THE WHAT AND WHY OF Med DRA Samina

THE WHAT AND WHY OF Med. DRA Samina Qureshi, M. D. PSI INTERNATIONAL, Inc Proprietary and Confidential – All Rights Reserved – PSI International

Med. DRA Medical Dictionary for Regulatory Activities § The drug and biologic Industry uses the terminology in its clinical trial data and safety databases for collection of adverse events. § Clinically validated international medical terminology used by regulatory authorities and the regulated biopharmaceutical industry through the entire regulatory process, from pre-marketing to post-marketing; and for data entry, retrieval, evaluation and presentation. Proprietary and Confidential – All Rights Reserved – PSI International

Safety Reporting Regulations § Postmarketing drugs § Generic drugs § Therapeutic biologics § “Grandfather” drugs (pre 1938) § IND Safety reports, NDA/BLA report Proprietary and Confidential – All Rights Reserved – PSI International

FDA Guidance for Industry Premarketing Risk Assessment § “Because individual investigators may use different terms to describe a particular adverse event, FDA recommends that sponsors ensure that each investigator’s verbatim terms are coded to standardized, preferred terms specified in a coding convention or dictionary. Proper coding allows similar events that were reported using different verbatim language to be appropriately grouped. Consistent and accurate coding of adverse events allows large amounts of data regarding these events to be analyzed and summarized and maximizes the likelihood that safety signals will be detected… § In general, FDA suggests that sponsors use one coding convention or dictionary (e. g. , Med. DRA) throughout a clinical program…” Proprietary and Confidential – All Rights Reserved – PSI International

FDA Guidance for Industry Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment § “FDA suggests that sponsors initially evaluate a signal generated from postmarketing spontaneous reports through a careful review of the cases and a search for additional cases. Additional cases could be identified from the sponsor’s global adverse event databases, the published literature, and other available databases, such as FDA’s Adverse Event Reporting System (AERS)…, using thorough database search strategies based on updated coding terminology (e. g. , the Medical Dictionary for Regulatory Activities (Med. DRA). When available, FDA recommends that standardized case definitions …” Proprietary and Confidential – All Rights Reserved – PSI International

Med. DRA If current trends are followed, this may also be mandated for the tobacco industry. Proactively: Good terminology to compile and analyze health data. Is medically validated and allows consistent, standardized application for capture of both health effects AND Product quality issues. Implementation with internal coding guidelines will leave little room for “soft coding”. Proprietary and Confidential – All Rights Reserved – PSI International

Scope: Med. DRA Covers. . . § § § § Signs and symptoms Disease Diagnosis Therapeutic indications Name and qualitative results of investigations and lab results Medical, social, family history, and risk factors Surgical and Medical procedures Proprietary and Confidential – All Rights Reserved – PSI International

Applications of Med. DRA § To report ADRs/AEs, to capture and present product indications, investigational results and patient history § To aggregate reported terms in medically meaningful groupings for reviewing, analyzing, summarizing and communicating safety data § To enable consistent retrieval of specific cases or medical conditions from a database and to identify their frequencies § To facilitate electronic data exchange Proprietary and Confidential – All Rights Reserved – PSI International

Med. DRA: Basic Structure § Standardized terminology: • 5 -level Hierarchy • Multiaxiality • Granularity § Retrieval groupings: • Standardized Med. DRA Queries (SMQ) Proprietary and Confidential – All Rights Reserved – PSI International

Structure Overview Med. DRA (version 19. 0) SOC 27 System Organ Class HLGT 335 High Level Group Term HLT 1, 732 High Level Term PT SMQ Standard Med. DRA Queries 21, 920 Preferred Term LLT 75, 818 Low Level Term Proprietary and Confidential – All Rights Reserved – PSI International 10

