Contains Nonbinding Recommendations FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions ____________________________________________________________________________ Guidance for Sponsors, Clinical Investigators, Industry, Institutional Review Boards, and Food and Drug Administration Staff Document issued on December 5, 2017. The draft of this document was issued on June 1, 2016. This document supersedes IDE Guidance Memorandum #95-2 “Implementation of the FDA/HCFA Interagency Agreement Regarding Reimbursement Categorization of Investigational Devices” issued on September 15, 1995. For questions about this document as applied to devices regulated by the Center for Devices and Radiological Health (CDRH), contact CDRHClinicalEvidence@fda.hhs.gov. For questions regarding this document as applied to devices regulated by the Center for Biologics Evaluation and Research (CBER), contact the Office of Communication, Outreach and Development in CBER at 1-800-835-4709 or 240-402-8010 or ocod@fda.hhs.gov. U.S. Department of Health and Human Services Food and Drug Administration Center for Devices and Radiological Health Center for Biologics Evaluation and Research 1 Contains Nonbinding Recommendations Preface Public Comment You may submit electronic comments and suggestions at any time for Agency consideration to https://www.regulations.gov. Submit written comments to the Dockets Management Staff, Food and Drug Administration, 5630 Fishers Lane, Room 1061, (HFA-305), Rockville, MD 20852. Identify all comments with the docket number FDA-2016-D-1159. Comments may not be acted upon by the Agency until the document is next revised or updated. Additional Copies CDRH Additional copies are available from the Internet. You may also send an e-mail request to CDRH- Guidance@fda.hhs.gov to receive a copy of the guidance. Please use the document number 1500074 to identify the guidance you are requesting. CBER Additional copies are available from the Center for Biologics Evaluation and Research (CBER), Office of Communication, Outreach, and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Room 3128, Silver Spring, MD 20993-0002, or by calling 1-800-835-4709 or 240-402- 8010, by email, ocod@fda.hhs.gov, or from the Internet at https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid ances/default.htm. 2 Contains Nonbinding Recommendations Table of Contents I. Introduction ............................................................................................................................. 4 II. Background ............................................................................................................................. 5 III. FDA Interpretation of Medicare Coverage Categories A and B ............................................. 8 IV. Considerations When Changing from Category A to B .......................................................... 9 V. Examples ............................................................................................................................... 11 VI. Conclusions ........................................................................................................................... 13 Appendix A: Category Decision Flowchart .................................................................................. 14 3 Contains Nonbinding Recommendations FDA Categorization of Investigational Device Exemption (IDE) Devices to Assist the Centers for Medicare and Medicaid Services (CMS) with Coverage Decisions Guidance for Sponsors, Clinical Investigators, Industry, Institutional Review Boards, and Food and Drug Administration Staff This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff or Office responsible for this guidance as listed on the title page. I. Introduction This guidance modifies the Food and Drug Administration’s (FDA’s or the Agency’s) current policy on categorizing investigational device exemption (IDE) devices, which assists the Centers for Medicare & Medicaid Services (CMS) in determining whether or not an IDE device should be covered (reimbursed) by CMS. On December 2, 2015, FDA’s Center for Devices and Radiological Health (CDRH) and CMS’s Coverage and Analysis Group (CAG) executed a Memorandum of Understanding (MOU)1 to 1 The MOU can be accessed at https://www.fda.gov/AboutFDA/PartnershipsCollaborations/MemorandaofUnderstandingMOUs/DomesticMOUs/uc m477091.htm. 4 Contains Nonbinding Recommendations streamline and facilitate the efficient categorization of investigational medical devices in order to support CMS’s ability to make Medicare coverage (reimbursement) determinations for those investigational devices under 42 CFR 405 Subpart B. The MOU noted the need for FDA and CMS to revise their shared understanding regarding categorization. This guidance document is intended to implement the MOU by further explaining the framework that FDA (both CDRH and the Center for Biologics Evaluation and Research (CBER)) intends to follow for such decisions. This guidance applies to all devices reviewed by CDRH and CBER. The MOU took effect June 2, 2016 (six months following signature by both FDA and CMS, as stated in the MOU). The framework in this guidance represents the Agency’s current thinking on categorization. II. Background 1995 Final Rule and FDA-HCFA Interagency Agreement In September 1995, the Health Care Financing Administration (now known as CMS) published a final rule and entered into an Interagency Agreement (IA) with FDA regarding reimbursement categorization of investigational devices. 