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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 DA domain represents details on the amount of study product dispensed and returned.  

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. 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. 

Example

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In this example, the EC domain is not used by the sposnor to represent collected exposure. Expoure was represented based on the volume of the e-nicotine liquid cartridges. 

Example

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In this example, both the EC and EX domains are used.  Exposure was based on the weight of the e-nicotine liquid cartridges. 

Example

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.    

da.xpt

xx.xpt

RowSTUDYIDDOMAINUSUBJIDDASEQDAREFIDDATESTCDDATESTDACATDASCATDAORRESDAORRESUDASTRESCDASTRESNDASTRESUVISITNUMDADTC
1TEDP07DA10001

1

CRT8754DISPAMTDispensed AmountSTUDY PRODUCTE-LIQUID25.3g2525g12004-06-06
2TEDP07DA10001

2

CRT8754RETAMTReturned AmountSTUDY PRODUCTE-LIQUID23g2323g12020-06-06
3TEDP07DA10001

3

CRT9756DISPAMTDispensed AmountSTUDY PRODUCTE-LIQUID25.1g2525g12020-06-07
4TEDP07DA10001

4

CRT9756RETAMTReturned AmountSTUDY PRODUCTE-LIQUID10g1414g22020-06-08
5TEDP07DA10001

5

CRT9955DISPAMTDispensed AmountSTUDY PRODUCTE-LIQUID25.2g2525g22004-06-08
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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.           

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ec.xpt

Row

STUDYID

DOMAIN

USUBJID

ECSEQ

ECTRT

ECDOSE

ECDOSTXT

ECDOSU

ECDOSFRM

ECROUTE

ECLOCECLATECDIREPOCH

ECSTDTC

ECENDTC

1TEDP07EC10001 1ENDS  10
PUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-01T08:002020-06-01T08:10
2TEDP07EC10001 2

 PATCH 

1
PATCHPATCHTRANSDERMALARMRIGHTUPPERPRODUCT EXPOSURE2020-06-012020-06-02
3TEDP07EC10001 3ENDS 
AD LIBITUMPUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-01T12:102020-06-02
4TEDP07EC10001 4ENDS  
AD LIBITUMPUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-022020-06-03
5TEDP07EC100015PATCH 1
PATCHPATCHTRANSDERMALARMLEFTUPPERPRODUCT EXPOSURE2020-06-022020-06-03
6TEDP07EC100016ENDS 
AD LIBITUMPUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-032020-06-04
7TEDP07EC100017PATCH 1
PATCHPATCHTRANSDERMALLEGLEFTUPPERPRODUCT EXPOSURE2020-06-032020-06-04
7TEDP07EC10001 8ENDS 
AD LIBITUMPUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-042020-06-05
8TEDP07EC10001 9PATCH 1
PATCHPATCHTRANSDERMALLEGLEFTLOWERPRODUCT EXPOSURE2020-06-042020-06-05
9TEDP07EC1000110ENDS 10
PUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-10T8:302020-06-10T8:40
10TEDP07EC1000111 PATCH 1
PATCH PATCH TRANSDERMALLEGRIGHTLOWERPRODUCT EXPOSURE2020-06-102020-06-11
11TEDP07EC1000112ENDS 
AD LIBITUMPUFFCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE2020-06-10T12:402020-06-11
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 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.
$titleHtml

ex.xpt

Row

STUDYID

DOMAIN

USUBJID

EXSEQ

EXTRT

EXDOSE

EXDOSU

EXDOSFRM

EXROUTE

EXLOCEXLATEXDIREPOCH

EXPSTRG

EXPSTRGU

EXSTDTC

EXENDTC

1TEDP07EX10001 1e nicotine liquid 1.7gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-01T08:002020-06-01T:8:10
2TEDP07EX10001 2e nicotine liquid 15.1gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-01T12:102020-06-02
3TEDP07EX10001 3e nicotine liquid 13gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-022020-06-03
4TEDP07EX100014e nicotine liquid 12gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-032020-06-04
5TEDP07EX10001 5e nicotine liquid 9gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-042020-06-05
6TEDP07EX100016e nicotine liquid 7gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-10T08:302020-06-10T08:40
7TEDP07EX100017e nicotine liquid 5gCARTRIDGERESPIRATORY (INHALATION)


PRODUCT EXPOSURE5%2020-06-10T12:402020-06-11
8TEDP07EX20001 1

nicotine replacement therapy

1PATCHPATCHTRANSDERMALARMRIGHTUPPERPRODUCT EXPOSURE14mg2020-06-012020-06-02
9TEDP07EX200012nicotine replacement therapy1PATCHPATCHTRANSDERMALARMLEFTUPPERPRODUCT EXPOSURE14mg2020-06-022020-06-03
10TEDP07EX200013nicotine replacement therapy1PATCHPATCHTRANSDERMALLEGLEFTUPPERPRODUCT EXPOSURE14mg2020-06-032020-06-04
11TEDP07EX20001 4nicotine replacement therapy1PATCHPATCHTRANSDERMALLEGLEFTLOWERPRODUCT EXPOSURE14mg2020-06-042020-06-05
12TEDP07EX200015nicotine replacement therapy1PATCH PATCHTRANSDERMALLEGRIGHTLOWERPRODUCT EXPOSURE14mg2020-06-102020-06-11
$warningHtml

In this example, subjects were exposed to mulitple study products. The actual dates and times of use for each product is represented. 

