NAEC Meeting Minutes - October 12, 2018

National Advisory Eye Council
One Hundred Fiftieth Meeting
October 12, 2018

• Videocast

The National Advisory Eye Council (NAEC) convened for its one hundred and fiftieth meeting at 8:30 am on Friday, October 12, 2018 at the Conference Center at 6700B Rockledge Drive, Rockville, Maryland, 20852. Paul A. Sieving, MD, PhD, the Director of the National Eye Institute (NEI), presided as Chair of the Council, Paul A. Sheehy, PhD, as Executive Secretary, and Santa Tumminia, PhD, as Deputy Director of NEI. The meeting was open to the public from 8:30 am until 1:20 pm. The meeting was closed to the public from 1:20 pm until 3:00 pm for the reviews of confidentiality and conflict of interest procedures, and grant and cooperative agreement applications.

Dr. Eduardo Alfonso
Dr. Jose-Manuel Alonso
Dr. Steven Bassnett
Dr. Jane Gwiazda
Dr. Dennis Levi
Dr. Carol Mason
Dr. Louis R. Pasquale*
Dr. Douglas Rhee*
Dr. Sylvia Smith
Dr. Mary Ann Stepp
Dr. Russell Van Gelder
*Participated via telephone

Dr. Houmam Araj
Dr. Neeraj Agarwal
Dr. Sangeeta Bhargava
Dr. Steven Becker
Mr. Gary Berkson
Ms. Cindy Best
Ms. Sylvia Braxton
Ms. Pamela Bobbitt
Dr. Brian Brooks
Ms. Monique Clark
Mr. Jay Colbert
Ms. Karen Colbert
Ms. Ashley Dash
Ms. Linda Dingle
Ms. Kathryn DeMott
Ms. Courtney Dodson
Dr. Lesley Earl
Mr. Don Everett
Dr. Martha Flanders
Dr. Shefa Gordon
Dr. Thomas Greenwell
Mr. Dustin Hays
Dr. Brian Hoshaw
Dr. Jeanette Hosseni
Dr. Ellen S. Liberman
Dr. George McKie
Dr. Sheldon Miller
Dr. Lisa Neuhold
Dr. Maryann Redford
Ms. Karen Robinson-Smith
Dr. Gale Saunders
Dr. Anne Schaffner
Dr. David Schneeweis
Dr. Peter Shan
Dr. Paul A. Sheehy
Dr. Grace L. Shen
Dr. Paul A. Sieving
Ms. Karen Robinson Smith
Dr. Michael Steinmetz
Ms. Chantell Stevenson
Mr. Brian Trent
Ms. Melissa Trinchet
Dr. Santa Tumminia
Ms. Veronica Van Wagner
Ms. Leslie West-Bushby
Dr. Cheri Wiggs
Ms. Keturah Williams
Dr. Charles Wright
Dr. Jerome R. Wujek
Ms. Maria Zacharias

Dr. Michael Chaitin, CSR
Dr. Nataliya Gordiyenko, CSR
Dr. Peter Guthrie, CSR
Dr. Kristin Kramer, CSR
Dr. Paek Lee, CSR

Mr. Adam R. Glassman, Director of Clinical Quality Assurance, Jaeb Center for Health Research
Mr. James Jorkasky, National Alliance for Eye and Vision Research
Mr. Jensen A. Jose, American Optometric Association (AOA)
Daniel F. Martin, MD, PhD, Professor of Ophthalmology, Cole Eye Institute, Cleveland Clinic
Jennifer K. Sun, MD, MPH, Beetham Eye Institute, Harvard Medical School
Mr. Matt Winsor, ARVO

8:30 am

Dr. Paul Sieving, NEI Director

Dr. Sieving thanked those present and reminded the audience that 2018 was the 50 year anniversary of the National Eye Institute. He thanked the Council members present. Due to the government shutdown in December the new Council slate had not been vetted in a timely fashion and Drs. Bassnett, Gwiazda and Rhee had their terms extended through 5/30/2019 to cover important areas of vision science.

Personnel changes included the appointment of Dr. Santa Tumminia as the Deputy Director of the Eye Institute, after a national search; the committee was chaired by Dr. George Koob, the Director of NIAAA. Dr. Tumminia started her career in 1991 as a postdoctoral fellow in the Laboratory of Mechanisms of Ocular Disease, went to the Foundation Fighting Blindness as a program director, and returned in 2003 as a Special Assistant to the NEI Director. She was awarded an NIH Director’s award in 2018 for mentorship. The Director thanked Dr. Michael Steinmetz for filling in as Acting Deputy Director while maintaining his job as the Director of the Division of Extramural Science Programs (DESP). He also mentioned the fact that Dr. Steinmetz has had a long history of participating on a Department of Defense (DoD) panel. The DoD has a significant vision research portfolio with studies in the areas of both basic science and ocular injury. Matt Montano, the NEI’s highly respected CIO, is retiring, and the NEI will be conducting a search for his replacement.  

