PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL 3: 7-1 3 (1994)

SPECIAL REPORT

The Medical Dictionary for Drug Regulatory Affairs (MEDDRA) Project

K. L. WOOD'. on behalf of the MEDDRA WORKING PARTY

Co-orihutor, MEDDRA Project, Room 1027, Murket Towers, Vuu.ultull, London S W8 5NQ

SUMMARY Electronic transmission of information is a key component of the Future System for medicines regulation in the European Union (EU). Data sets and terminology will have to be standardized in order to ensure effective information exchange between organizations. The Medical Dictionary for Drug Regula- tory Affairs (MEDDRA) is a medical terminology being prepared by an international Working Party for use by regulatory authorities, pharmaceutical companies and other relevant organizations. It incor- porates terms relevant to all areas of drug regulation, including the marketing authorization (MA) process, MA maintenaricelrenewal and pharmacovigilance.

KEY WORDS - MEDDRA, medical terminologies, EU Future System, electronic data transmission, dictionaries, pharmacovigilance, drug regulation.

INTRODUCTION

During the last few years, pharmaceutical com- panies and drug regulatory authorities have shown increasing interest in the submission of regulatory data by electronic means. Several diverse systems have been developed; these have tended to be tailored to the requirements of individual compa- nies, regulatory authorities and, in some cases, to specific compounds. A degree of standardization is required if the systems are to have wider applica- bility. One key area in need of standardization is medical terminology. Implementation of the EU Future Systems Directives and Regulation, from I January 1995, places some urgency on such stan- dardization, particularly since the success of the system will rest on effective communication through information networks. It is considered important for there to be one medical terminology to support the computerized exchange of infor- mation pertaining to uN aspects of drug regulation between the European Medicines Evaluation Agency (EMEA), the EU Commission, Member States, pharmaceutical companies, other drug regu- latory bodies and drug safety organizations.

Historically, medical terminologies have been

separated into morbidity terminologies, e.g. the International Classification of Diseases (ICD-9,' in future ICD-10') and adverse drug reaction (ADR) terminologies, e.g. the World Health Organizations Adverse Reaction Terminology '( WHO-ART) and the US Food and Drug Administration's (FDA) Coding Symbols for a Thesaurus of Adverse Reac- tions Terms4 (COSTART). The precedent of separ- ating ADR and morbidity terminologies is undesirable, since ADRs often mimic sponta- neously occurring diseases and symptoms and the use of separate terminologies for ADRs and other medical terms adds unnecessary complexity to any computer system.' An initiative was therefore required to develop a single medical terminology for the purposes of drug regulation. This initiative would also be of help to those concerned with event reporting as distinct from ADR reporting.

DEVELOPMENT O F A SINGLE MEDICAL TERMINOLOGY FOR THE PURPOSES OF

DRUG REGULATION

The Medicines Control Agency (MCA) started the development of a new computer system in 1989

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- the Adverse Drug Reactions On-line Infor- mation Tracking (ADROIT) system to facilitate its work in pharmacovigilance.h The options for a medical terminology to support ADROIT were reviewed at that time. The ability to capture the original terms on a document, flexible data retrieval and analysis capabilities and contribution to in- house signal generation programmes were regarded as key attributes. Furthermore, since it was required to support the classification of all medical terms found on post-marketing reports and to be used in the MCA’s new product licence database, i t needed to cover terms relevant to all aspects of drug regulatory affairs. None of the terminologies available met the user requirements and a termin- ology was created which incorporates medical terms relevant to all aspects of drug regulation in an hierarchical multi-axial structure.

Nearly three years experience with this termin- ology in active daily use at the MCA has shown it to be robust in supporting data entry and retrie- val. Hence, it was considered that the terminology could provide a useful basis for an international terminology for drug regulation. A Personal Com- puter version of the terminology, called the Medical Dictionary for Drug Regulatory Affairs (MED- DRA), was developed to facilitate review and a Working Party was established to investigate whether MEDDRA has wide applicability and rele- vance to drug regulation internationally.

THE MEDDRA WORKING PARTY AND AIMS O F THE MEDDRA PROJECT

The Working Party membership is shown in Table 1 and comprises representatives from three drug regulatory authorities, with the US Food and Drug Administration attending as observers, eight phar- maceutical companies and the American Pharma- ceutical Manufacturer’s Association (PMA). A representative of the World Health Organization (WHO) has also attended. It was considered important to have a relatively small membership initially, in order to permit a detailed review of the terminology’s relevance to the requirements of pharmaceutical companies and to other drug regu- lators. Although input into the Working Party is co-ordinated by one representative for each organi- zation, who attends meetings, most have involved staff from multiple disciplines and sites to ensure a breadth of expertise and experience relevant to the review.

