Medical model of tumor and vasculature
The intent of this chapter is to familiarize the reader to the role of the FDA in medical device development and regulation and to hopefully clear up some misconceptions and provide guidance in the application of these technologies in patient care.
10.2 The FDA’s Role
The FDA is charged with ensuring that medical products sold in the United States, including drugs, devices, and biologics, are safe and effective for their marketed use. 3D printing is an emerging technology that has brought many new users to the field who may not be familiar with the federal regulations and requirements for medical device clearance or approval. The FDA has a decade of experience with 3D printed medical devices across the industry, the FDA has worked with and provided resources for small businesses developing medical devices. This chapter provides an overview of the overall FDA regulatory framework for medical devices . Discussion topics will include how devices are classified by the agency, premarket regulatory pathways, FDA guidance for specific device types, and resources available to help device developers, users, and clinicians. It will also include a brief summary of FDA’s Technical Considerations for Additive Manufacturing of Medical Devices (FDA 2016a). These considerations were published in a Draft Guidance released in May 2016, pending finalization. They are based on internal research performed in the FDA’s Office of Science and Engineering Laboratories, with direct input from stakeholders (industry, academia, patient groups) from FDA’s first 3D printing workshop held on October 8–9, 2014, and subsequent scientific conferences and public meetings.
10.3 Brief Overview of FDA Regulatory Pathways for Medical Devices
Medical devices span a wide range of products from tongue depressors, to total knee replacements, to implantable cardiac defibrillators, all regulated under the Center for Devices and Radiologic Health (CDRH) . A medical device is defined in the Food Drug and Cosmetic Act (FDCA Section 201(h)) as “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 Pharmacopoeia, 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 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 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 any of its primary intended purposes.”
The FDA evaluates devices using a risk-based framework that outlines the premarket regulatory requirements that a device must satisfy before being marketed in the United States. Several factors in addition to risk help to determine the regulatory classification and evaluation; these include but are not limited to the intended use and indications for use. These two terms are often conflated but they are distinct, as clarified by FDA Guidance, on the 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications, Section D.1. “Intended use means the general purpose of a device or its function and encompasses the indications for use” (FDA 2014a, b). The more specific term, “indications for use as defined in 21 CFR 814.20(b)(3)(i), describes the disease or condition the device will diagnose, treat, prevent, cure, or mitigate, including a description of the patient population for which the device is intended.” Understanding the basic regulatory framework and terminology can be useful for new device developers, engineers, and clinicians.
Interacting with the FDA may seem like a daunting task, but in fact, 99% of the device manufacturers that contact the FDA are small businesses. Moreover, 74% of those businesses have ten employees or fewer. The medical device industry in particular is a place for small innovative groups to develop new products and technologies. CDRH aims to provide resources to foster that innovation. The FDA website contains a wealth of information for new and experienced medical product developers, manufacturers, sponsors,1 and consumers. Websites referenced throughout this document will be listed with their hyperlinks in the Additional Online Resources section. Specifically, the CDRH website includes a section called “Device Advice” with comprehensive regulatory information and a series of webinars called “CDRH Learn” that describe FDA practices and regulations. Topics include summary information and how to study and market your device, special topics for specific situations, and postmarket activities. 3D printing has its own set of pages on the FDA site which talk about the types of medical applications for 3D printing as well as providing more details on the FDA’s role. More generally, one of the most common ways for FDA to describe policies, interpretations of regulations, and product-specific concerns is through the release of guidance documents, available through a searchable database. CDRH Guidance Documents describe the process and requirements for each type of submission, recommendations for best practices, and specific data that certain device submissions require for thorough evaluation. It is often advantageous to discuss potential devices or medical products with the FDA early in the development or testing process to understand what the FDA will want to see for clearance or approval.
All medical devices that are currently marketed in the United States are classified by the FDA and can often be used as a guide to determine the regulatory classification of new devices. This information is found in the Code of Federal Regulations (CFR), Title 21, Sections 800–1299 and maintained by the Government Publishing Office website. Searchable information on the classification of marketed medical devices can also be found in the FDA’s Product Classification Database. If a device does not fit into one of the existing product classifications (presents a potential new intended use or may raise new questions of safety or effectiveness), its regulatory classification should be discussed with the FDA. There is an official process, called 513(g), established for sponsors to request a classification of any product if none exists or if the classification is unclear (FDA 2012a, b).
Generally, devices can be divided into three classes. Each class has a specific path to market, requiring a different amount of data. To support submission, there are several ways to formally and informally communicate with the FDA to ask questions about a specific product before it is ready to bring to market (Fig. 10.2).
Low-risk (Class I) devices which are generally exempt from premarket review.
