MedDRA® Coding Training – Boston Biomedical Associates 25 October 2006 MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Course Overview Overview of MedDRA Terminology MedDRA Rules and Conventions Change Request Process Overview of “MedDRA Term Selection: Points to Consider” Document

Course Overview MedDRA Browser Demonstration, Instruction, and “Warm-Ups” Coding Exercises Coding QA and Synonym Lists Devices and MedDRA Browser Choices

Overview of MedDRA Terminology

Overview of MedDRA Definition Scope Structure Rules and conventions

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.

Scope of MedDRA OUT IN Drug product terms Population-level qualifiers Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history Patient demographic terms Numerical values for results . Terms from: COSTART© WHO-ART© HARTS© J-ART© Severity descriptors Clinical trial study design terms Equipment, device, diagnostic product terms

Overview of MedDRA Structure of MedDRA Hierarchy Multi-Axiality Special Search Categories Being retired as of MedDRA Version 10.0 Standardised MedDRA Queries

MedDRA Structure System Organ Class (SOC) (26) High Level Group Term (HLGT) (332) High Level Term (HLT) (1,682) Preferred Term (PT) (17,505) Lowest Level Term (LLT) (64,620)

Lowest Level Term System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lowest Level Term (LLT)

Lowest Level Term (cont) LLT Characteristics An LLT has one or more of the following relationships to a PT: Synonym Lexical variant Sub-element Constitutes the entry level of the terminology and is linked to a single PT Can have current or non-current status

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 very vague, ambiguous, out-dated, truncated, or misspelled Terms derived from other terminologies that do not fit MedDRA rules

Preferred Term System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lowest Level Term (LLT)

Preferred Term (cont) PT represents a single unique medical concept No limit to the number of LLTs that can be linked to a single PT An identical LLT is created for every PT One path within a SOC

High Level Term System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lowest Level Term (LLT)

High Level Group Term System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lowest Level Term (LLT)

System Organ Class System Organ Class (SOC) High Level Group Term (HLGT) High Level Term (HLT) Preferred Term (PT) Lowest Level Term (LLT)

System Organ Class (cont) Highest level of the hierarchy Provides the broadest concepts for data retrieval SOCs identified by: Anatomical or physiological system Etiology Purpose

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

Examples of LLTs SOC = Hepatobiliary disorders HLGT = Gallbladder disorders HLT = Cholecystitis and cholelithiasis PT = Cholecystitis ___________ LLT ____________ LLT ____________ LLT ____________ LLT ____________ LLT

Examples of PTs SOC = Hepatobiliary disorders HLGT = Gallbladder disorders HLT = Cholecystitis and cholelithiasis ____________ PT ____________ PT ____________ PT

High Level Term Subordinate to HLGTs and superordinate descriptor for the PTs linked to it SOC = Hepatobiliary disorders HLGT = Gallbladder disorders ____________ HLT ____________ HLT ____________ HLT

SOC = Hepatobiliary disorders High Level Group Term Subordinate only to System Organ Classes and superordinate descriptor for one or more HLTs SOC = Hepatobiliary disorders ____________ HLGT ____________ HLGT

A Multi-Axial Terminology Terms can be represented in more than one SOC Allows analysis through different retrievals and presentations Primary SOC: Represents path from PT to SOC for primary viewing Prevents a PT from being represented more than once in data retrieval from all SOCs

A Multi-Axial Terminology (cont) Primary SOC SOC = Cardiac disorders SOC = Psychiatric disorders SOC = Nervous system disorders SOC = Congenital, familial and genetic disorders SOC = Musculoskeletal and connective tissue disorders HLGT = Congenital cardiac disorders HLGT = Cognitive and attention disorders and disturbances HLGT = Mental impairment disorders HLGT = Musculoskeletal and connective tissue disorders congenital HLT = Congenital cardiac valve disorders HLT = Mental retardations HLT = Musculoskeletal and connective tissue disorders of face, neck and jaw congenital PT = Rubinstein-Taybi syndrome

Rules for Primary SOC Allocation PTs relating to diseases or signs and symptoms are assigned to the prime manifestation site system or organ-based SOC PT Dry skin = Primary SOC Skin and subcutaneous tissue disorders