Table I - MEDDRA Working Party Members

Regulatory authorities France Spain United Kingdom US (Observer)

Pharmaceutical companies Behringwerke Bristol Myers Squibb Ci ba-Geigy Glaxo Marion Merrell Dow Merck, Sharp & Dohme Pfizer Zeneca

Other Pharmaceutical Manufacturers Association (USA)

At the first Working Party meeting in November 1993, there was unanimous agreement that MED- DRA could provide a good foundation for an inter- national medical terminology for use in drug regulatory affairs. The aims of the project are as follows:

to work towards international acceptance of one medical terminology for use in drug regulatory affairs; to review comprehensively the present version of the terminology to produce a version in elec- tronic format, for wider consultation in Summer 1994; commence piloting the use of MEDDRA for a variety of regulatory purposes; development of options and procedures for maintaining MEDDRA.

CHARACTERISTICS OF THE MEDDRA TERMINOLOGY

The key features of the MEDDRA terminology are summarized in Fig. I .

/ncorporntes t e r m relevant to ail nrem of drug regulut ion The terminology includes terms relevant to symp- toms, signs, diagnoses, investigations, procedures, family and social history. In addition to facilitating implementation and compliance with the EU Future Systems Regulation and Directives, use of a single medical terminology to classify data from clinical trials and other studies, spontaneous ADRs

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and adverse events (AEs), regulatory submissions and product information such as the EU’s Sum- mary of Product Characteristics (SPC) can help to optimize in-house drug assessment and review pro- cedures. For example, it permits pre-marketing data to be integrated rapidly with post-marketing data to provide an overview of product efficacy and safety and allows easy comparison of ADR profiles with product SPC information. Interest- ingly, some pharmaceutical companies e.g. Glaxo, Merck, Sharp & Dohme,’ have developed their own terminologies for classifying both pre- and post- marketing data. However, many companies con- tinue to have separate terminologies for these pur- poses.

Large number of terms at the data entry level Provision of a large number of terms at the lowest level enables capture of the original terms used on any document. Lowest level terms (LLT) allow con- siderable specificity of data entry and, in addition, can be used to support on-line validation at data entry, which is of importance to data quality and accuracy. The paucity of terms at the data entry level in other terminologies has resulted in many organizations adding their own terms to these ter- minologies8 in an uncontrolled fashion. Alterna- tively, organizations have used the closest term available, the choice of which is subjective and likely to be highly variable, resulting in inconsisten- cies and lack of reproducibility.

Inclusion of inany terms from other terminologies The first draft of MEDDRA will contain all data entry terms from WHO-ART and COSTART, allowing easy transfer of historical data for organi- zations currently using these terminologies. Terms which are ambiguous or obsolete will be flagged as ‘non current’ so that they may not be used for future data entry. MEDDRA also contains terms from ICD-9 and its clinical modification ICD-9- CM and ICD- 10.

Multi-axial hierarchy for flexible data retrieval and ana Iysis MEDDRA terms are classified in a five level multi- axial hierarchy shown diagrammatically in Fig. 2. As mentioned above, data entry is at the lowest level. Data may be retrieved at any level, providing flexibility for specific or broad searches. Lowest

level terms are grouped together under Preferred Terms. Preferred Terms related functionally, ana- tomically or by aetiology, are usually linked to High Level Terms and these, where appropriate, to High Level Group Terms. The System Organ Classes (SOC), listed in Table 2, represent disorders of body systems and/or groups of organs which together perform a particular function, plus other categories e.g. injury and poisoning, family and social history.

The classification hierarchy is multi-axial. Thus, a Preferred Term may be represented in as many SOCs as is appropriate, hence permitting retrieval by different classification groupings, e.g. by aetio- logy or by manifestation site. A multi-axial struc- ture is also an important means of ensuring comprehensive retrieval if only one SOC is used for data retrieval. However each Preferred Term is allocated a primary SOC, so that terms do not appear more than once on routine data output pro- grammes.

Special search categories allow searches on groups of Preferred Terms which have a common link, for example, by aetiology, but which cross hierarchical boundaries, e.g. the various presen- tations of anaphylaxis or the features of a syn- drome, such as eosinophilia myalgia syndrome.

