Medical Device Submissions Chapter 18 21 April 2015

Objectives Discuss the types of submissions made to the Center for Devices and Radiological Health (CDRH) Explain how medical devices are classified and how the classification affects the types of submissions required Describe the Investigational Device Exemption (IDE) requirements for clinical device studies Review the types of 510(k) Premarket Notification submissions, when 510(k) submissions are needed and what information is required Review the types of Premarket Approval (PMA) submissions, when PMA submissions are needed and what information is required Explain when Humanitarian Device Exemption (HDE) is appropriate and what information is required Discuss when Expedited Review should be requested Provide an overview of the nature and status of current proposals for changes in FDA’s decision making

Background Medical devices were first regulated by the Federal Food Drug & Cosmetic (FD&C) Act of 1938 FD&C Act was amended in 1976 to include premarket review of medical devices FDA, primarily through the Center for Devices and Radiological Health (CDRH) is responsible for assuring that medical devices are safe and effective Per the FDA Intercenter Agreement (31 October 1991) the Center for Biologics Evaluation and Research (CBER) has responsibility for devices related to blood and cellular products

Medical devices, referred to as “devices” are defined in Section 201(h) of the FD&C Act: “The term ‘device”’ means an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is: recognized in the official National Formulary, or the United States Pharmacopeia, or any supplement to them, intended for use in the diagnosis of disease or other conditions, or in the cure , mitigation, treatment, or prevention of disease, in man or other animal, or 3) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes 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 its primary intended purposes.”

Medical Device Classification (21 CFR 860): Class I: Low-risk devices such as non prescription sunglasses. Safety and effectiveness is assured by guidelines or general controls. In rare circumstances, some Class I devices also require premarket clearance through the 510(k) process. Class II: Intermediate-risk devices such as blood glucose test systems or infusion pumps. Safety and effectiveness is assured by general controls and special controls. Most Class II devices are subject to premarket review and clearance through the 510(k) process. Class III: Greatest-risk devices such as life-sustaining, life-supporting or implantable devices, or devices that have a new intended use or employ a unique, new technology that is not substantially equivalent to a legally marketed predicate device. Safety and effectiveness is assured by most rigorous controls. Unless a Class III device is the subject of a 510(k) premarket notification, a Premarket Approval (PMA) application is required. If classification is not clear, the device submitter can request an assignment of classification from FDA (Request for Designation), a provision in Section 513(g) of the FD&C Act.

Predicate device: A preamendment device (a currently marketed device that was on the market prior to 1976) A device reclassified from Class III to Class II or I A device found to be substantially equivalent to a device in one of the above two categories Substantially equivalent: A medical device is determined to be substantially equivalent to a predicate device if the new device has: Same intended use, and FDA has determined that it has either the same technological characteristics as the predicate device or different technological characteristics does not raise new questions of safety and effectiveness and demonstrates the device is at least as safe and effective as a legally marketed device Intended use: Intended use of a device is determined by an evaluation of the proposed labeling for the device. “Ordinarily, intended use is determined by reference to ‘labeling’ or promotional claims; only in rare cases might it be necessary to infer intended use from other types of information.”

General controls for Class I devices: Compliance with the applicable portions of FDA’s Quality System Regulation (QSR) for manufacturing and recordkeeping, Requirements for issuing notices about repair, Replacement or refund of money for devices presenting an unreasonable risk of substantial harm, Facility registration and product listing, Reporting of adverse medical events, and Appropriate truthful and non misleading labeling, advertising and promotional materials. Special controls for Class II devices: General controls (as per Class I devices), FDA-issued guidance documents, Appropriate performance standards, Special labeling requirements, Device tracking of implantable devices, and Any other actions that FDA deems necessary to assure safety and effectiveness. Most rigorous controls for Class III devices: General controls (as per Class I and Class II devices), Any relevant special controls (as per Class II devices), Most cases, premarket approval which requires submission of evidence to establish reasonable assurance of the device’s safety and effectiveness, Detailed manufacturing information, Panel of outside experts to recommend the action to be taken to assure safety and effectiveness.