Rules for Primary SOC Allocation (cont) All congenital and hereditary anomalies are placed in the SOC Congenital, familial and genetic disorders Example PTs: Cleft palate Cerebral palsy Trisomy 21

Rules for Primary SOC Allocation (cont) All infections and infestations are placed in the SOC Infections and infestations Example PTs: Varicella Rubella Hepatitis C

Rules for Primary SOC Allocation (cont) Neoplasms are placed in the SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps) PT Benign lung neoplasm = Primary SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps) EXCEPT: Cysts and polyps are placed in the prime manifestation site as their Primary SOC PT Aural polyp = Primary SOC Ear and labyrinth disorders

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

Rules for Primary SOC Allocation 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

MedDRA Rules and Conventions

MedDRA Rules and Conventions Spelling Capitalization Abbreviations Word order Punctuation NEC NOS MedDRA codes

MedDRA Rules and Conventions (cont) Body site Abdominal wall is gastrointestinal structure E.g., PT Abdominal wall disorder Combined cardiac and vascular congenital anomalies linked (secondarily) to SOC Cardiac disorders E.g., PT Congenital cardiovascular anomaly Chest wall is musculoskeletal structure E.g., PT Chest wall necrosis

MedDRA Rules and Conventions (cont) Body site (cont) Eyelid terms – in general, linked primarily to SOC Eye disorders and secondarily to SOC Skin and subcutaneous tissue disorders E.g., PT Eyelid oedema Pharynx and diaphragm are respiratory structures E.g., PT Pharyngeal erythema, PT Diaphragmatic hernia Pinna terms (including earlobe) are primary to SOC Ear and labyrinth disorders E.g., LLT Perichondritis of pinna

MedDRA Rules and Conventions (cont) General word usage In general, “cervical” terms = neck; “cervix” terms = uterine cervix Except if “cervical” could only refer to uterine cervix For “cervical” term related to uterine cervix, term may be qualified with the word ‘uterine’ “Dilation” = procedure; “dilatation” = disorder E.g., LLT Vasodilation (PT Vasodilation procedure) “Drainage” = procedure; “discharge” = disorder E.g., PT Biliary drainage is a procedure; PT Urethral discharge is a disorder Some exceptions made for “drainage” terms that fall outside the realm of procedures

MedDRA Rules and Conventions (cont) General word usage (cont) “Failure” and “insufficiency” are synonyms in MedDRA E.g., LLT Ventricular insufficiency linked to PT Ventricular failure “Tumo(u)r” = neoplastic; “mass” and “lump” = non-neoplastic Congenital and acquired conditions More common form of a disease/condition is at PT level without qualifier (e.g., PT Hypothyroidism) Less common form also at PT level but with qualifier (e.g., PT Congenital hypothyroidism)

MedDRA Rules and Conventions (cont) General word usage (cont) Polyp terms Existing unqualified “polyp” terms are classified as benign (e.g., PT Gallbladder polyp) Newly added “polyp” terms will not have qualifier and will be classified as benign No longer adding “malignant polyp” terms to MedDRA; use “malignant neoplasm” term for coding

Change Request Process

Change Request Process Criteria Must be a MSSO core subscriber Maintenance rights Simple change requests Changes at the PT level and below in the MedDRA terminology structure Routine: Notified of supplemental change within 7-14 days; 100 simple requests per month per subscriber Complex changes above PT level once a year Maximum of 9,000 simple change requests per year, all subscribers combined

Use of Supplemental Terms Supplemental terms have been approved by the MSSO but have not yet been updated to the official version Supplemental terms may be found in the core subscriber area of the MSSO website http://www.meddramsso.com Supplemental terms are used at a subscriber’s risk

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

“MedDRA Term Selection: Points to Consider” An ICH-endorsed guide for MedDRA users A “companion document” to MedDRA Applies to adverse events/reactions, medical and social history, and indications Developed to promote medically accurate and consistent use of MedDRA in exchange of data (ultimately, for “medically meaningful” retrieval and analysis)