60 Federal Register (FR) 48417 (September 19, 1995). The rule established that certain devices with an IDE approved by FDA (and certain services related to those devices) may be covered under Medicare, and set forth the process by which FDA would assist CMS in identifying such devices. FDA would assign a device with an FDA- approved IDE to one of two categories: Experimental/Investigational (Category A) devices or Non-experimental/Investigational (Category B) devices based on the level of risk the device presented to patients. The IA set forth criteria, agreed upon by CMS and FDA, that FDA would use to categorize devices. The categorization would then be used by CMS as part of its determination of whether or not items and services met the requirements for Medicare coverage under Section 1862(a)(1)(A) of the Social Security Act (the “reasonable and necessary” clause). That is, to be eligible to be covered (e.g., to have a benefit category determination) under Medicare, the device must be reasonable and necessary for the diagnosis or treatment of an illness or injury, or to improve the functioning of a malformed body member.2 Under the 1995 CMS final rule, Category A devices were devices believed to be in class III for which “absolute risk” of the device type had not yet been established. That is, initial questions of safety and effectiveness had not been resolved and FDA was unsure whether the device type could be safe and effective. The IA contained two sub-categories which provided criteria indicating that a given device met this standard and should be placed into Category A: those devices for which no marketing application had been approved through the premarket approval (PMA) process for any indication for use, and devices that would otherwise be a Category B (discussed below), but had undergone significant modification for a new indication or use. An example of a significant modification might be the addition of a drug to a legally marketed device where the drug previously had not been used on this type of device. 2 Implementation of the FDA/HCFA Interagency Agreement Regarding Reimbursement Categorization of Investigational Devices, Att. A Interagency Agreement, Att. B Criteria for Categorization of Investigational Devices, & Att. C List. #D95-2 (IDE Guidance Memorandum #95-2, Sept. 15, 1995), available at https://www.fda.gov/RegulatoryInformation/Guidances/ucm080302.htm. 5 Contains Nonbinding Recommendations Under the 1995 CMS final rule, Category B devices were those devices believed to be in Class I or II, or devices believed to be in Class III for which the incremental risk was the primary risk in question. That is, with respect to Category B devices, the underlying questions of safety and effectiveness of that device type had been resolved, or it was known that the device type could be safe and effective because, for example, other manufacturers had obtained FDA approval for that device type. The IA identified six sub-categories of investigational devices that were of a device type for which the underlying questions of safety and effectiveness had been resolved and, thus, should be placed in Category B. Under the IA, Category B devices included those that were under investigation to demonstrate substantial equivalence to a predicate device (legally marketed device) through the 510(k) process and devices comparable to a PMA-approved device. Several examples of Category A and B devices can be found later in this document. Importantly, CMS and FDA both recognized that experience in categorizing devices might require changes to the IA.3 2013 Amendment to 42 CFR 405 Subpart B CMS, with FDA’s concurrence, published a final rule in the FR on December 10, 2013 (78 FR 74230, 74809) that, among other things, modified the definitions for Category A and Category B. These definitions can be found in the Code of Federal Regulations (CFR) at 42 CFR 405.201: Category A (Experimental) 42 CFR 405.201(b): “…a device for which ‘absolute risk’ of the device type has not been established (that is, initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.” Category B (Nonexperimental/investigational) 42 CFR 405.201(b): “…a device for which the incremental risk is the primary risk in question (that is, initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.” CMS uses FDA’s categorization determination as a factor in evaluating whether or not an IDE device receives Medicare coverage. Medicare may make payment for an investigational device and routine care items and services furnished in an FDA-approved Category B (Nonexperimental/Investigational) IDE study if CMS (or its designated entity) determines, prior to the submission of the first related claim, that the Medicare coverage IDE study criteria in 42 CFR 405.212 are met.4 If the criteria are not met for a Category B device, neither the device nor other elements of the study will be covered. With respect to Category A devices, if CMS (or its designated entity) determines that Medicare coverage IDE study criteria in 42 CFR 405.212 are met, Medicare may cover only routine care items and services furnished in an FDA-approved 3 The IA was published as an addendum to the final rule in 1995. The FR noted that: “As experience is gained in the categorization process, this addendum may be modified.” 