Gap analysis between Article 57(2) of EC Regulation and the epSOS eP Giorgio Cangioli , HL7 International Foundation Paolo Alcini, European Medicines Agency Member States authorities and Competence Centres Engagement Workshop. Luxembourg, 21st April, 2015

Table of Contents The context The epSOS experience.. …what’s happening now… (EXPAND, openMedicine,..) …the EMA Art. 57 Database How Art. 57 Db can help the cross-border eP The epSOS Art. 57 Gap Analysis Proposed approaches Conclusions

The Context The epSOS project, its “children” (EXPAND, openMedicine) and the EMA Art. 57 database

The epSOS experience The epSOS project piloted the cross-country exchange of medications information in several use cases: ePrescription / eDispensation Patient Summary Healthcare Encounter Report Medication Related Overview Without a common European Drug Nomenclature (like RxNorm in US) drugs have been “identified” in epSOS using a set of attributes (ingredients, strengths, form code, route of administration, …) that describe them

The epSOS experience Those data are conveyed using epSOS defined CDA extensions, based on standard models, relying on commonly available coding systems: ATC (for substances) , EDQM (form code, route of administration, …),… Several shortages have been however experienced in epSOS: Capability of providing structured and coded information (particularly for multiactive ingredients products) Mapping issues with local codes Concepts in EDQM which countries cannot map nor translate to Suitability of the ATC code system for the identification of the active ingredients (ATC is not conceived for that) Management of the “complex” packages Display of the received information (e.g. non physical units: tablets, puffs,…=> Unit of Presentation) …….

…what’s happening now… The EXPAND Thematic Network [2014-2015] (http://www.expandproject.eu) has taken over most of the issues identified in epSOS and some mitigation actions has been agreed for facilitating the prosecution of the pilot, leaving however the most relevant topics to the openMedicine project The openMedicine Coordination & Support Action (http://www.open-medicine.eu) [2015-2016] aims to Contribute towards and enhance the safety and continuity of cross-border (and also national level) healthcare through interoperable ePrescriptions Develop concrete solutions to: “The challenge in ePrescription is how medicines can be communicated in the cross border setting.”

Then ? EXPAND provided solutions for short term eP pilots openMedicine is looking for long term comprehensive answers (based on the ISO IDMP Identification of Medicinal Products standards) What can be done in the medium term for improving the eP interoperability ?

Fundamental questions from epSOS Can the EMA work, undertaken because of the pharmacovigilance legislation, contribute towards improving interoperability of databases and safety and interoperability of ePrescriptions? YES «It – could – work!»

How the Art. 57 DB can help the cross-border eP epSOS vs Art. 57 Gap analysis, Proposed approaches

...the Article 57 Database (governance) The submission of data on medicines by marketing-authorisation holders is a legal requirement introduced by the Article 57(2) of Regulation (EU) No 1235/2010 (2010 pharmacovigilance legislation) NCAs & EC grant/ amend Marketing Authorisations of Medicinal Products following evaluation and approval of product information 15 days from initial marketing authorisations 30 days from variation of marketing authorisations Article 57 Database Article 57 database contains regulated information on Medicinal Products in Europe