“Points to Consider” Term Selection Document (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 website http://www.meddramsso.com/MSSOWeb/activities/PTC.htm

“Points to Consider” Term Selection Document (cont) Points addressed Quality of source data Level of term selected Use of “Current”/”Non-current” Lowest Level Terms (LLTs) Choice of term “Do not subtract or add information” Quality assurance Human oversight of automated coding results Qualification of coder/review staff Errors should be addressed by Change Requests to MSSO; no ad hoc structural alterations to MedDRA

“Points to Consider” Term Selection Document (cont) 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 When left with data that cannot be clarified, refer to section 3.3 REMEMBER: No terminology (including MedDRA) will help in understanding data that is of poor quality; best to get good information at the beginning

“Points to Consider” Term Selection Document (cont) Lowest level term(s) that “most accurately reflects the reporter’s words ” should be selected e.g., “Abscess on face”  select “Facial abscess,” not simply “Abscess” e.g., “Bleeding at injection site”  select “Injection site bleeding,” not simply “Injection site reaction” Select current LLTs only

“Points to Consider” Term Selection Document (cont) Avoid company-specific “work-arounds” for MedDRA deficiencies. If there is no concept in MedDRA to represent your term, submit Change Request to MSSO There may be no exact match for your term in MedDRA, but use medical judgment to match to an existing MedDRA term that adequately represents the concept

“Points to Consider” Term Selection Document - Choice of Term If a single MedDRA term does not represent your term’s concept, it is appropriate to use more than one term (and possibly submit Change Request) e.g., “Metastatic gallbladder cancer”  “Gallbladder cancer” and/or “Metastasis” can be selected One term selected, loss of specificity Both terms selected, possibly redundant counts Document your strategy

“Points to Consider” Term Selection Document “Do not subtract or add information” Do not make a diagnosis if only signs/symptoms are reported e.g., “Abdominal pain” + “Increased serum amylase” + “Increased serum lipase”  inappropriate to select “Pancreatitis”

“Points to Consider” Term Selection Document “Do not subtract or add information” (cont) If have both signs/symptoms and diagnosis, may code both or just diagnosis e.g., “Anaphylactic reaction” also reported with “rash, dyspnea, hypotension and laryngospasm”  “Anaphylactic reaction” and “Rash,” “Dyspnea,” “Hypotension,” and “Laryngospasm” can be selected OR, only “Anaphylactic reaction” can be selected

“Points to Consider” Term Selection Document“ Do not subtract or add information” (cont) If signs/symptoms and diagnosis are reported, appropriate to also code signs/ symptoms that are not characteristic of diagnosis e.g., “Myocardial infarction” also reported with “chest pain, dyspnea, diaphoresis, ECG changes and jaundice”  appropriate to select at least “Myocardial infarction” and “Jaundice”

“Points to Consider” Document Term Selection Points Term Selection Points addressed: Provisional diagnoses Death and other patient outcomes Conflicting/ambiguous/vague information Combination terms Body site vs. Event specificity Location vs. Infectious agent Pre-existing medical conditions Congenital terms Medical/surgical procedures

“Points to Consider” Document Term Selection Points (cont) Term Selection Points addressed (cont): Investigations Medication/administration errors and accidental exposures Overdose/Toxicity/Poisonings Drug interactions No adverse effect Unexpected therapeutic effect Modification of effect Use of SOC Social circumstances Medical and/or social history Indication for product use

“Points to Consider” Document Term Selection Points (cont) Conflicting information: e.g., if “Hyperkalemia with a serum potassium of 1.6 mEq/L”  “Serum potassium abnormal” can be selected Ambiguous information: e.g., “GU pain”  “Pain” can be selected (“GU” could be “genito-urinary” or “gastric ulcer”) Vague information: e.g., “Patient experienced every listed adverse event”  “Unevaluable event” can be selected

“Points to Consider” Document Term Selection Points (cont) Combination terms If one term is more specific than the other(s), the most specific term should be selected. E.g., “Arrhythmia due to atrial fibrillation”  “Atrial fibrillation” can be selected If a MedDRA term exists that adequately describes the combination, that term should be used. E.g., “Retinopathy due to diabetes”  “Diabetic retinopathy” can be selected

