Drug and related concepts
Concept design
The concepts Drug, Drug Article, Drug Administration Event, and Drug Prescription are of significant importance for the representation of processes concerning medication and treatment. The concepts are defined as follows:
“Drug” is defined as “any substance with the intent to prevent, diagnose, treat, or relieve symptoms of a disease or abnormal condition”.
“Drug Article” represents “general details identifying a medication on the level of its commercial article”. Often, several commercial articles of the same drug exist, e.g., in different packaging sizes. Hence, Drug article is not to be confused with a drug on the level of a product.
“Drug Prescription” specifies the “plan that defines at which frequency a drug should be administered to a patient with a given quantity; at every frequency time point a drug administration event should occur”.
Notably, the Drug Prescription concept is limited to a single drug for technical reasons, unlike for example the prescription paper issued by a doctor. In case multiple drugs are prescribed, multiple Drug Prescriptions need to be instantiated. It is important to emphasize that one Drug Prescription can trigger multiple Drug Administration Events.
“Drug Administration Event” represents a “single event at which a drug was administered to the patient; this could be a single time point in case of a pill/cream or a duration in case of a single infusion pack or a single patch; one or many drug administration events are initiated by a drug prescription depending on the frequency stated in the prescription”.
Notably, the Drug Administration Event concept is limited to a single drug for technical reasons. In case multiple drugs are administered, multiple Drug Administration Events need to be instantiated.
Note that there is no direct link between a Drug Prescription and a Drug Administration Event as this linkage information is often not available in hospitals. The concepts are linked, however, via Administrative Case, Subject Pseudo Identifier, and Source System.
The active substance is of key importance for a drug administration rather than the drug itself. Therefore the drug prescribed and the drug administered may in practice differ since there are often multiple drugs with the same active substance, e.g., Aspirin, Dolopirin, Alka Seltzer etc. all having acetylsalicylic acid as active ingredient. Compare “Example for data delivery”.
Figure 1: Overview of the design of Drug-related concepts
Examples for data delivery
The example from Figure 2 shows the hypothetical case of a 78 year old patient (as of 2024-06-21) who had been diagnosed with a form of atherosclerotic heart disease (ICD-10-GM code I25.10) several years ago (on 2022-03-07). The patient gets prescribed ASPIRIN CARDIO 300 mg (GTIN: 7680517950598) film-coated tablets for prophylactic reasons on 2024-06-21. Note that the information that one tablet contains 300 mg of acetylsalicylic acid (master data from HCI Compendium) is not explicitly contained! The patient shall take 2 tablets (non-standard unit {#}) orally 3 times per day, and intake is supposed to start on 2024-06-24 and end on 2024-09-24. The amount of the active ingredient acetylsalicylic acid (ATC code: B01AC06) per single Drug Administration Event triggered by the Drug Prescription is intended to be 600 mg (2 tablets with 300mg each per intake). The tablets also contain methylcellulose (ATC code: A06AC06) as an inactive ingredient.
In the example, the patient uses a drug from a different manufacturer (“ASS CARDIO Zentiva 100 mg”, GTIN: 7680686590014) with a different formulation yet the same active ingredient (acetylsalicylic acid (ATC code: B01AC06)). The pharmaceutical dose form of the alternative product are gastro-resistant oral tablets with 100 mg acetylsalicylic acid (ATC code: B01AC06) per tablet. Again, this information on pharmaceutical strength is not explicitly represented in the graph! The tablets also contain 60 mg “Lactose-1-Wasser” per tablet as inactive ingredient (HCI Compendium master data). The patient takes an oral dose of 6 tablets (each with 100 mg acetylsalicylic acid) on 2024-06-24 at 08:01:30, reaching the intended total amount of 600 mg per intake.
For each medication (prescribed and administered) several packaging sizes are available, therefore the GTIN of the smallest packaging size was used (7680517950598 and 7680686590014, respectively).
Please note that in Figure 2 the connections to Administrative Case, Subject Pseudo Identifier, and Source System are only shown for Drug Prescription and Drug Administration Event for clarity, and to Source System for Drug and Drug Article.
In this example, Drug, Drug Prescription, and Drug Administration Event use the same Source System while Drug Article information is stored on another Source System.
