NDA 21-399 ZD1839 for Treatment of NSCLC FDA Review Division of Oncology Drug Products.
FDA NDA Submission Support
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Transcript of FDA NDA Submission Support
FDA NDA Submission Support
For CDISC Compliance amd ISS/ISE
RAISING THE STANDARD OF EXCELLENCE
Key personnel
with PhD or
Master
degrees and
over 10 years
of industry
experience
Proven strong
track record
of drug
approvals
20 year old
specialty
CRO
Strong and
stable team
Commitment
to quality and
timelines
80+ full time
employees in
the USA
Clients
ranging from
small biotech
to large
pharma
Accountability Innovation Leadership Quality Partnership
SERVICES OVERVIEW
Medical and Regulatory Consultation
Clinical Operations
Biostatistical Design and Analysis
SAS Programming CDISC Standardization
Data Management
Safety Management / Pharmacovigilance
Medical Writing
Application Development
GLOBAL BRANCHES AND OFFICES
Locations: USA, S. Korea, Armenia, Japan, HK, Taiwan, Singapore (adding UK and France)
Mainland China: first tier cities BJ, SH, TJ, GZ
second tier cities NJ, CD, SY, WH
11 Main Offices
34 Cities within China
600+ Employees Globally
GLOBAL RESOURCES
Number of Employees Per Location
USA Asia Europe
80+
500+
50+ Services by Location
USA
DM, Biostat, Prog, CO, PV
Asia
DM, Biostat, Prog, CO, PV,
MA, RA, SMO, Translation
Europe
DM, Biostat, Prog, CO, PV
U.S. RESOURCES
Statisticians – 12
Statistical Programmers /
Analysts – 40+
Data Managers – 10
Project Managers – 4
IT – 4
QA – 2
Operations & Administration
BIOMETRICS PROJECT TEAM STRUCTURE AND COMMUNICATION
Project Manager Lead Statistician
Lead Validator
Lead Programmer
Senior Statistical
Reviewer
Sponsor Team
QC Checking
Data Manager
KEY PERSONNEL DATA MANAGEMENT
Lily Zhu: MD, Director, 18 years pharma and 6 years hospital
Merck, Xiamen First Hospital
Alene Shepherd-Rose: Manager, 30+ years pharma
Merck
Jeannette Sickel: Manager, 25+ years pharma
Merck
Kelly Miller: Sr. Data Manager, 15+ years pharma
CLINLOGIX, Merck, Sanofi-Aventis, RPS
Jonathan Zimmerman: MS, Sr. Data Manager, 10 years pharma
Medidata, Covance, CoreLab Partners, ICON
KEY PERSONNEL BIOSTATISTICS
Henry Wu: PhD, VP, 15+ years pharma
Kendle, Forest Lab, Roche, Pfizer
Tiepu Liu: MD, PhD, VP, 15+ years pharma, 10 years academia
PPD, UBC, Graceway, The Medicines Company
Kevin Chen: PhD, Senior Director, 15+ years pharma, 13 years academia
UNC, Sanofi, Shering Plough, Eisai, Genta
Pei-Yun Chen: PhD, Director, 15+ years pharma
Merck
Lynn Wang: MS, MA, Director, 15+ years pharma
Eli Lilly, Pharmacia, Sanofi-Aventis, Wyeth
Weining Volinn: PhD: Director, 15+ years pharma
Averion, Actavis
Wenjiong Zhou, PhD: Director, 15+ years pharma and CRO
BMS, UBC
KEY PERSONNEL PROGRAMMING
Yuguang Zhao: MS, VP, 18 years pharma
Sanofi-Aventis, Eisai
Carrie Zhang: MS, Assoc. Director, 8 years pharma
Merck
Sheng Zhang: MS, Assoc. Director, 12 years pharma
Eli Lily, Eisai, Merck
Tina Wu: MS, Assoc. Director, 11 years pharma
Clinforce, Salix
Philamar Atienza: MS, Principal Programmer, 12 years pharma
Alcon, Schering-Plough
Dan Szeto: MS, Principal Programmer, 15 years pharma
PPD, Covance, BMS
THERAPEUTIC EXPERIENCE
• Oncology
• Anti-Inflammatory / Pain
• Neurology / CNS
• Cardiovascular
• Gastroenterology
• Ophthalmology
• Allergy
• Vaccine
• Anti-Infective / Anti-Viral
• Diabetes & Metabolic Disease
• Dermatology
• PK / PD
• Women’s Health
CURRENT PROJECTS BY THERAPEUTIC AREA
Anti-Infective
4%Autoimmune
2% Cardiovascular
2%Consumer Health
5%
Device
2%
Diabetes & metabolic
disease
8%
Musculoskeletal
6%
Neurology/CNS
28%
Oncology
14%
Ophthalmology
17%
Respiratory
5%
Urology
5%
Women’s Health
2%
