Perspective: E2B transmission

I2B(M) Information about the safety report itself A.1 Report identification A.2 Primary source of information A.3.1 Who sends the information A.3.2 Who receives it Case information B.1 Patient characteristics B.2 Adverse reaction/event B.3 Investigation test and procedures B.4 Information about drugs (both suspect and concomitant) B.5 Narrative case summary and further information 2

ICH E2B(M) Guideline Patient Characteristics (B.1) Structured info relevant medical history (B.1.7.1) Relevant past drug history indication (B.1.8) Reported cause(s) of death (B.1.9.2) Autopsy-determined cause(s) of death (B.1.9.4) Relevant medical history parent (B.1.10.7) Relevant past drug history/parent indication (B.1.10.8) 3

ICH E2B(M) Guideline ICH ICSR Section Reaction(s) (B.2) Reaction in MedDRA terminology (B.2.i.1) ICH ICSR Section Tests and Procedures (B.3) Tests/investigation of the patient (B.3.1) ICH ICSR Section Drug(s) Information (B.4) Indication for use in the case (B.4.k.11) Which reaction(s) recurred? (B.4.k.17.2) ICH ICSR Section Narrative case summary (B.5) Sender s reclassification of reaction (B.5.3) 4

ICH EDI Coordination M2 (ESTRI) - the transport vehicle and format definitions M1 Medical Terminology Regulatory Authority Pharmaceutical Company E2b Clinical Safety Data Management: Content of Report 5

Regulatory Communications Goal EU FDA MHW INTERNATIONAL STANDARDS EFPIA PhRMA JPMA INDUSTRY 6

Coding with MedDRa

System Organ Classes Blood and lymphatic Cardiac Congenital, familial and genetic Ear and labyrinth Endocrine Eye Gastrointestinal General and administration site conditions Hepatobiliary Immune Infections and infestations Injury, poisoning and procedural complications Investigations Metabolism and nutrition Musculoskeletal and connective tissue Neoplasms benign, malignant and unspecified (incl cysts and polyps) Nervous Pregnancy, puerperium and perinatal conditions Psychiatric Renal and urinary Reproductive and breast Respiratory, thoracic and mediastinal Skin and subcutaneous tissue Social circumstances Surgical and medical procedures Vascular 8

A Multi-Axial Terminology (cont) Primary SOC SOC = Cardiac SOC = Psychiatric SOC = Nervous SOC = Congenital, familial and genetic SOC = Musculoskeletal and connective tissue HLGT = Congenital cardiac HLT = Congenital cardiac valve HLGT = Cognitive and attention and disturbances HLT = Mental retardations HLGT = Mental impairment HLGT = Musculoskeletal and connective tissue congenital HLT = Musculoskeletal and connective tissue of face, neck and jaw congenital PT = Rubinstein-Taybi syndrome 9

A Multi-Axial Terminology (cont) 10

Legacy Data Conversion Comparing Verbatim to Coded Term Approach Verbatim (R) knee effusion MedDRA PT (based on verbatim) Orig coded term (COSTART) MedDRA PT (based on orig COSTART term) Joint effusion ARTHROSIS Osteoarthritis Common cold Nasopharyngitis INFECTION Infection Periorbital edema Seasonal allergies Periorbital oedema Seasonal allergy FACE EDEMA ALLERGIC REACTION Face oedema Hypersensitivity Skin injury Skin injury SKIN DISORDER Skin disorder 11

Legacy data to MedDRA VERBATIM COSTART PT COSTART BODY SYSTEM abnormal liver liver function tests digestive enzymes abnormal abnormal bone marrow depression hematologic and marrow findings lymphatic pseudolymphoma lymphoma like hematologic and reaction lymphatic proteinuria albuminuria metabolism and nutrition bilateral knee swelling edema metabolism and nutrition ards respiratory distress syndrome respiratory MEDDRA PT MEDDRA SOC liver function tests nos investigations abnormal biopsy bone marrow investigations abnormal pseudo lymphoma neoplasms benign, malignant and unspecified (incl cysts and polyps) proteinuria investigations joint swelling acute respiratory distress syndrome musculoskeletal and connective tissue respiratory, thoracic and mediastinal blood blister vesiculobullous rash skin blood blister injury, poisoning and procedural complications (p) skin and subcutaneous tissue (s) abnormal hair growth hair disorder skin hair growth abnormal skin and subcutaneous tissue all over body rash rash skin rash generalised skin and subcutaneous tissue central artery occlusion retinal artery occlusion special senses retinal artery occlusion eye (p) (s) red urine urine abnormality urogenital chromaturia renal and urinary 12

