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Transcript of Update regulatory standards landscape
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Regulatory Informatics Consulting
Fred MillerRegulatory Informatics ConsultingNovember 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
HL7RCRIM
CEN 251ISO 215
CDISC
BRIDGEICH
MedDRAMSSO
HarmonizationHarmonization
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 Participatio
n
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
IDMP / ICSR
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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/catalogue_tc/catalogue_tc_browse.htm?commid=54960
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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
RPS (eCTD 4.0)
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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 Consulting
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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
Clinical Study Data
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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/
Questions?
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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
Backup Slides
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from: Armando Oliva, FDA
Clinical Trial Repository (Janus)
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ISO 11239 – Dosage Forms, Routes of Administration, Units of presentation