ISS & ISE: How Integrated Clinical Summaries Drive FDA Approval

Integrated summaries

Why the FDA Cares?

The ISS and ISE are pooled analyses of data integrated from multiple clinical studies for effectiveness and safety endpoints of the drug. As single studies rarely tell the entire story and safety events may be too rare to be seen within a single trial, integrated analyses allow to understand the many dimensions of a treatment and their effects across diverse populations. For example, multiple Single-Arm Phase III studies for the same drug treatment on hepatic cancer may have variations on treatment strategy and included patient demographics, as well as efficacy and safety outcomes of varying degrees of success. Pooling patients’ data from these studies gives regulators a deeper understanding of the treatment across the entire program.

The regulatory context

Part of a Bigger Process

As detailed as these summaries are, they represent only a small part of Module 5 of the Common Technical Document for submissions in the United States. The CTD is the harmonized format developed through the International Council for Harmonisation (ICH) and adopted by major regulatory agencies, including the FDA, EMA and Japan’s Ministry of Health, Labour and Welfare (MHLW) [1]. It has also been adopted by Health Canada and Australia’s Therapeutic Goods Administration [2, 3].

Although not mandatory, the FDA recommends including Module 5 as part of Biologics License Applications, alongside analyses of ongoing individual studies [4]. Ideally, these analyses would be performed sequentially. In practice, evolving submission timelines mean that ongoing studies, integrated summaries and submission deliverables frequently overlap, requiring careful resource planning and cross-functional coordination.

While we might think that these big packages have extremely rigid structures and contents, guidelines leave a lot of flexibility (if not to say ambiguity) in their interpretation and application. Some of the information provided through the integrated summaries can also be referenced in other modules of the CTD: For example, differences in PK/PD between trials can be included in module 5 but also in module 2 (Quality non-clinical and clinical information of the drug). The interpretability of these documents is a double-edged sword as it can give leeway for less conventional studies but also create confusion and delays as teams evaluate the best ways to proceed.

Integrated summaries

What’s inside the ISE and ISS?

Despite their names, these are not simply summaries of key endpoints but integrated analyses of all data in the clinical studies. As these documents contain large quantities of results, all analyses must be clearly defined in the Statistical Analysis Plan (SAP) and the programming of datasets and TLFs is rock solid.

The ISE provides a full picture of the drug’s effectiveness by comparing and pooling individual trial patient data to present the estimates of treatment effect for primary and important secondary endpoints at common timepoints in the overall populations and subgroups of interest. Patient demographics, the effect of different dosage and dosing intervals between the studies are analyzed to contextualize the variations of treatment effectiveness. While it is tempting to perform many analyzes to prove the significance of treatment in specific subgroups, we must remember that these analyzes have a primary function of supporting the statistical interpretation on the overall population [5].

As the authorities need a clear understanding of the effectiveness of the drug, it must include the good, the bad and the ugly: studies that failed to show effectiveness are as important as those that did and critical limitations in studies like selection bias and as data collection issues must be justified and if possible, mitigated.

Likewise, the ISS allows the regulators to assess the benefit-risk balance through safety endpoints, most notably through extent of exposure, adverse events, their outcome (seriousness, discontinuation, deaths) and in subgroups of interest. For a more comprehensive understanding of the patients’ safety in the program, the laboratory results, vital signs and ECG results, and their evolution during the study follow-up are analyzed.

Unlike the ISE, there are no specific guidelines by the FDA detailing the contents of the ISS, and it may vary case-by-case. To define the contents necessary in the ISS for a given drug, the most appropriate strategy is to perform an analysis of previous Medical Reviews for New Drug Applications (NDAs) or BLAs published by the FDA that are adapted to the characteristics of the drug and study.

Important implementation decisions often remain project-specific. Decisions like which analysis of endpoints can be integrated require scientific justification rather than strict compliance with predefined rules.

Successful ISS and ISE preparation typically require close collaboration between biostatistics, statistical programming, data management, clinical development, and regulatory affairs. The CRO partner provides submission experience, scalable resources, and knowledge of regulatory expectations.

Integrated Pools, Risk Strategy and CDISC Readiness

In Part 2 of this series, we will explore one of the most challenging aspects of submission preparation: defining integrated analysis pools, and how different strategies of pooling can mitigate different risks. We will also discuss the creation of CDISC packages and the principles that can prevent costly submission delays.

[1]

International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), n.d. M4: The Common Technical Document (CTD). Available at: ICH Common Technical Document [Accessed 7 September 2026].

[2]

Health Canada, 2024. Guidance for industry on the preparation of the quality information for drug submissions in the CTD format: Biotherapeutic and blood products. Ottawa: Government of Canada. Available at: Health Canada CTD guidance [Accessed 7 September 2026].

[3]

Therapeutic Goods Administration (TGA), 2014. Understanding the Common Technical Document (CTD). Australian Government Department of Health and Aged Care. Available at: TGA Common Technical Document guidance [Accessed 7 September 2026].

[4]

U.S. Food and Drug Administration (FDA), n.d. Biologics License Applications (BLAs) for CBER-Regulated Products. Available at: FDA guidance on CBER-regulated BLAs [Accessed 7 September 2026].

[5]

U.S. Food and Drug Administration (FDA), 2015. Integrated Summary of Effectiveness: Guidance for Industry. Center for Drug Evaluation and Research (CDER). Available at: FDA Integrated Summary of Effectiveness guidance [Accessed 7 September 2026].