Introduction to MedDRA® MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Course Objectives To provide an introduction to: MedDRA’s structure, scope, and characteristics Coding and the “MedDRA Term Selection: Points to Consider” document MedDRA’s application in data retrieval and analysis: MedDRA Data Retrieval and Presentation: Points to Consider” document Standardised MedDRA Queries (SMQs)

MedDRA Background

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

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 Core slide 5

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, resources, and money Core slide 6

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) Core slide 7 7

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. Core slide 8

Regulatory Considerations

Regulatory Status of Mandate US FDA Used in FDA’s adverse event database (AERS) Proposed Rule for Safety Reporting Requirements (2003): MedDRA for postmarketing safety reports Proposed Rule for Electronic Submission Requirements (2009): MedDRA for electronic submission of 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 Core slide. Updated v13.0. JH. Added 3rd bullet under FDA for 2009 proposed rule. If adopted, this would mandate that postmarketing safety reports be submitted electronically using MedDRA. Goes hand-in-hand with the 2003 proposed rule. Both will have to be adopted together.

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 Core slide

Regulatory Status of Mandate (cont) European Union (cont) Interface between EudraVigilance and EU Risk Management Plan To code indications, risks, interactions (potential and identified) Summary of Product Characteristics guideline MedDRA to be used throughout; in particular for Contraindications, Special warnings and precautions for use, and Undesirable effects sections Core slide. Updated v13.0 JH. Updated last bullet for SmPC based on Sep 2009 revision. MedDRA to be used throughout SmPC. 12 12

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 Core slide. Updated v13.0 JH. Format . Changed Canada draft guidance for Adverse Reactions to “Guidance Document for Industry” as the guidance was finalized in 2009. 13 13

MedDRA’s Structure and Scope

Scope of MedDRA OUT IN Not a drug dictionary Frequency qualifiers Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history Medication errors Product quality, device issues Numerical values for results Patient demographic terms Core slide. Updated v13.0 based on discussions with trainers. JH. Changed wording for drug product terms and equipment, device, diagnostic product terms (outside circle). Added medication errors, product quality and device issues inside circle. Referred to “other terminologies” instead of listing them. Clinical trial study design terms Severity descriptors Terms from other terminologies Not an equipment, device, diagnostic product dictionary 15

MedDRA Structure System Organ Class (SOC) (26) High Level Group Term (HLGT) (335) High Level Term (HLT) (1,709) Preferred Term (PT) (18,786) Lowest Level Term (LLT) (68,258) Core slide. Updated v13.0 term numbers. JH.

MedDRA Term Level Definitions SOC - Highest level of the terminology, and distinguished by anatomical or physiological system, etiology, or purpose HLGT - Subordinate to SOC, superordinate descriptor for one or more HLTs HLT - Subordinate to HLGT, superordinate descriptor for one or more PTs PT - Represents a single medical concept LLT - Lowest level of the terminology, related to a single PT as a synonym, lexical variant, or quasi-synonym (Note: All PTs have an identical LLT) Core slide. 17

System Organ Classes Blood and lymphatic system disorders Cardiac disorders Congenital, familial and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous system disorders Pregnancy, puerperium and perinatal conditions Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Social circumstances Surgical and medical procedures Vascular disorders Core slide. 18

Examples of LLTs SOC = Cardiac disorders HLGT = Cardiac arrhythmias HLT = Rate and rhythm disorders NEC Core slide. PT = Arrhythmia LLT Dysrhythmias LLT Arrhythmia NOS LLT Arrhythmia LLT (Non-current) Other specified cardiac dysrhythmias 19

Non-Current Terms Non-current terms are flagged at the LLT level within MedDRA Not recommended for continued use Retained within the terminology to preserve historical data for retrieval and analysis Terms that are vague, ambiguous, out-dated, truncated, or misspelled Terms derived from other terminologies that do not fit MedDRA rules Core slide. 20

MedDRA Codes Each MedDRA term assigned an 8-digit numeric code The code is non-expressive Codes can fulfill a data field in various electronic submission types (e.g., E2B) Initially assigned alphabetically by term starting with 10000001 New terms are assigned sequentially Supplemental terms are assigned codes Core slide. 21

