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This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.
FDA seeks to encourage medical device research and innovation to address important clinical needs and improve patient care. In many cases, device development and evaluation includes clinical investigation. This guidance document has been developed to promote the initiation of clinical investigations to evaluate medical devices under FDA’s Investigational Device Exemptions (IDE) regulations, Title 21 Code of Federal Regulations (CFR) Part 812.
FDA approval of an IDE submission allows the initiation of a clinical investigation of a significant risk 1 device. This guidance is intended to provide clarification regarding the regulatory implications of the decisions that FDA may render based on review of an IDE and to provide a general explanation of the reasons for those decisions.
In an effort to promote timely initiation of clinical investigations in a manner that protects study subjects, FDA has developed methods to allow a clinical investigation of a device to begin under certain circumstances, even when there are outstanding issues regarding the IDE submission. These mechanisms, including approval with conditions, staged approval, and communication of outstanding issues related to the IDE through future considerations, are described in this guidance. 2
FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.
FDA’s regulations describe FDA actions on an IDE:
Thus, FDA’s regulations provide for three FDA actions on IDE applications:
FDA must inform the sponsor 5 or sponsor-investigator 6 of its decision, or must notify the sponsor that the investigation may not begin, within 30 days from the date of receipt of the IDE application, or the IDE application will be deemed approved. If an IDE application is approved or approved with conditions, the sponsor may begin subject enrollment with the number of subjects and investigational sites specified in FDA’s decision letter upon receipt of Institutional Review Board (IRB) approval; the IRB approval may occur prior to FDA approval.
If FDA does not have outstanding issues that must be addressed to support the study of the subject cohort under the proposed investigational plan, then the IDE will be approved without conditions 7 . Alternatively, if FDA has identified issues that must be addressed but do not preclude initiation of the clinical investigation, the IDE will be approved with conditions. In the case of approval with conditions, approval is granted on the condition that, within a specified timeframe from the date of FDA’s decision letter, usually 45 days 8 , the sponsor submits information addressing the issues identified in FDA’s letter. Examples of the types of issues that may be identified in an approval with conditions letter are discussed later in this document. In certain instances, resolution of outstanding issues before subject enrollment may be necessary. In these instances, the IDE will be disapproved, meaning that the sponsor may not initiate enrollment in the clinical investigation until the sponsor responds to the issues identified in FDA’s letter and receives an approval or approval with conditions letter.
If FDA approves an IDE application and IRB approval is obtained, the sponsor may begin subject enrollment in accordance with the limits described in FDA’s decision letter, including the maximum number of subjects and investigational centers. FDA will approve an IDE application without conditions when the IDE sponsor has submitted data and an adequate clinical investigation plan that support initiation of the study in humans. This assessment is based primarily on FDA’s review of the considerations discussed in Section 8 of this document, in addition to other issues specific to the application.
In some cases, FDA may determine that an outstanding issue remains but that the IDE application can still be approved and the issue can be addressed with data that will be gathered in parallel with the enrollment of some portion of study subjects (i.e., staged approval). In other cases, FDA may inform the sponsor of an issue that FDA believes should be considered in preparation for a marketing application or a future clinical investigation (i.e., future consideration). These options are discussed in Sections 5 and 6, respectively, of this document.