Structure Overview Med. DRA (version 11. 1) SOC 26 System Organ Class HLGT 332 High Level Group Term HLT 1, 699 High Level Term SMQ PT Standard Med. DRA Queries Preferred Term LLT Low Level Term Proprietary and Confidential – All Rights Reserved – PSI International 18, 483 67, 195

System Organ Class (SOC) § Top level of hierarchy, the broadest concept of standardized terminology, used for data grouping § SOCs may reflect: - anatomical functional body systems - etiology (Infections and infestations SOC), - purpose (Surgical and medical procedures SOC) Proprietary and Confidential – All Rights Reserved – PSI International

27 System Organ Classes (SOCs) § Blood and lymphatic system disorders § Cardiac disorders § Congenital and familial and genetic disorders § Ear and labyrinth disorders § Endocrine disorders § Eye disorders § Gastrointestinal disorders § General disorders and administration site conditions § Hepato-biliary disorders § Infections and infestations § Immune system disorders § Injury, poisoning and procedural complications § Investigations § Metabolism and nutrition disorders § Neoplasms benign, malignant and unspecified (including cysts and polyps) § Nervous system disorders § Pregnancy, puerperium and perinatal conditions Product issues § Psychiatric disorders § Renal and urinary disorders § Reproductive system and breast disorders § Respiratory, thoracic and mediastinal disorders § Musculoskeletal and connective tissue disorders § Skin and subcutaneous tissue disorders § Social circumstances § Surgical and medical procedures § Vascular disorders Proprietary and Confidential – All Rights Reserved – PSI International

High Level Group Term (HLGT) § HLGTs are broad levels of terminology directly under a SOC and composed of HLTs § HLGTs group related HLTs by anatomy, pathology, physiology, etiology or function § HLGTs are used for data retrieval, presentation and analysis Proprietary and Confidential – All Rights Reserved – PSI International

High Level Term (HLT) § HLT is directly under the HLGT and above the PT § An HLT groups related PTs by anatomy, pathology, physiology, etiology or function The HLT level represents medical entities which are detailed by the distinct, unique concepts expressed by the PTs § HLTs are used for data retrieval, presentation and analysis Proprietary and Confidential – All Rights Reserved – PSI International

Preferred Term (PT) § PT is a distinct, unique medical concept § Regulatory authorities exchange information at the PT level § PT is the reporting level to FDA and MHLW, LLT-PT to EMEA § An identical current LLT exists for every PT § PT (with its component LLTs) may be multiaxial, associated with more than one SOC Proprietary and Confidential – All Rights Reserved – PSI International

Hierarchy SOC-HLGT-HLT-PT SOC Blood and lymphatic disorders HLGT White blood cell disorders HLT Neutropenias PT Agranulocytosis PT Febrile neutropenia PT Neutropenia PT Idiopathic neutropenia… Proprietary and Confidential – All Rights Reserved – PSI International

Lowest Level Term (LLT) § Verbatim is coded to the closest LLT § An LLT is linked to a single PT (Preferred Term) § LLTs linked to the same PT are: § § Lexical variants Synonyms British and American spellings May represent an aggravation of the concept § LLT may be current or non-current § Reporting to EMEA: LLT-PT Proprietary and Confidential – All Rights Reserved – PSI International

Hierarchy PT - LLT PT Febrile neutropenia Proprietary and Confidential – All Rights Reserved – PSI International PT Neutropenia

Hierarchy PT – LLT example from Med. DRA 8. 0 PT Dizziness Proprietary and Confidential – All Rights Reserved – PSI International

Hierarchy PT – LLT example from Med. DRA 10. 1 PT Dizziness PT Presyncope Proprietary and Confidential – All Rights Reserved – PSI International

Med. DRA Multi-axiality § Multi-axiality: the representation of a medical concept in multiple SOCs, depending on its meaning o Allows grouping by different classifications o Allows retrieval and presentation via different data sets § Purpose of Primary SOC o Determines which SOC represents multi-axial PTs in cumulative data outputs o A standard supporting/enabling consistent data presentation for reporting to regulators Proprietary and Confidential – All Rights Reserved – PSI International

