what medical writers need to know about meddra®
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What Medical Writers Need
to Know about MedDRA®
Patricia Mozzicato, MD Chief Medical Officer Judy Harrison, MD Senior Medical Officer MedDRA Maintenance and Support Services Organization (MSSO)
MedDRA® is a registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA)
Disclaimer
• The views and opinions expressed in the following PowerPoint slides are those of the individual presenter and should not be attributed to Drug Information Association, Inc. (“DIA”), its directors, officers, employees, volunteers, members, chapters, councils, Special Interest Area Communities or affiliates, or any organization with which the presenter is employed or affiliated.
• These PowerPoint slides are the intellectual property of the individual presenter and are protected under the copyright laws of the United States of America and other countries. Used by permission. All rights reserved. Drug Information Association, Drug Information Association Inc., DIA and DIA logo are registered trademarks. All other trademarks are the property of their respective owners.
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Disclosure
• Patricia Mozzicato is an employee of Northrop
Grumman Information Systems/MedDRA
MSSO
• Judy Harrison is a consultant with Northrop
Grumman Information Systems/MedDRA
MSSO
• MedDRA MSSO provides MedDRA via
subscription to its users and provides training
and other MedDRA-related services
3
Learning Objectives
• Discuss why a simple listing of MedDRA terms
may not suffice to understand safety data
• Recognize how to ask the right questions of
MedDRA-coded data, such as, should we do a
secondary SOC analysis?
• Describe the structure and characteristics of
MedDRA, how they affect data retrieval, and how
they can help to understand the full safety profile of
a product
4
Workshop Overview
• Review of MedDRA’s scope, structure, rules
• Key aspects of the Data Retrieval and
Presentation: Points to Consider document
• Introduce Standardised MedDRA Queries
(SMQs)
• Apply principles in multiple exercises
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Product Life Cycle: Where MedDRA is Spoken
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Drug Discovery &
Pharmaceutical Development
Preclinical Testing
Phase I
Phase II
Phase III
Marketed Product
Phase IV
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.
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Scope of MedDRA
Diseases Diagnoses
Signs Symptoms
Therapeutic indications Investigation names &
qualitative results Medical & surgical procedures Medical, social, family history
Medication errors Product quality, device issues
Not a drug dictionary
Not an equipment, device, diagnostic product dictionary
Clinical trial study design terms
Patient demographic terms
Frequency qualifiers
Numerical values for results
Severity descriptors
IN
OUT
Terms from other terminologies
8
MedDRA Structure
System Organ Class (SOC) (26)
High Level Group Term (HLGT) (335)
High Level Term (HLT) (1,713)
Preferred Term (PT) (19,550)
Lowest Level Term (LLT) (70,177)
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MedDRA Version 15.0
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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
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HLT = Rate and rhythm disorders NEC
HLGT = Cardiac arrhythmias
SOC = Cardiac disorders
PT = Arrhythmia
LLT
Arrhythmia
LLT
Dysrhythmias
Examples of LLTs
LLT
Arrhythmia
NOS
LLT (Non-current)
Other specified cardiac
dysrhythmias
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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
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SOC = Respiratory, thoracic and mediastinal disorders
HLGT = Respiratory tract infections
HLT = Viral upper respiratory tract infections
HLT = Influenza viral infections
HLGT = Viral infectious disorders
SOC = Infections and infestations
PT = Influenza
A Multi-Axial Terminology (cont)
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Rules for Primary SOC Allocation
• PTs for diseases, signs and symptoms are assigned to prime manifestation site SOC
• Congenital and hereditary anomalies terms have SOC Congenital, familial and genetic disorders as Primary SOC
• Neoplasms terms have SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps) as Primary SOC – Exception: Cysts and polyps have prime manifestation site SOC
as Primary SOC
• Infections and infestations terms have SOC Infections and infestations as Primary SOC
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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
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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
MedDRA Maintenance
• Twice yearly official updates
– 1 September X.1 release (Simple changes only)
– 1 March X.0 release (Complex and simple
changes)
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MedDRA Term Selection:
Points to Consider (MTS:PTC)
• An ICH-endorsed guide for MedDRA users
• Promote accurate and consistent use of MedDRA in coding and exchange of data (ultimately, for “medically meaningful” retrieval and analysis)
• Coding principles and examples such as diagnosis with reported signs/symptoms, medication errors, etc.
