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FDA Consumer magazine (December 1996)
VOL. 30 NO. 10


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Features

FDA and Medical Devices: After 20 Years, a Look Back, a Look Ahead 
Marking the 20th anniversary of the Medical Device Amendments, Bruce
Burlington, M.D., director of the FDA center that regulates the devices,
reviews accomplishments and previews the future.

Sulfites Safe for Most, Dangerous for Some 
Only about 1 out of 100 people--including 5 percent of those who have
asthma--are sensitive to sulfites. But their reactions to foods
containing these additives can threaten their lives.


Homeopathy: Real Medicine or Empty Promises? 
Marigolds, onions, poison ivy, and hemlock are just a few of the
substances used--in minute quantities--to make homeopathic medicines. In
many ways, FDA regulates them differently from other drug products.


Non-Hodgkin's Lymphoma Becomes More Common, More Treatable 
A cancer of the immune system, non-Hodgkin's lymphoma is now the sixth
most common cancer in the United States, increasing 75 percent in the
last 20 years. Treatments include drugs, radiation, and bone marrow
transplants--and researchers are looking at new possibilities.


Inside FDA: Hazardous Duty in the Bering Sea 
Investigators from FDA's Puget Sound resident post volunteer to inspect
fish-processing boats in the icy and dangerous Bering Sea off the coast
of Alaska. 

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Departments

Updates 

The latest information on FDA-related issues, gathered from FDA Press
Releases, Talk Papers, and other sources.


Notebook 

A potpourri of items of interest gathered from the Federal Register and
other sources.


Investigators' Reports 

Selected cases illustrating regulatory and administrative actions--such
as inspections, recalls, seizures, and court proceedings--by FDA's
regional and district offices across the country


Summaries of Court Actions 

Cases involving seizure, criminal and injunction proceedings.

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FDA and Medical Devices:
After 20 Years, a Look Back, a Look Ahead

by Tamar Nordenberg 

FDA has just marked the 20th anniversary of the Medical Device
Amendments to the Food, Drug, and Cosmetic Act.

Until 20 years ago, FDA was ill-equipped to protect Americans from
dangerous or useless medical devices, because the agency had to prove a
device was unsafe or ineffective before it could take action to remove
the device from the market. In 1976, the landmark Medical Device
Amendments were signed into law by President Gerald Ford. The law
requires manufacturers of most medical devices--particularly moderate-
or high-risk devices--to provide FDA with safety and effectiveness data
before marketing.

FDA's Center for Devices and Radiological Health is charged with
implementing the device law. The center has many functions, including
working with FDA's field force to inspect device manufacturing plants;
keeping track of problems with devices already in use and taking prompt
action to correct them; and helping manufacturers produce better
products by conducting laboratory research on the ways companies test
their products and on specific device safety problems.

One of the most visible and important functions of the center is to
review devices for safety and effectiveness before they are marketed.
The center clears for marketing everything from contact lenses and
artificial joints to x-ray machines. More than 550 categories of
low-risk medical devices, including surgical gloves and therapeutic
massagers, are exempted from premarket approval.

Challenged to speed product approvals without compromising consumer
safety, the center has made some changes in the way it does business.
(See "Inside FDA: Agency Changes Include Medical Device Review" in the
November 1996 issue of FDA Consumer.)

In the following interview, center director D. Bruce Burlington, M.D.,
talks about what the medical device program has accomplished and what
remains to be done.


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Q. Twenty years have passed since enactment of the landmark Medical
Device Amendments of 1976. Are Americans better cared for as a result of
the amendments? 

A. I think the American people are significantly better off for having
the medical device law. Today, Americans can really rely on devices.
When a medical device is used in a doctor's office or hospital, patients
can be confident that the operator knows how to use the device well and
that it will work for them.

Americans can count on devices because of the system of pre- and
postmarket oversight made possible by the 1976 amendments. To ensure
that products are well-manufactured, FDA inspects companies to see that
they are following good manufacturing practices, keeping appropriate
records on the design and manufacture of products, and maintaining a
system for handling complaints.

Before a product even goes to market, a company must present data to FDA
showing not only that it will be well-manufactured, but also that it is
safe and effective--that it won't harm people and will deliver its
expected benefits. And if a product causes unforeseen problems, there's
a feedback loop, a requirement that manufacturers report any serious
problems to FDA so rapid action, including a product recall if
necessary, can be taken to protect people from a faulty device.

