dia_2016_turner_ers 2015 lessons learned 2.9.16

Adair Turner, MS, RACDIA ERS Community ChairpersonArivis, Inc.

Electronic Regulatory Submissions 2015 Lessons Learned

Disclaimer

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© 2016 DIA, Inc. All rights reserved.

Agenda

DIA ERS Community UpdateMany Changes, Many LessonsTools and Tips


DIA Electronic Regulatory Submissions Community

Community meetings are held the 4th Tuesday of each month

eCTD Technical

Conformance Guide

Comments

Annual ERS Community Survey• Now accepting

questions until the end of March

• Survey to run from April to June

Reg Ops Blog (

http://www.regopsblog.com/

)

FDA eSub FAQ

Repository

https://siac-ers.diaconnex.org/



https://siac-ers.diaconnex.org/

ERS Community Comments on the eCTD Technical Conformance Guidance

Section Guidance Text Comment2.5. eCTD Life Cycle N/A Should we be using "append" or "new" every time we

submit a STF?2.6 Presubmissions "Any information submitted in eCTD format

before the “original-application” should be coded as "presubmission" and should use sequence 0001."

Our understanding is that we should never use sequence 0000 and that it unacceptable to use 9990 (or any such number) for presubmissions.

2.6 Presubmissions "There is no requirement for the IND serial number and the eCTD sequence number to match."

Our understanding is that we need to include both the serial number and the sequence numbers in the cover letter.

3.1.2. Cover Letter "Technical description of the submission, including the approximate size of the submission."

Please clarify how the Agency uses this information as it is inconvenient to add post-publishing.

3.1.2. Cover Letter "A regulatory and technical point of contact for the submission..."

If applicable, should this be the eCTD vendor?

3.1.3. Reviewer's Guide "Rather an outline format describing the submission's content is preferred, including tables or lists…"

We are not familiar with the "tables and lists" that should be included. Please add detail/clarification around what should be included.

3.4.2. Literature References

N/A Do we need to include bookmarks for literature references?

3.5.2. Study Reports "If a document has been provided in a previous submission, provide only an eCTD leaf reference…"

Please provide additional information on cross-leafs.

3.5.5. IND Safety Reports

"Each IND safety report should be submitted as “new” without replacing any previously submitted information."

Should the "replace" lifecycle operation be used for a Follow-Up to an IND Safety Report?

Why was 2015 different?

Submissions <10 GB MUST be submitted via Electronic Submission Gateway (ESG).

October 2015eCTD Technical Conformance Guide Issued

Dec 17, 2016 Clinical and animal study datasets MUST be submitted in CDISC format.

May 5, 2017NDAs, BLAs, ANDAs, & DMFs MUST be submitted in eCTD format.

May 5, 2018INDs MUST be submitted in eCTD format.


Submissions that do not adhere to these requirements

will be subject to rejection.

Major Lesson Learned

Understand eCTD fundamentals!!!

1) Being a super smart scientist is not enough2) Being an expert on the drug approval regulations is not enough

You need experienced

and dedicated resources

Make training a

priority

Trust the experts

Appreciate the

complexity

Allow enough

time

AuthoringESG PDFAttributes DatasetsBookmarking/Linking

Training

Who needs it?• Authors (to write documents correctly)• Management (to understand why they need to invest

in tools, training, etc.)• eCTD worker bees (to submit)Where can I get it for free?• FDA's eCTD Training

http://www.accessdata.fda.gov/scripts/cder/training/eCTD/intro/intro/index01.htm



Training Resources

Read the relevant guidance documents, regulations, and presentations on the FDA eCTD Webpage.• eCTD Basics and Getting Started• Electronic Submissions Gateway• eCTD Submission Standards

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/ucm153574.htm





http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/default.htm

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM446272.xls

http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/UCM446272.xls

Electronic Submissions Gateway Setup

FDA’s preferred method of transmissionThe FDA ESG is able to receive and process regulatory submissions up to 100 GB in sizeMake sure to check FDA website each time you set up a new account to ensure nothing changed• Checklist for Setting up a WebTrader Account with the

FDA Electronic Submissions Gateway (ESG)Requires a personal digital certificateRequires registration, load testing, and a guidance compliant test submission before receiving a production account


ESG Tips

To ensure all files were successfully transmitted, check the number of files information in the acknowledgement.


Attribute Options

Note: FDA wants to see the Drug Product name although it is technically not required

Highlighted items are suggestions for keeping your XML outline flexible

Not required

Required

Presubmissions

Any information submitted in eCTD format before the “original-application” should be coded as "presubmission" and should use sequence 0001.

The original application will use the next available sequence number (0002 in this case) depending on the number of submitted “presubmissions.”

Signed FDA forms are not required for presubmissions.

If you are going to submit using the Electronic Submission Gateway (ESG), include a completed fillable form without a signature.

For INDs, the serial number field can be left blank for presubmissions and should be used only starting with the original application.

There is no requirement for the IND serial number and the eCTD sequence number to match.


Referencing Previously Submitted Documents

Do not resubmit documents already submitted in paper or other electronic format. Provide only new or changed information.Reference previously submitted information in 1.4.4 Cross reference to other applications. If a document has been provided in a previous submission (e.g., protocol), provide only an eCTD leaf reference to the protocol in the eCTD backbone file, rather than resubmitting the protocol file.


Referencing Previously Submitted Documents

If a document was previously submitted in paper, you should reference the document as with any paper submission.In the text of the document, you should reference the document by including the:

• Application or master file number • Date of submission• Submission identification (e.g. serial number for INDs)

PDF Errors

Render PDFs from source documents so that they are text-based and searchable• Avoid scanned documents • Use OCR if you must scan a document • Talk to your vendors early about how they plan to

provide final documentsUse only standard fonts (fully embed all non-standard fonts if you must use them)PDF file size limit is 400MB per the Specifications for eCTD Validation Criteria


Datasets

Datasets need lifecycle operations too!Not every dataset will be “new”.Replace old datasets with new datasets.Describe changes in the cover letter and update your reviewers guide.Work with data providers to establish processes for notifying Reg Ops of dataset lifecycle operations.Run datasets through the free CDISC validator to check for errors.

Allow Enough Time

ESG can take more than 1 month to setupStandard publishing timelines:– General Correspondence – 24 hours or more– Information/Labeling Amendment – 2 days or more – Report/Document – 2 days or more– Clinical Study Report – 2 days or more– Annual Report – 4 days prior to agency due date– Original Applications and Supplements – 2 weeks or more

Submission Tracker

Complete the Submission Tracker to communicate details of the submission:

What’s “the gap”?

Compliant?

Does it make

sense?Content

Final Thoughts

Take the time to understand eCTDJoin industry groups and take advantage of FDA resourcesPut yourself in the reviewer’s shoes