NARRATIVE #1 A 75-year-old male developed anginal pain on 21 Feb 2017 resulting in hospitalization while enrolled in a randomized, open-label study. The patient s medical history is significant for triple bypass graft surgery 2014, postural hypotension and stage D prostate carcinoma. On 26 Feb 2017, the patient underwent percutaneous transluminal coronary angioplasty with stent placement in the right coronary and proximal left anterior descending arteries. 13

NARRATIVE #1 A 75-year-old male developed anginal pain on 21 February 2017 resulting in hospitalization while enrolled in a randomized, open-label study. The patient s medical history is significant for triple bypass graft surgery 2014, postural hypotension and stage D prostate carcinoma. On 26 February 2017, the patient underwent percutaneous transluminal coronary angioplasty with stent placement in the right coronary and proximal left anterior descending arteries. 15

New terms and re-coding Reported event 10.0 10.1 GVHD (?) GVHD skin GVHD liver GVHD intestine GVHD (as a whole). No diferentiation. Undetermined Skin Liver Intestine 16

New terms and re-coding Reported event 10.0 10.1 GVHD (?) GVHD skin GVHD liver GVHD intestine GVHD (as a whole). No diferentiation. Undetermined Skin Liver Intestine 17

Version update v18.0 v18.1 v19.0 v19.1 v20.0 2 MedDRA versions per year (March and September) Study A data lok Study B data lock Integrated analysis: MedDRA v20.0 Study C data lock Pharmacovigilance 18

Analysis and SMQs

Data Retrieval PTC : Multi-Axiality SOC Hepatobiliary Blood and lymphatic Renal and urinary Skin and subcutaneous tissue PT Autoimmune hepatitis Coombs positive haemolytic anaemia Nephritis allergic Stevens-Johnson syndrome 20

Data Retrieval PTC : Multi-Axiality SOC HLGT HLT PT Hepatobiliary Hepatic and hepatobiliary Hepatocellular damage and hepatitis NEC Autoimmune hepatitis Blood and lymphatic Haemolyses and related conditions Anaemias haemolytic immune Coombs positive haemolytic anaemia Renal and urinary Nephropathies Glomerulonephritis and nephrotic syndrome Nephritis allergic Skin and subcutaneous tissue Epidermal and dermal conditions Bullous conditions Stevens-Johnson syndrome 21

HLT Bullous conditions Acquired epidermolysis bullosa Application site vesicles Benign familial pemphigus Blister Blood blister Bullous impetigo Cervical bulla Dermatitis bullous Dermatitis herpetiformis Diabetic bullosis Epidermolysis Epidermolysis bullosa Erythema multiforme Herpes gestationis Implant site vesicles Infusion site vesicles Injection site vesicles Linear IgA disease Lip blister Oculomucocutaneous syndrome Paraneoplastic pemphigus Pemphigoid Pemphigus Penile blister Porphyria non-acute Pseudoporphyria Staphylococcal scalded skin syndrome Stevens-Johnson syndrome Toxic epidermal necrolysis 22

HLT Exfoliative conditions Application site exfoliation Dermatitis exfoliative Dermatitis exfoliative generalised Exfoliative rash Eyelid exfoliation Implant site desquamation Injection site desquamation Keratolysis exfoliativa acquired Keratolysis exfoliativa congenital Nikolsky's sign Recall phenomenon Skin exfoliation Infusion site desquamation 24

Data Retrieval PTC : Multi-Axiality SOC HLGT HLT PT Immune Autoimmune Hepatic autoimmune Blood autoimmune Autoimmune hepatitis Coombs positive haemolytic anaemia Allergic conditions Allergic conditions NEC Nephritis allergic Stevens-Johnson syndrome 26

Data Retrieval PTC : Multi-Axiality SOC HLGT HLT PT Hepatobiliary Hepatic and hepatobiliary Hepatocellular damage and hepatitis NEC Autoimmune hepatitis SOC PT Blood and lymphatic Haemolyses and related conditions Anaemias haemolytic immune Coombs positive haemolytic anaemia Hepatobiliary Blood and lymphatic Renal and urinary Autoimmune hepatitis Coombs positive haemolytic anaemia Nephritis allergic Renal and urinary Skin and subcutaneous tissue Nephropathies Epidermal and dermal conditions Glomerulonephriti s and nephrotic syndrome Bullous conditions Nephritis allergic Stevens-Johnson syndrome Skin and subcutaneous tissue Stevens-Johnson syndrome SOC HLGT HLT PT Immune Autoimmune Hepatic autoimmune Autoimmune hepatitis Blood autoimmune Coombs positive haemolytic anaemia Allergic conditions Allergic conditions NEC Nephritis allergic Stevens-Johnson syndrome 27