The 2018 Association for Research in Vision and Ophthalmology (ARVO) Champalimaud award went to a group of 7 scientists, including NEI intramural investigator Dr. T. Michael Redmond. The award was based on Dr. Redmond’s significant contributions to the research pathway that laid the groundwork for gene therapy for Leber’s congenital amaurosis (LCA), an inherited, monogenic retinal disease. It began with gene discovery in animals and culminated in the development of the drug, Luxturna^TM, the first in vivo gene therapy approved by the FDA for the treatment of LCA.

The NEI budget for 2018 was $772M. NEI was awarded a higher budget in 2019, but details were left for Ms. Karen Colbert to discuss. Congress allotted another $425M for Alzheimer’s research to the Aging Institute (NIA), and made additional increases to Precision Medicine and the BRAIN Initiative. The vision community has benefitted greatly from BRAIN monies. Dr. Sieving commented on the Nonrecurring Expense Fund that allows for money to go beyond the fiscal year. The NIH took a hit of $400M, money that covered building maintenance, infrastructure and IT. Those funds will be reappropriated. The NEI Extramural Loan Repayment Program helps young clinicians pay off student loans. Council members were told to contact Dr. Neeraj Agarwal, the NEI training officer, for information. Dr. Sieving asked Council members for referrals for the NEI diversity program, DIVRO (Diversity in Vision Research and Ophthalmology) https://www.nei.nih.gov/grants-and-training/training-nei/internships-and-student-programs/divro-summer-internship-program. Students from high school through medical school perform work in intramural labs. The NEI has hosted 65 students over the past 8 years of the program.

Dr. Sieving touched on the status of the NEI AGI for Regenerative Medicine. The first topic was a workshop that was recently convened entitled, Pathways for Retinal Cell Replacement Therapies. Participants included academic researchers, biotech and the FDA. The second topic was a special meeting of Council to discuss applications submitted in response to an RFA calling for the development of translation-enabling models to evaluate survival and integration of neurons in the visual system. Five research teams were funded, with the hope that the work will eventually lead to FDA approval of INDs. The Director felt that the AGI was on a very good course, given the two prior initiatives on functional imaging and neuromaintenance.

Drs. Sun and Martin along with Mr. Adam Glassman will give a presentation on the highly successful DRCR (Diabetic Retinopathy Clinical Research) network. Protocol T was a high impact protocol that looked at the possibility of using the anti-VEGF compounds to target diabetic macular edema.

Council was updated on NEI 50^th anniversary activities. There have been 4 symposia thus far, the most recent being on low vision rehabilitation. The final symposium, Future of Vision Research, is scheduled for October 18, and will feature 6 speakers focusing on new frontiers in visual processing, prosthetic devices, engineered eye tissue and image analysis including the use of AI in retinal imaging.

Ms. Karen Colbert

NEI Budget Officer, Karen Colbert, summarized the FY 2018 and FY 2019 budgets. On September 28, 2018, the Defense/Labor-HHS-Ed minibus was signed into law, establishing a full-year, FY 2019 NEI budget at $796.5M. This represented a ~3% increase. A full year appropriation prior to October 1 hadn’t occurred in over 2 decades! The NEI success rate continued to outpace the overall NIH rate by several percent. However, buying power continued to decrease, meaning that increases in the budget did not necessarily translate to greater numbers of funded grants.

Ms. Colbert shared highlights of the 21^st Century Cures Act. They included the creation of an NIH Innovation Fund, promotion of Prize Competitions, data sharing, and funding of high-risk high reward research, the establishment of renewable 5-year terms for IC Directors, and an exemption of scientific meetings from the restrictions they were bound by in the past.

Dr. Sieving made the point that the budget increase to the NEI is never on par with the budget increase to the NIH. That is because of earmarks such as increased funding for Alzheimer’s, Regenerative Medicine, or Opioid research for example. In addition, buying power in 2016 was equivalent to the year 2000. The cost of doing NEI-related regenerative medicine, especially involving NHPs was, and will continue to be, very expensive.

