MedDRA® Overview NCI Vocabulary and Common Data Elements Workspace Presented by: Ann Setser, MSSO June 16, 2011 MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Agenda Background of MedDRA Regulatory status of MedDRA Introduction to MedDRA’s structure and scope Demonstration of MedDRA Desktop Browser Standardised MedDRA Queries (SMQs) Examples of NCI’s use of MedDRA

What is MedDRA? Med = Medical D = Dictionary for R = Regulatory A = Activities

Objectives for MedDRA Development Result of an ICH initiative (M1) To provide: An international multi-lingual terminology Standardized communication between industry and regulators Support of electronic submissions Application through all phases of the development cycle 4

Objectives for MedDRA Development (cont) To provide (cont): Classification for a wide range of clinical information Support for multiple medical product areas A terminology that saves time and resources 5

MedDRA and the MSSO International support and development of terminology Foster use of MedDRA through communications and educational offerings “Custodians”, not owners, of the terminology JMO (partner organization for Japanese-language MedDRA) Governed by a Management Board (industry, regulators, multi-national, other interested parties) 6 6

MedDRA Definition MedDRA is a clinically-validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry. The terminology is used through the entire regulatory process, from pre-marketing to post-marketing, and for data entry, retrieval, evaluation, and presentation. 7

MedDRA Subscribers Worldwide 2847 organizations as of 31 March 2011

Regulatory Status of Mandate US FDA Used in several FDA databases (AERS, VAERS, and CAERS) Proposed Rule for Safety Reporting Requirements (2003): MedDRA for postmarketing safety reports Japanese Ministry of Health, Labour and Welfare Mandatory use for electronic reports Used in Periodic Infection and Safety Reports For medical devices with biological components, infections to be described with MedDRA terms

Regulatory Status of Mandate (cont) European Union Clinical trials SUSARs (Suspected Unexpected Serious Adverse Reactions) – use MedDRA LLTs (current or previous version) Volume 9A (all authorized medicinal products, including OTC) Individual Case Safety Reports (ICSRs) – use MedDRA LLTs (current or previous version) For adverse reactions in Periodic Safety Update Report Standardised MedDRA Queries (SMQs) recommended for signal detection

ICH Standard Work together with other ICH standards for electronic submission: ICH E2B form: data elements for transmission of ICSR MedDRA

MedDRA and E2B MedDRA-coded fields B.1.7.1 Structured information on relevant medical history including onset and resolution date as well as relevant comments B.1.7.1a.1 MedDRA version for medical history B.1.7.1a.2 Structured information B.1.8 Relevant past drug history B.1.8f.1 MedDRA version for indication B.1.8f.2 Indication B.1.8g.1 MedDRA version for reaction B.1.8g.2 Reaction B.1.9.2 Reported cause(s) of death B.1.9.2.a MedDRA version for reported causes(s) of death B.1.9.2.b Reported cause(s) of death (repeat as necessary) B.1.9.4 Autopsy-determined cause(s) of death B.1.9.4a MedDRA version for autopsy-determined cause(s) of death B.1.9.4b Autopsy-determined cause(s) of death (repeat as necessary) B.1.10.7 Relevant medical history and concurrent conditions of parent B.1.10.7.1a.1 MedDRA version for parent medical history B.1.10.7.1a.2 Structured information

MedDRA and E2B (cont) B.1.10.8 Relevant past drug history B.1.10.8f.1 MedDRA version for indication B.1.10.8f.2 Indication B.1.10.8g.1 MedDRA version for reaction B.1.10.8g.2 Reactions (if any and known) B.2 Reaction(s)/Event(s) B.2.i.1.a MedDRA version for reaction/event term LLT Reaction/event in MedDRA terminology (LLT) B.2.i.2.a MedDRA version for reaction/event term PT Reaction/event in MedDRA terminology (PT ) B.3 Results of tests and procedures relevant to the investigation of the patient B.3.1c Structured information (tests) relevant to the investigation of the patient B.4.k.11 Indication for use in the case B.4.k.11a MedDRA version for indication B.4.k.11b Indication for use in the case B.4.k.17.2 Effect of rechallenge (or re-exposure), for suspect drug(s) only B.4.k.17.2a MedDRA version for reaction(s)/event(s) recurred B.4.k.17.2b If yes, which reaction(s)/event(s) recurred? B.4.k.18.1 Relatedness of drug to reaction(s)/event(s) B.4.k.18.1a MedDRA version for Reaction assessed B.4.k.18.1b Reaction assessed B.5.3 Sender's diagnosis/syndrome and/or reclassification of reaction/event

Regulatory Status of Mandate (cont) European Union (cont) Interface between EudraVigilance and EU Risk Management Plan To code indications, risks, interactions (potential and Summary of Product Characteristics guideline MedDRA to be used throughout; in particular for Contraindications, Special warnings and precautions for use, and Undesirable effects sections 14

Regulatory Status of Mandate (cont) ICH M4E Guideline on Common Technical Document Recommended in adverse event summary tables Canada Guidance Document for Industry - Reporting Adverse Reactions to Marketed Health Products Recommended as standard for adverse reaction reports Guidance for Industry - Product Monograph (labeling) Preferred terminology for adverse drug reactions 15 15

WHO and MedDRA MedDRA implemented in WHO’s Global Safety Database (Vigibase) WHO National Centres can review data, conduct analyses in both WHO-ART and MedDRA Vigibase (>5.5 million ICSRs) provides a global repository of MedDRA-coded safety data Substantial pharmacovigilance tool Significant benefit to global patient safety WHO receives most of its ICSRs coded in MedDRA 16

