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CAP Home > CAP Reference Resources and Publications > CAP TODAY > CAP Today Archive 2003 > Cache register - the risky business of tissue banking
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Cache register - the risky business of tissue banking

May 2003
Anne Paxton

It could have been another CLIA.

Only two years ago, a familiar stage was set, and U.S. tissue banks that collect and distribute tissue for transplantation appeared prime for stepped-up scrutiny by the Food and Drug Administration.

Anxiety was high about the possibility of transmitted infections. Then a newspaper exposé cued outrage about profits made on body parts. Senate hearings followed. Pressure was building to hurry up stricter regulatory proposals that had languished at the FDA.

On May 24, 2001, Senator Susan Collins (R-Me.) had convened a hearing on the FDA’s regulation of the industry, and key media, including “60 Minutes,” attended. William Minogue, MD, then chairman of the board of the Washington Regional Transplant Consortium, recalls that a media sensation seemed to be in the making.

But events in another Senate office intervened. Dr. Minogue had just completed testifying before the Senate subcommittee on investigations about the problems that new federal regulation in tissue banking could address. “We finished at noon. But in the same hour Senator Jim Jeffords from Vermont reported he was no longer a Republican.”

Tipping the Senate majority to the Democratic side, Jeffords threw the committee chairmanships into a cocked hat. “And Senator Collins was no longer chair of that committee. So it was high noon, and we got swamped by the events of the hour.”

The turn of events in 2001 may have temporarily stalled new regulation.
But the marketing of innovative biomedical products made with human tissue has never flagged—and new incidents have renewed concern for better standards.

A few months after the 2001 hearing, a Minnesota man’s death was attributed to contaminated cartilage provided by Georgia-based CryoLife Inc. Twenty-five other cases of bacterial infection from CryoLife products then emerged. AlloSource Inc., based in Colorado, got a warning after one patient who received AlloSource tissue contracted a severe E. coli infection.

Last fall, a Portland man acquired hepatitis C after a transplant from a midwest tissue bank that sent tainted tissue to at least 40 other people (attributed to the window period). In February of this year, Canada closed the British Columbia Ear Bank because of spotty record keeping and uncertain screening and sterilization practices.

Unlike organs, tissue intended for transplant can be processed into about 400 different forms for use in orthopedic, neurologic, plastic, cardiovascular, and oral reconstructive surgery. Since 2001, tissue banking has doubled to become a billion-dollar industry, but questions have been rife: How much commercialization should attend human tissue donated for free? Even though one U.S. tissue bank has been forced to partially suspend operations and recall products, why are there still no federal laws about how old or healthy a donor must be? Or even how long after death the tissues can be collected?

Three FDA rules have been in the works over the past decade that would cover registration, good tissue practices, and donor suitability. The first of these, which took effect in April 2002, requires tissue banks to register and list their products. It covers skin, tendons, bone, heart valves, and corneas, as well as manipulated human cells to treat viral infections, Parkinson’s disease, and diabetes, and reproductive tissues and stem cells from umbilical cords.

But some of the registration rule’s deadlines have been extended to coincide with the good tissue manufacturing rule, which is reportedly still far from final. A donor suitability rule also awaits final approval.

Senator Collins, who once again chairs a subcommittee on investigations, is planning another hearing this month. Her concern, says P. Robert Rigney, chief executive officer of the American Association of Tissue Banks (AATB), is that while progress has been made, the good tissue practices regulation has yet to be implemented.

Until that happens, tissue banks not accredited by the AATB or licensed
in the two states that regulate—New York and Florida—are subject only to FDA’s current authority over donor testing, record keeping, tracking, or the recall or destruction of tissue. The new regulations would give the FDA more specific authority over tissue processing and strengthen the donor suitability rules.

Members of the AATB focus on musculoskeletal tissue, says CEO Rigney. “What our banks typically provide are bones, tendons, skin, primarily for burn and trauma victims, and cardiovascular tissues—mainly heart valves and also veins.”

About 150 tissue banks operate in the U.S., Rigney estimates, but the FDA will register far more when the registration deadline hits because it counts them differently. “What they’ve done is require everyone involved with tissue to register with them—a tissue bank has to register each one of its sites or facilities, and if you’ve got retrieval teams, or representatives with different hospitals in the field that merely cover a broad territory, each one also has to register.”

Tissue banks have actually been regulated since 1992, he says. After HIV was transmitted through organ transplants in the 1980s, the FDA adopted a “tissue action plan.” “I’ve read statements, including in the New York Times, that say they’re not regulated, and that’s totally false,” Rigney says.

“The FDA has authority under current regulations to inspect tissue banks at any time, announced or unannounced, to look at their standard operating procedures, their testing criteria, donor screening, and they have authority to apply sanctions including everything from seizing tissues to shutting the place down. Just ask CryoLife.”