A Council member asked about Eye Bonds. Dr. Sieving gave a brief history. A concept was originated by economist Andrew Lo at MIT to get private money to fund very expensive and novel therapies, notably for cancer. That idea was incorporated into a House bill called Faster Treatments and Cures for Eye Disease with a price tag of $1B ($250M/year for 4 years). The bill will need to be reintroduced in 2019 and put to a vote. Thus far there has been no action. Operationally, this involves private money but would be backed by a government guarantee for a certain portion of the $1B. The bonds would pay interest and would be redeemable after 10 years. This is company investment not individual laboratory investments. The role of the NEI would be as an adjudicator of the quality of the science; the IC would put out a call for translational science from interested companies, look at the proposed projects, rank them and pass that to bond underwriters who would then handle the appropriation of the money. It was not clear who would be responsible for putting out the solicitation or have scientific and fiduciary oversight. Most important, there was concern that the NEI might acquire substantial liability if the bonds didn’t pay off. Another issue is whether monies be put up to cover NEI’s review costs. A Council member asked if business or only science projects would be considered. Dr. Sieving didn’t have an answer for that question.

Dr. Neeraj Agarwal

Dr. Neeraj Agarwal, program director for research training, presented an overview of NEI’s Loan Repayment Program. The NEI made awards in FY 2018 totaling $1.7M. The funding success rates for new and renewal awards were 67% and 68% respectively, again, above the NIH success rates (43% and 67% respectively). To answer a Council member’s question, Neeraj described the application, which is not highly structured and includes only a limited, 2-3 page description of the science. He also mentioned that most of the recipients are already on K grants, so the quality of the applicants and their science are high. Another question posed was if LRP recipients go on to get R01 awards. Neeraj said that most of the LRP recipients are already K awardees, and about 55% of them go on to get an R01 within 6 years of completing their K. However, he didn’t have data for LRP recipients who were not K awardees. R01 recipients are still eligible for the LRP, but they don’t have to have a mentor at that point. Neeraj mentioned that there are current efforts to raise the loan payment from $35,000 to $50,000 per year. The program has been in existence for over 25 years and is open to PhDs as well as MDs.

Also noted, the application period for the NIH Intramural Summer Internship Program, including the Diversity in Research and Ophthalmology (DIVRO) Program, begins in November. For more information visit the NEI training page on the web at https://www.nei.nih.gov/grants-and-training/training-nei/internships-and-student-programs.

Dr. Steven Becker

Dr. Steve Becker, special assistant to the NEI Office of the Director, provided further updates on the NEI Audacious Goals Initiative (AGI) for Regenerative Medicine. Dr. Becker introduced his talk with a recap of the goals of the initiative and the timeline to date. The 3 AGI RFAs were described: the first on Functional Imaging, the second on Identifying Neural Regeneration Factors and the third on the development of Translation-Enabling Models. Included were the number of awards and the budgets for these awards. The recent workshop on Pathways for Retinal Cell Replacement Therapies was designed to learn what was needed for IND-enabling studies for cell therapy trials, share lessons from stem-cell derived RPE trials and other stem cell trials, highlight challenges to retinal neuron manufacturing and transplantation and get perspectives from industry and biotech on the challenges for retinal cell therapy. Six sessions covered issues from preclinical and clinical trial considerations to cell sources and cell manufacturing. There were representatives from academic institutions from around the country, a substantial cohort from biotech, and industry and other federal partners.

The initial takeaways from the workshop were making the choice of an appropriate animal model, careful consideration of endpoints, and the necessity to work out the cell manufacturing/ product development details early on in the process.

There will be 2 principal investigator meetings at the end of 2018 for those grants funded out of the first 2 initiatives, Imaging and Neural Regenerative Factors. The purpose will be to review project milestones, share results, discuss challenges and promote collaboration. Members of the associated ESOC (External Scientific Oversight Committee) will be present at each meeting. Dr. Becker also presented a slide with the PI names, institutional affiliations and project titles of the 5 Functional Imaging awards and the 6 Neural Regeneration Factors awards. Future plans for 2019 included a symposium at ARVO highlighting how functional imaging technologies can support cell therapy efforts and a symposium at SfN to showcase advances in retinal organoids and retinal neuron characterization to inform cell replacement therapies.

A Council member raised the problem of immune rejection and cell-based therapy and the fact that those issues must be dealt with in order to move forward to clinical trials. FDA approval is also a complex process.

