DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health
National Eye Institute
NATIONAL ADVISORY EYE COUNCIL
Minutes of Meeting
Thursday, June 16, 2011
The National Advisory Eye Council (NAEC) convened for its one hundred twenty-eighth meeting at 8:30 am on Thursday, June 16, 2011, at 5635 Fishers Lane, Rockville, MD. Paul A. Sieving., M.D., Ph.D., Director of the National Eye Institute (NEI), presided as Chair of the Council. The meeting was open to the public from 8:30 am until 2:30 pm. The meeting was closed to the public from 2:30 pm until 4:30 pm for the review of grant and cooperative agreement applications. Attachment A provides a roster of Council members.
COUNCIL MEMBERS PRESENT:
Dr. James Chodosh
Dr. David R. Copenhagen
Dr. Scott W. Cousins
Dr. Donald Gagliano
Mr. Ronald J. Gardner
Dr. Charles D. Gilbert
Dr. Bernard F. Godley
Dr. John C. Morrison
Ms. Alberta Orr
Dr. K. Krishna Sharma
Dr. Marco A. Zarbin
COUNCIL MEMBERS ABSENT:
Dr. Joseph Bonanno
Dr. Sheila K. West
NEI STAFF PRESENT:
Dr. Neeraj Agarwal
Dr. Houmam Araj
Ms. Pamela Bobbitt
Dr. Deborah Carper
Ms. Preethi Chander
Dr. Hemin R. Chin
Ms. Monique Clark
Ms. Kym Collins-Lee
Ms. Janet Craigie
Mr. William W. Darby
Ms. Linda Dingle
Mr. Donald Everett
Dr. Richard Fisher
Dr. Shefa Gordon
Dr. Tom Greenwell
Ms. Anna Harper
Mr. Dustin Hays
Mr. Tom Hoglund
Ms. Jean Horrigan
Mr. Kurt John
Ms. Tina Jones
Mr. J. Kevin Keating
Dr. Dan Kenshalo
Dr. Natalie Kurinij
Ms. Marilyn Laurie
Dr. Ellen S. Liberman
Dr. Andrew P. Mariani
Mr. Matthew McMahon
Dr. Loré Anne McNicol
Ms. Jenny Mehren
Dr. Sheldon S. Miller
Dr. Lisa Neuhold
Dr. Steve Oversby
Dr. Maryann Redford
Ms. Neyal Ammary-Risch
Ms. Karen Robinson-Smith
Dr. Annie E. Schaffner
Dr. Grace L. Shen
Dr. Eleanor Schron
Dr. Paul A. Sieving
Dr. Sarah Sohraby
Dr. Michael A. Steinmetz
Dr. Chris Thomas
Dr. Santa Tumminia
Ms. Donna Wells
Ms. Keturah Williams
Dr. Jerome R. Wujek
OTHER NIH STAFF PRESENT:
Dr. Kapil Bharti, NINDS
Mr. Michael Chaitin, Center for Scientific Review (CSR)
Ms. Mary Frances Deutsch, Office of the NIH Director (OD)
Dr. René Etcheberrigaray, CSR
Dr. Yuan Luo, CSR
Dr. George McKie, CSR
Dr. Eduardo Montalvo, CSR
Dr. Joe Rudolph, CSR
Dr. Mary Schueler, CSR
Dr. Jerry Taylor, CSR
Dr. Kirk Thompson, CSR
MEMBERS OF THE GENERAL PUBLIC PRESENT AT THE OPEN SESSION:
Ms. Joanne Angle, Association for Research in Vision and Ophthalmology (ARVO)
Dr. Bobbie Austin, ARVO
Dr. Ross Brechner, Centers for Medicare and Medicaid Services (CMS)
Mr. John Langer, RTI International
Dr. Israel Goldberg, Health Research Associates
Mr. James Jorkasky, National Alliance for Eye and Vision Research
Dr. Dan Martin, Cole Eye Institute
Ms. Lori Methia, ARVO
Ms. Phyllis Richman, Richman Associates
Dr. Philip Rosenfeld, Bascom Palmer Eye Institute
Mr. Jack Mitchell, Senate Special Committee on Aging
OPEN SESSION OF THE MEETING
CALL TO ORDER AND OPENING REMARKS
Dr. Paul Sieving welcomed everyone attending the meeting. He introduced and welcomed two new Council members. Dr. Krishna K. Sharma is Professor of Ophthalmology and Biochemistry from the Mason Eye Institute with a Ph.D. in biological chemistry and expertise in lens, cataract, and crystallins. Dr. John C. Morrison is a professor of ophthalmology at the Oregon Health Sciences University whose clinical areas of focus are glaucoma and cataract surgery. Dr. Sieving thanked them for joining Council.
Dr. Sieving read over the agenda and stated that there were several important and interesting topics to review such as a CSR’s mandate to periodically look at the portfolio and the review of mechanisms. Mr. Ron Gardner was to give a report about the National Federation of the blind. NEI/NIH Science updates will be presented, and presentations on treatment of age-related macular degeneration (AMD).