CryoLife, based in Atlanta, is one of the 90 or so tissue banks that have never applied for AATB accreditation. In a report to Congress in 2000, deputy HHS inspector general George F. Grob testified: “These banks are under no obligation to meet the standards or policies set by the [AATB], and for many banks there is no incentive to seek accreditation.”

But CryoLife is also one of the nation’s leading tissue suppliers. It was forced to suspend part of its operations last fall and recall all soft tissue processed in the previous year, after the FDA found it had distributed infected tissue leading to complications and one fatality.

A probe by the Centers for Disease Control and Prevention uncovered 54 infections associated with soft tissue grafts, 26 of them involving CryoLife tissues. After negotiations with the company, the FDA allowed it to resume tissue distribution with extensive precautions and disclosures required.

Theodore Malinin, MD, professor of orthopedics and director of the University of Miami Tissue Bank, one of the first and largest institutional tissue banks, believes that the history of transplanting tissue, considering the number of tissues involved, has been remarkably good.

“There is always a potential, with whatever you do in transplantation, of transmitting something from recipient to donor. But there are a number of
adequate safeguards to prevent this if you choose to exercise them,” he says.

The CryoLife-infected transplant that resulted in the death of a recipient after elective surgery was obviously the kind of tragic occurrence that everyone seeks to avoid, Dr. Malinin says. CryoLife did not obtain and culture enough microbiological samples in this particular case, he says, and that was one of the problems that led the FDA to stop the company from producing further musculoskeletal tissues.

Despite this assertion of regulatory authority, he maintains that the FDA has limited powers at the moment. Moreover, the draft rules on the table have duplicated previous efforts in some ways, he says. “The FDA does have in place the so-called good manufacturing practices for devices, and if implemented in tissue processing, these would cover all these areas. The University of Miami tissue bank is subject to cGMP standards, since it produces dura mater allografts, which are classified by the FDA as a device. It is also registered as a device manufacturer.”

The proposed good tissue manufacturing standards are not identical to cGMPs and are different from AATB’s, he adds. “They’re much more stringent, and a number of tissue banks are not keen on having them in place because they require the same attention to procedures as in the device industry under cGMP standards.”

Pathologist Charles P. Garrison, MD, medical director and chief executive officer of Cell Dynamics LLC in Smyrna, Ga., operates one of the few tissue banks that is regulated by the FDA’s Center for Biologics Evaluation and Research. His company supplies kidney cells from donors to a pharmaceutical company that uses the cells to manufacture a clot-busting drug. Cell Dynamics supplies other cells for research as well.

Cell Dynamics has been classified as a biologicals manufacturer—making it subject to cGMP standards. “That means paperwork and more paperwork, and cross-checking and more cross-checking,” Dr. Garrison says.

Rigney of the AATB believes what’s holding up the good tissue practices regulation is the intricacy of applying such standards to all tissues. “The problem is there are serious issues that have to be dealt with, and the FDA has limited resources and limited staff,” he points out. “We in fact urged them to go ahead and publish the final rule on donor suitability so that gets out, but what Collins is concerned about is the good tissue practices.”


These standards are especially important because the available methods to decontaminate tissue are not flawless. Dr. Malinin notes that radiation sterilization has long been available but is by no means ideal since it can alter the biomechanical properties of tissues like tendons. “In addition, you may omit irradiating something thinking you have already done it. This has in fact happened with one tissue bank.”

Ethylene oxide, exposure to iodine solutions, or patented mixtures that usually include hydrogen peroxide are other means of sterilizing. “But whatever means you use, there is no such thing as foolproof,” he says.

Some tissue banks’ practices of selecting donors with malignancies and various additional pathologies “are ones I would not engage in myself,” Dr. Malinin adds. And the orthopedic surgery community has been poorly educated on this matter. “We sent a questionnaire to a number of hospitals where bone grafts were being used, and the majority of doctors did not know how they were acquired,” he says. A study presented at an American Academy of Orthopaedic Surgeons meeting, he reports, found that hospital personnel other than the surgeons were acquiring the grafts in response to advertising and promotional tactics.

Among the most controversial processing techniques is pooling of tissues like bone to make specialty pins, screws, and dowels for surgery. The AATB banned pooling in 1988 after some 40 deaths in Japan were linked to tissue processed in batches. But Regeneration Technologies, a for-profit spinoff of the University of Florida Tissue Bank, originally developed its BioCleanse process, which uses ultrasound, heat, and pressure to decontaminate tissues, using batch sterilization. Last summer the
company began to use a new version of BioCleanse that does single-donor sterilization.

Even thornier is the issue of commercialization, which dominated the newspaper articles that put tissue banking on the regulatory reform map—the 2000 “Body Brokers” series in the Orange County Register.