A Multi-Axial Terminology Multi-axial = the representation of a medical concept in multiple SOCs Allows grouping by different classifications Allows retrieval and presentation via different data sets Purpose of Primary SOC Determines which SOC will represent a PT during cumulative data outputs Is used to support consistent data presentation for reporting to regulators Core slide. 22

A Multi-Axial Terminology (cont) A PT can be associated with one or more SOCs One of the associations is primary; all others are secondary A PT will have one and only one path to any particular SOC MedDRA can express multi-axiality at the PT, HLT, or HLGT level Core slide. 23

A Multi-Axial Terminology (cont) SOC = Respiratory, thoracic and mediastinal disorders SOC = Infections and infestations HLGT = Respiratory tract infections HLGT = Viral infectious disorders Core slide. HLT = Viral upper respiratory tract infections HLT = Influenza viral infections PT = Influenza

A Multi-Axial Terminology (cont) PTs in the following SOCs only appear in that particular SOC and not in others, i.e., they are not multi-axial Investigations Surgical and medical procedures Social circumstances Core slide. 25

Rules for Primary SOC Allocation PTs for diseases, signs and symptoms are assigned to prime manifestation site SOC Congenital and hereditary anomalies terms have SOC Congenital, familial and genetic disorders as Primary SOC Neoplasms terms have SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps) as Primary SOC Exception: Cysts and polyps have prime manifestation site SOC as Primary SOC Infections and infestations terms have SOC Infections and infestations as Primary SOC Core slide. 26

Primary SOC Priority If a PT links to more than one of the exceptions, the following priority will be used to determine primary SOC: 1st: Congenital, familial and genetic disorders 2nd: Neoplasms benign, malignant and unspecified (incl cysts and polyps) 3rd: Infections and infestations Core slide. 27

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) Core slide. New in v13.0. Suggest showing this slide before doing browser demonstration. 28

Browser Demonstration SOC View

MedDRA Maintenance

MedDRA Maintenance MedDRA is a user responsive terminology Subscribers may submit change requests to the MSSO for consideration Per core subscriber: 100 change requests per month For simple changes (PT and LLT levels), notification of supplemental change within 7-10 working days Weekly supplemental changes posted on MSSO Web site Complex changes above PT level received all year round. Posted for subscribers’ comments mid-year. Core slide. Updated v13.0. Changed bullet about 100 simple CRs per month to 100 CRs per month (includes simple and complex per Anna). Also added text about supplementals being posted on MSSO Web site. Deleted info about complex release being in March from last bullet since it is duplicated on following slide. Added sentence about being posted for subscriber comment. 31

MedDRA Maintenance (cont) Twice yearly official updates 1 September X.1 release (Simple changes only) 1 March X.0 release (Complex and simple changes) Core slide. Updated v13.0. Deleted info about what are the current and next versions because this will change.

WebCR Web-based tool for Change Requests (CR) URL: https://mssotools.com/webcr/ Via the Change Request Information page Ability to submit CRs online Immediate confirmation Review unsubmitted CRs online Ability to query CR history back to v5.1 Core slide. 33

Change Request Justification Statements Justification statement always required Inadequate justification – “Term does not exist in MedDRA” Adequate justification – statement of need Support with definitions and references (PDFs preferred) Examples of need: Term needed to code an indication Concept is being reported in a clinical trial Core slide. 34 34

Coding with MedDRA

What Is “Coding”? Code 1 : a systematic statement of a body of law; especially one given statutory force 2 : a system of principles or rules <moral code> 3 a : a system of signals or symbols for communication b : a system of symbols (as letters or numbers) used to represent assigned and often secret meanings 4 : genetic code 5 : a set of instructions for a computer Core slide. 36

Why Do We Code? Retrieve Present Analyze Communicate Core slide. 37

What Does MedDRA Offer? Size and specificity (“granularity”) Hierarchy/grouping terms “Support” SOCs widen data collection/analysis options Up-to-date and medically rigorous User-responsive STANDARDIZATION Core slide. 38