Facility t o j a g ‘alert terms’ MEDDRA provides the facility to flag Preferred Terms as ‘alert terms’ for use in in-house signal generation programmes.

Translation into languages of all users Users naturally expect to be able to enter and retrieve data in their native language, hence the need to translate an international terminology into all users’ languages. There has been some concern that multi-language translations of existing termi- nologies have been purely literal. Although it is difficult for terminology to accommodate nuances relevant to cultural differences in clinical practice, this can be optimized by ensuring that translations are performed by clinicians.

User friendly Data entry and retrieval is text and not code based. This enhances the quality of data entry and better understanding at data retrieval. In addition, user

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THE MEDDRA PROJECT

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Fig. 2 - MEDDRA terminology classification hierarchy

friendly instruction manuals have been developed for use with MEDDRA.

Easy to update and maintain The maintenance and updating of MEDDRA is controlled through rigorous medical and technical quality and integrity checks, with full audit trails. A major problem with existing terminologies is that they have been relatively static, with few updates over years - which is why users have added their own terms to the international terminologies. Reg- ular, rapid, quality-controlled updates must be a key feature of any terminology if it is to respond to the needs of users and achieve international acceptability. Updates may involve the addition of new terms, changes to the links of terms, e.g. in the light of new knowledge about aetiology, or more major changes to SOC hierarchies in response to user needs.

The Working Party perceive the need for any internationally accepted medical terminology for drug regulatory affairs to be updated on a monthly basis. A designated organization with appropriate expertise and funding, overseen by a Board with representatives of users, could provide such a func- tion. There would need to be rigorous control, qua- lity assurance and audit of the maintenance process, which would include translation into rele- vant languages. Mechanisms would need to be set in place to ensure that the terminology was respon- sive to users needs.

MEDDRA PROJECT CURRENT STATUS

MEDDRA was endorsed by all member states of the EU at the December 1993 meeting of the Com- mittee on Proprietary Medicinal Products (CPMP).

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Table 2 - List of MEDDRA System Organ Classes (20/ 1/94)

Cardiac disorders Congenital anomalies Disorders ofmetabolism and nutrition Disorders of the ear Disorders of the eye Disorders of the immune system Endocrine disorders Family and social history Gastrointestinal disorders General disorders Haemopoietic disorders Hepato-biliary disorders Infections and infestations Injury and poisoning Investigations Musculoskeletal, connective tissue and bone disorders Neoplasms Neurological disorders Pregnancy, puerperium and perinatal conditions Psychiatric disorders Renal and urinary disorders Reproductive disorders Respiratory disorders Skin and subcutaneous tissue disorders Surgical and medical procedures Vascular disorders

By March 1994, 1 1 of the 26 System Organ Classes (Table 2) had been reviewed by the Working Party which is on target to meet the Summer 1994 dead- line for the release of a version of MEDDRA for wider consultation. The European Community Pharmaceuticai Information Network (ECPHIN) at Ispra, Italy will be piloting the use of MEDDRA for the indexing of SPC information. Several phar- maceutical companies will be piloting MEDDRA extensively in various aspects of their work, includ- ing clinical trials.

MEDDRA will be demonstrated at a number of international conferences this year. Newsletters about MEDDRA are being distributed to inform interested organizations about the project, prior to wider consultation.

DISCUSSION

A large number of terminologies exist for a variety of specialist purposes.' 4.y " Those used for adverse drug reaction monitoring, including WHO-ART' and COSTART,4 have significant limitations. Hence, there have been recent proposals for an

international adverse dru reaction dictionary" or adverse event dictionary. It is intended that these would be provided with definitions of terms and it is envisaged that there will be development over several years.

There is no terminology presently available inter- nationally which fulfils the requirements of all aspects of drug regulation. Yet there is a clear need for such a terminology which both incorporates older terminologies and encompasses terms rele- vant to all aspects of drug regulatory affairs. The impetus for its development at this time is the need of the Future System of drug regulation in the EU which will commence in January 1995. The MED- DRA project has thus been set up to develop a terminology to meet the regulatory needs of the EU, the timescale for development of the first draft of the terminology being dictated by the start of the Future System. Nevertheless, the MEDDRA Working Party believe the proposed terminology to be applicable to the needs of the wider interna- tional community and are keen to interact with organizations who have a similar vision for a global medical terminology. We consider that such a ter- minology must include terms relevant to all stages of product development, not just ADRs or AEs; it could thus be used by all organizations involved in drug regulatory affairs.

