3 T3 S2 Paul S. Chung.ppt

1st DIA China Annual Meeting | November 1-3, Beijing, China

Global Standards: Starting ith th E d i Mi dwith the End in Mind

Paul S. ChungExecutive Vice PresidentImage Solutions, Inc.


• Drug Development Process and

Agenda

• Drug Development Process and Regulatory Requirements

• Standards in Clinical Trials Data• Standards in Clinical Trials, Data Management and Regulatory Submissions

• Issues with Non Compliance• Issues with Non-Compliance• Guidelines for Internal Operations

T d ith th R l t St d d• Trends with the Regulatory Standards• Final Thoughts


ISI Facility in China• Located in TianjinLocated in Tianjin

– Fourth largest city (pop. 10M+)– Third strategic development area

C Gby Central Government– Lower operating cost– Port city to Beijing (30 min by train)Port city to Beijing (30 min by train)– Infrastructure to hold global

companiesR l ith l t t– Resource pool with lower turnover rate

– dQuK6EkxI

3


• Inspection for Food Adulteration

Snapshot of FDA History

• Inspection for Food Adulteration• Led by chemists

F d l f ti• Federal function• Addressed imported food• Work condition• Public Health

Chicago meat inspectors in early 1906

• Over 25% of consumer goodsunder FDA governanceg


Drug Development Process

Research Discovery Development Registration Launch/Marketingy p g / g

Preclinical Phase 1 Phase 2 Phase 3 Phase 4

Data Management and Statistics


Speed Demon Companies*• Median Development and Regulatory Cycle Times, 2000-2005

Source: Tufts Center for the Study of Drug Development (Bayer, Astra-Zeneca, Allergan, Boehringer Ingelheim, and Merck)


Standards in Clinical Trials

les GCP (GMP, GLP)

CFR Part …

mpl

CFR Part …

Data and systems for CFR Part 11

V lid ti GAMP

Exa

m Validation – GAMP

Systems require IQ/OQ/PQ

E Source document (PHR/HIPPA)


Implementation of GCP

Investigator • Training

• Enforcement

• Corrective• External/Internal Pressures

gAwareness • Prevention of

problems

• Sponsors, Corrective procedures

Setting

Pressures

• Inappropriate Motivation

p ,agencies, patients

Compliance Standards with Guidance


D t ll ti (CRF/EDC)

Standards in Data Management

les Data collection (CRF/EDC)

Data Management (RDBMS)mp Data Transfer (CDISC/XML)

• ODM, SEND, CDASH …

Exam Data Submission

• SAS XPORT FilesE • CDISC STDM/ADaM

• Define.xml


Issues with Data Management

•Set up of good study design

•Ensure compliance

•Require IRB/IEC approval (some organizations take up to 6 months for approval)

•Effective and efficient, good practice

•Forgery prevention audit trail

CRF documents

•Accuracy and consistency

•Comparable to SDTM, PRO

•Avoid missing data

•Strategy for legacy data i d d

•CTD compliance, style guide for consistency, templates for ffi i i f

CSR

to 6 months for approval)

Protocol

•Forgery prevention, audit trail (DCF) source documents accessible for future reference and audit

•Examples of PDF, multiple visit in one page, site numbers, patient id, HIPPA (no names, addresses)

conversion as needed

Clinical data

efficiency, margins for A4/Letter size, bookmarks/linking (submission ready documents), DMS for version control and archive


CDISC Standards

Study Data Tabulation Model (SDTM)

Case Report Tabulation Data Definition

Specification (CRT‐DDS)

Clinical Data Acquisition Standards

Harmonization (CDASH)

Analysis Data Model Laboratory Data Model CDISC Terminology

y([ADaM])

y(LAB)

CDISC Terminology

Standard for Exchange of Non‐clinical Data

(SEND)

Operational Data Model (ODM)


FDA Requires

CDISC

• “Requirements” are stated in regulations published in the Code of Federal Regulations, for example 21 CFR Part 314 Applications for FDA Approval to Market a New Drug.

5/5/08 Federal Register announcement

• 129. ELECTRONIC SUBMISSION OF DATA FROM STUDIES EVALUATING HUMAN DRUGS AND BIOLOGICS

Revised Guidance, June 2008 – Risk of RTF

• FDA may refuse to file an application or supplement under our regulations (e.g., 21 CFR 314.101 and 601.2) if the submission is illegible, uninterpretable, or otherwise clearly inadequate, including having incompatible formats or inadequate organization.

