update regulatory standards landscape

Regulatory Informatics Consulting

Fred MillerRegulatory Informatics ConsultingNovember 20, 2012

Update: Regulatory Standards Landscape

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)

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”

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”

Standards Development Organizations

ICH ISO TC215 CEN TC251 HL7 CDISC BRIDG IHTDO (SNOMED) MedDRA MSSO

Standards Development Organizations

HL7RCRIM

CEN 251ISO 215

BRIDGEICH

MedDRAMSSO

HarmonizationHarmonization

IHT SDO

Modified from Nick Halsey, EMA, International Standards

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

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.

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)

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.

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.

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

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

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

Regulated Products

Product Information

Labeling

Product Listing

Facility Listing

Submissions

Regulated Studies

Stability Study

Filtered Query Service ECGs Clinical

Study Data

Study Design

Study Data

Study Reporting

Study Participatio

Clinical Trial Lab

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

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.

ISO TC215

Technical Committee on Health Informatics– IDMP

Identification of Medicinal Products – ICSR

Individual case safety reports (ICSRs) in pharmacovigilance

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

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)

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.

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)

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

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

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’

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

FDA – IDMP an extension of SPL

From: Vada Perkins (FDA)

ISO ICSR

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

ISO ICRA

From: Nick Halsey, EMA, Presentation on International Standards

ICSR B.4 Drug(s) information

RPS (eCTD 4.0)

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

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

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

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

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

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

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

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

Study Participation

Xform demo – FDA Form 1571

Clinical Document Architecture

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.

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

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

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).

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?

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

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

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

from: Armando Oliva, FDA

Clinical Trial Repository (Janus)

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

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