Use of single terminology within all clinical phases of drug development and at all company subsidiaries will help to prevent the problems of comparing data from different sources e.g. allo- cation of terms to different Primary System Organ Classes in different terminologies confounds counts of reactions within each SOC. This applies to data received from different regulatory authorities too.

It has been argued that drug regulatory authori- ties and pharmaceutical companies are hindered in interpreting and assessing data because of a lack of uniformity in the definition of terms and in diag- nostic validating criteria. The Council for Interna- tional Organizations of Medical Sciences (CIOMS) commenced important work in the definition of ADR terms several years ago.'4 I' One of the frust- rations and challenges of spontaneous reporting schemes is that all the relevant data are not pro- vided and may indeed not be available. Agreed defi- nitions are useful in this context for indicating the information required in the follow-up of cases, for helping reporters to improve the quality of their reports and for identifying pivotal cases that fulfil all the agreed criteria. The development of defini- tions are an important complementary component

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THE MEDDR A PROJECT 13

f o r the development of an internationally accepted terminology f o r drug regulatory affairs. It is planned t h a t MEDDRA users will be able t o view CIOMS definitions of terms on screen.

Once accepted, a terminology f o r d r u g regula- tory affairs must be maintained and kept up-to- date . I t should evolve with time responding t o the needs o f the users and t o changes in medicine, sci- ence and d r u g regulation. Hence t h e MEDDRA Working Par ty consider it a fundamental part of their work to include proposals on how this could be ensured.

REFERENCES

1 . World Health Organisation. Interncitioncil Clussijcci- tion of Diseases. 9th revision. WHO, Geneva, 1977.

2. World Health Organisation. Internritionul Stutisticul Clussi jcdon of Diseases and Relrited Heultli Proh- Ienzs. 10th revision. WHO, Geneva, 1992.

3. Internutionul Monitoring of Adverse Reuctions to Drugs. Adverse Renction Terminology. WHO Col- laborating Centre for International Drug Monitor- ing, Uppsala, Sweden, 1992.

4. Coding Sjvnhols f o r u Tliesuurus of Adverse Reaction Terms. 3rd ed. US Food and Drug Administration, Rockville, MD, 1989.

5. Talbot, J . C. C. The collection, storage, retrieval and management of adverse drug reaction data. In: Tlie Detection of New Adverse Drug Reuctions. Stephens, M. D. 9. (Ed.) Macmillan Press, 1985.

6. Wood, S. M. and Coulson, R. A. Adverse drug reac- tions on-line information tracking (ADROIT). Phur- muceuticul Medicine 1993; 7: 203-21 3.

7. Leitmeyer, J. and Gillum, T. Consistency in adverse

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event terminology: Merck's modified clinterm. Drug Infi)rtn~ition Journd 1993; 27: 43 1--435.

8. Schneiweiss, F. Adverse reaction thesauri used in the pharmaceutical industry. Dixg Infi,rtnution Jour- nit1 1993; 21: 299-302.

9. Cote, R . A. (editor-in-chief) SNOMED Sy.ste/niitisecl Noinenclrture of Medicine. 2nd edn. College of American Pathologists, Skokie I l l , 1979.

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1 1. Chisholm, J. The Read clinical classification. British Mr(lictrl Journul 1990; 300: 1092.

12. Benichou, C. Towards an adverse drug reactions dic- tionary. Should existing terminologies be harmo- nized? Pliuri~iucoepi(~emiolog!, imd Drug Su/i.tj, 1993; 2: 185-188.

13. Edwards, I. R., Herman, R., Dreis, M. and Raynor, C. Towards a new adverse event dictionary. Plictrmu- coepidetniology cind Drug Sujkty 1993; 2: 175-1 76.

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15. Basic requirements for the use of terms for reporting adverse drug reactions (11). Pliur/nrrcoepi~lemiolog~~ undDrugSaj2ty 1992; 1: 133-137.

16. Basic requirements for the use of terms for reporting adverse drug reactions (III). P/icirinacorpide/niology und Drug Sq/>tjx 1992; 1: 191-196.

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18. Basic requirements for the use of terms for reporting adverse drug reactions (V). Pliurtnricoepi(len1iology m t I Drug Sujkty 1993; 2: 189- 193.

PHARMACOEPIDEMIOLOGY A N D DRUG SAFETY. VOL. 3: 7-13 (1994)