Introduction to MedDRA

Transcription

1 Introduction to MedDRA MedDRA trademark is owned by IFPMA on behalf of ICH 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 i and Healthcare products Regulatory Agency (MHRA) of the UK, Health Canada, and the WHO (as Observer). 2 1

2 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. 3 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) Customized searches 4 2

3 MedDRA Background What is MedDRA? Med = Medical D = Dictionary for R = Regulatory A = Activities 6 3

4 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 7 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 8 4

5 MedDRA and the MSSO International support and development of terminology Foster use of MedDRA through communications and educational offerings Custodians, not owners, of the terminology JMO (partner organization for Japaneselanguage MedDRA) Governed by a Management Board (industry, regulators, multi-national, other interested parties) 9 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. 10 5

6 Regulatory Considerations US FDA Regulatory Status Used in several ldatabases including FAERS(drugs and biologics), VAERS (vaccines), and CAERS (foods, dietary supplements, cosmetics) FAERS and VAERS accept LLTs and PTs CAERS accepts PTs Recommended terminology for adverse event reporting in several Proposed Rules Japanese Ministry of Health, Labour and Welfare Mandatory use in electronic reporting LLTs and PTs accepted 12 6

7 Regulatory Status (cont) European Union EudraVigilance database Clinical trial SUSARs (Suspected Unexpected Serious Adverse Reactions) Post-authorization Individual Case Safety Reports (ICSRs) Use MedDRA LLTs (current version or the one previous to it) New PV legislation covers suspected adverse reactions from: Use inside and outside terms of marketing authorization Overdose, misuse, abuse, and medication errors Occupational exposures Good pharmacovigilance practices (GVP) specifically mention MedDRA 13 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 Recommended/preferred terminology for adverse reaction reporting and Product Monograph (labeling) 14 7

8 MedDRA s Structure and Scope Not a drug dictionaryi Patient demographic terms Clinical trial study design terms Scope of MedDRA 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 16 8

9 MedDRA Structure System Organ Class (SOC) (26) High Level Group Term (HLGT) (334) High Level Term (HLT) (1,717) Preferred Term (PT) (20,057) Lowest Level Term (LLT) (71,326) MedDRA Version MedDRA Term Level Definitions SOC - Highest level l of the terminology, and representing an anatomical or physiological system, etiology, or purpose HLGT - Subordinate to SOC, superordinate grouping for one or more HLTs HLT - Subordinate to HLGT, superordinate grouping 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 quasisynonym (Note: All PTs have an identical LLT) 18 9

10 System Organ Classes Blood and lymphatic system disorders Cardiac disorders d Congenital, familial and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary bl disorders d 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 19 Examples of LLTs SOC = Cardiac disorders HLGT = Cardiac arrhythmias HLT = Rate and rhythm disorders NEC PT = Arrhythmia LLT Arrhythmia NOS LLT Arrhythmia LLT Dysrhythmias LLT (Non-current) Other specified cardiac dysrhythmias 20 10

11 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, outdated, truncated, or misspelled Terms derived from other terminologies that do not fit MedDRA rules 21 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 New terms are assigned sequentially Supplemental terms are assigned codes 22 11

12 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 23 A Multi-Axial Terminology (cont) SOC = Respiratory, thoracic and SOC = Infections and mediastinal disorders infestations HLGT = Respiratory tract infections HLGT = Viral infectious disorders HLT = Viral upper respiratory tract infections HLT = Influenza viral infections PT = Influenza 24 12

13 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 25 Rules for Primary SOC Allocation PTs for diseases, signs and symptoms are assigned to prime manifestation ti 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 26 13

14 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 27 MSSO s MedDRA Browsers MedDRA Desktop Browser Download from MSSO Web site View/search MedDRA and SMQs Export functionality MedDRA Web-Based Browser Requires specific user ID and password Access to all MedDRA versions in English and available EU languages (and Chinese, if subscribed) View/search MedDRA and SMQs Export functionality 28 14

