Update regulatory standards landscape

v1
Regulatory Informatics Consulting
Fred Miller
November 20, 2012
Update: Regulatory Standards Landscape

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Agenda
 Legislation - global regulatory standards
 Overview of Standards Development
Organizations (SDO)
 Significant projects/initiatives
– IDMP / ICSR
– RPS (eCTD 4.0)
– Exchange of clinical study information / data
 CDISC-HL7, now Study Data
 Clinical Document Architecture (CDA)

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FDA - Legislation
 PDUFA V
– AKA - The Food and Drug Administration Safety and Innovation Act
(FDASIA)
– Sec 1123 – Global Clinical Trials
 “Work with other regulatory authorities of similar standing, medical
research companies, and international organizations to foster and
encourage uniform, scientifically driven clinical trial standards with
respect to medical products around the world”
– Sec 1136 – eSubmissions
 “Beginning no earlier than 24 months after the issuance of a final
guidance… shall be submitted in such electronic format”
– Sec 1140 – eLabeling
 “Electronic patient labeling of prescription drugs, as a complete or
partial substitute for patient labeling in paper form”
– Sec 1141 – Interoperability
 “Open standards that are freely available, without cost and without
restriction, in order to promote broad implementation”

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EMA Legislation
 Pharmacovigilence (1235/2010)
– xEVMPD
– PSUR / DSUR
– “The format and content of the electronic transmission
of suspected adverse reactions by Member States and
marketing authorisation holders, … should be
established.”
– Individual suspected adverse reaction reports and
follow-ups submitted to the Eudravigilance database by
marketing authorisation holders shall be transmitted
electronically upon receipt to the competent authority
– “the use of internationally agreed terminology,
formats and standards for the performance of
pharmacovigilance activities”

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Standards Development Organizations
 ICH
 ISO TC215
 CEN TC251
 HL7
 CDISC
 BRIDG
 IHTDO (SNOMED)
 MedDRA MSSO

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Standards Development Organizations
HL7
RCRIM
CEN 251
ISO 215
CDISC
BRIDGE
ICH
MedDRA
MSSO
Harmonization
Harmonization
GS1
IHT SDO
Modified from Nick Halsey, EMA, International Standards

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ICH - International Conference on Harmonisation
of Technical Requirements for Registration of
Pharmaceuticals for Human Use
 Q - Quality Guidelines
 S - Safety Guidelines
 E - Efficacy Guidelines
 M - Multidisciplinary Guidelines

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ICH
 ICH is concerned with harmonization of
technical requirements for the registration of
pharmaceutical products among three
regions: The European Union, Japan, and the
United States.
 2006: ICH decides to no longer internally
develop its own technical specifications.

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ICH – Multidisciplinary
 M1 MedDRA
 M2 ESTRI
 M3 Non-Clinical Safety Studies
 M4 Common Technical Document
 M5 Data Elements and Standards for Drug
Dictionaries
 M6 Gene Therapy
 M7 Genotoxic Impurities
 M8 eCTD (RPS)

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ICH (E2B) - ICRS
 Successful electronic transmission of ICSRs
relies on the agreement of common data
elements and on the syntactical definition of
the electronic message.

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HL7 – Health Level Seven
- ANSI / ISO Standards Organization
- Primarily focused on electronic health records (EHR)
- Very well defined methodology
- Many different workgroups governed by Technical
Steering Committee (TSC)
- Standards
- DSTU – Draft Standard for Trial Use – 2 year expiration
- Informative – for Information Only
- Normative – approved standard for implementation.

