Coding with MedDRA 1

Coding with Coding with MedDRA 1

4/3/2015 Coding with MedDRA MedDRA was developed under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The activities of the MedDRA Maintenance and Support Services Organization (MSSO) are overseen by an ICH MedDRA Management Board, which is composed of the six ICH parties (EU, EFPIA, MHLW, JPMA, FDA, PhRMA), the Medicines and Healthcare products Regulatory Agency (MHRA) of the UK, Health Canada, and the WHO (as Observer). MSSO-DI-6017-18.0.0 2 1

4/3/2015 Disclaimer and Copyright Notice This presentation is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the presentation is acknowledged at all times. In case of any adaption, modification or translation of the presentation, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original presentation. Any impression that the adaption, modification or translation of the original presentation is endorsed or sponsored by the ICH must be avoided. The presentation is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original presentation be liable for any claim, damages or other liability arising from the use of the presentation. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. MSSO-DI-6017-18.0.0 3 Course Overview MedDRA background MedDRA s structure, scope, and characteristics MedDRA maintenance Coding conventions Synonym lists Quality assurance (QA) of coding MedDRA Term Selection: Points to Consider document Hands-on coding exercises MSSO-DI-6017-18.0.0 4 2

4/3/2015 MedDRA Background What is MedDRA? Med = Medical D = Dictionary for R = Regulatory A = Activities MSSO-DI-6017-18.0.0 6 3

4/3/2015 MedDRA s Purpose Facilitate the exchange of clinical information through standardization Important tool for product evaluation, monitoring, communication, electronic records exchange, and oversight Supports coding (data entry) and retrieval and analysis of clinical information about human medical products including pharmaceuticals, biologics, vaccines, and drug-device combination products MSSO-DI-6017-18.0.0 7 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) MSSO-DI-6017-18.0.0 8 4

4/3/2015 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. MSSO-DI-6017-18.0.0 9 Where MedDRA is Used Regulatory Authority and Industry Databases Individual Case Safety Reports and Safety Summaries Clinical Study Reports Investigators Brochures Core Company Safety Information Marketing Applications Publications Prescribing Information Advertising MSSO-DI-6017-18.0.0 10 5

4/3/2015 Regulatory Status US FDA Used in several databases including FAERS (drugs and biologics), VAERS (vaccines), and CAERS (foods, dietary supplements, cosmetics) Recommended terminology for adverse event reporting in several Proposed Rules and Guidances Effective June 2015, electronic submission required for postmarketing safety reports for drugs, biologics, and vaccines (relies upon ICH standards) Japanese Ministry of Health, Labour and Welfare Mandatory use in electronic reporting MSSO-DI-6017-18.0.0 11 Regulatory Status (cont) European Union EudraVigilance database Clinical trial SUSARs (Suspected Unexpected Serious Adverse Reactions) Post-authorization Individual Case Safety Reports (ICSRs) Requires current version of MedDRA or the one previous to it Good pharmacovigilance practices (GVP) specifically mention MedDRA Pharmacovigilance legislation covers suspected adverse reactions from: Use inside and outside terms of marketing authorization Overdose, misuse, abuse, and medication errors Occupational exposures MSSO-DI-6017-18.0.0 12 6

4/3/2015 Regulatory Status (cont) European Union (cont) Used in interface between EudraVigilance and EU Risk Management Plan Used throughout Summary of Product Characteristics (labeling) ICH M4E Guideline on Common Technical Document Recommended in adverse event summary tables Canada Used in Canada Vigilance database Recommended/preferred terminology for adverse reaction reporting and Product Monograph (labeling) Electronic reporting via Gateway requires current version of MedDRA MSSO-DI-6017-18.0.0 13 MedDRA Overview 7

4/3/2015 Scope of MedDRA Not a drug dictionary Patient demographic terms Clinical trial study design terms OUT IN Medical conditions Indications Investigations (tests, results) Medical and surgical procedures Medical, social, family history Medication errors Product quality issues Device-related issues Pharmacogenetic terms Toxicologic issues Standardized queries Frequency qualifiers Numerical values for results Severity descriptors Not an equipment, device, diagnostic product dictionary MSSO-DI-6017-18.0.0 15 MedDRA Structure System Organ Class (SOC) (26) High Level Group Term (HLGT) (335) High Level Term (HLT) (1,721) Preferred Term (PT) (21,345) Lowest Level Term (LLT) (74,229) MedDRA Version 18.0 MSSO-DI-6017-18.0.0 16 8

4/3/2015 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 MSSO-DI-6017-18.0.0 17 27 th System Organ Class MedDRA Management Board endorsed creation of an additional (27 th ) SOC To accommodate non-clinical/non-patient concepts covering issues related to medical products Important because they may affect patient safety Will include product quality issues Existing HLGT Product quality issues Supplemented by new terms relating to manufacturing product quality issues Planned implementation date March 2016 (MedDRA Version 19.0) MSSO-DI-6017-18.0.0 18 9

4/3/2015 High Level Group Terms Subordinate only to SOCs and superordinate grouping for one or more HLTs SOC Cardiac disorders HLGT Coronary artery disorders HLGT Cardiac arrhythmias HLGT Cardiac valve disorders MSSO-DI-6017-18.0.0 19 Not all HLGTs shown High Level Terms Subordinate to HLGTs and superordinate grouping for the PTs linked to it SOC Cardiac disorders HLGT Cardiac arrhythmias HLT Cardiac conduction disorders HLT Rate and rhythm disorders NEC HLT Supraventricular arrhythmias MSSO-DI-6017-18.0.0 20 Not all HLTs shown 10