…the Article 57 Database (Content) Structured Medicinal Product Information: P1: MAH (Legal Entity) P2: QPPV P3: PhV Enquiries P4: PSMF P5: Authorisation country code P6: Authorisation procedure P7: Authorisation status P8: Authorisation number P9: Authorisation date P10: MRP/DCP/EU number P11: Date of withdrawal/revocation/suspension P12: Package description P13: Orphan drug designation P14: Comments (e.g. paediatric use) P15: Medicinal product name P16: Medicinal product invented name P17: Product generic name P18: Product company name P19: Product strength name P20: Product form name P21: Pharmaceutical Form P22: Route of administration(s) P23: Active ingredient(s), Adjuvant(s) P24: Excipients P25: Medical device(s) P26: Strength of active ingredient(s)/adjuvant(s) P27: Therapeutic Indication(s) P28: ATC code P29: Medicinal Product type/Legal Basis Unstructured Medicinal Product Information: P30: Summary of Medicinal Product Characteristics Substance controlled terminology: S1: Substance names S2: Substance Translations S3: Substance synonyms S4: Substance class S5: Reference source S6: International Codes Multilanguage Reference controlled terminology: R1: Pharmaceutical form R2: Route of Administration R3: ATC codes R4: Units of Measurement (UCUM) R5: Units of presentation R6: Reference source ). The following structured information is electronically submitted and therefore available in the XEVMPD: 1. description of the (invented) name of the medicinal product; 2. details of the marketing authorisation holder (including the name, address and a description of the size of the organisation i.e. SMEs); 3. details of the marketing authorisation such as the status and date (e.g. withdrawal, valid); marketing authorisation procedure and legal basis; marketing authorisation country and related authorisation numbers; Orphan drug designation; 4. description of the pharmacodynamic properties based on the ATC code(s) of the medicinal product; 5. description of the therapeutic indications coded in MedDRA and a declaration that the medicinal product is "authorised for the treatment in children"; 6. details of the qualitative and quantitative composition of the medicinal product, including the list of active substance(s), adjuvant(s) and excipients, and the strength (amount) of the active substance(s) (and adjuvants where applicable); 7. description of the medical device(s) for combined advanced therapy medicinal products in accordance with Regulation (EC) No 1394/2007 as applicable; 8. the authorised and administrable pharmaceutical form(s); 9. description of the posology and method of administration (i.e. Route(s) of administration); 10. pharmacovigilance information such as the name and contact details of the Qualified Person Responsible for Pharmacovigilance (QPPV), the location of pharmacovigilance system master file, and the organisation contact e-mail and phone number for pharmacovigilance enquiries; 11. an electronic copy of the latest approved Summary of Product Characteristics (SmPC) including version date, document reference number(s) and document language(s). Most of the information available in the XEVMPD is encoded based on a set of controlled terminologies e.g. XEVMPD substance controlled vocabulary, pharmaceutical form(s) and routes of administration(s). Organisation controlled terminology: O1: MAH (Legal Entity) details O2: QPPV O3: PhV Enquiries O4: PhV System Master File

…the Article 57 Database (Content) Product Report Repository Brand name 1 Brand name 2 Brand name 1 XEVPRM Format XEVPRM Format Brand name 2 Scientific Product Repository Paracetamol 100mg Tablet Paracetamol 100mg Paracetamol Tablet Paracetamol Abstract composition codes represents the Pharmaceutical Product independently from its commercial form, identified as Non Proprietary Medicinal  Preparation

Art. 57 Vs epSOS gap Analysis The project team performed a gap analysis with the perspective of supporting the epSOS use cases using the EMA “facilities” Data models comparison Vocabulary comparison I.e. is out of the scope of this analysis to consider how the epSOS

Art. 57 Vs epSOS gap Analysis Data Model Information available in the EMA database is substantially a superset of what is required by epSOS the only exception concern the type of outer package, coded in epSOS and provided as general description in the EMA DB. Not a critical issue I.e. is out of the scope of this analysis to consider how the epSOS

Art. 57 Vs epSOS gap Analysis Vocabulary The adoption of some XEVMPD (eXtended EudraVigilance Medicinal Product Dictionary) vocabularies may resolve most of the epSOS known issues (e.g. the identification of the active ingredients) Substance names Pharmaceutical form Route of Administration ATC codes Units of Measurement Units of Presentation I.e. is out of the scope of this analysis to consider how the epSOS

Art. 57 Vs epSOS gap Analisys Main gaps are Different versions of adopted code system: WHO ATC, EDQM (European Directorate for the Quality of Medicines) Usage of EMA specific code system extensions (mainly for EDQM) (i.e. pre-adoption of concepts not yet included in the official release) Different approach on the management of the units of measure, both based on UCUM (Unified Code for Units of Measure) Notation : case sensitive Vs case insensitive Adopted Logic : prefix and unit (e.g. ‘m’ and ‘g’ as separate fields) Vs pre-coordinated unit (e.g. mg) Usage context: specific (strength denominator; strength numerator) Vs broad scope (any field where units are used) EMA provides suitable vocabularies, currently not foreseen in epSOS (ingredients (non ATC); unit of presentations)

Possible approaches Two possible - not mutually exclusive - approaches have been identified: Use the ART 57(2) Database for filling the epSOS data structure: i.e. communicate the detailed and complete information on the prescribed product (medication description) Use the ART 57 services for resolving the identification of the Products cross-borders. No constrains have been specified about how each country will determine and provide this information in the issued cross-border ePrescription. For example: determined by the prescriber as part of the information available in the local drug DB; assigned when the prescription is transmitted outside the national borders by a software component on the basis of the data present in the prescription; ….