60 FR at 48419. 4 42 CFR 405.211(b). 6 Contains Nonbinding Recommendations Category A (Experimental) IDE study, but not the device itself.5 In other words, Medicare cannot cover device expenses with respect to studies involving devices that FDA has categorized as Category A (Experimental). Reasons for Modification of the Previous FDA Policy In the more than twenty years since the IA was signed, FDA has received a number of IDEs which do not easily fit into any of the eight sub-categories identified in the IA. In 2013, FDA published a final guidance document entitled “Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies” (available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocumen ts/ucm279103.pdf). That document provides guidance on the development and review of IDE applications for early feasibility studies (EFS) of significant risk devices. EFS are feasibility studies that are very small in size and allow for early clinical evaluation of devices that may not be a final design. They are intended to provide proof of principle and initial clinical study data. Traditional feasibility studies, on the other hand, are completed with a device design that is near- final or final and are commonly used to capture preliminary safety and effectiveness information which may be used to inform a pivotal study design. They are typically larger than EFS. The general term “feasibility studies” may refer to EFS or traditional feasibility studies. Pivotal studies are clinical investigations designed to collect definitive evidence of the safety and effectiveness of a device for a specified intended use, typically in a statistically justified number of subjects. The previous FDA policy regarding reimbursement categorization did not adequately articulate categorization criteria that are relevant to certain feasibility studies, particularly those for devices similar to approved devices but with modifications which raise significant new safety questions. As a result of this, and the recent increase in EFS submissions subsequent to the publication of the guidance document referenced above, FDA has determined that additional clarification of FDA’s approach to these categorization criteria is warranted. It is important to note that the category designation is made independent of study type and instead is based on the criteria described in this document. In addition to the above consideration, there are situations when adequate data are provided to resolve initial questions of safety and effectiveness (e.g., data from a feasibility study becomes available) and, therefore, it is appropriate to change the device category for subsequent studies of the same device from Category A to Category B. In these circumstances, a device that had previously been categorized as experimental could now be considered nonexperimental/investigational. However, the IA did not describe a pathway for changing categorization from Category A to Category B when approving subsequent studies for the same device. In order to outline a mechanism to revisit the categorization of IDE devices when new information is gathered, the previous FDA policy for categorization of IDE devices is being modified. 5 42 CFR 405.211(a). 7 Contains Nonbinding Recommendations Lastly, in its changes to the regulations (42 CFR 405 Subpart B), effective January 1, 2015, CMS, with FDA’s concurrence, added criteria for coverage of IDE devices within CMS approved studies. This was a change from local Medicare Administrative Contractor (MAC) review. The change to a centralized IDE review further reinforced the need for CMS and FDA to revisit the policy that FDA used to categorize IDE devices. CMS and FDA recognized the need to revise their shared understanding regarding the categorization of IDE devices to help ensure that reimbursement of devices will not be precluded due to an inappropriate reimbursement categorization determination. Rather than amending their 1995 IA, FDA and CMS entered into an MOU on December 2, 2015 that became effective on June 2, 2016. The policies and framework in this guidance represent the Agency’s current thinking on categorization. III. FDA Interpretation of Medicare Coverage Categories A and B After receipt of an IDE application, FDA will determine whether the sponsor has provided enough information to support initiation of the clinical study. An IDE application is “approved,” or “approved with conditions,” if FDA has determined that the sponsor has provided adequate data to support initiation of a human clinical study, no subject protection concerns preclude initiation of the investigation, and the benefit-risk profile is sufficiently favorable to justify enrollment.6 A study which has been approved or approved with conditions may be staged such that preliminary data can be reviewed prior to full patient enrollment. FDA intends to use the criteria described below to assign a device to Category A or B when the IDE is approved or approved with conditions. Please refer to Appendix A for a flowchart depicting the decision- making process. Category A: Experimental 42 CFR 405.201(b): “…a device for which ‘absolute risk’ of the device type has not been established (that is, initial questions of safety and effectiveness have not been resolved) and the FDA is unsure whether the device type can be safe and effective.” FDA intends to consider a device to be in Category A if one or more of the following three criteria are met:  No PMA approval, 510(k) clearance, or De Novo request has been granted for the proposed device or similar devices, and data on the proposed device or other similar devices do not resolve initial questions of safety and effectiveness and FDA is unsure whether the device type can be safe and effective.  