Hello, my name is Soma Kalb and I'm the Acting Director of the IDE Program in CDRH. This presentation is on IDE Basics. After watching this program, I hope you'll have a better understanding of the regulatory context of device clinical investigations; when an IDE is required; the IDE application process and FDA decisions on those applications; and the roles and responsibilities of key players in IDE studies.
Let's start with the regulatory authority and framework for device clinical investigations. The authority governing the clinical investigation of medical devices can be found in section 520(g) of the Food Drug and Cosmetic Act. The opening of that section starts with the text you see on the screen: “It is the purpose of this sub-section to encourage, to the extent consistent with the protection of public health and safety, and with ethical standards, the discovery and development of useful devices intended for human use and to that end, to maintain optimum freedom for scientific investigators in their pursuit of that purpose.”
You'll see that I've highlighted two phrases in this text: the protection of public health and safety, and the discovery and development of useful devices. Those are two tenants that underscore the work of FDA - the protection of public health, and fostering innovation. The law is interpreted for us in the regulations. Title 21 of the Code of Federal Regulations regards food and drugs, and includes medical devices. There are several parts of the CFR that pertain to IDEs. These include Part 812, which is Investigational Device Exemptions, and is the primary subject of this presentation. Also relevant are Parts 50 on Informed Consent; 54 on Financial Disclosure of Investigators; and 56 on Institutional Review Boards.
In addition to these regulations, the FDA Safety and Innovation Act was passed in 2012 and is relevant for IDEs. Part 1 of Section 812 immediately describes what an Investigational Device Exemption is. An Investigational Device Exemption permits a device that would otherwise be required to comply with a performance standard, or to have premarket approval, to be shipped lawfully for the purpose of conducting investigations of that device. Simply, an IDE is a regulatory submission that permits clinical investigation of devices.
IDEs are exempt from several regulations that would otherwise be required in order to use that device. The regulations that are exempt are listed on this slide. In addition to exempting a device from complying with several regulations, the IDE regulations also have other provisions. They describe the applicability of the IDE regulations. They provide administrative information; they outline the contents of the IDE application, and describe the FDA actions on those IDE applications. They also assign responsibilities for participants in clinical investigations.
I'll now talk about studies that require an IDE. There are several different ways to describe studies, and on this slide, I have several terms that may be familiar to you.
A “pivotal study” is a study that is often conducted by a manufacturer to support a marketing application. It's designed to collect definitive evidence on safety and effectiveness for a specified intended use, and it’s typically in a statistically justified number of subjects.
Often “feasibility studies” are also conducted by manufacturers. These capture preliminary safety and effectiveness data, usually in a small number of subjects, and often these are designed to inform a pivotal study. In addition to those types of studies conducted by manufacturers, there are also studies conducted by other entities, often referred to as “sponsor investigator studies”. In many cases, these are not intended to support a marketing application. An example of a sponsor investigator study might be a study on a new indication for use for a commercially available device. This might require an IDE, and it may not be intended to support a future marketing application.
Another type of study that you may hear about is an “early feasibility study”. These are studies that are typically conducted on a small number of subjects, and the device may be early in the development before its final design. There is a guidance available that outlines some of the provisions that may be followed in order to conduct an early feasibility study. The guidance is entitled Investigational Device Exemptions for Early Feasibility Medical Device Clinical Studies, including Certain First in Human Studies.
One of the guiding principles in this guidance is that approval might be based on less non-clinical data than would be needed to support the initiation of a larger clinical study on more final device design. Not all types of studies require IDEs, and you can look to the regulations for information on when an IDE is required. Typically, device studies are either exempt or not exempt, and if they’re not exempt, they're either significant risk or non-significant risk, which determines what the scope of requirements is for that IDE.
We'll first talk about “exempt studies”. Exempt studies are outlined in the Code of Federal Regulations in 21 CFR Section 812.2(c). So those devices that do not require an IDE are commercial devices used in accordance with their labeling, many diagnostic devices, testing of consumer preference of a modification or a combination of devices when you're not determining safety or effectiveness, and you’re not putting subjects at risk. Veterinarian device studies and research on or with laboratory animals are also exempt, as are custom devices, which are defined in Section 812.3(b). Now, in addition to those studies that are exempt and are outlined in the regulations, there are two other groups of device use for which an IDE is not required. First of all, there is practice of medicine.