15 Browser Demonstration ti SOC View MedDRA Maintenance 15

16 MedDRA Maintenance MedDRA is a user responsive terminology Subscribers may submit change requests to the MSSO for consideration Core and basic subscribers: 100 change requests (CRs) per month For simple changes (PT and LLT levels), notification of final disposition 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. 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) 32 16

17 WebCR Web-based tool for Change Requests (CR) URL: 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 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 MSSO-DI

18 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. Example: Consider consolidation of HLTs with only one PT Evaluation of proposals MSSO is not obligated to respond Proactive approach does not replace usual CR process 35 MedDRA Version Analysis Tool (MVAT) Web-based based ( Free to all subscribers 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) 36 18

19 Coding with MedDRA 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 38 19

20 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) i Even with an autoencoder, may still need manual coding 39 Overview of MedDRA Term Selection: Points to Consider Document 20

21 MedDRA Term Selection: Points to Consider (MTS:PTC) An ICH-endorsed guide for MedDRA users 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 the basis for individual organizations coding conventions 41 MedDRA 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 Updated twice yearly with each MedDRA release Available on MSSO, JMO, and ICH Web sites English and Japanese Variety of file formats for ease of viewing and editing Summary of Changes document 42 21

22 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) Versioning methodologies Timing of version implementation 43 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 44 22

23 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 45 Do Not Alter MedDRA MedDRA is a standardized di d 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 46 23

24 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 Example: Abscess on face select Facial abscess, not simply Abscess Select current LLTs only Non-current terms for legacy conversion/historical purposes 47 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 48 24

25 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 49 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 If diagnosis reported with characteristic signs and symptoms, preferred option is to select term for diagnosis only 50 25

26 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 p to assign an LLT for diagnosis of pancreatitis 51 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) Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER 52 26

27 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: Rash subsequently diagnosed as Stevens Johnson syndrome coded as rash Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER 53 Term Selection Points Diagnoses and Provisional Diagnoses with or without Signs and Symptoms Death and Other Patient t 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 existing Conditions Exposures During Pregnancy and Breast Feeding Congenital Terms Neoplasms Medical and Surgical Procedures Investigations 54 27

28 Term Selection Points (cont) Medication/Administration 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 55 Overview of MedDRA Data Retrieval and Presentation: Points to Consider Document 28

29 MedDRA Data Retrieval and Presentation: Points to Consider An ICH-endorsed Guide for MedDRA users Provides data retrieval and presentation options for industry or regulatory purposes Most effective when used in conjunction with MedDRA Term Selection: Points to Consider document Objective is to demonstrate how data retrieval options impact the accuracy and consistency of data output Recommended to be used as the basis for individual organizations data retrieval conventions 57 MedDRA Data Retrieval and Presentation: Points to Consider (cont) Developed by a working group of the ICH Steering Committee Regulators and industry representatives EU, Japan, USA Canadian observer, MSSO, JMO Updated twice yearly with each MedDRA release Available on MSSO, JMO, and ICH Web sites English and Japanese Variety of file formats for ease of viewing and editing Summary of Changes document 58 29

30 Data Retrieval PTC Points Addressed General Principles Quality of Source Data Documentation of Data Retrieval and Presentation Practices Do Not Alter MedDRA Organization-Specific Data Characteristics Characteristics of MedDRA that Impact Data Retrieval and Analysis MedDRA Versioning General Queries and Retrieval Standardised MedDRA Queries Customized Searches 59 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 60 30

31 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) Quality assurance procedures MedDRA version used for search Search strategy methods Version update processes Processes for customized MedDRA queries 61 Organization-Specific Data Characteristics Database structure (storage and use of hierarchy) Data storage (level of term, synonym/reported term) Data conversion (if applicable) 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 62 31