4/3/2015 Preferred Terms Represents a single medical concept SOC Cardiac disorders HLGT Cardiac arrhythmias HLT Rate and rhythm disorders NEC PT Arrhythmia MSSO-DI-6017-18.0.0 PT Bradycardia PT Tachyarrhythmia Not all PTs shown 21 Lowest Level Term Synonyms, lexical variants, sub-elements SOC = Cardiac disorders HLGT = Cardiac arrhythmias HLT = Rate and rhythm disorders NEC PT = Arrhythmia LLT Arrhythmia NOS MSSO-DI-6017-18.0.0 LLT Arrhythmia LLT Dysrhythmias LLT (Non-current) Other specified cardiac dysrhythmias Not all LLTs shown 22 11

4/3/2015 Non-Current Terms Flagged at the LLT level in MedDRA Not recommended for continued use Retained 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 MSSO-DI-6017-18.0.0 23 MedDRA Codes Each MedDRA term assigned an 8-digit numeric code starting with 1 The code is non-expressive Codes can fulfill a data field in various electronic submission types (e.g., E2B) New terms are assigned sequentially MSSO-DI-6017-18.0.0 24 12

4/3/2015 Codes and Languages MSSO-DI-6017-18.0.0 25 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 All PTs assigned a primary SOC Determines which SOC will represent a PT during cumulative data outputs Prevents double counting Supports standardized data presentation Pre-defined allocations should not be changed by users MSSO-DI-6017-18.0.0 26 13

4/3/2015 A Multi-Axial Terminology (cont) SOC = Respiratory, thoracic and mediastinal disorders (Secondary SOC) SOC = Infections and infestations (Primary SOC) HLGT = Respiratory tract infections HLGT = Viral infectious disorders HLT = Viral upper respiratory tract infections HLT = Influenza viral infections PT = Influenza MSSO-DI-6017-18.0.0 27 Rules for Primary SOC Allocation PTs represented in only one SOC are automatically assigned that SOC as primary 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 MSSO-DI-6017-18.0.0 28 14

4/3/2015 Primary SOC Priority If a PT links to more than one of the exceptions, the following priority will be used to determine primary SOC: 1 st : Congenital, familial and genetic disorders 2 nd : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 3 rd : Infections and infestations MSSO-DI-6017-18.0.0 29 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 MSSO-DI-6017-18.0.0 30 15

4/3/2015 SOC Congenital, familial and genetic disorders - PT HLT HLGT SOC Congenital HIV infection Viral infections congenital Congenital neonatal infections Infections and infestations congenital Neonatal and perinatal conditions Retroviral Viral infectious infections disorders Acquired Immunodeficiency immunodeficiency syndromes syndromes Congenital, familial and genetic disorders (P) Pregnancy, puerperium and perinatal conditions Infections and infestations Immune system disorders MSSO-DI-6017-18.0.0 31 MedDRA Maintenance 16

4/3/2015 MedDRA Maintenance MedDRA is a user-responsive terminology Users may submit change requests (CRs) to the MSSO for consideration Each organization: up to 100 CRs per month For simple changes (PT and LLT levels), notification of final disposition within 7-10 working days Complex changes above PT level received all year round. Posted for users comments mid-year. Twice yearly official updates 1 March X.0 release (Complex and simple changes) 1 September X.1 release (Simple changes only) MSSO-DI-6017-18.0.0 33 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 MSSO-DI-6017-18.0.0 34 17

4/3/2015 Proactive MedDRA Maintenance What is the proactive approach? Corrections/improvements made internally by the MSSO General changes suggested by users Submitting ideas Send to MSSO Help Desk. Justification is helpful. : Review placement of bruise and contusion terms to facilitate coding and analysis Evaluation of proposals Final disposition is not time limited; MSSO may take time to review Proactive approach does not replace usual CR process MSSO-DI-6017-18.0.0 35 MedDRA Version Analysis Tool (MVAT) Web-based (https://mssotools.com/mvat) Free to all users Allows for comparison of any two versions Features Version Report Generator (produces exportable report comparing any two versions) Data Impact Report (identifies changes to a specific set of MedDRA terms or codes uploaded to MVAT) Search Term Change (identifies changes to a single MedDRA term or code) MSSO-DI-6017-18.0.0 36 18

4/3/2015 MSSO s MedDRA Browsers MedDRA Desktop and Web-Based Browsers View/search MedDRA and SMQs Support for all MedDRA languages New MedDRA Web-Based Browser (WBB) launched on 1 December 2014 https://tools.meddra.org/wbb/ MedDRA ID and password needed MedDRA Desktop Browser (MDB) update scheduled for 2 nd half of 2015 New search features to match WBB Language specific interface MSSO-DI-6017-18.0.0 37 MedDRA Browser Demonstration and Instruction 19

4/3/2015 Coding Exercises Assessing the Reported Information Consider what is being reported. Is it a: Clinical condition - Diagnosis, sign or symptom? Indication? Test result? Injury? Procedure? Medication error? Product quality issue? Social circumstance? Device issue? Procedural complication? Is it a combination of these? The type of report will influence the way you search for a suitable LLT. It may indicate in which SOC you expect to find the closest match. MSSO-DI-6017-18.0.0 40 20

4/3/2015 MedDRA Browsing Tips First, try using actual words from reporter Use top-down and bottom-up approaches Look at the neighbors Check the hierarchy Consider synonyms, e.g., Liver and Hepatic Use word stems, e.g., Pancrea Search different word orders, and, or, etc. Use available resources for difficult verbatim terms (web search, medical dictionaries, colleagues) MSSO-DI-6017-18.0.0 41 Exercise 1 The patient states she has been experiencing headaches, dizziness and vertigo. LLT PT LLT PT LLT PT MSSO-DI-6017-18.0.0 42 21

