Exposure Assessments During a Trial

Tobacco products come in a variety of forms that are used in different ways. They are available as skin patches, chewing gum, nasal and oral sprays, inhalers, lozenges and tablets. 

The nicotine may be delivered using electronic nicotine delivery systems (ENDS). These are some of the terms used to describe electronic nicotine delivery systems (ENDS):  Vapes, vaporizers, vape pens, hookah pens, electronic cigarettes (e-cigarettes or e-cigs), e-cigars, and e-pipes. These products use an “e-liquid” that usually contains nicotine derived from tobacco, as well as flavorings, propylene glycol, vegetable glycerin, and other ingredients. The liquid is heated to create an aerosol that the user inhales.

Self-reporting of nicotine exposure often may be biased and lead to inaccurate measures of exposure. Hence, biomarkers are often used to provide objective measures of nicotine exposure. Studies on tobacco products typically collect the quantities of the tobacco product used through self-reporting, while the actual nicotine exposure is measured by biomarkers. 

Studies evaluate the protocol-specified study product exposure. These products are typically supplied by the sponsor. However, sponosr may also collect exposure to other nicotine sources.      

The subject's normal nicotine product usage (e.g., usually brand of cigarettes, nicotine replacement patches) may be allowed, or discouraged in the study.  These products are not supplied by the sponsor, and are not considered a study product. The use of these products would be represented in the SU ( for cigarettes and CM (for nicotine replacements patches) domains.     

Studies may be performed under controlled circumstances in clinics, to ensure that the only nicotine exposure is the product itself. 

Exposure data on the study product of interest are reported in the Exposure as Collected (EC) and/or the Exposure (EX) domains as well as the Product Accountability Domain (DA).

• The Product Accountability (DA) is a findings domain that represents the accountability of study products, such as information on the receipt, dispensing, return, and packaging.
• The Exposure as Collected (EC) is an interventions domain that represents information about protocol-specified studyproduct administrations, as collected. 
• The Exposure (EX) is an interventions domain that represents a subject's exposure to protocol-specified study product.  Study product is usually an intervention that is prospectively defined as a test material within a study, and is typically but not always supplied to the subject.

The Exposure as collected (EC) domain is typically used to reflect amounts at the product-level (e.g., number or cigarettes, number of cartridges, number of patches etc and not the actual exposure to the product. The actual exposure to the product would then be represented in EX. The EX data exposure is derived from EC, Product Accountability Domain (DA) and the protocol-specific details on the study product.    

The domains needed to represent the exposure in a tobacco product study is decided by the sponsor. Some sponsors use the EC domain to reflect the collected exposure data, and then derive EX. The degree of summarization of records from EC to EX is sponsor-defined and is used to support the study purpose and analysis. EX derivations must be described in the Define-XML document. More detail summarization may also be performed in ADaM. For example, the estimated daily nicotine exposure may based on self-reported nicotine exposure may be provided. Since, these are estimates, they are typically not reported in EX.     

Sponsors may find it easier to report both the collected data in EC  and the derived EX data to provide tracking of the summarized exposure to what was collected.

In some situation, sponsors may elect to only use the EX, and if needed the DA domains. EX would be used-when little relevant information is represented in EC, in a sense EC and EX are essentially duplicates of each other. For example, the derivation for EX may just be the unmasking of the product, and a sponsor may decide not to show the EC because the derivations used for EX are obvious.  

The EX domain is required for all studies that include protocol-specified study product exposure. Exposure records may be directly or indirectly determined; metadata should describe how the records were derived. Common methods for determining exposure (from most direct to least direct) include the following:

1. 1. Derived from actual observation of the administration of  study product by the investigator
   2. Derived from an automated dispensing device that records administrations
   3. Derived from subject recall
   4. Derived from product accountability data
   5. Derived from the protocol. When a study is still masked and protocol-specified study product exposure cannot yet be reflected in the protocol-specified unit due to blinding requirements, then the EX domain is not expected to be populated. 

The example below illustrate various methods for displaying study product exposure data, as well as data that may be collected on the usage of other nicotine sources.   

In the following example, the sponsor reported protocol described usage of a nicotine inhaler using the EX and EC domains. Usage of non-protocol defined product usage (alcohol and other tobacco products) were represented in the SU domain. Additionally, any usage of nicotine patches to reduce dependency on tobacco were reported in the CM domain. Study product exposure was represented as the number of cartridges used. The pharmaceutical strength of each cartridge was represented.