The FDA Investigational Device Exemption (IDE) regulation has been in place since 1976, and is applicable to some clinical genomics research. The purpose of the IDE regulation is to oversee clinical research involving "investigational" medical devices - those that have not yet been cleared or approved by FDA - and to protect human research participants from undue risk. FDA defines genomic tests, like all other in vitro diagnostics (IVDs), as medical devices (21 USC 321 (h)). The agency considers software, reagents, instruments, and other components across the testing pipeline, from sample to test report, to be part of a single device. In some cases, investigators leading clinical genomics investigations must obtain an IDE before they can initiate their studies (21 CFR 812).
In the context of genomics research, the purpose of the IDE process is to demonstrate that a test has plausible analytical validity and to protect the interests of study participants who might receive test results that could affect their clinical care. If a study proposes to use a genomic test that is not FDA-cleared or -approved, the investigator of the study - must consider FDA's IDE regulation before proceeding with enrollment. There are also some situations when clinical genomics research is exempt from the IDE regulation, or "IDE exempt". Factors that make a study IDE exempt are outlined in the section, "Does the IDE Regulation Apply to Your Study?"
If the IDE regulation does apply, then a critical part of compliance starts with determining the risk of the study. When a study involving a research test is determined to pose "significant risk" for participants, investigators must apply to FDA for an IDE before they begin their research. A significant risk (SR) study, for example, might involve genome sequencing of healthy participants with an intent to return variants of unknown significance (VUS). In this instance, the risk might stem from concern that test results with unknown clinical significance would lead healthy individuals to pursue unnecessary treatments that could expose them to harm. If this study design does not also include appropriate risk-mitigating measures, it could be considered SR. A study determined to pose "nonsignificant risk" (NSR) study, can begin without FDA review but still requires compliance with a set of "abbreviated IDE requirements" that will be discussed later in this resource.
Together with their Institutional Review Board (IRB), investigators play a role in determining whether a study poses SR or NSR, thereby influencing which pathway must be followed in order to comply with the IDE regulation. If a study is deemed to be SR, investigators should be aware of the time and resources that are necessary to prepare an IDE submission and see it through FDA review, as investigators bear much of the responsibility in the IDE process.
This resource provides points for genomics researchers to consider when deciding whether and how the IDE regulations apply to their research. It also describes the IDE submission process and other related steps that investigators may need to take in order to fulfill regulatory requirements. The points to consider resource attempts to answer questions investigators may have and serves as a complementary resource to FDA's existing "Device Advice" webpages that can be found here.
The following graphic depicts the IDE process and identifies the parties responsible at each step. The steps in the graphic are described in closer detail in the following sections of this resource.
FDA regulates genomic tests and other IVDs under its authority to regulate medical devices. The primary division of the FDA that implements device regulations is the Center for Devices and Radiological Health (CDRH). When reviewing genomic tests, FDA considers the entire pipeline, from sample to test report generation, to be a single device.
The first step of the process is to decide if the IDE regulations are applicable to a particular study or if the study is exempt from these regulations. The study sponsor or sponsor-investigator has the primary responsibility for determining whether an IDE is needed. IDE regulations apply to studies that expect to learn about the safety and effectiveness of an investigational device, even if this is not the primary purpose of the research. Therefore, if an investigator proposes to sequence participants' genomes with a platform that is not FDA-cleared or -approved, then the IDE regulation applies. If the investigator wants to use a sequencing platform that has received FDA approval or clearance but would like to use this platform outside of its specified intended use, the IDE regulations would apply. IDE regulations would not apply if the investigator wants to use the FDA-cleared or -approved device for its specific intended use. For example, FDA cleared Illumina's MiSeqDx System for cystic fibrosis testing. If an investigator wants to use this platform to test for cystic fibrosis, then this is within the cleared intended use and the IDE regulations would not apply. Here, the genetic test would not be considered "investigational". However, if the investigator wants to use the MiSeqDx system to interrogate other regions of the genome, the IDE regulations would apply and the test would be considered investigational.
If the investigator does not propose to return results to participants or their physicians, and the results will not otherwise be used to direct or inform the clinical care of that participant, then the investigational device study is exempt from the IDE regulation.
A study may also be IDE exempt if results from the assay are confirmed using a second, "medically established" procedure. FDA does not have a formal definition of "medically established", but generally, a medically established procedure is one that is part of the standard of care for the study population. For instance, in some cases, FDA considers Sanger validation of next-generation sequencing (NGS) test results to be a medically established procedure. If an investigator proposes to return Sanger validated variants with known clinical relevance, then the study could be IDE exempt. If, however, the research entails discovery and return of new variants with unknown clinical relevance, the study might not be exempt despite the use of Sanger confirmation of variant information.
