Introduction

Ontologies are a representation of domain knowledge using defined concepts and the relationships between those concepts in a manner understandable to both humans and machines.

With the IDMP Ontology, we can express statements about things such as substances or medicinal products. While some statements are universally true (e.g., "Amlodipine is a chemical substance" or "Amlodipine is included in Norvasc"), some statements are true only in specific situations/contexts, e.g., the strength of a certain substance makes sense only in the context of a product.

To capture the context, an established pattern in ontology modelling is to use "roles". E.g., a human Max can play the role "patient" in the context of a treatment. Or a substance can play the role "active ingredient" in the context of one pharmaceutical product while the same substance may play the role "excipient" in the context of a different product.

The role concept (hereafter referred to as 'role') and corresponding ontological role model pattern provide a structured and modular way to capture many different real-world complexities.

Relation to ISO-IDMP Standards

There is no general role pattern described in the ISO IDMP standards. However, roles are mentioned, e.g., for describing an ingredient in the context of a pharmaceutical product. See also Pattern: Ingredient - DRAFT

Modeling Pattern

In the following, we incrementally explain why we need roles, how contextualized roles are modeled in general and instantiated with examples.

Universal Statement without Role Pattern

Diagram 1: Simple statement that is universally true and doesn't require context.

Example: Amlodipine Mesylate Monohydrate is included Amlodipine EMC (a pharmaceutical product)

Diagram 2: Example for universal statement "Amlodipine mesylate monohydrate is included in Amlodipine EMC"

Basic Role Pattern

In order to further specify a relationship, we use the basic role pattern that allows us to provide details about the role and about where the role is realized, appears, or occurs (through property "is manifested in")

Diagram 3: The basic role pattern

The relationships "plays role" and "is played by" as well as the relationships "is manifested in" and "manifests" are inverse relationships respectively. Of course, these general classes "Thing" and "Role" are instantiated with more specific subclasses, as illustrated in the next example:

Example: Amlodpine Mesylate Monohydrate plays role active ingredient in Amlodipine EMC

Diagram 4: Example for the basic role pattern: ingredient in a product

The important thing is that we can now attach all information that further specifies the role of Amlodipine mesylate monohydrate in Amlodipine EMC to the middle role node in the graph, e..g., the strength or further context specification (see below).

If multiple roles need to be further grouped or a role doesn't uniquely connect an object with its manifestation, then the Pattern: Constituencies - DRAFT needs to be applied.

Role Hierarchy in IDMP-O

The role (https://www.omg.org/spec/Commons/PartiesAndSituations/Role) is modeled as a class and can be specialized with sub-classes, some of which are shown in the next figure

Diagram 5: Role hierarchy

Optional Context Definition

The context is a "situation" or frame of reference in which something applies, exists, happens, or is used, and that helps to illustrate or explain it.

Diagram 6: Contextualization of Roles

As for roles, "context" can have subclasses to further specify its nature, e.g., jurisdiction, regulatory, scientific or similar.

Examples

Modeling the different active moiety roles for Aripiprazole Lauroxil in different contexts

The contextualized role pattern is used here to model interpretations of the active moiety role for Aripiprazole in different situations. Aristada is a drug developed by Alkermes and is composed of Aripiprazole lauroxil. Aripiprazole lauroxil is first metabolized to N-hydroxymethyl aripiprazole, which is then further metabolized to Aripiprazole which exerts pharmaceutical effects in the body. From a regulatory perspective, Aripiprazole is thus the active moiety. However, based on the interpretation of a patent by the US court, based on the fillings by the owner of the intellectual property (IP) on Aripiprazole lauroxil, the active component is stated as the N-hydroxymethylated product instead. Diagrams 5 and 6 below demonstrate how in different contexts, the active moiety for Aripiprazole lauroxil can be either N-hydroxymethyl Aripripazole or Aripiprazole itself.

NOTE: The differences in interpretation of active moiety for Aripiprazole lauroxil came about, as Otsuka Pharmaceuticals challenged FDA's approval for a new drug application for Alkermes's drug Aristada (Aripiprazole lauroxil) stating that it ultimately metabolizes to Aripiprazole which is the active moiety for Otsuka Pharmaceutical's drug Abilify (Aripiprazole). However, under USP's salt policy, the active moiety for Aripiprazole lauroxil is designated as N-hydroxymethyl aripiprazole.

In the third example, the USP salt policy context is considered when naming the active moiety for Aripiprazole lauroxil. The USP (United States Pharmacopeia) Salt Policy outlines a naming and labeling approach for drug products containing an active ingredient that is a salt, and applies to drug product monograph titles published after the 1st of May 2013. According to the USP salt policy, Aripiprazole lauroxil is designated as the active moiety for Aripiprazole lauroxil (Diagram 7).

Active Moiety Role for FDA Exclusivity

Diagram: Modeling N-hydroxymethyl aripiprazole as the active moiety for Aripiprazole lauroxil in a FDA patent exclusivity context

Active Moiety Role FDA GSRS

Diagram: Modeling Aripiprazole as the active moiety for Aripiprazole lauroxil in a regulatory FDA GSRS context

Active Moiety Role: USP Salt Policy

Diagram: Modeling Aripiprazole lauroxil as the active moiety for Aripiprazole lauroxil in a USP salt policy context

USP documentation

USP Salt Policy (December 2014) - YouTube

Pattern: Contextualized Roles - DRAFT