; (B) the number of human subjects that are to be involved in such testing; (C) the need to permit changes to be made to the in vitro clinical test involved during testing conducted in accordance with a plan required under subsection (c)(6); or (D) 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) Application for investigational use The following shall apply with respect to in vitro clinical tests for investigational use: (1) Significant risk and other studies In the case of an in vitro clinical test the investigational use of which poses a significant risk to the human subject or involves an exception from informed consent for emergency research, 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 in vitro clinical test in accordance with paragraphs (3) and (4). (2) Non-significant risk studies In the case of an in vitro clinical test, the investigational use of which is not described in paragraph (1)— (A) the sponsor of such investigation shall— (i) ensure such investigation is conducted in compliance with an investigational plan approved by an institutional review committee and the labeling of the in vitro clinical test involved clearly and conspicuously states, For investigational use only , as specified in paragraph (4)(A)(ii); (ii) ensure each investigator obtains informed consent as required under part 50, 54, and 56 of title 21, Code of Federal Regulations (or any successor regulations), subject to the exceptions set forth in paragraph (6)(C); (iii) establish and maintain records with respect to all requirements in this subparagraph; (iv) maintain records and make reports as required by the Secretary pursuant to regulations issued under subsection (b)