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RCRIM - HL7 Work Group
Regulated Clinical Research Information Management
- 15+ Projects currently
- Projects don’t get the same level of attention or leadership
- Volunteer organization
- Only HL7 members can vote or lead
- Work groups elect co-chairs
- Use case / model driven
- Implementation guides are required
- For RCRIM, most standards are driven by health
authorities, i.e. FDA

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HL7 - RCRIM
 Regulated Products (PORP)
Standards developed as a part of the family of
messages targeted for the exchange of information
about regulated products and the exchange of the
data needed to provide approval for such products

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HL7 - RCRIM
 Regulated Studies (PORT)
Standards developed as part of the family of
messages targeted for the exchange of information
about the conduct of regulated studies, and the
exchange of data collected during those studies

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RCRIM
Regulated Products
Product
Information
Labeling
Product
Listing
Facility
Listing
Submissions
RPS
Regulated Studies
Stability
Study
Filtered Query
Service
ECGs
Clinical Study
Data
Study
Design
Study Data
Study
Reporting
Study
Participation
Clinical Trial
Lab

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RCRIM– Projects
- Regulated Product Submission ( R3 = eCTD 4)
- Common Product Model Update
- Study Design Structured Document
- With Structured Document Work Group
- Clinical Trial Registry (Janus)
- Clinical Trail Registration & Results
- Medical Product Information (SPL r5)
- Drug Stability Reporting (eStability)
- CDISC Content to Message (now Study Data)
- Individual Case Study Report (ICSR)
- With Patient Safety WG ISO/CEN
- ePSUR, eRMT
- With Patient Safety WG

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ISO - International Standards Organization
ISO (International Organization for Standardization) is the world's
largest developer and publisher of International Standards.
ISO is a network of the national standards institutes of 162
countries, one member per country, with a Central Secretariat in
Geneva, Switzerland, that coordinates the system.
ISO is a non-governmental organization that forms a bridge
between the public and private sectors. On the one hand, many of
its member institutes are part of the governmental structure of
their countries, or are mandated by their government. On the
other hand, other members have their roots uniquely in the
private sector, having been set up by national partnerships of
industry associations.

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ISO TC215
 Technical Committee on Health Informatics
– IDMP
 Identification of Medicinal Products
– ICSR
 Individual case safety reports (ICSRs) in
pharmacovigilance

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CEN TC251
 European Committee for Standardisation
 TC251 - Technical Committee on Health
Informatics
 Working Groups
– WG1 - Information models
– WG2 - Terminology and knowledge representation
– WG4 - Technology for interoperability

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BRIDG
 Biomedical Research Integrated Domain Group
 Domain Analysis Model (DAM) covering protocol-
driven clinical research
 The BRIDG Project is a collaborative effort engaging
stakeholders from four organizations:
– Clinical Data Interchange Standards Consortium (CDISC)
– US Food and Drug Administration (FDA)
– HL7 Regulated Clinical Research Information Management
(HL7 RCRIM) Work Group
– US National Cancer Institute (NCI)

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BRIDG
 The aim of the BRIDG project is to have a shared
view of the data, relationships, and processes
which collectively define the domain of clinical
and pre-clinical protocol-driven research and its
regulatory artifacts. In other words, BRIDG is a
communication tool for bringing together a
variety of stakeholders and for bridging medical
research experts from standards development
organizations, government organization,
academia, and the biopharmaceutical industry.

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BRIDG
 Release 3.2
– CDISC Statistical Analysis Domain Analysis Model
– Hematopoietic Cell Transplant (HCT) Database
– FDA Clinical Trials Repository (CTR)/Janus
 CDISC SDTM format and emerging HL7 v3 study data
exchange standards.
– HL7 Clinical Trial Registration and Results (CTRR)
 electronic exchange of both the protocol-related
descriptive information needed to register a clinical trial
 exchange of clinical trial summary-level data and will not
be used to transport individual patient-related data.
– NCI Clinical Trials Reporting Program (CTRP)
– FDA HL7 Study Design Structured Document (partial)

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Industry organizations
 DIA
– Drug Information Association
 PhRMA
– Pharmaceutical Research and Manufacturers of America
 IFPMA
– International Federation of Pharmaceutical Manufacturers Associations
 TransCelerate
– 10 pharma/biotech companies to develop Clinical Data Standards
 IRISS
– Implementation of Regulatory Information Submission Standards
 TOPRA
– The Organisation for Professionals in Regulatory Affairs
 BIO
– Biotechnology Industry Organization
 TIGes
– Telematics Implementation Group for electronic submission and ICH Implementation
 AESGP
– Association of the European Self-Medication Industry
 EUROPABIO
– The European association for bio-industries
 EUCOMED
– Represents the medical technology industry in Europe
 EGA
– European Generic Medicines Association

