tiepu liu, md, phd fmd k&l - cdisc · under section 745(a) of the federal food, drug, and...

© CDISC 2017

Tiepu Liu, MD, PhD

President of Global Biometrics

FMD K&L

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Understanding the Guidance to Prepare

Submission Packages

© CDISC 2017

Common Acronyms

• IND: Investigational New Drug Application

• NDA: New Drug Application

• BLA: Biologics License Application

• ANDA: Abbreviated New Drug Application

• ICH: International Conference on Harmonization

• CTD: Common Technical Document

• eCTD: electronic Common Technical Document

• CDER: Center for Drug Evaluation and Research

• CBER: Center for Biologic Evaluation and Research

• RTF/RTR: Refuse To File/Refuse To Receive

• EMA: European Medicines Agency

• PMDA: Pharmaceuticals and Medical Device Agency, Japan

• CFDA/SFDA: China Food and Drug Administration

• CDE: Center for Drug Evaluation

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Pharmaceutical R&D

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R: Research Discovery of compounds, series of testing with cell lines, pre-clinical trials with animals including toxicology studies

D: Development Clinical Development

Phase I, Phase II, Phase III,

and Phase IV

Phase I, II, and III are before marketing approval.

Phase IV is post marketing

Submission (NDA, BLA, etc.) is the step to get marketing approval

Pharmaceutical R&D

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Submission: Standardization

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Paper Submissions

ICH E3, E6, and E9

Common Technical Document (CTD)

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Paper Submission Challenges

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Paper Submission Challenges

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21 CFR Part 11

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• Federal Register of March 20, 1997 (62 FR 13430), the

FDA published the Electronic Records; Electronic

Signatures Regulation (21 CFR Part 11)

• A voluntary submission of parts of all regulatory records in

electronic format without an accompanying paper copy

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FDA 99 Guidance

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1999: Guidance for the Industry: Providing Regulatory Submissions in Electronic Format – General Considerations

File Formats for Electronic Documents

• Portable Document Format (PDF, www.adobe.com)

• PDF replaced papers

File Formats for Electronic Datasets

• SAS System XPORT Transport Format (Version 5)

• Little details on the dataset names and variable names

• File size < = 25 M

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eCTD

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Electronic Submission Challenges

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CDER receives 150,000 submissions each year

amounting to millions of pieces of data.*

Source: Data Standards Panel Discussion

November 30, 2011 CDISC

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Electronic Submission Challenges

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1997: CDISC

CDISC: Clinical Data Interchange Standards Consortium

No standards

Companies have their own standards

Even the same company has different standards

FDA Medical and Statistical Reviewers have to learn all these to review the NDA/BLA filing; big headache for the reviewers

© CDISC 2017

US Food & Drug Administration

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““New” Mission Statement per Dr. Wilson from the FDA

• The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.

• The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

© CDISC 2017

FDASIA

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Food and Drug Administration Safety and Innovation Act

Signed into law since 1992

Expands FDA authority to collect user fees (approx. 2 million dollars with clinical piece) to fund product reviews and promote innovation to speed patient access to safe and effective products.

sixth reauthorization of the PDUFA VI (Prescription Drug User Fee Act) (must be reauthorized every 5 years)

© CDISC 2017

CDISC and FDA

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• July of 2004, Study Data Specification referenced in eCTD guidance

• December of 2006, FDA announced intention to make SDTM required by regulation

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Milestones

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• FDA published two guidance documents and four technical specification documents on 12/17/2014

• Providing Regulatory Submissions in Electronic Format –Submissions Under Section 745(a) of the Federal Food, Drug, and Cosmetic Act

• Providing Regulatory Submissions in Electronic Format –Standardized Study Data (eStudy Data Guide)

• Data Standards Catalog

• Study Data Technical Conformance Guide: Technical Specifications Document

• FDA-specific SEND Validation Rules

• FDA-specific SDTM Validation Rules

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Why Implement These Changes?

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“The submission of standardized study data enhances a reviewer’s ability to more fully understand and characterize the

efficacy and safety of a medical product.” *

*Source: FDA “Study Data Standards for Regulatory Submissions Position Statement,” 9/13/2013

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Binding Guidance

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• Providing Regulatory Submissions in Electronic Format – Submissions

Under Section 745(a) of the Federal Food, Drug, and Cosmetic Act

• Requires electronic submissions 24 months following the issuance

of final guidance for NDAs, ANDAs, BLAs and INDs (36 months)

• If not submitted electronically, will result in Refuse To File (RTF) or

Refuse To Receive (RTR)

• Timetable of further standards

• Criteria for waivers and exemptions

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Binding Guidance

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• Providing Regulatory Submissions in Electronic Format - Standardized

