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

EMA’s Important Medical Events

Topic for later presentation at this meeting

Thank you

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

Thank you

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

Thank you!

Sabine Bayle

Medical Data Quality and Tools Project Manager

Claudine Gontier

Medical Data Coding Project Manager

Servier

Topic 1: Ontological thesaurus

Topic 2: How do we use MedDRA to carry out medical

data cleaning

Topic 1

Ontological thesaurus

Semiologic thesaurus Clinical Knowledge

For human consultation

Semiological Ontology Artificial intelligence

For IT purposes Guidelines

MedDRA Terms selection-Points to consider for multiple diagnosis

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 »

A dropdown list of medical conditions is available:

The MetaDRA interface

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

Thank you for your attention!