SOC - MedDRA

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.
2
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
5
Product Life Cycle: Where MedDRA is Spoken
Drug Discovery
&
Pharmaceutical
Development
Preclinical
Testing
Phase I
Phase II
6
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.
7
Scope of MedDRA
OUT
Not a drug
dictionary
Patient
demographic
terms
Clinical trial study
design terms
IN
Frequency qualifiers
Diseases
Diagnoses
Signs
Symptoms
Therapeutic indications
Investigation names &
Numerical values for
qualitative results
results
Medical & surgical procedures
Medical, social, family history
Medication errors
Product quality, device issues
Severity descriptors
Terms from other
terminologies
Not an equipment, device,
diagnostic product dictionary
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)
MedDRA Version 15.0
9
9
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
10
Examples of LLTs
SOC = Cardiac disorders
HLGT = Cardiac arrhythmias
HLT = Rate and rhythm disorders NEC
PT = Arrhythmia
LLT
Arrhythmia
NOS
LLT
Dysrhythmias
LLT
Arrhythmia
LLT (Non-current)
Other specified cardiac
dysrhythmias
11
11
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
12
12
A Multi-Axial Terminology (cont)
SOC = Respiratory, thoracic and
mediastinal disorders
HLGT = Respiratory tract
infections
SOC = Infections and
infestations
HLGT = Viral infectious
disorders
HLT = Viral upper respiratory
tract infections
HLT = Influenza viral
infections
PT = Influenza
13
13
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
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:
1st: Congenital, familial and genetic
disorders
2nd: Neoplasms benign, malignant and
unspecified (incl cysts and polyps)
3rd: Infections and infestations
15
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
16
MedDRA Maintenance
• Twice yearly official updates
– 1 September X.1 release (Simple changes only)
– 1 March X.0 release (Complex and simple
changes)
17
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.
18
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
Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER
19
Exercise
20
What Term to Select?
• Unintended overdose, dispensing error
Accidental overdose?
Adverse event?
Drug dispensing error?
Medication error?
21
What Term to Select?
• Headache + drowsiness; diagnosis =
ruptured cerebral aneurysm
Headache?
Drowsiness?
Aneurysm ruptured?
Ruptured cerebral aneurysm?
Combination of terms?
22
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
23
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
24
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
25
Exercise
26
What’s The Frequency?
Reported event
(% subjects)
Hyperglycemia (4.1)
MedDRA Version 15.0
PT
(% subjects)
SOC
(% subjects)
Hyperglycaemia (4.1)
Metabolism and
nutrition disorders (4.1)
Increased blood sugar (2.7) Blood glucose
increased (6.4)
Glucose increased (2.2)
Investigations (6.4)
Blood glucose was high
(1.0)
Increasing glucoses (0.5)
27
27
What’s the Safety Problem with
My Drug?
Adverse Event (MedDRA v15.0)
25 mg MyDrug
(N=44)
SOC Investigations
Placebo
(N=15)
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
28
28
What’s the Safety Problem with
My Drug? (cont)
Adverse Event (MedDRA v15.0)
25 mg MyDrug
(N=44)
SOC Investigations
Placebo
(N=15)
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
29
29
What’s the Safety Problem with My Drug?:
Use of Grouping Terms
Adverse Event (MedDRA v15.0)
25 mg MyDrug
(N=44)
SOC Investigations
Placebo
(N=15)
13 (29.5%)
2 (13.3%)
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
HLT Liver function analyses
30
30
Explain What Has Occurred
No. of Events
at PT Level
MedDRA v14.1
Operative haemorrhage
15
Procedural haemorrhage
5
No. of Events
at PT Level
MedDRA v15.0
Operative haemorrhage
0
Procedural haemorrhage
20
31
Explain What Has Occurred
MedDRA v14.1
No. of Events
SOC Respiratory, thoracic and mediastinal
disorders
PT Diaphragmatic hernia
MedDRA v15.0
20
No. of Events
SOC Respiratory, thoracic and mediastinal
disorders
0
SOC Gastrointestinal disorders
PT Diaphragmatic hernia
20
32
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
33
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
34
Primary SOC Graphical Display Example
35
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
36
Exercise
37
Effect of Aspirin on Risk of Death
due to Cancer
Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of cancer
deaths
>5 years’ followup
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.
38
38
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.
39
39
Aspirin and Cancer Death:
Secondary SOC Analysis
Primary Tumor
(Converted to MedDRA v15.0 PT)
No. of
cancer
deaths
>5 years’ followup
HR (95% CI)
p value
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
SOC Blood and lymphatic system
disorders
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
Metastatic neoplasm
36
0.56 (0.09-3.38)
0.53
Neoplasm malignant
93
1.01 (0.51-1.98)
0.98
31
1.28 (0.36-4.54)
0.70
SOC Neoplasms benign, malignant
and unspecified (incl cysts and
polyps)
SOC Renal and urinary disorders
Malignant urinary tract neoplasm
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
37
0.52 (0.20-1.34)
0.17
198
0.68 (0.42-1.10)
0.11
SOC Reproductive system and breast
disorders
Prostate cancer
SOC Respiratory, thoracic and
mediastinal disorders
Lung neoplasm malignant
Adapted from Rothwell et al. Lancet 2011; 377:31-41.
42
42
Use of MedDRA at the FDA
Acknowledgement: Dr. Chuck Cooper, Office of Translational Sciences, CDER, FDA
43
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
44
Connect the DOTSSS!
45
Exercise
46
Let’s build a query for
DEPRESSION!!
47
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
48
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
49
Narrow vs. Broad Example
Lactic acidosis (SMQ)
50
SMQ Narrow Search Results Example
51
SMQ Broad Search Results Example
52
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 (preclinical 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)
53
Use of SMQs at the FDA
Acknowledgement: Dr. Chuck Cooper, Office of Translational Sciences, CDER, FDA
54
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
Exercise
56
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
57
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
58
Acronyms Used
Acronym
ADR
AE
Meaning
Adverse drug reaction
Adverse event
CBER
FDA Center for Biologics Evaluation and Research
CDER
FDA Center for Drug Evaluation and Research
DRP: PTC
FDA
HLGT
Data Retrieval and Presentation: Points to Consider
US Food and Drug Administration
High Level Group Term
HLT
High Level Term
ICH
International Conference on Harmonisation of Technical
Requirements for Registration of Pharmaceuticals for Human
Use
59
Acronyms Used (cont)
Acronym
Meaning
JMO
Japanese Maintenance Organization
LFTs
Liver function tests
LLT
Lowest level term
MedDRA
MSSO
Medical Dictionary for Regulatory Activities
Maintenance and Support Services Organization
NEC
Not elsewhere classified
NOS
Not otherwise specified
PT
Preferred term
SMQ
Standardised MedDRA Query
SOC
System Organ Class
60