1. Regulatory Considerations for Investigational Assays: Planning for Success Elizabeth Mansfield, PhD OIVD/FDA “Next-Generation DNA Sequencing as a Tool for Clinical Decision-making in Cancer Patient Management” May 3-4, 2012

2. Overview What defines an investigational assay? How are levels of risk assessed? What types of information and data are needed? How do I submit this information to FDA (if required)?

3. Investigational Use Per 21 CFR 812, an investigation means “a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device” Applies when device is being studied for –Its own safety and effectiveness –Its safety and effectiveness in the context of other investigational products

4. What is FDA’s Interest in Investigations? SAFETY of / risk to the patient when exposed to investigational use of a device (performance and use) Appropriate oversight of investigation (IRB) Adequate informed consent for subjects Compliance of investigators

5. Investigational Assays An assay is considered to be used in an investigational manner when: –It has not been cleared or approved for the use to which it is being put This encompasses LDTs, which have generally not been cleared or approved for any use –The investigational use is applied to subjects (humans, whether whole or in parts)

6. Assessing Level of Risk for IVDs: Exempt No risk of harm to patient –Results not used for clinical management Generally not returned to physician/patient If returned, must be confirmed by another accepted (approved or cleared) procedure –No invasive procedures related to test required that might harm the patient Doesn’t include sample collection for other medically necessary reasons Doesn’t include venipuncture

7. Assessing Level of Risk for IVDs: Significant Risk Presents a potential for serious risk to the health, safety, or welfare of the patient –Invasive sampling solely for use in testing –Results returned for patient management without confirmation by another procedure –Management of patient according to results could result in harm Esp. when test results are incorrect

8. Assessing Level of Risk for IVDs: Non-significant Risk Doesn’t meet requirements to be exempt, but does not present a potential for serious risk to patient –No significant risk invasive sampling needed –If results are returned, unlikely to harm patient even if result is incorrect

9. What Should Sponsor Do? Familiarity with Part 812 Submit study to IRB for assessment Prepare informed consent Prepare a detailed protocol for how the test will be used Obtain good investigator agreements Submit IDE/IND to FDA if needed

10. IDE: What Does FDA Want? 21 CFR Parts 50 and 56 apply Exempt investigations: No submission to FDA, but FDA may disqualify an investigator. Non-significant risk investigations: abbreviated requirements, no submission to FDA Significant risk investigations: IDE submission required

11. IDE Review Subjects’ safety Knowledge to be gained from investigation Alignment with plans for later development and FDA review Usually includes analytical validation data

12. Device “ready” for use to guide accrual, treatment, or asses outcome in a clinical trial? Fully specified device, for purposes of the trial Analytical performance adequately assessed Pre-clinical or clinical information justifies subjects’ “exposure” Well-posed question or hypothesis can be answered/tested by the trial

13. Submitting an Investigational Application IDE: Submission to CDRH, identified as an IDE application 30-day review clock Decision: –Approved –Approved with modifications –Disapproved Can resubmit with new info if disapproved If part of non-exempt IND, can be submitted to IND If part of an exempt IND, must submit IDE

14. Thanks! Elizabeth.mansfield@fda.hhs.gov