Why Do We Need Coding Conventions? Differences in medical aptitude of coders Consistency concerns (many more “choices” to manually code terms in MedDRA compared to older terminologies) Even with an autoencoder, may still need manual coding Core slide. 39

Overview of “MedDRA Term Selection: Points to Consider” Document

“MedDRA Term Selection: Points to Consider” An ICH-endorsed guide for MedDRA users Developed to promote medically accurate and consistent use of MedDRA in exchange of data (ultimately, for “medically meaningful” retrieval and analysis) In some cases with more than one option for selecting terms, a “preferred option” is identified but this does not limit MedDRA users to using that option Core slide. 41

Term Selection PTC (cont) Developed by a working group of the ICH Steering Committee Regulators and industry representatives EU, Japan, USA Canadian observer, MSSO, JMO Current version available on MedDRA MSSO Web site (http://www.meddramsso.com/subscriber_library_ptc.asp) Core slide. Updated v13.0. JH. Updated the weblink.

General Principles Quality of source data Level of term selection Use of “Current”/”Non-current” Lowest Level Terms (LLTs) Choice of term Do not subtract or add information Quality Assurance Core slide.

Quality of Source Data Obtain clarification of data that are confusing, ambiguous, or unintelligible Can be optimized by careful design of data collection forms and proper training of relevant staff REMEMBER: No terminology (including MedDRA) will help in understanding data that is of poor quality; best to get good information at the beginning Core slide.

Level of Term Selection Use of “Current”/”Non-current” LLTs Lowest level term(s) that “most accurately reflects the reporter’s words ” should be selected Example: “Abscess on face”  select “Facial abscess,” not simply “Abscess” Select current LLTs only Non-current terms for legacy conversion/ historical purposes Core slide.

Choice of Term Avoid company-specific “work-arounds” for MedDRA deficiencies. If concept not adequately represented in MedDRA, submit Change Request to MSSO. If no exact match in MedDRA, use medical judgment to match to an existing term that adequately represents the concept Core slide.

Do Not Subtract or Add Information Select terms for every ADR/AE reported, regardless of perceived relationship to drug If diagnosis reported with characteristic signs and symptoms, acceptable to select term only for diagnosis Do not make diagnosis if only signs/symptoms reported Example: “Abdominal pain” + “Increased serum amylase” + “Increased serum lipase”  inappropriate to select “Pancreatitis” Core slide.

Quality Assurance Human oversight of automated coding results Qualification of coder/review staff Errors in MedDRA should be addressed by submission of Change Requests to MSSO; no ad hoc structural alterations to MedDRA Core slide.

FDA-Defined Coding Errors Missed Concepts All medical concepts described after the product is taken should be coded Example: “The patient took drug X and developed alopecia, increased LFTs and pancreatitis”. Manufacturer only codes alopecia and increased LFTs (missed concept of pancreatitis) Example: “The patient took drug X and developed interstitial nephritis which later deteriorated into renal failure”. Manufacturer only codes interstitial nephritis (missed renal failure concept) Core slide. Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER

FDA-Defined Coding Errors (cont) “Soft Coding” Selecting a term which is both less specific and less severe than another MedDRA term is “soft coding” Example: “Liver failure” coded as hepatotoxicity or increased LFTs Example: “Aplastic anemia” coded as unspecified anemia Example: “Stevens Johnson syndrome” coded as rash Core slide. Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER

Term Selection Points Diagnoses and provisional diagnoses with or without signs and symptoms Death and other patient outcomes Suicide and self-harm Conflicting/ambiguous/vague information Combination terms Age vs. Event specificity Body site vs. Event specificity Location vs. Infectious agent Pre-existing medical conditions Exposure during pregnancy and breast feeding Congenital terms Neoplasms Medical/surgical procedures Core slide.

Term Selection Points (cont) Investigations Medication/administration errors and accidental exposures Transmission via medicinal product of infectious agent Overdose/Toxicity/Poisonings Device terms Drug interactions No adverse effect Unexpected therapeutic effect Modification of effect Social circumstances Medical and/or social history Indication for product use Off label use Core slide.

