What is MedDRA

The Medical Dictionary for Regulatory Activities (MedDRA) is a rich and highly specific standardized medical terminology developed to facilitate sharing of regulatory information internationally for medical products used by humans.  It is the preferred adverse event coding tool for regulatory authorities, including the FDA, Health Canada and the European Medicines Agency.

For additional information see “What is MedDRA and How is it Used?”

Why Code Adverse Event Data

Adverse event data is collected as free text “natural language” from doctors, nurses, study participants and coordinators. Different individuals have freedom of expression and their free text is difficult to analyse. It is therefore coded with a standardized terminology that allows individual events to be analysed by category.This facilitates data analysis.

Using MedDRA each adverse event is coded using one or more Low Level Terms (LLTs). LLTs are essentially synonyms for medical signs, symptoms, diagnoses and procedures. Each of these LLTs maps to a Preferred Term (PT) . Preferred Terms are grouped into a hierarchical arrangement that allows them to be analysed at a number of different levels. At the top of this hierarchy is the System Organ Class (SOC). For DSMB reporting, summary reporting and analysis most academic studies will list AEs based on their PT and SOC. However, each PT can exist in more than one SOC. To avoid double counting events each PT is assigned to a single Primary SOC.

MedDRA Coding Tools

License

MedDRA is licensed free of charge by the University of Alberta library. It can therefore be used in any clinical trial sponsored by the University of Alberta.

• https://guides.library.ualberta.ca/az/meddra

Coding

REDCap’s text box fields include a special feature that can be enabled to provide auto-suggest functionality for real-time searching within biomedical ontologies, such as RxNorm, ICD-9, ICD-10, Snomed CT, LOINC, and MedDRA. WCHRI’s REDCap support team has developed standardized forms for both collecting and coding adverse events. Email redcap@ualberta.ca for additional information.

Additionally the MedDRA website includes a number of tools, the most useful of which is the Web Based Browser. This can be found at https://tools.meddra.org/wbb/. The site requires a login. This can be obtained from the University of Alberta library, referenced above.

Analysis

Coding an adverse event assigns it one or more MedDRA terms. However, for analysis, this data must be exported from REDCap and merged with the rest of the MedDRA hierarchy. For this the full MedDRA dictionary is required. It can be obtained from the download from the MedDRA website at https://www.meddra.org/software-packages.

Performing the Coding

Consistent coding of adverse events is important. For this reason:

• Adverse events should be coded by individuals who are trained in adverse event coding and MedDRA (as per GCP).

• Coding should be done based on Sponsor or study specific coding requirements.

• Coding should not be performed by individual coordinators at study sites. (REDCap coding forms should not be made available to individual study sites).

• Coding is not considered to be part of the AE report and does not need to be signed off or approved by the qualified Investigator. For this reason, coding fields should not be present on the main adverse events form but should be on a separate coding form.

See the "MedDRA® TERM SELECTION: POINTS TO CONSIDER" document for additional information.

REDCap

WCHRI’s AE coding instrument is a repeating instrument. Each instance of the form has an instance number and this number maps directly to the adverse event form with the same instance number. I.e. there is a one to one relationship between AE forms and AE coding forms.

Each coding form shows a read only copy of the AEs reported term or description. It then displays three or more text fields which are used for searching and allocating MedDRA terms. Three coding fields are provided because each adverse event may require more than one term to be assigned. This will be explained in more detail below.

To assign a MedDRA code to the adverse event simply tab to the MedDRA term field and start typing a search term. REDCap will search the Bioportal MedDRA database for corresponding terms and will display a list of terms that match. Select the most appropriate term from the list.

To add another term to the adverse event simply check “Add another term” and start typing a term in the new, empty field.

Selecting a Term

Terms should be selected based on the most current “MedDRA® TERM SELECTION: POINTS TO CONSIDER” document, which can be obtained from the MedDRA website. Key points are summarised below.

• Select the MedDRA term that most accurately reflects the reported verbatim information from the adverse event. Be aware of how grammar and context may affect the term selection. For example:

  • Lip sore - Preferred term - lip pain

  • Lip sores - Preferred term - cheilitis

• Select the most specific term that matches the information in the adverse event.

  • Vomiting

  • Vomiting of medication

• Use medical judgement to select an appropriate term.

  • If an exact match cannot be found, use medical judgement to select an appropriate term.

  • If you are not certain which term to use, seek advice from a suitably qualified member of the study team.

  • Adverse event descriptions that are unclear or cannot be coded accurately may be queried.

• Selecting more than one term

  • Where an adverse event report contains more than one medical concept then additional terms may be added to accurately code the event.

  • Study teams generally consider signs, symptoms and diagnoses that are related and occur together to be a single event (see the diarrhea and vomiting example above). Some within the data management community would consider separate medical concepts to be separate AEs. This is not our approach. Instead, we apply additional terms to code the individual AE report correctly.

  • “Diarrhea and vomiting secondary to gastroenteritis” each medical concept should be coded so as to maintain the original detail in the safety report.

• Code the diagnoses or signs/symptoms, and do not assume a diagnosis.

  • “Diarrhea and vomiting” would be allocated two terms - “diarrhea”, “vomiting” and no diagnosis is assumed.

  • “Diarrhea and vomiting secondary to gastroenteritis” each medical concept should be coded so as to maintain the original detail in the safety report, even though diarrhea and vomiting are common symptoms of gastroenteritis.

• Adverse event reports that are unclear or cannot be coded should be queried with the study site.

  • “Lip sore”. Is the participant’s lip sore or do they have a sore on their lip?

Review the Term Hierarchy

The tools available in REDCap simply display individual MedDRA terms and do not include any information relating to the position of the term in MedDRA’s hierarchy. For this reason we suggest that unless individuals are very familiar with the AE terms and the study subject matter they should review the terms in the MedDRA Web Based Browser as part of the coding process. Using the example above of “lip sore” vs. “lip sores”, this distinction, and therefore the correct term, becomes very obvious when reviewing the term in the browser.

Coding Review

In order to confirm that adverse events have been coded correctly and consistently, listings of coded data, including the MedDRA hierarchy, should be reviewed by the Principal Investigator at intervals throughout the study and especially before performing any kind of reporting or analysis such as for DSMB reporting or interim/final analysis.

Advice for Study Sites

The way an adverse event is reported can influence the way the adverse events are coded and analysed and therefore should be considered carefully.

• Adverse event data must be reviewed and signed off by appropriately qualified medical staff. Usually this would be the qualified investigator (QI) at the study site. At this time the QI should ensure that the reported term for the event accurately reflects the event using the most appropriate terminology.

• If a set of signs and symptoms occur together and the QI believes them to be a single event then they should be reported as a single event on the CRF.

• If the event can be adequately described as a single diagnosis then that is what should be reported.

• If there is no single, formal diagnosis that adequately describes the event then the report should include the signs and symptoms.

• If a diagnosis is provisional, then the provisional diagnosis should be reported along with signs and symptoms. (The diagnosis may change, but not the signs and symptoms). If a formal diagnosis is obtained then the record can be updated later.

• If the QI believes that additional information is important, then it can be included so as not to lose detail in the safety analysis.

For example:

" Pneumonia, secondary to sepsis" is only a single adverse event (assuming that is the diagnosis). If the causative agent is known then that should be included (" Pneumonia, secondary to E.coli sepsis")  . However, if the pneumonia and sepsis started at different times, they should be reported as separate AEs even though the pneumonia was caused by the sepsis.