There is yet another vital benefit of our regulation of devices under
the medical device law: information. The largest source of risk in using
a medical device isn't the product itself, but the interface between the
user and the device. It is especially important for doctors to know how
and when to use the product. Serving as a reliable, unbiased evaluator
of this information may be the most important service FDA can provide to
health professionals.


Q. What are some of the most significant accomplishments of the center
during your service as director to date? 

A. Several breakthrough devices have been approved by the center. One of
the most important is our recent approval of the use of implantable
defibrillators to prevent sudden death in people who have had heart
attacks. This was the first approval for this use in the world, and it
should save thousands of lives each year. Also in the area of
cardiology, we approved a coronary stent, a cage-like device that's
permanently implanted in a diseased coronary artery to expand it and
allow normal blood flow. This is really changing the way cardiologists
are performing balloon angioplasty to open up clogged arteries feeding
the heart, making the procedure available to many patients who before
would have had to undergo major surgery.

To help detect cervical cancer more reliably, we've approved a device
that scans all pap smears read as normal by the technologist and
identifies suspicious ones for a second review.

Also, we've approved a new microwave device to treat symptoms of
enlarged prostate, a condition affecting millions of men. This device
gives patients an alternative to treatment with drugs or surgery.

Two newly approved devices can potentially help millions of women who
suffer from urinary incontinence. One is a disposable balloon-type
device that the patient inserts into her urethra, and the other is an
adhesive-backed foam pad that's placed over the urinary opening.

Another approval that's been prominent in the news is the use of excimer
lasers to treat certain cases of nearsightedness, giving many people an
alternative to eyeglasses or contact lenses.

An additional major accomplishment has been the center's recent emphasis
on clinical trials--controlled studies in humans--for evaluating the
safety and effectiveness of new devices. For 20 years, we'd been
concentrating primarily on assuring that devices were well-designed and
well-made. It goes without saying that these things are still important.
But we've come to realize that for some devices--probably less than 10
percent--we also need clinical data from human studies. This gives us
information on how the device will perform in actual patients, and gives
the physician information about which patients are likely to benefit
from the device and under what conditions. In the long run, I think the
focus on clinical trials may have a bigger impact on the public than
anything else we're doing.


Q. Government agencies are often criticized for making decisions that
don't reflect the interests of the public and the regulated industry.
Has FDA taken steps to avoid this pitfall? 

A. Yes. To help the agency make decisions on policy matters or on
specific devices, we want input from the public and industry. For policy
issues, we often have grass-roots meetings--we've had several in the
last year--to get suggestions on how to approach an issue. When we have
a particular device in front of us that may be ready for marketing, very
often we will have an advisory committee meeting. Most meetings are
open, and consumer protection groups and members of the public are
welcome to attend and tell us what they expect.

Because I also work as an emergency room physician, I get an additional,
hands-on perspective. I can see the devices in action and can learn from
patients and other physicians what they expect from the devices and from
government oversight. It helps me to know which issues are peripheral so
I can focus on the issues that really make a difference.

After balancing everyone's input, and with the intent of the law
foremost in mind, FDA is ultimately responsible for deciding whether to
allow a product on the market and whether it's necessary to take action
against a product already on the market. In the end, the government
official charged with making the decision is accountable to the public,
and he or she must "take the heat" if a decision is criticized.


Q. Some critics say FDA is too slow in approving medical devices. Is the
criticism justified, and what is the agency doing to speed up Americans'
access to safe, effective medical devices? 

A. We should take seriously those critics who raise valid points, and
use their negative appraisals to improve our performance. We at FDA have
to understand that new products do bring real benefits, and that
delaying availability of a safe, effective medical device can harm
people just as much as approving a faulty product.

At the same time, we must bear in mind that our goal is not simply to
get products to the market, but to get products that work and that we
know how to use. So we can't lose sight of our consumer protection
mission as we look at changing the way FDA does business.

A little over three years ago, when I came to the center, we had a
mountain of work that had built up over the previous couple of years. We
had been through a period of incredibly intense internal scrutiny and
external review, and we responded to that review by modifying the way we
operate.

We've substantially dug out from under the mountain. Abbreviated
applications--applications for a device that's essentially the same as
something already on the market--are reviewed on time, usually within 90
days. For more complicated applications, we still have some work to do.
We're making real headway, though, towards a record of timeliness.

Some people question whether patients in other countries get access to
new devices sooner than patients in the United States. When it comes to
products that are really new--those that represent breakthrough
technologies or are the first of their kind--we use a system of
expedited review which allows these kinds of devices to go to the head
of the queue and receive review very quickly.

