MedDRA Term Groupings: Use in clinical, drug safety and ...
Transcript of MedDRA Term Groupings: Use in clinical, drug safety and ...
MedDRA Term Groupings:
Use in clinical, drug safety and regulatory
departments
INTRODUCTION
Christina Winter
GlaxoSmithKline
MedDRA hierarchy
• MedDRA hierarchy:
– SOCs, HLGTs, HLTs and PTs
gather terms below them so could
be considered “groupings”
– LLT is the lowest level and there
are no official MedDRA terms
below LLT
– However some browsers use
synonyms behind the scenes to
aid retrieval (e.g. If synonyms are
used, searching for “hepatic
necrosis” will also retrieve LLT
Liver necrosis.)
Synonym Lists
• Synonym lists
– Some users maintain synonym lists
within their own systems
– linked to LLTs
– aid consistency of coding
– aid the autoencoder function
– need maintenance for each
MedDRA version
Paediatric / Gender Lists
MSSO maintains
• Paediatric adverse event list
• Gender adverse event list
– Intended to improve data quality of adverse event reporting
– May be used in conjunction with database fields
– Unlike SMQs, these lists are not intended to identify a medical condition
or area of interest.
Standardised MedDRA Queries
Standardised MedDRA Queries (SMQs)
– Produced by CIOMS and MSSO collaboration; tested on regulatory and
company databases prior to release
– Maintained by MSSO; guidance available in
– Introductory guide for SMQs
– Data Retrieval and Presentation: Points to Consider
– Intended to identify a medical condition or area of interest
– Recommended by regulatory authorities as first strategy for searching
safety data
– May be applied to signal detection
– Medical review of data retrieved is necessary
– Quality of data retrieved is highly dependent on accurate coding
In-house MedDRA groupings (1)
• Created and maintained by individual users/companies
• Used globally or tailored for product
• Generally topics not covered by SMQs
• Constructed with any level of MedDRA hierarchy, sub-SMQs, modified
SMQs etc
– “Home grown queries”
– In-house searches (MedDRA terms with/without database fields)
– “Drug/Event pairs”
– Refer to group(s) of terms reflecting condition(s) of interest for specified drug
– Incoming data: alert for expedited manual review
– If term coded, alert case handler that special follow up questionnaire is needed
In-house MedDRA groupings (2)
– Grouping terms for labelling
– Narrow list of search terms to aggregate safety data to create labelling (regulatory use)
– Narrow list of terms to interpret labelling
– E.g. “Myocardial infarction” in product label:
PTs Myocardial infarction, Acute myocardial infarction, Post procedural
myocardial infarction, Silent myocardial infarction considered “listed/expected”
– Designated Medical Events (DMEs)
– Grouping of terms reflecting serious medical conditions that are
– typically due to drug
– lead to benefit/risk review
– DME medical concepts include Stevens Johnson syndrome, Aplastic
anaemia, Seizure
E<EMA Important Medical Events list
Identification of serious events in Drug Safety
Christina Winter
GlaxoSmithKline
EMA’s Important Medical Events (IME)
• EMA’s Eudravigilance expert working group created and maintain
IME list
• IME List (PTs) and inclusion/exclusion criteria on EMA Eudravigilance
website
http://eudravigilance.ema.europa.eu/human/textforIME.asp
• Very large list (>7,900 PTs in v19.0)
• Intended as aid to select events of higher priority for
pharmacovigilance
Use by Drug Safety Departments
• Post marketing reports require expedited reporting if they are serious
• Serious includes regulatory serious criteria and “medically serious” if
none of the regulatory serious criteria applied to the case
• Post marketing reports from any source; reporter may not be
healthcare professional
• Medically serious judgement varied between drug safety physicians
• For consistency of “medically serious”, drug safety departments may
apply a medically serious list in the database.