Dr. Sieving discussed the origin and mission of the National Center for Advancing Translational Sciences (NCATS) which came about through the interest of Dr. Collins and others to meet the need to move into therapeutics and translational care. This formally began in 2010, when a letter was sent to Congress. The launch date is set for the first day of the fiscal year 2012. The money will come from a variety of sources including a number of components that already exist in the National Center for Research Resources which will be moved into NCATS as well as other programs including the molecular libraries program, office of rare disease research and some training mechanism that currently exist. It is estimated that $500 Million a year is going to support translational and clinical science through NCATS.
Dr. Sieving introduced three new NEI employees. The first was Dr. Matthew McMahon, Senior Advisor for Translational Research in the Office of the Director, who has a broad neuroscience background in academic and industry-sponsored vision research. Dr. McMahon spent five years as principal scientist at Second Sight Medical Products which is in the lead in developing a retinal prosthetic device being marketed in Europe. Dr. McMahon is here to help the institute interface with company interests, needs, and more specifically to pay attention to NCATS and how the NEI will engage in that arena. Next, Dr. Sieving introduced Mr. Dustin Hayes, a molecular scientist & science writer who has been writing for NIDDK. Mr. Hays has more than 10 years of lab research experience in a variety of fields including neuroscience, digestives diseases, immunology, and molecular cancer diagnostics. Thirdly was Dr. Christopher Thomas also from NINDS, who is a writer and previously was a post doc with Jeff Diamond. Dr. Thomas has 20 years of research experience in a variety of fields including synthetic organic chemistry, neurodegenerative diseases, fast neuronal communication, and glial cell physiology. Dr. Thomas has knowledge of neural & sensory systems and will be doing science writing for the NEI. These two new science writers are in the newly renamed office of scientific publications.
STUDY SECTION REORGANIZATION
Dr. René Etcheberrigaray from the Center for Scientific Review (CSR) thanked Dr. Sieving for inviting him and presented an overview of the CSR peer review of grant applications assigned to the NEI. He discussed CSR’s obligation to review all the areas of science in light of the NIH Institutes’ needs to identify the best science noting there is always room for improvement and to get a different perspective.
A current review of NEI’s applications showed three main areas as Anterior Eye Disease (AED), Biology and Diseases of the Posterior Eye (BDPE), and Central Visual Processing (CVP). When combining the three study sections it was found that 80% of NEI R01 applications are reviewed in these 3 venues while 20% are reviewed in other study sections, most including 5 or fewer NEI applications per meeting. Other venues with more NEI applications are Cognitive Neuroscience (COG), Cognition and Perception (CP), and Genetics of Health and Disease (GHD), Neurodifferentiation, Plasticity, Regeneration (NDPR), and Sensorimotor Integration (SMI).
Dr. Etcheberrigaray presented several alternatives to current review practices of NEI applications including revisiting the use of anatomical anterior/posterior division as guiding principle. A new focus on scientific content with a clinical/translational study section on Diseases and Pathophysiology of the Visual System (DPVS), a basic study section on Biology of the Visual System (BVS), and merging CVP and COG was proposed. He discussed the convening of a Working Group in April 2011 and the summary with input from members of the working group who endorsed the general concept.
Council had many comments and questions. Dr. Gilbert asked about the clinical central brain processing from the eye to cognition, which is so broad that could not be represented in one study section. He wondered how would one deal with that issue in a single study section and how could they prioritize. He thought CSR might impact the structure of the institutes themselves. Dr. Etcheberrigaray replied that CSR does not think this will impact these institutes. This study section will be at least 50% dedicated to eye topics and there are some other areas of interests that will be related.
Dr. Gilbert asked about the other partitions as the way this is described this seems to be all sections of neural systems. Dr. Etcheberrigaray stated there are no issues with NIMH. He asked SRO Dr. Kirk Thompson to speak on this topic. Dr. Thompson stated that both of these study sections are broad and overlapping. Central vision processing is low level vision but also gets into the cognitive levels of vision which is covered by the cognitive study section. The basic problem is that the numbers of application are so low and by combining CVP and COG there would be better coverage and fewer reviewers.
Dr. Chodosh remarked that this was the first that he heard of the reorganization and he did not view it favorably. He thought this would create study sections within the study sections. As a former chair he knows there are serious problems with review but I did not know if the reorganization would address the issues. He thought the current study section environment was very healthy and all study sections appreciate the basic grants. He commented that this was creating a concept where grants that go to the wrong study section may be in trouble and slip through the cracks.
Dr. Etcheberrigaray stated he was less concerned as CSR did a mock study of recent data to see where applications would be reviewed and that CSR will pay careful attention to put each and every grant in the right place. CSR is aware of the issues and will monitor carefully to address any problems.
Dr. Zarbin stated with all due respect to his colleague Dr. Chodosh, one can make many systems work and one has to make a system work when adopted. If the reviewers aren’t careful, there will be bad output no matter the organization.
