THE WHAT AND WHY OF MedDRA Samina Qureshi, M.D. PSI INTERNATIONAL, Inc

Medical Dictionary for Regulatory Activities MedDRA 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.

Safety Reporting Regulations Postmarketing drugs Generic drugs Therapeutic biologics “Grandfather” drugs (pre 1938) IND Safety reports, NDA/BLA report

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., MedDRA) throughout a clinical program…”

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 (MedDRA).  When available, FDA recommends that standardized case definitions …”

MedDRA 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”.

Scope: MedDRA 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

Applications of MedDRA 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

MedDRA: Basic Structure Standardized terminology: 5-level Hierarchy Multiaxiality Granularity Retrieval groupings: Standardized MedDRA Queries (SMQ) Basic MedDRA structure is hierarchial and multi-axial, plus a Special Search Category. MedDRA terminology is grouped in five levels, with the broadest category, called the SOC – System Organ Class - at the top, sequentially broken down into more and more specific categories. This is known as ‘hierarchy’. A single Preferred term (PT level of terminology) may be found within more than one major top level grouping – this is known as multi-axiality. Special Search Category section of MedDRA is not used for coding, and was developed after the rest of the dictionary. Special Search Categories are intended for data retrieval. There are currently 13 SSC in MedDRA, for example ‘Anaphylaxis’, ‘Pain”, ‘Oedema, ’etc. Each is an associative grouping of Preferred terms across different MedDRA System Organ Classes; this grouping is indicative of a given medical condition. Special Search Categories can be created in-house to serve the specific retrieval/analysis needs of a company. The ones contained in MedDRA provide an example of a data retrieval technique with such a granular dictionary. The concept is to cast a wide net to ensure complete data retrieval. Special Search Categories can be created at any MedDRA terminology level. Outside of the Special Search Categories, the main body of MedDRA cannot be customized in-house.

Structure Overview MedDRA (version 19.0) SOC System Organ Class 27 HLGT High Level Group Term 335 HLT High Level Term 1,732 This slide represents the MedDRA levels. The top level is the System Organ Class, known as SOC. There are 26 SOCs in MedDRA 6.0 and their number has been constant since the beginning. MedDRA SOCs correspond to the main anatomical/functional body systems – Cardiac Disorder SOC, Endocrine disorder SOC, Gastrointestinal disorder SOC, etc. Among the 26, there is also a ‘General disorder’ SOC, an ‘Infections’ SOC, ‘Investigations’ SOC, ‘Congenital disorders’ SOC, ‘Neoplasms’ SOC, and a ‘Social circumstances’ SOC. A SOC consists of at least one, but usually more, High level Group Terms, HLGTs, which represent the second level of MedDRA terminology.There are 332 HLGTs in MedDRA 6.0. For example, Immune System Disorders SOC consists of Allergic conditions HLGT, Autoimmune disorders HLGT, Immunodeficiency syndromes HLGT, and Immune disorders NEC HLGT. A HLGT consists of at least one, but usually more, High Level Terms, known as HLTs. There are 1,682 HLTs in MedDRA 6.0. For example, Allergic conditions HLGT consists of Allergies to foods, additives, drugs, chemicals HLT, Anaphylactic responses HLT, Angioedemas HLT, Allergic conditions NEC HLT, Urticarias HLT, and Atopic disorders HLT. Both the HLGTs and HLTs are broad groupings of terminology. They are not used directly for coding, but for understanding the meaning of a term from lower levels of terminology. However, HLGTs and HLTs are used directly for data retrieval and data presentation. An HLT consists of at least one, but usually more, Preferred terms, known as PTs. MedDRA 6.0 contains 16,102 PTs. A Preferred term is a single distinct medical concept. It can represent anything in MedDRA – sign, symptom, lab result, indication, history term. It must be unique – there is no overlap at the PT level. A Preferred term consists of at least one but usually more Low Level Terms, known as LLTs. There are 49,721 current LLTs in MedDRA 6.0 (and 8,839 non-current LLTs, to be explained later). A Preferred term is described and defined by its Low level terms. This implies that a LLT belongs to one and only one PT. Low level terms are mainly synonyms of the PT and dialectic and lexicant variants of the PT. An LLT most closely resembles the original reporter’s words. In some cases, an LLT may represent more clinical information than its corresponding PT, but this information is generally not considered crucial by the regulatory authorities. Thus, regulatory authorities are exchanging information at the PT level. However, pharmaceutical companies are coding at the LLT level. MedDRA reporting to the Food and Drug Administration in the USA and the Ministry of Health Labor and Welfare in Japan is done at the PT level. However, the European authority, EMEA requires reporting of both the LLT and its corresponding PT term. Each MedDRA term, on every level, consists of a text string and a unique8-digit numeric identifier. SMQ Standard MedDRA Queries PT Preferred Term 21,920 LLT Low Level Term 75,818 10 10