The proposed device is being studied for a new indication, or new intended use, for which information from the proposed or a similar device related to the previous indication or intended use does not resolve initial questions of safety and effectiveness. 6 For more information on how IDE Decisions are made please refer to the FDA Guidance document “FDA Decisions for Investigational Device Exemption Clinical Investigations,” available at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279107.pdf. 8 Contains Nonbinding Recommendations Available non-clinical and/or clinical data on the proposed device or similar devices relative to the new indication or intended use also do not resolve these questions and FDA is unsure whether the device type can be safe and effective.  The proposed device has different technological characteristics compared to a legally marketed device, and information related to the marketed device does not resolve initial questions of safety and effectiveness for the proposed device. Available non-clinical and/or clinical data on the proposed device or similar devices also do not resolve these questions and FDA is unsure whether the device type can be safe and effective. Category B: Nonexperimental/Investigational 42 CFR 405.201(b): “…a device for which the incremental risk is the primary risk in question (that is, initial questions of safety and effectiveness of that device type have been resolved), or it is known that the device type can be safe and effective because, for example, other manufacturers have obtained FDA premarket approval or clearance for that device type.” FDA intends to consider a device to be in Category B if one or more of the following three criteria are met:  No PMA approval, 510(k) clearance, or De Novo request has been granted for the proposed device or similar devices; however, available information (e.g., feasibility study data) from the proposed device or a similar device resolve the initial questions of safety and effectiveness.  The proposed device is being studied for a new indication or new intended use; however, information from the proposed or a similar device related to the previous indication or intended use resolves the initial questions of safety and effectiveness. In some cases, additional non-clinical and/or clinical data on the proposed device may also have been used to resolve these questions.  The proposed device has similar technological characteristics compared to a legally marketed device, and information related to the marketed device resolves the initial questions of safety and effectiveness for the proposed device. In some cases, additional non-clinical and/or clinical data on the proposed device may also have been used to resolve these questions. IV. Considerations When Changing from Category A to B As mentioned previously in this document, there are situations in which clinical and/or non- clinical evaluations provide adequate data to resolve initial questions of safety and effectiveness and, therefore, it is appropriate to change the device category from Category A to Category B. Data can come from different sources and may become available at different points in time. Therefore, a category change from A to B could occur in a variety of circumstances and the 9 Contains Nonbinding Recommendations change may or may not coincide with the completion of a clinical study, or a stage of a clinical study, on the investigational device. One situation when a categorization change would be appropriate is when a completed study in which the device was designated as Category A has resulted in clinical data that resolve the initial questions of safety and effectiveness. In this case, the device should be designated as Category B in the subsequent study. Another situation where a category change may be warranted is when an IDE study receives a staged approval or staged approval with conditions. 7 In a staged approval, FDA may grant IDE approval or approval with conditions for a portion of the intended study cohort, enabling certain outstanding questions to be answered concurrently with enrollment in this initial stage cohort. The sponsor will be permitted to expand enrollment once an IDE supplement containing the necessary additional information is submitted to FDA and found to be acceptable. In cases in which the device has been designated as Category A because there are questions relevant to initial safety and effectiveness, data gathered from the first (or subsequent) enrollment stage(s) may resolve initial questions of safety and effectiveness such that the device category may be changed from Category A to Category B during continued study in the full study subject cohort. FDA will evaluate whether adequate data are present to resolve the initial questions of safety and effectiveness; a categorization decision will be made upon study approval (for a new study), upon submission of a request to change the category, or upon review of other IDE supplements related to the study (e.g., study expansion request). FDA assigns a category independently for a new study and may initiate a categorization change either independently or in response to a sponsor’s request. A request to change the IDE category (either from Category A to B or Category B to A8) can be submitted at any time as an IDE supplement and FDA intends to render a decision within thirty days. The supplement should include data which would support meeting the criteria as identified in 42 CFR 405.201(b). Examples of data that may support a change from Category A to Category B can include but are not limited to:  Peer-reviewed studies on the same or a similar device.  