“Points to Consider” Document Term Selection Points (cont) Combination terms (cont) If “splitting” provides more information, it is appropriate to select more than one term. E.g., “DIC due to sepsis”  “DIC” and “Sepsis” can be selected In all cases of combination terms, apply medical judgment

“Points to Consider” Document Term Selection Points (cont) Combination terms (cont) If combination of event and pre-existing condition which has not changed, and if combination term does not exist in MedDRA, sufficient to select term for event. e.g., “Pain due to cancer”  “Cancer pain” can be selected e.g., “Shortness of breath due to cancer”  “Shortness of breath” can be selected

“Points to Consider” Document Term Selection Points (cont) Pre-existing medical conditions If they have changed, may be considered ADRs/AEs “Modifiers” include: aggravated, exacerbated, worsened, intermittent, recurrent, progressive or improved The specific MedDRA term should be selected, if such term exists. E.g., “Exacerbation of myasthenia gravis”  “Myasthenia gravis aggravated” can be selected

“Points to Consider” Document Term Selection Points (cont) Pre-existing medical conditions (cont) If no modified term exists in MedDRA, one of the following three options may be employed: Option 1: Term for condition should be selected, and capture modification in a consistent, documented way. E.g., “Halitosis worsened”  “Halitosis” only can be selected Option 2: Term for condition AND a separate modifier term should be selected. E.g., “Progression of Alzheimer’s disease”  “Alzheimer’s disease” AND “Disease progression” can be selected Option 3: Request term from MSSO per Change Request process

“Points to Consider” Document Term Selection Points (cont) Medical/Surgical procedures Use of terms in SOC Surgical and medical procedures: When a procedure is the only reported information. E.g., “Patient had gallbladder surgery”  “Gallbladder operation” can be selected If procedure reported with diagnosis, sufficient to code only diagnosis. Optionally can code both diagnosis and procedure. E.g., “Liver transplantation due to liver failure”  “Liver failure” alone OR both “Liver failure” and “Liver transplant” can be selected

“Points to Consider” Document Term Selection Points (cont) Investigations Medical condition vs. laboratory result “Hypoglycemia”  “Hypoglycemia” can be selected “Decreased glucose”  “Glucose decreased” can be selected Unambiguous laboratory result Value reported is clearly out of reference range. E.g., “Glucose 40 mg/dL”  “Glucose low” can be selected Ambiguous laboratory result “Glucose was 40” (note: no units)  “Glucose abnormal” can be selected

“Points to Consider” Document Term Selection Points (cont) Investigations (cont) If diagnosis/condition and diagnostic (test) result provided, appropriate to code only diagnosis/ condition. E.g., “Elevated potassium, K 7.0 mmol/L, and hyperkalemia”  “Hyperkalemia” can be selected Code any diagnostic (test) terms inconsistent with diagnosis/condition reported. E.g., “Alopecia, rash and potassium 7 mmol/L”  “Alopecia,” “Rash,” and “Potassium increased” can be selected

“Points to Consider” Document Term Selection Points (cont) Investigations (cont) Non-specific laboratory result terms should be used only when more specific terms are not available Do not combine separate tests results into one single term. E.g., “Increased alkaline phosphatase, increased SGPT, increased SGOT and increased LDH”  “Alkaline phosphatase increased,” “SGPT increased,” “SGOT increased,” and “LDH increased” can be selected

“Points to Consider” Document Term Selection Points (cont) Investigations (cont) SOC Investigations includes test names with and without qualifiers Terms without qualifiers can be used to capture/record test names If reported as “Bilirubin”  “Bilirubin” can be selected If reported as “Cardiac output”  “Cardiac output” can be selected Caution with test name terms and result terms “Blood urine” is test name “Blood urine present” is result term

Points to Consider about “Points to Consider” A “living document,” intended to grow and change as MedDRA advances from version to version A “companion document” to MedDRA Recommended to be used as the basis for individual organizations’ post-MedDRA implementation coding conventions

MedDRA Browser Demonstration, Instruction, and “Warm-Ups”

