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The FDA’s Role in the Regulation of New Diagnostic and Surgical Devices

Julie Kim, MD; Tieuvi Nguyen, PhD; and Malvina Eydelman, MD

In the United States, a device is defined as an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory that is:

• Recognized in the official National Formulary, or the US 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 human or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes. The term device does not include software functions excluded pursuant to Section 520(o).¹

Companies that design, manufacture, repackage, relabel, and/or import medical devices into the United States are regulated by the Food and Drug Administration’s (FDA) Center for Devices and Radiological Health (CDRH). The CDRH mission is to protect and promote the public health by ensuring that US patients and providers have timely and continued access to safe, effective, and high-quality medical devices and safe radiation-emitting products. CDRH is responsible for the total product life cycle of medical devices. CDRH facilitates medical device innovation by advancing regulatory science; providing industry with predictable, consistent, transparent, and efficient regulatory pathways; and ensuring consumer confidence in devices marketed in the United States. In addition, CDRH monitors the performance and promotion of devices in commercial use. The post-market surveillance of medical devices is achieved by mandated as well as voluntary reporting (eg, MedWatch) of adverse events by manufacturers, physicians, and other health care practitioners. The FDA provides several publicly available resources that the clinical community and patients may access to confirm the legality and safety of an approved or cleared device.^2–4

CLASSIFICATION OF DEVICES

Every medical device has an indication for use—a general description of 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. Each device also has an intended use—the objective intent of the persons legally responsible for the labeling of devices, as reflected in labeling and advertising claims, as well as the circumstances surrounding the distribution of the article. The intended use is used to determine what level of regulatory control is necessary to provide reasonable assurance of device safety and effectiveness.

The FDA assigns devices into class I, II, or III based on the level of regulatory controls necessary to reasonably ensure the safety and effectiveness of the device. Classification is risk based, that is, the probable risks to health the device poses to the patient and/or the user is a major factor in the class it is assigned. Generally, class I includes devices with the lowest risk, and class III includes those with the greatest risk. Because class I devices are deemed to be low risk, these are subject to the least regulatory controls and generally do not require premarket authorization to be legally marketed in the United States. Ophthalmic examples of class I devices include most visual acuity charts, autorefractors,5 perimeters,⁶ gonioscopic prisms,⁷ and ophthalmic knives.⁸ Class II devices are moderate risk and require greater regulatory controls to provide reasonable assurance of safety and effectiveness. Devices such as most phacoemulsification instruments,⁹ tonometers,¹⁰ slit-lamp microscopes, ophthalmic lasers,¹¹ optical coherence tomography,¹² and implantable glaucoma devices intended to reduce intraocular pressure (IOP) in patients with neovascular glaucoma or with glaucoma when medical and conventional surgical treatments have failed.¹³ Devices classified into class III are the highest risk devices and must be approved by the FDA before these may be legally marketed. Ophthalmic examples of class III devices include intraocular lenses,¹⁴ viscoelastics,¹⁵ and implantable glaucoma devices intended to reduce IOP in eyes that have not failed conventional medical and surgical treatment.¹⁶ Device sponsors can confirm the classification of their device type through the FDA database or by submitting a 513(g) Request for Information.^17,18

MARKETING SUBMISSIONS

Most class I devices are considered exempt and are not required to submit a premarket submission to the FDA to be legally marketed. Most class II devices pose moderate risk and are subject to premarket notification (510[k]). In a 510(k) a sponsor must demonstrate that the proposed device is “substantially equivalent” to a predicate device by comparing intended use, technological characteristics, and using performance testing, as needed. A predicate device is a legally marketed device that has the same intended use. “Substantial equivalence” does not mean the new and predicate devices must be identical. In fact, the FDA has found this case to be very rare given the diversity and rapid changes in technology. The 510(k) paradigm has been established to accommodate evolving technology while maintaining predictability and consistency to promote confidence among device developers, practitioners, and patients.

