The jurisdiction of the US Food and Drug Administration (FDA) encompasses human and animal drugs; therapeutic agents of biological origin; most food products (other than meat and poultry); tobacco products; radiation-emitting products for consumer, medical, and occupational use; cosmetics; animal feed; and medical devices.

Although it was not known by its present name until 1930, the FDA’s modern regulatory functions began with the passage of the 1906 Pure Food and Drugs Act which prohibited interstate commerce in adulterated and misbranded food and drugs. It was not until passage in 1938 of the Food, Drug, and Cosmetic Act that medical devices were placed under FDA control; however, this legislation did not require premarket approval for devices. The 1976 Medical Device Amendments, following a public health disaster in which thousands of women were injured by an intrauterine device, provided for three classes of medical devices, each requiring a different level of regulatory scrutiny. This classification scheme depends on the intended use of the device and is based on risk.

Ophthalmic examples of class II devices include most vitrectomy and phacoemulsification instruments, tonometers, slit lamp microscopes, glaucoma lasers, and implantable glaucoma devices for the “refractory” patient population. Ophthalmic examples of class III devices include intraocular lenses, excimer lasers, endotamponades, viscoelastics, and implantable glaucoma devices for the “non-refractory” patient population.

A 510(k) is a premarket submission made to the FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA. 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 present a potential, unreasonable risk of illness or injury.

Depending on the nature of the technology, the indications for use, and the claims being made by the company marketing the device, non-implantable devices (i.e., surgical instruments and tools) used to lower IOP may be class I (exempt from a 510(k) submission), class II requiring FDA clearance, or class III requiring FDA approval via a PMA prior to marketing in the United States. For example, the FDA cleared the Trabectome as a class II device via the 510(k) pathway in 2006 for the general claim of “removal, destruction and coagulation of tissue.” The iTrack (iScience Interventional) ophthalmic microcannula received 510(k) marketing clearance from the FDA in 2004 for the general purpose of “fluid infusion and aspiration, as well as illumination, during surgery.” Subsequently, in 2008 the iScience Microcatheter was specifically cleared for “catheterization and viscodilation of Schlemm’s canal to reduce intraocular pressure in adult patients with open-angle glaucoma.” Furthermore, in 2004, the FDA cleared the Endo Optiks E2 MicroProbe for endoscopic cyclophotocoagulation (ECP) in patients who have failed conventional topical and systemic medical therapy, previous laser photocoagulation, trabeculectomy, or cyclocryotherapy. The clinical evidence, if any, on which these 510(k) clearances of manual instruments were based is not readily apparent in the FDA database of marketing decision summaries [1].

Lasers used for IOP reduction historically have been treated by the FDA as class II devices and were cleared under the general ophthalmic laser regulation, 21 CFR 886.4390¹ under product codes HQF and LQJ; however, claims for specific therapeutic procedures (e.g., trabeculoplasty and iridotomy) can be found in the labeling. The clinical evidence, if any, on which these laser 510(k) clearances were based is not readily apparent in the FDA database of marketing decision summaries.

Like the non-implantable examples listed above, implantable aqueous shunts intended to reduce intraocular pressure (IOP) “refractory” glaucoma² patients are usually treated by the FDA as class II consistent with 21 CFR 886.3920 (under product code KYF). What constitutes failure of “medical and conventional surgical treatment” has not been clearly defined and standardized neither by the academic community nor by the FDA. In 1998, the FDA issued a guidance document which describes preclinical and clinical testing requirements for the regulation of class II aqueous shunts through the submission of premarket notifications [510(k)s] [2]. The first generation Ahmed (New World Medical), Baerveldt (Advanced Medical Optics), Krupin (Eagle Vision), and Molteno (Molteno Ophthalmic) aqueous shunts received marketing clearance from the FDA between 1989 and 1993; modified Ahmed and Molteno devices were subsequently cleared in 2006. The Ex-PRESS™ Mini Glaucoma Shunt received 510(k) marketing clearance in 2002 [3].

The FDA considers aqueous shunts intended to reduce intraocular pressure in “non-refractory” eyes which have not failed conventional medical and surgical treatment to be higher risk and as such are regulated as class III devices under product code OGO. An increasing number of companies are pursuing FDA approval of their devices for this patient population. The AquaFlow™ Collagen Glaucoma Drainage Device received PMA approval from the FDA in 2001 for the maintenance of subscleral space following non-penetrating deep sclerectomy in patients with open-angle glaucoma where intraocular pressure remains uncontrolled while on maximally tolerated medical therapy [4]. The Glaukos iStent® Trabecular Bypass Stent Model GTS100 was PMA approved in 2012 for use in conjunction with cataract surgery for the reduction of intraocular pressure in adult patients with mild to moderate open-angle glaucoma who receiving treatment with ocular hypotensive medication [5].

In addition to aqueous shunts intended for the “non-refractory” glaucoma population, an implantable device intended for the refractory population could be considered class III if there is no legally marketed predicate device that can serve as the basis of a substantial equivalence comparison in a 510(k) notification.

The FDA evaluates medical devices using information provided by the sponsor of the submission. This information typically consists of a technical description and “valid scientific evidence”. Among the types of evidence that may be required, when appropriate, to determine that there is reasonable assurance that a device is safe and effective are investigations using animal models, nonclinical investigations including in vitro studies, and investigations involving human subjects. Among the types of nonclinical information evaluated by the FDA review team for an implantable shunt are its mechanical, material, dimensional, and flow characteristics. For lasers intended to lower IOP, the nonclinical aspects of the FDA review may involve an optical radiation safety evaluation and testing in an animal model.

For all class III devices and some class II devices, clinical performance data are required to be included in the premarket regulatory marketing submissions. All clinical evaluations of investigational IOP-lowering devices in the United States, unless exempt or nonsignificant risk [6], must have an approved investigational device exemption (IDE) before the study is initiated.

Clinical data provided in support of any FDA marketing application, including a 510(k) when those data are relevant to a substantial equivalence determination, should also fit the definition of “valid scientific evidence”. According to the federal regulation 21 CFR 860.7(c)(2) [7], the FDA defines “valid scientific evidence” derived from a clinical study as, “Evidence from well-controlled investigations, partially controlled studies, studies and objective trials without matched controls, well-documented case histories conducted by qualified experts, and reports of significant human experience with a marketed device, from which it can fairly and responsibly be concluded by qualified experts that there is reasonable assurance of the safety and effectiveness of a device under its conditions of use….The valid scientific evidence used to determine the effectiveness of a device shall consist principally of well-controlled investigations.” The regulation goes on to define a well-controlled clinical investigation as one with a documented study plan or protocol, well-defined study objectives and study population, a clear description of the study methods, and a comparison of the results of treatment with a pre-specified control (no treatment, placebo, active treatment, or historical control). Finally, a description of the methods of analysis should be included in the protocol.

The regulations permit the FDA to calibrate the level of clinical evidence required according to the characteristics of the device, its conditions of use, the existence and adequacy of warnings and other restrictions, and the extent of experience with its use. The agency can accept evidence from studies that do not meet all the criteria above if the agency determines that they are “not reasonably applicable to the device.” Therefore, the FDA typically handles non-implanted devices differently than permanently implanted devices, and the evidentiary standards for class II implantable devices are not always the same as those for class III implantable devices.