# Presentation: 679627

## ISS/ISE:  Where Do They Fit in the CTD/eCTD?

**Justina A. Molzon, M.S. Pharm., J.D.**
**Associate Director for International Programs**
**Center for Drug Evaluation and Research **
**U.S. Food and Drug Administration**
**Session 317**
**Medical/Scientific Writing Track **

## Learning objectives At the conclusion of this session, participants should be able to: 

- Differentiate between ICH guidelines and FDA requirements for the CTD/eCTD.
- Identify the goals of the CTD/eCTD for both industry and regulators.
- 3. 	Identify strategies to include the ISS/ISE in the CTD and eCTD submission formats.

## I C H

- INTERNATIONAL CONFERENCE ONHARMONIS/ZATIONof Technical Requirements for the Registration of  Pharmaceuticals for Human Use
- _[http://www.ich.org](http://www.ich.org/)_
- Hosted by ICH Secretariat
- IFPMA-Geneva, Switzerland

## A Unique Approach

-  ICH was created in 1990
- Agreement between the EU, Japan and the USA to harmonize different regional requirements for registration of pharmaceutical drug products
- Unique because joint effort by regulators and associated pharmaceutical industry  trade associations

## ICH Objectives

- Identification and elimination of the need to duplicate studies to meet different regulatory requirements
- More efficient use of resources in the R&D process, as a consequence
- Quicker access for patients to safe and effective new medicines

## Harmonized Guidelines 

**Efficacy** - 13 topic headings/18 guidelines
**Safety** - 8 topic headings/16 guidelines
**Quality** - 9 topic headings/25 guidelines
**Multidisciplinary  **(Regulatory Communications)
**Medical Dictionary** - MedDRA
**Electronic Standards** -  ESTRI, E2B
- In 1996 ICH industry representatives proposed assembling the information generated by these harmonized guidances in the same order
- Goal was to decrease the amount of time and staff needed to assemble and disassemble documents for submission to ICH regions

## Slide 7

## Common Technical Document

**Module**** ****1**

**Module 3**

**Module**** ****4**

**Module 5**

**2.1**

**2.2**

**2.3**

**2.4**

**2.5**

**2.6**

**2.7**

**1.0**

**Quality**
**3.0**

**Nonclinical**
**Study Reports**
**4.0**

**Clinical**
**Study Reports **
**5.0**

**  ****Module 2**

**Source: ICH Implementation Coordination Group**

**Notes:**

One of the integrating uniform numbering system for the entire CTD.
measures that was agreed to in May was a Here we have a “refinement” of the CTD pyramid reflecting that system. 

## Format vs. Content

- The CTD provides a common format for the submission of information to regulatory authorities in the three ICH regions.
- However, the CTD does not address the content of submissions.
- Regional requirements (ISS/ISE)
- Applicants preferences
- Dossier using the CTD format (Modules 2 to 5) will not be identical for all ICH regions

## July 1, 2003CTD mandatory in the EU and Japan

**“****Highly Recommended”** by FDA
- ICH documents have always been considered GUIDANCE by FDA
- Good Guidance Practice  (GGPs)
- Final Rule September 19, 2000
- GGPs require that the CTD not be mandatory
- Due to Regulation--Not an indication of lack of commitment to ICH or the CTD
- Submissions indicate that sponsors are following this recommendation

## CTD Major Issue Integrated Summary of Safety Integrated Summary of Efficacy

- The name ”summary” has caused great confusion
- Not a *summary* but an *integrated **analysis*
- Critical components of the safety and efficacy review and expected to be part of  FDA submission.

## CTD- Efficacy Question # 10

***Integrated Summary of Safety and Effectiveness--****Does the *
*	**CTD section on safety **in** Module 2 replace the section under 21 CFR 314.50(d)(5)(v)-(vi) calling for integrated summary of safety and effectiveness (ISS/ISE)?*

## ANSWER

- The ISS/ISE are critical components of the safety and effectiveness submission and  expected to be submitted in the application in accordance with the regulation.  FDA’s guidance *Format and Content of Clinical and Statistical Sections of Application* gives advice on how to construct these summaries.  Note that, despite the name, these are integrated analyses of all relevant data, not summaries.

- The Clinical Safety sections of the CTD follow approximately the outline of the sections of the ISS/ISE, although they are somewhat modified by experience with ICH E-3 (*Structure and Content of Clinical Study Reports*).  The CTD Clinical Overview and Summary in Module 2 will not usually contain the level of detail expected for an ISS.  It may contain the level of detail needed for an ISE, but this would need to be determined on a case-by-case basis.

- If the requirements of 21 CFR 314.50 can be met for a particular application by what is in the CTD Module 2 summary, the CTD Module 2 section ***would*** fulfill the need for an ISS/ISE.  In some cases, it will be convenient to write much of what is needed in the CTD Module 2 with appropriate appendices in Module 5.  In other cases, the ISS/ISE would be summarized in Module 2, with detailed reports in Module 5.
- Any questions about these matters can be raised with the reviewing division.

## Updated CTD-E Q&A #10

- Based on experience with CTD/eCTD submissions
- Language submitted to ICH Secretariat for discussion with ICH Steering Committee
- Discussed during ICH SC meeting held in Yokohama June 8-9, 2006
- Decided that since this is a US FDA requirement  a link from current Q&A to CDER website for updated information was appropriate

## Today’s Session

- Will share ISS and ISE analysis placement tactics various sponsors have used successfully and unsuccessfully
- Objective is to help you understand how the information should be correctly submitted in CTD/eCTD
- Information presented will be posted on CDER website with link to current Q&A

## Session 317—Medical Writing Track

- Background on CTD Efficacy and ISS/ISE
- Dr. Robert Temple
- Director, Medical Policy, CDER
- Overview of CTD Efficacy and ISS/ISE
- Dr. Armando Oliva
- Associate Director for Policy, Office of New Drugs, CDER
- eCTD Efficacy Submission Format
- Gary Gensinger
- Director, Regulatory Review Support Staff, Office of Business Process Support, CDER