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ISO - IDMP
 Identification of the medicinal product involved in the
adverse event report is critical
– Unique and unambiguous identification of :
 Active substance
 Units of measure
 Ingredients
 Dosage form
 Units of presentation
 Route of administration
– Specificity within an ICSR report
– Clear and accurate communication across jurisdictions (countries & regions)
– More specificity leads to more accuracy in analysis and improved quality of
the science
 Based on HL7 Common Product Model

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ISO - IDMP
 ISO 11615 - Data elements and structures for the unique
identification and exchange of regulated medicinal product
information
 ISO 11616 - Data elements and structures for the unique
identification and exchange of regulated pharmaceutical product
information
 ISO 11238 - Data elements and structures for unique
identification and exchange of regulated information on
substances’
 ISO 11239 Data elements and structures for unique
identification and exchange of regulated information on
pharmaceutical dose forms, units of presentation, routes of
administration and packaging’
 ISO 11240 - Data elements and structures for unique
identification and exchange of units of measurement’

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ISO - IDMP
 Standards designed to allow unambiguous identification
of products across regions to improve the robustness of
Pharmacovigilance and other regulatory activities.
 Can be applied to both marketed and development
products
 Developed in response to a worldwide demand for
internationally harmonized standards for medicinal
products
 The ISO IDMP standards have now been
published and can be purchased at the ISO
website: http://www.iso.org/iso/home/store/cat
alogue_tc/catalogue_tc_browse.htm?commid=54
960

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FDA – IDMP an extension of SPL
 From: Vada Perkins (FDA)

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ISO ICSR
 ISO EN 27953-2, Health Informatics
‘Individual Case Safety Reports (ICSRs) in
pharmacovigilance’ Part 2: Human
pharmaceutical reporting requirements for
ICSR

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ISO ICRA
From: Nick Halsey, EMA, Presentation on International Standards

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ICSR B.4 Drug(s) information

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RPS Highlights
 One XML file
 No defined TOC, no defined file structure
– Inter-document hyperlinks will be a challenge
 One sequence to many products, e.g.
manufacturing change
 Attributes at the file level
 All FDA centers on one standard
 Two way communication, e.g. receive
approval letters from regulators
Regulatory Informatics

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Global Standard
 ICH
– M8 Expert Working Group
 Requirements
 Draft implementation guide (6/2012)
 EU
– TIGes RPS subgroup (2009)
– FR, NL, DE, AT, UK, IRL, GR, EMA, EFPIA, EGA, EuropaBio
and AESGP
– RPS allows regional differences
 FDA
– Working directly with HL7
 Health Canada
– Plans to implement 6 months behind FDA
– Will implement for Devices, Vet Med and Human Pharmaceutics

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RPS - timeline
 HL7 Draft Standard ballot Sept 11
 HL7 Normative Standard ballot Jan 13
 FDA Implementation – Mid 2013*
 ANSI Standard June 13
 ISO standard Jan 14
*Consensus is FDA Implementation will be Mid 2014

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FDA new Module 1
 Based on experience since 2003
 Updated Table of Contents
 Mini-step to RPS
 Bundled submissions
– One submission to be submitted to multiple applications
– A.K.A Global Supplements
 CDER OPDP (ne:DDMAC)
 CBER APLB
 FDA Target Implementation: September 2013
 FDA Module 1 website

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FDA new Module 1
 Added
– Id (Company id)
– Submission description
– Contact information (e.g., regulatory, technical)
– Cross reference application number
– Submission type
– Submission sub-type
– Supplement effective date type
– Submission id
 Removed
– Date of submission
– Product Information
– Related sequence number

