More than seven years since unveiling the draft document, the US Food and Drug Administration (FDA) on Wednesday finalized its guidance on how an Integrated Summary of Effectiveness (ISE) should be prepared for new drug applications (NDAs) and biologics license applications (BLAs).
In terms of the changes between the draft and final versions, FDA has revised the definition of integrated analyses, clarified the components that constitute integrated analyses, defined pooled analyses, included new recommendations on when it’s appropriate to pool data and noted the difference between the document included in Module 2, section 2.7.3, Summary of Clinical Efficacy from ICH M4E, and the ISE.
FDA defines the ISE as a “comprehensive integrated analysis of the effectiveness of a study drug,” with the purpose of describing the available effectiveness information, delineating strengths and weaknesses and highlighting important missing information.
“Generally, analyses in the ISE are based primarily on the clinical effectiveness data included in the application, but they may also include other sources of information relevant to efficacy,” including nonclinical studies; clinical pharmacology studies (e.g., pharmacokinetic (PK), pharmacodynamic, and in vitro studies) that describe dose-response, concentration-response and drug-drug and drug-disease (e.g., renal dysfunction) interactions; human factor studies for drug-device combinations; and in vitro studies that clarify drug activity, FDA says.
The guidance also details what should be included in the sections on: Listing and Brief Results of Individual Studies; Analysis of Study Designs; Overall Analysis of Effectiveness Results; Comparison of Results in Subpopulations; Analysis of Clinical Information Relevant to Dosing Recommendations; Time Course of Effect; Persistence of Effect and/or Tolerance; Distribution of Responses; and Exploratory Investigations.
Both Pfizer and Sanofi offered comments on the draft guidance back in 2008 and sought further clarification on the differences between an ISE and the Summary of Clinical Efficacy (SCE).
Pfizer even went so far as to claim that the draft “argues unconvincingly that the ISE is somehow different to the SCE.” The company also called on FDA to reposition the guidance as supplemental guidance on how to present the SCE, which would remove confusion over “duplicate, redundant documentation.”
Similarly, Sanofi called on FDA “to better delineate the differences between the SCE and the ISE.”
As far as the differences between the ISE and SCE, FDA says that the SCE should be a compact summary of the critical findings reported in the ISE, while the ISE should be a “self-contained, detailed analysis that comprehensively examines relevant data from multiple sources intended to provide the substantial evidence of effectiveness for a given drug, and describes additional information related to that effectiveness, such as dose-response, effects in population subsets, or timing of response.”
The SCE also should not contain any information or data not discussed or explained in the ISE, FDA says.
FDA also notes in a footnote that some of the section headings in the guidance “may be different from the section headings” in 2.7.3, Summary of Clinical Efficacy from ICH M4E, and that the headings in this guidance have been amended to correspond to the content within each section.
However, in some cases, the SCE can serve as the ISE, FDA says, if appropriate data can be included within the space limitations of the SCE.
“This approach can be feasible for relatively simple drug development programs such as those that rely on a single adequate, and well-controlled effectiveness trial, or a few trials of similar design. With respect to location of information within the CTD, the ISE should be included in Module 5, section 220.127.116.11, and the SCE in Module 2, section 2.7.3, as described in the guidance for industry Integrated Summaries of Effectiveness and Safety: Location Within the Common Technical Document,” FDA adds.
Meanwhile, FDA clarified that “integrated analysis” is a sponsor’s use of all relevant data from controlled trials, as well as other sources (e.g., clinical pharmacology trials), to enhance the understanding of the overall evidence of effectiveness.
“The integrated analysis is not a substitute for the analysis of individual studies. Instead, it is intended to provide a clearer understanding of responses across studies, different populations (e.g., demographic, disease-related), and dosing regimens. Differences in responses among studies should be described,” FDA says.
Final ISE Guidance