Optimal Strategies for Preparing Integrated
and Clinical Summaries for a New Drug
Application: Making it Work Under Any
Circumstance
Lisa A. Pierchala, MPH
Principal Medical Writer
MMS Holdings, Inc.
1
Disclaimer
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2
Overview of Presentation
Integrated documents vs summary documents
Integrated Summary of Safety (ISS) and
Summary of Clinical Safety (SCS)
– Overview of content
– Ideal timing for document preparation
– Other alternatives for timing of document preparation
Integrated Summary of Efficacy (ISE) and
Summary of Clinical Efficacy (SCE)
– Overview of content
– Ideal timing of document preparation
– Other alternatives for timing of document preparation
Conclusion
3
Overview of Presentation
Integrated documents vs summary
documents
ISS and SCS
– Overview of content
– Ideal timing for document preparation
– Other alternatives for timing of document preparation
ISE and SCE
– Overview of content
– Ideal timing of document preparation
– Other alternatives for document preparation
Conclusion
4
Integrated Documents vs Summary
Documents
Integrated summaries (ISE and ISS) reside in
Module 5.3.5.3
– Format and Content of the Clinical and Statistical
Sections of an Application (Clin-Stat guidance)
includes outlines of the ISE and ISS; updated in
International Conference on Harmonization (ICH) M4
guidance
Clinical summaries (SCE and SCS) reside in
Module 2.7 (2.7.3 and 2.7.4, respectively).
– ICH M4E Guideline describes the structure and
format of the clinical data (both efficacy and safety) in
an NDA, including summaries and detailed summary
reports
5
Integrated Documents vs Summary
Documents
The FDA requires the ISS and the ISE in
addition to the SCS and SCE (SCS and
SCE alone do not satisfy regulatory
requirement).
The SCS and SCE
are usually derived
from the ISS and
ISE.
Source: http://pixshark.com
6
Integrated Documents vs Summary
Documents
SCS and SCE are not intended to
provide the same level of detail as
presented in the ISS and ISE.
– ISS and ISE are intended to be
comprehensive, integrated analyses of all
relevant data from the clinical study reports.
– SCS and SCE provide a more succinct
summarization of key clinical information.
7
Overview of Presentation
Integrated documents vs summary documents
ISS and SCS
– Overview of content
– Ideal timing for document preparation
– Other alternatives for timing of document preparation
ISE and SCE
– Overview of content
– Ideal timing of document preparation
– Other alternatives for timing of document preparation
Conclusion
8
ISS/SCS – Overview of Content
Summarizes data relevant to safety in the
intended population.
Display of safety related data including:
– Extent of exposure
– Common AEs and changes in laboratory examinations
– Deaths, SAEs, and other significant AEs
9
ISS/SCS – Overview of Content
Content and organization of the SCS
approximately follows the ISS.
What to omit from the ISS:
– Not all tables in the ISS need to be included in
the SCS
– May omit some pooled populations
– May omit full presentation of subgroups
– May omit some special safety topics
10
ISS/SCS – Ideal Timing for Document
Preparation
Key inputs will limit availability to start writing
documents
Pivotal
CSR(s)
All Other
CSRs
(ex. ongoing
long-term safety
studies with interim
data cut)
11
Pooled
TLGs
ISS
SCS
ISS/SCS – Ideal Timing for Document
Preparation
Will present “ideal” scenario for ISS and
SCS preparation assuming:
– Shell/TOC, 2 drafts, QC, final draft
– All inputs are available at the time of writing draft
1 of the documents
For alternatives for timing of ISS and SCS
preparation, will modify assumptions
including:
– Shortened durations
– Parallel development of ISS and SCS
– One less draft of the SCS
– Writing from draft tables
12
ISS/SCS – Ideal Timing for Document
Preparation
Staggered writing of ISS and SCS
Write
shell
~ 15 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISS
changes
changes
1
~5d
~ 20 d
Receipt of final
pooled
TLGs
~ 10 d
~ 10 d
~5d
~5d
~5d
~5d
Incorp
Incorp
Determine
Write Review
Review
draft 1
draft 2 QC
SCS
draft
1
draft
1
draft
2
changes
changes
content
Final
SCS
~5d
~5d
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
13
~5d
ISS/SCS – Ideal Timing for Document
Preparation
Staggered writing of ISS and SCS
Benefits
Content for ISS has largely been determined by the
time you start writing the SCS; more straightforward to
write the SCS and ensures higher quality.