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FDA-Defined Coding Errors
• Missed Concepts – 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)
• “Soft Coding”
– Example: “Liver failure” coded as hepatotoxicity or
increased LFTs
– Example: “Rash subsequently diagnosed as Stevens
Johnson syndrome” coded as rash
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Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER
What Term to Select?
• Unintended overdose, dispensing error
Accidental overdose?
Adverse event?
Drug dispensing error?
Medication error?
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What Term to Select?
• Headache + drowsiness; diagnosis = ruptured cerebral aneurysm
Headache?
Drowsiness?
Aneurysm ruptured?
Ruptured cerebral aneurysm?
Combination of terms?
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MedDRA Data Retrieval and Presentation:
Points to Consider
• An ICH-Endorsed Guide for MedDRA users on Data Output
• 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
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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
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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
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What’s The Frequency?
Reported event (% subjects)
MedDRA Version 15.0
PT (% subjects)
SOC (% subjects)
Hyperglycemia (4.1) Hyperglycaemia (4.1) Metabolism and nutrition disorders (4.1)
Increased blood sugar (2.7) Blood glucose increased (6.4)
Investigations (6.4)
Glucose increased (2.2)
Blood glucose was high (1.0)
Increasing glucoses (0.5)
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What’s the Safety Problem with
My Drug? Adverse Event (MedDRA v15.0) 25 mg MyDrug
(N=44)
Placebo
(N=15)
SOC Investigations 13 (29.5%) 2 (13.3%)
PT Aspartate aminotransferase increased 6 0
PT Alanine aminotransferase increased 5 0
PT Gamma-glutamyltransferase increased 4 0
PT Blood creatine phosphokinase increased 2 1
PT Blood alkaline phosphatase increased 2 0
PT Blood glucose increased 1 1
PT Blood lactate dehydrogenase increased 2 0
PT Lipase increased 2 0
PT White blood cell count decreased 2 0
PT Amylase increased 1 0
PT Faecal fat increased 0 1
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What’s the Safety Problem with
My Drug? (cont)
Adverse Event (MedDRA v15.0)
25 mg MyDrug
(N=44)
Placebo
(N=15)
SOC Investigations 13 (29.5%) 2 (13.3%)
PT Blood pressure increased 1 0
PT Blood urea increased 1 0
PT Occult blood positive 1 0
PT Liver function test abnormal 1 0
PT Monocyte count decreased 1 0
PT Protein urine present 1 0
Patients may have more than one event reported
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What’s the Safety Problem with My Drug?:
Use of Grouping Terms
Adverse Event (MedDRA v15.0)
25 mg MyDrug
(N=44)
Placebo
(N=15)
SOC Investigations 13 (29.5%) 2 (13.3%)
HLT Liver function analyses 16 0
HLT Tissue enzyme analyses NEC 4 0
HLT Digestive enzymes 3 0
HLT White blood cell analyses 3 0
HLT Skeletal and cardiac muscle analyses 2 1
HLT Carbohydrate tolerance analyses (incl
diabetes)
1 1
HLT Faecal analyses NEC 1 1
HLT Vascular tests NEC (incl blood pressure) 1 0
HLT Renal function analyses 1 0
HLT Urinalysis NEC 1 0
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Explain What Has Occurred
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MedDRA v14.1 No. of Events
at PT Level
Operative haemorrhage 15
Procedural haemorrhage 5
MedDRA v15.0
No. of Events
at PT Level
Operative haemorrhage 0
Procedural haemorrhage 20
Explain What Has Occurred
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MedDRA v14.1 No. of Events
SOC Respiratory, thoracic and mediastinal disorders
PT Diaphragmatic hernia
20
MedDRA v15.0 No. of Events
SOC Respiratory, thoracic and mediastinal disorders
0
SOC Gastrointestinal disorders
PT Diaphragmatic hernia 20
Overall Presentation of Safety Profiles
• Highlight overall distribution of ADRs/AEs
• Identify areas for in-depth analysis (focused
searches)
• Approaches: full listing of terms to sophisticated
statistical methods
• Standard approach: present by SOC and PTs
– This approach not always optimal due to unique
characteristics of MedDRA
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Overview by Primary SOC
• Use Internationally Agreed Order of SOCs when applicable (see DRP: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
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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
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Effect of Aspirin on Risk of Death
due to Cancer Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer deaths
>5 years’ follow-up
Hazard ratio (95% CI)
p value
SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps)
627 0.62 (0.47-0.82) 0.001
Colorectal cancer 54 0.41 (0.17-1.00) 0.05
Gastric cancer 36 3.09 (0.64-14.91) 0.16
