THE PANELISTS' BACKGROUNDS
Lewis: The focus of today's discussion is on innovation,particularly in the field of glaucoma. Many of you have
gone through the process of innovation, started companies,
and spun off companies. Some succeeded. Some
failed. I think all of you have worthwhile experiences to
share with Glaucoma Today's readership. Let's begin with
a brief description of your backgrounds.
Humayun: I am a retina specialist and a biomedical engineer. My colleagues and I have been developing bioelectronic implants, recently including a miniature drug pump that is programmable and refillable in the clinic after its implantation in the OR.
Brown: I have a long interest in new technology and devices for glaucoma surgery and have worked on a number of new devices.
Johnson: My main interests have been the evaluation of noninvasive diagnostic techniques and establishing reading centers for visual fields, optical coherence tomography (OCT), and other modalities. I hold several patents, but they have all died on the vine.
Shields: I only have one patent, which is for a suprachoroidal drainage device. My colleagues and I started a company that was bought by a larger company (Opko Health, Miami, FL). The device is currently in clinical trials.
Latina: My background is in the development of laser applications for ophthalmology. I developed the first gonioscopic ab interno laser sclerostomy and, later, selective laser trabeculoplasty (SLT). Now, my colleagues and I are working on the selective targeting of the retinal pigment epithelium for the treatment of macular degeneration and drug delivery. I hold several patents.
THE BEST AND WORST IDEAS
Lewis: What have been the best and the worst ideas in
glaucoma in the past decade?
Latina: I think one of the worst ideas in glaucoma that made it to the market was the pneumatic trabeculoplasty. The technology received a lot of hype but never really became anything. I do not think it had much clinical or basic science behind it. A lot of good ideas have occurred. I think SLT is one of them, because it changed the way we approach glaucoma. With SLT, we are more likely to use laser therapy earlier, which helps with compliance.
Shields: The glaucoma graveyard is overflowing with great ideas that never made it. A look through the literature of the past 50 years would show thousands of methods of treatment that people claimed worked, but of course, the vast majority never did. We have been doing basically the same operations for glaucoma for over a century. I would say one important advance is the modulation of wound healing. Another is microscopic surgery, the guarded sclerectomy or trabeculectomy. Anthony Molteno, MD, deserves credit for the concept of the plate with the drainage tube. Unfortunately, nothing has come along yet to replace subconjunctival drainage or tubes.
Johnson: I am a big fan of Thomas Kuhn's view of paradigm shifts in science. He says it takes a while before people will accept new ideas.1 I view glaucoma from the standpoint of treatment and of diagnostics. I do not think we really understand what glaucoma is. I think we need a paradigm shift, a new look at glaucoma's underlying mechanisms, the treatment modalities, and the diagnostic techniques.
Brown: I take a more charitable view of the mistakes, because you can learn from them. One of the problems in glaucoma is we do not understand why something does or does not work.
Lewis: What would you say has been the best idea of the last decade?
Brown: I have mixed feelings about wound modulation. It has been responsible for increased success but also a lot of headaches.
Shields: It is definitely a double-edged sword.
Humayun: As an outsider, I consider the biggest improvement in the field of glaucoma during the past 10 years to be the prostaglandin analogues. There is a gap, however, in terms of devices. One of the worst was the home tonometer. A false measurement could negatively influence patients' adherence to prescribed medical therapy. I think what is needed is a better way to monitor IOP, a better way to deal with compliance, and a better method for getting drugs into the eye.
Lewis: I have always felt that one of the biggest handicaps in glaucoma is the inadequate way we make the diagnosis. For at least 50 years, we have depended on an open versus a closed angle. A genotypical type of diagnosis would probably enable us to direct therapy more specifically. Now, so much depends on pressure. The inadequacy in diagnosis really hurts us in terms of innovation.
Brown: The retinal field seems to offer more opportunity for innovation than does glaucoma. Dr. Humayun, what is the difference?
Humayun: Both subspecialities involve chronic disease and neurological conditions dealing with the retina and the ganglion cells. Retina seems to be a more surgical field, whereas surgery appears to be a last resort in glaucoma after drops and laser therapy. Another difference is basic science. There is a lot more tissue to work with in retina than in glaucoma. It is very hard to perform experiments in the latter because of the small amount of trabecular tissue.
UNMET CLINICAL NEEDS
Continuous IOP Monitoring
Brown: What are the major unmet clinical needs in
glaucoma?