If FDA approves an IDE application with conditions, the sponsor may begin subject enrollment upon receipt of IRB approval on the condition that, within 45 days from the date of FDA’s decision letter, the sponsor submits information addressing the issues identified in FDA’s letter. An IDE may be approved with conditions if FDA has determined that, despite some outstanding issues, the information provided is sufficient to justify human clinical evaluation of the device and the proposed study design is generally acceptable. Previously known as “conditional approval,” the phrase “approval with conditions” will now be used to convey that the outstanding issues do not raise concerns that preclude FDA from granting approval for initiation of the clinical investigation . Therefore, resolution of those issues is not required prior to initiation of enrollment in the study, with exception of issues related to the informed consent document. If FDA identifies issues with an informed consent document, those issues must be addressed before enrollment begins in order to ensure that informed consent is obtained in accordance with 21 CFR Part 50 - Protection of Human Subjects. Outstanding issues that may lead to approval with conditions include:
The sponsor must submit a supplement 9 to the IDE to completely respond to the issues raised in FDA’s approval with conditions letter, usually within 45 days; otherwise, the IDE will be disapproved. See 21 CFR 812.30(b). For each issue identified in FDA’s letter, an acceptable response provides the specific information or modification(s) requested by FDA. In some cases, the sponsor may choose to provide a scientifically valid alternative to FDA’s request or to provide a scientifically valid rationale for why the information or modification(s) is not needed. FDA will inform the sponsor of its decision within 30 calendar days from the date of receipt of the supplement. If FDA determines that the issues have been adequately resolved, FDA will grant approval without conditions. However, if any issues remain, FDA may again grant approval with conditions and will communicate the remaining outstanding issues to the sponsor by letter. In this case, the sponsor may continue to enroll subjects in the study on the condition that, within 45 days, the sponsor responds to the remaining issues identified in FDA’s letter. In some cases, a sponsor’s unsatisfactory response to FDA’s questions could result in FDA withdrawing approval of the IDE.
This guidance defines a process, termed “staged approval” or “staged approval with conditions” 10 by which FDA may grant IDE approval or approval with conditions, while certain outstanding questions are answered in parallel with enrollment in the clinical investigation. Staged approval permits the clinical investigation to begin in a timely manner while maintaining appropriate subject protections.
Under staged clinical investigations, FDA will grant approval or approval with conditions for a subset of the planned subject cohort while the particular outstanding questions are addressed. If FDA and the sponsor have agreed to the additional data that will be provided and there are no other outstanding issues to be addressed (i.e. under approval with conditions), a staged clinical investigation can receive approval without conditions, with enrollment limited to the number of subjects to be enrolled in the first stage. The size of the enrollment stages and the timing for the reporting of additional information should ideally be designed so that study enrollment does not need to be halted during the trial if the data submitted to address the outstanding issue(s) are acceptable. The sponsor will be permitted to expand enrollment once an IDE supplement, which includes the necessary additional information, is submitted to FDA for review and found to be acceptable.
A staged clinical investigation may be appropriate in the following situations:
Staged approval is most common for pivotal studies 11 (i.e., studies that are designed to provide the primary clinical evidence to support a marketing application) in which many subjects will be enrolled over an extended period of time, but may be applicable to other clinical investigations as well. Some additional considerations that are specific to staged pivotal studies include:
Future considerations are issues or recommendations communicated in an approval, approval with conditions, or disapproval letter that FDA believes the sponsor should consider in preparation for a marketing application or a future clinical investigation. Future considerations are intended to provide helpful advice to sponsors regarding important elements of the future application that the IDE may not specifically address. Examples of typical future considerations include discussion of:
If an IDE application is disapproved, the sponsor may not initiate the clinical investigation until the sponsor submits an amendment 14 to the IDE to respond to the deficiencies identified in FDA’s letter and subsequently receives a new letter from FDA granting approval or approval with conditions. There are five major reasons why FDA may disapprove an IDE, as discussed in 21 CFR 812.30(b):
Consistent with this regulation, FDA will generally disapprove an IDE for any of the following reasons:
As noted in 21 CFR 812.30(c)(1), a disapproval letter will contain a complete statement of the reasons for disapproval. If the sponsor submits an IDE application that contains major fundamental flaws that preclude approval, FDA’s identified deficiencies may describe broad concerns rather than contain a comprehensive list of each of FDA’s specific concerns. In addition, FDA’s review may not focus on elements of the IDE that are likely to be substantially changed by the sponsor in order to address FDA’s broader concerns. In such cases, FDA’s complete statement of the reasons for disapproval will clearly identify the fundamental deficiencies. Once the sponsor submits an amendment to the IDE submission to address the broad concerns that have been identified, FDA can complete a substantive review of the submission. FDA may advise the sponsor that a pre-submission discussion may be helpful prior to the sponsor formally responding to the IDE disapproval. Where appropriate, sponsors should consider requesting a pre-submission meeting before submitting an IDE.