Premarket or postmarket data from studies conducted outside the U.S. on the same or a similar device.  Reference to commercialization of a device of a similar type.  Preliminary clinical data on the device (e.g., initial data from a staged study, feasibility study).  Additional non-clinical data on the same or a similar device may be included as supportive information. FDA also occasionally receives requests from study sponsors to change from Category B to Category A. In order to support a change from Category B to Category A, there should be 7 See “FDA Decisions for Investigational Device Exemption Clinical Investigations” at https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm279107.pdf. 8 FDA expects most category changes to be from A to B as additional information about the device is obtained. However, the category designation may also change from B to A. 10 Contains Nonbinding Recommendations directly relevant new information which demonstrates that initial questions of safety and effectiveness have not been resolved. For example, a comparison of the proposed device to a commercialized device of a similar type could be supplied along with an explanation to support why initial questions of safety and effectiveness related to the proposed device still remain that warrants a categorization change. The categorization decision will be included in the IDE (original or supplement) approval letter to the sponsor. In addition to the formal communication by FDA to CMS, it is at the sponsor’s discretion to communicate to CMS when IDE categorization changes. It should be noted that a categorization change for a given device will not automatically apply to similar devices. V. Examples Category A: Experimental The list below provides examples of when a Category A determination may be appropriate, but it does not represent an exhaustive list of when a device should be classified as Category A.  A device is completely novel and has no, or limited, previous human use and there are initial questions of safety and effectiveness. There is adequate non-clinical information to support initiation of an early feasibility study that will provide data to inform potential device design or procedural improvements.  A drug is added to a previously approved or cleared device. While substantial information is known about the previously approved or cleared device, the drug has not previously been used on this type of device, and relevant non-clinical or clinical data are not available to address the initial questions of safety and effectiveness associated with the addition of the drug.  An already-approved or -cleared device is being evaluated for a new intended use or indication for which the device will be placed in a different anatomical location. The device’s technology is unchanged from what was initially approved or cleared. While some non-clinical data on this device may be used to anticipate certain aspects of device performance, it is still uncertain as to whether the device can be safely placed, and be effective, in the new anatomical location. Therefore, there are inadequate data to resolve the initial questions of safety and effectiveness relative to the new intended use or indication, and FDA is unsure whether or not the device type can be safe and effective.  The initial question of safety has been answered with the submission of non-clinical data and short-term clinical data from a small study. However, additional performance data will be needed to resolve initial questions related to effectiveness. Therefore, this device will be designated as Category A.  The initial question of effectiveness has been answered with the submission of data that demonstrate similar performance to a previously approved device. There is inadequate 11 Contains Nonbinding Recommendations evidence to resolve initial questions related to safety because this will require follow up in a clinical study; however, the benefit-risk profile supports initiation of a study. Category B: Nonexperimental/Investigational The list below provides examples of when a Category B determination may be appropriate, but it does not represent an exhaustive list of when a device should be classified as Category B.  The insertion system of an approved device has been modified to improve ease of use for the clinician. Non-clinical test data resolved initial questions of safety and effectiveness related to this change; however, confirmatory clinical information about the device performance is required due to the inherent differences between the non-clinical test environment and the clinical setting.  