Moderate-risk or controlled risk (Class II) devices which typically require review through the Premarket Notification [510(k)] process.
High-risk or life-sustaining (Class III) devices which typically require review through the premarket approval (PMA) process. Most require clinical study data gathered under an investigational device exemption (IDE).
The three primary classifications of medical devices used by the FDA and their approximate correlation to European classifications
10.3.2.1 Class I
The vast majority of Class I devices are exempt from the premarket review requirements of Class II and Class III. Instead, these devices need to comply with what are termed general controls that include labeling, manufacturing quality standards, and reporting requirements as well as registration and listing with the FDA (FDA 2014a). One of the principle qualities of a Class I device that is exempt from premarket review is that it presents a very low risk to the patient. However, if a Class I device is being marketed for a new indication for use or employs a fundamentally different technology to achieve the intended use, then it may require a Premarket Notification submission [510(k)] or premarket approval (PMA) based on several factors including the risk that the device may pose to the user or patient.
10.3.2.2 Class II: Premarket Notification [510(k)]
Class II devices include a wide variety of devices that may present moderate risks to patients and users and that do not sustain life. The agency expects that the risks these devices may present can be mitigated through the use of device-specific special controls. These controls describe the data the FDA needs to effectively evaluate the device as well as best practices for preparing a device for market. They may include but are not limited to preclinical bench testing, animal studies, risk assessment, and suggested labeling. In a minority of cases, clinical data may be required if other data cannot resolve questions of safety and effectiveness brought about by new or different technological characteristics. The majority of Class II devices are required to submit a Premarket Notification [510(k)] for review by the FDA before they can be cleared for marketing in the United States (FDA 2014a, b). Sponsors of 510(k) submissions must demonstrate that their submission is substantially equivalent to a legally marketed predicate, or previously cleared medical device, that has comparable technological characteristics, intended use, and indications for use.
10.3.2.3 Class III: Premarket Approval (PMA)
Devices in the highest-risk classification require premarket approval that demonstrates the safety and effectiveness of the device using all available evidence: preclinical testing, animal studies if applicable, and clinical trials. Risk for Class III devices may come from a variety of sources, such as their use of novel or untested technologies, materials, or indications for use that make special and general controls insufficient to ensure safety and effectiveness.
10.3.3 Clinical Studies
All clinical studies must be performed with oversight from and approval of an Institutional Review Board (IRB), and significant risk device studies must be approved by the FDA through an investigational device exemption (IDE). Factors that determine if a study poses nonsignificant risk include but are not limited to the type of device, the type of intervention, how much the intervention differs from standard clinical practice, and anticipated adverse events. The FDA is the final arbiter of all clinical study risk determinations. Sponsors may use pre-submission meetings to discuss study protocols, risk determination, endpoints, or other relevant factors that will help collect the correct data to support a PMA or other regulatory submissions. IRB and IDE approvals, as required, must be obtained before enrolling subjects, and IDE submissions should include a report of all previous investigations (e.g., preclinical testing, animal studies) of the device and an investigational plan among other items. See CDRH’s Device Advice on IDEs for more information. The CDRH Device Advice website also contains information and guidance on determining if a device is a significant risk and how to apply for an IDE.
The speed of technological development is increasing rapidly and with it, the potential for innovation in medical devices. CDRH has implemented early feasibility studies as a way to “allow for early clinical evaluation of devices to provide proof of principle and initial clinical safety data” (FDA 2013a, b). As with all clinical studies, there must be appropriate benefit-risk analyses and human subject protections. However, unlike traditional IDE studies, early feasibility studies are designed for devices in early development, often before the design has been finalized. The subject enrollment is typically small (ten subjects or less), and the data collected may help gain insight that is not available through preclinical testing or to guide device modifications.
Perspective: Many times, the question is asked, “How do we prove to the FDA that the benefits of the device outweigh the risks and that there is reason to believe the device will be effective?” While the FDA is able to give the final legal approval for a significant risk clinical study to proceed, they are not the target audience for the device (only the submissions). Patients are the beneficiaries and the ones who will be most affected by the device. A more appropriate question might be, “Would a patient who is well informed about the function of the device, the risks of the study, and the potential benefit choose to participate?” The FDA uses benefit-risk analysis (FDA 2012b, 2016d) to make its determinations including the submitted data on the engineering safety, manufacturing controls, potential effectiveness, and patient tolerance for risk (Hunter and Califf 2015) among others. Most devices require understanding a complex mix of medicine, engineering, biology, and other sciences that contribute to the manufacture, use, and function of the device. The FDA staff includes reviewers and scientists from a wide range of disciplines and expertise. In addition, each division has an unmatched knowledge of the history of devices in their area that give them a unique perspective.
