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FDA Consumer magazine

May-June 2005 Issue

Keeping Human Tissue Transplants Safe

By Linda Bren

When the surgeon put in a special request for an elbow, Donor Alliance of Denver started searching immediately. The elbow bone and surrounding cartilage had to fit specific dimensions and be from the right arm of a female donor of a certain age. A match was found, and the surgeon transplanted the live joint tissue into 18-year-old Nikki Fix.

Fix had fought leukemia with drugs that saved her life but that had a painful and debilitating side effect. "My joints started to collapse," says the Eaton, Colo., resident, who received her new elbow in September 2004. It wasn't the first such surgery for Fix. The year before, she got a new knee joint from another donor.

"I have a few limitations," says Fix. "I'm not supposed to run or jump, and I have to watch how much I'm lifting." But Fix considers herself fortunate. She is pain-free, has use of her arm again, and walks without limping. And her leukemia has been in remission for two years.

Fix is one of the many people who have benefited from tissue donations. The nation's tissue banks distributed more than 1 million tissue grafts in 2003, according to the American Association of Tissue Banks (AATB). Most tissues come from people who have chosen to donate their organs and tissues after death to help others live longer or to improve their quality of life.

"One donor can save eight lives through organ donation and enhance up to 50 through tissue donation," says Steve Mansfield, vice president of tissue banking operations at Donor Alliance, a nonprofit organization that helps procure organs and tissues, including Fix's elbow and knee.

Organ transplants are usually lifesaving and involve the replacement of whole organs--the kidneys, liver, heart, lungs, pancreas, or intestine. Tissue transplants also are used sometimes to save lives, says Mansfield, but most tissue transplants enhance the lives of recipients. Tissues that can be transplanted include bone, skin, corneas, tendons, ligaments, and heart valves.

Bone tissue can restore function to damaged joints, as in Fix's case. Or it can prevent limb amputation by replacing cancerous bone. A covering of donated skin may prevent infections in severely burned people until new skin can regrow. Donated corneal tissue, the outer coating of the eyeball, can restore sight to people with eye disease. And healthy leg veins can replace damaged arteries in people with poor circulation.

Donated heart-valve tissue can be a lifesaving gift for a person with a failing heart valve. And reproductive tissue, provided by living donors, can be a gift that allows an infertile couple to have children.

But like blood and other body fluids, these living materials can transmit disease. Concern over this potential has led the Food and Drug Administration to strengthen its oversight over the human tissue industry. And the tissue industry and state governments are working with the agency to safeguard patients who receive these life-enhancing and lifesaving tissues.

The Risk

"The overall risk of disease transmission through tissue transplantation is believed to be very low," says Jesse Goodman, M.D., M.P.H., director of the FDA's Center for Biologics Evaluation and Research. But in the rare incidents of disease transmission, the results have been tragic. In 2001, for example, a 23-year-old Minnesota man died four days after receiving a transplant of bone and cartilage to reconstruct his knee. He had acquired a deadly infection from toxic bacteria in the tissue. A delay in refrigerating the donor cadaver before the tissue was harvested was believed to have triggered the growth of the bacteria, according to the Centers for Disease Control and Prevention (CDC).

In 2002, five tissue recipients in the United States were believed to be infected by hepatitis C from a single donor's tissues. And in 2003, contaminated corneas resulted in infections and vision loss in two people.

Over the years, the development of new processing and surgical techniques has expanded the use of human tissues. Blood stem cells from umbilical cord blood are now used in experimental therapies to treat cancers such as leukemia. And insulin-producing islet cells are now cultured in the laboratory. Researchers hope that injecting islet cells into people with diabetes may one day eliminate the need for pancreas transplants and daily insulin injections, says Ruth Solomon, M.D., acting director of the FDA's Division of Human Tissues.

The expanded use of tissues and the emergence of new infectious diseases bring new safety concerns--and a need for new regulations.

Making Tissue Safer

The FDA has been working to make human tissues safer since it first started regulating the tissue industry in 1993. That year, the agency published an interim regulation that called for certain screening requirements to be met before donated tissues were considered safe for transplant. This regulation, finalized in 1997, also gave the FDA the authority to recall and order the destruction of potentially unsafe human tissue and to inspect tissue banks--organizations that provide a range of services, including donor screening, tissue recovery, and processing, storage, and distribution of tissue.

