 Good morning. I'm Dr. Paula Cappacino. I work with David in the Office of Invitrodiagnostics and Radiological Health. And I have been asked today to define what an investigational device is in the context of genomics research. So first I will go over the definition of the device. This is from section 201 subpart H of the Food, Drug, and Cosmetic Act. A device is an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or other similar or related article, including a component, part, or accessory, which is recognized in the official national formulary or the United States Pharmacopia or any supplement to them. And intended for use in the diagnosis of disease or other condition or in the cure mitigation treatment or prevention of disease in man or other animals or intended to affect the structure or any function of the body of man or other animals and which does not achieve its primary intended purpose through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes. So this is the definition of the device from the Food and Drug Act. The in vitro diagnostic device includes those reagents, instruments, and systems intended for use in the diagnosis of disease or other conditions, including a determination of the state of health in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the body. These products are devices as defined in the Federal Food, Drug, and Cosmetic Act. And this definition of the device comes from 21 CFR 8093. That is our code of federal regulations. The term investigation does have different meanings and different parts of our regulations. This is actually from the investigational device exemption regulations. So an investigation is defined as a clinical investigation or research involving one or more subjects to determine the safety or effectiveness of a device. Here it's important to note that even if determining the safety and effectiveness of a device is not the specific goal of an investigation, if you're learning about the device or learning about its safety or effectiveness, then you are performing an investigation. A subject is a human who participates in an investigation, either as an individual on whom or on whose specimen an investigational device is used or as a control. A subject may be in normal health or may have a medical condition or disease. So I think it's very important to understand what, you know, the concept of the intended use as, you know, we use the term in FDA. And it's really a very critical to understand, you know, when your device may be investigational and when we receive anything from any company or any investigator, this is the first thing we look for is the intended use. So we can understand what this device is and what it is supposed to do. The intended use explains what the device measures and we call this the analyte. The intended use indicates who is eligible to receive the test. We call this the intended use population. And it also includes the indications for use and that is how the test result is used. As an example, we provide the intended use of the MAMA print. And we have had this slide forever. I wonder if you guys have seen it a thousand times. David actually asked me maybe to update it, but I didn't have time. So the MAMA print is a qualitative and vitro diagnostic test service performed in a single laboratory using the gene expression profile of fresh frozen breast cancer tissue samples to assess a patient's risk for distant metastases. The test is performed for breast cancer patients who are less than 61 years old with stage one or stage two disease with tumor size less than or equal to 5 centimeters and who are lymph node negative. The MAMA print result is indicated for use by physicians as a prognostic marker only along with other clinical pathological factors. So in this case, the analyte is that gene expression profile of fresh frozen breast cancer tissue samples. The intended use population are the breast cancer patients who are less than 61 years old with stage one or stage two disease with the tumor size of less than 5 centimeters and who are lymph node negative. And the indications for use or how the test should be used, it is by physicians as a prognostic marker along with other clinical pathological factors. So that's the information that we are typically looking for in an intended use and it really drives our thinking into what types of information to have and what kind of questions we may have. So taking all of that together for us, an investigational device is the device that is the object of an investigation. For example, if the use of the device is included in a clinical protocol then the device may be investigational. So that's sort of a first step is if it's being included in a clinical protocol then it may be investigational. How do you determine if the use of the device in your clinical protocol is investigational? If the device is not legally marketed for the intended use or indications for use identified in the clinical protocol, whether or not it's been previously cleared or approved for a separate intended use, then the device is investigational. We distinguish investigational use from off-label use or practice of medicine and investigational use requires an exemption from pre-market approval requirements for new drugs and devices. Some examples of medical devices include instrumentation in vitro diagnostic kits, reagents used for laboratory testing, maybe some apps. Although we recognize that most apps would not be considered medical devices, depending on what these do they could meet the definition of a medical device. For example, if someone develops an app that actually makes a diagnosis then it would be likely a medical device. And software can also be a component of a medical device. Medical devices are subject to regulatory requirements even though they may be only investigational. So we try to give you an idea of what we would consider the device in terms of next generation sequencing. So this slide illustrates the different components that could comprise the test. These components can include the instrumentation, the reagents, software, and databases. The device is all of the components that will take a specimen whether it is DNA, whole blood, saliva, urine, or any other sample type and transforms it into a result that will be included in the lab report. In this illustration the area that we boxed in typically is what we would consider the device and what we would be looking for information either in a pre-submission if you are seeking feedback on it or if it is in an IDE. This is the part that we would want analytical validation and the most information on. It is important to understand that some of this work may be done by a third party. For example, maybe a third party sequences the samples or maybe a third party performs the analysis and interpretation of the raw signals. These components even when performed by a third party are still part of the investigational device. So when is someone an investigator? The term investigator is defined in the IDE regulations as the individual who actually conducts a clinical investigation. That is under whose immediate direction the test article is administered or dispensed or used involving a subject or in the event of an investigation conducted by a team of individuals is the responsible leader of that team. The investigator does not initiate the study. This is different from the definition of a sponsor. The term sponsor is defined in the IDE regulations as the 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 has initiated is a sponsor, not a sponsor investigator and the employees are investigators. The third possibility here is the sponsor investigator. The term is defined in the IDE regulations as the 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. So who is responsible for the investigational device? In this case, it's the sponsor or the sponsor investigator. And one of these is responsible for the regulatory requirements of the investigational device. And these are some common misconceptions that we hear related to this topic, that something is not a test, it's a process. It's not an in vitro diagnostic if it's in the research and development stage. It's not an in vitro diagnostic if they don't plan to market the test. The IDE regulations do not apply. If you're not developing a test that you intend to market and that if you have CLIA certification, you don't need to worry about the IDE regulations. So what if you're not sure about the use of a device in your protocol? If you're not sure that it meets the definition of an investigational device? If you're not sure you need an IDE? Or if you have any questions regarding the regulatory requirements of your investigation? You can use the pre-submission program and we are mindful about the time requirements that people have or the constraints that you may have. This program is free and it's non-binding. We do have 75 days, but we're reasonable with the content. If we get something that we can review within 45, 50, 60 days, our aim is to be reasonable with the time that we take with our review. You can use the pre-submission program to meet with the FDA for non-binding discussions and advice. The program can be used to get questions answered or for study risk determinations. There's a specific type of submission where we help you with the risk determination. We can review your protocol to determine if you're exempt from the IDE regulation, if you're non-significant risk and subject to the abbreviated requirements of the IDE or if the study is a significant risk study. We do encourage early interactions with FDA before you conduct your studies, sort of when you're designing your studies. It's probably the best time to talk to us to get timely interaction with the agency in case there are regulatory requirements that you are responsible for. Our link to the program is provided here and this provides details and instructions if you choose to use the program. This is voluntary. These are some other resources that may help you figure out your regulatory requirements as needed and it's some guidance documents. We have a device advice section on our webpage which is actually very, very helpful. I use it often myself when I'm looking through questions. That's it for me. There are, on the agenda, there's other more specific things about the IDEs and a more of description on the process and that's going to be discussed later by David. Thank you.