• In addition to expedited reporting, list may be applied to periodic
reports (separating non-serious from serious)
Use by Drug Safety Departments
• GSK initially maintained its own list
• High maintenance effort
• Always of interest in audits by regulatory agencies (who may have different
opinions on terms selected)
• GSK now uses the entire IME list
• Adds a few terms that are specifically required for vaccine expedited reporting
(e.g. Vaccination failure)
• Simpler (only need to maintain vaccine list)
• Less likely to have queries in regulatory audits
• Other companies remove terms from the IME list
• Requires maintenance
MedDRA User Group Meeting Hamburg April 5, 2016
Carol-Ann Wilson
EMA Important Medical Event list for the identification of serious adverse events in clinical studies
Scope of IME list
MedDRA User Group meeting• 5 April 2016 Page 2
• A serious adverse event is any untoward medical occurrence in clinical studies
that:
1. Results in death
2. Is life-threatening
3. Requires in-patient hospitalization or prolongation of existing hospitalization
4. Results in persistent or significant disability or incapacity
5. Is a congenital anomaly or birth defect
6. Is another medically important serious event as judged by the investigator, i.e.
may not be immediately life-threatening or result in death or hospitalization
but may jeopardize the patient or may require intervention to prevent one of
the other outcomes listed in the definitions above
• The IME list includes MedDRA PTs that represent these outcomes. It is quite
broad because it also intends to cover the last outcome category
Use of IME list in clinical studies
MedDRA User Group meeting• 5 April 2016 Page 3
• The IME list is provided and maintained by the EMA and was created to facilitate
the seriousness classification of suspected adverse reactions and to support
aggregated data analysis and case assessment in day to day pharmacovigilance
activities of stakeholders in the EU
• Consistent classification of seriousness of adverse events/reactions is
difficult to achieve when relying on Investigator assessment alone
• It has a guidance purpose only and is not a mandatory requirement for
seriousness assessment and regulatory reporting. Thus, organizations have the
option to use it for their purposes depending on their individual needs
• Within Bayer, the IME list is used in clinical trials to support the medical review
process in terms of consistency of the seriousness definition of adverse events
Use of IME list in clinical studies Process (1)
MedDRA User Group meeting• 5 April 2016 Page 4
• The IME list can be adapted on a project and study level by excluding PTs that
are already covered by e.g. study inclusion criteria or study endpoints
• The IME list with justification for exclusion of specific PTs is attached to the
Medical Review Plan and has to be approved by the responsible medical
experts in Clinical and Drug Safety
• The Study Data Manager regularly runs an IME based macro on non-serious
AEs and provides listings of potentially serious AEs that were identified by the
(adapted) IME list
• An additional tab identifies excluded PTs in the study
• A complementary medical history listing will provide information about medical
history findings that have the same MedDRA PT assignment as the listed AEs
for the relevant patients
• Another tab lists all documented AEs for the respective patients with grading/
severity information
Process: Use of IME list in clinical studies (2)
MedDRA User Group meeting• 5 April 2016 Page 5
• The Study Medical Expert regularly performs the medical review of the listing of
potentially serious AEs
• After each review, queries to the Investigator are raised for the upgrading of
non-serious AEs to serious AEs, where medically appropriate
• A listing with the acceptable non-serious adverse events is sent back to the
Study Data Manager
• Any further created report will be up-to-date concerning latest comments by
Study Medical Expert
• The creation of the IME derived listing will be cumulative. New records will be
highlighted and AEs classified as serious will be removed
• The Study Medical Expert evaluates the Investigator’s response and either
closes the query or posts a re-query
• If the site disagrees with the upgrading, the adverse event will remain
classified as non-serious
Process: Use of IME list in clinical studies (3)
MedDRA User Group meeting• 5 April 2016 Page 6
• New versions of the IME list are implemented in each study when a new
MedDRA version is released into production
• All processes will be run for all subjects as described before, based on the
new version of the IME list
• If a query was posted before implementation of the new version of the IME list,
the query will not be withdrawn
• If the Investigator has classified an AE as serious based on a previous version
of the IME list but the PT has been removed from its new version, the previous
classification will not be re-queried or revised
• The process is iterative until study completion and all queries are resolved
• Study Medical Expert confirms the final status of the IME derived listing as part of
the confirmation of completion of medical review
• Any non-serious AE that is upgraded to an SAE near data base closure will
require SAE reconciliation macros to be re-run
Process: Use of IME list in clinical studies (4)
MedDRA User Group meeting• 5 April 2016 Page 7
Subject
Number Investigator verbatim
Real
No.
