1 Optimal Strategies for Preparing Integrated and Clinical Summaries for a New Drug Application:...

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Optimal Strategies for Preparing Integrated and Clinical Summaries for a New Drug Application: Making it Work Under Any CircumstanceLisa A. Pierchala, MPH

Principal Medical Writer

MMS Holdings, Inc.

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The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Communities or affiliates, or any organization with which the presenter is employed or affiliated.

These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners.

Disclaimer

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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

Overview of Presentation

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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


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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

Integrated Documents vs Summary Documents

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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

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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.


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ISE and SCE– Overview of content– Ideal timing of document preparation– Other alternatives for timing of document preparation

Conclusion


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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

ISS/SCS – Overview of Content

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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

ISS/SCS – Overview of Content

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Key inputs will limit availability to start writing documents

ISS/SCS – Ideal Timing for Document Preparation

ISS

Pivotal CSR(s)

All Other CSRs

(ex. ongoing long-term safety

studies with interim data cut)

Pooled TLGs

SCS

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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


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Staggered writing of ISS and SCS


Write shell

Review shell

Incorp shell changes/ write draft

1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 20 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

Overall time frame: ~ 100 days

Not

drawn

to scale!

Receipt of finalpooledTLGs

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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.


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Shorter durations in the timeline

ISS/SCS – Alternatives for Timing of Document Preparation

Write shell

Review shell


1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 10 d ~ 5 d ~ 15 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 3 d ~ 5 d ~ 3 d ~ 5 d ~ 5 d ~ 5 d

Receipt of pooledTLGs


Not

drawn

to scale!

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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.


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Parallel writing of ISS and SCS


Write shell

Review shell


1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 20 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d


Not

drawn to

scale!

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Parallel writing of ISS and SCS

Benefits


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.


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One less draft of the SCS


Write shell

Review shell


1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 20 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

Receipt of pooledTLGs


Not

drawn to

scale!

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One less draft of the SCS

Benefits


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.


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Writing from draft TLGs


Write shell

Review shell


1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 20 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d


Receipt of draft

pooled TLGs

Receipt of final

pooled TLGs

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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.


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Conclusion


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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.

ISE/SCE – Overview of Content

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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


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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)


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Key inputs will limit availability to start writing documents

ISE/SCE – Ideal Timing for Document Preparation

ISE

Pivotal CSR(s)

Other CSRs (ex. long-term efficacy

studies with interim data cut)

Pooled TLGs

SCE

Pop PK

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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.


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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


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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.


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Staggered writing of ISE and SCE


Write shell

Review shell


1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISE

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCE

Determine SCE

content

~ 15 d ~ 5 d ~ 20 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d


Not

drawn

to scale!

Receipt of final CSR(s)

and final pooled TLGs

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ISE/SCE – Ideal Timing for Document Review

Staggered writing of ISE and SCE (with all sources available)

BenefitsContent 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.

DrawbacksOverall duration to write the 2 documents is longer.Changes requested to later draft of SCE cannot be applied to ISE.

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ISE/SCE – Alternatives for Timing of Document Preparation

Writing from draft CSRs with final pooled TLGs

Write shell

Review shell

Draft 1a

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 15 d ~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d


Receipt of draft CSR(s)

and final pooled TLGs

Draft 1b

~ 5 d


Not

drawn

to scale!

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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.

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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.

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ISE/SCE – Alternative for Timing of Document Preparation

Write shell

Review shell

Prepare Draft 1

Review draft 1

Incorp draft 1 changes; incorp final

TLGs

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 15 d ~ 10 d ~ 15 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d



Receipt of final pooled TLGs

Not

drawn

to scale!

Varying when final inputs are available

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Write shell

Review shell

Prepare Draft 1

Review draft 1

Incorp draft 1 changes; incorp final

TLGs

Review draft 2

Incorp draft 2

changesQC

Final ISS

Write draft 1

Review draft 1

Incorp draft 1

changes

Review draft 2

Incorp draft 2

changesQC

Final SCS

Determine SCS

content

~ 15 d ~ 5 d ~ 15 d ~ 10 d ~ 15 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d

~ 10 d ~ 10 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d ~ 5 d


Receipt of draft CSR(s)

and draft pooled TLGs

Receipt of final pooled TLGs

Not

drawn

to scale!



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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.

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Conclusion


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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.

Conclusion

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Lisa A. Pierchala, MPH

Principal Medical Writer

MMS Holdings, Inc.

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