Scope of MedDRA OUT IN Drug product terms Population-level qualifiers Diseases Diagnoses Signs Symptoms Therapeutic indications Investigation names & qualitative results Medical & surgical procedures Medical, social, family history Patient demographic terms Numerical values for results . Terms from: COSTART© WHO-ART© HARTS© J-ART© Severity descriptors Clinical trial study design terms Equipment, device, diagnostic product terms

Included in MedDRA Symptoms The patient states she has been experiencing headaches, dizziness and vertigo. _______________ LLT  _______________ PT

Included in MedDRA Symptoms A 24 year old was admitted to the hospital for abdominal pain, nausea, vomiting, and diarrhea (gastroenteritis). _______________ LLT  _______________ PT OR

Included in MedDRA Signs Lab results indicate an increase in erythrocytes. _______________ LLT  _______________ PT

Included in MedDRA Therapeutic indications PC, a 44 year old diabetic, was started on an oral diabetic medication for non insulin-dependent diabetes mellitus. _______________ LLT  _______________ PT

Included in MedDRA Medical/surgical procedures A 40 year old male had a colon polypectomy performed last week. _______________ LLT  _______________ PT

Included in MedDRA Medical/surgical procedures As part of his new health prevention lifestyle, the 50 year old male had his first colonoscopy. _______________ LLT  _______________ PT

Excluded from MedDRA Population-level qualifiers Patient discontinued her study medication because she was experiencing frequent nose bleeds. _______________ LLT  _______________ PT

Excluded from MedDRA Population-level qualifiers - Exception Patient experienced frequent bowel movements after eating chili. _______________ LLT  _______________ PT

Excluded from MedDRA Numerical values for results Blood tests of a 32 year old patient showed hemoglobin of 9.0 g/dl and hematocrit of 28.1%. _______________ LLT  _______________ PT

Devices Equipment, device, diagnostic product terms A 32 year old female had a contraceptive implant in her left arm. On a follow-up visit, the insertion site was noted to be infected. _______________ LLT  _______________ PT

Devices Device failure terms A diabetic patient attempting to inject himself with insulin broke the syringe. _______________ LLT  _______________ PT

Devices Device failure terms An 80 year old male experienced a cardiac pacemaker malfunction. _______________ LLT  _______________ PT

Coding Exercises

Coding QA and Synonym Lists

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

Why do we Code? Retrieve Present Analyze Communicate

Role of a Terminology Provides a TOOL to represent data/ concepts using “place-holder” terms Assists in retrieval, analysis, and comprehension of data

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

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, and conventions should be applied for reasons noted above

Can I make Coding Conventions Specific to my Company/product? MedDRA may reduce the need to do this because: Increased size/granularity will result in better (i.e., more accurate) representation of data Secondary SOC allocations allow for different “views” of the data This type of approach should be done cautiously

QA Reports Allows reviewers to check for consistency (both autoencoded and human-coded terms) Check for adherence to/deviation from coding conventions Check for emerging drifts/biases Multiple data views (verbatims to coded terms; coded term to verbatims; by SOC, etc.)

Synonym Lists Can be derived from existing term lists or directly from verbatims For recurring, but unusual, verbatims – one-time assignment to a MedDRA term Enforces consistency by limiting choices once MedDRA term is assigned Increases likelihood of autoencoding “hit” Natural outgrowth of a legacy data conversion Maintenance required

Devices and MedDRA

MSSO Statement Regarding Medical Devices (on MSSO web site) The MSSO has recently received a large number of requests for medical device terms. In the spirit of transparency, the MSSO would like to inform the MedDRA users of the activity in this area. Traditionally, MedDRA has had a biopharmaceutical focus, and the number of device-related terms has been minimal. Through interaction with device manufacturer subscribers and regulatory representatives, we have begun to explore the possibility of allowing MedDRA to adopt terms related to device regulatory needs. We want to emphasize that the MSSO is in the early stages of exploring this concept, and as usual, we will try to keep the user community informed and solicit input as issues arise. In the meantime, we encourage you to monitor this website and related communications (e.g., MedDRA Messenger) for updated information.