4/3/2015 Exercise 2 Lab results indicate an increase in erythrocytes. LLT PT MSSO-DI-6017-18.0.0 43 Exercise 3 Drug was contaminated with Staphylococcus. LLT PT MSSO-DI-6017-18.0.0 44 22

4/3/2015 Exercise 4 A six year old boy was admitted for antipsychotic toxicity after accidentally ingesting the remaining tablets in the bottle. LLT PT LLT PT MSSO-DI-6017-18.0.0 45 Exercise 5 The patient s urinary catheter was blocked. LLT PT MSSO-DI-6017-18.0.0 46 23

4/3/2015 Coding with MedDRA 47 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 MSSO-DI-6017-18.0.0 48 24

4/3/2015 Can I Make Coding Conventions Specific to My Company/Product? MedDRA may reduce the need to do this because: Increased size/granularity results in more accurate representation of data Secondary SOC allocations allow for different views of the data This type of approach should be done cautiously MSSO-DI-6017-18.0.0 49 Synonym Lists Recurring verbatims one-time assignment to an LLT Promotes consistency Increases likelihood of autoencoding hit Maintenance required Verbatim LLT Comment Throbbing above temple Aching all over head Headache Pulsing pain in head Muscular pain in legs Myalgia of lower extremities LLT Myalgia of lower extremities is a better choice than LLT Muscular pain since it captures both the event and body site MSSO-DI-6017-18.0.0 50 25

4/3/2015 Quality Assurance (QA) Reports Allows reviewers to check for consistency (both auto-encoded 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.) MSSO-DI-6017-18.0.0 51 MSSO-DI-6017-18.0.0 52 26

4/3/2015 MedDRA Term Selection: Points to Consider (MTS:PTC) Provides term selection advice for industry and regulatory purposes Objective is to promote accurate and consistent term selection to facilitate a common understanding of shared data Recommended to be used as basis for individual organization s own coding conventions MSSO-DI-6017-18.0.0 53 MedDRA Term Selection: PTC (cont) Developed by a working group of the ICH Steering Committee Regulators and industry representatives from EU, Japan, and USA Canadian and Korean regulatory authorities WHO MSSO and JMO Updated twice yearly with each MedDRA release Available on MedDRA and JMO websites English and Japanese Variety of file formats for ease of viewing and editing Summary of Changes document MSSO-DI-6288-18.0.0 54 27

4/3/2015 MTS:PTC Points of Note In some cases with more than one option for selecting terms, a preferred option is identified but this does not limit MedDRA users to applying that option. Organizations should be consistent in their choice of option. Section 4.1 Versioning (Appendix) 4.1.1 Versioning methodologies 4.1.2 Timing of version implementation MSSO-DI-6017-18.0.0 55 General Term Selection Principles Quality of Source Data Quality Assurance Do Not Alter MedDRA Always Select a Lowest Level Term Select Only Current Lowest Level Terms When to Request a Term Use of Medical Judgment in Term Selection Selecting More than One Term Check the Hierarchy Select Terms for All Reported Information, Do Not Add Information MSSO-DI-6017-18.0.0 56 28

4/3/2015 Quality of Source Data Quality Assurance Quality of original information impacts quality of output Obtain clarification of data Can be optimized by careful design of data collection forms and proper training of staff Organizations coding guidelines should be consistent with MTS:PTC Review of term selection by qualified individuals Human oversight of automated coding results MSSO-DI-6017-18.0.0 57 Do Not Alter MedDRA MedDRA is a standardized terminology with a pre-defined term hierarchy Users must not make ad hoc structural alterations, including changing the primary SOC allocation If terms are incorrectly placed, submit a change request to the MSSO MSSO-DI-6017-18.0.0 58 29

4/3/2015 Always Select a Lowest Level Term Select Only Current LLTs Lowest Level Term that most accurately reflects the reported verbatim information should be selected Degree of specificity may be challenging : Abscess on face select Facial abscess, not simply Abscess Select current LLTs only Non-current terms for legacy conversion/historical purposes MSSO-DI-6017-18.0.0 59 When to Request a Term Use of Medical Judgment 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 MSSO-DI-6017-18.0.0 60 30

4/3/2015 Selecting More than One Term Check the Hierarchy Can select more than one LLT to represent reported information. Document procedures. Selecting one term may lead to loss of specificity Selecting more than one term may lead to redundant counts Check the hierarchy above a selected LLT (PT, HLT, HLGT, SOC) to ensure placement accurately reflects meaning of reported term MSSO-DI-6017-18.0.0 61 Select Terms for All Reported Information Select terms for every AR/AE reported, regardless of causal association Select terms for device-related events, product quality issues, medication errors, medical and social history, investigations and indications as appropriate MSSO-DI-6017-18.0.0 62 31

4/3/2015 Do Not Add Information Do not make diagnosis if only signs/symptoms reported Reported LLT Selected Comment Abdominal pain Abdominal pain, increased serum amylase, and increased serum lipase Serum amylase increased Lipase increased It is inappropriate to assign an LLT for diagnosis of pancreatitis MSSO-DI-6017-18.0.0 63 Autoencoder Pitfalls Inappropriate terms may be selected by autoencoder Review all autoencoding carefully Allergic to CAT scan autoencoded as: LLT Allergic to cats Myocardial infarction in the fall of 2000 autoencoded as: LLT Myocardial infarction LLT Fall MSSO-DI-6017-18.0.0 64 32

