Is your clinical data ready for submission?

Presented by: Gil Harari, Eyal WultzApril 2014

Strategy and statistical considerations in clinical trials planning (Gil Harari, MediStat)

Clinical data submission – which way to go? (Eyal Wultz, Bioforum)

Q&A

IATI ROUNDTABLE - AGENDA

Bioforum Regulatory Services Clinical Data Standardization – importance and

priority Legacy-based submission CDISC-based submission Which way to go?

CLINICAL DATA SUBMISSION

BIOFORUM SERVICES

• Documents publishing• eCTD compilation• Lifecycle management

• Clinical programming – study support (tables, listings, figures)

• Prepare data for submissions

Bioforum Regulatory Services

Regulatory Operations

Clinical Programming

BIOFORUM REGULATORY SERVICES

Over 100 studies to date

Over 40 submissions to the FDA, EMA, UK, Germany, Spain

Pharmacovigilence Operations

• Adverse events processing and reporting

• CIOMS, MedWatch,…• PSURs, DSURs,

THE IMPORTANCE OF CLINICAL DATA STANDARDS

• There has been a sharp increase in Refuse-to-File (RTFs) issued by the FDA from 2009 onwards1

• Main reasons include2 – Clinical data deficiencies and ‘Data Presentation’

(~39%) CMC issues (~28%) eCTD issues (25%) Other (8%)

1 June 2011 issue of Nature Reviews: Drug Discovery, Volume 10, page 4032 Based on publically-available RFTs.

Sanofi, Bayer’s Lemtrada receives FDA refuse-to-file letter in relapsing MSBy Lianne Dane , Created 08/27/2012 - 08:35

Sanofi’s Genzyme unit on Monday announced that it received a refuse-to-file letter from the FDA regarding its application for the approval of Lemtrada (alemtuzumab) as a treatment for relapsing multiple sclerosis. "We have had constructive dialogue with the FDA, and we are very confident in our ability to address the agency’s request and resubmit rapidly," remarked Genzyme CEO David Meeker. Genzyme, which is developing the therapy with Bayer, said regulators requested that the company "modify the presentation of the data sets to enable the agency to better navigate the application." However, the agency did not request additional data or further studies, the company noted. The drugmaker indicated that a filing submitted to the European Medicines Agency was accepted and the review process is underway. Last week, Sanofi announced that it was withdrawing a stronger dose of the therapy, which is sold under the brand name Campath, in the US and EU to prepare for the launch of Lemtrada.

THE IMPORTANCE OF CLINICAL DATAS STANDARDS

PREPARING CLINICAL DATA FOR SUBMISSION

Prepare clinical data for

Submission

Submission Data

Package

Legacy Package

ConversionCDISC

Conversion

LEGACY-BASED CONVERSION

CRT Changes

Legacy Package Conversion

Case Report Tabulation Change study data to comply with

FDA Study Data Specification Guidance

Standardize common datasets across all studies

Standardization changes

• Formats – remove variable formats. Split formatted variables into two variables.

• Labels – add labels to datasets and to variables, confirm uniqueness of variable names and labels

• Dates/time format – verify consistency throughout the studies

• Change variables order – according to FDA guidance • Verify the key variables (subject ID, visit) in all datasets• Split variables with value greater than 200 characters• Split datasets greater than 1GB.• Convert datasets to SAS Transport format.

CRT REQUIRED CHANGES

• Standardize common datasets across all studies Compare common domains (demographics,

adverse events, labs, physical exams etc.) Create a standard domain structure

specification given the varies studies including– Standard variable names, labels, types, value codes, order– Approach for handling clinical significance and out of range

Standardize dataset names and labels Change each study according to specification

STUDY STANDARDIZATION

• Analysis datasets are a must!• Apply the same standardization and CRT changes to

derived variables• Add core variables (as defined by the FDA) to all

datasets (study, center/site, country, treatment, sex, age, race, etc.)

• Revise the analysis programs according to the updated clinical data.

• Verify existing outputs (tables, listings, figures) haven’t changed

ANALYSIS DATASETS CHANGES

PREPARING CLINICAL DATA FOR SUBMISSION

Prepare clinical data for

Submission

Submission Data

Package

Legacy Package

ConversionCDISC

Conversion

• CDISC – The Clinical Data Interchange Consortium, non-profitable organization, that defines the world-wide standards for representing clinical data, required by the regulatory authorities as part of submissions

• SDTM – Study Data Tabulation Model, representing the collected clinical data in standardized structure and controlled terminology.

• ADaM – Analysis Data Model, representing study analysis data in defined datasets structure.

• CDASH - Clinical Data Acquisition Standards Harmonisation , describes the basic recommended data collection fields for 18 domains

• SEND - Standard for Exchange of Nonclinical Data, defining the structure, and format of standard nonclinical tabulation datasets

CDISC and its Standards

• SDTM and ADaM are the only two standards supported at FDA for submission of study data “By supported, we mean that the listed FDA component has

established processes and technology infrastructure to support the receipt, processing, review, and archive of study data using these standards. The submission of standardized study data using any standard not listed… should be discussed with the Agency in advance”

FDA’S VIEWPOINT ON CDISC

FDA Study Data Standard Catalog

• Submitting Non-standard legacy data “The submission of non-standardized datasets is not recommended…

There are no further specifications for organizing legacy datasets”

FDA Study Data Specifications, 7/18/2012

• The FDA has published several new guidances on standardized study data for electronic submissions

• The FDA has listed the CDISC standards as the only acceptable standards to be used for study data submission

• The FDA will still accept legacy-based clinical data for studies that are starting within 24 months after the FDA register their new notice (planned within the next 6 months)

• After that, only CDISC-based clinical data will be accepted

FDA’S VIEWPOINT ON CDISC (cont.)