Querying through multiaxiality Nervous Vascular Central nervous haemorrhages and cerebro accidents Central nervous NEC Cerebrovas cular venous and sinus thrombosis Transient cerebro events Traumatic central nervous haemorrhages and spinal necrosis and insufficiency Cerebral infarction Transient ischaemic attack embolism and thrombosis Cerebral artery embolism Cavernous sinus thrombosis Nervous haemorrhagic Intraventricular haemorrhage Traumatic intracranial haemorrhage and spinal NEC disorder 29

Nervous Vascular Central nervous haemorrhage s and cerebrovascul ar accidents Central nervous NEC Cerebrov ascular venous and sinus thrombo sis Transient cerebro events Traumatic central nervous haemorrhag es Nervous Vascular Central nervous haemorrhage s and cerebrovascul ar accidents Central nervous NEC Cerebrov ascular venous and sinus thrombo sis Transient cerebro events Traumatic central nervous haemorrhag es and spinal necrosis and insufficiency Cerebral infarction Transient ischaemic attack and spinal necrosis and insufficiency Cerebral infarction Transient ischaemic attack embolism and thrombosis Cerebral artery embolism Cavernous sinus thrombosi s embolism and thrombosis Cerebral artery embolism Cavernous sinus thrombosi s Nervous haemorrhagic Intraventricular haemorrhage Traumatic intracranial haemorrhage Nervous haemorrhagic Intraventricular haemorrhage Traumatic intracranial haemorrhage and spinal NEC Cerebrovascul ar disorder and spinal NEC Cerebrovascul ar disorder Nervous Vascular Central nervous haemorrhage s and cerebrovascul ar accidents Central nervous NEC Cerebrova scular venous and sinus thrombosis Transien t cerebro events Traumatic central nervous haemorrhag es Nervous Vascular Central nervous haemorrhage s and cerebrovascul ar accidents Central nervous NEC Cerebrov ascular venous and sinus thrombo sis Transient cerebro events Traumatic central nervous haemorrhag es and spinal necrosis and insufficiency Cerebral infarction Transient ischaemic attack and spinal necrosis and insufficiency Cerebral infarction Transient ischaemic attack embolism and thrombosis Cerebral artery embolism Cavernous sinus thrombosis embolism and thrombosis Cerebral artery embolism Cavernous sinus thrombosi s Nervous haemorrhagic Intraventricular haemorrhage Traumatic intracranial haemorrhage Nervous haemorrhagic Intraventricular haemorrhage Traumatic intracranial haemorrhage and spinal NEC Cerebrovascul ar disorder and spinal NEC Cerebrovascul ar disorder 34

SENSITIVITY / SPECIFICITY Cases of viral hepatitis in a hospital Selection of patients with transaminases > twice the normal value (very sensitive but not specific, too many cases, false positive present) Selection of patients with transaminases > 1000 UI (very specific, but not sensitive, cases lost, false negative present) 38

Acute Renal Failure 39

Hierarchy Example 40

Hierarchy Example 41

MedDRA Update Gaithersburg, MD 29 September 2017

MedDRA Users Profile As of August 2017 ~5,000 Subscribing organizations (MSSO+JMO) 109 Countries Graph shows type of organizations (self identified) 43

MedDRA Users by Region and Top 20 Countries 44

2017 MedDRA Subscription Rate Table Note: 76% of all MedDRA users pay no fee or $724 (or less) 45

Implemented Changes in MedDRA 46 0 1000 2000 3000 4000 5000 6000 7000 8000 9000 2.2 2.3 2.4 3.0 3.1 3.2 3.3 4.0 4.1 5.0 5.1 6.0 6.1 7.0 7.1 8.0 8.1 9.0 9.1 10.0 10.1 11.0 11.1 12.0 12.1 13.0 13.1 14.0 14.1 15.0 15.1 16.0 16.1 17.0 17.1 18.0 18.1 19.0 19.1 20.0 Rejected Implemented