4/3/2015 FDA-Defined Coding Errors Missed Concepts All medical concepts described after the product is taken should be coded : The patient took drug X and developed alopecia, increased LFTs and pancreatitis. Manufacturer only codes alopecia and increased LFTs (missed concept of pancreatitis) : The patient took drug X and developed interstitial nephritis which later deteriorated into renal failure. Manufacturer only codes interstitial nephritis (missed renal failure concept) Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER MSSO-DI-6017-18.0.0 65 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 : Liver failure coded as hepatotoxicity or increased LFTs : Aplastic anemia coded as unspecified anemia : Rash subsequently diagnosed as Stevens Johnson syndrome coded as rash Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER MSSO-DI-6017-18.0.0 66 33

4/3/2015 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-Specific vs. Microorganism-Specific Information Modification of Pre-existing Conditions Exposures During Pregnancy and Breast Feeding Congenital Terms Neoplasms Medical and Surgical Procedures Investigations MSSO-DI-6017-18.0.0 67 Term Selection Points (cont) Medication Errors, Accidental Exposures and Occupational Exposures Misuse, Abuse and Addiction Transmission of Infectious Agent via Product Overdose, Toxicity and Poisoning Device-related Terms Drug Interactions No Adverse Effect and Normal Terms Unexpected Therapeutic Effect Modification of Effect Social Circumstances Medical and Social History Indication for Product Use Off Label Use Product Quality Issues MSSO-DI-6017-18.0.0 68 34

4/3/2015 Diagnoses and Provisional Diagnoses SINGLE DIAGNOSIS DEFINITIVE DIAGNOSIS Single diagnosis without signs and symptoms PROVISIONAL DIAGNOSIS Single provisional diagnosis without signs and symptoms Diagnosis (only possible option) Provisional diagnosis (only possible option) : Myocardial infarction select Myocardial infarction : Possible myocardial infarction select Myocardial infarction (select term as if definitive diagnosis) Similar principles apply for multiple diagnoses MSSO-DI-6017-18.0.0 69 Diagnoses and Provisional Diagnoses (cont) SINGLE DIAGNOSIS DEFINITIVE DIAGNOSIS Single diagnosis with signs/ symptoms Preferred: Diagnosis only PROVISIONAL DIAGNOSIS Single provisional diagnosis with signs/symptoms Preferred: Provisional diagnosis and signs/symptoms : Anaphylactic reaction with rash, dyspnoea, hypotension, and laryngospasm select Anaphylactic reaction : Possible myocardial infarction with chest pain, dyspnoea, diaphoresis select Myocardial infarction Chest pain, Dyspnoea, and Diaphoresis MSSO-DI-6017-18.0.0 Similar principles apply for multiple diagnoses 70 35

4/3/2015 Diagnoses and Provisional Diagnoses (cont) SINGLE DIAGNOSIS DEFINITIVE DIAGNOSIS Single diagnosis with signs/ symptoms PROVISIONAL DIAGNOSIS Single provisional diagnosis with signs/symptoms Alternate: Diagnosis and signs/symptoms Alternate: Signs/symptoms only (as provisional diagnosis may change : Anaphylactic reaction : Possible myocardial with rash, dyspnoea, hypotension, infarction with chest pain, and laryngospasm select dyspnoea, diaphoresis select Anaphylactic reaction, Rash, Chest pain, Dyspnoea, and Dyspnoea, Hypotension, and Diaphoresis Laryngospasm MSSO-DI-6017-18.0.0 Similar principles apply for multiple diagnoses 71 Diagnoses and Provisional Diagnoses (cont) Always include signs/symptoms not associated with diagnosis Reported LLT Selected Myocardial infarction, chest pain, dyspnoea, diaphoresis, ECG changes and jaundice Myocardial infarction Jaundice (note that jaundice is not typically associated with myocardial infarction) MSSO-DI-6017-18.0.0 72 36

4/3/2015 What Terms to Select? Sepsis leading to shock from possible spontaneous bacterial peritonitis or bowel perforation Sepsis? Shock? Septic shock? Spontaneous bacterial peritonitis? Bowel perforation? MSSO-DI-6017-18.0.0 73 Conflicting/Ambiguous Information First, try to obtain more specific information Reported LLT Selected Comment Hyperkalaemia with a serum potassium of 1.6 meq/l GU pain Serum potassium abnormal Pain LLT Serum potassium abnormal covers both of the reported concepts (note: serum potassium of 1.6 meq/l is a low result, not high) GU could be either genito-urinary or gastric ulcer. If additional information is not available, then select a term to reflect the information that is known, i.e., LLT Pain MSSO-DI-6017-18.0.0 74 37

4/3/2015 Vague Information First, try to obtain more specific information Reported LLT Selected Comment Turned green Patient had a medical problem of unclear type Unevaluable event Ill-defined disorder Turned green reported alone is vague; this could refer to a patient condition or even to a product (e.g., pills) Since it is known that there is some form of a medical disorder, LLT Illdefined disorder can be selected MSSO-DI-6017-18.0.0 75 What Terms to Select? Clinical complication of IUD IUD complication (PT Medical device complication)? Intra-uterine death (PT Foetal death)? Unevaluable event? Hypoglycemia (blood glucose = 200 mg/dl) Blood glucose abnormal? Blood glucose increased? Hypoglycemia? MSSO-DI-6017-18.0.0 76 38

4/3/2015 Combination Terms One condition is more specific than the other Reported LLT Selected Arrhythmia due to atrial fibrillation Atrial fibrillation Hepatic function disorder (acute hepatitis) Hepatitis acute A MedDRA combination term is available Reported Retinopathy due to diabetes Rash with itching LLT Selected Diabetic retinopathy Itchy rash MSSO-DI-6017-18.0.0 77 Combination Terms (cont) If splitting provides more clinical information, select more than one term In all cases of combination terms, apply medical judgment Reported Diarrhoea and vomiting Wrist fracture due to fall LLT Selected Diarrhoea Vomiting Wrist fracture Fall MSSO-DI-6017-18.0.0 78 39