De Novo Process The Food and Drug Administration Modernization Act of 1997 (FDAMA) created a process for the classification of certain low-risk devices for which there is no predicate. Before FDAMA, such a device would automatically be designated Class III. Reclassification would be required to move the device to Class I or II. Sponsors had to go through a 510(k) review process and receive a Not Substantially Equivalent (NSE) determination before applying for a risk-based determination. The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on 9 July 2012, amended, Section 513(f) of the FD&C Act. It eliminated the requirement of undergoing a 510(k) review process and allows sponsors to directly request a de novo classification.

Combination Products Until 1990 and the introduction of the Safe Medical Devices Act, there was no formal process to establish which FDA center would regulate combination products, such as drug-device, device-biologic or biologic-drug products Regulations have now been established that FDA makes a determination based on the primary mode of action of the combination product FDA decides whether item is a drug, a device or a biologic and which center is the primary reviewer (CDER, CBER or CDRH) However representatives of the other appropriate centers are included on the review committee

Investigational Device Exemption (IDE) (21 CFR 812) IDE regulations provide a means of distributing device that are not cleared or approved to be marketed (i.e., by 510(k), PMA or Class I exemption) for the purposes of clinical research or to gather clinical evidence of safety and effectiveness. Definition of IDE: “An investigational device exemption (IDE) allows the investigational device to be used in a clinical study in order to collect safety and effectiveness data required to support a Premarket Approval (PMA) application or a Premarket Notification [510(k)] submission to FDA. Clinical studies are most often conducted to support a PMA. Investigational use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All clinical evaluations of investigational devices, unless exempt, must have an approved IDE before the study is initiated. An approved IDE permits a device to be shipped lawfully for the purpose of conducting investigations of the device without complying with other requirements of the Food, Drug, and Cosmetic Act (Act) that would apply to devices in commercial distribution. “

IDE (Continued) IDE application includes: Sponsor name and address Complete report of prior investigations of the device Description of methods, facilities and controls used for the manufacture, processing, packing, storage, installation of device (where appropriate)… Example of agreements to be entered into by all investigators Certification of investigators who will participate in the investigation List of IRBs If device is to be sold… Claim of categorical exclusion under 21 CFR 25.30 or 25.34 or an environmental assessment under 25.40 device labeling Forms and informational materials for informed consent Any other relevant information requested by FDA Risk analysis under 21 CFR 812.25

IDE (continued) The Pre-IDE Meeting: In order to establish a good working relationship with FDA, prior to the submission of an IDE, it is suggested that the sponsor meet with FDA to determine: 1) whether sufficient information is available to submit the IDE. 2) to alert FDA about the program and device. Supplemental Applications: Supplemental Application are required for changes in the investigation plan. Institutional Review Board (IRB) Approval: IRB approval is necessary before an investigation begins.

IDE (continued) A device is exempt from the IDE requirements if it is: Nonsignificant risk device, Device in commercial distribution prior to May 28, 1976 Device, other than a transitional device “introduced into commercial distribution on or after May 28, 1976, that FDA has determined substantially equivalent to a device marked prior to May 28, 1976, Noninvasive diagnostic device, Device for veterinary use or research on animals Device undergoing consumer preference testing, if testing is not for determining safety and effectiveness

510(k) Premarket Notification 510(k) refers to the type of submission to FDA described under 21 CFR 807 Subpart E in which the applicant must establish that their device is substantially equivalent to a legally marketed device. This type of submission is used for most Class II devices and some Class I devices. Information to be submitted for 510(K) (21 CFR 807.87): Device name and class Establishment registration number Indications for Use Statement 510(k) summary of the submission’s safety and effectiveness information Proposed labels, labeling, instructions for use, intended use and promotional materials Substantial equivalence comparison with predicate device Disclosure of any financial arrangements between the sponsor and clinical investigators who performed studies, or a certification attesting to the absence of any financial arrangements. Additional specific information for a 510(k) claiming substantial equivalence to a class III device on the market prior to 1 December 1990 and for which a PMA has not been required. A truthful and accurate statement attesting to the truthfulness and accuracy of the information contained within the submission. Any additional information, when requested by FDA.