What Occurred in MedDRA Version 8.1 In May 2005 MedDRA Management Board agreed to include previously suspended To support combination products Specific device terms were added Management Board and MSSO are coordinating efforts with Global Harmonization Task Force GHTF is an international organization focused on harmonization of regulations for medical devices

Comparison Version 8.0 vs. Version 8.1

What Occurred in MedDRA Version 9.0 HLT Device failure and malfunction was renamed to HLT Device malfunction events HLT Device component findings added to HLGT Procedural and device related injuries and complications NEC

Comparison Version 8.1 vs. Version 9.0 (and Version 9.1)

Future for Device Terms in MedDRA For now, discussions continue between Management Board, MSSO and other device entities Device company subscribers are increasing Slow, steady increase in number of Change Request related to devices No change in MedDRA scope for now

Browser Choices

Choosing a MedDRA Browser Browsers should: Display all relevant MedDRA term information (primary SOC, term detail, legacy terms links, etc.) Display multi-axial links in a comprehensive, simple to view format Indicate primary and secondary SOC for all PTs Display Standardised MedDRA Queries Allow comprehensive searching based on both MedDRA and legacy terminology terms and codes Allow the user to view multiple versions Support simple update based on new terminology versions Support MedDRA specific printing and reporting

Where to Find A Browser MSSO cannot recommend specific browsers A small number of vendors provide standalone browsers (an internet search for “MedDRA browser” will find a number of tools) Many vendors offer MedDRA browsing/coding functions or add-in modules for their clinical data management and adverse event management systems

MSSO Contacts Mail Telephone Fax Products and Services VAR1/MSSO 12011 Sunset Hills Road Reston, VA, USA 20190-3285 Telephone Toll-free Worldwide 877.258.8280 (AT&T) Fax 703.345.7791 Products and Services

MSSO Contacts (cont) To Subscribe by E-mail Web site Help desk 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): 703.345.7799 mssohelp@ngc.com

Acknowledgements MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) COSTART Thesaurus Fifth Edition Copyright 1995 US Food and Drug Administration (FDA) Hoechst Adverse Reaction Terminology System (HARTS)© 1992 Aventis Pharma

Acknowledgements (cont) ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification, Copyright© 1998 Medicode, Inc. ICD-10 Source: World Health Organization Japanese Adverse Reaction Terminology (J-ART), is a product of the Japanese Ministry of Health, Labour and Welfare (MHLW) WHO Adverse Reaction Terminology (WHO-ART), Copyright World Health Organization Collaborating Centre for International Drug Monitoring

MedDRA® Training Boston Biomedical Associates Supplemental Topics 25 October 2006 MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)

Supplemental Topics Overview Introduction to Standardised MedDRA Queries (SMQs) SMQ Demonstration (Browser) – Haemorrhages (SMQ) and Ischaemic heart disease (SMQ) MedDRA Data Retrieval and Presentation: Points to Consider

Introduction to Standardised MedDRA Queries (SMQs)

Definition of SMQ Groupings of terms from one or more MedDRA System Organ Classes (SOCs) that relate to a defined medical condition or area of interest Intended to aid in case identification

Definition of SMQ (cont) Included terms may relate to signs, symptoms, diagnoses, syndromes, physical findings, laboratory and other physiologic test data, etc., related to the medical condition or area of interest

SMQ Data Characteristics (cont) Broad and narrow Accommodates those instances in which user may look to identify cases that are highly likely to represent the condition of interest (a “narrow” scope) - Specificity Also accommodates instances in which user seeks to identify all possible cases, including some that may prove to be of little or no interest on closer inspection (a “broad” scope) - Sensitivity

SMQ Data Characteristics (cont) Algorithms Some SMQs are designed to utilize algorithms Better case identification among broad search terms may result if cases are selected by a defined combination of selected terms

Algorithm Example (cont) Category B – Upper airway/Respiratory Category C – Angioedema/ Urticaria, etc. Category D – Cardiovascular/Hypotension Acute respiratory failure Allergic oedema Blood pressure decreased Asthma Angioneurotic oedema Blood pressure diastolic decreased Bronchial oedema Erythema Blood pressure systolic decreased Case = A (Narrow terms) Or Term from Category B and term from Category C Or Term from either Category B or Category C plus Term from Category D