Dr. Etcheberrigaray thanked everyone and stated he appreciated their input. If needed, CSR will create overflow study sections or create a mirror image study sections. Modeling predicted the study sections will be a healthy size and reviewers would each review between 8-10 applications. Dr. Zarbin stated he could read an article and have an opinion but that does not make him an expert, but for one individual to review 8-9 grants is quite an expectation.
Dr. Etcheberrigaray stated that CSR invited the NAEC’s opinion and agreed that translational sections have large coverage and if the study sections became too broad other models could be employed but he didn’t think that would be the case.
Dr. Gilbert reinforced Dr. Chodosh’s point of view asking saying that what CSR is doing is not encouraging the culture moving forward as a basic scientist may want to stretch a little more and the translational study section may say this person is not an expert and give it a low priority. He opined that one would want basic scientists to take a more open view and unless there are reviewers in the translational study section to encourage basic scientists to explore more translation in their work that won’t happen if the review groups become divided.
Dr. Gilbert stated that a concern is how CSR will evaluate this change. Dr. Morrison asked about the timeline on the implementation of the new study sections.
Dr. Etcheberrigaray stated the February review cycle is the timeframe but if CSR has to delay then they will. Their general objective is to apply step-wise approach.
Dr. Copenhagen had questions whether CSR can evaluate these changes in a timely manner stating that someone from CSR came one or two meetings ago to talk about the A1 change and there were several of us who read the data much differently from CSR. Some were appalled by how many didn’t like the new system, and we commented on that, and there seems to be no change that he was aware of. You’re saying we can change things and then have a lot of feedback but in going to the A1 and not having a second revision is bad. He disagreed with what he called a top down approach.
Dr. Etcheberrigaray stated that the A1 was a corporate NIH decision and not a CSR decision and he was not involved in the decision. Several translational folk have looked at this decision and a significant amount of applicants do not like it but it will take time to be reviewed by the NIH. Not everyone is in agreement that this is a top down approach. We did involve many people from different areas and this is a review change we can address and monitor very quickly if we need to and we have much more control on how to address this.
Dr. Copenhagen asked how will we know how you are looking at these changes? Will you report back to the Council?
Dr. Etcheberrigaray stated the next council will be business as usual but we will have guidelines and expect feedback and we can report back on what worked and what didn’t work. It will be by the summer Council next year that we will have a review to report.
Dr. Zarbin agreed with Dr. Copenhagen saying we do not all agree with the data that was very striking at the last meeting. We don’t want to make a mistake and neither do you. Presumably, we as individuals can have input but they should have some sort of standing committee that interacts that you will know from a chorus of voices whether this is working or not working. We have representatives from those societies here now and I think this is something you would want to do. You need some representatives from some groups of people who are involved in the work and can advise you what is going on. That data talk should be given to this group so that you can get an idea of what is going on. Depending on the Council, it is not enough for this group alone as we don’t meet often enough.
Dr. Etcheberrigaray stated that was a good idea and he would be happy to meet with Council to discuss continuous monitoring.
FY 2011 BUDGET
Ms. Marilyn Laurie, Chief, Financial Management Branch, NEI gave a budget overview and stated that the NEI’s Research Project Grant (RPG) success rate had historically exceeded the NIH average. NEI has received consecutive increases in its budget from 2007 through 2010. In FY 2011, the NEI’s appropriation decreased by $6.2M. With the cycling of noncompeting awards and NIH’s revised inflationary policy, NEI maintain approximately the same number of awards as in FY 2010. In FY 2012, NEI is planning for further reductions to our appropriation and a transfer of funds to NCATS to support TRND.
Dr. Gilbert asked if that number, i.e., success rate, takes into account resubmissions. Ms. Laurie referred the question to DER Director, Dr. Lore Anne McNicol, who stated no. The NIH has calculated success rates since 1996 in the same way and there is no structural change in how it’s done. Double submissions within the same fiscal year do not affect the total.
Dr. Sieving thanked Ms. Laurie for managing in a difficult time, stating as you showed in your slide, everyone wants to manage the budget. The NEI does not get a check that says spend as you like. The amounts of dollars that you can transfer from one line to another cannot be done without getting approval from those higher up. We had seven continuing resolutions and one might think this is simply a promise from Congress and we would have these dollars come through but until a month or so ago, our management of the budget was extremely constrained. When you have a dollar number that is designated to grants such as R01s there is a question of how NIH is going to manage. Is it better to have more grantees funded with fewer dollars or is it better for the science to have a number of dollars going to each grantee? NEI has managed to balance that by having approximately the same number of grantees under the promise that the diverse number of science improves the pool. When I am visiting a venue, in fact, the voices to Congress that count on science funding are not the institute voices but the voices of the American people and you are they.
THE NATIONAL FEDERATION OF THE BLIND
Mr. Ron Gardner stated it was a pleasure to be here and stated that although he does not have a medical degree or Ph.D., he does understand blindness and has been for a little over 60 years. I have chosen not to have slides and since I started on the National Advisory Eye Council, I haven’t seen your slides and turnabout is fair play. I do want to say thank you for your service and the way you improve the lives of many people. I want to talk about the research for the quality of life that you are doing and your work for we are the beneficiaries of so much research. The results of some of the research you do, not the front or back of the eye, but for people who benefit and whose lives are improved by this Council. There are too many problems that blind people deal with and understanding what that is will be beneficial.