Substantial equivalence is established when the device has the same intended use as the predicate and it has been determined that the device has the same technological characteristics as the predicate device, or that any differences in technological characteristics do not raise different questions of safety and effectiveness, and the information submitted contains information (ie, appropriate clinical and/or nonclinical scientific data) that demonstrates the device is as safe and effective as a legally marketed device.

If a 510(k) submission for a class I or class II device is determined to be not substantially equivalent or if there is no legally marketed predicate device, the De Novo classification process provides a pathway for devices to be Class I or II.¹⁹ This is a particularly useful regulatory tool for emerging technologies. The number of De Novo submissions has been rapidly growing. In 2017, CDRH received more than double the number of De Novo applications as in 2013.²⁰ Under the Medical Device User Fee Amendments of 2017 (MDUFA IV), FDA review of De Novo submissions is targeted for 150 days. Devices that are classified into class I or class II through the De Novo process may be marketed and used as predicates for future 510(k) submissions. As of 2017, the Sensimed Triggerfish is the only De Novo device granted for a glaucoma-related indication.²¹ This device is classified as a diurnal pattern recorder system used to detect changes in ocular dimension for monitoring diurnal patterns of IOP fluctuations.

Most class III devices are subject to a premarket approval (PMA) application, which is the most stringent type of premarket submission. A PMA is based on valid scientific evidence demonstrating reasonable assurance of safety and effectiveness for the intended use of a device. Unlike the 510(k) review standard where a new device need only demonstrate substantial equivalence to a legally marketed predicate device to obtain clearance, the PMA standard relies on an independent demonstration of a reasonable assurance of safety and effectiveness before the device can be legally marketed. The PMA must contain adequate nonclinical laboratory studies and clinical investigation data to demonstrate that the device is safe and effective under the conditions of use prescribed, recommended, or suggested in the labeling. Implants used to lower IOP in a glaucoma population that has not yet failed conventional medical and surgical treatment are an example of a class III glaucoma device.²² Approved devices under PMA include the Glaukos iStent Trabecular and iStent Inject W Micro-Bypass Stent, the Alcon CyPass System, and the Ivantis Hydrus Microstent. The summary of safety and effectiveness data provided in support of the approval of these and other PMAs are made publicly available through the FDA website.²³

To address the challenge of encouraging medical device innovation for rare diseases or conditions that affect small (rare) populations, the FDA developed the Humanitarian Device Exemption (HDE) program. Prior to submission of an HDE marketing application, a manufacturer must first obtain a Humanitarian Use Device (HUD) designation for their device. Since the passage of the 21st Century Cures Act of 2016 (December 13, 2016), a HUD designation may now be obtained for a medical device intended to benefit patients in the treatment or diagnosis of a disease that affects or is manifested in “not more than 8000” individuals in the United States per year.²⁴ The approval of an HDE is based upon a determination that the device demonstrates that the probable benefit to health from use of the device outweighs the risk of injury or illness from its use. There are also specific restrictions on profit, and the device is subject to certain use restrictions.²⁵ While currently there are no approved HDEs specific to glaucoma populations, this could potentially be a good pathway for devices indicated for certain pediatric glaucomas (ie, primary congenital) and/or rare syndromes (ie, Axenfeld-Rieger syndrome, iridocorneal endothelial syndrome).

An investigational device exemption (IDE)26 allows an investigational device to be legally used in a US clinical study to collect safety and effectiveness data. All clinical evaluations of investigational devices, unless exempt, must comply with the IDE regulations.

