What Medical Writers Need to Know about MedDRA · What Medical Writers Need to Know about MedDRA ... HLT Liver function analyses 16 0 ... 36 . Exercise 37

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

6

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.

7

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)

9

MedDRA Version 15.0

9

10

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

11

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

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

12

13

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)

13

14

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

15

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

16

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)

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

19

Acknowledgement: Dr. Toni Piazza-Hepp, Office of Surveillance and Epidemiology, CDER

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)

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)

27 27

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

28 28

What’s the Safety Problem with

My Drug? (cont)

Adverse Event (MedDRA v15.0)

25 mg MyDrug

(N=44)

Placebo

(N=15)


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)

Placebo

(N=15)


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

30 30

Explain What Has Occurred

31

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

32


SOC Respiratory, thoracic and mediastinal disorders

PT Diaphragmatic hernia

20



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

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’ 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.

38 38

Effect of Aspirin on Risk of Death

due to Cancer (cont)

Primary Tumor




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


39 39

Aspirin and Cancer Death:

Secondary SOC Analysis Primary Tumor




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


40 40


Secondary SOC Analysis (cont)

Primary Tumor




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


41 41


Secondary SOC Analysis (cont)

Primary Tumor




HR (95% CI)

p value

SOC Reproductive system and breast disorders

Prostate cancer 37 0.52 (0.20-1.34) 0.17


Lung neoplasm malignant 198 0.68 (0.42-1.10) 0.11


42 42

Use of MedDRA at the FDA

43

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

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

50

Lactic acidosis (SMQ)

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 (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)

53

Use of SMQs at the FDA

54

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

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 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

59

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

60

Documents

What Medical Writers Need to Know about MedDRA · What Medical Writers Need to Know about MedDRA ... HLT Liver function analyses 16 0 ... 36 . Exercise 37