Gastrointestinal carcinoma 24 0.20 (0.04-0.91) 0.04
Haematological malignancy 50 0.34 (0.09-1.28) 0.11
Lung neoplasm malignant 198 0.68 (0.42-1.10) 0.11
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
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Effect of Aspirin on Risk of Death
due to Cancer (cont)
Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer deaths
>5 years’ follow-up
Hazard ratio (95% CI)
p value
Malignant urinary tract neoplasm
31 1.28 (0.36-4.54) 0.70
Metastatic neoplasm 36 0.56 (0.09-3.38) 0.53
Neoplasm malignant 93 1.01 (0.51-1.98) 0.98
Oesophageal carcinoma 23 0.43 (0.11-1.72) 0.23
Pancreatic carcinoma 45 0.25 (0.07-0.92) 0.04
Prostate cancer 37 0.52 (0.20-1.34) 0.17
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
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Aspirin and Cancer Death:
Secondary SOC Analysis Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer deaths
>5 years’ follow-up
HR (95% CI)
p value
SOC Blood and lymphatic system disorders
Haematological malignancy 50 0.34 (0.09-1.28) 0.11
SOC Gastrointestinal disorders 182 0.46 (0.27-0.77) 0.003
Colorectal cancer 54 0.41 (0.17-1.00) 0.05
Gastric cancer 36 3.09 (0.64-14.91) 0.16
Gastrointestinal carcinoma 24 0.20 (0.04-0.91) 0.04
Oesophageal carcinoma 23 0.43 (0.11-1.72) 0.23
Pancreatic carcinoma 45 0.25 (0.07-0.92) 0.04
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
40 40
Aspirin and Cancer Death:
Secondary SOC Analysis (cont)
Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer deaths
>5 years’ follow-up
HR (95% CI)
p value
SOC Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic neoplasm 36 0.56 (0.09-3.38) 0.53
Neoplasm malignant 93 1.01 (0.51-1.98) 0.98
SOC Renal and urinary disorders
Malignant urinary tract neoplasm 31 1.28 (0.36-4.54) 0.70
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
41 41
Aspirin and Cancer Death:
Secondary SOC Analysis (cont)
Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer deaths
>5 years’ follow-up
HR (95% CI)
p value
SOC Reproductive system and breast disorders
Prostate cancer 37 0.52 (0.20-1.34) 0.17
SOC Respiratory, thoracic and mediastinal disorders
Lung neoplasm malignant 198 0.68 (0.42-1.10) 0.11
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
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Use of MedDRA at the FDA
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Acknowledgement: Dr. Chuck Cooper, Office of Translational Sciences, CDER, FDA
Query Strategy Tips
• Define the condition
• Develop inclusion/exclusion criteria
• Good browser is key component
• Search “non multi-axial” and “other/support” SOCs
• Search a term’s “neighbors”, including secondary locations
• Store for future use
• Review for impact of new MedDRA versions
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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
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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
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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)
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Use of SMQs at the FDA
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Acknowledgement: Dr. Chuck Cooper, Office of Translational Sciences, CDER, FDA
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
55
Modified SMQ – Exercise
• SMQ Lack of efficacy/effect often needs to be modified based on the particular characteristics of a product
• Consider how you would create a Modified MedDRA Query based on SMQ Lack of efficacy/effect for:
– An inhaled bronchodilator indicated for use in asthma
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Summary
• In this workshop, we:
– Reviewed MedDRA’s scope, structure, and
characteristics
– Reviewed key aspects of the MedDRA Data
Retrieval and Presentation: Points to Consider
document
– Reviewed key points for developing queries
using MedDRA
– Worked on exercises to illustrate these
principles
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Acronyms Used
Acronym Meaning
ADR Adverse drug reaction
AE Adverse event
CBER FDA Center for Biologics Evaluation and Research
CDER FDA Center for Drug Evaluation and Research
DRP: PTC Data Retrieval and Presentation: Points to Consider
FDA US Food and Drug Administration
HLGT High Level Group Term
HLT High Level Term
ICH International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use
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Acronyms Used (cont)
Acronym Meaning
JMO Japanese Maintenance Organization
LFTs Liver function tests
LLT Lowest level term
MedDRA Medical Dictionary for Regulatory Activities
MSSO Maintenance and Support Services Organization
NEC Not elsewhere classified
NOS Not otherwise specified
PT Preferred term
SMQ Standardised MedDRA Query
SOC System Organ Class
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