SEND Example.In vivo Study Design with Toxicokinetic Subjects

This example assumes a design in which the applicant-defined protocol specifies the following information. All subjects are to be screened for 7 days prior to randomization into 3 protocol groups:

Group 1 is a control group of 20 subjects, 10 male and 10 female, dosed with vehicle once per day for 28 to 30 days. Three subjects of each sex will be subject to blood sampling for the purpose of toxicokinetic (TK) analysis and all remaining animals will be scheduled for necropsy.
Group 2 is a low-dose group of 20 subjects, 10 male and 10 female, dosed at 100 mg/kg once per day for 28 to 30 days. Three subjects of each sex will be subject to blood sampling for the purpose of TK analysis and all remaining animals will be scheduled for necropsy.
Group 3 is a high-dose group of 20 subjects, 10 male and 10 female, dosed at 500 mg/kg once per day for 28 to 30 days. Three subjects of each sex will be subject to blood sampling for the purpose of TK analysis and all remaining animals will be scheduled for necropsy.

Group Number	Group Label	Dose Level	Number of Animals (Both Sexes Combined)
Group Number	Group Label	Dose Level	Non-Toxicokinetic	Toxicokinetic
1	Group 1, Control	Vehicle Control	14	6
2	Group 2, 100 mg/kg	100 mg/kg/day	14	6
3	Group 3, 500 mg/kg	500 mg/kg/day	14	6

There are no other experimental factors of interest specified in the study design. In this case the design consists of 3 trial arms, depicted in the following figure.

Figure. Example Trial 2 Design

Trial Elements

In this study, dosing started on one date and the necropsy is scheduled, for an individual animal, after 28 to 30 days of dosing. The necropsy for a subset of animals per exposure group per day will be staggered over a 3-day period.

te.xpt

Row	STUDYID	DOMAIN	ETCD	ELEMENT	TESTRL	TEENRL	TEDUR
1	TDM2	TE	SCRN	Screen	Start of Pre-exposure	1 week after start of Element	P7D
2	TDM2	TE	TRT01	Vehicle Control	First day of dosing with vehicle control	Date of necropsy: 28 to 30 days after start of Element
3	TDM2	TE	TRT02	100 mg/kg Drug A, once daily	First day of dosing with 100 mg/kg Drug A	Date of necropsy: 28 to 30 days after start of Element
4	TDM2	TE	TRT03	500 mg/kg Drug A, once daily	First day of dosing with 500 mg/kg Drug A	Date of necropsy: 28 to 30 days after start of Element

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Trial Arms

There are 3 trial arms in this study. The fact that some subjects are being selected for blood sampling is an experimental factor that is separate from the dosing being received; this is described in the TS example.

ta.xpt

Row	STUDYID	DOMAIN	ARMCD	ARM	TAETORD	ETCD	ELEMENT	TABRANCH	EPOCH
1	TDM2	TA	1	Control	1	SCRN	Screen	Randomized to Group 1	PRE-EXPOSURE
2	TDM2	TA	1	Control	2	TRT01	Vehicle Control		EXPOSURE
3	TDM2	TA	2	100 mg/kg	1	SCRN	Screen	Randomized to Group 2	PRE-EXPOSURE
4	TDM2	TA	2	100 mg/kg	2	TRT02	100 mg/kg Drug A		EXPOSURE
5	TDM2	TA	3	500 mg/kg	1	SCRN	Screen	Randomized to Group 3	PRE-EXPOSURE
6	TDM2	TA	3	500 mg/kg	2	TRT03	500 mg/kg Drug A		EXPOSURE

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Trial Sets

Assuming that the protocol also specifies that subjects with blood sampling for TK analysis are experimentally distinct, the factors of interest are the dosing levels and whether the subject is sampled for TK analysis; this leads to 6 trial sets.

