Is your clinical data ready for submission? Presented by: Gil Harari, Eyal Wultz April 2014

IATI ROUNDTABLE - AGENDA Strategy and statistical considerations in clinical trials planning (Gil Harari, MediStat) Clinical data submission – which way to go? (Eyal Wultz, Bioforum) Q&A

CLINICAL DATA SUBMISSION Bioforum Regulatory Services Clinical Data Standardization – importance and priority Legacy-based submission CDISC-based submission Which way to go?

BIOFORUM SERVICES

BIOFORUM REGULATORY SERVICES Clinical Programming Regulatory Operations Pharmacovigilence Operations Clinical programming – study support (tables, listings, figures) Prepare data for submissions Documents publishing eCTD compilation Lifecycle management Adverse events processing and reporting CIOMS, MedWatch,… PSURs, DSURs, Over 40 submissions to the FDA, EMA, UK, Germany, Spain Over 100 studies to date

Clinical data deficiencies and ‘Data Presentation’ (~39%) 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 403 2 Based on publically-available RFTs.

THE IMPORTANCE OF CLINICAL DATAS STANDARDS Sanofi, Bayer’s Lemtrada receives FDA refuse-to-file letter in relapsing MS By 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.

Submission Data Package PREPARING CLINICAL DATA FOR SUBMISSION Legacy Package Conversion CDISC Conversion Prepare clinical data for Submission Submission Data Package

LEGACY-BASED CONVERSION Legacy Package Conversion CRT Changes Standardization changes Case Report Tabulation Change study data to comply with FDA Study Data Specification Guidance Standardize common datasets across all studies

CRT REQUIRED 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.

STUDY STANDARDIZATION 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

ANALYSIS DATASETS CHANGES 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

Submission Data Package PREPARING CLINICAL DATA FOR SUBMISSION Legacy Package Conversion CDISC Conversion Prepare clinical data for Submission Submission Data Package

CDISC and its Standards 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

FDA’S VIEWPOINT ON CDISC 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 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

FDA’S VIEWPOINT ON CDISC (cont.) 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

INDUSTRY PERSPECTIVE 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

SDTM CONVERSION – EXAMPLE Subj. id Date Albumin Alkaline Phosphatase Leukocytes 001 01/04/12 30 g/L 398 IU/L 5.9 10^9/L Lab - external Subj. id Site Visit Visit date Test Category Status Comment 001 3 01/04/12 Chemistry Done Subject wasn’t in 8 hours fast Hematology Two samples were taken Lab - CRF 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 ALP 398 IU/L 44 147 WBC 5.9 10^3/uL 4.0 11.0 Two samples were taken LB SDTM

DATA VALIDATION WITH CDISC 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)

STUDY DATA SUBMISSION PACKAGE Standardized clinical Data Standardized analysis data Analysis Programs Define.pdf/xml for clinical and analysis data Annotated CRF Reviewers guide Programs Guide

CDISC VS. LEGACY – SUMMARY Pros Less invasive -> less effort in conversion and verification Cons Not recommended by FDA (but acceptable in the short term in certain cases) CDISC FDA’s favorite Usually more invasive More effort performing conversion More validation required

TIMES ESTIMATES CDISC – ~3-5 months Legacy – 5-10 weeks ADaM creation and verification 1.5-2.5 months 2 weeks 3 weeks 1 week SDTM conversion and verification Define xml Define xml PKG 2-3 weeks Analysis data conversion & verification Legacy – 5-10 weeks 2-3 weeks 1 week 1 week 1 week Clinical data preparation & verification Define. pdf Define. pdf PKG

SUBMISSION OPTIONS 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 (cont.) Criteria Legacy SDTM+ Legacy Analysis SDTM + ADaM Standardization and FDA Acceptance √ √√ √√√ Effort & cost Time Required Sponsor required Involvement Manipulation of Clinical Data As recommended by the agency, sponsor should consult with the designated project manager at the FDA prior to work inception

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Legacy-based conversion

LEGACY CONVERSION - WORKFLOW 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 (cont.) Studies materials Submission Std. & CRT Spec Approved Spec Project Timelines Submission Std. & CRT Spec Study-specific spec Revise clinical data Revise annotated CRFs Submission-ready clinical data Submission-ready clinical data Analysis data spec Revise analysis data Adjust TLG programs Submission-ready analysis programs, analysis data Comments for derived vars Define.pdf1 Reviewer’s guide Analysis programs guide Study Submission documentation 1 Two Define.pdf files are required – one for clinical data and one for analysis data

Study submission package PREPARING CLINICAL DATA FOR SUBMISSION Legacy Package Conversion CDISC Conversion Prepare clinical data for Submission Study submission package

CDISC-based conversion

LEGACY CONVERSION - WORKFLOW Create Submission Conversion Spec Creating SDTM domains from raw data Preparing ADaM datasets from SDTM domains Metadata (Define.XML) and study documentation

SDTM Conversion Domains Programming SDTM Domains and SUPP-- aCRF Source – target mapping Mapping practices Controlled terminology SDTM Domains and SUPP-- Conversion mapping spec SDTM aCRF Verification reports aCRF Raw datasets Including external data Protocol / CTR Conversion Verification ‘Mirror’ Programming Open CDISC Manual verification

SDTM Domains and SUPP-- ADaM ADaM Datasets Analysis programs Verification reports SDTM Domains and SUPP-- SAP CTR tables Datasets Programming Datasets Verification ADaM-SDTM comparison Double programming for imputed variables Compare to CTR (if available)

DOCUMENTATION & PACKAGING Raw/SDTM domains Same process is applicable for Legacy and CDISC conversion Analysis/ADaM domains Study Submission metadata and documentation Define.xml or Define.pdf1 Reviewer’s guide Analysis programs guide Comments for derived vars SAP & CTR 1 Two Define.xml/pdf files are required – one for clinical data and one for analysis

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