10.3.4 Pre-Submission Meetings
Sometimes sponsors may have questions about their device, about the data that FDA may require, or endpoints for their clinical study. Pre-submission meetings (pre-submissions) allow a sponsor to ask specific questions of the agency about their device, study, or aspects of their submission (FDA 2014b). A sponsor can request a pre-submission at any point in the regulatory process including the preclinical testing phase or in response to feedback from FDA about a device submission. Early pre-submissions are especially important for devices using a novel technology or innovation because it gives the agency a glimpse at the device before the marketing (e.g., 510(k), PMA) or IDE submission. When the agency can take time to understand the features and technology in a very novel device, reviewers and scientists are better able to evaluate it and ask appropriate questions to assess safety and effectiveness. This can also benefit sponsors by reducing the number of questions or review rounds needed to come to a final decision.
10.3.5 Other Regulatory Pathways
Premarket notifications [510(k)], premarket approval (PMA), and investigational device exemptions (IDE) are the most common submissions to CDRH for medical devices. There are, however, other pathways that can be used for certain devices.
10.3.5.1 Humanitarian Use Device (HUD) /Humanitarian Device Exemption (HDE)
Some diseases affect small populations, and some specialized treatments are only right for small population within a more prevalent disease. For these cases, the FDA has the HUD/HDE process. Someone who has a potential treatment for one of these small populations can request a Humanitarian Use Device designation for the patient population and indications for use of the device. If the expected patient population is less than 4000 per year (incidence) and other criteria are met, then an HUD may be granted. Other requirements and restrictions are described on the CDRH Device Advice website and in FDA Guidance on Humanitarian Use Device (HUD) Designations (FDA 2013a, b). Once an HUD is granted, the sponsor may submit a Humanitarian Device Exemption (HDE) to allow for the device to be marketed in the United States. In this submission, a sponsor must show that the device is safe and that the probable benefits of the device outweigh the risks, typically with a clinical study.
10.3.5.2 De Novo
Technology is developing at a rapid rate and not all devices with low or moderate risk will have a predicate for a 510(k) submission. To address this, congress and the FDA created a new regulatory submission through the 1997 Food and Drug Administration Modernization Act (FDAMA) (FDA 1997a, b) and the 2012 FDA Safety and Innovation Act (FDASIA) (FDA 2016b). This submission is called for de novo, Latin for “from the beginning” or “newly started.” Any person who has a device for which a Class III regulation does not exist and has either “received a determination of Not Substantially Equivalent (NSE) in response to a 510(k) submission” or “who determines there is no legally marketed device upon which to base a determination of substantial equivalence may submit a de novo request.” This request reevaluates the automatic Class III designation of the device (FDA 2017). In order to change the classification, data and testing should show that the risk to the patient posed for the de novo device is similar to that of a Class II or Class I device. Likewise, the benefits and risks should be understood well enough to be mitigated through use of general and special controls. Once the reclassification is granted, a de novo device can be used as a predicate to support future 510(k) submissions.
10.3.5.3 Combination Products
Combination products typically use elements of two or more regulated areas such biologic/device or drug/device to function as a single product. The Code of Federal Regulation defines a combination product more fully (21 CFR 3.2(e)). Some research and development areas such as tissue engineering frequently yield combination products due to the incorporation of cells within a scaffold or other physical structure. The FDA’s Office of Combination Products makes the final determination if a product is a combination product and which regulatory center has the lead review role for that product based on its primary mode of action. Other centers may use different regulatory pathways than those described here.
10.4 Regulatory Landscape for 3D-Printed Medical Devices
10.4.1 Medical Implants and Accessories
Medical device manufacturers were early adopters of 3D printing, but interest in 3D printing medical devices has grown exponentially since 2010. As of 2016, the FDA has over a decade of regulatory experience with 3D-printed products with dozens of cleared medical devices (Fig. 10.3). All of these clearances, approvals, and authorizations have occurred under the existing regulatory framework.
Distribution of 510(k) cleared medical devices using 3D printing by discipline
Additive manufacturing is inherently a manufacturing process. The capability to make very complex shapes increase the innovative potential for designers is still only a part of the process of creating a device. As with any manufacturing process, there are factors that must be considered in the evaluation of safety and effectiveness, but it does not necessarily change the categorization or regulatory classification of a device. In fact, many 3D-printed devices have presented enough evidence to receive 510(k) clearance as substantially equivalent to a more traditionally manufactured device. CDRH is organized into divisions that specialize in certain product areas and have access to expert scientists and clinicians.2 This specialization allows reviewers to consider devices in their current and historical clinical context. Specialized consultants in areas like 3D printing (additive manufacture) can bring expertise on specific technologies where needed.