Johnson: Continuous IOP monitoring is one.
Brown: Why is that so important?
Humayun: We need to get a handle on the fluctuations in IOP that are occurring.
Brown: I agree that monitoring could reveal helpful information such as IOP spikes in some patients. If we could effectively and safely reduce IOP, however, then monitoring would be much less important. The need to monitor something is inversely proportional to our ability to control it.
Shields: In terms of glaucoma pharmacology, I think we need to look more at drugs that enhance trabecular outflow. Most of our drugs either reduce inflow (aqueous suppressants) or affect uveoscleral outflow. Another area of needed research is ocular blood flow. Also, we need new noninvasive methods of analyzing the metabolism of the optic nerve. With the last two, we could approach the paradigm shift that Dr. Johnson mentioned. We would not just lower the IOP. We would better understand why people lose retinal ganglion axons and could better diagnose the problem.
Latina: One unmet clinical need that I think is important is to understand how to prevent the nerve from continuing to lose ganglion cells or dying. In normaltension glaucoma, lowering the IOP does not always solve the problem. A better understanding of the disease's pathophysiology would permit the development of new approaches to treatment.
Johnson: Dr. Shields raised a good point. We look at structure and function from a clinical or from a basic science standpoint as separate issues. Ocular blood flow, IOP, risk factors—the tendency is to look at each one separately. They go together. A paradigm shift would be to consider them in an integrated fashion.
Drug Delivery
Shields: Dr. Humayun, tell us a little bit about the drug delivery system you are working on.
Humayun: The small pump implanted is much like a glaucoma drainage device with a tube extending into the anterior chamber. You fill the pump once and set the dosage and the time of its delivery. A sophisticated drugmetering system checks everything to the ±2% of drugdose accuracy. Three to 4 months after implantation, the device can be refilled transconjunctivally at the clinic through a customized refilling kit. The battery can be recharged in 10 to 20 minutes.
I began this work because of all of the injections retina specialists make into the vitreous cavity for macular degeneration, but I have received a lot of interest in the device from the glaucoma community. An issue in commercializing any device is cost. The fact that glaucoma medications are available as generics or will be going off patent in the near future has to be taken into consideration when commercializing the drug pump.
Shields: Most companies are not terribly interested in glaucoma devices, because the number of tubes being implanted is not very high. The total glaucoma population, however, is huge. I think we do not intervene surgically more often because we do not have good surgery. We push the medicines further and use them more because we do not like trabeculectomies and tubes. An implantable device that releases medicine to lower the IOP so the patient will not have to comply might be different.
Shields: Most companies are not terribly interested in glaucoma devices, because the number of tubes being implanted is not very high. The total glaucoma population, however, is huge. I think we do not intervene surgically more often because we do not have good surgery. We push the medicines further and use them more because we do not like trabeculectomies and tubes. An implantable device that releases medicine to lower the IOP so the patient will not have to comply might be different.
Brown: Why not make it a drainage device and see how that works, or maybe it would do both? Placing a device in the eye carries a different set of risks than instilling a topical medication.
Thirty years later, the Molteno Implant (Molteno Ophthalmic Limited, Dunedin, New Zealand) is almost identical to when it was introduced. I hold some patents in the area of glaucoma devices, and I have shown to the manufacturers of tube shunts ideas that I think would enhance the devices' operation. The companies do not seem to care. Maybe they do not think the market can increase. Since the results of the Tube Versus Trabeculectomy (TVT) Study, however, I have felt that the opportunity to expand the market has never been greater.2
Humayun: It would be easy to have the drug pump I described also act as a sophisticated, controlled drainage device, but it could deliver a drug in a closedloop fashion such that, when the IOP exceeds a certain level, the device delivers the drug. The question becomes, why would a third-party payer pay for a novel drug delivery device? We would have to demonstrate improved compliance and a better effect with this technology.
Because the microcontroller is very sophisticated and can last for more than 5 to 10 years in the eye, it can perform multiple functions such as record the amount of drug delivered, the time it was dispensed, and the IOP at the time the drug was administered.
Shields: Have you looked at using that pressure sensor as a telemetric way of monitoring pressure all the time as well?
Humayun: The device has a flash memory, so it could record diurnal IOP information. The data could be retrieved at the clinic using a wireless coil my colleagues and I have already developed. The patient would wear a special pair of glasses that would download the data while simultaneously repowering the implant. During that time, the patient could watch an educational video.