Scope of MedDRA OUT IN Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history Medication errors Product quality, device issues Not a drug dictionary Not an equipment, device, diagnostic product dictionary Clinical trial study design terms Patient demographic terms Frequency qualifiers Numerical values for results Severity descriptors IN OUT Terms from other terminologies 17

MedDRA Structure System Organ Class (SOC) (26) High Level Group Term (HLGT) (335) High Level Term (HLT) (1,710) Preferred Term (PT) (19,086) Lowest Level Term (LLT) (69,019) MedDRA Version 14.0

MSSO’s MedDRA Browsers MedDRA Desktop Browser Download from MSSO Web site View/search MedDRA and SMQs Export functionality MedDRA Web-Based Browser https://www.meddrabrowser.org/dsnavigator/ Requires specific user ID and password Access to all MedDRA versions in English and available EU languages (and Chinese, if subscribed)

MedDRA Desktop Browser

MedDRA Desktop Browsers (Cont)

MedDRA Web-Based Browser 22

MedDRA Maintenance MedDRA is a user responsive terminology Subscribers may submit change requests to the MSSO for consideration Twice yearly official updates 1 September X.1 release (Simple changes only) 1 March X.0 release (Complex and simple changes) Resources: “What’s New” document Version report Recommendations for MedDRA Implementation and Versioning for Clinical Trials

ICH-Endorsed Guides for MedDRA Users Developed by a working group of the ICH Steering Committee Regulators and industry representatives EU, Japan, USA Canadian observer, MSSO, JMO 1. MedDRA Term Selection: Points to Consider Developed to promote medically accurate and consistent use of MedDRA in exchange of data (ultimately, for “medically meaningful” retrieval and analysis) 2. MedDRA Data Retrieval and Presentation: Points to Consider Objective is to promote understanding of implications that various options for data retrieval have on accuracy and consistency of final output Current versions available on MedDRA MSSO Web site (http://www.meddramsso.com/subscriber_library_ptc.asp)

Standardised MedDRA Queries (SMQs) Result of cooperative effort between CIOMS and ICH (MSSO) Groupings of terms from one or more MedDRA System Organ Classes (SOCs) related to defined medical condition or area of interest Included terms may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc., related to medical condition or area of interest Intended to aid in case identification 25

SMQs in Production - Examples As of Version 14.0, a total of 85 in production (One is inactive) Agranulocytosis Anaphylactic reaction Cerebrovascular disorders Convulsions Depression and suicide/self-injury Hepatic disorders Ischaemic heart disease Lack of efficacy/effect Osteonecrosis Peripheral neuropathy Pregnancy and neonatal topics Pseudomembranous colitis Rhabdomyolysis/myopathy Severe cutaneous adverse reactions Systemic lupus erythematosus

SMQ Benefits and Limitations Application across multiple therapeutic areas Validated reusable search logic Standardized communication of safety information Consistent data retrieval Maintenance by MSSO/JMO Limitations Do not cover all medical topics or safety issues Will evolve and undergo further refinement even though they have been tested during development

SMQ Applications Clinical trials Where safety profile is not fully established, use multiple SMQs on routine basis as screening tool Selected SMQs to evaluate previously identified issue (pre-clinical data or class effect) Postmarketing Selected SMQs to retrieve cases for suspected or known safety issue Signal detection (multiple SMQs employed) Single case alerts Periodic reporting (aggregate cases for safety and other issues, e.g., lack of efficacy)

How to “Run” SMQs Query 29

Browser Demonstration SMQ View

MedDRA Use for AE Reporting: Industry vs. NCI Verbatim/text terms coded to MedDRA for regulatory reporting Clinical trial data Post-marketing pharmacovigilance (spontaneous reports by healthcare professionals, companies, patients; post-marketing studies; literature reports) NCI Industry AE Subcommittee: When industry uses CTCAE, generally verbatim terms are also required which are coded to MedDRA Some also recode CTCAE terms to MedDRA NCI CTCAE

MedDRA Use at NCI List MedDRA Number of terms % ‘Mapped’ to MedDRA CTCAE v3 V10.0 ‘Mapped’ - CTCAE v4.0 V12.1 LLTs 790 Simplified Disease List (SDC) 245 94% Pre-existing conditions 38 100% Therapies 19 53%

CTCAE v4.0 and MedDRA Safety Profiler (CTCAE ‘Index’) Assistance to identify appropriate CTCAE term Utilizes all LLTs associated with CTCAE terms Example: search for ‘rigors’ or ‘shivering’ returns CTCAE v4.0 term ‘Chills’ ‘Other, specify’ assistance to select valid MedDRA term http://safetyprofiler-ctep.nci.nih.gov/CTC/CTC.aspx

CTCAE ‘Other, specify’ and MedDRA Verbatim (non-MedDRA) CTCAE v4.0 revision project analysis of ~450 verbatim 41% match 23% algorithm 36% uncoded caAERS pilot MedDRA integration with ‘Other, specify’ When all AE data is MedDRA (CTCAE + ‘Other, specify’), MedDRA tools can be applied for analysis (hierarchy, SMQs)

MedDRA Training Resources Free Training Open Registration Webinars Onsite Training Coding with MedDRA What’s New in MedDRA MedDRA Safety Data Analysis and SMQs MedDRA Versioning Webinar-MedDRA Coding Basics Introduction to MedDRA Webinar-Introduction to MedDRA Data Analysis and SMQs for Physicians Medication Errors and Product Quality Issue Concepts in MedDRA Shorter courses are available upon request. Please contact MSSO Help Desk for details.

Discussion www.meddramsso.com