Update regulatory standards landscape


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An update on standards development organizations and their impact on the exchange of regulatory information with health authorities.

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  • Generic Drug User Fee Amendment (GDUFA)Biosimilar User Fee Act (BSUFA).
  • International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use Clinical Data Interchange Standards Consortium, IncLiaisons A: Organizations that make an effective contribution to the work of the technical committee or subcommittee for questions dealt with by this technical committee or subcommittee. Liaisons B: Organizations that have indicated a wish to be kept informed of the work of the technical committee or subcommittee. Liaisons C: Reserved for ISO/IEC JTC1. IHTDO International Health Terminology Development Organizationthe Medical Dictionary for Regulatory Activities - Maintenance and Support Services Organization Biomedical Research Integrated Domain Group
  • GS1 – standards for supply and demand chains – standard for barcodes comes from GS1M3(R2)Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for PharmaceuticalsFinalised Guideline:June 2009M3(R2)Concept PaperPresentation on M3(R2)Description: The recommendations of this revised guidance further harmonise the nonclinical safety studies to support the various stages of clinical development among the regions of European Union (EU), Japan, and the United States. The present guidance represents the consensus that exists regarding the type and duration of nonclinical safety studies and their timing to support the conduct of human clinical trials and marketing authorisation for pharmaceuticals.Implementation: Step 5EU: Approved by CHMP June 2009, issued as CPMP/ICH/286/95. Coming into operation in December 2009MHLW: Adopted on 19 February 2010, PFSB/ELD notification No. 0219-4FDA: Published in the Federal Register, Vol. 75, No 13, Docket No. FDA/2008/D/0470, p. 3471, 21 January 2010M3(R2) Q&As R2Questions & Answers: Guidance on Non-Clinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals
  • E3, E6, E8 – what are they?
  • The formal ICH procedure consists of 5 Steps : Step 1: Consensus Building Step 2: Confirmation of six-party consensus Step 3: Regulatory Consultation and Discussion Step 4 Adoption of an ICH Harmonised Tripartite Guideline
  • Step 4 signoff likely 11/12 – Final implementation probably July 2016 – not 2015.
  • HL7 – huge organization, very formal processes, everything takes a long time Run by a few exceptional individuals, difficult to get wide spread participationHL7 v3 – complexity is a problem,
  • DIA – EDM – essentially eCTD meta-data as document meta-dataIRISS – focus on EVMPD at the momentPhRMA - PhRMA EDC/eSource Taskforce, Electronic Regulatory Submissions (ERS) groupTIGes – RPS subgroup formed 2009– composed of FR, NL, DE, AT, UK, IRL, GR, EMA, EFPIA, EGA, EuropaBio and AESGP.
  • EU – an extension of xEVMPD
  • Update regulatory standards landscape