Adequate data have been gathered from non-clinical testing, and the clinical results of a feasibility study such that initial questions of safety and effectiveness have been resolved. A pivotal study will be initiated to provide the primary clinical evidence for the safety and effectiveness of the device in support of a future marketing application.  A new device will be studied for an indication for which substantial safety and effectiveness information exists from other similar device(s) of the same type that are used for the same or a similar indication. Clinical information from similar devices and non-clinical test data for the new device that have been provided can answer initial safety and effectiveness questions regarding this indication.  A modification has been made to an approved device in order to improve its performance. Non-clinical and clinical data available from the previous version of the device, along with additional testing on the modified device, resolved initial questions of safety and effectiveness. The purpose of the study will be to gather further data regarding device performance for this modified version of the device.  New device sizes will be added to a product matrix for an approved device. Initial questions of safety and effectiveness have been resolved based on experience with the approved device, and it is generally understood how the new device sizes will perform. The new device sizes will be evaluated in a clinical study such that confirmatory safety and effectiveness information relevant to these sizes can be gathered.  An approved device will be evaluated in a new patient population. Non-clinical and clinical data from use in the previous patient population resolved initial questions of safety and effectiveness for the new patient population. The new study to be conducted will provide further data regarding device performance for this new patient population.  An approved device will be evaluated for a new indication. Data exist on the approved device for a similar indication, and non-clinical data have also been supplied such that the initial questions of safety and effectiveness related to the new indication have been resolved. The new study to be conducted will provide further data regarding device performance for this new indication. 12 Contains Nonbinding Recommendations Change from Category A to Category B If the device was previously designated as Category A, but the initial questions of safety and effectiveness of the device have since been resolved, it may be appropriate to change the Category from A to B. The list below provides examples of when a change from Category A to Category B may be appropriate, but it does not represent an exhaustive list of when a device may change from Category A to Category B.  A novel insertion procedure will be used to place an already-approved or -cleared device, and there are initial questions of safety and effectiveness regarding the novel insertion procedure that have not been resolved. In this case, these questions of safety and effectiveness may be answered in a short timeframe with a limited number of subjects in the context of a larger clinical study. Therefore, the device will be evaluated in a staged clinical study where the first stage falls under Category A. If the initial questions of safety and effectiveness are resolved, and the study continues, the device may be re- categorized to Category B.  Adequate data have been gathered on a device from non-clinical testing and an early feasibility study has been conducted within the U.S., such that initial questions of safety and effectiveness have been resolved. Additional data are needed to help inform a pivotal study design; therefore, a traditional feasibility study will be initiated. Although the EFS was originally designated as Category A, adequate data as described above have since been gathered (in the EFS) to support a change to Category B for the traditional feasibility study.  A device is currently being evaluated in a clinical study and has been designated Category A. While the study is being conducted, clinical study results for similar devices become available which resolve initial questions of safety and effectiveness for the device. This information will be used to support a categorization change from Category A to Category B for the device evaluated in the ongoing clinical study. VI. Conclusions FDA categorizes IDE devices based on whether available data demonstrate that initial questions of safety and effectiveness have been resolved. This guidance document describes the process and information that will be used to help determine the appropriate category for a device to be studied. This guidance document also describes when it is appropriate to change the device category from Category A to Category B. The categorization of IDE devices is used by CMS as part of its determination of which devices meet the requirements for Medicare coverage under Section 1862 (a)(1)(A) of the Social Security Act (the “reasonable and necessary” clause). IDE device categorization is only part of the information used to determine coverage by CMS. Please refer to the website “Medicare Coverage Related to Investigational Device Exemption (IDE) Studies” (https://www.cms.gov/medicare/coverage/IDE/index.html) for guidance on requesting coverage and for contact information. 13 Contains Nonbinding Recommendations Appendix A: Category Decision Flowchart 14