MedDRA (Medical Dictionary for Drug Regulatory Activities)- pharmacovigilance-material

MedDRA (Medical Dictionary for Drug Regulatory Activities)

In the late 1990s, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) developed MedDRA, a rich and highly specific standardised medical terminology to facilitate sharing of regulatory information internationally for medical products used by humans. ICH’s powerful tool, MedDRA is available to all for use in the registration, documentation and safety monitoring of medical products both before and after a product has been authorised for sale. Products covered by the scope of MedDRA include pharmaceuticals, biologics, vaccines and drug-device combination products. Today, its growing use worldwide by regulatory authorities, pharmaceutical companies, clinical research organisations and health care professionals allows better global protection of patient health.

Governance ensures the integrity of MedDRA

ICH has created a governance structure to nurture and protect the integrity of MedDRA. The ICH MedDRA Management Board, appointed by the ICH Steering Committee, has overall responsibility for the direction of MedDRA, and oversees all the activities of the ICH MedDRA Maintenance and Support Services Organization (MSSO) which is tasked to maintain, develop and distribute MedDRA. ICH has also established a Japanese Maintenance Organization (JMO), which works in close collaboration with MSSO, to support users in Japan.

Multilingual 

In addition to the original English master and Japanese translation, MedDRA has been translated and is maintained in the following languages: Chinese, Czech, Dutch, French, German, Hungarian, Italian, Portuguese and Spanish. Each MedDRA term has an associated 8-digit numerical code which remains the same irrespective of the language. Multiple languages allow a wide number of users to operate in their native language which promotes accuracy and precision in assigning codes. This interoperability is very powerful and allows easy sharing of data internationally.

Affordable and free for government regulators

A MedDRA subscription is available without charge to all regulators worldwide, while paid subscriptions are on a sliding scale linked to annual turnover of companies. Academics and health care providers can also access MedDRA from MSSO at no cost and from JMO at a nominal cost.

Free training for Users

To further facilitate MedDRA implementation and correct use, free training is offered to all subscribers on a wide range of topics and in different formats (face-to-face training, online sessions - webinars, and recorded videocasts). The MSSO staff also offers training in a variety of languages: English, French, Spanish, German and Chinese. The JMO staff offers training in Japanese.

Free support tools

Under the governance of the ICH MedDRA Management Board, MedDRA is continuously enhanced to meet the evolving needs of its users worldwide. After use for more than a decade, MedDRA has a wealth of experience around it with a strong development and maintenance programme to keep it current and numerous tools to support its users.

The current ICH M1 Points to Consider Working Group develops and maintains two documents on the use of MedDRA for data entry (coding) and data retrieval/analysis. The latter includes guide on the use of StandardisedMedDRA Queries (SMQs), as powerful tools for assisting with safety signal detection. Both documents are updated twice a year, with every MedDRA release, and are available in English and Japanese.

Additional essential supporting documentation is also provided by the ICH to all MedDRA subscribers as part of their subscription. Included are Introductory Guides on MedDRA and SMQs, and guide on the use of the MedDRA electronic files with explanations of the file structure. These documents are updated by the MSSO with every MedDRA release and are available in all MedDRA languages.

The ICH tasked the MSSO to develop a variety of computer tools to help users navigate MedDRA (browser tool) and assess the impact of any changes in users’ data due to version changes of MedDRA (MVAT tool). MSSO has also developed a Change Request tool (WebCR tool) to facilitate user submission of proposed changes to MedDRA.

Direct support for Users

Subscribers can have direct support through helpdesk services. Annual MedDRA User Group meetings are also organised in Europe, USA and China by the MSSO and in Japan by the JMO. This forum provides an opportunity for users to network and exchange best practices, lessons learnt, challenges in implementation and potential MedDRA developments.

We hope that this summary provides you with a general understanding of how ICH ensures that this ICH terminology is developed to meet users’ needs and that appropriate guidance, training and support tools are available to facilitate its access and proper implementation.

MedDRA is a multilingual terminology allowing most users to operate in their native languages. The table below identifies the initial MedDRA version when each MedDRA language was made available to users.
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The most important reason to “code” data into a standardised terminology is to analyse it. A key benefit of MedDRA is in its support of straightforward as well as sophisticated analyses. MedDRA can be used to analyse individual medical events (e.g., “Influenza”) or issues involving a system, organ or etiology (e.g., infections) using its hierarchical structure. MedDRA can be used for signal detection and monitoring of clinical syndromes whose symptoms encompass numerous systems or organs using its multiaxial hierarchy or through the special feature of StandardisedMedDRA Queries.