Blind people struggle with access to information in this day and age. Unfortunately, blind people are many years behind. Do we have access to the internet? Certainly but only to those websites that are accessible. I serve on the access board on which the President of the United States makes appointments. The United States Access Board serves with governmental officials of the various cabinet offices such as transportation, etc. They control access to the world yet there is much to be done on gaining access which is done through rule making, by engineers, and by folks like you who are willing to do the work to find out the directions that work should go. One area is transportation. I put many miles on the airlines because that is my job to travel around to various organizations. I can get from the airport to the hotel where I present but it’s not that type of transportation I am referring to. It’s getting to and from work. We can walk but transportation is an issue. The biggest problem we of the National Federation of the Blind face is not the lack of vision but the misconceptions that exist about blindness and blind people. Where does this misunderstanding that is such a barrier for us come from? The social construct that says the blind people are unemployable is truly a barrier to any quality of life. For people who for one reason or another are forced to remain home on the couch because they cannot or do not get a job, choose to travel, or to use a white cane or guide dog. The self-esteem of that individual suffers to say nothing to the financial condition of that person or family. Transportation is the biggest barrier and it is real and worthy of research.
Here is one small anecdotal piece that demonstrates what we as blind people endure. I am an attorney, for many years served as a litigator, and enjoyed modest success. I was honored when I was asked to present to the legislature of the United States. I thought no problem. I’ll get to the Capitol and get a driver to take me home. I went to the Capitol, made my presentation, went with the driver from the agency that serves the blind and does the training for blind people. We got in the car, me and another passenger who had presented. The driver got into the drivers seat. Instead of facing forward she faced backward, she leaned over the back seat and started groping the body of the person next to me. When we asked, “what are you doing?,” she said she was buckling the seat belt. Then she turned to me. What is it about a blind professional that made her feel she needed to buckle the seat belts of two blind professionals who just finished making presentations before Congress? Seventy-five percent unemployment is simply unacceptable due to the myths and social constructs that say blind people are unemployable. This is not true.
In the 1920’s Congress created the rehabilitative services administration, a federal agency or division that could use taxpayer money to assist states to provide money to individuals we called handicapped but that program ignored blind people. There was no reason to fund rehabilitation for blind people because they are unemployable. It was much later due to the efforts of some organizations that Congress found that spending money on blind people would not be unbeneficial because we would be tax paying individuals. There’s a difference in getting people out of the entitlement mode. Blind people are getting more and more jobs, but unemployment still hovers near 70%. We make up a small percentage of the population. The National Federation of the Blind, the critical words being ‘of the blind,’ is an organization made up of blind people and their families and friends. We will have a national convention in Florida. Blind people make up a cross section of the society. The work that we do there is critical because we bring Congressmen, Senators and Governors to our convention to help them understand that it is not the lack of vision but the lack of understanding that is the barrier and this the social construct has continued over time.
I can gain access to Braille but not to all information. I have access to more information than ever. We have pieces of technology that has the brain of a Palm Pilot’s but we are a little behind. The development of and access to technology is not available to the individual blind person. This gadget makes it possible to have an outline and have a presentation and folks who learn Braille at a very young age can read as fast as you can. When I was at the University, I encountered several students who learned to read in Braille at the same rate of their sighted peers. If you learn Braille at a young age, they can read at the same rate as some read print. Can we do some research to figure out how to stimulate the part of the brain or neurological system to take it back to childhood so that learning basic things such as reading can be done efficiently in later life? The brain’s elasticity makes it harder to accomplish this.
Mr. Gardner presented a video clip of the National Federation of the Blind’s “Blind Driver Challenge.” This film clip was made in January 2011 and is on the development of technology. In 1960, John Kennedy said we’re going to walk on the moon. I think it was less critical to walk on the moon then to develop the technology to allow us to walk on the moon. The National Federation of the Blind supported research to invent a car that a blind person could drive. The critical part of that is the non-visual access to have a car that a blind person could drive at the Daytona International speedway (a clip was shown here). The driver was blind. The National Federation of the Blind has developed interfaces that transfers through gloves and the seat of the car. A few more things and I am finished. I was there in Daytona and witnessed in my own way the actual driving of a vehicle by a totally blind person around the speedway. A lead car was there to film and toss out obstacles which were driven around by the blind driver. He pulled out, passed, and drove in front of the lead car. Is it critical that blind people drive? The point is the barrier to a blind person driving is being removed. Although this car is not ready to drive among taxis in New York or on the freeway of San Diego, it is in the development process but will we be driving? No, it’s not the lack of vision or ability to drive, it’s going to be the social construct and the belief of others that this is not possible nor will there be legislation in Congress supporting this in my lifetime. The simple part of blindness not about the front or back of the eye or cortex, Dr. Chodosh, but purely what blindness is about. Thank you.