510(k) (continued) Device Modifications: New 510(k): A new 510(k) application is required for changes or modifications to an existing device when the modifications could significantly affect the device’s safety or effectiveness, or if the device is to be marketed for a new or different indication. Special 510(k): If a new 510(k) is needed for a device’s modification and if the modification does not affect the device’s intended use or alter its fundamental scientific technology, summary information resulting from the design control process can serve as the basis for clearing the application along with the required elements of a 510(k). It is recommended that a Special 510(k) submitters highlight all changes in the proposed labeling that may result from modifications to the legally marked device and clearly state that the intended use of the modified device has not changed as a result of the modification.

510(k) (continued) Abbreviated 510(k): Abbreviated 510(k) can be submitted when a guidance document already exists A special control has already been established FDA has recognized a relevant consensus standard

Premarket Approval (21 CFR 814) “Premarket approval (PMA) is the FDA process of scientific and regulatory review to evaluate the safety and effectiveness of Class III medical devices. Class III devices are those that support or sustain human life, are of substantial importance in preventing impairment of human health, or which present a potential, unreasonable risk of illness or injury. Due to the level of risk associated with Class III devices, these devices require a premarket approval (PMA) application under section 515 of the FD&C Act in order to obtain marketing clearance.” Essentially, there are two types of PMA Applications: Traditional PMA Product Development Process

PMA (continued) The PMA process is much more demanding and rigorous than the 510(k) premarket notification process. A PMA application is intended to demonstrate that the device is safe and effective, and generally must be supported by extensive data (detailed in 21 CFR 814.20(b), including: data from preclinical studies, frequently, human clinical trials, a full description of the device and its components, the methods, facilities and controls used for manufacturing, and the proposed labeling The fee for filing a PMA can be much higher than the fee for filing a 510(k)

PMA (continued) Information to be submitted for PMA: General description of the indication for use. Explanation of how the device functions, the scientific concepts upon which the device is based, general physical and performance characteristics, and the manufacturing process. Generic, proprietary and trade name of the device Description of existing alternative practices and procedures for which the device is intended Description of the device’s foreign and US marketing history Summary of studies and reports submitted with the PMA Complete description of device, each functional component/ingredient, device properties relative to its specific indication for use, principles of operation, methods, facilities and controls used to manufacture, process, package, store and install the device Reference to any performance standard in effect and any voluntary standard relevant to the device’s safety and effectiveness Technical data and information to enable approval or disapproval of the application. Bibliography of all published reports that are known concerning the device’s safety or effectiveness. Samples of the device and its components Copies of all proposed labeling including labels, instructions for use, installation, maintenance and servicing, and any information, literature and/or advertising that constitutes labeling. Disclosure of any financial arrangements between the sponsor and clinical investigators who performed studies, or a certification attesting to the absence of any financial arrangements. Additional specific information for a 510(k) claiming substantial equivalence to a class III device on the market prior to 1 December 1990 and for which a PMA has not been required. Any other information requested by FDA.

PMA (continued) The PMA Supplement: A supplement to the original PMA is required when a significant change to the device approved under a PMA affects the device’s safety or effectiveness. PMA supplements include: new indication for use, labeling changes, the use of a different facility or establishment to manufacture, process, sterilize, or package the device, changes in manufacturing facilities, methods or quality control procedures, change in sterilization procedures, change in packaging, changes in the performance or design specifications, circuits, components, ingredients, principles of operation, or physical layout of the device, and extension of the expiration date of the device.

