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SDTM Issue: Can we revise the rules for TIG that EX is not expected, but that EC can be submitted instead of EX since typically only the amount of product used is supplied.   EX is to be used  when an actual "nicotine"  exposure are provide as the dose.  Additionally, when pharmaceutical drugs are used  then the EC/EX rules in SDTM are followed-. We have no issues, because the treatment is not nicotine.     

Assumption for the SDTMIG that may be of concern.  

1. The EX domain is required for all studies that include protocol-specified study treatment. 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. Derived from actual observation of the administration of drug by the investigator
   2. Derived from 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 treatment doses cannot yet be reflected in the protocol-specified unit due to blinding requirements, then the EX domain is not expected to be populated.

Nicotine replacement therapy (NRT) comes in a variety of forms that are used in different ways. It is available as skin patches, chewing gum, nasal and oral sprays, inhalers, lozenges and tablets.

Vapes, vaporizers, vape pens, hookah pens, electronic cigarettes (e-cigarettes or e-cigs), e-cigars, and e-pipes are some of the many tobacco product terms used to describe electronic nicotine delivery systems (ENDS). 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.

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of nicotine exposure often may be biased and lead to inaccurate measures of exposure. Hence, biomarkers are often used to provide objective

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measures of nicotine exposure. Studies on tobacco

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products typically collect the quantities of the tobacco product used

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through self-reporting, while the actual nicotine exposure is measured by biomarkers. 

Studies evaluate the protocol-specified study product exposure. These study products are typically supplied by the applicant. However, applicants often collect exposure to other nicotine sources.      

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

Studies may be performed under controlled circumstances in clinics, to ensure that the only nicotine exposure is the study 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 (DA) domain.

• The DA domain is a Findings domain for representing the accountability of study products (e.g., information on receipt, dispensing, return, packaging).
• The EC domain is an Interventions domain for representing information about protocol-specified study product administrations, as collected. 
• The EX domain is an Interventions domain for representing 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 EC domain is typically Exposure as collected (EC) domain is 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 , which would be represented in EX. The actual exposure is typically EX data are derived from EC, DA, and the protocol-specific details on the study product used.  Product accountability details (e.g., amount dispensed, amount returned) are represented in the Product Accountability Domain (DA) domain, and not in EC or EX. .    

The domains needed to represent the exposure in a tobacco product study are decided by the applicant. Some applicants 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-applicant defined and is used to support the study purpose and analysis. EX derivations must be described in the Define-XML document. The 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; because these are estimates, they are typically not reported in EX.     

Applicants 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 situations, applicants may elect to only use the EX and, if needed, the DA domain. EX would be used when little relevant information is represented in EC (i.e., when EC and EX would essentially be duplicates). For example, the derivation for EX may just be the unmasking of the product, and a applicant 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:

• Derived from actual observation of the administration of  study product by the investigator
• Derived from an automated dispensing device that records administrations
• Derived from subject recall
• Derived from product accountability data
• 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.