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Preparing an eSubmission based on multiple trials, some of which are ongoing

– challenges for statistical programming

Åsa Carlsheimer, Statistical Programming Director

PhUSE October 9-11, 2011

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Outline

1.  Introduction 2. Data standards 3. Data repository 4. Output programs 5. Planning and communication 6. Key message

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Introduction

Drug FER123 was approved by FDA and EMEA in 2009

Different dose and longer treatment duration now investigated

1 pivotal phase III trial

17 completed phase II-IIIb trials

8 ongoing phase IIIb trials

Scope of new eSubmission

Combined safety & efficacy analysis for FER123

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Data standards

l  Implementation –  Early 2009 based on draft CDISC ADaM 2.1

l  Maintenance –  All new trials across all projects and therapeutic areas

l  Benefits –  One common standard –  Customization, recognition, facilitating communication

with other functions –  Easy to integrate in a repository –  Submission ready

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. . . . .

Study 1

Study 10

Study 2

Study Analysis Database

Compound Analysis Database (CAD)

*.SAS

Study 11

Study 12

Study 17

CAD

Studies included in the previous

submission

Migration process

CAD

Migration to ADaM

*.SAS Validation of repository

Integrate repository

*.SAS

Submission repository

MedDRA dictionary

Harmonize MedDRA codes

Study 18

Study 14

Study 25

Cut-off

*.SAS

Repository Database

*.SAS

Create combined treatment codes

Data repository

. . . .

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Repository learnings

Ø  Discuss expectations on level of data cleaning for cut-off

Ø  Include time for coding of ongoing trials after cut-off in timelines

Ø  Agree on version of MedDRA dictionary for pivotal trial and Integrated Summary of Safety (ISS)

Ø  Document outcome of repository validation together with actions and responsible programmer

Ø  Easy to underestimate the resources & time needed for cleaning up the ongoing trials

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ISS/ISE Statistical Analysis Plan (SAP)

Output specification

*.SAS

Grouping macros

*.SAS Standard programs

*.SAS

ISS/ISE unique programs

*.TAB *.CGM

ISS/ISE output

Subgroups (age, weight, race, geographic region, disease severity)

Pooled trials (phase 2/3, phase IIIb), dose/regimens, controlled/uncontrolled

Output program set-up

(>1100 TLFs)

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Output program learnings

Ø  Include an option to present data by multiple trials when developing standard programs (for ISS/ISE)

Ø  >1100 TLFs need to split in to several documents (consider numbering)

Ø  Test transfer to eCTD tool (pdf-size, templates, bookmarks, hyperlinks)

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Planning and communication

Submission team 13 statistical programmers (including biostatisticians and off-shore)

Weekly internal programming/biostat meetings (status, issues, validation strategies, assign tasks to person)

One representative in the regulatory led cross-functional team

Structured programming approach using planning tools

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Delivery times after database lock

ü  Pivotal phase III trial (500 TLF) within 1 week

ü  ISE (200 TLF) within 2 weeks

ü  ISS (900 TLF) within 3 weeks

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Key message To prepare for a submission based on multiple trials, some of which are ongoing is a complex and challenging task!

Utilizing the following will facilitate the work and ensure timely deliveries:

•  Implemented ADaM standards

•  Maintaining data repository

•  Clear programming and validation strategy

•  Good communication & planning

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Questions/comments?

Contact information: asa.carlsheimer@ferring.com

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Data format considerations

Read eCTD to FDA “Study Data Specifications 1.5”

Define file (metadata and logic) generated from ADaM specifications in Word

Format SAS transport files *.xpt maximum 400 MB

Ferring eCTD system limitation of 100 MB

ADLB > 830 MB = ADLB1, ADLB2,----,ADLB10

Split by subject, site, X number of observations?