Hierarchy Example

How to “run” SMQs SMQs can be viewed from the IT perspective as stored queries List of terms related to a medical condition Most organizations code at the LLT level of MedDRA SMQ ASCII files include PTs and LLTs assigned to each SMQ

How to “run” SMQs (cont)

How to “run” SMQs (cont) Load SMQs into a query tool (e.g., SAS) Use SMQ tuning options, if applicable Broad search Narrow search Algorithms Hierarchy

Summary of Ways to Use SMQs Broad (all terms) or narrow – determines the scope of the search for any given SMQ Employ the algorithm, if available – not necessary to use it; may “fine-tune” the search Hierarchy – use different levels to define the scope of topic (general, specific) Not at all

SMQs in Production As of Version 9.1, a total of 28 in production (Many other SMQs in development) Acute pancreatitis Acute renal failure Agranulocytosis Anaphylactic reaction Angioedema Anticholinergic syndrome Asthma/bronchospasm Cardiac arrhythmias Cerebrovascular disorders Depression and suicide/self-injury Dyslipidaemia Haematopoietic cytopenias Haemolytic disorders Haemorrhages Hepatic disorders Hyperglycaemia/new onset diabetes mellitus

SMQs (cont) SMQs (28) in production (cont) Interstitial lung disease Ischaemic heart disease Lack of efficacy/effect Lactic acidosis Neuroleptic malignant syndrome Peripheral neuropathy Rhabdomyolysis/myopathy Retroperitoneal fibrosis Severe cutaneous adverse reactions Shock Systemic lupus erythematosus Taste and smell disorders

SMQ Topics for Future Development Accidents and injuries ARDS Ear disorders Hypertension Hyponatraemia/SIADH Hypotension Immune reconstitution syndrome Immunogenicity Pulmonary hypertension Renal disorders (incl nephropathy and nephrotic syndrome) Thrombophlebitis

SMQ Resources Refer to MSSO Web site for current status of SMQs in production and development http://www.meddramsso.com/MSSOWeb/SMQ/smqlist.htm

SMQ Testing Summary Extensive testing procedure behind each SMQ Pre-production Phase (Phase I): tested on databases available to WG members; typically, at least one company and one regulator database Production Phase: continue to be fine tuned by MedDRA subscribers through the MSSO maintenance process

SMQ Production Maintenance This “phase” of SMQ maintenance begins once MedDRA MB authorizes final release of SMQs Essentially, a Change Request process for SMQs

SMQ Versioning MSSO recommends that organizations utilize the SMQs with data coded with the same version of MedDRA Match the MedDRA version of the SMQ with the MedDRA version of the coded data Mismatches of SMQ and MedDRA coded data could produce unexpected results

SMQ Demonstration (Browser) – Haemorrhages (SMQ) and Ischaemic heart disease (SMQ)

MedDRA Data Retrieval and Presentation: Points to Consider

MedDRA Data Retrieval and Presentation: Points to Consider An ICH-Endorsed Guide for MedDRA users on Data Output A “companion document” to MedDRA 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

Data Retrieval 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/MSSOWeb/activities/PTC.htm)

Data Retrieval PTC Points addressed Quality of Source Data Quality Assurance Organization-Specific Data Characteristics Impact of MedDRA’s Characteristics on Data Retrieval and Presentation Grouping terms Granularity Multi-axiality Special Search Categories Standardised MedDRA Queries MedDRA Versioning Queries and Retrieval Examples

Data Retrieval PTC 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

Legacy Data Conversion – Comparing Verbatim to Coded Term Approach MedDRA PT (based on verbatim) Orig coded term (COSTART) MedDRA PT (based on orig COSTART term) (R) knee effusion Joint effusion ARTHROSIS Osteoarthritis Common cold Nasopharyngitis INFECTION Infection Periorbital edema Periorbital oedema FACE EDEMA Face oedema Seasonal allergies Seasonal allergy ALLERGIC REACTION Hypersensitivity Skin injury SKIN DISORDER Skin disorder

