is your clinical data ready for submission? presented by: gil harari, eyal wultz april 2014
TRANSCRIPT
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
Conversion
CDISC 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
Conversion
CDISC 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
Conversion
CDISC 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