; (ii) the number of human subjects that are to be involved in such testing; (iii) the need to permit changes to be made in the in vitro clinical test involved during testing conducted in accordance with a plan required under paragraph (3)(B); or (iv) whether the clinical testing of such in vitro clinical test is for the purpose of developing data to obtain approval to offer such test. (C) Significant risk studies In the case of an in vitro clinical test the investigational use of which poses a significant risk, a sponsor of an investigation of such a test seeking an investigational use exemption shall submit to the Secretary an investigational use application with respect to the test in accordance with paragraphs (2) and (3). For purposes of this subparagraph, the term significant risk means, with respect to an in vitro clinical test that is a high-risk test, and that the use of the test— (i) is a use of substantial importance in performing an activity or activities described in subsection (ss)(1)(A) for, a serious or life-threatening disease or condition without confirmation of the diagnosis by a medically established means; (ii) requires an invasive sampling procedure that presents a significant risk to the human subject; or (iii) otherwise presents a reasonably foreseeable serious risk to the health of a human subject. (D) Non-significant risk tests In the case of an in vitro clinical test, the investigational use of which does not pose a significant risk— (i) the sponsor of such investigation shall— (I) conduct such investigation in compliance with an investigational plan specified in paragraph (5) and labeling specified in paragraph (3)(A)(ii); (II) ensure each investigator obtains informed consent under part 50 of title 21, Code of Federal Regulations (or any successor regulations), subject to the exceptions set forth in paragraphs (5)(A)(iii) and (5)(B); (III) submit a listing to the Secretary of such investigation; and (IV) maintain records with respect to all requirements in this subparagraph