Data Retrieval PTC Quality Assurance Documentation of coding conventions, data retrieval and presentation strategies, methods and QA procedures in organization-specific guidelines Review by individuals with medical background and MedDRA training Errors in MedDRA should be addressed by submissions of Change Requests to MSSO; no ad hoc structural alterations to MedDRA

Data Retrieval PTC 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

Data Retrieval PTC Multi-Axiality (cont) Main presentation is by Primary SOC Secondary SOCs used for alternate views and presentation of data

Primary SOC Analysis – SOC Infections and infestations Adverse Event (MedDRA 9.0) 25 mg MyDrug (N=44) Placebo (N=15) SOC Infections and infestations 14 (31.8%) 4 (26.7%) PT Upper respiratory tract infection 5 (11.4%) 2 (13.3%) PT Sinusitis 3 (6.8%) PT Urinary tract infection 2 (4.5%) 1 (6.7%) PT Ear infection PT Viral infection PT Bronchitis acute 1 (2.3%) PT Influenza PT Localised infection PT Lower respiratory tract infection PT Pneumonia PT Tooth abscess

Secondary SOC Analysis – SOC Infections and infestations Adverse Event (MedDRA 9.0) 25 mg MyDrug (N=44) Placebo (N=15) SOC Respiratory, thoracic and mediastinal disorders PT Upper respiratory tract infection 5 (11.4%) 2 (13.3%) PT Sinusitis 3 (6.8%) PT Bronchitis acute 1 (2.3%) PT Influenza PT Lower respiratory tract infection PT Pneumonia SOC Infections and infestations PT Viral infection 2 (4.5%) PT Localised infection 1 (6.7%)

Secondary SOC Analysis – SOC Infections and infestations (cont) Adverse Event (MedDRA 9.0) 25 mg MyDrug (N=44) Placebo (N=15) SOC Renal and urinary disorders PT Urinary tract infection 2 (4.5%) 1 (6.7%) SOC Ear and labyrinth disorders PT Ear infection SOC Gastrointestinal disorders PT Tooth abscess 1 (2.3%)

Data Retrieval PTC MedDRA Versioning MedDRA is updated twice a year Version used in data retrieval and presentation should be documented Terms used for queries should be in same version as data being queried

Data Retrieval PTC MedDRA Versioning (cont) Number of Events at PT Level Circulatory depression (PT) 15 MedDRA Version 9.0 Circulatory depression (no longer a PT) Cardiovascular insufficiency (newly added PT)

Data Retrieval PTC Queries and Retrieval Summary General Principles Data retrieval is performed for analysis of clinical trial data, pharmacovigilance, etc. Strategies, methods and tools used depend on intended use of output Update previously used searches Identify safety issues prior to retrieval - information from pre-clinical & clinical trials, postmarketing surveillance, similar products, regulatory queries Group related events Evaluate search results against original question

Data Retrieval PTC Queries and Retrieval Summary (cont) Examples 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 (e.g. searching medical history information)

Data Retrieval PTC Queries and Retrieval Examples Graphical displays Useful for large data sets Quick visual representation Histograms, bar charts, pie charts Complex, statistically driven displays (output of data mining algorithm)

Data Retrieval PTC Graphical display example

Data Retrieval PTC Queries and Retrieval Examples (cont) Overview by Primary SOC Internationally Agreed Order of SOCs (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

Data Retrieval PTC Primary SOC Output Listing Example

Data Retrieval PTC Queries and Retrieval Examples (cont) Focused search: Secondary SOC assignments Query the SOC, HLGT or HLT to include both primary and secondary SOC assignments in display If database does not allow automated output by secondary SOC, then query should be performed using available processes (e.g., programming a list of all individual PTs in primary and secondary SOC locations). Benefits - more comprehensive view of medically related events Limitations - display by primary and secondary SOC could lead to double counting

Data Retrieval PTC Secondary SOC Output Listing Example

Data Retrieval PTC Secondary SOC Graphical Display Example

Questions and Answers

Acknowledgements MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) COSTART Thesaurus Fifth Edition Copyright 1995 US Food and Drug Administration (FDA)