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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