Structure Overview MedDRA (version 11.1) SOC System Organ Class 26 HLGT High Level Group Term 332 HLT High Level Term 1,699 This slide represents the MedDRA levels. The top level is the System Organ Class, known as SOC. There are 26 SOCs in MedDRA 6.0 and their number has been constant since the beginning. MedDRA SOCs correspond to the main anatomical/functional body systems – Cardiac Disorder SOC, Endocrine disorder SOC, Gastrointestinal disorder SOC, etc. Among the 26, there is also a ‘General disorder’ SOC, an ‘Infections’ SOC, ‘Investigations’ SOC, ‘Congenital disorders’ SOC, ‘Neoplasms’ SOC, and a ‘Social circumstances’ SOC. A SOC consists of at least one, but usually more, High level Group Terms, HLGTs, which represent the second level of MedDRA terminology.There are 332 HLGTs in MedDRA 6.0. For example, Immune System Disorders SOC consists of Allergic conditions HLGT, Autoimmune disorders HLGT, Immunodeficiency syndromes HLGT, and Immune disorders NEC HLGT. A HLGT consists of at least one, but usually more, High Level Terms, known as HLTs. There are 1,682 HLTs in MedDRA 6.0. For example, Allergic conditions HLGT consists of Allergies to foods, additives, drugs, chemicals HLT, Anaphylactic responses HLT, Angioedemas HLT, Allergic conditions NEC HLT, Urticarias HLT, and Atopic disorders HLT. Both the HLGTs and HLTs are broad groupings of terminology. They are not used directly for coding, but for understanding the meaning of a term from lower levels of terminology. However, HLGTs and HLTs are used directly for data retrieval and data presentation. An HLT consists of at least one, but usually more, Preferred terms, known as PTs. MedDRA 6.0 contains 16,102 PTs. A Preferred term is a single distinct medical concept. It can represent anything in MedDRA – sign, symptom, lab result, indication, history term. It must be unique – there is no overlap at the PT level. A Preferred term consists of at least one but usually more Low Level Terms, known as LLTs. There are 49,721 current LLTs in MedDRA 6.0 (and 8,839 non-current LLTs, to be explained later). A Preferred term is described and defined by its Low level terms. This implies that a LLT belongs to one and only one PT. Low level terms are mainly synonyms of the PT and dialectic and lexicant variants of the PT. An LLT most closely resembles the original reporter’s words. In some cases, an LLT may represent more clinical information than its corresponding PT, but this information is generally not considered crucial by the regulatory authorities. Thus, regulatory authorities are exchanging information at the PT level. However, pharmaceutical companies are coding at the LLT level. MedDRA reporting to the Food and Drug Administration in the USA and the Ministry of Health Labor and Welfare in Japan is done at the PT level. However, the European authority, EMEA requires reporting of both the LLT and its corresponding PT term. Each MedDRA term, on every level, consists of a text string and a unique8-digit numeric identifier. SMQ Standard MedDRA Queries PT Preferred Term 18,483 67,195 LLT Low Level Term

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)