The ability to communicate adverse event data is another strength of MedDRA and has lead to MedDRA being an integral part of the ICH e-submission standards: eCTD (ICH M8) and ICSRs (ICH E2B).

The users of MedDRA have found it to be such an important tool that, in addition to the English Master, it has been translated into Chinese, Czech, Dutch, French, German, Hungarian, Italian, Japanese, Portuguese, and Spanish. Multiple languages allow most users to operate in their native language which promotes accuracy and precision of assigning terms. This interoperability is very powerful and allows easy multinational sharing of data. Essential supporting documentation is maintained with each release of MedDRA in all the languages.

All MedDRA terms are assigned a unique, 8-digit numeric code; the code is assigned to the translated term in each MedDRA language. This allows for electronic submission of the same concept (e.g., in an Individual Case Safety Report - ICSR) in any of its languages without loss of information or possible mistranslation by the sender or receiver.

The Japanese translation of MedDRA (MedDRA/J) is maintained by the Japanese Maintenance Organization (JMO) which works with the MSSO to assure that MedDRA/J is kept in synchrony with English MedDRA. The remaining MedDRA translations are centrally maintained by the MSSO (under the direction of the ICH MedDRA Management Board), and changes to English MedDRA are reflected in these translations also.

MedDRA Hierarchy

The structure of MedDRA is very logical. There are five levels to the MedDRA hierarchy, arranged from very specific to very general. At the most specific level, called “Lowest Level Terms” (LLTs), there are more than 70,000 terms which parallel how information is communicated. These LLTs reflect how an observation might be reported in practice. This level directly supports assigning MedDRA terms within a user database.

Each member of the next level, “Preferred Terms” (PTs), 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. Each LLT is linked to only one PT. Each PT has at least one LLT (itself) as well as synonyms and lexical variants (e.g., abbreviations, different word order).

Related PTs are grouped together into “High Level Terms” (HLTs) based upon anatomy, pathology, physiology, etiology or function. HLTs, related to each other by anatomy, pathology, physiology, etiology or function, are in turn linked to “High Level Group Terms” (HLGTs).

Finally, HLGTs are grouped into “System Organ Classes” (SOCs) which are groupings by etiology (e.g. Infections and infestations), manifestation site (e.g. Gastrointestinal disorders) or purpose (e.g. Surgical and medical procedures). In addition, there is a SOC to contain issues pertaining to products and one to contain social circumstances.

Multiaxiality

The 27 System Organ Classes (SOCs) represent parallel axes that are not mutually exclusive. This characteristic, called “multiaxiality,” allows a term to be represented in more than one SOC and to be grouped by different classifications (e.g., by aetiology or manifestation site), allowing retrieval and presentation via different data sets. Grouping terms are pre-defined in MedDRA and not selected on an ad hoc basis by data entry staff. Rather, the terminology is structured so that selection of a data entry term leads to automatic assignment of grouping terms higher in the hierarchy. Multiaxial links of terms are pre-assigned (and should not be changed), ensuring comprehensive and consistent data retrieval, irrespective of which SOC is selected at data retrieval.

Each MedDRA Preferred Term is assigned a primary hierarchy and, in some cases, secondary hierarchies. MedDRA users can produce a safety report with frequency counts using the primary SOC to highlight the distribution of adverse events in a data set. Using the primary SOC allocation will ensure that each event is only counted once for the report. It is also instructive to produce reports using the secondary SOC allocations to provide a more comprehensive view of the data. These features provide the user with great flexibility in accessing, displaying, and analysingMedDRA-coded data.

For example, the PT Influenza represents an important respiratory tract problem as well as an infection. For this reason, each PT is assigned to a primary SOC, but may also be assigned to one or more secondary SOCs. The PT Influenza is primary to the SOC Infections and infestations, but this PT is also secondary to the SOC Respiratory, thoracic and mediastinal disorders.

StandardisedMedDRA Queries

StandardisedMedDRA Queries (SMQs) are tools developed to facilitate retrieval of MedDRA-coded data as a first step in investigating drug safety issues in pharmacovigilance and clinical development. SMQs are validated, pre-determined sets of MedDRA terms grouped together after extensive review, testing, analysis, and expert discussion. SMQs are a unique feature of MedDRA and provide a strong tool to support safety analysis and reporting. The SMQ topics are intended to address the important pharmacovigilance topics needed by regulatory and industry users. SMQs have been developed with the CIOMS Working Group on StandardisedMedDRA Queries that provides pharmacovigilance expertise and validation of SMQs. The SMQs are maintained with each release of MedDRA by the MSSO.