FDA considers many factors when determining whether an IDE should be approved. The following section discusses several common, important factors that FDA considers, although it is not intended to be a comprehensive list.
8.1 Non-clinical Testing
FDA reviews the non-clinical test data provided to support the basic safety and performance of the device. The type and extent of non-clinical data needed depend on several factors, including: whether the device is an in vitro diagnostic, an implanted device, or a device external to the body; the duration of use; and the expected performance requirements. Examples of bench data that may be needed include testing to demonstrate acceptable biocompatibility, sterilization, electrical performance, mechanical performance and durability, drug or biologic characteristics for combination products, and software validation. In many cases, animal data may also be needed to demonstrate an acceptable safety and/or performance in in vivo conditions to support initiation of a clinical investigation.
8.2 Category of Clinical Investigation
The category (i.e., feasibility or pivotal) of the proposed clinical investigation may impact FDA’s assessment of which elements of the IDE application are most important with regard to IDE approval. For example, FDA would not expect all preclinical studies to be completed when an IDE for a feasibility study is submitted, as long as the existing data meet the standard for study initiation. Additional preclinical data may be generated as development proceeds, and as the manufacturer establishes device and performance parameters with greater certainty. For pivotal studies, in addition to an assessment of safety, FDA will consider whether the study is appropriately designed to support a marketing application.
8.3 Risk Assessment
FDA considers whether the expected risks to study subjects are reasonable. It is important to note that this assessment considers many factors, including the severity of the medical condition, the patient population being studied, the current treatment options that are available to potential study subjects, and the evidence provided to support the potential for benefit to study subjects. FDA may be more willing to accept a higher risk profile or a lesser initial demonstration of potential benefit if the medical condition is serious and/or the available treatment options are limited.
FDA recognizes that in rare cases, clinical investigations of devices are not designed to offer the potential of benefit to study subjects. For example, a feasibility study may be proposed in which subjects are briefly tested with an investigational device (which is expected to have no lasting effect) during an otherwise clinically-indicated procedure. For those clinical investigations, the tolerance for the incremental risk of the clinical investigation is generally lower than that for studies that have the potential to offer direct benefit to subjects, and that risk should be outweighed by the expected value of the data to be gathered.
8.4 Study Design Elements
The elements that FDA will consider in its review of the study design will depend on the device characteristics and risk profile, the medical condition being studied, and the goals of the clinical investigation. For feasibility studies, FDA’s review will generally focus on subject safety issues, enrollment criteria, clinical methodology, and whether the information that will be gathered is appropriate to support the study goals (e.g., to support the design and initiation of a future pivotal study). For pivotal studies, FDA will also focus on elements of the study design that may impact the ability of the study to provide valid scientific evidence 15 to support a future marketing application. These elements include primary safety and effectiveness endpoints, assessment methodologies, randomization and blinding, the statistical analysis plan, case report forms, monitoring plans, and the use of external review bodies (e.g., Data Monitoring Committees, Clinical Events Committees, and core labs). These elements are critical to ensuring that the clinical investigation is likely to generate valid data at its conclusion. If a proposed pivotal study is unlikely to generate data that would support marketing clearance or approval, FDA may consider it unreasonable to expose study subjects to the risks of the device and may therefore disapprove the study.
8.5 Informed Consent Document
The process of informing potential study subjects of the possible risks, benefits, and alternatives associated with participation in the clinical investigation is a necessary element of proper study conduct. FDA closely reviews the informed consent document as part of the IDE review. In order to support approval of the IDE, the informed consent document must meet the requirements of 21 CFR Part 50. Additional information on informed consent can be found on FDA’s website.