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

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

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

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

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…

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

PT Febrile neutropenia Hierarchy PT - LLT PT Febrile neutropenia PT Neutropenia This slide is an example of the Hierarchical relationship between a Preferred term and its constituent Low Level Terms. On the left side is the PT Dizziness. On the right is a listing of the LLTs under the PT Dizziness, in alphabetical order. The first listed is LLT Dizziness. It is exactly the same as the PT Dizziness; the text string and the unique numeric identifier are identical between the two levels. This represents one of the rules of MedDRA – every PT must have a current LLT which is its exact replica. This rule is intended to facilitate companies which may code at the PT level but need to report at the LLT and PT levels – the captured PT automatically translates into its identical LLT. Second listed is LLT Dizziness aggravated. As of MedDRA version 6.0, most terms representing an aggravation of a baseline condition exist at an LLT level only, grouped under the PT of the baseline condition. Third and fourth listed LLTs are preceded with ‘N/C’ meaning non-current. An inadequate Low Level term is never deleted from MedDRA, but may be designated as no longer current. This indicates that the term was active in a prior version of MedDRA, but is no longer an active term, and is not to be used for active coding. The original non-current LLTs were mostly complex terms incorporated from other dictionaries. New non-current LLTs appear from one MedDRA version to the next, as the dictionary undergoes medical clean-up procedures. Only an LLT can be made non-current; however, an inadequate PT may be demoted to its LLT, and as such made non-current, with any of its remaining LLTs re-assigned to different PT(s). PRI system will not allow for active coding with non-current LLTs- the database will simply not accept these terms since they are not a part of the current MedDRA version. However, existing non-current LLTs are designated as such and displayed in a comprehensive listing of LLTs by any browser. Several LLTs on the slide represent lexical variants and other synonyms of the PT. LLT Light headedness and LLT Lightheadedness represent lexical variants of each other. LLT Dizzy, LLT Woozy and LLT Felt faint represent synonyms of each other. Note the LLT Pre-syncope and LLT Presyncope. These two LLTs are an example of the 20% of LLTs which convey more clinical information than the corresponding PT. Thus, these are called ‘quasi-synonyms.’ Pre-syncope is clinically a more severe event than Dizziness. It is precisely to enable capture of this level of specificity that companies code at the LLT level, and that EMEA requires reporting at both the LLT and PT levels. Also notice that these two LLTs, LLT Pre-syncope and LLT Presyncope, represent lexical variants.

Hierarchy PT – LLT example from MedDRA 8.0 PT Dizziness This slide is an example of the Hierarchical relationship between a Preferred term and its constituent Low Level Terms. On the left side is the PT Dizziness. On the right is a listing of the LLTs under the PT Dizziness, in alphabetical order. The first listed is LLT Dizziness. It is exactly the same as the PT Dizziness; the text string and the unique numeric identifier are identical between the two levels. This represents one of the rules of MedDRA – every PT must have a current LLT which is its exact replica. This rule is intended to facilitate companies which may code at the PT level but need to report at the LLT and PT levels – the captured PT automatically translates into its identical LLT. Second listed is LLT Dizziness aggravated. As of MedDRA version 6.0, most terms representing an aggravation of a baseline condition exist at an LLT level only, grouped under the PT of the baseline condition. Third and fourth listed LLTs are preceded with ‘N/C’ meaning non-current. An inadequate Low Level term is never deleted from MedDRA, but may be designated as no longer current. This indicates that the term was active in a prior version of MedDRA, but is no longer an active term, and is not to be used for active coding. The original non-current LLTs were mostly complex terms incorporated from other dictionaries. New non-current LLTs appear from one MedDRA version to the next, as the dictionary undergoes medical clean-up procedures. Only an LLT can be made non-current; however, an inadequate PT may be demoted to its LLT, and as such made non-current, with any of its remaining LLTs re-assigned to different PT(s). PRI system will not allow for active coding with non-current LLTs- the database will simply not accept these terms since they are not a part of the current MedDRA version. However, existing non-current LLTs are designated as such and displayed in a comprehensive listing of LLTs by any browser. Several LLTs on the slide represent lexical variants and other synonyms of the PT. LLT Light headedness and LLT Lightheadedness represent lexical variants of each other. LLT Dizzy, LLT Woozy and LLT Felt faint represent synonyms of each other. Note the LLT Pre-syncope and LLT Presyncope. These two LLTs are an example of the 20% of LLTs which convey more clinical information than the corresponding PT. Thus, these are called ‘quasi-synonyms.’ Pre-syncope is clinically a more severe event than Dizziness. It is precisely to enable capture of this level of specificity that companies code at the LLT level, and that EMEA requires reporting at both the LLT and PT levels. Also notice that these two LLTs, LLT Pre-syncope and LLT Presyncope, represent lexical variants.