Under federal law, it is illegal to sell human tissues. But in practice, this mainly means that donors can’t get paid for donating. Many American organ procurement organizations sell skin, bone, heart valves, or tendons directly to for-profit companies that craft products from body parts—or to nonprofit tissue banks that do the selling for them.

For example, if a nonprofit organ procurement organization finds that a whole heart is unsuitable for transplant, it might be reimbursed for expenses by CryoLife; then CryoLife might use it to make thousands of dollars in
valve sales.

“Once it has been processed,” the OIG’s Grob noted at the Senate hearing, “tissue is treated more like a commodity than a donation. The packages in which human tissue is supplied—bottles, vials, containers shrink-wrapped in plastic—resemble many other medical supplies.”

A loophole in the National Organ Transplant Act has allowed commercialization to flourish. “Read the law,” Rigney advises. “It prohibits the sale of tissues but allows for reimbursement of certain costs. I can tell you every organ procurement agency in the country has financial relationships with for-profit companies.”


“What tissue banks are doing is retrieving tissue just the way blood banks retrieve blood—and it’s not cost-free.”

Even the rules pending at the FDA won’t address these issues. At the AATB annual meeting in September 2000, an FDA official told participants the agency was leaving concerns about the amount of money being made off donated body parts and the availability of tissue for emergency surgeries up to the industry and the HHS Office of the Inspector General.

“What is happening with commercial organizations’ involvement is there is a cost associated with processing these tissues,” Dr. Malinin notes. In general, the nonprofit organizations that do “full-service” processing themselves probably charge less than those that process tissues in a commercial setting. But “it’s very difficult to draw the line between appropriate and non-appropriate.”

For example, he says, for a long time CryoLife was the only tissue bank producing heart valves, which were life-saving and would not have been available otherwise.

“The majority of musculoskeletal transplantation is not performed for life-saving procedures but for quality of life,” Dr. Malinin adds. In cancer cases, for instance, in lieu of amputation, a resected tumor from an extremity can be replaced with an allograft leaving a reasonably functional limb. The University of Miami tissue bank specializes in osteoarticular and osseous allografts and has distributed more than 8,000 of them since its inception
in 1970.

“The majority of patients do not favor amputation, although it’s not a life-and-death issue. But if we were concerned only with curing the patient of the tumor, then amputation would be perfectly adequate.”

The same is true with failed metallic implants. “A great number of allografts are used for revision of failed hip and knee arthroplasty,” Dr. Malinin notes. “Again, these are not life-saving but quality-of-life-restoring procedures—unless you take the view, which is legitimate, that if you reduce people usually in advanced years to a sedentary life, then complications like veno-thrombosis would be much more prevalent.”

Some tissue bank directors contend that there are clear differences between commercial and noncommercial approaches to tissue banking.

Margery Moogk, MS, is director of the Northwest Tissue Center in Seattle. In her view, there are a fair number of tissue banks that, like hers, are blood center- or university-associated, focused on meeting the needs of the local community, and “completely nonprofit in the truest meaning of that word—accountable to the community via a board that monitors everything we do.” Even some large national programs like that of the American Red Cross retain their community focus with regional centers, she says.

But the trend toward commercialization of tissue has emerged partly in response to demand by device manufacturers for bone grafts. “Perhaps they want a tissue product equivalent to a titanium cage they’ve been using in spinal fusion surgery,” she says. “If you receive a human bone transplant, your body is likely not only to tolerate it but also to heal. It knows what to do with bone.”


Until recently, the explosion has been in spinal fusion products, but “now there’s a second wave coming and that is sports medicine: meniscus, cartilage, and tendons specifically for knee repair,” she says.

The Northwest Tissue Center specializes in osteochondral allografts—bone with cartilage for operations, especially in pediatric bone cancer, that allow the patient to avoid amputation, and it operates on a one-to-one basis, she says.

“We don’t have salespeople. A hospital calls us and tells us what they want, and if we’re already making it we’ll send it, or we may not have it immediately available and we may need to find a specific size.” Although some of the Northwest Tissue Center’s products are distributed nationally, about 85 to 90 percent of the 6,000 tissues it provides for transplant each year stays in the Northwest.

“As far as I know, nearly all the organizations that approach families and request to do tissue recovery are nonprofit. Our program is a fully integrated one, so we do everything. But many organ procurement organizations haven’t established any capability for tissue processing or distribution, so they may have a relationship with a large nonprofit like the Red Cross. Or they may have a relationship with a for-profit company that only processes, so it’s a processing service and they pay that company the same way we pay Federal Express to provide service to us.”

Moogk’s organization has always interpreted the Uniform Anatomical Gift Act to mean that because it is illegal to profit from selling human tissue, for-profit companies can’t sell tissue. But there has been a shift of opinion in the last five years. “It turns out that’s an unenforceable law. We charge a fee for our tissue to cover staffing costs, to buy supplies, to do our education in hospitals, and hopefully at the end of the year we have a small margin so we can ensure continuity of service or make capital improvements.” But she believes that some commercial entities are charging fees that are almost impossible to justify—perhaps $2,000 for a tiny piece of bone the size of a crouton.