If a study is not exempt from the IDE regulation, then the next task is to determine the risk of the study. Risk determination establishes whether or not the investigator has to engage with the FDA before proceeding with the research. As stated above, FDA has two classifications of risk for studies that require an IDE: significant risk (SR) and nonsignificant risk (NSR). These classifications are based solely on the risks posed to the study participants.
The sponsor/sponsor-investigator of a study is the first to assess whether a study poses SR or NSR. It is important for investigators to be familiar with the IDE regulation and understand FDA considerations about risk determination so that their classifications are aligned with how FDA reviewers might assess the study. Investigators should present their risk determination to the IRB when submitting their IRB protocol for review. The IRB will concur with the investigator's determination or reclassify the proposed study's risk. The IRB's role in the IDE process is discussed later in this document.
Aspects of the Study That May Affect Risk
FDA considers risk with a different lens than that commonly used by investigators and IRBs. To promote dialogue and bridge gaps in understanding between all parties, NHGRI held a workshop on June 10th, 2016, entitled, "Investigational Device Exemptions and Genomics" that featured a diverse set of panelists, including FDA reviewers, to comment on aspects of clinical genomics research that they consider when conducting IDE risk determinations. It is important to note that FDA evaluates risk on a case by case basis, and considers the risk of the worst-case-scenario. Some common themes about risk concerns for FDA reviewers that emerged from the workshop include, but are not limited to:
If false negative or false positive results could prevent participants from seeking necessary treatment or cause them to pursue dangerous, unnecessary treatment, then this may increase the risk of a study.
If receiving test results could cause participant care to deviate from standard of care, then this may increase the risk of a study.
If a study proposes to generate genome sequences for healthy individuals and return the research results, then this may increase the risk of a study.
If a study proposes to return incidental findings to participants, then this may increase the risk of a study.
If a study provides participants with genetic counseling services to accompany the return of research results, the risk of the study may be mitigated, but it is not automatically sufficient to diminish risk to the point of making the study NSR.
If the proposed sample collection procedure is invasive, then this may increase the risk of a study.
Aspects of the Study that Do Not Affect Risk Determination
There are aspects of study design that are not considered by FDA in their assessment of risks pertinent to IDE submissions. These include:
Approaching the Investigational Review Board (IRB) for a Risk Determination
Once an investigator has determined the risk of a study, they should present their assessment to the IRB in the course of submitting the study protocol for review. The IRB must review the risk assessment provided by the investigator and ultimately decide if the study is SR, NSR, or even IDE exempt. FDA's guidance for IRBs on this responsibility recommends that IRBs establish written procedures on how they distinguish between SR and NSR studies. 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 should questions arise later regarding the basis of IRB's decision-making. Next steps for investigators to comply with the IDE regulation depend on the IRB's risk determination, since there are different requirements for significant versus nonsignificant risk studies.
Note that FDA retains the legal authority to overrule an IRB's risk determination, but the agency encourages IRBs to make independent risk determinations. FDA's support for the IRB role in IDE risk determinations is evidenced by FDA's IDE guidance for IRBs, as well as ongoing dialogue between FDA and the research community regarding this issue.
Approaching the FDA for Clarification on Risk Determinations: FDA Pre-Submission Process
Since the relevance of the IDE regulation in the genomics field is relatively new, IRBs may be unfamiliar with making risk determinations that could affect regulatory compliance in this space. If investigators or their IRBs seeks more clarity on the IDE regulation's applicability to a given study, investigators can apply for a "Pre-Submission meeting" with FDA staff. The purpose of the pre-submission meeting is to communicate with FDA regarding a study's possible need for an IDE, including discussions of any risk factors. FDA provides guidance on requesting pre-submission meetings. Note that preparing a pre-submission meeting application could require some time, since the application packet must include components such as a detailed description of the genomic test in question, an intended use statement for the proposed study, and an overview of previous clinical data that has already been collected with the same test. FDA is required to respond within 75-90 days from receipt of a pre-submission meeting request. While reviewing a pre-submission meeting request, FDA may contact investigators frequently to ask for additional information. They may also set tight turnaround times for requested information. It is advised that investigators designate a point of contact who can be alert and highly responsive to FDA's communications.
When talking to FDA, investigators should be prepared to describe their clinical protocols in specific detail, so having an IRB-approved protocol before this step is 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. In addition, presenting FDA with an assay validation plan and asking the agency if it is adequate can be very helpful. Having an adequate assay validation plan is important because if an IDE submission is deemed necessary, FDA reviewers will ask investigators to include detailed validation data in their submission in order to verify that a test is plausibly analytically valid. Note that for pre-submission discussions, detailed information about a test's analytical performance is not required. This information would only be evaluated in an IDE submission, should one be required.
