Testing requirements, costs press supply and demand of corneal tissue

Corneal transplant tissue has approximately doubled in cost in the past decade. Changes in demand created by new transplant procedures such as Descemet’s membrane endothelial keratoplasty will likely further press supply issues as more surgeons attempt the challenging procedure, according to the surgeons and industry leaders involved in procuring, preparing and placing the tissue.

Some argue that the regulations for testing tissue for transmissible diseases are making it more difficult and more expensive to procure corneal tissue. Others counter that these regulations have been in place for 2 decades and that it is not just U.S. Food and Drug Administration regulations causing the price increase.

At stake is the supply of corneal tissue.

Increased costs

Patrick Gore, director of Business and Strategic Development for the Lions Eye Institute for Transplant and Research in Tampa., Fla., said that he has seen continual additions of regulations and oversight by the FDA.

“These regulatory changes have affected the donor tissue pool,” he said. “While on some levels we have seen an increase in donation, we have also seen an increase in tissue ruled out because of these additional regulatory changes.”

Many testing requirements have been in place for years, Gore said, but small changes in these requirements and exclusion of more tissue have an impact.

“It seems like every year there’s a new regulation that’s coming out that is aimed at increasing safety,” he said. “At the same time, [requirements are] increasing rule-outs, and requirements have led to an increase of tissue not being made available.”

For example, hepatitis B core antigen tests used on donors have not been evaluated for cadaveric blood specimens, but a positive test rules out corneal tissue.

“While I’m not a medical technologist, it raises a question of how accurate this test is,” Gore said. “We’ve seen this huge increase in rule-outs because of it.”

Monty Montoya, president and CEO of SightLife, agreed.

“When you factor in the uniqueness of the human cornea — it’s avascular, it doesn’t get its nutrients from blood — we end up falling in under this blanket of regulations that requires us to do certain things to ensure safety that probably technically don’t apply to the cornea,” he said.

Montoya said that the biggest impact that the FDA regulations have on corneal donation is upward pressure on cost, downward pressure on the available supply for needy recipients and negligible impact on safety of tissue.

Not only is the testing extensive, but documentation of that compliance is costly as well.

“That regulatory function within an eye bank, it’s really become a full-time position or more in every eye bank,” Montoya said.

Although corneas may have a degree of protection due to their avascularity, each cell in the human body has receptors for viruses and bacteria and can transmit communicable disease, 
Samuel B. Barone, MD, medical officer of the FDA’s Office of Cellular, Tissue and Gene Therapies, said.

For example, Barone said, “Human corneas have transmitted hepatitis B virus, human spongiform encephalopathy/Creutzfeldt-Jakob disease and rabies. HIV has been identified in donor cornea tissue, and there is evidence in an animal model that that cornea tissue can transmit Treponema pallidum, the agent of syphilis.”

It has recently been demonstrated that Chikungunya virus can be present in donor corneal tissue.

“While the exact risk for infectious disease transmission from donor to recipient is unknown and it is also unknown whether testing is the best way to address such risk, these findings serve as a reminder that corneal tissue does have the ability to transmit infectious diseases,” Barone said. “FDA encourages more collaborative research between government, industry and the allograft transplant provider community to help to address the gaps in scientific knowledge to enhance the safety of the transplantation of all tissues.”

The Centers for Disease Control and Prevention reported in the early 1990s that HIV had been transmitted through transplantation of human tissue. Hepatitis B and C became urgent concerns, and in December 1993, the FDA published a rule on communicable disease testing, donor screening and record-keeping for human transplantation tissue, Barone said.

“Infectious disease testing of donors of all tissues along with donor screening for risk factors for and clinical evidence of communicable disease are appropriate measures to identify potentially infected donors,” Barone said. “In most cases, a donor who tests reactive for a particular disease or who possesses clinical evidence of or risk factors for such a disease would be considered ineligible, and cells and tissues from that donor would not ordinarily be used.”

Safety first

Thomas John, MD, OSN Cornea/External Disease Board Member, said that he has not seen a shortage of corneal tissue in his clinical practice, although the costs have probably doubled in the past 10 years. Despite the higher costs, increased regulations are needed for safety, he said.

“Even though these tests are more applicable to vascularized tissue, you need all those tests for avascular tissue until proven otherwise,” John said. “It’s an added layer of protection for the recipient. One or more potentially lethal disease transmissions via the donor corneal conduit may be a significant price to pay.”

