Medical Dictionary for Regulatory Activities: MedDRA, the Medical Dictionary for Regulatory Activities Terminology is an international medical terminology developed under the auspices of the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use.
Prior to the development of MedDRA, there had been no internationally accepted medical terminology for biopharmaceutical regulatory purposes. Most organizations processing regulatory data used one of the international adverse drug reaction terminologies in combination with morbidity terminology. In Europe, most of these organizations used a combination of the World Health Organization’s Adverse Reaction Terminology (WHO-ART) and the International Classification of Diseases Ninth Revision (ICD-9). In the United States, the Food and Drug Administration’s (FDA) Coding Symbols for a Thesaurus of Adverse Reaction Terms (COSTART) was usually used in conjunction with Clinical Modification of ICD-9 (ICD-9-CM). The Japanese developed their own versions of these international terminologies, Japanese Adverse Reaction Terminology (J-ART) and Medical Information System (Japan) (MEDIS). In addition, many organizations modified these terminologies to suit their needs. Established terminologies lacked specificity of terms at the data entry level, provided limited data retrieval options (e.g., too few levels in the hierarchy, or capacity to retrieve data via one axis only), and did not handle syndromes effectively. Organizations with sufficient resources developed their own “in-house” terminologies to address some or all of these deficiencies. The use of multiple terminologies raised several problems. Using different terminologies at various stages in a product’s life complicates data retrieval and analysis, making it difficult to cross-reference data. For example, safety data had frequently been classified for pre-registration clinical trials using ICD terminology and for post-marketing surveillance using J-ART, WHO-ART, or COSTART. Furthermore, using different terminologies in separate geographic regions impaired international communication and necessitated the conversion of data from one terminology to another. This data conversion had the potential to cause time delays and loss or distortion of data. In particular, these problems affected multinational pharmaceutical companies whose subsidiaries used multiple terminologies to fulfill the different data submission requirements of regulators. The use of multiple terminologies also affected communication between companies and clinical research organizations. It became increasingly difficult to manage the information required for product registration applications and to meet the time scale requirements for data exchange between regulatory authorities and the medical product industries. These difficulties prompted an industry-wide commitment to exploit developments in communication and information technology. However, electronic communication still required a standardized data set and structure to be successful.
DEVELOPMENT OF THE MEDICAL DICTIONARY FOR REGULATORY ACTIVITIES (MedDRA) TERMINOLOGY
The ICH terminology was developed from a pre-existing terminology. The MEDDRA Working Party enhanced the United Kingdom MCA’s(now MHRA - Medicines and Healthcare products Regulatory Agency) medical terminology to produce MEDDRA Version 1.0. This was adopted as the basis for the new ICH terminology. MedDRA Version 2.0 was signed off as the implementable version of the terminology at the ICH-4 conference in July 1997. A change in name and modified acronym were agreed upon at this meeting. Hence, MEDDRA is used for versions up to Version 1.5, while the implementable version (Version 2.0) and future versions are known as the MedDRA terminology.
SCOPE OF THE TERMINOLOGY
The MedDRA terminology applies to all phases of development of medical products for human use, excluding animal toxicology. The scope of MedDRA encompasses medical, health-related, and regulatory concepts pertaining to such products. The terminology also addresses the health effects and malfunction of devices (e.g., PT Device related infection and PT Device failure). Furthermore, the terminology may also support other types of products which are regulated in at least one region such as food or cosmetics. The categories of terms classified as “medical and health-related” for these purposes are as follows: • signs • symptoms • diseases • diagnoses • therapeutic indications – including signs, symptoms, diseases, diagnoses, diagnosis or prophylaxis of disease, and modification of physiologic function • names and qualitative results of investigations – e.g., increased, decreased, normal, abnormal, present, absent, positive, and negative • medication errors and product quality terms • surgical and medical procedures
EXCLUSION CRITERIA The exclusion criteria used in the development of the terminology do not necessarily limit the terminology’s expansion scope. Since this is a medical terminology, the following terms used in regulatory affairs are out of scope: • Drug/product terminology (Note: The generic names of some commonly used products, such as digoxin, that are included with their associated adverse events) • Equipment/device/diagnostic product terminology • Study design • Demographics (including patient sex, age, race, and religion).
The hierarchy provides degrees or levels of superordination and subordination. The superordinate term is a broad grouping term applicable to each subordinate descriptor linked to it. Hierarchical levels thus represent vertical links in the terminology.
Structural Hierarchy of the MedDRA Terminology :
System Organ Class (SOC)
High Level Group Term (HLGT)
High Level Term (HLT)
Preferred Term (PT)
Lowest Level Term (LLT)
LOWEST LEVEL TERMS : LLTs are subordinate to PTs.