Study Data

• Applies to all NDAs, ANDAs, BLAs, and INDs

• 24 months after issuance of final guidance, data must submitted in

standardized formats for NDAs, ANDAs and BLAs

• 36 months for INDs

• Standardized formats: SEND, SDTM and ADaM

• No waivers for eStudy requirement, though possible for data standard

versions in the Data Standards Catalog (DSC)

• Submissions not in electronic format(s) will not be filed (RTF) or received

(RTR) if the study data does not conform to required standards, formats,

and/or terminologies

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Non-Binding Guidance

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• Study Data Technical Conformance Guide

• Replaced Study Data Specifications and CDER Common Data

Standards Issues Document

• Data Standards Catalog (DSC) lists formats for exchange format,

study data, and controlled terminology standards that the FDA can

process, review, and archive.

• Exchange format: PDF, XPT and XML

• Study Data: SEND, SDTM and ADaM

• Controlled Terminology: NDF (National Drug File), CDISC CT, and

MedDRA, etc.

• Includes required and/or supported versions

• Key dates for each standard requirement and support begins/ends

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Required Study Data standards

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Pre-Clinical

Research

I

N

D Clinical Studies

N

D

A

Phase I

Phase II

Phase III

NDA Review

Submission Stage Submission Stage

SEND ModelSDTM / ADaM /Define XML

SDRG / ADRG

Standardized Study Plan

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Timetable for implementation

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Topic 2013 2014 2015 2016 2017 2018

Draft

Guidance

90-day

comment

Final

Guidance

DSC

NDA, BLA,

ANDA IND

Electronic

Format

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Data Standards Catalog

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Planning With the end in Mind

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Study Data Standardization Plan (SDSP)

What studies will be in required standards?

What studies will be in legacy study data formats?

eCTD test submission?

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Communication with the FDA

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Sponsor/FDA meetings such as pre-IND, end of phase II, Type C, pre-NDA

Email to FDA (CDER: [email protected];

CBER: [email protected])

Discuss Study Data Standardization Plan (SDSP) no later than end of phase II meeting; pre-NDA/pre-BLA meetings considered too late

eCTD Test Submission: Prepare data and documents and send to FDA for comments

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Standardized Study Data Package

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• SEND Data Package

• acrf.pdf

• xpt files

• define.xml

• Study Data Reviewer’s Guide (nSDRG.pdf)

• SDTM Data Package

• acrf.pdf

• xpt files

• define.xml

• Study Data Reviewer’s Guide (cSDRG.pdf)

• ADaM Data Package

• xpt files

• define.xml

• Analysis Data Reviewer’s Guide (ADRG.pdf)

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Legacy Study Data Package

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• Legacy Data: Data not in SEND, SDTM and ADaM formats

• FDA Binding Guidance: Studies initiated 24 months after the

issuance of final guidance need standardized study data. Study

Initiation: The earliest date of a subject signed informed consent.

• Raw Data Package

• acrf.pdf

• xpt files

• define.pdf

• Analysis Data Package

• xpt files

• define.pdf

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Study Data: Legacy to Standardized Conversion

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Plan early for the re-mapping tasks. It can be done early if the decision is to convert legacy study data to standardized study data.

• Clinical Study Report (CSR) based on legacy data

• Key data verification with SDTM/ADaM datasets

Traceability is critical

• Pool at SDTM or ADaM level

• SDTM/ADaM version, CT version

• WHO Drug dictionary version

• MedDRA dictionary version

Pooling strategy for ISS/ISE

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Guidance from CDE

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• 2017-05-30• 药品电子通用技术文档结构（征求意见稿）• 化学仿制药电子通用技术文档申报指导原则（征求意见稿）

• 2016-06-27 • 药物临床试验数据管理工作技术指南

• 为了提高临床试验数据质量以及统计分析的质量和效率，方便数据的交流与汇总分析，在新药上市注册申请时，建议采用CDISC标准递交原始数据库和分析数据库。

• 药物临床试验数据管理与统计分析的计划和报告指导原则

• 药物临床试验的电子数据采集技术指导原则

• 药物临床试验的生物统计学指导原则

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Guidance from CDE

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• 2017-06-01

• 关于补交“临床试验数据库”资料的通知

• 2、已锁定的“临床试验数据库”（光盘）中应包括原始数据库、分析数据库及相应的变量说明文件，且数据库应为SAS XPORT传输格式（即xpt格式）。

• 3、已锁定的数据库光盘一式两份，并分别装入光盘盒中，盒上须注明文件类型：数据库，同时注明受理号、品名、申报单位(须加盖申报单位公章)、统计软件名称、数据管理单位、数据统计单位等。

© CDISC 2017

Challenge and Opportunity

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• Guideline vs. Notice

• Lifecycle Management

• Multiple Regional Submission

• XML vs XPT

• Quality