In section 1006 of the FD&C Act, it states “nothing in this act shall limit or interfere with authority of healthcare practitioner to prescribe or administer legally marketed device to a patient for any condition or disease within a legitimate healthcare practitioner/patient relationship”. That means that FDA doesn't interfere with the practice of medicine. If a physician determines that the use of a device is appropriate for their patient, as long as they're not studying the safety and effectiveness of that device, they may use the device under practice of medicine. Under practice of medicine, the physician should be well informed about the product, and use firm scientific rationale and sound medical evidence to determine whether they should use the device. They should maintain records on the use of the device, and any adverse effects that might occur. An IDE is not required, although the institution might require IRB approval and informed consent. Other prohibitions, such as prohibition on promotions, still apply.
Another area that might not require an IDE is called ”basic physiological research.” This is research where you're investigating a physiological principle. There is no intent to develop the device for marketing, you are not evaluating the safety and effectiveness of the device, but you are using the device to address a research question. In these cases, the device is often used as a tool. For these cases no IDE is needed, although IRB approval and informed consent should be obtained. So those are the areas where an IDE is not required.
Let's start talking about when they're not exempt from the IDE. There are Significant Risk studies and Non-Significant Risk studies. Significant Risk is a term defined in the regulation in 21 CFR Section 812.3(m). It’s a device that presents a potential for serious risk to the health, safety and welfare of a subject, and is an implant, or used in supporting or sustaining human life, or of substantial importance in diagnosing, curing, mitigating or treating disease or preventing impairment of human health, or otherwise poses a risk.
Now who makes a determination about the risk of a device study? The sponsor makes the initial determination. Then the IRB reviews that determination. The sponsor should provide the IRB with the device description, information on prior investigations, the investigational plan, the subject selection, the risk assessment and the rationale used in making it Significant Risk or Non-Significant Risk, SR or NSR determination. If the IRB disagrees with the sponsor’s NSR assessment, the IRB must inform the clinical investigator, and where appropriate, the sponsor and that is outlined in the regulation. Non-Significant Risk studies do not require the submission of IDE to FDA. But they are subject to abbreviated requirements such as labeling, IRB approval, informed consent, monitoring, some reporting and prohibition on promotion. For Non-Significant Risk studies, the IRB serves as the FDA surrogate for review, approval and continuing review of these studies. And an NSR study can start at the institution as soon as the IRB reviews and approves the study.
For Significant Risk studies, the study cannot begin until an IDE is submitted and approved by FDA. Now FDA is available to help in making risk determinations. In these cases, the sponsor should submit a study risk determination Q-submission to FDA. FDA will issue a letter in response, indicating whether the study is considered basic physiological research, exempt, not exempt, and if not exempt, whether it’s Significant Risk or Non-Significant Risk. Information on how to submit a Q-submission can be found in the Pre-submission Program and Meetings with FDA Staff Guidance which is shown on this slide. Note that when FDA makes a study risk determination, FDA is the final arbiter. It is not necessary for the IRB to conduct an independent separate assessment.
We'll now move to the IDE application, and FDA decisions on those applications. The contents of the IDE application are outlined in the regulations in Section 812.20. Here on the slide, you see the required components: the name and address of the sponsor, the report of prior investigations and investigational plan. This is the heart of the application and more information on that aspect can be found in Section 812.25. Information on how the device is manufactured, processed, packaged and stored should also be provided. A copy of the investigator agreement, not necessarily the signed agreement, but your draft agreement with the required components, should be included. A list of the name, address and chairperson of each IRB that has been identified so far, as well as participating institutions, any charge for the device to demonstrate that you're not commercializing under the IDE, environmental assessment of the study, labeling materials, as well as any subject materials, including the informed consent that will be provided to study participants, as well as any additional information requested by FDA.
Once your application is submitted, FDA will send an acknowledgment letter to you with your IDE number. This will be a number that starts with the letter G, that’s followed by two digits designating the year and four digits, which are assigned sequentially. The IDE is sent to the appropriate review division, based on intended use - for example, the cardiovascular devices or orthopedic devices. The lead reviewer in that division will then assemble a team of experts to review the application. There may be interactive review that occurs between the sponsor and the review team within 30 days.
A decision is made within 30 days with management concurrence, and FDA issues a decision letter to the sponsor at that point. After an IDE is approved, the sponsor will continue to make submissions to FDA until the IDE is closed. These include supplements for things like changes in your protocol, or changes in your device, and these are described in section 812.35, as well as reports. There are required reports and optional reports that can be submitted to FDA, and these are outlined in Section 812.150.