The applicant has chosen to provide the associated arm code, applicant-defined group code, group label, set label, dose level and units, control type, whether the trial set is being sampled for TK analysis, and planned number of males and females for each set.

tx.xpt

Row	STUDYID	DOMAIN	SETCD	SET	TXSEQ	TXPARMCD	TXPARM	TXVAL
1	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	1	ARMCD	Arm Code	1
2	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	2	SPGRPCD	Applicant-Defined Group Code	1
3	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	3	GRPLBL	Group Label	Group 1, Control
4	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	4	SETLBL	Set Label	Group 1, Control
5	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	5	TRTDOS	Dose Level	0
6	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	6	TRTDOSU	Dose Units	mg/kg/day
7	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	7	TCNTRL	Control Type	VEHICLE CONTROL
8	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	8	TKDESC	Toxicokinetic Description	NON-TK
9	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	9	PLANMSUB	Planned Number of Male Subjects	7
10	TDM2	TX	1	Control Group, Vehicle Control once daily, Non-TK	10	PLANFSUB	Planned Number of Female Subjects	7
11	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	11	ARMCD	Arm Code	1
12	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	12	SPGRPCD	Applicant-Defined Group Code	1
13	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	13	GRPLBL	Group Label	Group 1, Control
14	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	14	SETLBL	Set Label	Group 1, Control - TK
15	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	15	TRTDOS	Dose Level	0
16	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	16	TRTDOSU	Dose Units	mg/kg/day
17	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	17	TCNTRL	Control Type	VEHICLE CONTROL
18	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	18	TKDESC	Toxicokinetic Description	TK
19	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	19	PLANMSUB	Planned Number of Male Subjects	3
20	TDM2	TX	1.TK	Control Group, Vehicle Control once daily, TK	20	PLANFSUB	Planned Number of Female Subjects	3
21	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	21	ARMCD	Arm Code	2
22	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	22	SPGRPCD	Applicant-Defined Group Code	2
23	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	23	GRPLBL	Group Label	Group 2, 100 mg/kg/day
24	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	24	SETLBL	Set Label	Group 2, 100 mg/kg/day
25	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	25	TRTDOS	Dose Level	100
26	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	26	TRTDOSU	Dose Units	mg/kg/day
27	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	27	TKDESC	Toxicokinetic Description	NON-TK
28	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	28	PLANMSUB	Planned Number of Male Subjects	7
29	TDM2	TX	2	Low-Dose Group, 100 mg/kg Drug a once daily, Non-TK	29	PLANFSUB	Planned Number of Female Subjects	7
30	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	30	ARMCD	Arm Code	2
31	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	31	SPGRPCD	Applicant-Defined Group Code	2
32	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	32	GRPLBL	Group Label	Group 2, 100 mg/kg/day
33	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	33	SETLBL	Set Label	Group 2, 100 mg/kg/day - TK
34	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	34	TRTDOS	Dose Level	100
35	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	35	TRTDOSU	Dose Units	mg/kg/day
36	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	36	TKDESC	Toxicokinetic Description	TK
37	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	37	PLANMSUB	Planned Number of Male Subjects	3
38	TDM2	TX	2.TK	Low-Dose Group, 100 mg/kg Drug a once daily, TK	38	PLANFSUB	Planned Number of Female Subjects	3
39	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	39	ARMCD	Arm Code	3
40	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	40	SPGRPCD	Applicant-Defined Group Code	3
41	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	41	GRPLBL	Group Label	Group 3, 500 mg/kg/day
42	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	42	SETLBL	Set Label	Group 3, 500 mg/kg/day
43	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	43	TRTDOS	Dose Level	500
44	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	44	TRTDOSU	Dose Units	mg/kg/day
45	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	45	TKDESC	Toxicokinetic Description	NON-TK
46	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	46	PLANMSUB	Planned Number of Male Subjects	7
47	TDM2	TX	3	High-Dose Group, 500 mg/kg Drug a once daily, Non-TK	47	PLANFSUB	Planned Number of Female Subjects	7
48	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	48	ARMCD	Arm Code	3
49	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	49	SPGRPCD	Applicant-Defined Group Code	3
50	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	50	GRPLBL	Group Label	Group 3, 500 mg/kg/day
51	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	51	SETLBL	Set Label	Group 3, 500 mg/kg/day - TK
52	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	52	TRTDOS	Dose Level	500
53	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	53	TRTDOSU	Dose Units	mg/kg/day
54	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	54	TKDESC	Toxicokinetic Description	TK
55	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	55	PLANMSUB	Planned Number of Male Subjects	3
56	TDM2	TX	3.TK	High-Dose Group, 500 mg/kg Drug a once daily, TK	56	PLANFSUB	Planned Number of Female Subjects	3

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SEND Example.In vivo Study Design with Toxicokinetic Subjects