Dr. Sieving stated that this gives us a perspective on the needs of the blind and he thought everyone was fascinated. I hope there will be a time that this won’t be fascinating.
Dr. Gagliano remembered when he and Mr. Gardner were crossing the street and Ron said, “You are trying to get me killed. Why don’t you follow me?” He learned that skills that were meaningful. Last July, I spoke at an NFB convention and it was an experience. We move people back into their lives and raised functionally to the maximum extent possible. We’re about to launch into some efforts to try to begin programs. Unemployment is due to lack of education and opportunities. The Blindness Veterans Association is a counterpart to The National Federation of the Blind and I’m using that forum to develop a technology to eliminate the gaps in communications, mobility, sports and athletics, and the last is driving. We think there are opportunities for those with vision impairment who are not fully blind who may have more opportunities. Their lives have changed as they once did drive but now cannot. The paralympics is a component of the US Olympics that is trying to provide higher level challenges. I’m using athletics to highlight, design and develop technology to enable people. One bronze medalist in judo was able to compete in the sighted Olympics. Last year there was a downhill skier who was allowed to participate in the Olympics. Ron, do you have anything to add?
Mr. Gardner stated that Dr. Gagliano was well received at the NFB Convention because there is progress in this area. There are many organizations working on this and in the low vision field including the NEI on the quality of life. Blindness is one of the leading causes of disability among seniors. They are in a very different situation than I am, as I’ve been blind since birth. These seniors have been working, driving, reading newspapers, and now have macular degeneration and are unable to do many of these things. Someone is helping them to learn they can do some of them.
Dr. Godley asked, “Of the 25% of the blind who are employed, what parts of the economy do they fulfill?”
Mr. Gardner noted that ninety percent of those who are employed read or write Braille and they came from an economic background that helped them learn to read or write Braille. If taught as children the unemployment rate among them is only 40% though that is still way too high. There are other disabilities whereas blindness is the least of their problems. If the is blindness is combined with another disability, they often representing that other disability instead of just blindness. One barrier is that people believe blindness is a cognitive impairment.
Dr. Godley asked, “More specifically what types of jobs do they migrate into?”
Mr. Gardner replied, “My brother is a PhD, another is an attorney. We have chemists, people in radio and entertainment such as the Stevie Wonders who are doing it with music, web page designers, lots and lots of other professions. There are some who believe you can only have the watermelon or picking cotton type jobs that too is just as misplaced. There are blind people who can only be on the telephone or in sheltered workshops. That they believe that they can only work in sheltered workshops is a myth we are trying to break.”
NEI/NIH SCIENCE UPDATES: STEM CELLS
Dr. Sheldon Miller’s presentation was entitled “Stem Cells for Identifying Disease Pathways & Therapeutic Interventions: A new paradigm for translational science.” He noted that there are two main types of pluripotent stem cell; embryonic and induced pluripotent (iPS) cells and reviewed the various cell types are derived from iPS cells including RPE, photoreceptors, eye cups, bone, neurons, skeletal muscle, blood cells, hepatocytes, cardiomyocytes, and pancreatic cells. He then reviewed studies showing the functionality of some of the cell types derived from iPS cells. He concluded that Stem cell biology was a new driving force for translational science. There would be pitfalls ahead, but their resolution will provide a much deeper understanding of human developmental biology, epigenetics, & its molecular basis
Looking to the future, he stated that stem cell biology provides a basis for identifying mechanisms of disease at the molecular and cellular level, discovering therapeutic interventions using high-throughput drug screens, and designing cell-based therapies, e.g. transplantation.
Looking slightly further ahead with regards to in vivo transdifferentiation, 2 steps are completed. 1) Direct in vitro conversion of fibroblasts into neurons, cardiomyocytes, muscle, & blood cells and 2) In vivo transdifferentiation of exocrine cells into functional ß cells (diabetic mouse blood glucose levels normalized).
For transdifferentiation of photoreceptors to RPE, Dr. Miller noted that we are in process of identifying transcription factors (MITF, OTX2, PAX6) and small molecules that can be used to directly convert any cell into RPE. In the early stages of AMD (RPE drop out), one could sacrifice a few “altruistic” photoreceptors to preserve RPE function over the long run.
Dr. Gilbert stated that as challenging as the issue of getting, once you have the cell, to achieve the right phenotype, once injected it has to find the right layer of neural tissue and make the right kinds of connection. It’s very different than dealing with beta cells in the pancreas.
Dr. Chodosh pointed out that there was an editorial on the risk of stem cells and difficulties in mutation over time.
Dr. Miller stated he could not comment on the exact details of the editorial and stated that the point is that this is an enormous opportunity to look at human stem cell biology and the field is rapidly advancing.
Dr. Miller discussed how last year, NIH Director Dr. Francis Collins initiated in the intramural program on stem cells and set aside money for five years for this initiative. There is much activity in the institutes and the first inter-institute symposium will be held in July. Because the field of collaborators is stretched around the whole NIH community, the effort should become self sustaining.
