The rush of innovation in ophthalmology – both in drugs and devices – is driving the Food and Drug Administration to adopt guidelines and standards to help expedite approvals. Two key players within the agency, Dr. Wiley Chambers and Dr. Malvina Eydelman, sat down for an open Q&A with Emmett Cunningham, MD, co-chair of OIS@AAO. Dr. Eydelman is director of the Division of Ophthalmic and Ear, Nose and Throat Devices, and Dr. Chambers is a supervisory medical officer of the Division of Transplant & Ophthalmic Products.
The FDA’s desire to standardize clinical trials of devices for minimally invasive glaucoma surgery (MIGS) grew out of a large number of applications for those devices and lack of recognized standards or guidance, Dr. Eydelman said. “As of couple months ago, there was really no consensus for a consistent definition of MIGS, and we found there was no clear direction as to what patient population should be studied in MIGS clinical trials and what are the appropriate safety and effectiveness endpoints,” she said.
Representatives from the FDA and the American Glaucoma Society held a workshop earlier in 2014 where they achieved “an unprecedented amount of agreement” on clinical trial design for MIGS devices, she said. “The goal is to facilitate innovation and to speed bringing MIGS devices to U.S. market,” Dr. Eydelman said. A manuscript summarizing the workshop has been submitted to Ophthalmology.
Additionally, the FDA has utilized the information obtained from the workshop to develop a LeapFrog Guidance for MIGS Devices. Leapfrog Guidance is a new mechanism via which FDA can share their initial thoughts regarding the content of premarket submissions for emerging technologies to speed development and approval of future submissions. “We are making very good progress with the Leapfrog Guidance and are hoping to post a draft for comment in the next couple of months.” Dr. Eydelman said.
Prompted by “exponential growth” in new product applications , the agency is pursuing a similar track to bring consistency to the clinical trials for premium IOLs, Dr. Eydelman noted. . “We have seen every variation of IOLs that you can think of in the last couple of years,” she said. “Unfortunately, we don’t have recognized standards or guidance that address every aspect of premium IOLs that are needed to develop clinical trials.”
The agency co-sponsored a workshop with the American Academy of Ophthalmology in March to discuss challenges in assessing premium IOLs. Topics included clinical safety assessments, patient-reported outcome measures and assessments of accommodation. This workshop also served as the forum for the first public discussion of preclinical and clinical requirements a new category of IOLs – Extended Depth of Focus (EDOF). FDA’s goal for this workshop was to facilitate collaboration of all interested parties to increase the efficiency of tool development through joint efforts.
Following the workshop, the AAO Task Force was formulated to address priority recommendations from workshop’s breakout sessions. The Medical Device Manufacturers Association has been providing input from IOL manufacturers for the Task Force’s Preclinical Subcommittee. Under the leadership of Jack Holladay, MD, this task force plans to publish its recommendations upon completion. (In an upcoming OIS Podcast, Dr. Hollady will detail the Task Force’s progress.)
New methods of drug delivery and mechanisms for extending the delivery time of existing drugs is driving inophthalmic drug development. Some of these involve submitting applications that reference trials that the applicant did not conduct or obtain a right to reference. Dr. Cunningham asked Dr. Chambers to explain how the FDA handles those applications, nicknamed 505(b)(2) applications.
The 505(b)(2) process relies on the same scientific data that other new drug applications must have: establishing safety and efficacy of products based on substantial evidence from adequate and well controlled clinical trials, Dr. Chambers said. “The routine is still at least two trials,” he said. “But, two trials does not mean two trials that are new; you can use an old trial. Good data is good data regardless of where it was generated.”
Applicants can reference the FDA’s findings from past trials, if the drug for which they submit an application has already been proven to be safe and effective. “If all you are changing is the formulation or something along those lines, you can still potentially reference old trials as one of the two,” he said.
Nonetheless, the agency prefers at least one trial with the final form of the product that would go to market. “So if you’ve changed dosing or changed the concentration, we would like at least one trial done in the product you’re taking into the market,” he said. Two trials is not always the requirement, he said. “We look at totality of the information,” he said, but a single trial is the exception, not the rule.
Dr. Cunningham also asked Dr. Chambers to explain how the agency views, in his words “multiple shots on goal to get two clinical trials.” Specifically, how would the agency look upon an application where six trials were done before the company could register two confirmatory trials.
“Negative trials are not neutral; negative trials do count against you,” Dr. Chambers said. “If it ends up taking multiple trials, there is a question about which was the real answer, whether it was four trials that failed or the two trials that succeeded. It should be expected that we would ask for an explanation of why do you think the clinical trial that failed did so. If there are reasonable explanations, those all get counted.”
When it comes to relying on outside consultants, the device and pharma sides within the FDA do things differently. On the pharma side, Dr. Chambers said, his unit rarely uses outside consultants to advise on applications. Not so on the device side, Dr. Eydelman told OIS attendees. “We tend to ask for help frequently when we feel it’s warranted,” she said. “With devices especially the technology is very, very rapidly progressing and it is impossible to know everything about every single scientific area.”
Dr. Eydelman highlighted the newly established Network of Experts as one avenue for obtaining outside scientific input. Network of Experts is based on agreements with professional organizations and is aimed to provide staff of the FDA’s Center for Devices and Radiological Health the ability to reach out to scientific experts and have an answer in a matter of weeks. “My Division has been fortunate to partner with many ophthalmic organizations and have been using this new tool very successfully,” she said.
The best advice when an applicant has a question is to call the responsible person at the FDA directly, Dr. Cunningham said. “Personally, I find both Wiley and Malvina incredibly approachable‑and helpful,” he said.