Figure 2: Example of mock instantiation of Drug Prescription and Drug Administration Event where a patient got prescribed a certain medication (Aspirin Cardio 300mg) and gets administered an alternative product (ASS CARDIO Zentiva 100 mg) with a different dosage and formulation, however, receiving the same total amount of active ingredient. Note that the instances are randomly numbered, e.g., “drug prescription 1”, “quantity 14”, or “substance 4”.
Guideline for data delivery
Drug Article
The “Drug Article”-concept provides metainformation on the “Drug” associated with “Drug Prescription” and “Drug Administration Event”. This includes a GTIN-code and the pharmaceutical dose form. A name can also be provided as a string if no GTIN is available. Note that Pharmacodes are not in scope as code standard for the “Drug Article”-concept as Pharmacodes do neither represent an international standard nor are they openly available but need to be licensed from HCI Solutions.
Note that GTINs do not represent a product code! Instead, GTINs are article codes which vary for different packaging sizes of the very same medication. This may lead to the false conclusion that patients have been treated with different drugs when only taking into account differing GTINs. It is therefore recommended to use the GTIN of the smallest available packaging size for Drug article, regardless of the package size prescribed or the package size the medication has in fact been administered from.
Please note that the current Drug-related concepts (release 2024.2) do not allow to represent the “drug strength” of a drug (NCIT code C53294 “pharmaceutical strength”: “The content of an active ingredient expressed quantitatively per dosage unit, per unit of volume, or per unit of weight, according to the pharmaceutical dose form.”). Such master data is currently only available to the data providers which have licensed this information from HCI solutions. Notably, once metadata would become available which features normalized names and unique identifiers for medicines and drugs like for example RxNorm it could be readily connected to Drug Article. Such a terminology would also resolve the issues associated with different GTINs for different packaging sizes.
Quantities
Semantically, attributes refer to the parent concept, therefore a “quantity”-attribute has context-dependent meanings:
Since release 2024.1, Drug Prescription and Drug Administration Event do not hold a “quantity”-attribute any more as this has repeatedly led to confusion about what information to provide there. A “quantity” of “Drug Prescription” and “Drug Administration Event” would indicate the number of drug prescriptions or drug administrations, not an amount of drug prescribed or administered.
A “quantity”-attribute of “Drug” refers to the drug amount, e.g., 3 tablets or 5 mL.
A “quantity”-attribute of “Substance” (as attribute of “Drug”) refers to the amount of active or inactive components within the drug, e.g., 500 mg or 20 IU. This quantity does NOT represent the amount of active or inactive ingredient per dosage form (“drug strength”) but the amount of active or inactive ingredient for the amount of drug as specified by the “quantity”-attribute of Drug!
For multiple drug prescriptions, multiple instances of “Drug Prescription” shall be instantiated. A Drug Administration Event represents by its definition (see above) a “single event at which a drug was administered”, i.e., a quantity-attribute is not meaningful. As for Drug Prescription, multiple drug administration events shall be represented by multiple instances of “Drug Administration Event”.
Along with the removal of the “quantity”-attribute from Drug Prescription and Drug Administration Event a “quantity”-attribute has been introduced in the “Drug”-concept, in line with the design of the “Substance”-concept. Notably, the quantity of the drug is not to be confused with the quantity of the active or inactive substances contained in the drug.
Following the concept definitions, the composedOf ‘quantity’ of the Drug concept represents the following different aspects in the context of Drug Prescription and Drug Administration Event:
Drug Prescription: ‘quantity’ of the Drug represents the quantity intended to be administered during a single Drug Administration Event. It corresponds to the quantity prescribed or written in the Drug Prescription, e.g. “2 tablets” if “2 tablets 3 times per day” are prescribed: “2 tablets” is covered by the quantity of the Drug, “3 times a day” by the frequency of the Drug Prescription.
Drug Administration Event: The ‘quantity’-attribute of the Drug represents the total quantity of a drug administered during a single Drug Administration Event, e.g., 2 tablets between start and end datetime, or 500 ml during the duration.
Note: The ‘quantity’-attributes of the active and inactive ingredients of Drug represent the total amount of the specific ingredient administered during the Drug Administration Event.
Units
The unit of the “quantity”-attribute of Drug shall be represented in UCUM units whenever possible, e.g., mL or mg.
