International Conference on Harmonisation of TechnicalRequirements for Registration of Pharmaceuticals for Human Use

Pharmacovigilance and the role of MedDRA in Regulatory Reporting

Pre-ICDRA ConferenceWorkshop B - 14:00-15:30 Terminologies, Informatics and Management

Singapore, 28 November 2010

CAPT Justina A. Molzon, M.S. Pharm., J.D.Associate Director for International Programs

Center for Drug Evaluation and Research / USFDA CDER ICH Steering Committee Representative

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Topics

Background: need for safety monitoringICH medical terminology and its governance Regulatory status WHO and MedDRAFacilitating the use of MedDRALong-term benefits of MedDRA

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BackgroundWhy monitor the safety of medicines?

Medicines are authorized on the basis that likely benefits in respect of efficacy outweigh perceived risks At the time of authorization “limited” data available on which to assess risk

Animal toxicology data may be of limited relevanceClinical Trials have limitations

Medicines tested in small number of individualsCarefully controlled conditions & close follow-upCareful adherence to dosage regimenExclusion of patients who are frail, on multiple therapiesUnlikely to detect Adverse Drug Reactions (ADRs) occurring with incidence of lower than 1/3,000

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BackgroundWhy monitor the safety of medicines?Real life situation

Large number of patients in a less controlled environmentUnexpected and rarer Adverse Drug Reactions (ADRs) may be seen

Need for post-authorization surveillance to:Monitor the use of medicines in everyday practice to identify previously unrecognized adverse effects or change in the patterns of adverse effectsOn-going assessment of risks and benefits of medicines in order to determine what action, if any, is necessary to improve their safe useProvide information to health care professionals and patients to optimize safe and effective use of medicinesAn example is Thalidomide in early 1960’s

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Background How do we collect safety information?

Spontaneous Reporting of Adverse Drug Reaction (ADR) to Drug Regulatory Agencies

Healthcare ProfessionalsMarketing Authorization HoldersPatients

Post-Authorization/marketing studiesPublished literature

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Background What do we need to report safety information?

In both pre- and post-authorization situations, a recognized terminology is an essential requirementFor protection of global public health: need for an international, standardized, multi-lingual, robust, medically validated terminology and allowing electronic communication .

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What is MedDRA?

Med = MedicalD = Dictionary for

R = RegulatoryA = Activities

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Development of MedDRA under the auspices of I C H

INTERNATIONAL CONFERENCE ONHARMONIS/ZATION

of Technical Requirements

for the Registration of Pharmaceuticals for Human Use

http://www.ich.org

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What is MedDRA? MedDRA has been developed by an ICH Working Group to provide:

An international, multi-lingual, medical terminology

Medical personnel can code ADR data in their native languageSafer – less likely to miscode data

Standardized communication between regulators and industry/sponsors of clinical trials

Within regions and between regions

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What is MedDRA? (cont)

A single terminology for use through all phases of development cycle (both pre- and post-marketing)

Clinical Trials (medical information, adverse events)Registration (study reports, analyses, summary of product characteristics / labeling – undesirable effects section) Post-authorization (adverse events)

Support for electronic submissions Each MedDRA term is assigned a unique 8-digit numeric code Codes can fill certain data fields in e-submission types (E2B: ICSR-Individual Case Safety Reports, eCTD: e-Common Technical Document)Codes easier to transmit as no language boundaries

MedDRA Support - Maintenance & Development-

MedDRA is actively maintained and developedSuccess of the terminology depends on its long-term maintenance and developmentMedDRA evolves to meet needs of both regulators, industry and other users

ICH contracted a MedDRA Maintenance and Support Services Organization (MSSO)All operations of MSSO governed by the ICH MedDRA Management Board

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MedDRA Governance:ICH MedDRA Management BoardConsists of:- 6 ICH Parties: EU, EFPIA, FDA, PhRMA, MHLW and