Minimal overlap between the 2 documents prevents
reviewers from having to request the same revisions
multiple times for the same text in both documents.
Drawbacks
Overall duration to write the 2 documents is longer.
Changes requested to later draft of SCS cannot be
applied to ISS.
14
ISS/SCS – Alternatives for Timing of
Document Preparation
Shorter durations in the timeline
Write
shell
~ 10 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISS
changes
changes
1
~5d
~ 15 d
Receipt of pooled
TLGs
~5d
~5d
~5d
~5d
~5d
Incorp
Incorp
Determine
Write Review
Review
draft 1
draft 2 QC
SCS
draft
1
draft
1
draft
2
changes
changes
content
Final
SCS
~5d
~5d
~ 10 d
~ 10 d
~3d
~5d
Overall time frame: ~ 76 days
15
~5d
~3d
~5d
ISS/SCS – Alternatives for Timing of
Document Preparation
Shorter durations in the timeline
Benefits
Overall duration to write the 2 documents is shorter.
Drawbacks
These documents can be HUGE and the same
amount of work will need to go into them regardless
of the number of days provided to write.
This is the first time integrated data across the
program are available. Time is needed to fully
review and describe data.
Risk to quality.
Employee burnout.
16
ISS/SCS – Alternatives for Timing of
Document Preparation
Parallel writing of ISS and SCS
Write
shell
~ 15 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISS
changes
changes
1
~5d
~ 20 d
~ 10 d
~ 10 d
~5d
~5d
~5d
Determine
Incorp
Incorp
Write Review
Review
SCS
draft 1
draft 2 QC
draft
1
draft
1
draft
2
content
changes
changes
~ 10 d
~ 10 d
~5d
~5d
~5d
~5d
~5d
Overall time frame: ~ 80 days
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~5d
Final
SCS
~5d
ISS/SCS – Alternatives for Timing of
Document Preparation
Parallel writing of ISS and SCS
Benefits
Overall duration to write the 2 documents is shorter.
Drawbacks
The text for the same data is being written twice in 2
different documents, therefore, there will likely be
discrepancies in content.
The reviewers are reviewing the same/similar text at
almost the same time; challenging to ensure that
appropriate changes are being made in both
documents.
SCS is finalized first. Changes requested to later draft
of ISS cannot be applied to SCS.
18
ISS/SCS – Alternatives for Timing of
Document Preparation
One less draft of the SCS
Write
shell
~ 15 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISS
changes
changes
1
~5d
~ 20 d
Receipt of pooled
TLGs
~ 10 d
~ 10 d
~5d
~5d
~5d
Determine
Incorp
Write Review
SCS
draft 1 QC
draft
1
draft
1
content
changes
~ 10 d
~ 10 d
~5d
Overall time frame: ~ 90 days
19
~5d
~5d
~5d
Final
SCS
~5d
ISS/SCS – Alternatives for Timing of
Document Preparation
One less draft of the SCS
Benefits
Overall duration to write the 2 documents is
shorter.
Drawbacks
Reviewers only have 1 opportunity to review the
SCS. Requires a commitment from the team to
provide a very detailed review of a critical
submission document.
20
ISS/SCS – Alternatives for Timing of
Document Preparation
Writing from draft TLGs
Write
shell
~ 15 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISS
changes
changes
1
~5d
~ 20 d
Receipt of
draft
pooled
TLGs
~ 10 d
~ 10 d
~5d
~5d
~5d
~5d
Receipt of
Incorp
Incorp
Determine
final
Write Review
Review
Final
draft 1
draft 2 QC
SCS
pooled
SCS
content draft 1 draft 1 changes draft 2 changes
TLGs
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
21
~5d
~5d
~5d
ISS/SCS – Alternatives for Timing of
Document Preparation
Writing from draft TLGs
Benefits
Overall duration is not shorter, but you can
start Draft 1 sooner, therefore finishing sooner.
Drawbacks
If corrections are made to tables between draft
and final, an additional step needs to be
added to ensure data in the document is
accurate.
Risk to quality.