Clinical evaluation of devices that have not been authorized for marketing requires an investigational plan approved by an institutional review board (IRB). If the study involves a significant risk (SR) device (ie, device that is either an implant or is for a use in supporting or sustaining human life, and that presents a potential for serious risk to the health, safety, or welfare of a subject; is of substantial importance in diagnosing, curing, mitigating, or treating disease; or otherwise presents a potential for serious risk to the health, safety, or welfare of a subject), an IDE must also be approved by the FDA. Devices that do not meet the definition of an SR device are identified as nonsignificant risk (NSR) devices. NSR device studies do not need to have an IDE application approved by the FDA, but must comply with abbreviated IDE requirements as well as IRB approval.²⁷ For clinical evaluations of the safety and effectiveness of investigational devices, the investigational plan must be approved by an IRB, informed consent must be obtained from all patients, labeling must clearly state that the device is for investigational use only, adequate monitoring procedures must be established, and the sponsor must maintain required records and reports.

PRESUBMISSIONS

The presubmission program offers a powerful mechanism for manufacturers and medical device innovators to request the FDA’s feedback prior to a premarket device submission.²⁸ Potential topics include nonclinical testing, clinical trial design (eg, endpoints, inclusion/exclusion criteria, statistical analysis plan), and proposed indications for use. Feedback can be requested in the form of written comments or a meeting (in-person or teleconference). The FDA will provide written feedback addressing specific questions raised in the presubmission within 70 calendar days of receipt date or 5 calendar days prior to a schedule meeting, whichever comes first. For emerging technologies (ie, implantable IOP sensors) without FDA guidance or recognized standards, the presubmission program can be important in providing clarity and guiding device development. For sponsors preparing IDEs, 510(k)s, or PMAs, the feedback may facilitate a more efficient clearance/approval process.

THE FDA’S PROMOTION OF INNOVATION

Facilitating innovation is a top priority for CDRH. CDRH seeks to foster the development of medical devices via several mechanisms. One of these is through development of guidance. Some examples specific to glaucoma devices include:

• Guidance for Industry and FDA Staff: Premarket Studies of Implantable Minimally Invasive Glaucoma Surgical (MIGS) Devices²⁹
  
• Guidance for Industry and FDA Staff: Tonometers—Premarket Notification (510[k]) Submissions³⁰

The MIGS Guidance was the Agency’s first ophthalmic Leapfrog Guidance and was intended to serve as a mechanism by which the Agency can share initial thoughts regarding emerging technologies that are likely to be of public health importance early in product development. The FDA encourages the use of recognized consensus standards to simplify and streamline the premarket review process. These documents address aspects of safety and/or effectiveness relevant to medical devices. CDRH staff collaborates with many external stakeholders on the development of national and international consensus standards. As a voting member organization of the American National Standards Institute (ANSI), the American Glaucoma Society is one of these stakeholders. Some examples of FDA-recognized standards for glaucoma devices include:

• ANSI Standard for Ophthalmics: Ophthalmic Instruments—Tonometers³¹
  
• ANSI Standard for Ophthalmics: Implantable Glaucoma Devices³²

To ensure that patients in the United States have access to high-quality, safe, and effective medical devices as quickly as possible, CDRH has developed many programs directed toward providing the necessary resources to evaluate innovative technologies expeditiously. The Breakthrough Devices Program was developed to help patients have more timely access to devices and breakthrough technologies that provide for more effective treatment or diagnosis for life-threatening or irreversibly debilitating diseases, for which no approved or cleared treatment exists or that offer significant advantages over existing approved or cleared alternatives. Through this program, the FDA provides interactive and timely communication with the sponsor during device development and throughout the review process with the goal of reducing the time and cost from development to marketing decision. Specific advantages of this program include the involvement of senior-level FDA management to ensure efficient and timely resolution of complicated/novel issues, priority review status, and expedited review of manufacturing and quality systems compliance for class III devices. Participation in this program may be made at the request of the sponsor through a presubmission. It is encouraged that sponsors seek guidance during the early stages of development (prior to initiation of a clinical trial) to ensure that the data collected are supportive of a future premarket application.