The explosion in tissue technology did not catch the FDA by surprise. The 1993 interim regulation included wording to indicate that the FDA would strengthen its tissue regulations in the future.

The final 1997 regulation applied only to certain tissues, such as skin, eyes, and bones, tendons and ligaments (musculoskeletal tissues). Screening under the regulation focused on preventing the transmission of HIV, hepatitis B, and hepatitis C.

More recently, the FDA finalized three new rules that give the agency more authority and oversight over a broader range of tissues and the establishments that process them. The rules also expand on the communicable diseases that are checked for, and they strengthen procedural and recordkeeping requirements for facilities that handle tissues. Before finalizing the rules, the agency held public forums and considered comments from a broad range of consumer representatives, health and science professionals, and industry.

"Some of the same approaches that have been used successfully to improve the safety of blood are also being used to make tissue safer," says Goodman. The goal is "to improve protection of the public health without imposing unnecessary restrictions on research, development, or the availability of new or existing products."

The three rules concern registration and listing, donor eligibility, and good tissue practices related to human cells, tissues, and cellular and tissue-based products, known as HCT/Ps. These products include skin, eyes, musculoskeletal tissue, eggs and sperm, veins, blood stem cells, the membrane covering the brain (dura mater), and more. The agency has tailored its regulations to the degree of risk posed by each product.

The FDA's rules do not cover certain bone marrow or whole organs for transplant. These are managed under separate programs in the federal Health Resources and Services Administration (HRSA), part of the Department of Health and Human Services.

Registration and Listing

This rule was finalized for certain HCT/Ps in 2001 and for all HCT/Ps in 2004. It requires all establishments that recover, process, store, label, package, or distribute HCT/Ps, or that screen or test donors, to register with the FDA and list all the products they manufacture. This regulation provides, for the first time, a complete database of tissue banks and other establishments that work with human cells and tissues. Its aim is to increase the efficiency of the FDA's inspection and monitoring and help the agency better communicate with facilities about its policies and guidances.

Donor Eligibility

"A critical component of enhancing the safety of tissues is excluding donors who may pose a higher risk of transmission of infectious diseases," says Goodman. The FDA's donor eligibility rule requires that tissues for transplant come from an eligible donor, based on the results of screening for risk factors and testing for certain diseases. This is an extensive process that involves examining the body, testing for disease-causing agents, interviewing the donor's family or other close contacts, and conducting multiple reviews of a donor's medical records, lab test results, coroner and autopsy reports, and other relevant records.

Finalized in May 2004, the rule takes effect on May 25, 2005. In addition to screening and testing for HIV and hepatitis, as was done under an earlier regulation, the new regulation requires screening for diseases such as syphilis, West Nile virus, severe acute respiratory syndrome (SARS), and the neurological condition Creutzfeldt-Jakob disease (CJD).

No lab tests are currently available to test for West Nile virus, SARS, and CJD. To identify a potential risk for these diseases, a tissue bank representative interviews the family of the deceased donor. Interviewers at Donor Alliance typically have social work or psychology backgrounds, says Mansfield, and they ask about 50 questions to gain extensive information about the donor's medical and lifestyle history that may signal a risk, including sexual practices, injectable drug use, and travel history. Donors who lived in Britain, for example, at the height of the "mad cow" epidemic are excluded from donating because they are considered at risk for the human form of mad cow disease, variant CJD.

To further protect transplant recipients, the donor eligibility rule builds in flexibility for the FDA to require screening for new disease threats as they emerge and reliable tests become available.

Donor tissue cannot be released for use until all screening and testing processes are completed and medical experts review and evaluate the results. An exception may be made in the event of an urgent medical need where no suitable tissue is available and the recipient is likely to become gravely ill or die without the tissue.

Any donor found to have infected tissue or found to be at risk for infection is considered ineligible, and, with rare exceptions, all tissue from that donor is destroyed or used only for research or educational purposes. "We can send tissue that cannot be transplanted out for research if the family has agreed for it to be used for research," says Mansfield.

