To ensure that research use of new medical devices (those that have not yet been cleared or approved by FDA) have appropriate oversight and do not put human research participants at undue risk, FDA requires that certain clinical research projects (or "investigations") be granted an Investigational Device Exemption (IDE) before the study is initiated (21 CFR 812).
FDA defines molecular diagnostics, like all in vitro diagnostics, as medical devices (21 USC 321). In the case of genome sequencing applications, FDA currently considers the entire test pipeline to be the device. Therefore, the sequencing platform, its analysis and informatics pipeline, and interpretation of the results for return to a clinician or participant represent a single device (as opposed to many individual devices). IDEs are required for research where FDA believes there is the potential for significant risk to the participants as a result of acting on false positive diagnosis (or as a result of inaction due to a false negative diagnosis).
Not all clinical studies involving genome sequencing (or other new devices) require IDEs. If you do not intend to return the medically relevant results of a genomic assay to a participant, their physician, or will enter those results into their medical record, and the results are not being used to direct or inform the clinical care of that participant, an IDE is not required (i.e., the study is IDE exempt).
A study may also be IDE exempt if results from the assay are confirmed using a second, "medically established" procedure. Currently, FDA considers Sanger sequencing to be a 'medically established' diagnostic device; the Illumina MiSeqDX platform has been cleared by FDA for targeted sequencing applications, and the Thermo Fisher Ion PGM DX platform has been registered with FDA as an equivalent device to the MiSeqDX. Therefore, an investigator confirming DNA sequence-based research findings with these methods is unlikely to need to apply to the FDA for an IDE.[i]
If, in contrast, you intend to use a genomic assay to diagnose a medical condition or inform a participant's clinical care, or to return potentially actionable health information to a participant or their physician, you may need to apply for an IDE. The level of risk posed to the research participant through the clinical study is the key factor in this determination.
FDA's regulations distinguish between two classifications of risk (to an individual participant) in clinical studies that require an IDE:
If you are the study's sponsor or sponsor-investigator (see glossary), you should make the determination of whether a study poses significant or nonsignificant risk to the participants, and present this to your IRB IRB when seeking approval to initiate the study.
For molecular diagnostic devices, there are a number of factors to consider when determining risk:
Risks from incorrect results: With regard to molecular diagnostic devices, the key question when assessing risk is to consider the consequences of either a false positive or false negative result:
If the answer to either of those questions is yes, FDA might view the risk as significant.
Participant health: The health of the research participants, as well as the availability of any treatment options, is important when determining risk for the purposes of IDE submissions. For instance, if a participant has a serious or life-threatening condition with no available treatment options outside the use of the device, that study would be considered to pose less risk than a study that potentially exposes healthy participants to an unnecessary medical intervention due to a false positive result. Thus, each study must be evaluated based on the intended use of the genomic test (device) in the study and in the context of the study population.
Sampling procedure: Does the sampling procedure constitute a risk? Typically the answer is no for genomics studies. For example, in the case of studies where the sampling is a venous blood sample, the risk is not significant because it is not considered an invasive procedure.[ii]
If you are the study sponsor or sponsor-investigator (see glossary), you have the primary responsibility for determining whether an IDE is needed. If an IDE is needed, the next question is to consider whether the use of DNA sequencing technology in the study is of significant or nonsignificant risk. You should present their assessment to the IRB along with the study protocol before beginning the study.
Your IRB must then review the risk assessment and agree or disagree. FDA's guidance for IRBs on this responsibility recommends that established written procedures explain how the IRB distinguishes significant from nonsignificant risk. The IRB should provide a written justification or description explaining why the proposed study poses either significant or nonsignificant risk for the study records. This can be helpful in providing clarity to FDA (and to you) regarding the basis of IRB decision-making.
Nonsignificant risk: If you determine that the use of genomics technology poses nonsignificant risk to your participants, and your IRB concurs, you does not need to submit an IDE application to FDA before enrolling participants. FDA considers the study in these cases to have an approved IDE for a nonsignificant risk device even though FDA has not been consulted. Your study must comply with the abbreviated IDE requirements, which include labeling, monitoring participants, and keeping certain records. It is important to note, however, that FDA retains the authority to overrule the IRB's determination and require you to submit an IDE application to the agency.