32 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 63 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 e locations o in SOC HLT Bullous conditions PT Stevens-Johnson syndrome HLT Exfoliative conditions PT Dermatitis exfoliative 64 32

33 Granularity Other No. of MedDRA Version 16.0 No. of Terminology Events Preferred Terms Events Preferred Terms INFECTION 15 Upper respiratory tract infection Nasopharyngitis Infection Lower respiratory tract t infection Skin infection Multi-Axiality Pi Primary SOC allocation rules affect tthe 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) 66 33

34 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 MedDRA Version Analysis Tool (MVAT) Terms used for queries should be in same version as data being queried 67 MedDRA Versioning (cont) - Effect of Primary SOC Change MedDRA Version 15.1 Number of Events SOC Pregnancy, puerperium and perinatal conditions PT Anaesthetic complication foetal MedDRA Version Number of Events SOC Pregnancy, puerperium and perinatal conditions SOC Injury, poisoning and procedural complications PT Anaesthetic complication foetal

35 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 69 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) 70 35

36 Overall Presentation of Safety Profiles Highlight ht overall distribution ib ti 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 71 Overview by Primary SOC Use Internationally Agreed Order of SOCs when applicable, e.g., the EU SPC guideline See MedDRA Introductory Guide, ASCII files Consider use of HLTs and HLGTs Line listings, tables, graphs Benefits - Broad overview, PTs displayed only once Limitations - Incomplete groupings due to SOC allocation rules, lengthy output 72 36

37 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 73 Introduction to Standardised MedDRA Queries (SMQs) 37

38 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 75 SMQ Benefits and Limitations Benefits 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 76 38

39 SMQs in Production - Examples As of Version 16.0, a total of 90 in production Agranulocytosis Anaphylactic reaction Cerebrovascular disorders Convulsions Depression and suicide/self-injury Hepatic disorders Hypersensitivity Ischaemic heart disease Lack of efficacy/effect Osteonecrosis Peripheral neuropathy Pregnancy and neonatal topics Pseudomembranous colitis Rhabdomyolysis/myopathy y y y Severe cutaneous adverse reactions Systemic lupus erythematosus 77 Narrow and Broad Searches Narrow scope specificity (cases highly likely to be condition of interest) t) Broad scope sensitivity (all possible cases) Broad search = All broad + all narrow terms 78 39

40 Narrow vs. Broad Example Lactic acidosis (SMQ) 79 SMQ Applications Clinical trials Where safety profile is not fully established, use multiple SMQs on routine basis as screening tool Selected SMQs to evaluate previously identified issue (pre-clinical data or class effect) Postmarketing Selected SMQs to retrieve cases for suspected or known safety issue Signal detection (multiple SMQs employed) Single case alerts Periodic reporting (aggregate cases for safety and other issues, e.g., lack of efficacy) 40

41 Practical Applications of SMQs Use of SMQ Depression and suicide/self-injury injury for case identification (FDA s AERS database) Moore TJ, Furberg CD, Glenmullen J, Maltsberger JT, Singh S (2011) Suicidal Behavior and Depression in Smoking Cessation Treatments. PLoS ONE 6(11): e doi: /journal.pone Use of SMQ Convulsions for case identification (Spanish FEDRA database, EudraVigilance, and VigiBase) Lertxundi U, et al. Antipsychotics and seizures: Higher risk with atypicals? Seizure: Eur J Epilepsy (2012), 81 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 82 41

42 Customized Searches Ad Hoc Queries Need medical knowledge Need knowledge of structure and characteristics of MedDRA and of your data Refer to the MedDRA Data Retrieval and Presentation: Points to Consider document for query construction tips Save query for future use; maintenance needed for MedDRA version changes Consider submitting ad hoc query to MSSO via change request for possible development as an SMQ 83 Browser Demonstration ti SMQ View 42

43 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) Learned about customized searches 85 Web site MSSO Contacts Telephone International AT&T Toll Free: Direct Dial (USA): Fax (USA)