NIH/FDA USE OF FUNCTIONAL VISION ENDPOINTS IN VISUAL PROSTHESES
Dr. Matt McMahon presented a synopsis of the NEI/FDA Endpoints Symposia on the use of functional vision endpoints in visual prostheses product development held May 6, 2011 at
Masur Auditorium, NIH and chaired by Drs. Neil Bressler, Wilmer Eye Institute, Johns Hopkins, Rick Ferris, NEI Clinical Director, and Malvina Eydelman, FDA Center for Devices and Radiological Health. This was the fifth in a series NEI/FDA Endpoints Symposia.
The goal was to determine how functional vision-related endpoints for clinical trials of visual prostheses will be analyzed and correlated with objective measures of visual acuity, visual fields and contrast sensitivity. The symposium was attended by clinical researchers/basic scientists in the visual prostheses field, retina specialists, pharmaceutical company representatives, device company representatives, low vision/vision rehabilitation researchers, and daily living activities researchers
The FDA perspective was to draft Investigational Device Exemption (IDE) Guidance for Retinal Prostheses. The question being is visual acuity enough? Sessions covered topics on what are the critical elements to be measured in orientation and mobility assessments, activities of daily living, development and validation of objective functional vision endpoints, and issues relevant to current clinical trials.
Dr. Gagliano asked what the Europeans are doing to bring these devices to market. Dr. McMahon stated the US and European processes are different. Many European Companies do international clinical trials. The pathway is clearer in Europe than in the U.S. Congress and the FDA are aware of that and are working to ease the approval process here.
CURRENT USE OF AVASTIN AND LUCENTIS FOR NEOVASCULAR AMD
Dr. Philip Rosenfeld discussed normal disease progression in age-related macular degeneration (AMD) with intermediate high risk dry AMD progressing to neovascularization or geographic atrophty. He discussed how OCT Identifies VEGF-induced exudation and that OCT is a VEGF-Meter as VEGF induces macular fluid, intra-retinal fluid, sub-retinal fluid, and sub-RPE fluid (PED). With anti-VEGF therapy, 1 month post-injection there is a dry macula and multiple injections are needed to maintain a dry macula.
Commercially Available Anti-VEGF Drugs for Neovascular AMD are Ranibizumab (Lucentis™) and Bevacizumab (Avastin™). Bevacizumab (Avastin™, Genentech) was FDA approved in February, 2004 as a systemic treatment for metastatic colon, lung, and brain cancers. It is legal to compound Avastin for intravitreal injections as long as thyere is compliance with the standard guidelines for compounding sterile preparations found in Chapter 797 of the United States Phamacopeia (USP).
Ranibizumab (Lucentis™, Genentech) was FDA approved in June, 2006 and at the end of 2007, restrictions were placed on sale of Avastin to compounding pharmacies.
Lucentis and Avastin bind all the biologically active forms of VEGF. Avastin is 3X Larger than Lucentis and Avastin is 2.5X Higher in Concentration than Lucentis. The question is, “When Lucentis and Avastin have equivalent number of molecules in equal volumes, is one drug better than the other?”
Lucentis has an approximately 20X higher affinity than Avastin for VEGF-A. Is one drug better than the other? Lucentis has higher affinity but Avastin may last longer. Does it matter? Prior to the CATT results, only retrospective studies and small prospective studies guided clinicians.
How do clinicians decide? Globally, decisions are driven by on-label vs. off-label ethical debate, legal restrictions, cost of drugs, and economic incentives.
Medicare incentivizes the use of expensive drugs. Medicare pays a 6% commission: 6% of the average sales price (ASP) of Lucentis ($1950) is $117. This fee covers ordering, storage, and invoicing. Physicians are paid more for using more expensive drugs. Medicare Part B paid $600 million in 2009 for these commissions.
The New York Times reported the Lucentis Rebate Program in the BUSINESS DAY section on November 04, 2010 in an article, “Genentech Offers Secret Rebates For Eye Drug” by Andrew Pollack. This raises interesting questions including legal issues, how common is rebate in clinical practice, ethics, should patients be informed, and who should get the rebate, perhaps CMS?
Dr. Rosenfeld discussed the unit cost and Medicare allowable payments for Lucentis and Avastin and then an analysis of the CMS Database from 2008 and 2009 done by Dr. Ross Brechner, CMS Lead Medical Officer/Consultant on Medicare Fee-For-Service (FFS) patients (~34.2 million) that excluded HMO patients (~11 million: 24%). The unique Part B FFS Medicare beneficiaries receiving AVASTIN or LUCENTIS injections for wet AMD IN 2008-2009 remained equivalent.
In considering Lucentis vs. Avastin, the question arises, why is there variation in practice patterns? Possible explanations include secondary insurance status (copay), local CMS carrier coverage of Avastin, access to compounding pharmacies, state tax on drug revenues, hospital ± DSH/340B vs. private practice, ratio of retina specialists to beneficiaries, penetration of HMOs, and awareness of costs and benefits.