Dr. Thomas Greenwell

Dr. Thomas Greenwell, NEI program director for retinal diseases, summarized five newly funded AGI projects that utilized the U24 mechanism (RFA-EY-17-003). The FOA was entitled, Translation-Enabling Models to Evaluate Survival and Integration of Regenerated neurons in the Visual System. Check out the NEI press release for more information. These projects will complement ongoing AGI research, which includes 5 imaging projects and 6 discovery-based projects. Dr. Greenwell went on to describe the 5 newly funded projects in some detail. The animal models ranged from 13-lined ground squirrel and tree shrew to dog and several species of NHPs. The PIs have developed innovative models of retinal and visual system diseases including cone dystrophies, glaucoma, heritable disorders and visual trauma. The approaches are varied in terms of placing stem cells into these systems, and evaluation and integration of function will be evaluated using a combination of standard and novel methods. As with the other consortia, an ESOC was convened to oversee scientific progress.

Tom then presented a concept clearance to Council based on what was learned from the last FOA. Reviewers noted insufficient data demonstrating adequate initial characterization of the models. This was likely due in part to the time from publication of the FOA to receipt of applications, which was less than 90 days. The NEI would like to put out a small scale FOA (R21) to support a dozen or so projects for short-term work to enable investigators to generate preliminary data for the characterization of other translation-enabling models appropriate for regenerative medicine approaches. The floor was opened for questions/comments. In answer Council members’ questions, the projects would not have the same oversight as the larger projects, more than 5 or 6 would be funded, and it would give applicants time to put together collaborations. There was a motion to approve the concept, a second, and all members were in favor.

An additional comment was that the NEI should invite speakers from outside the US to the symposia and workshops. For example, Botond Roska from Basel, who has made great advances in retina attached to brain organoids. Dr. Paul Sheehy said that there were several foreign invitees at the last symposium. Dr. Greenwell added that industry partners are also desirable. A Council member suggested that oversight be modeled against the nanotechnology PN2 mechanism where students, postdocs etc. were invited to a yearly meeting of all the site PIs and where there was much more stringent oversight.

Dr. Sangeeta Bhargava

Dr. Bhargava presented an overview of the Collaborative Clinical Research (CCR) Group and NEI-funded clinical studies and clinical trials. The portfolio includes testing of new agents, technologies and other interventions, population-based studies to determine prevalence of eye diseases, the identification of risk factors for the development and progression of eye diseases, secondary data analysis, and development of new statistical methods. The funding mechanism for clinical trials are various R mechanisms and the UG1, the latter of which involves input from NEI staff. She then described several epidemiological studies and clinical trials. Many of the studies involved minority populations as well as pediatric populations. Some clinical trials have been conducted overseas in India, Ethiopia and Nepal. The NEI supports 2 research networks, PEDIG (pediatric Eye Disease Investigator Group) and the DRCR.Net (Diabetic Retinopathy Clinical Research Network). The latter network has expanded its scope to include age-related macular degeneration (AMD) and other retinal diseases. The networks have hundreds of sites and conduct multiple protocols simultaneously. She introduced the DRCR.Net leadership: Mr. Adam Glassman (JHU), the Coordinating Center Director, and the 2 Co-Chairs, Dr. Jennifer Sun (Harvard), who heads the diabetic initiative, and Dr. Daniel Martin (CWRU), who heads the AMD/non-diabetic initiative.

Mr. Adam Glassman, Dr. Jennifer Sun, and Dr. Daniel Martin

Drs. Jennifer Sun, Daniel Martin, and Adam Glassman of the NEI Diabetic Retinopathy Clinical Research Network (DRCR.Net) summarized the network’s mission, history and progress since it began in 2002. The DRCR.Net included 155 active (352 total) sites. It has conducted 30 studies thus far. The main causes of vision loss in diabetic retinopathy (DR) are diabetic macular edema and proliferative diabetic retinopathy. The DRCR.Net has made a major impact on the treatment of DR and is expanding into other retinal diseases, including AMD. Before 2003, laser photocoagulation was the only treatment for these disorders. Major advances by the network in the treatment of DME included the finding that steroids are not efficacious over laser therapy in the long term (Protocol B), but anti-VEGF therapy resulted in a dramatic improvement in visual acuity (Protocol I). Protocol T was a comparative effectiveness study of 3 types of anti-VEGF drugs that varied in cost and availability, which showed a similar effect in eyes starting with acuity of 20/32-20/40, but for eyes with acuity of 20/50 or worse, Aflibercept (Eylea) > Ranibizumab (Lucentis) > Bevacizumab (Avastin). Anti-VEGF therapy was shown to be noninferior when compared to panretinal photocoagulation for PDR.

