Confused by FDA Guidance on Standardized Study Data for Electronic Submissions?

Ben Vaughn

• Principal Statistical Scientist

Rob Woolson

• Chief Strategist-Biostatistics & Standards for Regulatory Submissions

Context

FDA has been accepting electronic submissions (as we currently think of them) since the 1999 eNDA Guidance was issued

In 2003 the eCTD Guidance was issued, formalizing the structure of electronic submissions and made a requirement for electronic submissions in 2008

CDER began accepting SDTM in 2004, however FDA had not previously made this a formal requirement

ContextElectronic Standardized Study Data Timeline

(Source: Fitzmartin, PhUSE 2014)

FDASIA 745A(a) Guidance

Binding Guidance Requiring Submissions in Electronic Format

•“Beginning no earlier than 24 months after the issuance of a final guidance issued after public notice and opportunity for comment, submissions under subsection (b), (i), or (j) of section 505 of this Act or subsection (a) or (k) of section 351 of the Public Health Service Act shall be submitted in such electronic format as specified by the Secretary in such guidance.”

Which submissions must be

submitted electronically?

Certain INDs

NDAs

ANDAs

Certain BLAs

Also includes subsequent

submissions, including amendments.

FDA Implementation of New

Requirements

Draft guidances

will be posted for

review

Comment period

Finalization period

Final guidance

announced and posted

No earlier than 24 months

after a final guidance is

issued

Summary of FDASIA 745A(a)

GuidanceUmbrella document to describe the process

This is a BINDING GUIDANCE

Since this is a BINDING GUIDANCE, failure to follow the technical conformance rules can result in a REFUSAL TO FILE.

Assume that this Guidance, and subsequent technical guidances, will apply to all submissions to CDER and CBER.

eStudy Data Guidance

Binding Guidance Requiring a Standardized Data Format

• “This guidance implements the electronic submission requirements of section 745A(a) of the FD&C Act for study data contained in new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), and investigational new drug applications (INDs) to the Center for Drug Evaluation and Research (CDER) or the Center for Biologics Evaluation and Research (CBER) by specifying the format for the electronic submission of such submissions. Submissions that are not submitted electronically and electronic submissions that are not in a format that FDA can process, review, and archive will not be filed or received …”

Which submissions must follow a

standardized data format?

Certain INDs

NDAs

ANDAs

Certain BLAs

Also includes subsequent submissions, including

amendments.

Some exemptions: devices, some INDs.

What standardized formats

MUST be used?

Some examples

•Exchange format: .pdf, .xpt, .xml

•Clinical data: SDTM

•Analysis data: ADaM

•Terminology: CDISC controlled terminology, MedDRA

The standards, formats, and terminologies

specified in the Data Standards Catalog

posted to the FDA’s web page.

And what if standardized

formats are not used?

“The FDA will not provide waivers to submit data that do not conform to any FDA-supported study data standard. However, sponsors or applicants may apply for a waiver from the requirement to use specific versions of standards, formats, or terminologies.”

Timing of Specific Requirements

• Studies starting 24 months after the ‘Transition Date’ – the March 15th after the Federal Register notice

Guidance (e.g., a new

standard)

• Studies starting 12 months after the ‘Transition Date’ – the March 15th after the Federal Register notice

Standards Version Update

Working with the FDA

Meetings with FDA

• Use established FDA-sponsor meetings (e.g., pre-IND, EOP2, etc.) to discuss the study data standardization plan

• Technical questions related to data standards can be submitted at any time to the technical support team identified by each Center; a Type C meeting can be requested for substantive issues

Implementation Support

Summary of eStudy Data

GuidanceFirst Guidance document under the 745A(a) umbrella.

This is a BINDING GUIDANCE

Since this is a BINDING GUIDANCE, failure to follow the technical conformance rules can result in a REFUSAL TO FILE.

Assume that this Guidance, and subsequent technical guidances, will apply to all submissions to CDER and CBER.

Study Data Technical

Conformance GuideTechnical Specifications Document

• Guidance supplements eStudy Data Guidance

• Provides technical specifications briefly described in the eStudy Data Guidance

• Is a single document containing earlier recommendations contained in the Common Data Issues Document and the Study Data Specifications Document.

Study Data Tech Guide -

Contents

Study Data Tech Guide

Background

•Provides technical recommendations; non-binding

•FDA acknowledges that there may be variability in implementation

•Though, deviate at your own risk

•This is intended to be a living document where the FDA updates technical recommendations, preferences, and errors to avoid

Study Data Tech Guide

Study Data Standardization Plan (include in the IND). Should include the following:

• List of planned studies

• Types of studies

• Study designs

• Planned data standards

• List of justifications for studies that do not conform

Study Data Tech Guide

Study Data Reviewer Guide. Should include the following:

• Study protocol, title, number, version

• Study design

• Standards, formats, terminologies

• Description of study datasets

• Data standards conformance validation rules, versions, and issues

Study Data Tech

Study Data Submission Format:

• CDISC: FDA’s strongest endorsement of SDTM/ADaM

In Conclusion …

Read the Guidances

Start conversations with FDA at pre-IND stage regarding data standards

Educate, educate, educate