• The absence of electronic datasets in an acceptable format to permit review and analysis may be considered inadequate, resulting in a refuse‐to‐file

•Minimum for NDA: ISS/ISE integrated data submitted as CDISC

• Plan new studies using CDISC standardization

FDA’s expectation

• Bottom line, FDA staff review data using tools that require CDISC standardized data

• Therefore, all new individual clinical study and integrated analyses are required to be CDISC compliant


define.xml is machine-readable, define.pdf is not


• Models and guidelines are not necessarily t i ht f d

Legacy data conversion - Challenges

straight forward• Level of familiarization with model and

guidelines – require a team effort and frequent discussion to resolve details

• Judgment calls needed / custom domains• Depends on study design and CRF setup• Availability of suitable documents or

correct filescorrect files– Are legacy annotated CRFs available?– Are compiled blank CRFs suitable for annotation?

Scanned or searchable?– Are support documents i e protocol SAP– Are support documents, i.e. protocol, SAP,

available? In English?– Are formats catalog/dataset – incomplete?

Superset? Data based only?

• Timelines: unexpected issues may imply p y p yre-thinking and adjustments


Data quality

Is your submission data reviewable?Data quality

•Errors?

•Omissions?

Annotated CRF

•Trace to database

Are all in synch?

Easy navigation?

Documentation

•Accurate

•Complete

•Clear

•Consistent


Standards in Regulatory Submissions

NeeS

eCTD

• Regional Module 1

• Module 2 – 5

RPS

• FDA and HL7

• Evolution of eCTD

• Standardization

PDF based

• eNDA

NeeS

• Based on CTD (ICH)

• No XML

• Other hybrids in various regions

• STF

• SPL

• CDISC SDTM

• Standardization beyond drugs

CANDA

• One of a kind submissions

• eIND

• eBLA

• Beginning of electronic standards

various regions

submissions

• Systems and data


Electronic Submission Requirements

• All electronic submission to be in eCTD

• Paper is still accepted but reducing in numbers

• Electronic gateway (ESG) is used for eCTD submissions

US FDA: NDA/BLA/IND/ANDA

g y

• eCTD is strongly recommended

• 2009 Milestone dates

EU EMEA: MAA/IMPD

2009 Milestone dates

• NeeS (Non eCTD Electronic Submission) is popular

• Agency requirements vary by country

EU National submissions

• Agency requirements vary by country

•MRP and DCP choices

ASEAN CTD submissions

• Similar to CTD

• Summaries embedded within technical sections


ACTD in Comparison to CTD


FDA eCTD Experience

19*Data from Gary Gensinger’s presentation at DIA Annual 2009


EU Electronic Submission ExperienceSubmission Formats Procedure TypeSub ss o o ats ocedu e ype

20*Information from Rob DeHaan’s presentation at DIA Annual 2009


Submission Format (Worldwide)

eCTD Only SubmissioneCTD Only Submission

• Czech Republic

• Japan

• Korea

• Russia

• United States

eCTD Accepted

• 28 countries• 28 countries

NeES Accepted

• Most EU countries


Guidelines – Internal and Partners

• GuidanceRegulation

• Standard Operating ProcessGuidelines

• Document Style Guide

• Content Template

• Component/Topic Based AuthoringWork Instructions

• Record Management and Archive

Controlled Documents/(e)DMS( )


•Document Management

Tragedy is a Driver for Change…

• Consent Degree issued for improper record management

• $500B fine with government intervention for operations for many years

•Quality Manufacturing Process

• $500B fine along with criminal charges and investigations for executives

Improper Content Management

•Thalidomide Tragedy ‐ FDA Safety Regulations

•Product safety study ‐ Heavy law suits ($16B set a side for up to 20,000 cases)

•Off label promotion – Over $2B Fine

•Inadequate use of food additives ‐Melamine scandal with baby powder milk

Inadequate Safety Measures

•Ethics and conflicts related to the result of trials

•Monetary interest

•Academic and personal ambition

W k thi ith i ith th th ti it f th t i l ltIssues with Clinical Trials

•Work ethics with seriousness with the authenticity of the trial results

•Heavy workload and lack of time and resources

•Forgery in Clinical Trials – Investigator falsifying patient recordsFraudulent Clinical •Publication of study with manipulated data – Reputable researcher cloning stem

cells

•Falsifying data in federal grant applications ‐ 1 year jail term with debarment (2006)

Fraudulent Clinical Research


“Let’s not waste a good crisis…”

- Hillary Clinton


Trends with Standards

More Electronic Exchange of Information

Less Legacy Paper Documents (hopefully)