The Measurement of Progression
Johnson: A critical issue in glaucoma management is
variability in the rate of disease progression. Deciding
whether to observe or treat a patient and, in the latter
case, how to intervene requires the physician to know
whether the rate of glaucomatous damage is slow or
fast. We have some visual field information such as a
visual progression index or visual field index now, but
we really need a huge number of measurements. It is
not feasible to the patient for the physician to say, “I
have your baseline data, and in 5 or 6 years, I will be
able to tell how you are doing.”
Brown: What technology do you think is the most promising?
Johnson: It has to be something practical. My colleagues and I have spent a lot of time studying multifocal visual evoked potential, but that technology is too difficult and time consuming. We do not know enough about determining the rate of progression with advanced imaging technology, because it has not been around long enough. I am interested in the multicenter trials by Harry Quigley, MD, and some others and whether a meta-analysis will point to some areas for future research.3,4
Brown: I think these points are of academic interest, but as a clinician, I feel like I know which of my patients have worsening glaucoma.
Shields: Rather than look at progression as a way of determining if treatment is adequate, we should have a noninvasive way of looking at the optic nerve, either through metabolic measures or blood flow measurements. Then, I will not have to wait until a patient loses more field of vision to identify progression.
Humayun: My colleagues and I have been working with the Jet Propulsion laboratory for the last 5 years on a camera that looks at 57 spectral bands in under 3 milliseconds. We have successfully studied and recorded the different levels of oxygen saturation in retinal blood vessels as well as the optic nerve. We have created two prototypes, but the technology's development has been slowed. Companies do not see why anyone would pay for this technology. There is no CPT code. Nobody has paved the way for metabolic imaging of the optic nerve or retina. There are no large studies showing if it works, when you would use the technology, what it would replace or add to. My hope, however, is that we will be able to commercialize this soon.
Latina: My colleagues and I tried to determine if ocular blood flow could be used to monitor disease progression using the Heidelberg retinal flowmeter (Heidelberg Engineering GmbH, Heidelberg, Germany). We performed several studies. The data were equivocal, however, and we found they were not reproducible and could not be used clinically. So, while many glaucoma specialists consider ocular blood flow to be an important risk factor for glaucomatous progression, we still do not have methodology or clinically useful technology to measure it and use blood flow information clinically.
Brown: The issue of CPT coding is important. The idea of coding for advanced imaging in glaucoma was very controversial, but the availability of a code spurred innovation in that area. I expect the same sort of thing to occur when one of the newer glaucoma devices achieves FDA approval. Until there is a code, a large number of surgeons will not use the device, because they will not be reimbursed. I think it is a major problem to require additional studies for a CPT code after a company has spent a huge amount of time and money to achieve FDA approval of a product.
THE PATENT PROCESS
Legal Aid
Johnson: The patent process is all consuming. You
must be totally devoted to the project and see it through
to the end. I found that consulting was a much more
pleasant experience than the patenting process, because
once you get a patent, you have to deal with companies.
Manufacturers have far more funding, and they will compete
with you and try to find a way around your patent.
Latina: I have gone through the patent process as an individual and as part of an institution. I would emphasize that the process involves dealing with a world that is very unfamiliar to physicians. The most important lesson I learned is to retain your own attorney. You may think everybody at the institution is your friend, but the stakes can be high, especially when a patent becomes valuable. Those you thought were your friends may not be any longer. You should also be aware that patents can become costly business ventures when lawsuits occur.
Johnson: I recommend a patent attorney with a biomedical background.
Assignment
Latina: Another important issue to understand is the
assignment of the patent. Once you assign the patent to
an institution or a company, you basically have no rights
unless they are clearly defined in a contract. An assignment
is like a deed in real estate.
Johnson: Once I had assigned the patent, I was shut out of the negotiations between the university and the company. The former refused what I thought was a very nice offer by the latter to buy the patent outright
Latina: An assignment is basically a change of ownership.
Corporate Involvement and Funding
Humayun: The freedom to operate is a big issue. You
may hold a patent, but another patent may block you
from commercializing the technology or drug. Alternatively,
your patent may be contested, which will lead to
a long and costly legal fight. These problems are often
too expensive, complicated, and time consuming for the
individual and even an academic institution. That is why I
prefer to have corporate involvement early in the process
of commercialization so that we in academia can focus
on the research.
Brown: Readers who have an idea might like our advice on how to develop it. After retaining a patent attorney, how do you approach a company? What's the next step?