(Diff.
since
09FEB
2016)
EudraVigilance Important
Medical Event (IME) Term
(MedDRA PT)
Clinical
Trial
Number Country
Trial
unit
number
To
be
queri
ed
Comments
Queries
180060002 LIVER INJURY 1(0) Liver Injury 15626 POLAND 18006 Y It was non serious adverse event
180090016 HEART FAILURE WORSENING 1(0) Cardiac Failure 15626 POLAND 18009 Y this is not serious AE
300030003
EPIDERMOID CARCINOMARIGHT
CHEST 1(0) Squamous Cell Carcinoma Of Skin 15626
NETHERL
ANDS 30003 Y
no serious, It was operable and
no further treatment is necessary
400010002 BCC LEFT INFRACLAVICULAR 1(+1) Basal Cell Carcinoma 15626
AUSTRALI
A 40001
420030004 THORACIC TRAUMA 1(0) Chest Injury 15626
PORTUGA
L 42003 Y REPLY is PENDING
560040002 GASTRIC ULCER 1(0) Gastric Ulcer 15626
SOUTH
KOREA 56004 Y confirmed not serious
820110005
CRUSHING INJURY OF THE
FIFTH FINGER OF THE RIGHT
HAND 1(0) Limb Crushing Injury 15626 ROMANIA 82011 Y
"""We confirm that the event was
not serious. It was an accidental
injury of the finger which did not
require hospitalization."
890040004 HYPERTENSION CRISIS 1(+1) Hypertensive Crisis 15626 SERBIA 89004
710050010 UPPER GI BLEEDING 1(0)
Upper Gastrointestinal
Haemorrhage 15626 THAILAND 71005 Y Confirmed this event is not SAE.
400040004 PULMONARY ASPERGILLOSIS 1(0) Bronchopulmonary Aspergillosis 15626
AUSTRALI
A 40004 Y
Further investigator review
determined to be Not Serious
Sabine Bayle
Medical Data Quality and Tools Project Manager
Claudine Gontier
Medical Data Coding Project Manager
Servier
Topic 1
Ontological thesaurus
Semiologic thesaurus Clinical Knowledge
For human consultation
Semiological Ontology Artificial intelligence
For IT purposes Guidelines
Inspection findings
Major findings regarding 5 adverse events (on > 17000 AEs) where a symptom was not coded
330 000 AEs in our clinical trials
3 300 PT used in these studies
756 PT corresponding to 80% of AEs
490 PT diagnosis
90 medical concepts
Adverse events in our Clinical database
Semiologic thesaurus
10 medical areas represented
including 3 principal ones:
-Cardiovascular
-Psychiatry
-Neurology
90 Medical Concepts (diagnosis )
2248 characteristic signs
and symptoms (PT)
Semiologic Thesaurus
Medical condition Not to be coded in addition to the corresponding medical condition Bradycardia • Heart rate decreased
• Dizziness • Thoracic discomfort/pain • Asthenia (weakness), fatigue, malaise
Today we have 90 medical conditions with characteristic signs/symptoms NOT to be coded in addition to the medical condition if reported as part of a verbatim by investigator
9
From Thesaurus to Ontology
Creation of an Ontology structured database with links between Diagnosis PT and their main Signs and Symptoms PT
Aortic valve
stenosis
Dyspnoea on effort
Angina on exercise
Systolic murmur
Syncope exertional
Palpitation
Aortic valve calcification
Left ventricular
hypertrophy
Text Mining reminder
Reported Terms Split coded Terms by Text Mining
ATRIAL FIBRILATION / DISPNEA, PALPITATION / WHEN TACHIACARDIA (ATRIAL FIBRILATION ) PERSISTED, A PATIENT FELT PALPITATION SO HE CAME TO THE HOSPITAL
PTcod1 : ATRIAL FIBRILLATION PTcod2 : DYSPNOEA PTcod3 : PALPITATIONS PTcod4 : TACHYCARDIA
Medical Concept1, MC2, MC3, MC4
Reported Terms Split Coded Terms by Text Mining
PT1, PT2, PT3, PT4
Each medical concept of a reported adverse event is coded Splitting methodology (not recommended !)