Under this system, we've approved several significant new devices in the
past few years before they were approved anywhere else in the world.
These include a prenatal test for genetic abnormalities, an ultrasound
system to speed the healing of bone fractures, a bone growth stimulator
for treatment of old, unhealed fractures, and the use of an implanted
heart defibrillator to prevent sudden cardiac arrest in patients who
have suffered heart attacks.

Of course, we have little control over the time it takes for a company
to develop its product and collect data on its safety and effectiveness.
But the next step--the company's interaction with FDA--must be
productive and efficient. Long, drawn-out decisions aren't necessarily
better than prompt ones. We at FDA need to make timely decisions to
provide a clear and predictable business climate so that industry can do
its job and bring new products to market. But we can't make sacrifices
in the quality of data.

Complete, well-prepared applications move through the system more
quickly than others. Once we have the good science necessary to make a
decision, we should go ahead and make it, to reach closure on the issue
and move on. That culture of decisiveness is especially important when
we're dealing with the device industry, in which a product's market life
often is only a few years.

FDA is committed to doing the best we can with the budget provided. By
looking to the experience of businesses across America, we can learn
lessons about how to get our job done better and more cheaply.

To make the most efficient use of FDA's resources, we're looking for
ways to get the same results with fewer people. The agency has really
pushed the envelope regarding abbreviated device applications. We're
allowing many products that previously would have required a
comprehensive application to now be reviewed under an abbreviated
application, which is usually processed in only 90 days.

Also, we're pilot-testing a program of third-party reviews, which asks,
"Which part of the work does it make sense for the agency to turn over
to external parties?" We may be able to reduce review times by allowing
carefully selected outside groups to perform the first stage of review
of devices that don't present a substantial risk to the American public.


Q. Is it realistic to think that device regulation could be standardized
worldwide to lessen the burden on device manufacturers who want to
market their products internationally? 

A. Today, medical device manufacturers may have to develop different
sets of data for each country in which they seek approval. We are
working toward harmonizing standards among countries where we can.

People are much the same around the world, and many of their diseases
and injuries are the same. We ought to be able to reach agreement
worldwide on what constitutes a safe, well-manufactured product. But the
issue of whether a product delivers a sufficient benefit is harder
because there are different expectations of the regulatory systems in
the United States and, for example, Europe.

The United States has the gold standard for what is expected from
companies when they want to bring a product to market, a gold standard
not just in terms of knowing how a product is made but also of knowing
how it works and under what circumstances it works. In Europe, device
regulation focuses on whether devices are well-designed and
well-made--their mechanical performance characteristics. It doesn't
focus on efficacy--on whether the device works on patients--like our
system does. We're not prepared to ta ke a step down to a lower
standard, and other countries with different expectations of government
aren't ready to line up with the American system. So we don't expect to
see total harmonization soon, with one reviewing body getting the
product to the world market.

Q. What are the biggest challenges you expect your center to face over
the next decade? 

A. We have many of the same challenges that people have across
government. Given the realities of the federal budget, we have to figure
out how to get our job done with tight resources. We have to determine
what's most important about what we do, and, where possible, share the
public health responsibility with industry, academia, and health-care
providers. We've already begun that process through the pilot testing of
third-party reviews.

Also, in the last few years there's been a shift from the one-on-one,
individual doctor and patient model of health care toward a managed care
model where patient care is administered by large organizations like
HMOs. With cost-effectiveness considerations playing a much larger role
in medical decision-making, health-care organizations will need
information for "technology assessment"--information not only on whether
a device works, but how it compares to other devices and other forms of
treatment.

In some ways this will make FDA's job easier, because every company that
wants to market a product will know that its data will not only have to
pass review by the agency, but will also have to convince the
managed-care organizations that its product really makes a difference.

But this raises questions about FDA's role in this new era. Are we going
to continue to evaluate each new device essentially in isolation, simply
asking whether the product works and is safe, leaving it to others to do
the comparisons? Or will the agency jump into the technology assessment
arena? More and more, I think we'll have to focus on how to evaluate
products in the context of the whole health-care picture.

Tamar Nordenberg is a staff writer for FDA Consumer. 

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Sulfites: Safe for Most, Dangerous for Some

by Ruth Papazian 

It wasn't a special occasion--or even a fancy restaurant--but Karen, 37,
will never forget that meal:

My boyfriend and I were at a hamburger joint, and I had a burger and
fries. About 10 minutes after we finished eating, my throat began to
itch. I grabbed my [asthma] inhaler but I could feel my throat
constricting. I couldn't breathe and started to panic. When I passed
out, my boyfriend flagged down a passing police car. The officer radioed
for an ambulance, and I was rushed to the hospital. I was revived with a
massive dose of epinephrine to counteract the reaction caused by the
sulfite solution the potatoes had been soaked in before frying.