Over 300 Ongoing or Completed Studies
25%
65%
10%
Sales
Phase I Phase II / III Phase IV
Phase I
Phase II / III
Phase IV
PROJECT SUMMARY:PAST 36 MONTHS
Agency Submissions
15 US NDAs: 11 approved and 4 are pending
Submissions in other regions include EMA, PMDA,
Canada, Mexico, Singapore, South Korea, and others
PROJECT SUMMARY:PAST 36 MONTHS
DATA MANAGEMENT SERVICES
Study Set-Up Study Conduct Study Close-Out
- CRF Design
- Data Management Plan
- Data Validation Plan / Data
Review Plan
- CRF Tracking and Review
- EDC Site Support for Study
Conduct
- All DM Activities
Completed
- Final SAE Reconciliation
Before Database Lock
- eCRF Completion Guidelines
- Data Entry Guidelines
- CRF Annotation
- Database Design, Testing, and
Activation
- Data Validation and Discrepancy
Management
- Serious Adverse Events
Reconciliation
- Ongoing Dictionary Coding
- Final Clinical Review
Listings to Sponsor
- Final Data Management
Status Report to Sponsor
- Edit Check Programming, Testing
- External Data Import and Export
Set-up
- Dictionary Set-up
- External Data Transfer and
Management
- Ongoing Critical Data Points
Quality Control
- Database Audit as Specified
by Sponsor
- Database Lock and Freeze
- Data Transfer
- EDC Site Support Set-up
- Study Site Training
- Ongoing Data Management
Status Report
- Ongoing Clinical Review Listings
- Study Documentation
Maintenance, Return,
Archive, and Destruction
DATA MANAGEMENT – EDC
EDC Technology
Medidata® Rave and Balance - Accredited Services Partner
Oracle Clinical RDC - Certified
Oracle InForm – Certified
Oracle Argus - Certified
OpenClinica Enterprise Edition - Services Partner
“We couldn’t have accomplished this without K&L. You accomplished the impossible with our data! It was really
challenging and we couldn’t have done it without your heroics! I hope we work together again.”
Associate Director of Clinical Research
Major Pharmaceutical Company
DATA MANAGEMENT SYSTEMS & OPERATION MODELS
Work on K&L System
& SOPs, Processes,
and CDISC Standards
Work on Sponsor’s
SOPs and Processes
Use per Sponsor
required Data
Standards
EDC & DDE
IWR
Medical Coding
SAS Programming
Labs
DATABASE BUILD
Protocol Design/Review
Database Build Workflow
eCRF Spec/CRF Design/Review
Data Validation/Edit Check Testing
Data Validation/Edit Check Programming
Data Review /Validation Plan
Define/Construct Study Database
Setup Data Entry Screen
Validate Study Data Entry Screens
Database in Production
DATA MANAGEMENT
Statistics Analysis
External Data Reconciliation
Study Site Data Entry
Query Generation/Resolution
Medical Review
DMReview
Medical Coding
SAE Reconciliation
Medical Review
All Queries Resolved
Medical & Statistics Report
PI Signature
Study
Site
Lock Study Database
SDV
BIOSTATISTICS SERVICES
Exploratory Analysis
Clinical Study Report
Statistical Report
Annual Report (DSUR and PSUR)
ISS / ISE
Publications
Clinical Development Plan
Power / Sample Size Estimation/ Protocol Development
Randomization
Statistical Analysis Plan
Interim Analysis / DMC
Statistical Modeling and Simulation
STATISTICIAN’S ROLES
• Communicate with Sponsor to ensure key statistical considerations are incorporated into study design and planned analysis (Protocol and SAP).
• Interact with programmers to ensure analysis plans are accurately carried out.
• Statistical review and check analysis results.
• Programmatically verify the key results.
• Support interim and ad hoc analyses.
• Provide statistical interpretation of the results.
“I am extremely impressed with your sophisticated theoretical and applied statistical and programming
capabilities; especially the professionalism, quality and customer focus of your team.”