4/3/2015 What Terms to Select? Retinal disease from HIV with near total blindness (R and L) Retinal damage? Retinal disorder? HIV disease? Blindness? HIV retinopathy? Blindness both eyes? MSSO-DI-6017-18.0.0 79 Investigations Medical condition vs. investigation result Reported LLT Selected Comment Hypoglycaemia Hypoglycaemia LLT Hypoglycaemia links to SOC Metabolism and nutrition disorders Decreased glucose Glucose decreased LLT Glucose decreased links to SOC Investigations MSSO-DI-6017-18.0.0 80 40

4/3/2015 Investigations (cont) Unambiguous investigation result Reported LLT Selected Comment Glucose 40 mg/dl Glucose low Ambiguous investigation result Glucose is clearly below the reference range Reported LLT Selected Comment His glucose was 40 Glucose abnormal No units have been reported. Select LLT Glucose abnormal if clarification cannot be obtained. MSSO-DI-6017-18.0.0 81 Investigations (cont) Investigation results consistent with diagnosis Reported LLT Selected Comment Elevated potassium, K 7.0 mmol/l, and hyperkalaemia Grouped investigation result terms Reported LLT Selected Comment Increased alkaline phosphatase, increased SGPT, increased SGOT and elevated LDH Hyperkalaemia Alkaline phosphatase increased SGPT increased SGOT increased LDH increased It is not necessary to select LLT Potassium increased Select four individual terms. A single term such as LLT Liver function tests abnormal should not be selected. MSSO-DI-6017-18.0.0 82 41

4/3/2015 What Terms to Select? Testing showed increased serum creatinine and BUN, with increased BUN/creatinine ratio Increased serum creatinine? BUN increased? Blood urea nitrogen/creatinine ratio increased? Renal function tests NOS abnormal? CSF was positive for fungus Fungal meningitis? Fungus CSF test positive? MSSO-DI-6017-18.0.0 83 Medication Errors See Appendix B of MedDRA Introductory Guide or MedDRA Web-Based Browser for Concept Descriptions Top-down navigation in HLGT Medication errors is best approach for term selection Medication error with clinical consequences Reported LLT Selected Comment Patient was administered wrong drug and experienced hypotension Insulin was given using the wrong syringe resulting in the administration of an overdose. The patient developed hypoglycaemia. MSSO-DI-6017-18.0.0 Wrong drug administered Hypotension Wrong device used Accidental overdose Hypoglycaemia If an overdose is reported in the context of a medication error, the more specific term LLT Accidental overdose can be selected 84 42

4/3/2015 Medication Errors (cont) Medication error without clinical consequences Reported LLT Selected Preferred Option Intramuscular formulation administered by other route Medication was given intravenously instead of intramuscularly without sequelae Intramuscular formulation administered by other route No adverse effect MSSO-DI-6017-18.0.0 85 Medication Errors (cont) Important to record potential occurrence of medication error Unlikely to be reported as an adverse event but may need to be recorded in periodic safety reports Reported LLT Selected Comment Pharmacist notices that the names of two drugs are similar and is concerned that this may result in a medication error Drug name confusion Circumstance or information capable of leading to medication error Note: this example is a potential medication error and LLT Drug name confusion provides additional information about the nature of the potential medication error MSSO-DI-6017-18.0.0 86 43

4/3/2015 Overdose, Toxicity and Poisoning If overdose, poisoning or toxicity is explicitly reported, select the appropriate term Overdose with clinical consequences Overdose without clinical consequences MSSO-DI-6017-18.0.0 Reported Stomach upset from study drug overdose LLT Selected Stomach upset Overdose Reported LLT Selected Preferred Option Patient received an overdose of medicine without any adverse consequences Overdose Overdose No adverse effect 87 What Term to Select? The patient s renal function was measured every six months instead of on the monthly schedule recommended in the label for the drug Renal function test? Renal function test abnormal? Drug monitoring procedure incorrectly performed? Unintentionally took more than maximum recommended dose due to dispensing error Accidental overdose? Incorrect dose administered? Drug dispensing error? MSSO-DI-6017-18.0.0 88 44

4/3/2015 Misuse, Abuse and Addiction * Definitions of misuse may not always include the concept of therapeutic use; misuse may be similar to the concept of abuse in some regions. MSSO-DI-6017-18.0.0 89 HLGT Product use issues Improved organization of product use concepts in MedDRA Version 18.0 New HLGT Product use issues Medication errors, overdoses, underdoses, misuse, and off label use now in one SOC Facilitates coding and retrieval MSSO-DI-6017-18.0.0 90 45

4/3/2015 Coding Exercises Narratives and short verbatims Assess the reported terms Identify what concepts are reported (diagnosis, death, investigations, etc.) Refer to the appropriate sections of the MTS:PTC for guidance on term selection For example, Section 3.2 for death terms Use MTS:PTC preferred options (forget your organization s conventions) Use browser to search for and select LLTs (also record PT and primary SOC) MSSO-DI-6017-18.0.0 91 Specific Tips for Narrative Exercises Overall, coding principles are the same as for short verbatim exercises Code all of the following: Events (including procedures and investigations as needed) Indications Medical history Social history MSSO-DI-6017-18.0.0 92 46