I know enough to stay away from wine, shrimp and other foods that
contain sulfites, and take note whenever I don't feel right after eating
something. But I never expected french fries to be sulfited. I've had
allergic reactions to sulfites before, but this time I came close to
dying.

I was angry that this happened to me. I felt powerless--I was careful
and knowledgeable, and yet I couldn't protect myself. Who ever heard of
a lethal french fry? Afterward, I refused to eat out in restaurants for
almost two years, and I still can't visit people or go on vacation
without knowing there is a hospital nearby.

The Food and Drug Administration estimates that one out of a hundred
people is sulfite-sensitive, and that 5 percent of those who have
asthma, like Karen (who asked that her last name not be used), are also
at risk of suffering an adverse reaction to the substance. "By law,
adverse reactions to drugs must be reported to FDA by doctors or
pharmaceutical companies. But with sulfites and other food ingredients,
reporting is voluntary so it's difficult to say just how many people may
be at risk," cautions FDA consumer safety officer JoAnn Ziyad, Ph.D.

Complicating matters, scientists have not pinpointed the smallest
concentration of sulfites needed to provoke a reaction in a sensitive or
allergic person. FDA requires food manufacturers and processors to
disclose the presence of sulfiting agents in concentrations of at least
10 parts per million, but the threshold may be even lower. The assay
used to detect the level of sulfites in food is not sensitive enough to
detect amounts less than 10 ppm in all foods (that's 1 part sulfite to
100,000 parts of food--the equivalent of a drop of water in a bathtub)
so that's what the regulation has to be based on, explains Ziyad.

"The most rapid reactions occur when sulfites are sprayed onto foods or
are present in a beverage, but the most severe reactions occur when
sulfites are constituents of the food itself," says Ron Simon, M.D.,
head of Allergy, Asthma and Immunology at Scripps Clinic and Research
Foundation in La Jolla, Calif.

A person can develop sulfite sensitivity at any point in life, and no
one knows what triggers onset or the mechanism by which reactions occur.
"Doctors believe that asthmatics develop difficulty breathing by
inhaling sulfite fumes from treated foods," notes Dan Atkins, M.D., a
pediatrician at the National Jewish Center for Immunology and
Respiratory Medicine in Denver, Colo. He says that in a severe reaction
an overwhelming degree of bronchial constriction occurs, causing
breathing to stop. This can lead to lack of oxygen reaching the brain,
heart, and other organs and tissues and, possibly, a fatal heart rhythm
irregularity.

"We now know that asthmatics who have more severe symptoms and are
dependent on corticosteroids, such as prednisone or methylprednisolone,
are especially prone to sulfite sensitivity and are most at risk of
having a severe reaction," notes Atkins. But it's a chicken-and-egg
situation, notes Simon: "We don't know which comes first, the asthma or
the sulfite sensitivity, because some people's first experience with
asthma is a sulfite reaction, and as their asthma becomes more severe
they eventually become steroid-dependent."

Sulfite sensitivity can be tricky to diagnose. Karen went to an
internist and two pulmonary specialists without getting to the bottom of
her problem.

"People who do experience adverse reactions to sulfites know that it's
something they ate, but might not know what that something is," says
Atkins. "I'll ask a patient complaining of an adverse reaction what he
or she ate and drank when it occurred. If beer or wine doesn't seem to
be the problem, I tend to dismiss sulfite sensitivity. But if I think
sulfites may be the culprit, I'll do a challenge [a type of allergy test
in which a small amount of the suspect substance is administered in a
capsule or in a drink and the patient is monitored to see whether there
is a reaction]."

If a person develops hives after ingesting sulfites, the doctor will do
a prick test (a small concentration of sulfite is placed on the skin,
which is then pricked; the test is positive if a welt develops on the
spot). "People who have positive skin tests to sulfites are likely to be
allergic to the additive, rather than have a sensitivity. These people,
who are usually not asthmatic, are most at risk of anaphylactic shock,
[a life-threatening reaction]," says Simon.

Regulatory Status in Flux 

Sulfur-based preservatives, or sulfites, have been used around the world
for centuries to:

 * inhibit oxidation ("browning") of light-colored fruits and
   vegetables, such as dried apples and dehydrated potatoes

 * prevent melanosis ("black spot") on shrimp and lobster

 * discourage bacterial growth as wine ferments

 * "condition" dough

 * bleach food starches

 * maintain the stability and potency of some medications.