Convergence of Standards Across

Borders

Stringent Safety Measures to Ensure

More Generic and Alternative Drug,

Lower Profit Margins forMeasures to Ensure

Public Health

gBiologics, TCM

Products

Margins for Sponsors

Broader Market for Products esp. with

BRIC or MKT CountriesCountries


CDISC Standard – moving target

ODM 1 2

CDASH SEND Terminology

ODM 1.2 1.3

ODM 1.3+

SDTM 1.1 1.2

Impl’tn Guide (IG)

ADaM 2.0 2.1 / IG

CRT‐DDS

Data XPT p t Gu de ( G)

3.1.1 3.1.2 1.0 1.0 HL7 XML mgs


d ll b f

Metadata Storage

In most companies, metadata will be part of a Content Management system

Many content management Older systems may not haveNo standards, since agencies

can’t require it

Many content management systems insufficient for regulatory metadata

Older systems may not have requirements for Product

Information

Systems often made simple to ensure compliance

New Solutions with DIA EDM Reference ModelNew Solutions with DIA EDM Reference Model

Not a standardNot a product – just a model that any

company can adopt

Designed for submission documents

Sponsored by the DIA Document &

Records M SIAC

Released August 2008, currently in

version 1.1

Think of it as user requirements for a

content company can adopt documents

Management SIACversion 1.1

management system


• Authoring template like ISIWriter

So how to get it into the documents?Authoring template like ISIWriter prompts for information for each document

• EDMS can trade properties withEDMS can trade properties with MS Word. EDM Reference Model in MS SP, you can propagate that to ISIWriter with minor changes

• In the future, XML-Based document knowledge to have better control over information

d t f f d t tand transfer from document to document even without an EDM System


• Regulated Product Submissions

RPS is Metadata-Driven Standard

• Regulated Product Submissions– Organized more like an Index than a TOC– Instead of fixed XML elements, uses Context of Use

containing metadatacontaining metadata– Can update metadata you can’t in eCTD

• Change a clinical study’s indication• Change a manufacturer nameg• Previously you’d have to delete one, add another*

– Combined with above, should be able to auto-assemble submissions

* FDA has said not to change metadata in eCTDs, only content.


The Knowledge Process1. Propose and accept a new change

2 Auto-populate document templates from metadata2. Auto populate document templates from metadata

3. Auto-build and validate submission from document and submission metadata

• Send submission to agency via gateway or media

• Automatically record transaction in tracking log

Review and plan with dashboard reports

SubmissionBuilding &DMS

• Review and plan with dashboard reports

gManagement

S

initiate change

MetadataSubmission

GatewayChangeControl

change complete

Agencies

StrategicPlanning

RegistrationTracking


Regulatory Knowledge Future –Where can we go from here?

• Action-Oriented Knowledge (A-OK)– What you do creates knowledge

g

• Placement in repository• Use in a submission

– These things shouldn’t require typing!– But they require smart applications– But they require smart applications

• Virtualized Metadata– Metadata should be two-way between y

document content and repository properties

– Submission Compilation should grab latest version from metadatalatest version from metadata repository


Key for Electronic Standards

hts

Evolutionary Process

A D i b t I d t I fl C t

houg

Agency Driven but Industry Influence Counts

Compliance is Required

Internal Business Processes need to maintain

al T

h Internal Business Processes need to maintain competitive while adopting the standards

Need for robust electronic document and data t t t l ith l b l

Fin management system to comply with global

standards (CFR Part 11, GxP, eCTD, … etc.)


The world is no longer flat as today we are

Summary

ghts The world is no longer flat, as today we are

forced to deal with a constantly evolving and increasingly regulated global environment

Mi k d d d h

Tho

u Mistakes are made every day, and the consequences can be severe and costly

Regulation involves enforcement of law, but

nal T

g ,the guidance compliance can make your life easier

So are you ready to be a global citizen?

Fi So, are you ready to be a global citizen?

While it is wise to learn from our own mistakes, it is more profitable to learn from the mistakes of othersthe mistakes of others

他山之石


• Paul S Chung

Contact Information

• Paul S. Chung– Executive VP, Global Services– [email protected]

Whi NJ USA– Whippany, NJ, USA– T: +1-973-560-0404

• Haedoe LeeHaedoe Lee– General Manager, ISI China– [email protected]

Tianbao Industrial Park Area Tianjin China– Tianbao Industrial Park Area, Tianjin, China– T: +86-022-5821 8228 - 205

www.imagesolutions.com