Currently, over 100 SMQs have been created. Additional SMQs are created as the need arises. The following are a small sampling of SMQs that are available to users today:

• Anaphylactic reaction
• Cerebrovascular disorders
• Convulsions
• Depression and suicide/self-injury
• Drug abuse, dependence and withdrawal
• Hyperglycaemia/new onset diabetes mellitus
• Hypersensitivity
• Ischaemic heart disease
• Lack of efficacy/effect
• Medication errors
• Severe cutaneous adverse reactions

Electronic Communication

One of the important visions of ICH is the exchange of electronic documents and records.  In line with this, ICH has created important electronic standards such as the electronic Common Technical Document (ICH M8 eCTD) and the electronic Individual Case Safety Report (ICH E2B ICSR). MedDRA supports the use of these standards which increase the efficiency with which important regulatory information is shared.

eCTD

The CTD is used by pharmaceutical companies to assemble all quality, safety and efficacy information into one format for the submission of new drug applications to ICH regulatory authorities. The CTD is organised into five modules. Module 1 is region specific and Modules 2 (Quality Overall Summary), 3 (Quality), 4 (Safety) and 5 (Efficacy) are intended to be common for all regions. MedDRA is an important component of the CTD, being used within Module 5 to summarise adverse event data in a standardised way.

ICSR

The ICH E2B standard was developed to support the reporting of ICSRs for both pre- and post-approval periods in the ICH regions. MedDRA is a necessary part of the electronic submission of ICSRs and is required for use in the ICH E2B standard by the following elements (as stated in the ICH E2B(R3) Implementation Guide for ICSRs Version 5.01):

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Element ID	Element Name
D.7.1.r.1b	Structured Medical History Information (disease / surgical procedure / etc.)
D.8.r.6b	Indication (relevant past history)
D.8.r.7b	Reaction (relevant past history)
D.9.2.r.1b	Reported Cause(s) of Death
D.9.4.r.1b	Autopsy-determined Cause(s) of Death
D.10.7.1.r.1b	Medical History (disease / surgical procedure / etc.)
D.10.8.r.6b	Indication (relevant past drug history of parent)
D.10.8.r.7b	Reactions (relevant past drug history of parent, if any and known)
E.i.2.1b	Reactions / Event
F.r.2.2b	Test Name
G.k.7.r.2b	Indication
H.3.r.1b	Sender's Diagnosis / Syndrome and / or Reclassification of Reaction / Event

Change Requests

A MedDRA “Change Request” (CR) allows a MedDRA user to recommend the addition of new term, changes to existing terms, or improvements in the structure of MedDRA. These changes to MedDRA may help the user code and analyse data more accurately. MedDRA users may request up to 100 CRs per month.

The diagram below shows the process flow for CRs submitted to the MSSO.

MedDRA users can submit different types of change requests. Simple change requests are processed with each release of MedDRA and include changes to the LLT and PT levels of MedDRA. Complex changes are processed once a year and include changes above the PT level at the HLT, HLGT, and SOC levels of MedDRA. Users may also submit change requests related to StandardisedMedDRA Queries (SMQs). Change requests for SMQs include adding PTs to SMQs or making existing PTs in SMQs inactive or requesting a new SMQ. Lastly, users can submit change requests related to any of the translated versions of MedDRA.

WebCR is an online tool used for submitting CRs to the MSSO. WebCR supports all types of change requests described above: MedDRA changes, SMQ changes and Translation corrections. In addition to submitting requests, WebCR provides the following features:

• Verify if an English term exists in MedDRA
• Review when an English term was added to MedDRA
• Search the history of all change requests considered by the MSSO since MedDRA Version 5.1
• Resubmit a rejected request for reconsideration
• Track the progress of submitted requests
• Hold proposed CRs and submit them when ready

See the WebCR Quick Reference guide for getting started with using WebCR.

The MSSO also performs proactive maintenance (making corrections or improvements without receiving specific change requests from users). For example, proactivity changes can relate to making more general changes to MedDRA – perhaps correcting a series of outdated terms or addressing an area of inconsistency.