Overview of “MedDRA Data Retrieval and Presentation: Points to Consider” Document

MedDRA Data Retrieval and Presentation: Points to Consider An ICH-Endorsed Guide for MedDRA users on Data Output Developed by an ICH Expert Working Group Provides data retrieval and presentation options for industry or regulatory purposes Objective is to promote understanding of implications that various options for data retrieval have on accuracy and consistency of final output Current version available on MedDRA MSSO Web site (http://www.meddramsso.com/subscriber_library_ptc.asp) Core slide. Updated v13.0 JH. Updated weblink.

Data Retrieval PTC Points Addressed Quality of Source Data Documentation of Data Retrieval and Presentation Practices Organization-Specific Data Characteristics Characteristics of MedDRA that Impact Data Retrieval and Presentation MedDRA Versioning General Queries and Retrieval Standardised MedDRA Queries Customized Searches Core slide.

Quality of Source Data High quality data output is dependent on maintaining quality of original information reported by using consistent and appropriate term selection (Refer to “MedDRA Term Selection: Points to Consider” document) Method of conversion of data into MedDRA might impact retrieval and presentation - legacy data conversion using verbatims or coded terms Core slide.

Documentation of Data Retrieval and Presentation Practices Organization-specific guidelines Consistent with Points to Consider documents Coding conventions Data retrieval and output strategies (including SMQs) Versioning update process QA procedures Review by individuals with medical background and MedDRA training MedDRA is standardized and SOC assignments are pre-determined; no ad hoc structural alterations Core slide.

Organization-Specific Data Characteristics Database structure Data storage Data migration Coding practices over time Limitations/restrictions (inability to view secondary SOCs) Term selection principles More than one term selected increases counts Diagnosis term only selected reduces counts Core slide. 58

Impact of MedDRA’s Characteristics – Grouping Terms HLGTs and HLTs provide clinically relevant groupings HLGT Cardiac arrhythmias HLT Cardiac conduction disorders HLT Rate and rhythm disorders NEC HLT Supraventricular arrhythmias HLT Ventricular arrhythmias and cardiac arrest Core slide.

Impact of MedDRA’s Characteristics – Grouping Terms (cont) Caution - ensure all terms are relevant to output HLT Vascular tests NEC (incl blood pressure) PT Blood pressure decreased PT Blood pressure increased Caution - related PTs in different locations in SOC HLT Bullous conditions PT Stevens-Johnson syndrome HLT Exfoliative conditions PT Dermatitis exfoliative Core slide.

Granularity Other Terminology Preferred Terms # of Subj MedDRA Version 13.0 Preferred Terms #of Subj INFECTION 12 Upper respiratory tract infection Nasopharyngitis Localised infection Lower respiratory tract infection Nonspecific reaction 7 2 1 Core slide. Updated header to MedDRA 13.0 JH

Multi-Axiality Primary SOC allocation rules affect the way data are distributed across the terminology Impact on frequencies of medical condition of interest should be considered Example: for hepatic abnormality search in SOC Hepatobiliary disorders, SOC Investigations (laboratory test terms), SOC Surgical and medical procedures (e.g., PT Liver transplant) Core slide.

MedDRA Versioning MedDRA is updated twice a year 1 March X.0 release (all levels) 1 September X.1 release (LLT and PT levels only) Version used in data retrieval and presentation should be documented Resources: “What’s New” document Version report Terms used for queries should be in same version as data being queried Core slide.

MedDRA Versioning (cont) - Effect of Primary SOC Change Number of Events SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps) PT Ectopic hormone secretion 20 MedDRA Version 13.0 SOC Endocrine disorders Core slide. Updated primary SOC change example for v13.0. PT is not a neoplasm per se but a malignancy-related condition, therefore the primary SOCs were swapped. Now primary to Endocrine with secondary link to Neoplasms. 64 64

General Queries and Retrieval General Principles Data retrieval performed for multiple purposes; analysis of clinical trial data, pharmacovigilance, etc. Various strategies, methods, and tools Update previously used searches Identify safety issues prior to retrieval Consider data analysis plan Group related events Document strategy Evaluate search results against original question Core slide.