    1. 1. v1Update: Regulatory Standards LandscapeFred MillerRegulatory Informatics ConsultingNovember 20, 2012 Regulatory Informatics Consulting
    2. 2. v1Agenda 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) Regulatory Informatics Consulting
    3. 3. v1FDA - 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” Regulatory Informatics Consulting
    4. 4. v1EMA 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” Regulatory Informatics Consulting
    5. 5. v1Standards Development Organizations ICH ISO TC215 CEN TC251 HL7 CDISC BRIDG IHTDO (SNOMED) MedDRA MSSO Regulatory Informatics Consulting
    6. 6. v1Standards Development Organizations BRIDGE ICH HL7Harmonization RCRIM Harmonization MedDRA IHT SDO MSSO CDISC ISO 215 CEN 251 GS1 Modified from Nick Halsey, EMA, International Standards Regulatory Informatics Consulting
    7. 7. v1ICH - International Conference on Harmonisationof Technical Requirements for Registration ofPharmaceuticals for Human Use Q - Quality Guidelines S - Safety Guidelines E - Efficacy Guidelines M - Multidisciplinary Guidelines Regulatory Informatics Consulting
    8. 8. v1ICH 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. Regulatory Informatics Consulting
    9. 9. v1ICH – 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) Regulatory Informatics Consulting
    10. 10. v1ICH (E2B) - ICRS Successful electronic transmission of ICSRs relies on the agreement of common data elements and on the syntactical definition of the electronic message. Regulatory Informatics Consulting
    11. 11. v1HL7 – 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. Regulatory Informatics Consulting
    12. 12. v1RCRIM - 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 Regulatory Informatics Consulting
    13. 13. v1HL7 - 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 Regulatory Informatics Consulting
    14. 14. v1HL7 - 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 Regulatory Informatics Consulting
    15. 15. v1RCRIM Regulated Products Regulated Studies Product Submissions Stability Clinical Trial Filtered Query Information ECGs Lab Study Service Clinical Study Labeling RPS Data Study Study Data Product Design Listing Study Study Facility Participation Reporting Listing Regulatory Informatics Consulting
    16. 16. v1RCRIM– 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 Regulatory Informatics Consulting
    17. 17. v1ISO - International Standards OrganizationISO (International Organization for Standardization) is the worldslargest developer and publisher of International Standards.ISO is a network of the national standards institutes of 162countries, one member per country, with a Central Secretariat inGeneva, Switzerland, that coordinates the system.ISO is a non-governmental organization that forms a bridgebetween the public and private sectors. On the one hand, many ofits member institutes are part of the governmental structure oftheir countries, or are mandated by their government. On theother hand, other members have their roots uniquely in theprivate sector, having been set up by national partnerships ofindustry associations. Regulatory Informatics Consulting
    18. 18. v1ISO TC215 Technical Committee on Health Informatics – IDMP  Identification of Medicinal Products – ICSR  Individual case safety reports (ICSRs) in pharmacovigilance Regulatory Informatics Consulting
    19. 19. v1CEN 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 Regulatory Informatics Consulting
    20. 20. v1BRIDG 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) Regulatory Informatics Consulting
    21. 21. v1BRIDG 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. Regulatory Informatics Consulting
    22. 22. v1BRIDG 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) Regulatory Informatics Consulting
    23. 23. v1Industry 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 Regulatory Informatics Consulting
    24. 24. IDMP / ICSR
    25. 25. v1ISO - 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 Regulatory Informatics Consulting
    26. 26. v1ISO - 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‟ Regulatory Informatics Consulting
    27. 27. v1ISO - 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 Regulatory Informatics Consulting
    28. 28. v1FDA – IDMP an extension of SPL From: Vada Perkins (FDA) Regulatory Informatics Consulting
    29. 29. v1ISO ICSR ISO EN 27953-2, Health Informatics ‘Individual Case Safety Reports (ICSRs) in pharmacovigilance’ Part 2: Human pharmaceutical reporting requirements for ICSR Regulatory Informatics Consulting
    30. 30. v1ISO ICRA From: Nick Halsey, EMA, Presentation on International Standards Regulatory Informatics Consulting
    31. 31. v1ICSR B.4 Drug(s) information Regulatory Informatics Consulting
    32. 32. RPS (eCTD 4.0)
    33. 33. v1RPS 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 Regulatory Informatics Consulting
    34. 34. v1Global 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 Regulatory Informatics Consulting
    35. 35. v1RPS - 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 Regulatory Informatics Consulting
    36. 36. v1FDA 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 Regulatory Informatics Consulting
    37. 37. v1FDA 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 Regulatory Informatics Consulting
    38. 38. v1EU 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 Regulatory Informatics Consulting
    39. 39. v1Health Authority - submission unit typesCode DescriptionLoQ List of questionsLoI List of out-standing issuesAuthorLetter Authorisation letterConfirmReceipt Confirmation of receiptPrAR Preliminary Assessment ReportFAR Final assessment reportPrVAR Preliminary Variation AssessmentFVAR Variation Assessment ReportFRAR Renewal Assessment Report Regulatory Informatics Consulting
    40. 40. Clinical Study Data
    41. 41. v1Clinical 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 Regulatory Informatics Consulting
    42. 42. v1Study Participation Xform demo – FDA Form 1571 Regulatory Informatics Consulting
    43. 43. Clinical Document Architecture
    44. 44. v1Clinical 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. Regulatory Informatics Consulting
    45. 45. v1Characteristics 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 Regulatory Informatics Consulting
    46. 46. v1CDA „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> Regulatory Informatics Consulting
    47. 47. v1Schematron - 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. (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. (CONF:9546). Regulatory Informatics Consulting
    48. 48. v1Examples 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/ Regulatory Informatics Consulting
    49. 49. Questions?
    50. 50. v1References 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 Regulatory Informatics Consulting
    51. 51. v1References 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 Regulatory Informatics Consulting
    52. 52. v1References Vendors / Whitepapers / Webinars – Aris Global Whitepapers ArisG Whitepapers – Mission3 DIA EDM Presentation Mission3 DIA EDM – Life Science Leader Magazine Making RIM pay Regulatory Informatics Consulting
    53. 53. Backup Slides
    54. 54. v1 Clinical Trial Repository (Janus)from: Armando Oliva, FDA Regulatory Informatics Consulting
    55. 55. v1ISO 11239 – Dosage Forms, Routes ofAdministration, Units of presentation Regulatory Informatics Consulting