On April 12, 2018, the three FDA Centers jointly issued the draft guidance, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination” (draft available here). The draft guidance outlines a process for obtaining FDA’s feedback regarding whether an investigational IVD requires an approved Investigational Device Exemption (IDE) when used in the study of an Oncology therapeutic product. As we discussed in our earlier post (here), FDA’s December draft guidance regarding investigational IVDs includes an expansive definition, indicating that IVDs used in therapeutic product studies must be either investigational or cleared/approved. Thus, this guidance would apply to IVDs that are investigational or those that are currently marketed for non-diagnostic use (e.g., research use only).
The majority of IVD investigations have historically been exempt from the IVD studies pursuant to 21 C.F.R. § 812.2(c)(3). IVD investigations are exempt if the IVD is appropriately labeled as investigational pursuant to 21 C.F.R. Part 809, and it:
(i) Is noninvasive,
(ii) Does not require an invasive sampling procedure that presents significant risk,
(iii) Does not by design or intention introduce energy into a subject, and
(iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.
Id. § 812.2(c)(3). FDA issued guidance regarding interpretation of these four criteria in 2010 (available here). The 2010 guidance does not, however, cover all possible IDE exemptions nor does it discuss when/if a companion diagnostic fits within the above criteria. In recent years, investigational IVDs used in therapeutic product clinical studies where the IVD will ultimately be a companion diagnostic have not been exempt from the IDE requirements.
Prior to issuance of the draft streamlined oncology study risk determination guidance, study sponsors could seek a determination from CDRH as to whether an IDE was required for an investigational IVD by submitting a study risk determination pre-submission. The new draft guidance indicates that oncology therapeutic study sponsors can now request this feedback via FDA Form 1571 when it submits an Investigation New Drug (IND) application. CDER or CBER will seek input from CDRH in providing its feedback. The guidance states that sponsors should include the following information on their form when seeking FDA feedback regarding the IDE requirements applicable to IVDs used in the planned study:
- How the results from the investigational IVD will be applied in the clinical trial;
- What is known about the prevalence of the biomarker (evaluated by the investigational IVD) in the patient population; and
- The specimen type that will be collected for investigational IVD testing (including the anatomical site) and whether any biopsy required for investigational IVD testing could present a potential for serious risk to the health, safety, or welfare of the subject.
With regard to the third bullet, FDA notes that this process does not apply “if an invasive biopsy that presents a potential for serious risk to health, safety, or welfare of the subject is required for investigational IVD testing for enrollment.” The guidance appears to suggest that such invasive biopsies automatically require an IDE, a position which would be consistent with § 812.2(c)(3)(ii).
The guidance explains that FDA will provide its feedback regarding whether an investigational IVD requires an IDE in a “May Proceed Letter.” This timing seems appropriate if an IDE is not required. However, if an IDE is required, it would not seem ideal for the drug or device sponsor to need to begin the IDE approval process after the IND has already been approved. Thus, this process seems as though it may be helpful for therapeutic and IVD manufacturers when the sponsor is seeking – and obtains – confirmation that the investigational IVD is exempt from the IDE requirements. In addition, depending on the parties’ (IVD manufacturer and therapeutic manufacturer) relationship, it may be challenging for only the therapeutic sponsor to communicate with FDA via the IND application regarding the proposed diagnostic test.
In our view, this process may be modestly helpful; however, it only addresses part of the IVD-therapeutic product question. The often more important question is whether FDA will view the IVD as a companion diagnostic. The draft guidance doesn’t touch that topic. In order to be truly helpful to study sponsors, we suggest that FDA expand the proposed program to also allow study sponsors to seek a determination as to whether the IVD will be viewed as a companion diagnostic. It is important to note that largely similar information required for the study risk determination also apply when assessing whether an IVD is a companion diagnostic.