4/3/2015 Sample Narrative A 75-year-old male receiving Drug X for rheumatoid arthritis developed an area of darkened skin on his chest. The patient s medical history is significant for peripheral vascular disease and cigarette smoking. The skin lesion was excised; it was revealed to be a seborrhoeic wart. MSSO-DI-6017-18.0.0 93 Course Summary In this course, we covered: A review of MedDRA s scope and structure, including primary SOC allocation rules Coding conventions, synonym lists, and coding QA Introduction to the MedDRA Term Selection: Points to Consider document Coding exercises MSSO-DI-6017-18.0.0 94 47

4/3/2015 MSSO Contacts Website www.meddra.org Email mssohelp@meddra.org MSSO-DI-6017-18.0.0 95 48

Coding with MedDRA Version 18.0 Narratives ID Verbatim term LLT PT Primary SOC NAR1 A 75-year-old male developed anginal pain on 21 Feb 2015 resulting in hospitalisation while enrolled in a randomized, open-label study. The patient s medical history is significant for triple bypass graft surgery 2012, postural hypotension and stage D prostate carcinoma. On 26 Feb 2015, the patient underwent percutaneous transluminal coronary angioplasty with stent placement in the right coronary and proximal left anterior descending arteries. NAR2 A 74 year old woman had been receiving bisphosphonate therapy for 6 years to prevent postmenopausal osteoporosis. She presented to her dentist complaining of jaw pain and gum pain. On examination, a small area of exposed bone was noted in the left anterior maxilla. The dentist considered this to be a possible case of osteonecrosis of the jaw. NAR3 After taking the first dose of Drug X, the patient complained of facial and tongue swelling. The physician reports that the patient suffered from a hypersensitivity reaction to the drug. NAR4 On 20 Sep 2014, the patient was hospitalised following two episodes of near fainting. She was repositioning her oxygen cannula and saw blood on the nasal prongs. She also MSSO-DI-6017-18.0.0 1

Coding with MedDRA Version 18.0 ID Verbatim term LLT PT Primary SOC on the nasal prongs. She also reported increased fatigue and hip and leg pain. Her blood pressure was decreased to 85/55 mm Hg; her pulse remained normal at 88, and 1+ peripheral edema was noted. The patient recovered with treatment and was discharged on 23 Sep 2014. Short verbatims ID Verbatim term LLT PT Primary SOC 1 Disconnected feeling 2 Unspecified neurological condition 3 Echoing in ears 4 Severe bronchospasm on induction of anesthesia 5 Elderly woman complained her arm was tender where she had received her seasonal flu vaccine 6 PANDAS 7 Influenza with body aches, fever, cough 8 72 year old man with aphasia and right hemiplegia. Stroke in middle cerebral artery territory is suspected. 9 Patient said she received flu vaccine 3 months before she became pregnant 10 Fetus was inadvertently exposed to radiation MSSO-DI-6017-18.0.0 2

Coding with MedDRA Version 18.0 ID Verbatim term LLT PT Primary SOC 11 Baby born with intestinal obstruction 12 Developed an atrial septal defect at age 55 13 Large tumour in brain 14 Recurrence of hepatic cancer 15 Cartilage removed left knee 16 Total abdominal hysterectomy for worsening fibroids 17 Thrombocytopenia with decreased platelet count 18 BUN was 3.5 19 Doctor prescribed wrong dose of drug X 20 Nurse injected several patients with a syringe intended to be used for a single patient only 21 Elderly woman ingested her husband's blood pressure drug by mistake 22 Interventional radiologist exposed to radiation over many years 23 The drug was inadvertently administered for too long which resulted in the patient receiving an 24 Patient deliberately took drug X twice a day instead of once a day as prescribed 25 History of diuretic abuse 26 Man bought large quantities of pseudoephedrine from multiple shops for the purpose of manufacturing methamphetamine MSSO-DI-6017-18.0.0 3

Coding with MedDRA Version 18.0 ID Verbatim term LLT PT Primary SOC 27 Patient received an epidural steroid injection and subsequently developed meningitis due to Aspergillus. The steroid injection solution was tested and grew Aspergillus fumigatus. 28 Possible transmission of HIV infection via blood product 29 Chronic overdosing 30 Patient deliberately took overdose of several drugs 31 Patient complained that nasogstric tube was irritating her 32 Batteries failed 33 Patient was already taking drug X and when he started on drug Y, his paranoia worsened 34 Patient took drug X which interacted with the digoxin he was already taking, resulting in digoxin toxicity 35 Patient accidentally took an overdose of her blood pressure medication but reported no adverse effects. 36 Patient had a normal delivery 37 She died due to a stroke 38 Admitted to hospital for diagnostic workup 39 Patient was pleased that her eyelashes grew longer while she was being treated with a glaucoma drug MSSO-DI-6017-18.0.0 4

Coding with MedDRA Version 18.0 ID Verbatim term LLT PT Primary SOC 40 His anticonvulsant drug failed to control his seizures 41 Prolonged effect from sleeping pills 42 84 year old man with impaired ability to perform activities of daily living 43 Former drug abuser 44 She had breast cancer in 2002 45 Her mother and sister both had breast cancer 46 Drug X is indicated for the treatment of diabetes 47 Drug X is an antidiabetic agent 48 Drug Y is indicated for the prevention of DVT after hip surgery 49 Indicated for treatment of metastatic non-small cell lung cancer with EGFR exon 19 deletions 50 Calcium supplement 51 Doctor used drug A off label 52 Used off label for metastatic pancreatic cancer. Patient developed severe myelosuppression. 53 Nurse noticed that the injection solution was cloudy 54 Patient reported that the drug he obtained from an internet pharmacy was ineffective and that he thought it might be counterfeit 55 Her suicide attempt resulted in her death MSSO-DI-6017-18.0.0 5