Significant risk: If you or your IRB determines that the use of genomics technology in the study poses a significant risk to participants, you must acquire an IDE from FDA before conducting the study. Studies determined to pose significant risk may still be undertaken; however, the IDE application must be approved before you can begin enrolling participants (see below for more on this). In the event of that an IRB disagrees with your determination that the proposed study is significant risk, the IRB's determination (i.e., nonsignificant risk) would apply.
Pre-Submission: You may pursue pre-submission with FDA concurrent with seeking IRB protocol approval, because the application review by FDA and the IRBs are independent of one another (pre-submission is the process of communicating with FDA regarding a study and the possible need for an IDE). It might benefit you to wait for your IRB's approval before entering into discussion with FDA, since IRB action might clarify or modify some of the information FDA will need to review. However, this could increase the total time elapsed before the research can commence.
When the use of genome sequencing technology poses significant risk to participants, you are encouraged to contact FDA for guidance and discussion prior to submitting an IDE application. Early interaction between sponsors/sponsor-investigators and FDA is helpful both for you (increased understanding of FDA's rules and requirements as they apply to their specific study) and FDA (better understanding of the particular novel technologies involved with the submission).
While it is not required by FDA to do this, and may be seen as an "extra" step, ultimately the discussions may serve to speed up the process overall. In the course of a pre-submission, you can ask FDA to make a formal risk determination for the proposed study. It is possible to have more than one pre-submission discussion with FDA, which has been found to be helpful in previous cases.
When talking to FDA, you should be prepared to describe your clinical protocols in specific detail, which is why having an IRB approved protocol might be useful. In particular, details about the test (what it is, where and how will it be used, what sort of sample is required, etc.), the population that will be studied, and the types of treatment decisions that might be made based on test results should be clear. Presenting FDA with an assay validation plan and asking the agency if it is adequate can be very helpful.
In defining the diseases or conditions that will be seen in the study, you should describe the expected prognosis for patients, and, if it exists, what standard of care is for those condition. FDA must judge each study on its specifics details, so a lack of clarity on your part with regard to the proposed research makes it difficult for FDA to assess the need for an IDE, the level of risk posed to research participants, or to discuss options available to the investigator to mediate risk in any detail. Note that, for the purposes of risk determination during pre-submission discussions, detailed information about a test's analytical performance is not required. This information would be evaluated in an IDE submission, should one be required.
Formal Submission: If an IRB or FDA determines that a study poses significant risk to the research participants, or if pre-submission discussions with the FDA indicate so, you must submit a formal IDE application to FDA prior to commencing the study. FDA has 30 days to review your application and respond after its receipt. If an application is missing required elements, such that it cannot be reviewed completely, the application will be returned with a 'Refuse to Accept' decision. This will stop the review clock until the you resubmit a complete application. If the IRB has approved the investigation, and FDA does not respond in 30 days after receiving the IDE application, the IDE is considered approved and your study may commence.
Once the FDA has approved your IDE application, you can begin your study. However, you have additional responsibilities during the course of the study.
[i] The problem has been that if Sanger (or MiSeqDX or Ion PGM DX) is being used to confirm a variant for which the clinical/diagnostic interpretation is uncertain, then FDA would not consider that to be "medically established" and hence not confirmation for the purposes of determining IDE exemption.
[ii]If the research participants are young children or infants, FDA has required that the blood draw amounts be consistent with WHO guidelines. Alternatively, a tissue biopsy that carries > 2% risk of severe and/or life threatening complications (including overnight hospitalization) may be considered "significant risk". So investigators should explain what the risk of the biopsy is expected to be (and document this estimate) when presenting to IRB.
[iii] the term "accompanying" interpreted liberally to mean more than physical association with the product, and can include posters, tags, pamphlets, circulars, booklets, brochures, instruction books, direction sheets, fillers, etc. Note that journal articles, talks at conferences, and other activities that may include discussion of the test are fine as long as the investigator does not make unsupported claims about the performance or clinical relevance of the test. However, discussion of previously obtained results and presentations of hypotheses and models are permissible with appropriate disclaimers.