Shields: After patenting a suprachoroidal drainage device, I had ideas about how the product could help humanity and how it should work from a medical standpoint. Venture capitalists and companies wanted to know what the market was.
Brown: Do you need to have consultants help you prepare for this sort of meeting?
Shields: You need people who know how to develop marketing.
Latina: Once you have a patent, how do you develop the product? Do you involve venture capitalists to start a new company, do you go to an existing company, or do you do it all yourself?
Shields: There were four of us. We were never able to get the venture capital. Finally, we raised enough “angel money” to start our company. We had a little over $1 million, with which we were able to complete most of the preclinical trials. That was sufficient to interest a midlevel company, which bought our company.
Latina: So, the third approach is the angel or private investor, which is an important source of funding.
Shields: As our group raised the money, I was approached by a company that was anxious to buy the patent. It became clear, however, that the patent was all they wanted. They did not want me. That is why I did not go in that direction.
Latina: A risk in dealing with companies is that they can buy a patent specifically to put it on the shelf and protect their own technology.
Licensure
Latina: When you have multiple inventors on a patent, each one has equal rights to the patent. Usually, a patent
is assigned to one individual or one entity to facilitate
licensing agreements.
Shields: There are pros and cons to licensing a patent to an established company. One of the advantages is that the company may have the infrastructure in place to conduct the preclinical trials. That can work well if you are very clear about what your role is going to be with the company in terms of orchestrating the research.
Royalties and Milestone Payments
Latina: Royalties are a part of the assignment and of
the licensing process. Usually, the legal phrase is in consideration
for something. A company may pay the owner of
the patent a royalty, which can be a percentage of the
gross sales, a single payment, or a combination thereof. If
an institution owns the patent and is the licensor, then
the institution may hold the royalty funds until it pays its
expenses and then finally distribute the income to the
inventor.
Brown: What are the various ways to be paid for your patent?
Latina: You can be paid as a single buyout, a royalty stream over the lifetime of the patent (usually based on gross sales), an upfront licensing fee, a milestone fee, and stock options. I think stock options are less likely to be advantageous to the owner of the patent.
Brown: What would the range of royalty payments be?
Latina: For devices, I think it is around 3% to 5% of the gross revenue, depending on whether you are the sole owner of the patent. If you are the individual or entity that owns the patent and is the licensor, then you would get 100% of the royalty payment. If you work within an institution, however, you may get 5% to 50% of that royalty payment, depending on the agreement with the institution.
For someone at an institution, it is very important that he or she understands the institutional rules pertaining to intellectual property, including what the inventor's involvement or royalty percentage may be.
Johnson: That is when having an attorney is useful.
Latina: Milestones are a key component of the licensing contract. For instance, the first milestone for a device would be to obtain FDA approval within a reasonable period of time (eg, 2-3 years).
Brown: Would the owner of the patent then receive a milestone payment?
Latina: Not necessarily. Milestones protect the patent holder and licensor from a licensee that might not be able to commercialize the patent. For example, if the licensee did not meet a milestone to obtain FDA approval for a product, the licensor could terminate the licensing agreement with the company and go elsewhere. Technically, if a milestone payment is made, the inventor should get some portion of that payment based on the royalty agreement.
Brown: The consensus is that, in general, we physicians are not well prepared for this type of negotiation. We need some outside help, or our best interest will not be served.
Also, how much leverage you have depends on the product and the investors' sense of its potential in the marketplace. Your ability to be paid cash upfront is going to be limited if there has not been a market for the product in the past. For example, there is not an established history of people's making large amounts of money from glaucoma devices as opposed to products for cataract surgery. In the glaucoma surgical arena, you are more likely to be offered stock in a company that may or may not exist in 5 years.
Latina: Right or delayed payment
Brown: It seems as if you had a stronger position with SLT, because the laser had already been well established as a treatment and you were improving on an established treatment.
Latina: One advantage of getting Medicare to pay for the procedure with SLT was that the company knew, if SLT were approved, it would be approved under an existing code, which would provide an immediate market.
The process of innovation is arduous. It usually takes between 5 and 10 years to develop a product from an idea to full commercialization. It has taken over 10 years to commercialize SLT from the idea to the clinical product. Once commercialization has occurred, the next hurdle is whether the market will accept it.
Johnson: Clearly, patience is required.
Brown: Don't give up. Continue to innovate. Never quit.