Text mining to Ontology
Medical Concept1, MC2, MC3, MC4
Reported Terms Split Coded Terms by Text Mining
PT1, PT2, PT3, PT4
PT1, PT4
Ontology
Recommended
Diagnosis: Bradycardia
S&S: blurred vision and dizziness
Bradycardia/ 10006093 Blurred vision / 10005886
CODING
Today Manual selection of terms to be coded with help of thesaurus
Tomorrow Identification of medical concepts
(Text mining) Translation of all detected terms
(Medical ontology) Selection of terms to be coded
How did we fill in the « MetaDRA » ?
Translated the 90 medical conditions from the semiologic thesaurus into MedDRA terms to supply the MetaDRA database.
Semiological ontology: « MetaDRA »
Medical concept:
The Diagnosis LLT are the
codes that are considered as medical concepts.
Any characteristic sign or symptom reported in a verbatim would not be coded in addition
The MetaDRA interface
Topic 2 How do we use MedDRA in our daily work
in addition to our coding activities?
Medical data cleaning
The medical data cleaning is set up by our department in order to detect potential medical inconsistencies in the clinical trials database using automated and manual checks.
Medical data cleaning
Checks developed for: •AEs, medical and surgical histories, •Previous and concomitant medications, •biological data and vital signs.
And run on MedDRA lists of codes.
Medical data cleaning
Medical data cleaning
Liver disorder
Patient number Country Center
Patient identification Type of control Discrepancy message
Detection date Satuts Comments
1646 40 402 40040201646 AE_X PT ‘Liver disorder' is a vague PT and has to be checked 06NOV2015
Coding process
Liver disorder
Medical data cleaning
Patient number Country Center
Type of control Event number Discrepancy message
Detection date Satuts Comments
1717 112 4005 MR_AE_04_S
TD E01
The event is not related to study drug but the action taken regarding study drug is Dose
increased 06NOV2015
Medical data cleaning
Patient number
Patient identification Type of control
Disease verbatim PT code Discrepancy message
Detection date Satuts Comments
1717 400501717 MR_MH_05_STD Type 2
diabetes
Type 2 diabetes mellitus
This event is reported as treated but there is no corresponding treatment reported 06NOV2015
Type 2 diabetes mellitus
Drugs used in diabetes
Inconsistency
‘Not real’
Inconsistency
‘Real’
No query
needed
Change
code
List of codes
Not correct
or
DB error
Resolved
internally
Wait + comments
No query
Explanation
Query
already sent
+ open
Query
already answered
New
Wait Check if
new query needed
+/- Sent
Sent No action
Needed + comments
No query Query Sent
Review and handling of discrepancies
No action
Needed + comments
NEW Discrepancy
22
Step1: Verify if medical history reported in eCRF No MH
Step2: Issue a query in eCRF
Step3: Change status of discrepancy once query issued
Medical validation cleaning Example : Coherence between hematology and MH pages
Discrepancy message: « The HEMOGLOBIN(37 g/L) is less than 90 g/L but no corresponding
medical history is reported »
For hemoglobin values below 90g/l in eCRF. Check presence of medical history using MedDRA list of codes
Step 4: Query answer reporting error. Data corrected in eCRF by investigator
Step5: discrepancy closed automatically
Medical validation cleaning Example : Coherence between hematology and MH pages
STUDY COUNTRY CENTRE
PATIENT
IDENTIFICA
TION VISIT BIOP COMMENTS
STATUSME
D PANEL COMSTAT
10 76 525 4198 M000 HGB
The HEMOGLOBIN (37g/L) is
less than 90g/L but no
corresponding medical history
is reported CLOSED HEM1VAL Q sent
How we deal with Important Medical Events (IME)
EMA provides a list of MedDRA codes (Preferred Terms) called Important Medical Events
Non serious Adverse events coded with a PT from the IME list have to be reviewed according to predefined seriousness upgrade rules.
Any AE that is upgraded is transferred to the pharmacovigilance for declaration purposes
IME Process
IME PT ?
medical
review
Upgrade rules criteria
Criteria fulfilled
Missing data
Clinical Data Base
Yes
Wait
No
PV DB
interface
AE1
Trip
arti
te
me
eti
ng
Criteria not
fulfilled
Yes No
AE2
AE3
AE1