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EU eCTD 4.0 Module 1
 Initial draft implementation guide (v1.0) – June 30, 2012
 Only Module 1 but full v4.0 implementation
– Includes product / substance information (IDMP)
– Two way communication
 Will reference ICH IG for M2-M5
 Medicinal Product Info coded as keywords
– A replacement for eCTD attributes.
– Medicinal products identified by name in each country.
 EU eCTD 4.0 Mod 1 IG

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Health Authority - submission unit types
Code Description
LoQ List of questions
LoI List of out-standing issues
AuthorLetter Authorisation letter
ConfirmReceipt Confirmation of receipt
PrAR Preliminary Assessment Report
FAR Final assessment report
PrVAR Preliminary Variation Assessment
FVAR Variation Assessment Report
FRAR Renewal Assessment Report

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Clinical Study Data Working Group
 Was CDISC-HL7 working group
 Study Participation
– Sites, Investigators, IRBs, CROs, Labs
– Form 1572
 Study Design
– Draft Implementation Guides
 Subject Data (Patient Narrative)
– CDA document

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Study Participation
 Xform demo – FDA Form 1571

Clinical Document Architecture

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Clinical Document Architecture (CDA)
 A document markup standard that specifies the structure and
semantics of ‘clinical documents’ for the purpose of exchange.”
 Clinical documents, according to CDA, have the following
characteristics:
– Persistence
– Stewardship
– Potential for authentication
– Context
– Wholeness
– Human readability
 A CDA document is a defined and complete information object
that can include text, images, sounds, and other multimedia
content.

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Characteristics of a CDA document
• CDA documents are encoded in Extensible
Markup Language (XML).
• CDA documents derive their meaning from
the HL7 Reference Information Model (RIM)
and use the HL7 Version 3 Data Types.
• The CDA specification is richly expressive and
flexible. Document-level, section-level and
entry-level templates can be used to
constrain the generic CDA specification

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CDA ‘templates’
 Not ‘templates’ as normally defined.
 Set of rules, ‘constraints’, on the document in
a standard format
 Rules are directly translated to an XML
schema (Schematron) which can ‘validate’
the document before it is exchange.
 Consists of header and content sections
 Content can be either <nonXMLbody> or
<StructuredBody>

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Schematron - a schema language for XML
 ISO Standard (ISO/IEC 19757)
– Document Schema Definition Language (DSDL)
– Rule based validation
– Shall, should, may, shall not…
– Examples
 If structuredBody, the component/structuredBody SHALL
conform to the section constraints below (CONF:9540).
– SHALL contain 1..1 Allergies Section (entries optional)
(templateId:2.16.840.1.113883.10.20.22.2.6) (CONF:9542).
– SHALL NOT include a Chief Complaint and Reason for Visit Section
(CONF:10055).
– SHALL contain 1..1 Hospital Discharge Diagnosis Section
(templateId:2.16.840.1.113883.10.20.22.2.24) (CONF:9546).

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Examples of CDA documents
 SPL
 Continuity of Care Document (CCD)
– Meaningful use
 Subject Data (Patient Narratives )
 ~450 have been defined for EHRs.
 Challenge: managing templates
– Quality
– Guidance
– Versioning
 Trifolia - http://trifolia.lantanagroup.com/

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References
 Standards Development Organizations
– HL7 HL7
– ISO TC215 ISO TC215
– CDISC CDISC
– CEN TC251 CEN TC251
– GS1 GS1
– MedDRA MedDRA MSSO
– IHTSDO (SNOMED) IHTSDO
– BRIDGE BRIDG

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References
 Wikis / Blogs
– CDISC Blog CDISC Blog
– Technology Services Group Blog TSG Blog
– HL7 Wiki HL7 Wiki
– S&I Framework S&I Wiki
– CSC Blog CSC Blog

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References
 Vendors / Whitepapers / Webinars
– Aris Global Whitepapers ArisG Whitepapers
– Mission3 DIA EDM Presentation Mission3 DIA EDM
– Life Science Leader Magazine Making RIM pay

v1
from: Armando Oliva, FDA
Clinical Trial Repository (Janus)

v1
ISO 11239 – Dosage Forms, Routes of
Administration, Units of presentation

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