Coding with MedDRA Version 18.0 ID Verbatim term LLT PT Primary SOC 56 She attempted suicide by taking an overdose of pills 57 Increased heart rate (14 beats per minute) 58 Congestion 59 It looked red 60 Patient had some type of medical problem 61 DU pain 62 Arthritis due to SLE 63 25 year old man sustained multiple injuries in a motorcycle accident 64 Skin burn after being exposed to chemical 65 5 year old boy had a seizure 66 Newborn had a cardiorespiratory arrest 67 Pain in upper back 68 Pain in upper and lower back 69 Tinnitus became worse 70 Patient became more aggressive after he started taking drug A 71 Meningitis due to Exserohilum 72 Perinephric abscess due to Proteus spp. MSSO-DI-6017-18.0.0 6

MedDRA TERM SELECTION: POINTS TO CONSIDER ICH-Endorsed Guide for MedDRA Users Release 4.9 Based on MedDRA Version 18.0 1 March 2015 Disclaimer and Copyright Notice This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. MedDRA trademark is owned by IFPMA on behalf of ICH

Table of Contents SECTION 1 INTRODUCTION... 1 1.1 Objectives of this Document... 1 1.2 Uses of MedDRA... 1 1.3 How to Use this Document... 2 1.4 Preferred Option... 2 1.5 MedDRA Browsing Tools... 2 SECTION 2 GENERAL TERM SELECTION PRINCIPLES... 2 2.1 Quality of Source Data... 2 2.2 Quality Assurance... 2 2.3 Do Not Alter MedDRA... 3 2.4 Always Select a Lowest Level Term... 3 2.5 Select Only Current Lowest Level Terms... 4 2.6 When to Request a Term... 4 2.7 Use of Medical Judgment in Term Selection... 5 2.8 Selecting More than One Term... 5 2.9 Check the Hierarchy... 5 2.10 Select Terms for All Reported Information, Do Not Add Information... 5 SECTION 3 TERM SELECTION POINTS... 6 3.1 Definitive and Provisional Diagnoses with or without Signs and Symptoms... 6 3.2 Death and Other Patient Outcomes... 8 3.2.1 Death with ARs/AEs... 9 3.2.2 Death as the only reported information... 9 3.2.3 Death terms that add important clinical information... 9 3.2.4 Other patient outcomes (non-fatal)... 10 3.3 Suicide and Self-Harm... 10 3.3.1 If overdose is reported... 10 3.3.2 If self-injury is reported... 10 3.3.3 Fatal suicide attempt... 11 3.4 Conflicting/Ambiguous/Vague Information... 11 3.4.1 Conflicting information... 11 3.4.2 Ambiguous information... 12 3.4.3 Vague information... 12 3.5 Combination Terms... 12 3.5.1 Diagnosis and sign/symptom... 13 3.5.2 One reported condition is more specific than the other... 13 3.5.3 A MedDRA combination term is available... 13 3.5.4 When to split into more than one MedDRA term... 14 3.5.5 Event reported with pre-existing condition... 14 i

3.6 Age vs. Event Specificity... 15 3.6.1 MedDRA term includes age and event information... 15 3.6.2 No available MedDRA term includes both age and event information... 15 3.7 Body Site vs. Event Specificity... 15 3.7.1 MedDRA term includes body site and event information... 15 3.7.2 No available MedDRA term includes both body site and event information... 15 3.7.3 Event occurring at multiple body sites... 16 3.8 Location-Specific vs. Microorganism-Specific Infection... 17 3.8.1 MedDRA term includes microorganism and anatomic location... 17 3.8.2 No available MedDRA term includes both microorganism and anatomic location... 17 3.9 Modification of Pre-existing Conditions... 17 3.10 Exposures during Pregnancy and Breast Feeding... 18 Events in the mother... 18 3.10.1... 18 3.10.2 Events in the child or foetus... 19 3.11 Congenital Terms... 19 3.11.1 Congenital conditions... 20 3.11.2 Acquired conditions (not present at birth)... 20 3.11.3 Conditions not specified as either congenital or acquired... 21 3.12 Neoplasms... 21 3.12.1 Do not infer malignancy... 22 3.13 Medical and Surgical Procedures... 22 3.13.1 Only the procedure is reported... 22 3.13.2 Procedure and diagnosis are reported... 22 3.14 Investigations... 23 3.14.1 Results of investigations as ARs/AEs... 23 3.14.2 Investigation results consistent with diagnosis... 24 3.14.3 Investigation results not consistent with diagnosis... 24 3.14.4 Grouped investigation result terms... 24 3.14.5 Investigation terms without qualifiers... 25 3.15 Medication Errors, Accidental Exposures and Occupational Exposures... 25 3.15.1 Medication errors... 25 3.15.2 Accidental exposures and occupational exposures... 29 3.16 Misuse, Abuse and Addiction... 30 3.16.1 Misuse... 31 3.16.2 Abuse... 31 3.16.3 Addiction... 32 3.16.4 Drug diversion... 32 3.17 Transmission of Infectious Agent via Product... 32 3.18 Overdose, Toxicity and Poisoning... 33 3.18.1 Overdose reported with clinical consequences... 34 ii