“We hear so much about organ transplant—that it’s life-saving, that there are structured, federally enforced rules in place to make sure there isn’t favoritism,” Moogk says. “There’s suspicion even about organ donation when a star or a public figure gets a transplant. But it truly is a fair system, and I think families consenting to cornea or tissue donation expect those same kinds of rules apply across the board, and they don’t.”

“There’s a commercial aspect if you’re a device company and you need to show a profit for your shareholders,” she continues. “So you have ways of positioning your product. You’ve got sales guys out in the field who discount, who bundle, who say I’d like to sell you this if you buy this other stuff too, or who promise a surgeon he’ll be the only one in his area to have access to a product in short supply.”

“We all know that goes on in areas of commercial distribution—but it’s not the way we think of human gifts of donated organs, tissues, or corneas.”

Can a tissue bank talk to a family about all the subtleties of who’s going to distribute the donated tissue? “Our limited experience is, if you mention for-profit uses, they say no. There are many benefits of having a for-profit company involved—they have access to R & D money to provide a better product and they’ve done that—and there’s no reason they shouldn’t make a profit on the processing as far as I’m concerned. But there’s no reason they have to make a profit on the tissue itself.”

“Obviously, many companies are run by altruistic people with very high morals, and nonprofits can behave every bit as despicably as the worst for-profits,” Moogk adds. “It’s hard to discuss a nonprofit versus profit environment without sounding judgmental. But you know no family has ever been approached with the information that the tissue they donate will be provided to a company that makes a product used for penile enhancement.”


Pointing out that AATB has extensive standards on informed consent and what needs to be disclosed, Rigney says the time pressure and the sensitivity of requesting donations make it challenging.

“The family has lost a loved one and they don’t want to sit down and go through a lot of detail. The tissue bank or whoever is getting the consent is under the gun, because we have a 24-hour window period in which we have to retrieve tissue; otherwise it’s outside our time limits.”

The cosmetic-use issue keeps coming up but is “somewhat of a bogus issue,” he says. “A lot of reporters do not understand the difference between cosmetic procedures and reconstructive surgery. Number two, and this is where the kicker comes in, a licensed physician can prescribe whatever approved product or device they want for an off-label purpose as long as it’s not promoted as such.”

“I know of no product made with human tissue used in the U.S. that’s solely for cosmetic purposes.” The “penile enlargement” tissue that made a splash on “60 Minutes” was promoted for an off-label purpose by certain physicians, he says; it is actually an acellular product developed with human skin to be laid into the burn sites of burn patients.

Dr. Minogue testified before the Senate that commercialization was creating a more serious problem, because mistrust in the donation system risked the lives of people waiting for organ transplants. “To the public,” Dr. Minogue insisted, “organ and tissue donation constitute the same activity. People do not see any distinction between a person who recovers a loved one’s heart, lungs, liver, or kidney, and the person or organization that recovers skin, bone, and eyes.”

Existing consent requirements aren’t strict or detailed. The CAP Board of Governors filed a white paper in November 2001 addressing many consent issues. In it, the CAP’s Ad Hoc Committee on Tissue and Organ Procurement recommended that full disclosure include information about the donation process, harvesting of tissue, various ways tissue can be used or modified, and potential commercial applications.

The National Association of Medical Examiners, which inspects medical examiners’ offices using a checklist system like CAP’s laboratory inspection, does not have standards on consent. “It’s a very difficult situation trying to put together a one-size-fits-all standard,” says Garry Peterson, MD, chair of NAME’s committee on inspections and accreditation and chief medical examiner in Minneapolis. “We haven’t been asked to do that, and local laws and customs arrangements vary so much it would be a challenge to try to have something that would be useful.”

In the same way, the AATB does not track the costs or business practices of its member banks. “Antitrust law requires that we cannot discriminate even if we wanted to between for-profit and nonprofit tissue banks,” Rigney says. “But isn’t everybody in the health care system trying to make a profit? You may go to a for-profit doctor, who prescribes a drug or device made by a for-profit company, and sends your blood or other specimens away to a for-profit laboratory.”

Dr. Malinin believes tissue banking should be defined as the practice of medicine, just as blood banking is. Even though the U.S. remains the leader in tissue banking throughout the world, he argues, better safeguards are needed.

“Many organizations do not wish to overcome the difficulties or pay the expense to meet higher standards. Whether we should go the state or federal route, or the voluntary organization route, is really difficult to determine. But I think they all have a place, and the main concern is obviously to allow recipients to have access to grafts that are both effective and safe.”

Anne Paxton is a writer in Seattle.

   
 

 

 

   
 
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