Non-standard units of drugs, however, cannot be represented properly, e.g., drops, sachets, tablets, pills, or ampoules etc. In such cases the symbol {#} is to be used as a unit. The label of “{#}” is “number”. Information on the pharmaceutical dose form can be retrieved via the “pharmaceutical dose form”-attribute of the Drug Article associated with the Drug-instance.
The unit of the “quantity”-attribute of active or inactive substances associated with a drug shall be represented in UCUM units like mg or IU.
Total quantities
Drug amount
Total quantities of Drug over a specific period can (and need to) be calculated, either including all Drug Administration Events during the time period of interest, or spanning the time between first and last administration datetime for Drug Prescription.
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The total amount of drug (e.g., 6 tablets or 2 mL etc.) administered over a period of time involving multiple identical Drug Administration Events (DAEs) is calculated as follows:
Notably, this is not to be confused with the total amount of active or inactive ingredients! See section “(Active) Ingredients” below for further details.
For a single Drug Administration Event this therefore simplifies to:
The total amount of drug prescribed over a period of time is calculated as follows (assuming full days for the administration datetimes):
(Active) Ingredients
In the context of Drug Administration Events, not only the amount of drug but also the total amount of active ingredients(s) is of particular interest. For a single Drug Administration Event it is calculated as follows:
The total amount is to be stored under the ‘quantity’ of the respective active ingredient of the Drug as attributes are context-dependent and describe the instance of the concept they refer to.
Notably, this amount needs to be delivered pre-calculated by the data provider as the RDF schema (release 2024.2) holds no place to store the amount of active ingredient per dosage form, i.e., the pharmaceutical strength (e.g., amount of active ingredient per 1 tablet or 1 ml).
Notably, the total quantities of different active or inactive ingredients must NOT be summed up! Such a sum holds no meaningful information.
The total amount of active ingredient for multiple identical Drug Administration Events (DAEs) over a specific period of interest is often of particular clinical interest, e.g., in cancer therapy, and calculated as follows:
Limitations and caveats
Several specific use cases cannot currently be fully detailed, in part because an openly available terminology of drug metadata is missing.
Non-standard units of drugs, e.g., drops, sachets, ampoules etc, need to be represented using {#} as a unit, see section “Units” above.
Non-standard units like “drop” would need to be represented in SI-units for full transparency, e.g., 1 drop = 0.036 ml.
Example: GANFORT Gtt Opht (eye-drops for glaucoma treatment; GTIN #7680576300013 or 7680576300037).
This information is available in the HCI compendium (which needs to be licensed) or directly from the drug manufacturer but is not allowed to be represented in the current SPHN schema. Unfortunately, this undermines efforts to provide all elements for the calculation of amounts of active ingredients for a specific dose.
The representation of such a drug dosage equivalence involves a calculation which needs to be carried out by the data provider when retrieving the drug amount but is out of scope of the current SPHN concepts.
For some drugs the reference amount is not a single unit.
Example: SPRAVATO Nasenspray 28 mg (antidepressant nasal spray; GTIN # 7680671030013, 7680671030020, or 7680671030037) where a dose of 28 mg Esketamin is contained in 2 puffs (presumably one puff per nostril intended). Such a reference amount could be represented in an extended ‘Drug Article’-concept in the future but is out of scope of the current SPHN concepts.
Some drugs are not applied “as is” but need to be pre-processed, for example, dissolved.
Example: Fibrogammin 1’250 I.E.(GTIN # 7680006710061) containing 1’250 I.U. dried coagulation factor XIII (human) is to be dissolved in 20 ml water for injection or infusion. Without this reference amount information, the information that a specific volume was administered is not informative.
In this particular case, dissolving the drug represents a processing step which cannot be represented using the current SPHN concepts. The calculation of the administered quantity of active substance(s) needs to be carried out by the data provider.
Some drugs need to be diluted before use to reach a recommended concentration. This involves both a processing step and a calculation which again is out of scope of the current SPHN concepts. Corresponding calculations need to be carried out by the data provider when retrieving the quantity of active substance(s).
Example: of LAVASEPT Konz (GTIN # 7680504450704; containing 200 mg/ml Polihexanidum) which is recommended to be diluted to a final concentration of 0.2 to 0.4 mg/ml Polihexanidum before being administered.