Example

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.            

ex.xpt

ex.xpt

RowSTUDYIDDOMAINUSUBJIDEXSEQEXTRTEXCATEXDOSEEXDOSUEXDOSFRMEXROUTEEXPSTRGEXPSTRGUVISITNUMVISITVISITDYEPOCHEXSTDTCEXENDTC
1ALCS-REG-STUDYEXALCS-REG-STUDY_100011PRODUCT CUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg10DAY -1-1PRODUCT EXPOSURE2019-06-27T13:10:332019-06-27T13:38:49
2ALCS-REG-STUDYEXALCS-REG-STUDY_100012PRODUCT CUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg10DAY -1-1PRODUCT EXPOSURE2019-06-27T14:29:132019-06-27T14:54:53
3ALCS-REG-STUDYEXALCS-REG-STUDY_100013PRODUCT CCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg11DAY 11PRODUCT EXPOSURE2019-06-28T08:00:122019-06-28T08:30:21
4ALCS-REG-STUDYEXALCS-REG-STUDY_100014PRODUCT EUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL4mg11DAY 11PRODUCT EXPOSURE2019-06-28T14:01:522019-06-28T14:55:27
5ALCS-REG-STUDYEXALCS-REG-STUDY_100015PRODUCT EUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL4mg11DAY 11PRODUCT EXPOSURE2019-06-28T15:18:352019-06-28T15:57:33
6ALCS-REG-STUDYEXALCS-REG-STUDY_100016PRODUCT ECONTROLLED PRODUCT USE1POUCHPOUCHORAL4mg12DAY 22PRODUCT EXPOSURE2019-06-29T08:00:082019-06-29T08:30:13
7ALCS-REG-STUDYEXALCS-REG-STUDY_100017PRODUCT BUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg12DAY 22PRODUCT EXPOSURE2019-06-29T14:01:502019-06-29T14:50:11
8ALCS-REG-STUDYEXALCS-REG-STUDY_100018PRODUCT BUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg12DAY 22PRODUCT EXPOSURE2019-06-29T15:24:332019-06-29T15:59:46
9ALCS-REG-STUDYEXALCS-REG-STUDY_100019PRODUCT BCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg13DAY 33PRODUCT EXPOSURE2019-06-30T08:00:002019-06-30T08:30:00
10ALCS-REG-STUDYEXALCS-REG-STUDY_1000110PRODUCT DUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg13DAY 33PRODUCT EXPOSURE2019-06-30T14:12:322019-06-30T14:47:47
11ALCS-REG-STUDYEXALCS-REG-STUDY_1000111PRODUCT DUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg13DAY 33PRODUCT EXPOSURE2019-06-30T15:24:462019-06-30T16:04:57
12ALCS-REG-STUDYEXALCS-REG-STUDY_1000112PRODUCT DCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg14DAY 44PRODUCT EXPOSURE2019-07-01T08:00:002019-07-01T08:30:00
13ALCS-REG-STUDYEXALCS-REG-STUDY_1000113PRODUCT AUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg14DAY 44PRODUCT EXPOSURE2019-07-01T14:02:362019-07-01T14:47:33
14ALCS-REG-STUDYEXALCS-REG-STUDY_1000114PRODUCT AUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg14DAY 44PRODUCT EXPOSURE2019-07-01T15:37:452019-07-01T15:58:15
15ALCS-REG-STUDYEXALCS-REG-STUDY_1000115PRODUCT ACONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg15DAY 55PRODUCT EXPOSURE2019-07-02T08:00:002019-07-02T08:30:01
16ALCS-REG-STUDYEXALCS-REG-STUDY_1000116PRODUCT FUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg15DAY 55PRODUCT EXPOSURE2019-07-02T14:11:002019-07-02T14:54:08
17ALCS-REG-STUDYEXALCS-REG-STUDY_1000117PRODUCT FUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg15DAY 55PRODUCT EXPOSURE2019-07-02T15:38:522019-07-02T15:59:50
18ALCS-REG-STUDYEXALCS-REG-STUDY_1000118PRODUCT FCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg16DAY 66PRODUCT EXPOSURE2019-07-03T08:00:002019-07-03T08:30:00
19ALCS-REG-STUDYEXALCS-REG-STUDY_1000119PRODUCT GUNCONTROLLED PRODUCT USE3.37gQUIDORAL4mg16DAY 66PRODUCT EXPOSURE2019-07-03T14:13:142019-07-03T14:57:40