LLTs constitute the lowest level of the terminology. Each LLT is linked to only one PT.
LLTs have any of the following relationships to their parent PT: Synonyms: Different terms for the same concept inherent in the PT (e.g., PT Arthritis and its subordinate LLT Joint inflammation) Lexical variants: Different word forms for the same expression. These include full names vs. abbreviations and direct vs. inverted word order (e.g., PT Acquired immunodeficiency syndrome and its subordinate LLT AIDS or PT Biopsy tongue and its subordinate LLT Tongue biopsy). Quasi-synonyms: Quasi-synonyms are terms that are not precisely the same meaning as another term, but are treated as synonymous in a given terminology. These include site and laterality descriptions (e.g., PT Otitis externa and its subordinate LLT Bilateral otitis externa). Sub-concept: Sub-concepts (of the parent PT concept) are represented by LLTs with more detailed information such as anatomic specificity (e.g., PT Contusion with LLT Bruising of face or LLT Bruising of leg). Identical LLT: One LLT is identical to its PT for data entry purposes (e.g., PT Dementia Alzheimer’s type and its subordinate LLT Dementia Alzheimer’s type). In this instance, the LLT and parent PT have the same MedDRA code but appear at both levels.
PREFERRED TERMS : PTs are subordinate to HLTs. A PT is a distinct descriptor (single medical concept) for a symptom, sign, disease, diagnosis, therapeutic indication, investigation, surgical, or medical procedure, and medical, social, or family history characteristic. PTs should be unambiguous and as specific and self-descriptive as possible in the context of international requirements. Therefore, eponymous terms are only used when they are recognized internationally. The granularity/specificity of the PT level is such that clinical pathologic or etiologic qualifiers of the descriptors are represented at the PT level. For example, a variety of rhinitis and meningitis terms exist as separate entities at this level (e.g., PT Rhinitis perennial, PT Rhinitis ulcerative, PT Rhinitis atrophic, PT Meningitis aseptic, PT Meningitis cryptococcal, PT Meningitis viral, PT Meningitis bacterial, etc.). This level of specificity in PTs ensures that the multi-axial nature of the terminology can be maximally exploited. There is no limit to the number of LLTs that can be linked to a PT, however, a PT must have at least one LLT linked to it. When a new PT is added to the terminology, an identical LLT is created automatically for data entry purposes.
HIGH LEVEL TERMS An HLT is a superordinate descriptor for the PTs linked to it. It is an inclusive category which links PTs related to it by anatomy, pathology, physiology, etiology, or function. Examples of HLTs are: HLT Bronchospasm and obstruction, HLT Mediastinal disorders, HLT Pulmonary oedemas, and HLT Upper respiratory tract neoplasms. The terminology is not a taxonomy, so the specificity of HLTs is not uniform throughout the terminology (or between SOCs). HLTs are intended for data retrieval and presentation purposes; they are a grouping level and are not intended to be a coding level. HLTs are subordinate to HLGTs. An HLT must be linked to at least one SOC via an HLGT. It can only be linked to a particular SOC via one route (i.e., linked to only one HLGT per SOC). All HLTs linked to a particular HLGT will appear in every SOC to which the HLGT is linked.
HIGH LEVEL GROUP TERMS An HLGT is a superordinate descriptor for one or more HLTs related by anatomy, pathology, physiology, etiology, or function. For example, HLGT Vascular hypertensive disorders is used to link the following HLTs: HLT Accelerated and malignant hypertension, HLT Hypertension complications, HLT Portal hypertensions, HLT Pregnancy associated hypertension, HLT Pulmonary hypertensions, HLT Renal hypertensions, HLT Vascular hypertensive disorders NEC, and HLT Endocrine and metabolic secondary hypertension. HLGTs are intended for data retrieval and presentation purposes. HLGTs group HLTs to aid retrieval by broader concepts. HLGTs are subordinate to SOCs. An HLGT must be linked to at least one SOC and to at least one HLT (the next levels up and down in the hierarchy, respectively). There is no limit to the number of SOCs to which an HLGT can be linked.
SYSTEM ORGAN CLASS A SOC is the highest level of the hierarchy that provides the broadest concept for data retrieval. SOCs comprise groupings by: • Etiology (e.g., SOC Infections and infestations) • Manifestation site (e.g., SOC Gastrointestinal disorders) • Purpose (e.g., SOC Surgical and medical procedures) The exception from the above categories is SOC Social circumstances which contains information about the person, not the adverse event and provides a grouping for those factors that may give insight into personal issues that could have an effect on the event being reported. A SOC is related directly (superordinated) to at least one HLGT with no restriction on the number of links to HLGTs.