8.6 Least Burdensome
FDA is committed to fostering innovation and ensuring timely public access to safe and effective new products. FDA defines the term “least burdensome” 16 as a successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA. Application of the least burdensome principles to premarket requirements helps to reduce regulatory burden and save FDA and industry resources, while protecting the public health by maintaining the safety and effectiveness of medical devices.
Supplements to approved IDEs are submitted for several reasons, including the following:
For IDE supplements that require FDA approval, the FDA decision process is similar to that described for original IDE submissions, with the same decision options (i.e., approval, approval with conditions, and disapproval) and review and response timelines. A notable difference between FDA’s review of such supplements and the review of an original IDE submission is that FDA disapproval of the supplement does not imply that the IDE study itself is disapproved. For example, if a supplement to an approved IDE requests approval for changes to the clinical investigation and that supplement is disapproved, the sponsor may not implement the requested changes. However, the original IDE clinical investigation remains approved and may continue. For IDE supplements that are notifications or reports, FDA will respond to the sponsor within 30 days if FDA has questions or requests for additional information; otherwise, FDA may close the submission without issuing a formal response to the sponsor.
The following are generic examples of how different IDE decision mechanisms may be employed.
10.1 Example 1
A sponsor submits an original IDE application to request approval to conduct a 30-subject feasibility study for a permanently implanted device to treat a serious chronic medical condition. The study is intended to provide data to support a future pivotal study.
FDA’s review results in the following conclusions:
FDA determines that, while the informed consent document issue must be corrected before enrolling subjects, none of the other concerns should preclude the sponsor from initiating the feasibility study. Therefore, FDA issues an approval with conditions letter to the sponsor. The letter states that the sponsor may initiate enrollment in the study, using an informed consent document that is modified to include the potential risk discussed above, on the condition that, within 45 days from the date of FDA’s letter, the sponsor also modifies the follow-up visits to address FDA’s concern. The letter also informs the sponsor of a future consideration related to the likely need for a longer-term animal study prior to initiation of a future pivotal study unless the sponsor is able to provide additional data or a scientifically valid rationale for why such a study is not needed.
The sponsor submits a supplement to the IDE to respond to FDA’s approval with conditions letter within 45 days. The submission provides a modified clinical protocol and informed consent document which fully address the issues identified in FDA’s letter. Therefore, FDA approves the IDE without conditions. In the IDE approval letter, the sponsor is reminded of the future consideration communicated in FDA’s previous letter.
10.2 Example 2
A sponsor submits an original IDE application to request approval for a 300 subject pivotal study to evaluate the safety and effectiveness of a permanently implanted device to treat a serious chronic medical condition.
FDA identifies the following issues that must be addressed before study initiation:
FDA also identifies other issues which the sponsor must address, but do not preclude initiation of the study, including:
Based on the first two concerns, FDA disapproves the study. The deficiencies provided in FDA’s letter articulate each of FDA’s four concerns, specifically noting which deficiencies were the basis for disapproval.
In response to FDA’s letter, the sponsor submits an amendment to the IDE that includes additional test data and a modified clinical protocol. The amendment specifically responds to each deficiency, including those that were not the basis for disapproval. FDA’s review of the amendment does not identify any issues that preclude the sponsor from initiating the study. FDA determines that the durability test data that were provided strongly suggest good long-term performance of the device and are sufficient to support study of the device in a small group of subjects. However, the data are not adequate to fully address the identified deficiency and longer term non-clinical durability testing should be conducted before the entire study cohort is exposed to the risks of the study. FDA also identifies some minor outstanding concerns with other clarifications and modifications made in response to the deficiencies that FDA identified.
FDA issues a staged approval with conditions letter that allows the sponsor to begin enrollment in the study, for up to 50 subjects, on the condition that the sponsor addresses the issues identified in FDA’s letter within 45 days. One of the outstanding issues conveyed to the sponsor is a request that the sponsor conduct longer term durability testing concurrent to enrollment in the study and that the response to FDA’s approval with conditions letter include a detailed commitment to conduct this testing.