PMA (continued) PMA Supplement (180 days): Special PMA Supplement: There are several ways of filing a PMA supplement: PMA Supplement (180 days): This is for significant changes that affect the device’s safety and effectiveness and will require an in-depth review and approval by FDA. Special PMA Supplement: Generally used when the change enhances or increases the device’s safety. It does not require FDA approval before making the change. 30-day Notice and 135 PMA Supplement: This is used for modifications to manufacturing procedures or methods that affect the device’s safety and effectiveness. If FDA does not respond within 30 days after notification, the change can be made to the device and it can be marked accordingly. PMA Manufacturing Site Change Supplement: This is used when the manufacturing site is changed. The site must have received a Quality System/GMP inspection within the last 2 years. If not, a 180-days PMA supplement must be submitted. Annual Report/30 day supplement: Change can also be reported in the Annual Report instead of a formal supplement. An advisory opinion from the FDA is required when using this approach.

The Product Development Protocol (PDP): The PDP is an alternative pathway to IDE and PMA for device approval The FDA and sponsor agree early on all development process items needed for successful analysis of a Class III device’s safety and efficacy Successful completion of a PDP means essentially PMA approval and market clearance This approach is rarely utilized Device Reclassification: A primary advantage of reclassification from a PMA to a 510(k) route to marketing is the reduction of the fee required by FDA to review the submission. Generating reclassification data requires considerable effort and resources. The primary obstacle is the high level of scientific information that CDRH requires to support a device’s reclassification.

Humanitarian Device Exemption (HDE) - 21 CFR 814 Subpart H A Humanitarian Use Device (HUS) is intended to benefit patients by treating or diagnosing a disease or condition that affects or is manifested in fewer than 4,000 individuals in the US per year. HUD regulation provides financial incentive for the development of devices for these small populations because manufacturers’ research and development costs far exceed market returns for diseases or conditions affecting small patient populations. Sponsor receives Humanitarian Use status by submitting a Request for HUD Designation to FDA’s Office of Orphan Products Development (OOPD) Request should include: a statement that applicant is requesting a HUD designation for a rare disease or condition The applicant’s name and address A description of the rare disease or condition for which the device is to be used A description of the device

Expedited Review Devices appropriate for Expedited Review: FDA considers a device or combination product containing a device appropriate for expedited review if the device or combination product: Is intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition Addresses an unmet medical need, such as: breakthrough technology that provides a clinically meaningful advantage over existing technology, no approved alternative treatment or means of diagnosis exists, device offers significant, clinically meaningful advantages over existing approved alternative treatments, availability of the device is in the best interest of patients For more information refer to guidance (www.fda.gov/MedicalDevices/DevicesRegulationandGuidance/GuidanceDocuments/ucm08964 3.htm).

Laws, Regulations and Guidelines 21 CFR 801 Labeling 21 CFR 803 Medical Device Reporting 21 CFR 807 Establishment Registration and Device Listing, Premarket Notification 21 CFR 812 Investigation Device Exemptions 21 CFR 814 Premarket Approval 21 CFR 821 Medical Device Tracking Requirements 21 CFR 860 Medical Device Classification Procedures

References on FDA Website: CDRH Product Classification Database. FDA website. www.access-data.fda.gov/scripts/cdrh/cfdocs/cfPCD/PCDSimpleSearch.cfm Deciding When to Submit a 510(k) for a Change to an Existing Device (K97-1). FDA website www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm0 80235.htm How to Prepare a Traditional 510(k). FDA website. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Pr emarketSubmissions/PremarketNotification510k/ucm134572.htm How to Prepare an Abbreviated 510(k). FDA website. www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/Pr emarketSubmissions/PremarketNotification510k/ucm134574.htm Medical Device Databases: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm CDRH Learn: http://www.fda.gov/training/cdrhlearn/default.htm