Expected CMS expenditures in 2010 assuming a total number of injections of 1,270,836, and assuming 40% are Lucentis and 60% Avastin predicted a Lucentis cost of $813 million and an Avastin cost of $30.5 million. The estimated savings to CMS over the past 5 years from the use of Avastin is about $6 Billion.
The future of Avastin and Lucentis in the U.S. depends on understanding why docs use Avastin and forgo financial incentives, restoring $50 Avastin payment to hospitals, removing incentives that promote the use of the most costly alternatives (6% of ASP, the Lucentis rebate, the DSH discount for hospitals), and the impact of the CATT Trial.
The Future of Anti-VEGF Therapy depends on making it easier to use Avastin by lifting the restrictions on sales to pharmacies. The only FDA-approved drug with purchasing restrictions not due to limited supply or safety concerns is Avastin.
Dr. Zarbin stated that he had a concern with the repackaging. Dr. Rosenfeld explained that while preparing the drug is crucial and must be done according to the USP guidelines, it must also be shipped appropriately. He noted that his pharmacy has prepared thousands of doses with no contamination. If not stored properly, denaturation occurs and aggregates develop that produce inflammation. Dr. Rosenfeld stated Dr. Martin will address this point during his talk.
Dr. Cophenhagen noted that these are important studies, but as a biologist, one antigen is not the magic bullet. He stated that there should be a search for other antiangiogenic compounds. He referred to a study of healthy vessels that showed that after therapy stopped, there was a rebound. Those things have to be considered. He asked, “is anyone looking at these effects on the vascular system in the eye itself, and on the rebound effects?” The speaker noted that this question was on everyone’s radar.
COMPARISON OF AMD TREATMENT TRIALS (CATT)
Dr. Daniel Martin presented a report on the Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin Trial supported by Cooperative Agreements from the National Eye Institute. The Objectives of CATT were to determine the relative efficacy and safety of intravitreal Lucentis and Avastin for treatment of neovascular AMD, and to determine if less than monthly dosing of either drug compromises long term visual outcomes.
Policy Changes Associated with CATT were revised Medicare Clinical Trial Policy enacted July 9, 2007 allowed coverage of Lucentis in CATT, AMD Demonstration Project developed with CMS Staff to facilitate payment and masking of study drugs that was approved by CMS but not by OGC, the commitment of NEI funds to cover drug co-pay when no supplemental insurance available and thus ho out-of-pocket drug expense for patients, and the Medicare Act of July 2008 that allows CMS to create alternative payment mechanisms in support of NIH sponsored clinical trials.
Dr. Martin presented data on visual acuity results, anatomical results using OCT, and adverse events.
In Summary, Lucentis and Avastin were equivalent (virtually identical) for visual acuity at all time points when administered at the same dosing regimen. PRN dosing with monthly evaluation produced average gain that was 2 letters less than monthly dosing but overall results still excellent (equivalent for Lucentis, inconclusive for Avastin). PRN dosing resulted in 4-5 fewer injections over 1 year than monthly dosing. Avastin patients received mean 0.8 more injections than Lucentis. Both drugs produced an immediate and substantial decrease in fluid. Neither drug eliminated fluid in the majority of eyes although more eyes were completely dry with Lucentis monthly. There was no drug difference in leakage on FA but more leakage observed in both PRN groups. No lesion growth was detected with monthly treatment of either drug; but some growth detected with PRN over 1 year. No difference in death, stroke, MI, or HTN between drugs at 1 year was observed. Non-specific SAE differences require additional study.
Questions for future consideration are: Do visual acuity findings at one year remain through year 2?; Do the anatomical differences noted in year 1 alter long term visual outcomes?; What is the effect of PRN dosing after one year of monthly dosing?: Will SD OCT result in more fluid detection and subsequent injections?: Are there genetic findings that predict outcomes, durability of response, or number of injections required?
Dr. Sieving thanked Dr. Martin for the presentation and noted that this was a question that came out of considerations for efficacy and delivery, and originally, it was devoid of economic considerations which have now taken an interesting turn.
OFFICE OF SCIENCE COMMUNICATION, PUBLIC LIAISON AND EDUCATION
Dr. Deborah Carper spoke about the NEI’s Office of Science Communications, Public Liaison and Education (OSCPLE).” She is the acting associate director of this office. The mission statement is to effectively communicate with a variety of audiences about NEI-supported vision research and NEI goals, policies, programs and accomplishments. She discussed the organizational structure of the office and the various products and programs of each of the two branches.
With regard to the Public Liaison and Education Branch, Dr. Carper detailed enhancements to the NEI website and a children’s website “All You Can See.” She noted that OSCPLE responds to more than 800 public inquiries each month, providing health information and referrals. It distributes nearly 35,000 publications each month in both English and Spanish. This Branch also serves as a conduit for employee communications through the NEI Intranet, the Brown Bag Speaker Series and Eye Contact (Employee Newsletter).
