How do you envision the future of data submission?

Last week, I had the privilege of presenting the topic “Standards and Open-Source Hand-in-Hand: Leveraging Automation to Expedite Drug Market Request Review Process” at PharmaSUG-China in Nanjing. It was an honor to be invited as a keynote speaker to this event.

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In the first part of this post, I discussed the ongoing revolution, or maybe I should say evolution, we are living through with open-source initiatives and new standards development.

A good example to start with is the R-pilot initiative¹ by the r-consortium, which has already Read more »

Over the past years, probably the entire last decade, there have been several discussions on how to handle multiple subjects’ enrollments in CDISC data packages. Members of the CDISC SDS Multiple Subject Instances (MSI) team also shared some previews of future possible modifications of the SDTM standard to handle multiple subjects’ enrollment,^[i] and we might finally have something available with the upcoming future releases of the SDTM standard and Implementation Guidance (IG).
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Integrated Summaries of Safety (ISS) and Integrated Summaries of Effectiveness (ISE) bring together in one place data and analyses pertinent to assess the safety and efficacy of a new drug submitted to the regulatory authorities. Let’s take a closer look at these essential documents and important steps for planning the ISS and ISE.

 

What are the Integrated Summaries of Safety and Effectiveness?

An Integrated Summary of Safety (ISS) and an Integrated Summary of Effectiveness (ISE) are two distinct components of a regulatory submission, often prepared by pharmaceutical companies seeking approval for a new drug or medical product.

The ISS and ISE are used to support the SCS (Module 2.7.4 – Summary of Clinical Safety) and SCE (Module 2.7.3 – Summary of Clinical Efficacy) in the CTD submission. The SCS provides a comprehensive overview of the safety profile of the drug, and is a critical component in any New Drug Application (NDA) or similar market approval request submitted to regulatory authorities such as the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA). It summarizes data relevant to safety in the intended population, integrating the results of individual clinical study reports as well as other reports such as the integrated analyses of safety performed in the ISS.

The SCE provides a comprehensive overview of the efficacy of the drug. It utilizes two kinds of analyses: comparison of results of individual studies, and analysis of data combined from various studies performed within the ISE.

 

Important considerations when preparing your ISS/ISE

1. Plan early
It is important to plan for an early discussion of your submission strategy with the relevant regulatory agencies.

 

2. Understand regulatory requirements

Different regulatory authorities may have specific requirements for integrated analyses and efficacy/safety summaries as well as data submissions. Familiarization with the guidelines and expectations of the relevant authorities, such as the FDA or EMA, is critical.

 

3. Understand when to use data pooling

It is important at the start of a submission project to decide which data, from which studies or pooled analyses, will be used in each section of the Summary of Clinical Safety and Summary of Clinical Efficacy and whether an ISE or ISS will be required. When pooled analyses are needed, a “single database” is formed by pooling the results of all concerned clinical trials. Pooled analyses are not mandatory and should only be performed if they provide additional insights beyond those observed in individual clinical trials. If pooled analyses are done, the objectives/reasons need to be explained and the validity of the pooling has to be justified.

4. Expert advice
Creating an ISS/ISE is a collaborative effort. It’s important to get expert advice from statisticians and programmers who have submission experience to help you understand the regulatory requirements and when to pool data for your specific project/drug.

 

5. Plan your data integration strategy
The ISS and ISE integrate data from various sources into cohesive documents. Plan for how you will combine and present data. If pooled analyses are required, data integration from relevant studies and relevant details should planned in advance in a detailed Statistical Analysis Plan (SAP), one for ISS and one for ISE. How data will be pooled can also be anticipated in pre-submission meetings, such as Type C or pre-NDA with the FDA. For example, this can be done by sharing your Study Data Standardization Plan (SDSP) where you could explain to the reviewer your planned data integration approach. Details that can be anticipated are but not limited to how you plan to handle subjects participating in more than one trial, medical dictionaries up-versioning, and so on.

6. Prepare your data submission 
Health authorities such as the FDA have strict requirements with regards to submitting study data in support of market approval. Like any other “piece” submitted to the HA, submitted data packages should be of good quality. Attention should be paid to completeness of such data packages, traceability, and clarity of accompanying documentation so that the HA reviewer will be able to understand what you have done and eventually reproduce it.

 

Interested in learning more about data submission? Download our complimentary new eBook, “The Good Data Doctor on Data Submission and Data Integration.”

Data submissions are very regulated, but every drug and drug development are different. Therefore, the data presented in the Common Technical Document (CTD) needs to be tailored to the specific submission. It’s important for statisticians involved in submission projects to not only understand the guidelines, but also what makes sense in terms of data integration and pooling. What follows is an introduction to the ISS/ISE from a stats perspective, which I recently shared at the Italian CDISC User Network on May 12, 2023.

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For years CDISC data standards implementers have struggled to find good implementation examples and use cases beside those provided in the CDISC Implementation Guidance (IG). However, in the recent years, thanks to the efforts of several different experts, such as clinicians in the different Therapeutic Areas or data standards experts, several CDISC Therapeutic Area User Guidance (TAUG) have been made available ^{[1, 2, 3]}. As I write this blog, 46 TAUGs are available from various therapeutic areas, such as Oncology, Neurology, Endocrinology, Cardiovascular, Infective Diseases, Autoimmune Diseases, Mental Health, Gastrointestinal, and others. The use of and adherence to many of these TAUGs is recommended by the FDA in its Study Data Technical Conformance Guidance (SDTCG) ^[4], and as per the March-2022 version, 24 TAUGs are “supported”.

Moreover, regulatory agencies such as the FDA have also released some additional guidances either specific to an FDA division or covering any specific medical aspects, with the aim of reducing the variability in interpretation of CDISC IG. In a previous blog , I discussed the detailed ADaM specifications provided by the FDA Office of Oncologic Diseases in support of Real Time Oncology Review ^[5].

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