20ALCS-REG-STUDYEXALCS-REG-STUDY_1000120PRODUCT GUNCONTROLLED PRODUCT USE3.2gQUIDORAL4mg16DAY 66PRODUCT EXPOSURE2019-07-03T15:35:012019-07-03T16:07:25
21ALCS-REG-STUDYEXALCS-REG-STUDY_1000121PRODUCT GCONTROLLED PRODUCT USE2gQUIDORAL4mg17DAY 7/EARLY TERMINATION7PRODUCT EXPOSURE2019-07-04T08:00:042019-07-04T08:30:05
22ALCS-REG-STUDYEXALCS-REG-STUDY_100021PRODUCT EUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg10DAY -1-1PRODUCT EXPOSURE2019-07-04T14:06:092019-07-04T14:14:14
23ALCS-REG-STUDYEXALCS-REG-STUDY_100022PRODUCT ECONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg11DAY 11PRODUCT EXPOSURE2019-07-05T08:00:002019-07-05T08:30:00
24ALCS-REG-STUDYEXALCS-REG-STUDY_100023PRODUCT DUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL4mg11DAY 11PRODUCT EXPOSURE2019-07-05T14:02:392019-07-05T14:18:57
25ALCS-REG-STUDYEXALCS-REG-STUDY_100024PRODUCT DCONTROLLED PRODUCT USE1POUCHPOUCHORAL4mg12DAY 22PRODUCT EXPOSURE2019-07-06T08:00:002019-07-06T08:30:00
26ALCS-REG-STUDYEXALCS-REG-STUDY_100025PRODUCT CUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg12DAY 22PRODUCT EXPOSURE2019-07-06T14:00:002019-07-06T14:08:40
27ALCS-REG-STUDYEXALCS-REG-STUDY_100026PRODUCT CUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg12DAY 22PRODUCT EXPOSURE2019-07-06T15:52:532019-07-06T15:59:21
28ALCS-REG-STUDYEXALCS-REG-STUDY_100027PRODUCT CCONTROLLED PRODUCT USE1POUCHPOUCHORAL6mg13DAY 33PRODUCT EXPOSURE2019-07-07T08:00:002019-07-07T08:30:00
29ALCS-REG-STUDYEXALCS-REG-STUDY_100028PRODUCT FUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg13DAY 33PRODUCT EXPOSURE2019-07-07T14:01:122019-07-07T14:12:25
30ALCS-REG-STUDYEXALCS-REG-STUDY_100029PRODUCT FUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg13DAY 33PRODUCT EXPOSURE2019-07-07T14:57:492019-07-07T15:07:07
31ALCS-REG-STUDYEXALCS-REG-STUDY_1000210PRODUCT FCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg14DAY 44PRODUCT EXPOSURE2019-07-08T08:00:002019-07-08T08:30:00
32ALCS-REG-STUDYEXALCS-REG-STUDY_1000211PRODUCT BUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL0mg14DAY 44PRODUCT EXPOSURE2019-07-08T14:00:522019-07-08T14:17:31
33ALCS-REG-STUDYEXALCS-REG-STUDY_1000212PRODUCT BUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg14DAY 44PRODUCT EXPOSURE2019-07-08T14:46:072019-07-08T14:53:43
34ALCS-REG-STUDYEXALCS-REG-STUDY_1000213PRODUCT BCONTROLLED PRODUCT USE1POUCHPOUCHORAL2mg15DAY 55PRODUCT EXPOSURE2019-07-09T08:00:012019-07-09T08:30:01
35ALCS-REG-STUDYEXALCS-REG-STUDY_1000214PRODUCT GUNCONTROLLED PRODUCT USE2.69gQUIDORAL4mg15DAY 55PRODUCT EXPOSURE2019-07-09T14:06:242019-07-09T14:30:16
36ALCS-REG-STUDYEXALCS-REG-STUDY_1000215PRODUCT GUNCONTROLLED PRODUCT USE3.3gQUIDORAL4mg15DAY 55PRODUCT EXPOSURE2019-07-09T14:49:392019-07-09T15:15:16
37ALCS-REG-STUDYEXALCS-REG-STUDY_1000216PRODUCT GCONTROLLED PRODUCT USE2gQUIDORAL4mg16DAY 66PRODUCT EXPOSURE2019-07-10T08:00:002019-07-10T08:30:00
38ALCS-REG-STUDYEXALCS-REG-STUDY_1000217PRODUCT AUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg16DAY 66PRODUCT EXPOSURE2019-07-10T14:02:072019-07-10T14:35:40
39ALCS-REG-STUDYEXALCS-REG-STUDY_1000218PRODUCT AUNCONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg16DAY 66PRODUCT EXPOSURE2019-07-10T15:27:372019-07-10T15:58:24
40ALCS-REG-STUDYEXALCS-REG-STUDY_1000219PRODUCT ACONTROLLED PRODUCT USE1POUCHPOUCHORAL8mg17DAY 7/EARLY TERMINATION7PRODUCT EXPOSURE2019-07-11T08:00:002019-07-11T08:30:00
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