Under Rosemary Janiszewski, Chief, this branch runs the National Eye Health Education Program (NEHEP) a partnership of 65 organizations with the goal to ensure that vision is a health priority by translating eye and vision research into public and professional education programs. NEHEP supports collaboration among eye health professionals, healthcare providers, patients, and the public. It leverages its resources through publications, web resources, radio & print PSAs, social media, posters and magnets, fact sheets, and teaching toolkits. NEHEP also sponsors the Healthy Vision Community Awards Program, and a recent Times Square Public Service Announcement.
The Science Communications Branch under acting chief Tom Hoglund is responsible for science reporting, the development of a new science website and media relations. They prepare articles and white papers on translational research, comparative effectiveness research, and other topics. They are responsible for science advances and international activities web pages. Media Relations including statements, press releases, and videos are also the responsibility of this branch as well as media training for NEI Staff serving as spokespersons.
STATUS OF PROGRAM PLANNING
Dr. Richard Fisher provided an update on the current status of program planning currently which has been discussed at Council meetings over the past year. Six panels were convened in accordance with the NEI’s traditional programs of retina, cornea, lens and cataract, glaucoma, low vision, and strabismus, amblyopia, and visual processing (SAVP). Last December the co-chairs and program directors participated in panel selection. The six panels met at ARVO this year. A rough draft of the plan is going out the panel members and the end of June is the estimated date for the final draft. Once the draft is formatted, it will be sent to Council members around mid-July with a two to three week turn around time. He informed Council that this was an accelerated timeframe to meet a publication deadline on the web and in print form. He would schedule a phone conference to discuss comments. He noted that when Council receives a draft it is not just to be rubber stamped. It is to a second detached look apart from the NEI-convened panel members. The RFI went out to all of the vision research community. ARVO responded with a fairly extensive list of opportunities and the panel members were given this information to consider as they put things in order. This is a compilation of over a year and a half of work.
Dr. Copenhagen mentioned the Lasker/IRRF Initiative for Innovation in Vision Science meeting on Astrocytes and Glaucomatous Neurodegeneration and asked if this had any role as a model of program planning. Dr. Sieving replied that it was an interesting approach to disease research but did not fit as a model of program planning. Dr. Copenhagen stated that as a new way to look at a topic, did this meeting have an impact on new grants or as a way for NEI to think about glaucoma. Dr. Fisher stated the NEI was the first institute at NIH to do a strategic plan and there are many ways to approach this. There’s no single right way to do this. People in glaucoma were familiar with the workshop and it was interesting how they involved a number of different approaches.
A Council member asked Dr. Fisher about his conception of the pain workshop that was held last year? Dr. Fisher replied that he planned on having workshops on a yearly basis, last year was ocular pain sensitivity, to find gap areas in research where it may or may not be an area where there is a lot of funding. It was interesting we had people from all over and the workshop went really well. It was the first time many were talking with each other. As a result, we hope to be stimulating research, getting people outside the vision field to get interested in the research. There was an increase in applications. Pfizer saw the pain research we put on the web. We hope to get more interested in research outside the field.
Dr. Chodosh stated that we appreciated Dr. Sieving’s interest in the pain Workshop as the epidemiology of dry eye is different from other areas. He stated at lots of scientists were interested in this workshop and interest in the area has perked up.
CLOSED SESSION OF THE MEETING – 2:30 pm
The meeting was closed to the public at 2:30 pm in accordance with the determination that it was concerned with matters exempt from mandatory disclosure under Sections 552b(c)(4) and 552b(c)(6), Title 5, U.S. Code and Section 10(d) of the Federal Advisory Committee Act, as amended (5 U.S.C. Appendix2).
CONFIDENTIALITY / AVOIDANCE OF CONFLICT OF INTEREST
Dr. Andrew Mariani, Executive Secretary of the Council, reviewed policies and procedures regarding confidentiality and the avoidance of conflict of interest situations. To avoid conflict of interest, members of federal advisory committees must not participate in the discussion of any application or proposal in which they, their spouse, minor child, close professional associate, or organization has a financial interest or affiliation. The Council members signed a statement certifying that they were absent during such discussions.
Council members absented themselves from the meeting during discussion of and voting on applications from their own institutions, or other applications in which there was a potential conflict of interest, real or apparent. Members signed a statement to this effect.
REVIEW OF RESEARCH, RESEARCH TRAINING, AND COOPERATIVE AGREEMENT APPLICATIONS
The meeting was adjourned at 4:30 pm
I hereby certify that, to the best of my knowledge, the foregoing minutes and attachment(s) are accurate and complete.
Andrew P. Mariani, Ph.D.
National Advisory Eye Council
Division of Extramural Research
National Eye Institute
Paul A. Sieving, M.D., Ph.D.
National Advisory Eye Council
National Eye Institute
These minutes were submitted for the approval of the Council; all corrections or notations were incorporated. A complete, printed copy of the Council minutes, including attachments, may be obtained from:
Ms. Janet L. Craigie
National Eye Institute
5635 Fishers Lane, MSC 9300
Bethesda, MD 20892-9300
Telephone: (301) 451-2020
FAX: (301) 402-0528