Filling the epSOS elements using the Art 57 data epSOS Data Set Cyllaron* Pharmaceutical Product Amoxicillin and clavulanic acid, 875 mg/125 mg, Tablets, Oral; 20 tablets; …. The patient receives a prescription for ‘Pharmacillo’ from her Italian doctor…. … she then travels to Greece where she wants to redeem the prescription… 18 (*) Medicinal product names are fictional and for illustrative purposes only..

Filling the epSOS elements using the Art 57 data Proposed harmonization tasks Adopt the XEVMPD substance vocabulary for resolving the known issues about the identification of the active ingredients. Allow to use the substance ATC code and the active ingredient data as distinct information Recently approved EXPAND change proposals support this ! Align the epSOS ATC and EDQM based value sets with the XEVMPD ones Use the EMA tables of units for generating new value sets to be used in epSOS for filling strengths’ denominators and numerators. A 1 to 1 relationship between the epSOS and the ART. 57 used units can be defined.

Filling the epSOS elements using the Art 57 data Constraints for the adoption Country of Affiliation must have in its local database the coded information contained in Art 57 database for its authorised medicines –or – Country of Affiliation must perform a call to EMA Art 57 database to retrieve the coded data Country of Affiliation must upgrade the National Connector epSOS MVC and MTC have to be upgraded OpenNCP Semantic Components and Portal and eP scrutiny test tools must be updated Country of Treatment must have in its local database the coded information contained in Art 57 db for its authorised medicines to fill the eDispensation –or – Country of Treatment must perform a call to EMA Art 57 database to retrieve the coded data for the eDispensation Advantage of the adoption Preparatory to the adoption of ISO IDMP

Cross-borders identification with Art. 57 services Marketing Authorisation MHN: IT 479 6763 Italian name: Pharmacyllo* Authorised by: AIFA Marketing Authorisation MPID: GR 549 6731 Greek name: Cyllaron* Authorised by: ANSM Marketing Authorization Number e.g. IT 479 6763 The patient receives a prescription for ‘Pharmacyllo’ from her Italian doctor…. … she then travels to Greece where she wants to redeem the prescription… 21 (*) Medicinal product names are fictional and for illustrative purposes only..

Cross-borders identification with Art. 57 services The Pharmaceutical Products are resolved cross- borders using the ART 57 services The country that issues the prescription identifies the product through the national authorization number The dispensing country queries the Art. 57 services for obtaining which product(s), in that country, fit(s) with the prescribed one. Proposed harmonization tasks Introduce the concept of authorization number in the epSOS data set (as mandatory) This concept is already present in the implemented model adopted in the epSOS extension.

Cross-borders identification with Art. 57 services Constraints for the adoption Country of Affiliation who allows only to prescribe by “generics” or by Active Ingredients, must simulate a Dispensation retrieving a registration code of a medicine compliant to the ePrescription –or – Country of Affiliation must perform a call to EMA Art 57 database to retrieve the registration data (very unlikely…) Country of Treatment must perform a call to EMA Art 57 database to retrieve the list of medication equivalent to the receive ePrescription (suggested: through the portal) eDispensation is built using the registration code of the dispensed medicinal Advantage of the adoption Limited changes in OpenNCP and MVC are required No need for coded data in Country A and B Conceptually, no changes are needed in the portal display, being the Country B medicinals

Conclusions « It – could – work! » (Young Frankenstein, 1974)

Conclusions (1/2) A medium term solution for improving the EU cross- border eP interoperability based on the Art. 57 Database content and services can be realized. It covers registered pharmaceutical products It may evolve towards long terms sustainable future solutions based on IDMP, coherently with the evolution path foreseen by EMA for the Art. 57 and by the openMedicine project. Two possible - not mutually exclusive - approaches can be thought : Filling the epSOS elements using the Art 57 data Resolve the Pharmaceutical Products, cross-borders, using the ART 57 services

Conclusions (2/2) EMA is currently validating the information received in Art57 database and it is also discussing with MSs on how to ensure good data quality minimising the “a posteriori” validation. EMA is currently liaising with MSs to check the level of completeness of the data received in Art57 database. EMA will review the business process and the data workflow during the ISO IDMP implementation to improve data quality at source point

Fundamental questions from epSOS Can the EMA work, undertaken because of the pharmacovigilance legislation, contribute towards improving interoperability of databases and safety and interoperability of ePrescriptions? YES «It – could – work!»

Thank You ! Questions ? Our questions: Which solution do Member States prefer the most? Which Member States are ready for either solutions?