There is a right time and wrong time to up-version electronic data capture (EDC) coding dictionaries
It’s a common question we hear from sponsors, “When should we up-version our medical coding dictionaries for a study?” The question applies both to the Medical Dictionary for Regulatory Activities (MedDRA), a clinically validated medical terminology dictionary-thesaurus to code adverse events; and to the WHODrug Dictionary, which is used to code medications.
The short answer is the coding dictionary version should be defined at study start-up, and up-versioning should be avoided during the midst of a study, if possible. We offer this advice based on our own experience, informed by numerous collaborations with a wide range of study sponsors.
Staying current
The Maintenance and Support Services Organization (MSSO) and Uppsala Monitoring Centre (UMC), which respectively maintain MedDRA and WHODrug, recommend that all studies use the most current versions of their dictionaries available at the start of the study. For situations in which the target database open date is close to the release of a new version of either dictionary, one should consider waiting to finalize the coding setup until the new version is available.
Whereas sponsors may be tempted to use an earlier version of MedDRA or WHODrug for consistency with earlier studies, federal regulations do not support this practice for a new study. Rather, consistency can be managed in the Integrated Summary of Safety (ISS), which is an integrated analysis of a study drug’s safety (see below for additional information).
Notably, ongoing studies do not require dictionary upgrades and recoding during the life of a study. Moreover, mid-study upgrades and recoding can be expensive, especially if the upgraded dictionary file includes structural changes, such as new or revised variables (see the ‘Proceed with caution’ section further below for more details).
In our experience, sponsors will on occasion require dictionary upgrades. For example, a sponsor may prefer that the clinical study report (CSR) reflects the MedDRA and WHODrug versions that are current within six months of database lock. Additionally, some sponsors may have policies and processes in place to upgrade annually. In such situations, Precision for Medicine can provide the necessary support.
Regardless of when up-versioning takes place, the study budget should include upgrade-associated costs, which can be significant, especially if previously coded terms are to be recoded. Additionally, the study-specific data management plan should include time for setting up the new dictionary in the database build, performing a quality check of the upgrade, creating the associated documentation, and recoding previously coded terms. The plan should also specify the frequency of planned upgrades; whereas both MedDRA and WHODrug upgrade twice a year, it is not beneficial for a study to upgrade twice yearly.
Notably, there is no requirement to recode earlier or locked studies. A summary of FDA’s support of the most current version of MedDRA is available here.
Leveraging the Integrated Summary of Safety (ISS)
For new and ongoing studies, in lieu of using the same dictionary version as in earlier studies, coding consistency across studies is best managed in the ISS.
To avoid potential confusion or incorrect results, unless otherwise agreed with regulatory agencies, the preparation of the adverse event (AE) dataset for the ISS should include MedDRA terms from the most recent version available at the time that data across studies are pooled, or the most recent version of MedDRA from the most recent study. We recommend confirming the sponsor’s expectation with the regulatory agency during their pre-NDA meeting.
The reason for an ISS based on a single version of MedDRA is to ensure that the same adverse events reported in different studies are classified consistently. Pooled datasets supporting the ISS, based on a single MedDRA version, can then be submitted in Module 5 of the Electronic Common Technical Document (eCTD).
Additional information about the ISS is available in this FDA guidance document.
Licensure requirements
MSSO and UMC require that any company using the dictionaries (e.g., persons who perform medical coding), as well as any company that receives or reports coded terms (e.g., sponsors), must have an active license. “Receipt” of coded terms, in this context, applies to data transfers, data listings, coding reports, and/or terms presented in submissions, including drug safety update reports (DSURs), pediatric safety update reports (PSURs), and clinical study reports (CSRs).
This means that for a given study, both the coding company and the sponsor must have their own licenses in place. Each license holder must independently establish their licensing subscription with MSSO/UMC directly, and each is responsible for maintaining a current license. Additionally, the sponsor should have its license in place before receiving or viewing coded terms. This includes before they receive data transfers that contain coded data, as well as data listings, CSRs, or any files that contain coded data.
Our custom is to mention medical coding dictionary versions and licensure requirements at the project kickoff meeting (KOM), and to confirm that the sponsor has an active license with MSSO (for MedDRA) and UMC (for WHODrug) at that time. Once confirmed, the licensure is captured in the KOM minutes. Sponsors who lack a license, or are unsure of their licensure status, are encouraged to contact MSSO/UMC directly.
Proceed with caution
We advise clients to proceed cautiously when creating custom dictionaries for a study, particularly if there are any changes to file structure or other elements of dictionaries currently in use. It is also important to understand any downstream impacts of such changes. Structural changes will involve additional time for the programmer to complete the upgrade and may require updates to existing medical coding listings and reports. The larger consequential expense of the structural changes is the time required to complete a 100% recoding of all existing verbatim terms (previous and new).
Finally, we wish to reiterate that our recommendations reflect our own experience, and we are glad to help sponsors navigate the up-versioning process, but the decision to up-version must rest with the sponsor, based on clinical program objectives and timelines.
For more information about MedDRA and WHODrug up-versioning and licensure, consult the pertinent governmental and regulatory guidelines, or contact us.