Good Tissue Practice

The third rule addresses good tissue practice (GTP) and requires facilities to use specific methods and controls to prevent tissue from becoming contaminated. The GTP rule, finalized in November 2004, is effective on May 25, 2005.

The rule permits the FDA to inspect HCT/P manufacturers to ensure compliance with regulations and to order the recall or destruction of any tissue not meeting safety criteria.

"Where appropriate, information from FDA inspections can and will be used to take enforcement action," says Goodman. "However, it is preferable, wherever possible, to work with manufacturers to build quality into their procedures in an effort to prevent safety problems."

Quality controls begin with the recovery of tissues and extend through processing, storage, labeling, packaging, and distribution. Tissue recovery teams at Donor Alliance work in the sterile conditions of an operating room to protect the tissue from contamination, says Mansfield. "The donor is prepped as if having surgery and spends about five to six hours on the operating table."

Once tissues are recovered, they are sent to a processing facility where the donor's blood is tested for communicable diseases and the tissues are tested multiple times for possible bacterial or fungal contamination. The tissue is sterilized or disinfected and then packaged and labeled so it can be quickly tracked to its source if any questions arise about its safety. "We have a tracking system for every piece of tissue that allows us to track it from the donor to ultimate distribution to the hospital or surgical facility," says P. Robert Rigney Jr., the AATB's chief executive officer.

An important part of the GTP rule is a requirement for tissue transplant facilities to report to the FDA certain adverse reactions and product deviations. The tissue safety team, a group of medical experts within the FDA, then follows up on these events with the tissue bank and hospital or other facility involved. The agency may enlist the help of the CDC, the HRSA, or health department of the state where the event took place to investigate the source of infection.

Self-Regulation and Cooperation

Even before the FDA began regulating tissues in 1993, large segments of the domestic human tissue industry voluntarily complied with industry standards to regulate the quality and safety of their products. Trade groups such as the AATB and the Eye Bank Association of America (EBAA) sponsor voluntary accreditation programs requiring tissue and eye banks to adhere to standards and to pass periodic inspections. These standard-setting and accrediting organizations also certify tissue and eye bank personnel who have passed a rigorous exam.

The AATB estimates that 80 percent to 90 percent of tissue transplanted in the United States comes from a bank that it has accredited. The EBAA estimates that it has accredited 95 percent of the eye banks in the country.

In addition to federal government and industry standards, several state governments set their own tissue requirements. "Anyone who ships tissues into or out of New York or Florida has to comply with their departments of health," says Mansfield. "We have four primary auditing agencies. With the best practices we have in place, we are always prepared for an inspection."

Both the AATB and the EBAA require their member organizations to report adverse events. Their accreditation bodies investigate and take corrective and preventive actions if necessary.

Tissue safety depends on the cooperative and collaborative efforts of many entities, including the FDA, the CDC, state health departments, and the tissue industry. The FDA works with the CDC to investigate reported adverse events. The agency also works with states to resolve any potential conflicts of federal and state rules regarding tissue recovery and use. The FDA updates tissue banks on federal requirements through liaisons with AATB and EBAA committees. And the industry assists the FDA, says Solomon. "AATB and EBAA help us to leverage our resources," she says, "by writing draft guidance to help industry comply with our rules."

Meeting the Demand

There is a critical shortage of donor organs, but donor tissues are more available. "There are about four times as many tissue donors as cadaveric organ donors," says Rigney.

Unlike the half dozen organs that one person can donate, that same person can supply up to about 60 tissue grafts, and the window of time for tissue recovery is longer. For organs to be usable for transplant, a donor must be brain dead and on life support, meaning brain function has stopped permanently and the person cannot breathe on his or her own. Tissue may be used from a person who either is brain dead or has suffered cardiac death--the heart stops beating and breathing stops. "The tissue can be retrieved up to 24 hours later," says Rigney. Organs, which deteriorate more quickly than tissues, must be harvested sooner.

In 2002, the AATB's member tissue banks provided nearly 12,000 square feet of skin for transplant. "There has never been a critical shortage of skin," says Rigney, adding that the AATB's networking system with its banks enables skin to be supplied quickly to treat burn victims. "When 9/11 happened, we mobilized our skin banks to be able to ship skin to New York and to Washington D.C. within eight hours. We had about 2,500 square feet of skin ready to be shipped."