Hierarchy PT – LLT example from MedDRA 10.1 PT Dizziness This slide is an example of the Hierarchical relationship between a Preferred term and its constituent Low Level Terms. On the left side is the PT Dizziness. On the right is a listing of the LLTs under the PT Dizziness, in alphabetical order. The first listed is LLT Dizziness. It is exactly the same as the PT Dizziness; the text string and the unique numeric identifier are identical between the two levels. This represents one of the rules of MedDRA – every PT must have a current LLT which is its exact replica. This rule is intended to facilitate companies which may code at the PT level but need to report at the LLT and PT levels – the captured PT automatically translates into its identical LLT. Second listed is LLT Dizziness aggravated. As of MedDRA version 6.0, most terms representing an aggravation of a baseline condition exist at an LLT level only, grouped under the PT of the baseline condition. Third and fourth listed LLTs are preceded with ‘N/C’ meaning non-current. An inadequate Low Level term is never deleted from MedDRA, but may be designated as no longer current. This indicates that the term was active in a prior version of MedDRA, but is no longer an active term, and is not to be used for active coding. The original non-current LLTs were mostly complex terms incorporated from other dictionaries. New non-current LLTs appear from one MedDRA version to the next, as the dictionary undergoes medical clean-up procedures. Only an LLT can be made non-current; however, an inadequate PT may be demoted to its LLT, and as such made non-current, with any of its remaining LLTs re-assigned to different PT(s). PRI system will not allow for active coding with non-current LLTs- the database will simply not accept these terms since they are not a part of the current MedDRA version. However, existing non-current LLTs are designated as such and displayed in a comprehensive listing of LLTs by any browser. Several LLTs on the slide represent lexical variants and other synonyms of the PT. LLT Light headedness and LLT Lightheadedness represent lexical variants of each other. LLT Dizzy, LLT Woozy and LLT Felt faint represent synonyms of each other. Note the LLT Pre-syncope and LLT Presyncope. These two LLTs are an example of the 20% of LLTs which convey more clinical information than the corresponding PT. Thus, these are called ‘quasi-synonyms.’ Pre-syncope is clinically a more severe event than Dizziness. It is precisely to enable capture of this level of specificity that companies code at the LLT level, and that EMEA requires reporting at both the LLT and PT levels. Also notice that these two LLTs, LLT Pre-syncope and LLT Presyncope, represent lexical variants. PT Presyncope

MedDRA Multi-axiality Multi-axiality: the representation of a medical concept in multiple SOCs, depending on its meaning Allows grouping by different classifications Allows retrieval and presentation via different data sets Purpose of Primary SOC Determines which SOC represents multi-axial PTs in cumulative data outputs A standard supporting/enabling consistent data presentation for reporting to regulators

Multiaxiality – PT Level 2nd SOC Vascular disorders 10 SOC Endocrine disorders 2nd SOC Metabolism and nutrition disorders HLGT Hypothalamus and pituitary gland disorders HLGT Metabolism disorders NEC HLGT Vascular hypertensive disorders HLT Anterior pituitary hyperfunction HLT Metabolic disorders NEC HLT Endocrine and metabolic secondary hypertension This is an example of a multi-axial PT Acromegaly and its SOCs. In this case, Endocrine disorders SOC is Primary, the other two are secondaries. Notice that there is always a single PRIMARY pathway between a PT and a given SOC. PT Acromegaly (partial hierarchy display)

MedDRA 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 SOC Investigations HLGT – Neurological and special sense investigations HLT – Ear and labyrinth histopathology procedures PT – Biopsy ear abnormal Primary SOC Congenital HLGT – Cardiac and vascular disorders congenital HLT – Cardiac septal defects congenital PT Univentricular heart (Secondary SOC is Cardiac disorders)

Multiaxiality - HLT Level Primary SOC Congenital, familial and genetic disorders 2nd SOC Metabolism and nutrition disorders HLGT Inborn errors of metabolism HLGT Metabolic and nutritional disorders congenital This is an actual example from MedDRA. PT Alcaptonuria is a multi-axial PT. It is grouped under three SOCs, but pictured here is the pathway to only two of these three, to display multi-axiality at the HLT level. Notice that there is a common HLT, Inborn errors of amino acid metabolism, after which the path diverges to two separate HLGTs and two separate SOCs. Notice that, as with all congenital disorders, alkaptonuria is grouped under the Primary SOC Congenital, familial and genetic disorders. (The third pathway is to HLT Urinary abnormalities, HLGT Urinary tract signs and symptoms, grouped in the Renal and urinary disorders SOC.). HLT Inborn errors of amino acid metabolism (partial hierarchy display) PT Alkaptonuria

Standardized MedDRA Queries Standardised MedDRA Queries (SMQs) are groupings of MedDRA 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 v19.0 there are 101 SMQ’s

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

MedDRA Structure Summary SOC HLGT HLT SMQ PT LLT LLT

MedDRA PRODUCT QUALITY COMPLAINTS .