These might include annual progress report, which is required, unanticipated adverse device effect reports, which are required, follow-up completion reports, your current list of investigators and your final report, which is also required.
Now after you submit original IDE application, FDA will issue a decision lette, and the FDA decisions can either be approval, approval with conditions, or disapproval.
In an approval decision, your study is approved for a specified number of subjects at a specified number of sites. An enrollment can begin once IRB approval is obtained.
Approval with conditions approves the trial also for specified number of sites and subjects, provided conditions are addressed within 45 days. These conditions are referred to as deficiencies. Enrollment can begin also for approval with conditions as soon as IRB approval is obtained. This approval is a third decision that you might receive.
With a disapproval decision, the study may not begin, and the sponsor must address deficiency and submit an amendment and obtain FDA approval prior to starting the study. The regulations provide the regulatory basis for disapproval. There can be many circumstances under which your study might be disapproved and these are outlined specifically in the regulations. There may be a failure to comply with regulatory requirements, the application might contain untrue statement, or omit important information, the sponsor might fail to respond to a request for additional information. A study might be disapproved if there is reason to believe that the risks aren't outweighed by the anticipated benefit to the subject and the knowledge to be gained by conducting a study. If the informed consent is inadequate, if the investigation is considered to be scientifically unsound, or the device as used is considered to be ineffective, it can otherwise be disapproved if FDA believes it is unreasonable to begin by the way the device is used, or the inadequacy of the report of prior investigations, or the investigational plan, information on manufacturing processing, packaging, storage or installation of the device, or the monitoring and review of the investigation, as outlined in the investigational plan.
In 2012, the Food, Drug and Cosmetic Act was amended, and in it was a Provision - 601 - that stated that “FDA shall not disapprove an IDE because the investigation may not support the substantial equivalent or de novo classification determination, or approval of a device. Or the investigation may not meet a requirement, including a data requirement relating to the approval of clearance of device or an additional or different investigation may be necessary to support clearance or approval of the device.”
This means that an IDE can't be disapproved on the basis that FDA believes the study design is inadequate to support a future PMA, 510(k), HDE or de novo classification. Disapproval must be based on concerns related to subject safety and protections. Although FDA cannot disprove a study based on concerns related to the study design, we believe it is important to convey this information to our stake holders within our disapproval letter. There are new elements to the FDA decision letters to allow us to convey this information.
We provide this information under study design considerations and future considerations. Study design considerations are recommendations, but not requirements, regarding the study design that will help the study to achieve its goals, whether that goal is a future pivotal study or a future marketing application. On the other hand future considerations are issues that are relevant for the future submission for the future marketing application, not aspects of the study itself that FDA believes might be changed.
Sponsors are not required to respond to these elements, but they often do.
So in summary, the three decisions that tell you whether or not you can start the study are Approval, Approval with Conditions, and Disapproval. You can start the study with Approval, or Approval with Conditions, but you can't with Disapproval. Approval with Conditions and Disapproval decisions require that deficiencies are addressed. The letter will also include study design considerations and future considerations that do not require a response. They have no bearing on the IDE decision of approval versus disapproval. Information on these decisions can be found in a guidance called FDA Decisions for IDE Clinical Investigations.
I'll now talk about office level review of IDE application specific issues. One of the goals of the CDRH Clinical Trials Enterprise is to conduct device trials in the U.S. in a timely, efficient and cost-effective manner, while maintaining appropriate patient protections. To help achieve this goal, a standard operating procedure, or SOP, is in place to improve efficiency, consistency, and predictability of the IDE process. This SOP can be found at the link on your screen.
Typically, IDE approvability decisions are made at the division level. With the SOP, an office level clinical trials director is involved in selected submissions. This clinical trials director provides objective review of outstanding issues to help resolve specific challenges. The scope of this SOP is that it applies to original IDEs, new study supplements, and expansions of studies from feasibility to pivotal, for which a decision other than full approval is made.
The SOP has three main provisions. The first is a teleconference with sponsors. The second is review by the clinical trials director of Disapproval and Approval with Condition decisions, and the third is interactions of the clinical trials director during the review of third and subsequent round responses to disapproval or approval with conditions.