Highlights of the network’s approach and structure that have enabled the work included its open, collaborative and transparent structure, the rigorous scientific review of the studies, and the efficient, cost-effective study pipeline. The DRCR is an open network with both academic and community sites and engages investigators at every step from protocol development to reporting. The network has a public web site that includes network publications, protocols, slide sets and datasets. The protocol process was described and begins with solicitation of ideas, initial review by an Operations Group, and presentation of ideas at the semiannual meeting, followed by presentation to the Executive Committee. A Protocol Development Committee is then formed, and a complete study protocol is written, which goes through further internal review and revision. The protocol is then reviewed by 2 independent groups, an NEI-appointed External Protocol Review Committee (EPRC) and an internal Data and Safety Monitoring Committee (DSMC). Protocols are revised based on comments by the EPRC and DSMC, which culminates in a final protocol.

The network has completed 30 clinical trials in 15 years. The network is efficient; infrastructure is in place, and different stages of various protocols – development, implementation and reporting – are running in parallel. The network is also cost-effective; it has leveraged NIH funding with industry and foundation support. Guidelines assure that the DRCR.Net maintains control over design, implementation and reporting. The NEI provides 47% of the network’s funding (not including drug costs), 20% from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), 30% from industry, and 3% from the Juvenile Diabetes Research Foundation (JDRF). When drug costs are considered, industry is in at 59%, the NEI at 29%, NIDDK at 9% and JDRF at 3%. The network has been very productive with 93 publications since 2003, and 220 poster or platform presentations at 17 different national and international meetings. The network has been recognized by Congress for its innovative treatments. Additional research is required to discover ways to prevent DR onset or worsening, to better deal with the global burden of DR, and to make treatments more readily available. The major goals of the DRCR.Net over the next 5 years include trials to test the efficacy of noninvasive photobiomodulation for DME, conduct other comparative treatments for PDR and DME, look at genetic contributions to DR and how they might affect treatment response, take advantage of biobanking, and looking at AI and new imaging methods for DR detection and prediction of outcomes.

The network is planning an expansion to include trials for AMD and other retinal diseases. This is important because the network has several advantages over pharmaceutical companies for the conduct of such trials. Pharma trials rarely compare multiple drugs, there is seldom long-term follow of study subjects, and they don’t fully inform physicians and patients on optimal use of a drug. There are currently more than 30 industry trials underway for testing drugs for wet AMD. This provides opportunities for comparative trials and cooperation between the DRCR.Net and industry/ pharma. The first major AMD trial will be the Prevention of Exudative CNV in AMD (Protocol AF). Other possible studies include PVL (Pneumatic Vitreolysis) for vitreo-macular traction and macular hole, central serous retinopathy, surgical trials, and ROP. For more about the DRCR.Net, visit https://public.jaeb.org/drcrnet/view/Home_Page.

The group answered questions regarding protocol ideas and their ownership. Drs. Sun and Martin emphasized the collaborative nature of the network and their willingness to work with other investigators and keep them involved in all stages of a protocol. Another question involved protecting protocols from “over committee-ization” and conflicts of interest. Dr. Sun said that they avoid some of that by inviting comments from individual physicians in the network in the early stages of protocol development. There are well-laid out conflict of interest rules; no one in leadership can take money from an outside private entity. The majority of committee members and writing groups will have no conflict, although it is sometimes necessary to have input from individuals who have financial relationships with industry/ pharma. A question also arose regarding junior/ untenured investigators and large group authorship as a member of the network versus lead author on their own research papers. Drs. Martin and Sun said that these investigators have access to mentors and information that informs their research and vice versa. They also have an opportunity to take on leadership roles.

A Council member asked about the “new” definition of a clinical trial and what headway had been made to clarify what research fit the definition. Dr. Sheehy commented that the NIH noted that the basic science communities engaging in behavioral and psychological studies were most affected. There are now new parent FOAs, starting with January 2019 due dates, with the designation BESH (Basic Experimental Studies with Humans). These studies fall within the definition of a clinical trial and also meet the definition of basic research (Note: the NEI has not signed on to these BESH FOAs). The NIH is also flexible regarding investigators who submit on the wrong FOA. Those applications will go to review and be reviewed according to the review criteria in the FOA under which they were submitted. This flexibility will end with September 2019 due dates. A Council member asked about the Human Subjects course that was provided by the NIH, discontinued and then apparently re-provided at cost. Dr. Sheehy had no insight into that move. Another Council member had a question about the reorientation of study sections at CSR. Dr. Sheehy said that the NEI has approached issues on an ad hoc basis as they arise. Study sections do undergo an examination by outside academicians with regard to scientific areas they review. Dr. Stepp, a Council member, was a part of such a group, and she offered that what she was allowed to say, namely that the ocular surface group would become a chartered study section. CVP, which was merged into SPC, will remain a part of SPC. Those comments ended the Open Session, which was adjourned at approximately 1:20 pm.

Adjourn.................................................................................................. 1:20 pm

DoD Representative position is vacant