3.18.2 Overdose reported without clinical consequences... 34 3.19 Device-related Terms... 35 3.19.1 Device-related event reported with clinical consequences... 35 3.19.2 Device-related event reported without clinical consequences... 35 3.20 Drug Interactions... 35 3.20.1 Reporter specifically states an interaction... 35 3.20.2 Reporter does not specifically state an interaction... 36 3.21 No Adverse Effect and Normal Terms... 36 3.21.1 No adverse effect... 36 3.21.2 Use of normal terms... 36 3.22 Unexpected Therapeutic Effect... 37 3.23 Modification of Effect... 37 3.23.1 Lack of effect... 37 3.23.2 Do not infer lack of effect... 37 3.23.3 Increased, decreased and prolonged effect... 37 3.24 Social Circumstances... 38 3.24.1 Use of terms in this SOC... 38 3.24.2 Illegal acts of crime or abuse... 39 3.25 Medical and Social History... 39 3.26 Indication for Product Use... 39 3.26.1 Medical conditions... 40 3.26.2 Complex indications... 40 3.26.3 Indications with genetic markers or abnormalities... 41 3.26.4 Prevention and prophylaxis... 41 3.26.5 Procedures and diagnostic tests as indications... 42 3.26.6 Supplementation and replacement therapies... 42 3.26.7 Indication not reported... 42 3.27 Off Label Use... 43 3.27.1 Off label use when reported as an indication... 43 3.27.2 Off label use when reported with an AR/AE... 43 3.28 Product Quality Issues... 44 3.28.1 Product quality issue reported with clinical consequences... 44 3.28.2 Product quality issue reported without clinical consequences... 45 3.28.3 Product quality issue vs. medication error... 45 SECTION 4 APPENDIX... 46 4.1 Versioning... 46 4.1.1 Versioning methodologies... 46 4.1.2 Timing of version implementation... 47 4.2 Links and References... 48 4.3 Membership of the ICH Points to Consider Working Group... 49 4.3.1 Current members of the ICH Points to Consider Working Group... 49 4.3.2 Former members of the ICH Points to Consider Working Group... 50 iii

SECTION 1 INTRODUCTION The Medical Dictionary for Regulatory Activities terminology (MedDRA) was designed for sharing regulatory information for human medical products. However, unless users achieve consistency in how they assign terms to verbatim reports of symptoms, signs, diseases, etc., use of MedDRA cannot have the desired harmonising effect in the exchange of coded data. This MedDRA Term Selection: Points to Consider (MTS:PTC) document is an ICH-endorsed guide for MedDRA users. It is updated in step with new MedDRA versions and is a companion document to MedDRA. It was developed and is maintained by a working group charged by the ICH Steering Committee. The working group consists of regulatory and industry representatives of the European Union, Japan, and the United States, as well as representatives from the Canadian and Korean regulatory authorities, the MedDRA Maintenance and Support Services Organization (MSSO) and the Japanese Maintenance Organization (JMO) (see Appendix, Section 4.3 for list of members). 1.1 Objectives of this Document The objective of the MTS:PTC document is to promote accurate and consistent term selection. Organisations are encouraged to document their term selection methods and quality assurance procedures in organisation-specific coding guidelines which should be consistent with the MTS:PTC. Consistent term selection promotes medical accuracy for sharing MedDRAcoded data and facilitates a common understanding of shared data among academic, commercial and regulatory entities. The MTS:PTC could also be used by healthcare professionals, researchers, and other parties outside of the regulated biopharmaceutical industry. The document provides term selection considerations for business purposes and regulatory requirements. There may be examples that do not reflect practices and requirements in all regions. This document does not specify regulatory reporting requirements, nor does it address database issues. As experience with MedDRA increases, and as MedDRA changes, there will be revisions to this document. 1.2 Uses of MedDRA Term selection for adverse reactions/adverse events (ARs/AEs), device-related events, product quality issues, medication errors, exposures, medical history, social history, investigations, misuse and abuse, off label use, and indications is addressed in this MTS:PTC document. MedDRA s structure allows for aggregation of those reported terms in medically meaningful groupings to facilitate analysis of safety data. MedDRA can also be used to list AR/AE data in reports (tables, line listings, etc.), compute frequencies of similar ARs/AEs, and capture and analyse related data such as product indications, investigations, and medical and social history. 1

1.3 How to Use this Document The MTS:PTC document does not address every potential term selection situation. Medical judgment and common sense should also be applied. This document is not a substitute for MedDRA training. It is essential for users to have knowledge of MedDRA s structure and content. For optimal MedDRA term selection, one should also refer to the MedDRA Introductory Guide (see Appendix, Section 4.2). 1.4 Preferred Option In some cases, where there is more than one option for selecting terms, a preferred option is identified in this document. Designation of a preferred option does not limit MedDRA users to applying that option. Users should always first consider regional regulatory requirements. An organisation should be consistent in the option that they choose to use and document that option in internal coding guidelines. 1.5 MedDRA Browsing Tools The MSSO and JMO provide two browsers (a Desktop browser and a Web- Based browser) that allow for searching and viewing the terminology (see Appendix, Section 4.2). Users may find these browsers useful aids in term selection. SECTION 2 GENERAL TERM SELECTION PRINCIPLES 2.1 Quality of Source Data The quality of the original reported information directly impacts the quality of data output. Clarification should be obtained for data that are ambiguous, confusing, or unintelligible. If clarification cannot be obtained, refer to Section 3.4. 2.2 Quality Assurance To promote consistency, organisations should document their term selection methods and quality assurance procedures in coding guidelines consistent with this MTS:PTC document. Clear initial data can be promoted through careful design of data collection forms, and training of individuals in data collection and follow-up (e.g., investigators, drug sales representatives). Term selection should be reviewed by a qualified individual, i.e., a person with medical background or training who has also received MedDRA training. Human oversight of term selection performed by IT tools (such as an autoencoder) is needed to assure that the end result fully reflects the reported information and makes medical sense. 2