Tobacco Product Exposure

In this study, subjects were randomized to different doses of a nicotine inhaler. The recommended usage instructions for the nicotine inhaler were provided to the subject at each visit. At visits 1-3, subjects were to use 6-10 cartridges per day, and during visits 4-6 subjects were to use 3-6 cartridges per day. Subjects were encouraged not to use any other tobacco products, nicotine replacement therapies, or alcohol during the study. Data on usage of these products were collected using an e-diary, where subjects provided information on the products used each day. Only days where a product was used were represented. 

Alcohol usage and tobacco product usage were represented in the Substance Use (SU) domain. SUCAT allows the records to be grouped into tobacco-related data and alcohol-related data. In this example, the products were prespecified so SUTRT does not require a standardized SUDECOD equivalent. The applicant only includes SUSTDTC and SUENDTC as timing variables.   

Drugs used to treat nicotine dependency are considered drugs and were represented in the Concomitant Medication (CM) domain. This subject used a 14 mg nicotine replacement patch. The applicant included the CMCLASS, CMDECOD, and CMMODIFY. These were included to reflect standardized coding of the medication.  

The Product Accountability (DA) domain was used to represent the amount of study product transferred to or from the study subjects. At each visit, each subject was supplied with 90 cartridges per week for weeks 1-3, and 50 cartridges per week for weeks 4-6. The number of cartridges returned were counted. DACAT was used to indicate that the product of interest was the study product. DASPID and DAREFID can be used for code numbers that appeared on the study product label; in this case, no code numbers were included on the labels. The applicant included VISITNUM and DADTC as these variables are expected in this domain. DADTC was the date the supplies were dispensed or returned, these corresponded to the dates of the visits.   

The applicant used a patient diary (not shown here) to determine how many cartridges the subject used on each day, then created the EC data to represent the collected exposure data. Usage recommendations were represented in ECDOSRGM, which is the intended dose regimen. The ECMOOD permissible variable was used to reflect the prescribed and the actual usage of the inhaled nicotine. When this variable is used, it must be populated for all records. This variable cannot be used in EX.   

The EX dataset shows actual administrations. Scheduled records are not included, and only a few rows are shown for illustration purposes. The pharmaceutical strength was included to identify the dose of the nicotine inhaler used by the subject. Because EXENDTC is an expected variable, the applicant populated this timing variable with the start date.    

In this study, subjects were randomized to 1 of 3 nicotine dosage levels. At the baseline visit (week 0), they received an ENDS device that used 0, 8, or 24 mg/ml nicotine liquid. Self-reported daily cigarette consumption was recorded for each day of the study for 4 weeks. The subjects were supplied replacement nicotine cartridges at each weekly visit. The applicant used an e-diary to track when cartridges were inserted and removed, and the daily number of cigarettes smoked. Subjects used their normal brand of cigarettes; these were not supplied by the applicant, and are not considered a study product. Each cartridge was 8 mL. No other nicotine replacement products were allowed to be used. Multiple cartridges were dispensed at a visit.   

The applicant represented the cigarettes used in the SU domain. After the first visit, the number of cigarettes smoked for each day of the study were represented. If no cigarettes were smoked,(although "0" records are typically not included), 0 was recorded as the data was collected. Only a few rows are shown.    

The DA domain was used to represent dispensed and returned amounts. The ENDS product used in the study was assigned a product identifier (VAPE-Z27), and each cartridge had a uniquely assigned number. This unique number was represented in DAREFID. Multiple cartridges were dispensed at weekly visits, and each cartridge was tracked. At each weekly visit, all previously dispensed cartridges were returned and new cartridges dispensed. Cartridges were replaced at each visit. DADTC are the visit dates when the cartridge was returned or dispensed. Cartridges not used were recorded as having the full volume returned.     

Because the data in EC would be practically identical to the summarized EX domain, the applicant did not submit the EC domain. The applicant unblinded the study before creating the EX domain. The unblinded product name is provided in EXTRT; here, a dummy name is used for the tobacco product.

The applicant used an e-diary to collect the start and end date of the insertion and removal date of each cartridge in the ENDS device. For simplicity, in this example the actual times of insertion/removal were not collected, although this may often be collected.    

The total amount of liquid product used from each cartridge was determined using the data in the DA domain. The associated nicotine pharmaceutical strength of each cartridge was known. The applicant used this information in the analysis. The summaries included in the analysis were the estimated number of cartridges used per week, and the estimated nicotine exposure from the cartridges per day.    

In this study, subjects were randomized to either nicotine replacement patches or ENDS devices using e-nicotine liquid cartridges. In order to maintain the blind, subjects used both the nicotine replacement patches and the ENDS devices. Subjects were requested not to smoke, but the number of regular cigarettes used were collected. Subject were seen every day for 15 days. The nicotine patch was applied, at rotating sites, and the nicotine cartridge was replaced every day. The cartridge was weighed when dispensed and upon return. On days, 1, 5, and 10 subjects remained in the clinic for 4 hours for collection of biomarkers. On these days, a new ENDS nicotine cartridge was inserted and 10 puffs were taken over 10 minutes, and not used for the remaining collection period. A new cartridge was inserted at the end of the 4-hour collection period. A nicotine replacement patch was applied prior to using the ENDS device on these days.     

The SU domain was used to represent the number of cigarettes used, but is not shown.  

In this study, the weight of the contents in the cartridge was tracked. The DA domain was used to represent dispensed and returned weights of each cartridge. Only a few rows are shown. The product accountability information was not provided for the nicotine replacement patches.    

EC was used to represent the collected exposure data since a double-blind design was used. The EX domain was used to represent the subject's exposure to the actual product containing nicotine. The applicant represented each cartridge and patch used. The dose was represented as "1" to indicate 1 cartridge or patch. The actual date and specific time of usage of the cartridge was recorded on days 1, 5, and 10, while only the date of usage was recorded on other days.           

 Subject 10001 was randomized to the 5% pharmaceutical strength of the nicotine e-liquid, and subject 20001 was randomized to the nicotine patch with a pharmaceutical strength of 14mg. The applicant only represented the active product exposure for each subject in EX.

This is an example of a crossover study testing 7 smokeless tobacco products. All products contain nicotine except for product F, which was a nicotine-/tobacco-free product. Each subject first used the product ad libitum; the next day, the product usage was evaluated in the morning, as specified in the protocol. Subjects were confined to the site. Products were supplied to the subjects as needed by site staff. Each usage was recorded. The applicant did not submit a DA domain, nor an EC domain. The name of the actual product would be used, but a dummy name is used in this example.