More sponsors are now submitting CDISC-based clinical data

However, not all CDISC-based submissions are equal…

From CDER1

• “CDER has received numerous “SDTM-like” applications over the past several years in which sponsors have not followed the SDTM Implementation Guide completely”

• “aspects of particular sponsor implementations have actually resulted in increased review difficulty for CDER reviewers”

1CDER Common Data Standards Issues Document, Dec 2011

INDUSTRY PERSPECTIVE

Subj. id Date Albumin Alkaline Phosphatase

Leukocytes

001 01/04/12

30 g/L 398 IU/L 5.9 10^9/L

Subj. id Site Visit Visit date

Test Category

Status Comment

001 001 3 01/04/12

Chemistry Done Subject wasn’t in 8 hours fast

001 001 3 01/04/12

Hematology Done Two samples were taken

USUBJID VISITNUM

LBDTC LBTESTCD LBSTRESC LBSTRESU LBORNRLO LBORNRHI Comment

001-001 3 2012-04-01

ALB 3.0 g/dL 3.4 5.4 Subject wasn’t in 8 hours fast

001-001 3 2012-04-01

ALP 398 IU/L 44 147 Subject wasn’t in 8 hours fast

001-001 3 2012-04-01

WBC 5.9 10^3/uL 4.0 11.0 Two samples were taken

SDTM CONVERSION – EXAMPLE

Lab - external

Lab - CRF

LB SDTM

• Conversion with CDISC is ‘invasive’ -> validation is rigorous

• For SDTM ‘Mirror’ programming OpenCDISC® Manual verification

• For ADaM ADaM-SDTM comparison Double programming for imputed variables Compare to CTR (if applicable)

DATA VALIDATION WITH CDISC

• Standardized clinical Data • Standardized analysis data • Analysis Programs • Define.pdf/xml for clinical and analysis data• Annotated CRF• Reviewers guide• Programs Guide

STUDY DATA SUBMISSION PACKAGE

• Legacy Pros

– Less invasive -> less effort in conversion and verification Cons

– Not recommended by FDA (but acceptable in the short term in certain cases)

• CDISC Pros

– FDA’s favorite Cons

– Usually more invasive» More effort performing conversion» More validation required

CDISC VS. LEGACY – SUMMARY

ADaM creation and verification

SDTM conversion and verification Define xml Define xml

1.5-2.5 months

1.5-2.5 months

2 weeks 3 weeks

Analysis data conversion & verification

Clinical data preparation &

verification

Define. pdf

2-3 weeks

2-3 weeks

1 week 1 week

PKG

1 week

1 week

Define. pdf PKG

TIMES ESTIMATES

CDISC – ~3-5 months

Legacy – 5-10 weeks

• Legacy only• SDTM & ADaM• SDTM & legacy analysis datasets

The analysis datasets will be revised to use the new SDTM domains

• Hybrid Important studies – SDTM + ADaM or SDTM + Legacy

Analysis Less important studies – Legacy

SUBMISSION OPTIONS

SUBMISSION OPTIONS (cont.)

Criteria Legacy SDTM+ Legacy Analysis

SDTM + ADaM

Standardization and FDA Acceptance

√ √√ √√√

Effort & cost √ √√ √√√Time Required √ √√ √√√

Sponsor required Involvement

√ √√ √√√

Manipulation ofClinical Data

√ √√ √√√

As recommended by the agency, sponsor should consult with the designated project manager at the FDA prior to work inception

Thank you

www.bioforum.co.il

Legacy-based conversion

Create Submission Conversion Spec

Revise study clinical datasets and annotated CRFs

Revise study analysis datasets and TLG programs

Create study define.pdfs and guides

LEGACY CONVERSION - WORKFLOW

Studies materials

Submission Std. & CRT Spec

Submission-ready clinical

data

Comments for derived vars

Submission Std. & CRT Spec

Study-specific specRevise clinical data

Revise annotated CRFs

Analysis data specRevise analysis dataAdjust TLG programs

Define.pdf1

Reviewer’s guideAnalysis programs guide

Approved SpecProject Timelines

Submission-ready clinical data

Submission-ready analysis programs,

analysis data

Study Submission documentation

1 Two Define.pdf files are required – one for clinical data and one for analysis data

LEGACY CONVERSION – WORKFLOW (cont.)

PREPARING CLINICAL DATA FOR SUBMISSION

Prepare clinical data for

Submission

Study submission

package

Legacy Package

ConversionCDISC

Conversion

CDISC-based conversion

Create Submission Conversion Spec

Creating SDTM domains from raw data

Preparing ADaM datasets from SDTM domains

Metadata (Define.XML) and study documentation

LEGACY CONVERSION - WORKFLOW

SDTM Conversion

aCRF

Raw datasetsIncluding

external data

Protocol / CTR

SDTM Domains and

SUPP--

Conversion mapping spec

SDTM aCRF

Verification reports

Domains Programming• Source – target mapping• Mapping practices• Controlled terminology

Conversion Verification• ‘Mirror’ Programming• Open CDISC• Manual verification

ADaM

SDTM Domains and SUPP--

SAP

CTR tables

ADaM Datasets

Analysis programs

Verification reports

Datasets Programming

Datasets Verification• ADaM-SDTM comparison• Double programming for

imputed variables• Compare to CTR (if available)

DOCUMENTATION & PACKAGING

Comments for derived vars

Define.xml or Define.pdf1

Reviewer’s guideAnalysis programs guide

Study Submission metadata and

documentation

Raw/SDTM domains

Analysis/ADaM domains

SAP & CTR1 Two Define.xml/pdf files are required – one for clinical data and one for analysis

Same process is applicable for Legacy and CDISC conversion

Thank you

www.medistat.co.ilwww.bioforum.co.il