MedDRA is the Medical Dictionary for Regulatory Activities. It was developed in the 1990s and was based on an earlier version created by the UK drug regulatory agency (then called the Medicines Control Agencies and now called the Medicines and Healthcare products Regulatory Agency (MHRA)). ICH took it on and an international group developed it. An organization was created, the MedDRA Maintenance and Support Services Organization (MSSO) in Virginia, to administer and maintain it and MedDRA finally went live in early 1999. See their website for more detail: www.meddra.org.
MedDRA is a terminology (not really a dictionary as it doesn’t define the words) for medical coding and communication. It covers drugs, advanced therapies (e.g. biologics) and some device information. It contains terms for signs, symptoms, diseases, syndromes, diagnoses, indications, investigations, medication errors, some quality terms, procedures and some terms for medical and social history.
It has 5 levels and is hierarchical totalling over 81,000 terms:
- System organ classes (SOCs): 26 terms
- Higher level group terms (HLGTs): ~335 terms
- Higher level terms (HLTs): ~1,700 terms
- Preferred terms (PTs): ~18,800 terms
- Lowest level terms (LLTs): ~68,000 terms
Terms that are the most specific (said to be “granular”) are found in the LLT (lower level terms) and most high level, non-specific terms are found in the SOC level. The most common levels used in PV practice are the LLT and PT levels. These terms are all medical terms compared to reporters’ terms (“verbatim terms”) which may or may not be medical – vomiting or barfing for example.
MedDRA has multi-axiality meaning that a PT can be associated with more than one HLT (axis) with a primary axis and one or more secondary axes.
MedDRA is updated by the MSSO twice yearly. Users are generally expected to update their IT systems to the latest version within a month or two and use the latest version for coding. Some exceptions are made for clinical trials, particularly long ones running years where multiple versions of MedDRA could be used during the trial. In this case, companies will often not update twice yearly for the trial but update to the latest version only at the end of the trial.
Use of MedDRA is required by the EU for pharmacovigilance reporting and is recommended by the FDA for use. In practice, almost all companies use MedDRA for FDA reporting.
Due to the size of the MedDRA database, an electronic mechanism (a “browser”) must be used to code cases and a computer must be used to retrieve cases. MedDRA is just too big and complex, in practice, to use a paper based system. The MSSO supplies a browser to subscribers. Other companies also offer their own browsers.
There are, in effect, two major uses for MedDRA: data entry coding for cases and case retrieval by AEs. We’ll talk briefly about each.
Coding of Individual Cases for Data Entry into a Safety Database
The most common situation occurs when an individual case safety report (ICSR) containing adverse events (AEs) and/or serious adverse events (SAEs) comes into a company or health agency. The case is triaged and reviewed and the medically most important or “primary event” is chosen. It is usually an SAE. A MedDRA browser is used for coding. Some browsers have autoencoders where a word or sentence or paragraph is typed into the browser (cut and paste) and the browser provides a list of one or more terms for each medical idea in the words or sentences entered. The computer program picks what it perceives to be the “best fit” for each concept. This mechanical choice must be verified by a human being who is trained in MedDRA coding to ensure that the chosen term makes sense, is in the proper SOC and is the best choice if multiple choices are offered. MedDRA has lots of choices for some medical concepts making coding tricky.
Data Retrieval for Signaling, Document Preparation etc.
There are various ways to pull cases out of the safety database using MedDRA after they have been previously coded and entered into the database. One way is to simply search for one or more MedDRA terms and pull the cases that have been coded using these terms (either as AEs, medical history etc.).
Alternatively one may use a so-called SMQ or Structured MedDRA Query. These are groupings of related terms (usually PTs – preferred terms) from all appropriate System Organ Classes (SOCs) as determined by a panel of experts. The terms in an SMQ would cover one medical subject, for example lactic acidosis or acute renal failure, and list signs, symptoms, syndromes, diseases, diagnoses, lab findings etc. New SMQs are continuously being added and older ones are being revised as needed.
Tricky Coding Issues
Cascade or Indirect AEs
In complex cases, with multiple problems going on simultaneously, depending upon how obsessive and detailed one is, dozes of MedDRA codes could be used for the patient’s problems. However, the primary goal of MedDRA is to provide the major or key terms that describe the case. It is usually the practice to code direct AEs and not “indirect” AEs. That is, if a drug is suspected of causing a patient to become dizzy and then fall and fracture her hip, the direct AE is the dizziness and the indirect or secondary AEs are the fall and hip fracture. Many people here would only code the dizziness arguing that the drug really did not case a bone fracture directly.
How Many Codes?
Many companies limit the number of codes to under 6 or so for AEs/SAES in each case. One wants to understand the major issues and not get lost in the lesser issues or secondary cascade AEs. Usually the Goldilocks Principle should be used: “not too hot, not too cold but just right”. That is, not too many codes, not too few but the appropriate number for the case. This requires medical and clinical judgment as well as experience in coding.
Lumping vs Splitting
The general goal in coding is to capture the essence of the case and to use diagnoses or syndromes where possible. For example, it is usually preferable to use “flu-like syndrome” as the single code rather than coding fever, malaise, fatigue, muscle aches, headache, chills, runny nose etc. That is “lumping” – using a single term diagnosis or syndrome – is often better than “splitting”.
This may vary depending on the case. Edema can have a very different medical meaning and treatment if it is pulmonary edema (which may be life threatening) or leg edema (which may be only bad circulation and not life threatening). Here specificity is critical.
There are many synonyms in MedDRA – some would argue too many. For example one or more of the following codes may be used for a liver AE: “elevated liver enzymes,” “abnormal liver enzymes,” “elevated SGOT,” “elevated SGPT,” “elevated ALT,” or “elevated AST”. Similarly one may code low blood glucose or hypoglycemia. Ideally, where there are choices, the coders in a particular institution should standardize on one term and not use all the terms possible. This may require some arbitrary choices and decisions and setting up coding conventions or manuals. Some companies have a coding group that either does all coding or reviews everyone else’s codes for consistency and uniformity.
Cultural, Language and National Differences
Medicine is practiced differently around the world and some concepts may exist in one region and not be used in other regions (e.g. the term “neurasthenia” is rarely used in the US but is used frequently in Europe). Although MedDRA exists in several other languages (at the PT level and up), many coders in non-English speaking countries code in English which is the primary language of MedDRA. Depending upon language and medical skills this may or may not make a difference.
Sometimes an inappropriate term is chosen which, though technically correct, does not convey the real meaning of the AE. For example someone might code “emotional lability” rather than “suicidal ideation” which clearly conveys the problem better.
Points to Consider
The MSSO puts out an excellent document with each new version entitled “Points to Consider” giving tips and suggestions on coding. It is widely used and is highly recommended. See http://www.meddra.org/how-to-use/support-documentation
Clearly training in MedDRA is needed. It is possible but generally difficult for non-medical personnel to do good coding. If people without a medical background do perform coding for an organization, at the very least they should have a medical terminology course and experience with drug safety and pharmacovigilance or clinical trials and safety issues. A physician or other medical professional should review the coding of non-medical personnel.
Even with medical training, MedDRA coding is a bit of an art and courses are given by the MSSO and other organizations on how to code with real examples and “tricks of the trade”. It is advisable that such a course be taken by anyone new to coding. See the MSSO website for their courses: http://www.meddra.org/training/offerings. Note that the training material is available on line for review. There are other organizations also that do MedDRA training like Gratisol Labs. Courses are also given on using MedDRA for signals and reports.
In summary, MedDRA coding is a critical requirement in pharmacovigilance department. It is a skill and something of an art also.