John said that the FDA rules for corneal transplantation and the Eye Bank Association of America’s testing requirements for the most part have been in place for decades. Therefore, he asked, if the cost of corneal tissue is rising, is it from these tests or from other costs, including the application of new technologies in the presurgical site including the eye banks?

Another corneal transplant surgeon, Francis W. Price Jr., MD, OSN Cornea/External Disease Board Member, agreed that safe corneal tissue is needed. But the regulatory pendulum has swung toward being too risk-averse.

“The FDA has some indirect effects on corneal transplants,” Price said. “And that has to do with the mindset you shouldn’t have any risk. There should be nothing that goes wrong, and everything you do should be perfect.”

This mentality requires surgeons to try to prevent adverse events that rarely happen, he said.

“The cost of doing things increases exponentially if you try to eliminate every complication — not just the more common ones, but the very infrequent complications which seldom or rarely are an issue,” he said.

Supply chain steady, so far

While there are many requirements that corneal tissue must meet, the supply of tissue has remained steady. Part of this is because eye banks and other organizations have increased overall donations, even though 5% or more of tissue is discarded for failing a serology screening test, Montoya said.

More than likely, a lot of the discards are false positives, but confirmatory retesting is not allowed, he added.

“There are specific concerns around musculoskeletal transplantation that relate to hepatitis B core, but those really are not relevant to the cornea. Because of that one-size-fits-all paradigm, the regulatory structure that the FDA works under doesn’t allow the FDA to say this doesn’t apply to eye donations,” Montoya said.

“Some of the people that we work with directly in the FDA, they’re great people. They really are wonderful public servants. They are trying to do the best that they can,” he said. “But the structure and the mandates that they operate under really sort of force them to go a certain way that adds to the cost and drives the volume or supply for needy recipients down, and I don’t think there’s been any demonstrated improvement in the safety of the tissue since the FDA got involved.”

Economic factors have the supply-and-demand cycle in a holding pattern, Price said, noting that cornea transplant surgery rates have not recovered from the economic recession. The cost of $3,000 per cornea is a big barrier for some patients, depending upon their insurance coverage.

“We don’t have a shortage right now, but as soon as the economy picks up, we’re going to see a significant shortage,” he said.

“It’s not long before rules are instituted that cost-benefit ratios should be evaluated,” Price said. “We shouldn’t check for diseases unless we know that they’re transmitted or possibly transmitted through corneal tissues.”

Price said that he comes from the perspective of being an early advocate of screening donors for AIDS. But in the face of outbreaks such as West Nile virus, such testing could be required even if it is not yet proven that corneal tissue can transmit certain viruses.

Barone noted that the FDA has issued draft guidance recommending tissue donor testing for West Nile virus and Trypanosoma cruzi, the agent of Chagas disease. The draft guidance statement recommends a change in donor screening or testing and allows a period of public comment before the document is finalized.

“We have to protect the quality of our donor supply. We also have to do it realistically,” Price said.

“But in the face of outbreaks such as West Nile virus, such testing should only be required if there is both knowledge that the tissue can transmit the disease and that the donor is at significant risk of catching the disease,” he said. “West Nile virus is a disease that spreads very rapidly in birds across the country. I personally would like to see data on what the incidence of positive tests for this disease is in the general population, especially in locations with increased infection rates. It may be that most of us have already been bitten by a mosquito and have a positive titer. And of course, there is a difference between someone dying of an active disease where the tissue should never be used and someone who has had an infection in the past and should not pose a risk of infection to others.”

New technologies

New procedures such as DMEK have led to an increase in endothelial tissues with cell counts higher than 2,800 cells/mm², Gore said. He is part of an effort to prove the utility of a pre-loaded injector that will increase the consistency of the tissue that the surgeon receives.

John said pre-cut corneal tissues can be used for procedures such as Descemet’s stripping endothelial keratoplasty. Pre-cut tissues add about $1,000 to $1,500 to the cost of the procedure, but they save time for surgeons, which could ultimately drive down costs for surgeons and patients. Additionally, such an intrinsic system would absorb the cost of any potential tissue wastage during such corneal tissue processing.

John proposed using one tissue donation for as many as three recipients, a concept that is used in other countries but not in the United States.

DMEK requires only 15 µm of tissue, namely, corneal endothelium and Descemet’s membrane, John said. That leaves behind stem cells for stem cell transplantation and corneal stroma for anterior lamellar keratoplasty.

