ISS & ISE: How Integrated Clinical Summaries Drive FDA Approval

Author: Andrés Malatesta

, Biostatistician
Published on: 28/09/2026

Estimated Reading Time: 8 min

Excelya Biostatistics & Programming DEPARTMENT

Introduction

For pharmaceutical company executives, the FDA approval process is a strategic imperative as much as a scientific one. At the heart of every Biologics License Application (BLA) and New Drug Application (NDA) lie two documents that regulators scrutinize most closely: the Integrated Summary of Safety (ISS) and the Integrated Summary of Effectiveness (ISE). These integrated analyses synthesize data across your entire clinical development program into the cohesive benefit-risk narrative that determines approval outcomes. Understanding how these documents function what drives their complexity, where delays originate, and how expert statistical programming teams mitigate risk is essential knowledge for any executive responsible for development timelines and commercial readiness

As an FDA submission contains dozens of endpoints and millions of individual datapoints, yet the regulators must arrive at a single conclusion: does the benefit-risk profile support approval? The Integrated summary of effectiveness (ISE) and Integrated summary of safety (ISS) are the key to helping them answer this question. However, these packages can also be a trial by fire for statisticians and programming teams: Meticulous strategizing is as necessary as flexibility, and a deep understanding of the process and the data itself are paramount for a successful submission.

Jump to section

1Why it Matters?

2Integrated efficacy and safety

3Cross-functional submission strategy

4Part 2: Pooling & CDISC Readiness

5FAQ

Integrated summaries

Why the FDA Cares?

The ISS and ISE pool data from multiple clinical studies to evaluate a drug’s effectiveness and safety. Because a single study rarely tells the complete story, and uncommon safety events may not appear within one trial, integrated analyses help regulators assess a treatment across different populations, study designs and outcomes.

For example, several single-arm Phase III studies of the same treatment for hepatic cancer may differ in treatment strategy, patient demographics, efficacy and safety outcomes. Pooling patient data gives regulators a broader view of the treatment across the entire development 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 and adopted by major regulatory agencies, including the FDA, EMA and Japan’s Ministry of Health, Labour and Welfare [1]. It has also been adopted by Health Canada and Australia 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.

Despite the scale of these submission packages, regulatory guidelines leave considerable flexibility in how their structure and content are interpreted. Information from integrated summaries may also be referenced in other CTD modules. For example, differences in pharmacokinetics and pharmacodynamics between trials may appear in Module 5 and in Module 2, which covers quality, non-clinical and clinical information about the drug.

The challenge: interpretive flexibility can accommodate less conventional studies, but it can also create uncertainty and delays while teams determine the most appropriate path forward.

Integrated efficacy and safety

What’s Inside the ISE and ISS?

Integrated analyses connecting clinical evidence, regulatory interpretation and scientific judgment.

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.

ISE

Effectiveness

Integrated Summary of Effectiveness

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].

ISS

Safety

Integrated Summary of Safety

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.

          Pool evidence
          ›
          Interpret outcomes
          ›
          Support benefit-risk

Complete evidence

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.

Case-by-case content

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.

Scientific justification

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.

✓

ISE and ISS design depends on rigorous planning, complete evidence and scientifically justified implementation decisions.

Cross-functional submission strategy

Navigating ISS and ISE Complexity

Specialist collaboration, adaptable resourcing and submission experience working together.

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.

Excelya Statistics & Programming

Expertise that adapts as submission needs evolve

The team of experts at Excelya Statistics and Programming successfully performs the programming and analysis of BLA and NDA submissions that include ISS and ISE packages in addition to single studies, thanks to our adaptability to the evolving needs of a project. This is possible thanks to the FSP model that allows for flexibility in resources in parallel projects under the same team and the assignment of subject matter experts where they are needed.

What the model enables

Scalable resources for evolving submission activities

Flexibility across parallel projects under the same team

Subject matter experts assigned where they are needed

Coming in Part 2

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.

References

Sources and Supporting Evidence

[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].

About the Author

Andrés Malatesta

Biostatistician at Excelya

Biostatistician and programmer with over five years of experience
contributing to more than a dozen clinical trials and real-world evidence studies across oncology, endocrinology, and psychotherapy. Author of five peer-reviewed publications, including
two full research articles and three conference abstracts.

Frequently Asked Questions

What are the ISS and ISE in an FDA drug submission?

The Integrated Summary of Effectiveness (ISE) evaluates a drug’s efficacy by pooling and analyzing data from multiple clinical studies, including primary endpoints, key secondary endpoints, and relevant patient subgroups. The Integrated Summary of Safety (ISS) focuses on safety outcomes across the clinical development program, including adverse events, treatment exposure, laboratory findings, vital signs, ECG results, and other safety measures. Together, the ISS and ISE help regulators assess the overall benefit-risk profile of a drug during NDA and BLA reviews.

Why are ISS and ISE analyses important for FDA approval decisions?

Single clinical trials rarely provide a complete picture of a treatment’s safety and effectiveness. ISS and ISE analyses integrate patient-level data from multiple studies to identify trends, confirm treatment effects across populations, and detect safety signals that may not be visible in individual trials. By providing a comprehensive assessment of the clinical development program, these integrated summaries support regulatory decision-making and help demonstrate whether the benefits of a treatment outweigh its risks.

What are the biggest challenges in preparing an ISS or ISE submission package?

ISS and ISE preparation requires aligning data, analyses, and reporting across multiple studies that may differ in design, patient populations, dosing strategies, and endpoints. Common challenges include defining appropriate integrated analysis populations, ensuring consistent data standards, developing robust statistical programming deliverables, and managing overlapping submission timelines. Successful preparation typically requires close collaboration between biostatistics, statistical programming, data management, clinical development, and regulatory affairs teams.

How can a CRO help sponsors prepare ISS and ISE submissions?

An experienced CRO can support sponsors by providing specialized expertise in integrated analyses, statistical programming, submission planning, and regulatory expectations. CRO teams help develop analysis datasets, tables, listings, and figures, ensure consistency across studies, and manage the complex coordination required for NDA and BLA submissions. Partnering with a CRO can improve efficiency, reduce submission risks, and provide additional resources when internal teams are managing multiple concurrent projects.

How does Excelya support ISS and ISE preparation for NDA and BLA submissions?

Excelya Statistics and Programming supports the preparation of ISS and ISE packages through statistical programming, integrated analyses, and submission-focused expertise for NDA and BLA programs. Through its Functional Service Provider (FSP) model, Excelya offers flexible resourcing that allows sponsors to scale support as project needs evolve, while maintaining continuity across parallel studies and submission activities. This model enables the deployment of subject matter experts where they are most needed, helping sponsors navigate the complexity of integrated summaries and regulatory submissions efficiently.