# Presentation: 482670

## ISE/ISS Analyses: Clarity in a CTD or eCTD – Clinical Reviewer Perspective

**Armando Oliva, M.D.**
- Associate Director for Policy
- Office of New Drugs
- CDER

## Objectives

- How does the Clinical Reviewer use the ISS/ISE?
- The difference between a summary and an integrated analysis
- How to submit the ISS/ISE: EXAMPLES

## Use of the ISS/ISE

- IT VARIES
- Some read it first
- Some read it last (*i.e.,* after reviewing individual study reports and clinical data)

## Why Read It First?

- Serves as a good detailed integrated description of the clinical section of the application
- Can give a comprehensive “overall picture” or sense of the clinical development program with regard to safety or efficacy; its strengths and weakness
- Helps identify which studies require more in depth review

## Why Read It Last?

- Desire to review the individual studies first and do his/her own independent integration of the results
- ISE/ISS later used to compare the reviewers integrated safety and efficacy findings with those of the applicant

## ISE and ISS

- Are misnomers!
- Really should be called and considered as ***Integrated Analyses*** of Efficacy and Safety

## Summary vs. Integrated Analysis

**Summary**

**Analysis**

- High Level Overview

- Detailed, In Depth Discussion

- Text Only

- Text
- Supporting Tables/Appendices
- Datasets

- Brief

- Can Be Very Long

## Summary vs. Integrated Analysis

- Summary

- Text

- Text

- Tables &
- Appendices

- Datasets

- {

- Integrated Analysis
- (ISE / ISS)

## Remember

- ISE and ISS are still required by regulation and must be included in the CTD or eCTD:
- ISE: 21 CFR 314.50 (d) (5) (v)
- ISS: 21 CFR 314.50 (d) (5) (vi) (a)

## ISE & ISS

_*Question:*_ Where in the CTD do integrated analyses of more than one study go?
_*Answer:*_ Module 5.3.5.3 (ICH M4E)

## CTD: Module 5, Section 5.3.5.3 

*5.3.5.3 Reports of Analyses of Data from More than One Study (Including Any Formal **Integrated Analyses**, Meta-Analyses, and Bridging Analyses) *

## Summary vs. Integrated Analysis

- Summary

- Integrated Analysis
- (ISE / ISS)

- Text

- Text

- Tables &
- Appendices

- Datasets

- {

## Module 2

***Question:*** If ISE and ISS go in 5.3.5.3, what goes in Module 2 (2.7 – Clinical Summary)?
- 2.7.3: Summary of Clinical Efficacy
- 2.7.4: Summary of Clinical Safety
- Remember the recommended size limitation of 2.7 is 50-400 pages (ICH M4E FAQ#4)

## Module 2

_*Answer:*_ the Clinical Summary is a true summary:
- Brief: 50-400 pages
- Text only (no large section of supporting tables and appendices*)
- No datasets
- Fulfills the regulatory requirements for a Clinical Summary described in 21 CFR 314.50 (c)(2)(viii)

## Making Life Easier

_*Question:*_ How does one recycle information already contained in 5.3.5.3 for module 2?
_*Answer:*_ To the extent that the text portion of the ISE/ISS also meets the requirements of Module 2 (as described in ICH M4E), also include it in Section 2.7

## Summary vs. Integrated Analysis

- Summary

- Integrated Analysis
- (ISE / ISS)

- Text

- Text

- Tables &
- Appendices

- Datasets

- {

- 5.3.5.3

- 2.7

## Making Life Easier

_*HINT:*_ When writing the text portion of the ISE/ISS in 5.3.5.3, use the headings for sections 2.7.3 and 2.7.4.
- This way, these portions of the ISE/ISS can easily be recycled for module 2 when appropriate.

## EXAMPLE 1: 

- Summary

- Integrated Analysis
- (ISS)

- Text

- Text

- Tables &
- Appendices

- Datasets

- {

- 5.3.5.3

- same

- 2.7

-   200

- Pages

- 1000

- 1 GB

**Use text portion of ISS for 2.7**

## One Caveat

- The situations where the text portion of the ISS can also function as the clinical summary are **uncommon **in our experience
- e.g. safety and effectiveness derived primarily from a single study
- More often, the text portion of the ISS is too big for module 2 – not a true summary!
- Text portion of ISE more often can fit in module 2

## EXAMPLE 2: 

- Summary

- Integrated Analysis
- (ISS)

- Summary Text

- Text

- Tables &
- Appendices

- Datasets

- {

- 5.3.5.3

- 2.7

- 1000

- Pages

- 3000

- 4 GB

**Text portion of ISS is too big for module 2; needs to be summarized**

## EXAMPLE 3: 

- Summary (2.7.4)

- 5.3.5.3
- Nothing Submitted

- 1000

- Pages

- 3000

- 4 GB

**ISS incorrectly submitted in module 2; no true “Clinical Summary” submitted ... possible RTF**

- Text

- Tables &
- Appendices

- Datasets

## Paper CTD Considerations

_*Question:*_ When the text portion of the ISS (or ISE) located in 5.3.5.3 also serves as a true summary for module 2, should it be submitted twice?
_*Answer:*_ Check with review division. Some will appreciate a 2nd copy for convenience.
- IMPORTANT: If submitted only once, the corresponding section where it is missing should refer the reviewer to its correct location.

## Paper CTD Example 

- Summary

- Integrated Analysis
- (ISS)

- Text

- Tables &
- Appendices

- Datasets

- {

- 5.3.5.3

- 2.7.4

- Refers reader to 2.7.4 for text portion

## eCTD Considerations

_*Question:*_ When the text portion of the ISS/ISE located in 5.3.5.3 also serves as true summaries for module 2, should it be submitted twice?
_*Answer:*_ No. Submit only once but reference it in both locations (i.e., provide two leaf elements)

## Conclusions

- ISE/ISS are still required components of the CTD/eCTD submitted to the U.S. (21 CFR 314.50)
- They are misnomers: are really *integrated analyses *
- They go in 5.3.5.3
- The text portion of the ISE/ISS can be reused for 2.7 if it meets the requirements for a summary according to ICH M4E.
- No datasets in module 2!
- Remember the recommended size restrictions for 2.7

## Armando Oliva, M.D.
(301) 796-0700
armando.oliva@fda.hhs.gov

- (301) 796-0700
- _[armando.oliva@fda.hhs.gov](mailto:armando.oliva@fda.hhs.gov)_

- Thank You for your attention!!