LEAP FROG GUIDANCE

The US FDA, with public input from the American Glaucoma Society and other stakeholders, has devised recommendations to help speed the development of new minimally-invasive glaucoma drainage devices (MIGS), said Malvina B Eydelman MD, who is Director of the FDA’s Division of Ophthalmic and Ear, Nose and Throat Devices.

“The leap frog guidance for MIGS devices is a mechanism by which we can share our initial thoughts regarding the content of pre-market submissions for emerging technologies and speed development and approval of future submissions,” she said in a keynote lecture at a Glaucoma Day session at the XXXIII Congress of the ESCRS in Barcelona, Spain.

Dr Eydelman noted that, although in recent years there has been an explosion of peer-reviewed reports on MIGS in the literature, there has been a lack of consistency in clinical trials. Moreover, there remains some debate about the definition of MIGS as well as the indications for the surgery. Furthermore, there has been a lack of FDA guidance regarding the safety and efficacy endpoints to be used.

To remedy that situation the FDA and the American Glaucoma Society held a meeting on 26 February 2014, where they discussed the best clinical trial designs for MIGS devices including appropriate patient population, safety and effectiveness.

The definition they agreed upon for MIGS included those devices used to lower intraocular pressure (IOP) using an outflow mechanism with either an ab interno or ab externo approach, with little or no scleral dissection and minimal or no conjunctival manipulation.

The leap frog guidance includes recommendations for non-clinical testing related to device biocompatibility, physical and mechanical attributes, sterility, packaging, shelf-life, and shipping. Final guidance was issued by the FDA on 15 December 2015 (http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM433165.pdf).

The guidance also includes recommendations for clinical trial design. Subjects included in clinical trials for MIGS devices should have evidence of early or moderate open-angle (confirmed by gonioscopy) glaucoma with characteristic visual field and optic nerve changes.

The recommendations in this guidance document do not apply to implants used to reduce IOP in the anterior chamber of the eye in patients with neovascular glaucoma or with glaucoma when medical or conventional surgical treatments have failed. It is strongly recommended that all subjects be followed for a minimum of 12 months prior to submission of any pre-market application. If the benefit-risk analysis raises concerns beyond 24 months after implantation, longer follow-up may be appropriate.

The recommended primary effectiveness endpoint is the percentage of patients with a reduction of 20 per cent or more in mean diurnal IOP from baseline. The recommended secondary effectiveness endpoint is the mean diurnal IOP change from baseline, Dr Eydelman said.

HISTORY OF IMPROVEMENT

Dr Eydelman noted that the MIGS leap frog guidance, potentially expediting availability of more treatment options for glaucoma patients, was made possible by a long history of improvement in the understanding of the association between IOP and vision loss with glaucoma, and the increasing accuracy of medical devices used for diagnosis and treatment of glaucoma.

She pointed out that Hippocrates first described the visual changes associated with glaucoma in the fifth century BC, when he documented a condition he called hemianopsia. The first illustration of visual fields were done by Ulmus in 1602, followed by Mariotte’s identification of the physiological blind spot and its relationship to the location of the optic disc in 1668.

Building on these discoveries, von Graefe published his report in 1856 on quantitative visual field measurements and also documented the visual field-loss characteristics of glaucoma. That led in turn to development of several perimeters culminating in the development by Heijl and colleagues of the Humphrey field analyser, which was cleared for marketing in the US in 1985.

“Standardised quantitative measurement of visual fields is now a mainstay of clinical practice and trials,” she said.

The observed association
between IOP and glaucoma dates back to the 10th century, when the Arabian surgeon Al-Tabari reported an association between glaucomatous visual loss and increased ocular tension.

In 1826, William Bowman recommended digital palpation as part of the routine eye examination and in 1863 von Graefe developed the first indentation tonometer. In 1885-1888 Imbert and Fick discovered a key principle in applanation tonometry. Based on that principle, Hans Goldmann developed the applanation tonometer in 1955.

“Goldmann applanation tonometry began the era of truly accurate IOP measurement, revolutionising the field as can be seen in several landmark studies, which showed that reductions in elevated IOP delays or prevents glaucomatous damage,” Dr Eydelman said.

Many ophthalmic devices now used took centuries to evolve. Novel approaches for evaluating emerging technology can improve the speed of innovation. The FDA collaborated with several professional organisations, with that goal in mind, to outline non-clinical and clinical recommendations in its leap frog guidance.

However, measures of patient preferences to help inform benefit-risk decisions for MIGS devices still need to be developed. To consider these measures as valid scientific evidence, we must first advance the state of the science, Dr Eydelman said. The FDA is collaborating with academic centres and professional organisations to study patient-centric outcomes for MIGS devices which will lead to patient-centric device development, evaluation and delivery of innovations that benefit patients, she concluded.

Malvina B Eydelman: malvina.eydelman@fda.hhs.gov