22
Overview of Presentation
Integrated documents vs summary documents
ISS and SCS
– Overview of content
– Ideal timing for document preparation
– Other alternatives for timing of document preparation
ISE and SCE
– Overview of content
– Ideal timing of document preparation
– Other alternatives for timing of document preparation
Conclusion
23
ISE/SCE – Overview of Content
Summarizes efficacy and other information (ie,
demographics, baseline disease characteristics,
etc) from controlled studies and other pertinent
studies that evaluated efficacy specific to the
indication.
SCE provides summaries of data, not a
complete presentation of all integrated data that
is presented in the ISE.
24
ISE/SCE – Overview of Content
Content and organization of the SCE
approximately follows the ISE.
Differences between content of ISE and
SCE:
– Detailed descriptions of analytical methods
included in the ISE
– SCE may omit some secondary or exploratory
analyses that may be included in the ISE
– SCE may focus only on dose(s) sought for
approval
– Tables and figures should be used to enhance
understanding of the data; lengthy tables should
only be included in the ISE
25
ISE/SCE – Overview of Content
Pooling of data
“Individual controlled studies to a great extent
speak for themselves with respect to their ability
to provide evidence of effectiveness required by
law.”
Studies are not always pooled – depends on
the design of the studies. “…particular attention
should be paid to statistical considerations,
selection bias in choosing studies, etc.”
Guideline for the Format and Content of the Clinical
and Statistical Sections of an Application (FDA)
26
ISE/SCE – Ideal Timing for Document
Preparation
Key inputs will limit availability to start writing
documents
Pivotal
CSR(s)
Pooled
TLGs
Other CSRs
(ex. long-term efficacy
studies with interim
data cut)
27
Pop
PK
ISE
SCE
ISE/SCE – Ideal Timing for Document
Preparation
Often more variability in when inputs are
available for writing of efficacy documents:
– Programming of pooled TLGs can begin at
database lock of final pivotal study(ies); pooled
TLGs may be available before final CSR(s).
– If minimal data is being pooled (ex: only pooled
data for subgroups), the majority of the ISE
writing can begin once final pivotal CSRs are
available.
– Population PK reports can take a significant
amount of time after database lock of final pivotal
study(ies); often the last piece received for the
ISE/SCE.
28
ISE/SCE – Ideal Timing for Document
Preparation
Many of the scenarios described for the
ISS/SCS can also be duplicated for the
ISE/SCE (are not repeated in subsequent
slides):
– Shortened durations
– Parallel development of ISE and SCE
– One less draft of the SCE
29
ISE/SCE – Ideal Timing for Document
Preparation
Will present “ideal” scenario for ISE and SCE
preparation assuming:
– Shell/TOC, 2 drafts, QC, final draft
– All inputs (final pivotal CSRs and final pooled
TLGs) are available at the time of writing draft 1
of the documents
For alternatives for timing of ISE and SCE
preparation, will modify assumptions including:
– Writing from draft CSRs with final pooled TLGs
available OR writing from draft TLGs with final
CSRs available
– Varying when final inputs are available.
30
ISE/SCE – Ideal Timing for Document
Preparation
Staggered writing of ISE and SCE
Write
shell
~ 15 d
Incorp shell
Incorp
Incorp
Final
Review changes/ Review
Review
draft 1
draft 2 QC
shell write draft draft 1
draft 2
ISE
changes
changes
1
~5d
~ 20 d
Receipt of
final CSR(s)
and final
pooled TLGs
~ 10 d
~ 10 d
~5d
~5d
~5d
~5d
Incorp
Incorp
Determine
Write Review
Review
draft 1
draft 2 QC
SCE
draft
1
draft
1
draft
2
changes
changes
content
Final
SCE
~5d
~5d
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
31
~5d
ISE/SCE – Ideal Timing for Document
Review
Staggered writing of ISE and SCE (with all
sources available)
Benefits
Content for ISE has largely been determined by the
time you start writing the SCE; more straightforward to
write the SCE and ensures higher quality.
Minimal overlap between the 2 documents prevents
reviewers from having to request the same revisions
multiple times for the same text in both documents.
Drawbacks
Overall duration to write the 2 documents is longer.
Changes requested to later draft of SCE cannot be
applied to ISE.
