summaries (ie, SCE and SCS) in Module 2 and submit nothing in Module 5 of the CTD.

Impact: This guidance has provided a map for Applicants to develop a strategy for creating the ISE and ISS documents in Module 5 that can be readily condensed and/or mapped to produce the SCE and SCS documents that meet the US requirement for the clinical summary that is located in Module 2 of the CTD. By developing a strategy to produce the larger more comprehensive documents first, applicants can move towards producing better quality and consistency among documents at a much faster rate. This will have the added benefit of facilitating FDA’s review since the information between Module 2 and Module 5 is similar. FDA may choose to review both these sections together instead of taking a sequential approach in reviewing each module in order by number. It would make sense to review these modules in tandem to get a better comprehensive understanding of the efficacy and safety for the drug under review.
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1 Swartz D., Umen M., Nomides K., and Vanderhoof M., Understanding the differences and effectively transitioning between the US Integrated Summaries of Effectiveness and Safety (ISE/ISS) and the CTD Summaries of Clinical Efficacy and Safety (SCE/SCS). Drug Information Journal, Volume 44, pp 641-648, 2010.