“You have the same number of corneas but are meeting a higher number of transplantations with the same amount of tissue, a bigger bang for the donor cornea,” John said.

The issue will become more important as DMEK becomes less technically challenging and more surgeons begin to perform it, consequently leaving behind more potentially usable tissue, John said.

Price also advocated for pushing the envelope of new standards of care.

“We’ve gotten to the point where we don’t want any risk. And if you’re doing new things, there’s always risk, whether it’s medication, devices or shuttle flights. If people want to have new technology, at some point they’re going to have to accept that there’s risk and there’s going to be things that don’t always work the way you want it,” Price said.

“I’m not saying that with a cavalier attitude at all,” he said. “We should strive not to have any problems and make things as safe as possible. But you have to realize that if you’re doing things that people have not done before, then very often you haven’t learned all the things that you need to know about and there are going to be some procedures without perfect outcomes.”

But mistakes can create other problems, Montoya said.

“Some opportunistic senator is going to say, ‘This is my opportunity to get a little PR. This might help my campaign about how I’m going to be the champion of safe tissues,’” he said. – by Ryan DuBosar

How will emerging technologies affect the availability and costs of corneal tissue transplants?

New technologies will affect corneal transplants

The cost of corneal transplant tissue has been going up. To my memory, it has basically doubled in price over the past 20 years.

There has been a recent jump in cost due to two somewhat different phenomena. With regard to DSAEK and DMEK, increased cost is due to the substantial technical issues of tissue preparation at the eye bank. Significant rates of donor waste can occur. For DSAEK and DMEK lamellar tissue prepared by the surgeon, there is also increased cost in the context of time spent and wasted tissue when preparation of donor tissue fails. That is a charge to the surgery center that is not covered, and it is substantial, about $4,000, which is a very expensive failure. Furthermore, the patient who needs the transplant has to be rescheduled.

As far as femtosecond laser incision corneal grafts are concerned, again money is an issue. Femtosecond laser incisions have proven conclusively superior to trephine incisions, but there are two added costs. One is for the laser itself; there are costs of running and maintaining the laser and the per-use cost. The second is the cost in time. Doing the incisions at a laser center is a completely separate surgery, and that eats up a substantial amount of time.

In terms of reimbursement, we have viewed it as a research project, accepting that, for now, we are not getting reimbursed. In the United States, you are not going to receive more reimbursement from Medicare or insurance carriers for alternative means of performing covered services. Some surgeons regard the femtosecond laser incision portion of the procedure as a refractive component. Because one of the main advantages is optical, a significant number of centers bill this as a patient-shared cost, similar to billing for a premium IOL.

We are actively working on a technique for the femtosecond laser to prepare ultra-thin DSEK grafts. If we can prove that we have a reliable way of preparing the donor, that will have a major impact on how we perform these procedures. And it will be cost-effective because the procedure is done in a central location with a high degree of reliability.

Roger F. Steinert, MD, is an OSN Cornea/External Disease Board Member. Disclosure: Steinert is a consultant for Abbott Medical Optics.

Environment changing for eye banks

The environment is changing for eye banks, and it is going to continue to change at an accelerating pace. For a long time, the external environment was static. Now, more than in the past, developments in technology, in expectations, and certainly in the effect that government can have through the FDA through reimbursement rates and through CMS are causing uncertainty.

Eye banks depend upon their reimbursement fees for the majority of their organizational revenue. Increases in regulation result in increases in cost. Eye banks do not have the flexibility to recoup increased expenses indefinitely and continue to be financially viable. Eye banks are at risk of being caught in a squeeze between lower reimbursement and increased costs from regulations, and they are going to get caught in the middle. The Eye Bank Association of America is trying to guide our members through those changes by addressing regulatory needs for a safe tissue supply while enabling them to continue to serve their members and the country as a whole.

One thing we are doing at EBAA is being more actively engaged in working with government agencies to try to provide a better understanding of the issues and forces that are affecting eye banking. There is a need for regulation, and we want to educate them on the impact of all the regulations that we currently have and might be proposed in the future.

There are a number of eye banks that are very innovative, which enables them to be successful financially. We placed more tissue last year than we ever have in the history of the profession, and we expect those numbers to continue to rise.

Kevin P. Corcoran, CAE, is president and CEO of the Eye Bank Association of America.