In defining the diseases or conditions that will be seen in the study, investigators should describe the expected prognosis for patients, and, if it exists, what the standard of care is for those conditions. FDA must judge each study on its specific details, so any lack of clarity with regard to the proposed research makes it difficult for FDA to assess the need for an IDE or the level of risk posed to research participants. It also confounds the determination of options available to the investigator to mediate any risks.
If an investigator has determined that their study is NSR and the IRB concurs, the investigator does not need to submit an IDE application to the FDA before enrolling research participants. FDA considers NSR studies to have an IDE once the IRB concurs with the NSR determination, even though FDA has not been consulted for risk determination.
There are "abbreviated IDE requirements" that NSR studies must comply with in order to maintain the IDE. These requirements include:
If the investigator believes a study is NSR, but the IRB determines it is SR, then the IRB's ruling prevails and the investigator must submit an IDE application to the FDA before beginning research. It is possible for the investigator to consult the FDA and obtain a second opinion through FDA's pre-submission meeting mechanism. As noted previously, the FDA's risk determination would be final and would take precedence over the IRB's determination.
If the investigator has determined that their study is SR and the IRB concurs, the investigator must submit an IDE application to the FDA before beginning research. Studies determined to be SR may still be undertaken; however, the IDE application must be approved before you can begin enrolling participants.
To apply for an IDE, the investigator must gather information relevant to the genomic test and the study design and submit it in a paper and electronic format. While FDA does not have a template or specific format for IDE applications, the agency does require certain pieces of information to be included in the submission. Appendix II lists required components of an IDE application. General formatting tips are to be organized, descriptive, and to include a detailed table of contents in the application.
Upon receipt of an IDE application, FDA is required to make a decision within 30 days. The review process is dynamic and will require substantial communication between the investigators and FDA reviewers. Reviewers may reach out to ask for clarification on portions of the application or request supplementary information. If investigators are unable to fulfill FDA reviewers' information requests before the 30-day deadline, FDA may restart the clock and extend the total review time beyond 30 days. If FDA requests certain information between a 1 to 2-day turnaround period and investigators are unable to meet the deadline, the FDA may also decide to restart the clock. Therefore, investigators are advised to be alert and highly responsive to FDA communications. If the IRB has approved the investigation's protocol and FDA does not respond within 30 days of receiving the IDE application, the IDE is considered approved and the study may commence.
There are three different decisions that FDA can make on an IDE application. FDA has a guidance document describing these IDE decision outcomes.
Post-Approval Requirements for Significant Risk Studies
Significant risk studies may begin once the investigator has obtained an IDE from FDA in addition to IRB approval. The investigator should designate monitors for the study who are responsible for securing compliance with the IDE regulation. These monitors will:
Investigators should plan accordingly to fulfill the reporting requirements necessary to maintain the study's IDE. Annual and final reports should include the following information:
There are other instances when investigators may have to file additional reports with FDA. In the case of an unanticipated adverse event or withdrawal of IRB approval, investigators must immediately report to FDA. If an investigator wants to significantly modify their investigational plan or test pipeline in a way that could greatly affect the validity of the data or the safety of participants, they must submit an IDE supplement to FDA and receive approval before the modifications can take place. Less significant modifications that do not constitute a substantial change in the design of the study, affect the validity of data, or affect the safety of participants can be implemented immediately as long as the investigator provides notice to FDA within five working days of making those modifications.
Since genome sequencing technology is constantly evolving, it is commonplace for investigators to modify parts of their testing pipeline throughout the course of a study. Depending on the study, FDA may require submission of an IDE supplement when investigators make changes to the testing pipeline. In some cases, a five-day notice could be sufficient. It is best to discuss what type of modifications constitute an IDE supplement versus a five-day notice with FDA early on in the IDE process, whether in a pre-submission meeting or during the IDE review.
The FDA Device Advice online resource provides more information on IDE reports and suggested formats.
A complementary NHGRI resource on the suggested IDE Submission Format can be found here.
 Though it is true that Sanger has been referred to by some as the gold standard for sequencing, it has never gone through the FDA's premarket review process. Nevertheless, due to its long-standing history, Sanger sequencing has been grandfathered in as a medically-established technology and is frequently looked to for orthogonal validation of NGS.
 A case history could include case report forms and supporting data, signed and dated consent forms and medical records, physician notes, hospital charts, and nurse's notes.