JPMA- MHRA (Medicines and Healthcare products

Regulatory Agency of the UK)- Health Canada- WHO (participates as a non-voting Observer)- IFPMA acts as a non-voting Observer, and chairs the

Board

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Regulatory status on the use of MedDRA

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United States and JapanUS FDA

Used in FDA’s adverse event database (AERS)Proposed Rule for Safety Reporting Requirements (2003): MedDRA for postmarketing safety reportsProposed Rule for Electronic Submission Requirements (2009): MedDRA for electronic submission of reports

Japanese Ministry of Health, Labour and WelfareMandatory to use MedDRA for electronic reportsMandatory to use MedDRA in Periodic Infection and Safety ReportsFor medical devices with biological components, infections to be described with MedDRA terms

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European UnionClinical trials

SUSARs (Suspected Unexpected Serious Adverse Reactions) – mandatory to use MedDRA

Volume 9A (all authorized medicinal products)Individual Case Safety Reports (ICSRs) – mandatory to use MedDRA For adverse reactions in Periodic Safety Update Report – mandatory to use MedDRA Standardized MedDRA Queries (SMQs) recommended for signal detection and for data retrieval

Summary of Product CharacteristicsContraindications, Special warnings, Undesirable effects sections - mandatory to use MedDRA

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Canada

New pharmacovigilance information system implemented within Health Canada enabling compliance with the ICH adverse reaction reporting requirements, including MedDRARecent MedDRA implementation within the post-market surveillance environment, March 2008Future MedDRA implementation within the pre-market surveillance environment, 2011

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e-Reporting Transmission of individual case safety reports currently relies in many countries on paper-based formats or electronic media (usually by on-line access, tape or file transfer)Electronic reporting is becoming the main route for exchanging adverse event/reaction reports between companies, sponsors of clinical trials and regulators worldwide

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e-Reporting

E2B is the electronic standard for transfer of safety information (ICSRs) which has been developed by ICH, MedDRA being a required component of it

Work is underway with ISO (International Organization for Standardization) to develop ICSRs (E2B) as an international electronic standard

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WHO and MedDRA As of March 2008, MedDRA has been implemen-ted in WHO’s Global Safety Database (Vigibase)

WHO National Centres can review data and conduct analyses in both WHO-ART and MedDRA

Data can be sent/entered in either MedDRA or WHO-ARTReports generated in either MedDRA or WHO-ART

With Vigibase containing >5.5 million ICSRs, it now provides a global repository of MedDRA-coded safety data:

Substantial tool for pharmacovigilanceOf significant benefit to global patient safety

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WHO and MedDRA WHO Uppsala Monitoring Centre (UMC) has developed with ICH/MSSO a “bridge” or mapping from WHO-ART to MedDRA:

Allows conversion of legacy data from WHO-ART to MedDRA Maintained current with every version release of WHO-ART and MedDRADoes not work in the other direction since MedDRA is more granular than WHO-ART

WHO UMC receives most of ICSRs coded in MedDRA

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Facilitating the use of MedDRA

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ICH-endorsed Guide for users

Establishment of the ICH MedDRA Points to Consider (PtC) Working Group in 1999ICH MedDRA Points to Consider Documents:

How to best classify the data? MedDRA Term Selection document How to best retrieve and present the data? MedDRA Data Retrieval and Presentation document Both updated with Users feedback for every release of MedDRA

MedDRA Points to Considerhttp://www.ich.org

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Multi-lingual terminology

MedDRA maintained simultaneously in 10 languages

English (1999)Japanese (1999)French (2002)German (2002)Portuguese (2002) Future availability – Hungarian (2011)

Translation includes terms and supporting documentation

Spanish (2002)Dutch (2003)Italian (2005)Czech (2007)Mandarin Chinese (2009)

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MedDRA Software ToolsMedDRA comes with software tools

Browsers (Desktop and Web-based) to review and search the terminology

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Standardized MedDRA Queries (SMQs)Over 80 SMQs jointly developed by CIOMS WG on SMQs and ICH/MSSO

