Safety Analysis of Medicinal Drug Product Use: Implications for a Standard Drug Dictionary

The temporal association of an adverse event following exposure to one or more medicinal drug product(s) naturally raises questions of causality. Did the drug or a combination of drugs cause the adverse event? The determination of causality is a complex analysis and beyond the scope of this post, but suffice it to say that having detailed information about the drug product(s) involved in the exposure is a critical component of the analysis. One relies on basically two major data sources to conduct these analyses: clinical trials information and post-marketing safety information (i.e. both passive and active surveillance).  Also relevant are information from other regulatory agencies and the published literature.  

When the suspected drug is the investigational drug in a trial, sufficient information about the investigational drug product is typically available and the analysis can be fairly straightforward. However, because study subjects typically are on multiple medications, one also examines concomitant medication use.  The analysis of concomitant medication (CM) information in clinical trials is valuable to help identify drug-related safety signals that may not be associated with the investigational drug, but also to help identify clinically significant drug-drug interactions with the investigational drug. CM information can be particularly useful since clinical trial data provide reliable denominator counts to calculate incidences. Furthermore, since many trials are controlled, it permits comparisons of incidences with placebo or the control. Analysis, however, remains challenging because CM information is often incomplete and/or insufficiently standardized. Because drug product information is complex, being made up of various component concepts such as the proprietary name, active moiety, active ingredient, strength, dosage form, pharmacologic class, etc., the opportunity for missing/incomplete data is high. Knowing as much as possible about the CM, including exposure data, is important to support meaningful analysis of this information. Standardization of CM information is also important to maximize its usefulness, particularly when pooling data across clinical trials. Pooling across studies is often desirable to increase power to evaluate safety signals, particularly those with low incidences.

Similar problems exist with drug product information available from spontaneous post-marketing safety reports. The information may be incomplete or insufficiently standardized making data aggregation and analysis challenging. Post marketing cases submitted to the publicly available FAERS (the FDA Adverse Events Reporting System) often contain more than one suspect product, and frequently a number of CMs. In reviewing these cases, it would be most helpful to know all the attributes of the suspect products, to enable identification of instances where a specific formulation of a product is associated with a different risk then its other formulations, or instances where a specific lot is associated with new adverse reactions, not seen for that product overall. However, many product attributes are often not available, making product identification standardization critical. At this time, the Proprietary Name and active ingredient(s) are the two critical elements for identifying products in postmarketing reports, with the application number for the primary suspect, manufacturer, then dosage, route, etc., when available.

One often sees only the ingredient populated in the structured drug field, although the specific Trade name is stated in the narrative. Through informal discussions with companies who use WHO Drug Dictionary Enhanced (WHO-DDE) to code and report suspect products in post-marketing reports, it appears that most record both the Trade name and Active ingredient in their internal databases, but report only the ingredient (‘Preferred Name’ record ending in 001 in WHO-DDE for single ingredient products). Analysis would be improved if standard information for the Trade name (when known) as well as the active ingredient were routinely available.

For historical reasons (space limitation) the WHO-DDE hierarchy for multi-ingredient drugs is different. The Preferred Name (record ending with 001) is the first trade name on the market for that specific composition, not the ingredient combination. Thus reporting on this level may represent the name of a product which was not administered at all. Further, every new salt version of the specific ingredient combination gets a new numeric identifier (Drecno), making data aggregation very challenging. The Uppsala Monitoring Center (UMC), as the WHO-DDE maintenance organization, recognizes these challenges and is proposing changes to the dictionary to facilitate accurate reporting and aggregation of data for WHO-DDE users.

To support the clinical trials and postmarketing use cases, one needs to know the active moiety of each drug product, since important drug-related safety signals typically correlate with this concept (e.g. tacrine-associated hepatotoxicity). The moiety can be derived if the active ingredient is known.  Since some drug products are combination drugs containing two or more active ingredients / active moieties, it is important to identify each active moiety present in any multi-ingredient drug product. Drug-related safety signals sometimes also correlate with the pharmacologic class (“class effect,” e.g. bone fractures associated with proton pump inhibitors); therefore, one also needs to know the pharmacologic class of each product or of its active moiety. Pharmacologic class is itself a complex concept made up of other concepts such as mechanism of action, physiologic effect, or chemical structure. A single active moiety may have more than one recognized or clinically meaningful pharmacologic class. This gives rise to potentially 1:many:many relationships (Product:ActiveMoiety:PharmClass; see Figure below).

Key Product Information from a Drug Dictionary

A standard drug dictionary should support the validation and coding of each reported drug product by its name and active ingredient(s), or by the active ingredient(s) when that is the only available information.  A standard drug dictionary should further support the reporting and/or easy look-up of active moiety and pharmacologic class information for each drug product.

Identifying the pharmacologic class information for each drug product is not always straightforward because there may be multiple classes, and there is no concept of a primary default pharmacologic class. When the indication for a product use is known, this may provide information for selecting a class, but the product’s activity may always be considered as part of another assigned class. It is therefore useful to know all the pharmacologic classes associated with a drug product.