Under the first provision, FDA offers teleconference to occur within 10 days of a first round disapproval or second or later round Disapproval or Approval with Conditions. Under the second provision, the clinical trials director and the review team meet prior to the 10-day teleconference; discuss the IDE and the remaining issues.
Now in addition to just reviewing decisions after they have occurred, if a third or subsequent round response to this approval or approval with conditions comes in, the clinical trials director is involved during the review and helps facilitate discussions based on his or her understanding of issues from his review of submissions across the divisions.
The goals of the SOP are to help ensure consistency in decision-making, to help facilitate sharing of best practices across the division, to encourage higher levels of interaction and to help prepare the sponsor to respond. This occurs through the 10-day meeting and the outside perspective on the letter that is provided by the clinical trials director.
We'll now talk about the roles of the sponsors, investigators and IRBs in conducting clinical studies for devices. The key players, as outlined in regulations for device clinical studies, include the sponsor, the investigator, and the institutional review board or IRB. The sponsor initiates, but does not actually conduct, the investigation.
On the other hand, the investigator actually conducts a clinical investigation, and that is, the investigator is under whose immediate direction the test article is administered or dispensed to, or used, involving a subject.
The IRB reviews and approves biomedical research at a given institution. The IRB conducts initial review, as well as continuing review throughout the life of the study.
The sponsor's responsibilities are outlined in the regulations. The sponsor's responsible for selecting qualified investigators, and providing them with the information they need, including obtaining investigator agreements. The sponsor is responsible for ensuring proper monitoring of the study, selecting the monitors, and securing compliance with the protocol, and evaluating and handling any unanticipated adverse device effects that occur. The sponsor is responsible for obtaining both IRB and FDA approval of the study. This is for both study initiation and full resumption of any terminated studies. They're responsible for the IDE application and any supplements, and for keeping the IRB and FDA informed of significant new information.
The sponsor is responsible for keeping control of the devices, and for complying with other parts of the regulation, such as Sub-part A on labeling and promotion, as well as import and export of devices. The sponsor responsibilities are out lined in section 812 Sub-part G.
They’re responsible for maintaining adequate records, including records of correspondence, investigator agreement, device disposition and adverse effects complaints. They’re responsible for granting inspections to FDA, and for preparing and submitting reports to the FDA. These include unanticipated adverse device effect reports, any withdrawals of IRB approval, the current investigator list, progress reports, any recall and device disposition reports, a final report, any failures to obtain informed consent, and any significant risk device determinations.
The investigator responsibilities are outlined in Sub-part E of Part 812. The investigator is responsible for conducting the investigation, per the signed agreement; investigational plan; the FDA regulations and any conditions of approval. They are responsible for protecting the rights, safety and welfare of subjects under their care; for controlling the investigational devices, including supervising device use and appropriately disposing of any devices, and obtaining appropriate informed consent.
The responsibilities are similar to those for the sponsor. They must maintain adequate records, including correspondence; detailed case histories on subjects; including the case report forms, informed consent documents; and medical records; records on device disposition; as well as any adverse effects or complaints; and of course, the protocol. Similar to the sponsor, investigators must be able to grant inspections to FDA and they prepare and submit reports. These reports are sent to the sponsor and the IRB. These include any unanticipated adverse device effect reports; withdrawal of approval; progress report, a final report; again, failures to obtain informed consent and any protocol deviations that have occurred. Institutional review boards are discussed in detail in Part 56 of the CFR.
The purpose of an IRB is to protect the rights and welfare of human subjects involved in FDA regulated investigations and investigations that support applications for research, for example, IDEs or marketing permits. IRBs are responsible for risk determinations; review of protocols and informed consent; review of any changes to protocols, and continuing review of those protocols. The IRBs must comply with the IRB regulations, Part 56, as well as the IDE regulations in Part 812. Part 812 only briefly touches on the institutional review board responsibilities, but they are referenced and are an essential part of good clinical practice.
FDA does periodic inspections of the IRB's records and procedures to determine compliance with the regulations.
In this presentation, I've discussed the regulatory context of device clinical investigations, I've described when an IDE is required, the IDE application process and FDA decisions on those applications, as well as the roles of the key players in IDE studies.
For more information, you can turn to these three resources on your slide: the CDRH Learn modules, which are multi-media industry education; Device Advice, which is text-based education on our website; as well as the Division of Industry and Consumer Education – DICE. Their contact information is also shown on this slide. Thank you for your attention to this presentation.