The sponsor submits a supplement to the IDE to respond to the issues identified in FDA’s approval with conditions letter within 45 days. FDA determines that all of the responses are acceptable. Therefore, FDA issues a staged approval without conditions. The enrollment continues to be limited to 50 subjects while the durability testing is ongoing. A future consideration is included in the approval letter to remind the sponsor that the clinical investigation will not have a sufficient sample to support the overall study goals (e.g., support a marketing application) until the full planned cohort of subjects is studied.
Two months later, with 37 subjects enrolled in the study, the sponsor submits an IDE supplement to provide the results from the durability testing and requests approval to enroll up to 300 subjects. FDA finds the results acceptable and grants approval for the sponsor to enroll the entire study cohort.
FDA recognizes the public health benefit of permitting well-designed clinical investigations of medical devices to proceed in a timely and efficient manner while ensuring proper subject protections. When determining whether to approve an IDE application, FDA considers many factors, as discussed in this document. Where appropriate, FDA seeks to offer flexibility in how outstanding issues can be addressed (i.e., approval with conditions, staged approval, and future considerations) to allow clinical investigations to commence without unnecessary delay, while ensuring that human subjects are adequately protected.
1 21 CFR 812.3(m): A significant risk device means an investigational device that:
2 This guidance does not offer specific information related to the design of a clinical investigation, nor does this guidance discuss the specific content that should be provided in an IDE application. For additional information on those topics, please refer to FDA’s regulations (21 CFR 812.20 and 812.25) and to FDA’s Guidance on IDE Policies and Procedures .
4 FDA has traditionally referred to IDE approvals that have conditions as “Conditional Approvals.” FDA believes that the term “Approval with Conditions” is more appropriate because the term conveys that the IDE has been approved and may begin without awaiting further FDA review.
5 21 CFR 812.3(n): Sponsor means a person who initiates, but who does not actually conduct, the investigation, that is, the investigational device is administered, dispensed, or used under the immediate direction of another individual. A person other than an individual that uses one or more of its own employees to conduct an investigation that it has initiated is a sponsor, not a sponsor-investigator, and the employees are investigators.
6 21CFR 812.3(o): Sponsor-investigator means an individual who both initiates and actually conducts, alone or with others, an investigation, that is, under whose immediate direction the investigational device is administered, dispensed, or used. The term does not include any person other than an individual. The obligations of a sponsor-investigator under this part include those of an investigator and those of a sponsor.
The remainder of this document uses the term “sponsor” for both sponsor and sponsor-investigator.
11 Pivotal studies are discussed in more detail in the FDA draft guidance titled, “ Design Considerations for Pivotal Clinical Investigations for Medical Devices ”
12 Feasibility studies are developmental studies that are not intended to provide the primary clinical evidence to support a marketing application. A draft guidance document entitled “ Investigational Device Exemptions (IDE) for Early Feasibility Medical Device Clinical Studies, Including First in Human (FIH) Studies,” discusses the types of feasibility studies.
13 If the available information strongly indicate that the study will be underpowered and unlikely to produce valid scientific evidence, this concern may instead result in disapproval or approval with conditions.
14 If an IDE has not yet received approval or approval with conditions, subsequent submissions to FDA related to the IDE are designated as “IDE amendments.” There is no required timeframe within which a response to an IDE disapproval must be submitted.
15 21 CFR 860.7 (c)(2): Valid scientific evidence is evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use. The evidence required may vary according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. Isolated case reports, random experience, reports lacking sufficient details to permit scientific evaluation, and unsubstantiated opinions are not regarded as valid scientific evidence to show safety or effectiveness. Such information may be considered, however, in identifying a device the safety and effectiveness of which is questionable.
16 Additional information is provided in the guidance entitled “ The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles ”
17 The guidance document entitled “ Changes or Modifications During the Conduct of a Clinical Investigation ,” discusses the types of changes that require FDA approval and those that qualify for notification.
18 The guidance entitled “ Guidance on IDE Policies and Procedures ,” discusses Compassionate and Emergency Use.