SOC Product issues New (27th) SOC for implementation in MedDRA Version 19.0 (March 2016) Includes terms relevant for issues with Product quality Devices Manufacturing and quality systems Supply and distribution Counterfeit products Expert Working Group provided input on structure and contents PSI is part of WG Change requests for new terms

Structure Overview HLT HLT LLT 27th SOC Product issues HLGT Product quality, supply, distribution, manufacturing and quality system issues HLGT Device Issues HLT 13 High Level Terms HLT 8 High Level Terms PT Preferred Terms PT Preferred Terms This slide represents the MedDRA levels. The top level is the System Organ Class, known as SOC. There are 26 SOCs in MedDRA 6.0 and their number has been constant since the beginning. MedDRA SOCs correspond to the main anatomical/functional body systems – Cardiac Disorder SOC, Endocrine disorder SOC, Gastrointestinal disorder SOC, etc. Among the 26, there is also a ‘General disorder’ SOC, an ‘Infections’ SOC, ‘Investigations’ SOC, ‘Congenital disorders’ SOC, ‘Neoplasms’ SOC, and a ‘Social circumstances’ SOC. A SOC consists of at least one, but usually more, High level Group Terms, HLGTs, which represent the second level of MedDRA terminology.There are 332 HLGTs in MedDRA 6.0. For example, Immune System Disorders SOC consists of Allergic conditions HLGT, Autoimmune disorders HLGT, Immunodeficiency syndromes HLGT, and Immune disorders NEC HLGT. A HLGT consists of at least one, but usually more, High Level Terms, known as HLTs. There are 1,682 HLTs in MedDRA 6.0. For example, Allergic conditions HLGT consists of Allergies to foods, additives, drugs, chemicals HLT, Anaphylactic responses HLT, Angioedemas HLT, Allergic conditions NEC HLT, Urticarias HLT, and Atopic disorders HLT. Both the HLGTs and HLTs are broad groupings of terminology. They are not used directly for coding, but for understanding the meaning of a term from lower levels of terminology. However, HLGTs and HLTs are used directly for data retrieval and data presentation. An HLT consists of at least one, but usually more, Preferred terms, known as PTs. MedDRA 6.0 contains 16,102 PTs. A Preferred term is a single distinct medical concept. It can represent anything in MedDRA – sign, symptom, lab result, indication, history term. It must be unique – there is no overlap at the PT level. A Preferred term consists of at least one but usually more Low Level Terms, known as LLTs. There are 49,721 current LLTs in MedDRA 6.0 (and 8,839 non-current LLTs, to be explained later). A Preferred term is described and defined by its Low level terms. This implies that a LLT belongs to one and only one PT. Low level terms are mainly synonyms of the PT and dialectic and lexicant variants of the PT. An LLT most closely resembles the original reporter’s words. In some cases, an LLT may represent more clinical information than its corresponding PT, but this information is generally not considered crucial by the regulatory authorities. Thus, regulatory authorities are exchanging information at the PT level. However, pharmaceutical companies are coding at the LLT level. MedDRA reporting to the Food and Drug Administration in the USA and the Ministry of Health Labor and Welfare in Japan is done at the PT level. However, the European authority, EMEA requires reporting of both the LLT and its corresponding PT term. Each MedDRA term, on every level, consists of a text string and a unique8-digit numeric identifier. LLT Low Level Terms LLT Low Level Terms 31 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

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

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 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 Product origin unknown Product process control issue Product quality 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

Trending Capability of Product health data at Preferred Term (PT) level

Trending Capability of Product health data at System Organ Class (SOC) level

Trending Capability of Product quality data at Preferred Term (PT) level

MedDRA 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.

Thank you MedDRA MedDRA MedDRA