32
ISE/SCE – Alternatives for Timing of
Document Preparation
Writing from draft CSRs with final pooled TLGs
Incorp
Incorp
Write Review Draft Draft Review
Final
Review
draft 1
draft 2 QC
shell shell
1a
1b draft 1 changes draft 2 changes
ISS
~ 15 d
~5d
~ 15 d
Receipt
of draft
CSR(s)
and final
pooled
TLGs
~ 5 d ~ 10 d
Receipt
of final
CSR(s)
~ 10 d
~5d
~5d
~5d
~5d
Incorp
Incorp
Determine
Write Review
Review
draft 1
draft 2 QC
SCS
draft
1
draft
1
draft
2
changes
changes
content
Final
SCS
~5d
~5d
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
33
~5d
ISE/SCE – Alternatives for Timing of
Document Preparation
Writing from draft CSRs with final pooled TLGs
Benefits
Overall duration is not shorter, but you can start
Draft 1 sooner, therefore finishing sooner (ie, not
waiting for the pivotal CSR(s) to be final).
Preparation of ISE and SCE is still staggered.
Drawbacks
If there are changes between the draft and final
CSR(s), an additional step needs to be added to
ensure data in the document is accurate.
Risk to quality.
34
ISE/SCE – Alternatives for Timing of
Document Preparation
Writing from draft pooled TLGs with final CSRs
In general, the timing is the same as in the
previous example
– If there are changes between draft and final TLGs, an
additional step needs to be added to confirm that the
information in the document is accurate.
35
ISE/SCE – Alternative for Timing of
Document Preparation
Varying when final inputs are available
Incorp draft
Incorp
Write Review Prepare Review 1 changes; Review
draft 2 QC
shell shell Draft 1 draft 1 incorp final draft 2 changes
TLGs
~ 15 d
~5d
~ 15 d
Receipt
of final
CSR(s)
~ 10 d
~ 15 d
~5d
~5d
~5d
Final
ISS
~5d
Receipt
of final Determine Write Review Incorp Review Incorp
Final
draft 1
draft 2 QC
SCS
pooled
draft 1 draft 1 changes draft 2 changes
SCS
TLGs content
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
36
~5d
~5d
~5d
ISE/SCE – Alternative for Timing of
Document Preparation
Varying when final inputs are available
Incorp draft
Incorp
Write Review Prepare Review 1 changes; Review
draft 2 QC
shell shell Draft 1 draft 1 incorp final draft 2 changes
TLGs
~ 15 d
~5d
~ 15 d
Receipt
of draft
CSR(s)
and draft
pooled
TLGs
~ 10 d
~ 15 d
~5d
~5d
~5d
Final
ISS
~5d
Receipt of final CSR(s)
Receipt
of final
pooled
TLGs Determine Write Review Incorp Review Incorp
Final
draft 1
draft 2 QC
SCS
SCS
content draft 1 draft 1 changes draft 2 changes
~ 10 d
~ 10 d
~5d
~5d
~5d
Overall time frame: ~ 100 days
37
~5d
~5d
~5d
ISE/SCE – Alternative for Timing of
Document Preparation
Varying when final inputs are available
Writing from draft pooled TLGs or draft pivotal
CSR(s) is an option and when these inputs will be
received can vary.
Time must be given to verify the ISE/SCE against
the final CSR(s) and final pooled TLGs to ensure
data in the document is accurate.
Risk to quality.
38
Overview of Presentation
Integrated documents vs summary documents
ISS and SCS
– Overview of content
– Ideal timing for document preparation
– Other alternatives for timing of document preparation
ISE and SCE
– Overview of content
– Ideal timing of document preparation
– Other alternatives for timing of document preparation
Conclusion
39
Conclusion
Overall Summary
Staggered preparation of the ISS/SCS and
ISE/SCE is an optimal approach for preparing
the documents.
Utilizing the alternatives for timing of document
preparation depends on the level of risk that a
Sponsor is willing to assume.
It is possible to combine multiple approaches
(ex: shorter durations + one less draft of the
SCS), depending on how aggressive the
Sponsor is willing to be.
40
Thank You
Lisa A. Pierchala, MPH
Principal Medical Writer
MMS Holdings, Inc.
Join the conversation #DIA2015
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