According to the EBAA, eye banks are currently meeting the demand for corneal tissue in the United States. A corneal transplant cannot only restore sight, but can restore nearly perfect vision in many cases if the rest of the eye is healthy, says Edward Holland, M.D., professor of ophthalmology at the University of Cincinnati and director of cornea services at the Cincinnati Eye Institute.

Eye donors, who numbered more than 40,000 in 2003, supplied corneas for more than 32,000 transplants performed that year in the United States. Additional corneal tissue is used for research and training or is exported to other countries. According to the World Health Organization, corneal blindness is the second leading cause of blindness in the world, and there is a critical worldwide shortage of corneas. Even with U.S. exports of corneas, "We have not begun to make a dent in worldwide corneal blindness disease," says Holland.

Holland is also concerned about potential shortages of corneal tissue in the United States. As tissue banks screen for a growing number of diseases, more tissue is ruled out for transplant, he says. "We're finding more systemic infectious disease, and if we find something suspicious, we will not use the corneas for transplantation. We decline more and more tissue every year."

And the donor pool may be shrinking as LASIK, a surgery that uses a laser to improve vision by reshaping the cornea, continues to be popular. "We don't know the impact of refractive surgery on the health of the cornea after transplant," says Holland. "We do wonder about the 2 million to 3 million people each year we do LASIK on, when they get older and become 15 to 20 percent of the donor population."

Because of the uncertainty of long-term corneal health, Holland says LASIK corneas are not used for standard corneal transplants, which use the center two-thirds of the cornea. But he still encourages people who have had LASIK to become donors. LASIK does not affect the back layer of the cornea, he says, which is used in a new type of corneal transplant procedure to correct certain types of inherited eye defects and for corneal swelling after cataract surgery. And the white outer coat enclosing the eyeball (sclera), also not affected by LASIK, can be used to reinforce tissue in certain glaucoma procedures. Wearing glasses or contacts has no bearing on the suitability of corneas for transplant, adds Holland.

Rigney urges people to become tissue donors. Whether bone, skin, eye, heart-valve, or other tissue, he says, "the surgical demand for tissue increases as surgeons find more ways to use tissue to enhance or save lives."

Nikki Fix's knee and elbow transplants not only enhanced her life but made an impact on her whole family, says her mother, Lynn Fix. "It has made our family very aware of how donors can really help others." Because she has had leukemia, Nikki is ineligible to be a donor, but both of her parents are donors. "And when her sister turned 16 and got her driver's license, she signed up, too," says Lynn.

How to Become An Organ and Tissue Donor

HHS Secretary Mike Leavitt announced in March 2005 that 26,984 Americans received an organ transplant in 2004, setting a new national record. HHS began a national effort to encourage organ donation with its Gift of Life Donation Initiative in 2001.

Despite the increase in organ transplants, the waiting list in the United States for whole organs--kidneys, livers, hearts, lungs, intestines, and pancreases--on any given day, numbers more than 87,000 people, according to the United Network for Organ Sharing. Although there is no waiting list for tissues, some tissues, such as patellar tendons for knee surgeries, are in constant short supply, says P. Robert Rigney Jr., chief executive officer of the American Association of Tissue Banks. Continued donations are essential to meet the national need for eyes, skin, bone, tendons, heart valves, and other tissues.

"If you sign up to be a donor, it will generally include not only the organs but tissues and eyes," says Rigney. "But you do have the right to determine whether you want to donate all your organs and tissues or to specify only certain ones."

Trained personnel take great care and treat the donor's body with respect, says Rigney. Donated organs and tissues are removed surgically, and all incisions are closed after the surgery. An open casket funeral is almost always possible.

Neither age nor medical history should stop someone from becoming a donor. The transplant team decides at the time of transplantation if the organs or tissues can be transplanted.

You can sign up to be a donor in several ways:

Once you have decided to become a donor and documented your decision, the most important step is telling your family, says the Coalition on Donation. They may be asked to give consent.

For More Information

U.S. Department of Health and Human Services
(888) 894-6361

Coalition on Donation

American Association of Tissue Banks
(703) 827-9582

Eye Bank Association of America
(202) 775-4999

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