Vice President Clinical Development
Massachusetts Biotech
STATISTICAL PROGRAMMING QUALITY STANDARD / PROCESS
Analysis Data
• Based on SDTM with stable SAP and TLF shells
• Specifications development and team review
• Programming based on the specifications
• Double programming validation
• Key analysis data with stat verification
TLF Output Delivery
• Double programming validation
• Stat review and verification
• QC review
KEY STATISTICAL AND PROGRAMMING PROCESS
Stats and Programming Process
SAP
- First draft starts after protocol
and CRF finalization
- Senior statistical review before draft delivery
- Stable working draft: change tracking and summary to team members
- Sign off before DB lock (or at
other milestone per sponsor
requirement)
Dry Runs
- Start programming with a stable SAP
- First dry run to be conducted when
~30% of data become available.
Review of the first dry run is mainly
to ensure the format of the outputs are
appropriate.
- Second dry run (BDRM) to be
conducted when ~90% of data
become available. Review of the
second dry run is mainly to prepare
for DBL and ensure the contents of
the outputs are accurate.
Delivery after DB Lock
- The top line results are available in 1-3 days.
- All TLFs are available in 1-2 weeks.
SDTM DATA PACKAGE
PROCESS FLOW CHARTSDTM e-Submission Data Package Process Flow Chart
Raw
Data
aCRFs
Raw
Data
SDTM
Data
ADaM
Data
SDTM aCRFs
(aCRF.pdf)
SDTM Mapping
Specification
SDTM Mapping
Programs
SDTM Define
SDRG
Initial
Request ?
Change in
Raw Data
CRFs ?
Mapping Spec
Update ?
Final SDTM Mapping Spec
Approved ?
Validation
Y Y Y Y
N N N
ADaM DATA AND TLF FLOW CHART ADaM Data and TLF Flow Chart
Initial
Request ?
Change in
SAP or
TLF Shell ?
ADaM Spec Needs
Update ?
Validation
Y YY Y
N
Protocol Raw
DataaCRF Tables, Listings and
Figures
TLF Creation
Programs
SDTM
Data
ADaM
Data
ADaM Creation
Programs
ADaM
SpecificationADaM define
ADRG
SAP + TLF
Shell
Final ADaM Spec
Approved ?
NN
REGULATORY SUBMISSION EXPERIENCE
• Submission of CDISC compliance e-Submission data package• SDTM / ADaM / BIMO
• Submission package supporting eCTD• ISE / ISS / ISI
• Filing compliance check
• FDA response consultation
• Statistics / programming advisor committee• Agency defense rehearsal
• Post filing agency ad-hoc support
CDISC COMPLIANT NDA SUBMISSION SUPPORT
Legacy data conversion
SDTM & ADaM creation
Comprehensive eSubmission data
package for FDA submission
Metadata driven process for
development of data mapping
specifications
Create SDTM annotated CRF
(acrf.pdf)
Create SDTM / ADaM
eSubmission packages
Comprehensive tools and processes
for creating define.xml / define.pdf
Proven validation process of
SDTM & ADaM: accuracy and
compliance
Compliance checks with Pinnacle
21 and K&L’s toolkit
(SDTMChecker)
Create the reviewer’s guide
associated with SDTM / ADaM for
FDA reviewers
REGISTERED CDISC FOUNDATIONAL STANDARDS
K&L has worked with CDISC SDTM / ADaM since 2002
• CDISC Gold Member
• CDISC Registered Solution Provider
• Co-led a CDISC / FDA Data Integration Pilot
• Formal member of CDISC SDS Working Group
• Active Member of CDISC and ADaM Working Group
SDTM / ADaM EXPERIECE
From 2013 to 2016
Created SDTM / ADaM
for ISS / ISE packages.
One ISS included 38
protocols, from Phase I to
III. The studies were
conducted in the U.S.,
Europe, and Asia.
Submitted 15 NDA data
packages to the FDA
including SDTM /
ADaM. All were
accepted and 11 drugs
have been approved and
are on the market.
Prepared 400 SDTM /
ADaM study packages
across 75 compounds for
20 biotech /
pharmaceutical
companies.
EXPERIENCE OF LARGE STUDY DATA INTEGRATION
Legacy Data Processing
• 67 legacy studies for acetaminophen were included in this data
mapping project.
• The scope of work include data re-entry (18 studies), MedDRA
coding, SDTM mapping, ADaM derivation, and also key CSR result
verification.
• The mapped data sets will be used to perform meta data analysis and
to answer agency questions.
• Results were used to support Canadian filing.
• Project was successfully completed in 2013.
• The experience was shared with the industry at the PhUse conference
and CDISC User Group Meeting.