Multiaxiality – PT Level 2 nd SOC 10 SOC Endocrine disorders HLGT 2 nd SOC Metabolism and nutrition Vascular disorders HLGT Hypothalamus and pituitary Metabolism disorders NEC Vascular hypertensive disorders gland disorders HLT Anterior pituitary hyperfunction Metabolic disorders NEC PT Acromegaly Proprietary and Confidential – All Rights Reserved – PSI International HLT Endocrine and metabolic secondary hypertension (partial hierarchy display)

Med. DRA Structure Groupings § Primary SOC: Congenital, familial and genetic disorders HLGT – Cardiac and vascular disorders congenital HLT – Cardiac septal defects congenital PT – Univentricular heart § Secondary SOC: Cardiac disorders HLGT: Myocardial disorders HLT: Myocardial disorders NEC PT – Univentricular heart Proprietary and Confidential – All Rights Reserved – PSI International

Multiaxiality - HLT Level Primary SOC Congenital, familial and genetic disorders HLGT Metabolic and nutritional disorders congenital 2 nd SOC Metabolism and nutrition disorders HLGT Inborn errors of metabolism HLT Inborn errors of amino acid metabolism PT Alkaptonuria Proprietary and Confidential – All Rights Reserved – PSI International (partial hierarchy display)

Standardized Med. DRA Queries § Standardised Med. DRA Queries (SMQs) are groupings of Med. DRA terms, ordinarily at the Preferred Term (PT) level that relate to a defined medical condition or area of interest § SMQs are intended to aid in the identification and retrieval of potentially relevant individual case safety reports § Currently in v 19. 0 there are 101 SMQ’s Proprietary and Confidential – All Rights Reserved – PSI International

Examples of SMQs § § § § Acute pancreatitis Acute renal failure Agranulocytosis Anaphylactic reaction Angioedema Anticholinergic syndrome Asthma/bronchospasm Cardiac arrhythmias Cerebrovascular disorders Depression and suicide/self-injury Dyslipidaemia Haematopoietic cytopenias Haemolytic disorders Haemorrhages Hepatic disorders § Hyperglycaemia/new onset diabetes mellitus § Interstitial lung disease § Ischaemic heart disease § Lack of efficacy/effect § Lactic acidosis § Neuroleptic malignant syndrome § Peripheral neuropathy § Retroperitoneal fibrosis § Rhabdomyolysis/myopathy § Severe cutaneous adverse reactions § Shock § Systemic lupus erythematosus § Taste and smell disorders § Torsade de pointes/QT prolongation Proprietary and Confidential – All Rights Reserved – PSI International

Med. DRA Structure Summary SOC HLGT HLT SMQ PT LLT Proprietary and Confidential – All Rights Reserved – PSI International LLT

Med. DRA PRODUCT QUALITY COMPLAINTS . Proprietary and Confidential – All Rights Reserved – PSI International

SOC Product issues § New (27 th) SOC for implementation in Med. DRA Version 19. 0 (March 2016) § Includes terms relevant for issues with o Product quality o Devices o Manufacturing and quality systems o Supply and distribution o Counterfeit products § Expert Working Group provided input on structure and contents § PSI is part of WG § Change requests for new terms Proprietary and Confidential – All Rights Reserved – PSI International

Structure Overview 27 th SOC Product issues HLGT Product quality, supply, distribution, manufacturing and quality system issues HLGT Device Issues HLT 13 High Level Terms 8 High Level Terms PT Preferred Terms LLT Low Level Terms LLT Proprietary and Confidential – All Rights Reserved – PSI International Low Level Terms 31