General Queries and Retrieval (cont) Types of searches Overview of safety profile in summary reports Comparison of frequency of ADR/AE (spontaneous reports or incidence for studies) Analysis of a specific safety concern Identification of patient subpopulations at risk Searching medical history information Pediatric and gender-specific data (see MSSO and JMO Web sites for adverse event term lists) Core slide

Overall Presentation of Safety Profiles Highlight overall distribution of ADRs/AEs Identify areas for in-depth analysis (focused searches) Approaches: full listing of terms to sophisticated statistical methods Standard approach: present by SOC and PTs This approach not always optimal due to unique characteristics of MedDRA Core slide. Updated v13.0. Last bullet indented. 67

Overview by Primary SOC Use Internationally Agreed Order of SOCs when applicable (see PTC or MedDRA Introductory Guide) Consider use of HLTs and HLGTs for large data sets Line listings, tables, graphs Benefits - Broad overview, PTs displayed only once Limitations - Incomplete groupings, lengthy output Core slide

Focused Searches Useful when further investigating concepts of interest Secondary SOC assignments Programming required if database does not allow automated output by secondary SOC Benefits - more comprehensive view of medically related events Limitations - display by primary and secondary SOC could lead to double counting Grouping terms (HLGT/HLT) SMQ Customized search Modified SMQ Ad hoc query Core slide. Updated v13.0. Lists types of focused searches as described in fig. 10 in DRP:PTC

Introduction to Standardised MedDRA Queries (SMQs)

Definition of SMQ 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 Core slide. 71

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 Core slide. Updated v13.0. Changed 2nd bullet under Benefits from Reusable programming to Validated reusable search logic per changes in DRP:PTC v12.1.

SMQs in Production - Examples As of Version 13.0, a total of 82 in production (Other SMQs in development) Adverse pregnancy outcome/reproductive toxicity (incl neonatal disorders) Agranulocytosis Anaphylactic reaction Cerebrovascular disorders Convulsions Depression and suicide/self-injury Hepatic disorders Ischaemic heart disease Lack of efficacy/effect Peripheral neuropathy Pseudomembranous colitis Rhabdomyolysis/myopathy Severe cutaneous adverse reactions Systemic lupus erythematosus Core slide. Updated : 82 SMQs in v13.0 JH.

Narrow and Broad Searches “Narrow” scope – specificity (cases highly likely to be condition of interest) “Broad” scope – sensitivity (all possible cases) “Broad search” = All broad + all narrow terms MedDRA term can be broad or narrow depending on SMQ Example: PT Renal failure acute Narrow in Acute renal failure (SMQ) Broad in Rhabdomyolysis/myopathy (SMQ) Core slide.

Narrow vs. Broad Example Lactic acidosis (SMQ) Core slide.

SMQ Applications Clinical trials Postmarketing 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) Core slide.

Customized Searches – Modified SMQs Do not modify SMQ unless there is a compelling reason – makes it non-standard “Modified MedDRA query based on an SMQ” To be used to refer to an SMQ that has been modified All modifications must be documented Version updates and maintenance are responsibility of organization that created it Core slide.

SMQ Resources Refer to MSSO Web site for information on SMQs http://www.meddramsso.com/subscriber_smq.asp Core slide. Updated v13.0 JH. Updated weblink.

Browser Demonstration SMQ View

Summary In this course, we: Reviewed the structure, scope, and characteristics of MedDRA Were introduced to the “MedDRA Term Selection: Points to Consider” document and some of its specific principles Were introduced to the “MedDRA Data Retrieval and Presentation: Points to Consider” document and some specific retrieval and query examples Learned about Standardised MedDRA Queries (SMQs)

MSSO Contacts Mail Telephone Fax Products and Services MedDRA MSSO 3975 Virginia Mallory Drive Chantilly, VA, USA 20151 Telephone Toll-free Worldwide 877.258.8280 (AT&T) Fax 703.272.5635 Products and Services Core slide.

MSSO Contacts (cont) To Subscribe by Help desk E-mail Web site Phone mssosubscribe@ngc.com Web site www.meddramsso.com click on “Subscribe to MedDRA” Help desk Phone International AT&T Toll Free: 877.258.8280 Direct Dial (USA): 703.272.5849 mssohelp@ngc.com Core slide.