Providing Regulatory
Submissions
In Electronic Format
Standardized Study Data
Guidance for Industry
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
December 2014
Electronic Submissions
COALITION FOR ACCELERATING STANDARDS & THERAPIESTHERAPEUTIC AREA STANDARDS INITIATIVECDASH (CRF/EDC) > SDTM > ADAM > TLF > ECTD
UTILIZING A COLLABORATIVE APPROACH TO CREATE EFFICIENCIES WITH CDISC – CDASH STANDARDS
IDMC SUPPORT SERVICES
• Started offering this service since 2007 for anti-infectious and oncology studies
• Both as voting member and as independent supporting statistician
• Average about ~10 IDMC project support per year in recent years with a steady increasing trend both in the US and globally
• Services include:
• Project management: organization, coordination, and documentation
• IDMC charter and interim SAP
• Data analysis and presentation
• Follow up ad hoc analysis
• Project startup and ongoing management
• IDMC charter development / review
• IDMC SAP and shell
• Internal review and sponsor review
• Consideration of consistency to CSR SAP
• Programming support for IDMC and ongoing safety review
• Dry run for IDMC
• Support for ongoing safety review (blinded / unblinded outputs, patient
profiles, summary tables)
• Document and data transfer
• sFTP portal for sponsors and vendors
• sFTP portal for IDMC members
• Flash drive / card, etc.
KEY IDMC PROCESSES
DMC PROJECT TEAM STRUCTURE AND COMMUNICATION
Lead Statistician IDMC
Programming Lead
Project Manager
Sponsor
GLOBAL SAFETY MANAGEMENT
Client System Under FSP Arrangement (ARISg)
Staff are trained on the sponsor’s system and SOPs
B2B connection was set up in order to access the sponsor’s servers from our
server. Alternatively, sponsor-built laptops are distributed to the FSP staff in
order to access the sponsor’s VPN.
In-house Argus System
Installed and fully validated
State-of-art IT platform to support the Argus application. High performance
and high availability server. Rigorous system SOPs that have been audited by
many sponsors.
SAFETY MANAGEMENT EXPERIENCE
• Safety information translation and reporting to the customer • Multiple sponsors under paper process
• Data entry and processing of ICSRs in customer company database
• Global / local search of the scientific literature for adverse drug reactions• Multiple sponsors: FDA AERS, WHO ADR, company specific safety
DB, literature
• Scope of services including AE searching, trend detection, summary reporting, and medical writing for DSUR, PSUR
• Case submission• FDA, EMEA, CFDA
PROJECT MANAGEMENT PROCESS AND COMMUNICATION FLOW
Project Management Process and
Communication Flow
Kick-off Meeting
(internal/
external)
Internal
Management
Meeting
Project Closing
Meeting
Planning
Execution /
Implementation
Initiation
Closing
Project initiated, assign project manager, start initiation activities
Define project scope, deliverables and requirements, create project charter
Resource loading, form project team, develop project plan, timeline,
communication plan, perform risk assessment
Track and report project status, manage project issues, re-plan timeline and
resources and update budget as needed; ongoing risk assessment
Deliver final deliverables, project sign-off by sponsor, complete QA
documentation
Ensure work is performed within scope as agreed, manage change request/order, milestone
performance review
Project Team
Mtg, Status Mtg,
Status Report
Monitor &
Control
STATE-OF-THE-ART IT INFRASTRUCTURE
Heavily invested in advanced IT systems
and technology to ensure:
Availability
Confidentiality
Reliability
SecurityIT Infrastructure:
High Performance and Processing Power
Multiple Data Backups
System Redundancy
Disaster Recovery Site
We passed on-site audits from all of our clients.
QUALITY SYSTEM – KEY SOPS AND POLICIES
CATEGORY NUMBER
General Policy POL 01 - 08
General Procedure SOP 001 - 010
BioStat - Programming SOP 101 - 108
Facility / Project Management SOP 109 - 113
Data Management SOP 201 - 261
IT Management SOP 306 - 317
KEY SOPSBIOSTATISTICS AND PROGRAMMING
NUMBER SOP
101 Programming Standards
102 Good Programming Practice
103 SAS Programming Validation Procedure
104 Data Transfer Procedure
105 Development of Statistical Analysis Plan
106 Interim Statistical Analysis Plan
107 Randomization Schedules
108 Unblinding Clinical Studies
WHY K&L?
Our high standards for precision, quality, and rapid response combined with our ability to provide
solutions to complex issues will make K&L a valuable member of your team.
State-of-the-Art IT
Infrastructure
Strong and Stable
Global Team
Commitment to
Quality and
Accuracy
Effective
Communication