HLGT: Product quality, supply, distribution, manufacturing and quality system issues HLT’s § Counterfeit, falsified and substandard products § Manufacturing facilities and equipment issues § Manufacturing issues NEC § Manufacturing laboratory controls issues § Manufacturing materials issues § Manufacturing production issues § Product contamination and sterility issues § Product distribution and storage issues § Product label issues § Product packaging issues § Product physical issues § Product quality issues NEC § Product supply and availability issues Proprietary and Confidential – All Rights Reserved – PSI International

HLGT: Device issues HLT’s § Device computer issues § Device electrical issues § Device incompatibility issues § Device information output issues § Device issues NEC § Device malfunction events NEC § Device operational issues NEC § Device physical property and chemical issues Proprietary and Confidential – All Rights Reserved – PSI International

HLT: Product physical issues PT’s § § § § § Liquid product physical issue Product coating issue Product colour issue Product deposit Product dosage form issue Product friable Product gel formation Product odour abnormal Product physical consistency issue Product physical issue § § § Proprietary and Confidential – All Rights Reserved – PSI International Product reconstitution issue Product shape issue Product size issue Product solubility abnormal Product taste abnormal

HLT: Product quality issues NEC PT’s § § § § Product adhesion issue Product compounding quality issue Product difficult to remove Product difficult to swallow Product formulation issue Product impurity Product measured potency issue Product origin unknown § § § Proprietary and Confidential – All Rights Reserved – PSI International Product origin unknown Product process control issue Product quality issue Product substitution issue Product tampering

Advantages § Use of standardized terminology for product quality issues will facilitate data exchange § Potential uses of product quality terms, including manufacturing and distribution issues § Reporting product defects to regulatory authorities § Track and trend quality issues or deviations in own internal databases § Potential cost savings to utilize same terminology Proprietary and Confidential – All Rights Reserved – PSI International

Trending Capability of Product health data at Preferred Term (PT) level Figure 3. 1 January 2014 AE PT Data in Order of Frequency for Brand X cigarettes Throat irritation 15 Cough 14 Thermal burn 14 Headache 11 Oropharyngeal pain 9 Burns second degree 8 Dizziness 8 Nausea 8 Chest pain 7 Increased upper airway secretion 6 Lip injury 6 Vomiting 6 Abdominal discomfort 5 Abdominal pain upper 5 Oral discomfort 5 Paraesthesia oral 5 0 37 2 4 6 Proprietary and Confidential – All Rights Reserved – PSI International 8 10 12 14 16

Trending Capability of Product health data at System Organ Class (SOC) level Figure 3. 2 January 2014 AE SOC data in Order of Frequency for Brand Y e-cigarettes Respiratory, thoracic and mediastinal disorders 59 Gastrointestinal disorders 54 Injury, poisoning and procedural complications 54 Nervous system disorders 39 Skin and subcutaneous tissue disorders 10 General disorders and administration site conditions 8 Eye disorders 3 Ear and Labyrinth disorders 1 Endocrine disorders 1 Immune system disorders 1 Investigations 1 Musculoskeletal and connective tissue disorders 1 Psychiatric disorders 1 Vascular disorders 1 0 38 10 20 Proprietary and Confidential – All Rights Reserved – PSI International 30 40 50 60 70

Trending Capability of Product quality data at Preferred Term (PT) level Figure 3. 3 July 2016 Product Quality PT Data in Order of Frequency for Brand A Cigarettes Product tampering 25 Product quality control issue 22 Product supply issue 17 Product impurity 9 Product container issue 8 Product packaging issue 8 Product commingling 7 Product expiration date issue 6 Product label on wrong product 5 Product package associated injury 4 Manufacturing materials issue 4 0 39 5 10 Proprietary and Confidential – All Rights Reserved – PSI International 15 20 25 30

Med. DRA § Proactively: Good terminology to compile and analyze health data § Is medically validated and allows consistent, standardized application for capture of both health effects AND Product quality issues. Proprietary and Confidential – All Rights Reserved – PSI International

Thank you Med. DRA Proprietary and Confidential – All Rights Reserved – PSI International