Another program designed to assist device sponsors of novel technologies during the early stages of device development is the Early Feasibility Study (EFS) program. An EFS is a limited clinical investigation of a device that is in the early stages of development, typically before the device design has been finalized. The FDA has recognized that for some innovative technologies, exhaustive nonclinical testing would not likely provide the information needed to further device development. In these cases, early clinical use of the device in a limited number of persons is needed to provide initial insights into clinical safety and device function. This information can be used to inform future nonclinical and clinical testing, and/or finalize the device design. As described in the FDA’s EFS guidance document,33 for these cases, approval of an investigational study may be based on less nonclinical data than would be needed for a clinical study intended to support a marketing submission. However, approval of the initiation of an EFS study must still be supported by an appropriate benefit-risk analysis, including adequate scientific justification for the types and amount of data needed to support study initiation. Similar to the Breakthrough Devices Program, the device sponsor may have access to additional resources to assist them and are encouraged to engage with the FDA early in their development process.

Given the rapidly growing variety and complexity of medical devices, it is occasionally necessary to supplement existing knowledge and expertise within the CDRH with scientific, engineering, or medical expertise from sources outside the federal government on specific cutting-edge questions. The Network of Experts facilitates this exchange and broadens staff exposure to additional clinical and scientific viewpoints. It is a vetted network of partner organizations and their member scientists, clinicians, and engineers who volunteer to supplement internal knowledge and expertise. The American Glaucoma Society and its members have been early and enthusiastic supporters of the Network of Experts program. The FDA is greatly appreciative of the society’s membership, who have been extremely responsive to requests for volunteers to discuss important and novel clinical issues that have greatly impacted the regulatory science for glaucoma devices.

CDRH actively collaborates with professional societies, academia, health care, industry, and other stakeholders to determine the most appropriate clinical endpoints and study design that will provide adequate data on safety and effectiveness. FDA collaboration with the Association of Research in Vision and Ophthalmology and National Eye Institute resulted in Endpoints Symposia aimed at developing clinical trial endpoints in many areas, including glaucoma clinical trials,³⁴ patient-reported outcomes,³⁵ measures of structural change and visual function,³⁶ visual prosthesis development, diabetic retinopathy,³⁷ and age-related macular degeneration.³⁸ Recent public workshops organized by the FDA’s CDRH in collaboration with various ophthalmic professional societies and academic/research institutions have addressed emerging areas such as medical devices used in controlling myopia progression,³⁹ novel endpoints for premium intraocular lenses,⁴⁰ and an ophthalmic digital health workshop.⁴¹

The FDA has partnered with the American Glaucoma Society for workshops on validity, reliability, and usability of glaucoma imaging devices⁴² and on supporting innovation for safe and effective MIGS devices.⁴³ In the former, clinical and regulatory issues surrounding diagnostic imaging devices for glaucoma and approaches to evaluate the accuracy, agreement, and precision of optical coherence tomography measurements were elucidated. Discussions and recommendations from the MIGS workshop played a key role in the development of the FDA’s Leapfrog Guidance document for premarket studies of implantable MIGS devices.²⁹

Emerging technologies such as MIGS devices have expanded the treatment options available to patients beyond traditional therapies. The FDA has recognized the importance of incorporating the patient’s perspective into the evaluation of medical devices. The FDA has published guidance on how to collect this data through patient preference information.⁴⁴ Patient preference information assesses the relative value to patients of different attributes of benefit and risk and clarifies how patients think about the trade-offs of these benefits and risks for a given technology. The FDA has also published guidance on collecting patient-reported outcome measures⁴⁵ that report on the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by any outside party.

CONCLUSION

The past decade has been a particularly exciting time of growth and change for CDRH with developments in the De Novo pathway, regulatory science, close collaboration with stakeholders earlier in the device development process, and robust mechanisms for post-market surveillance. The Agency continues to uphold its commitment to public health protection and promotion so that patients with glaucoma and physicians have timely and continued access to safe, effective, and high-quality medical devices. With an emphasis on customer service, CDRH seeks to provide transparency to industry, as well as earn the confidence of patients with glaucoma and physicians in the United States.

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