Important signal detection toolsConsist of groupings of MedDRA terms that relate to a defined medical condition or area of interestIntended to aid in the identification and retrieval of potentially relevant individual case safety reportsMaintained with each version of MedDRAExamples:

Anaphylactic reactionIschaemic heart diseaseDepression and suicide/self-injury

Free Training MSSO offers two free training courses to MSSO Subscribers, be regulatory authorities or otherwise

Basic and Advanced topicsMultiple locations around the world

The MedDRA Board considers requests for training. Considerations based on:

Optimally, be regionally-basedLeverage existing regional training activities and events

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Access to MedDRAThe ICH Board has developed special licenses to provide access to low revenue companies

EMA has a special mechanism for small and medium sized companies to submit ICSRs

Includes free access to MedDRAUS FDA is developing a similar mechanism for small manufacturers to meet regulatory reporting requirements using MedDRA

The ICH Board is open to exploring other financing models to fit the local needs and culture

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Access to MedDRA (cont)

MedDRA is available at no charge to Academics Healthcare providersRegulatory authorities

Commercial organizations pay an annual subscription fee based on annual turnover

Subscription rates have been reduced or kept unchanged for the last six years

WORLDWIDE

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Long-term Benefits of MedDRA

Regulators and Pharmaceutical companies operate on a global scale – important to speak the same regulatory languageOne regulatory language removes the need for multiple terminologiesEase of data exchange between various partiesEnables data mining / signal detection using large databases (e.g., FDA AERs, WHO Vigibase)

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Long-term Benefits (cont)

Reduce impact on environment!

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ArgentinaAustraliaAustriaBelgiumBrazilBulgariaCanadaChileChinaChinese TaipeiCroatiaCyprusCzech RepublicDenmarkDominican RepublicEstoniaEthiopiaFinlandFranceGermanyGreece

Hong KongHungaryIcelandIndiaIrelandIsraelItalyJapanLatviaLithuaniaLuxembourgMalaysiaMaltaMauritusMexicoMontenegroNetherlandsNew ZealandNorwayPhilippinesPoland

PortugalRomaniaRussian FederationSaudi ArabiaSerbiaSingaporeSlovakiaSloveniaSouth AfricaSouth KoreaSpainSwedenSwitzerlandThailandUkraineUnited Arab EmirateUnited KingdomUnited States

MedDRA users in 60 countries

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Questions?

Contact the ICH MedDRA Management Board meddraboard@ich.org

ICH website: www.ich.orgMSSO site: www.meddramsso.com

MSSO Help Desk: mssohelp@ngc.com

AcronymsCTD: Common Technical Document e-CTD: electronic Common Technical Document E2B: Data Elements for Transmission of Individual

Case Safety Reports EFTA: European Free Trade AssociationEC: European CommissionEFPIA: European Federation of Pharmaceutical

Industries and Associations EU: European Union

Acronyms

FDA US: Food and Drug Administration United StatesICH: International Conference on Harmonisation of

Technical Requirements for Registration of Pharmaceuticals for Human Use

ICSR: Individual Case Safety Report IFPMA: International Federation of Pharmaceutical

Manufacturers & AssociationsISO: International Organization for Standardization

Acronyms JPMA: Japan Pharmaceutical Manufacturers

Association M1: Medical Dictionary for Regulatory Activities MedDRA: Medical Dictionary for Regulatory ActivitiesMHLW: Ministry of Health, Labour and Welfare MHRA: Medicines and Healthcare products

Regulatory Agency of the UKMSSO: MedDRA Support Services OrganizationNCA: National Competent Authority

Acronyms PhRMA: Pharmaceutical Research and Manufacturers

of America PSUR: Periodic Safety Update ReportSMEs: Small and Medium Sized EnterprisesSMQs: Standardized MedDRA Queries US: United States WHO: World Health OrganisationWHO-ART: World Health Organisation-Adverse

Reaction Terminology