When the Federal Food, Drug, and Cosmetic Act was amended in 1958 to
regulate preservatives and other food additives, FDA considered sulfites
to be generally recognized as safe (GRAS). But when FDA reevaluated
their safety and proposed to affirm the GRAS status of sulfiting agents
in 1982, the agency received numerous reports from consumers and the
medical community regarding adverse health reactions. In response, FDA
contracted with the Federation of American Societies for Experimental
Biology (FASEB) to examine the link between sulfites and reported health
problems that ranged from chest tightness or difficulty breathing to
hives to fatal anaphylactic shock.

In 1985, FASEB concluded that sulfites are safe for most people, but
pose a hazard of unpredictable severity to asthmatics and others who are
sensitive to these preservatives. Based on this report, FDA took the
following regulatory actions in 1986:

 * Prohibited the use of sulfites to maintain color and crispness on
   fruits and vegetables meant to be eaten raw (for instance, restaurant
   salad bars or fresh produce in the supermarket).

 * Required companies to list on product labels sulfiting agents that
   occur at concentrations of 10 ppm or higher, and any sulfiting agents
   that had a technical or functional effect in the food (for instance,
   as a preservative) regardless of the amount present. (This labeling
   requirement was extended to standardized foods, such as pickles and
   bottled lemon juice, in 1993.)

FDA requires that the presence of sulfites be disclosed on labels of
packaged food (although manufacturers need not specify the particular
agent used). This information will be included in the ingredient portion
of the label, along with the function of the sulfiting agent in the food
(for instance, a preservative).

When food is sold unpackaged in bulk form (as with a barrel of dried
fruit or loose, raw shrimp at the fresh fish counter), store managers
must post a sign or some other type of labeling that lists the food's
ingredients on the container or at the counter so that consumers can
determine whether the product was treated with a sulfiting agent.

In 1987, FDA proposed to revoke the GRAS status of sulfiting agents on
"fresh" (not canned, dehydrated or frozen) potatoes intended to be
cooked and served unpackaged and unlabeled to consumers (french fries,
for example), and issued a final ruling to this effect in 1990. However,
the rule was held null and void in 1990 after a protracted court battle
in which the "fresh" potato industry prevailed on procedural grounds.

This legal setback notwithstanding, "the agency continues to have
concerns about the safety of sulfiting agents, and plans further action
to protect the consumer," notes Ziyad. Steps the agency is considering
include establishing maximum residual levels for specific foods and
additional labeling rules.

"The ultimate goal of sulfite regulation is to make sure that there is
no higher level of sulfite residues in food than is absolutely necessary
and to encourage the use of substitutes for sulfites in food
processing," says Ziyad.


Sniffing Out Sulfites 

Since 1985, FDA's Adverse Reaction Monitoring System has been tracking
reactions to sulfites. Over a 10-year period, 1,097 such cases have been
reported. However, thanks to regulatory action taken by FDA over the
years, coupled with increased consumer savvy, the number of reported
sulfite-related health incidents has been dropping steadily. In 1995,
just six cases were reported.

Ten years ago, FDA banned the use of sulfites on fruits and vegetables
that are to be eaten raw (as with a salad bar)--and the vast majority of
those in the food service industry honor the prohibition--but consumers
who are sulfite-sensitive "shouldn't take anything for granted," says
Ziyad.

Current FDA regulations do not require managers of food service
establishments to disclose whether sulfites were used in food
preparation. "Consumers continually request FDA to extend the regulation
to include food service establishments because either waiters and other
staff members didn't know whether the food was treated with sulfites, or
gave erroneous information," notes Ziyad. "FDA's position on the issue
has been that consumers who see sulfites listed on the label of a
packaged food should be able to deduce that the same food sold in a food
service establishment would also contain sulfites," she explains.

In addition, sulfites are still found in a variety of cooked and
processed foods (including baked goods, condiments, dried and glaced
fruit, jam, gravy, dehydrated or pre-cut or peeled "fresh" potatoes,
molasses, shrimp, and soup mixes) and beverages (such as beer, wine,
hard cider, fruit and vegetable juices, and tea).

Since sulfites are added to so many foods, someone who is sensitive to
the additive must not assume that a food is safe to eat, says Atkins. He
recommends these measures to avoid sulfites when buying unlabeled foods
at the deli or supermarket and ordering at a restaurant:

 * If the food is packaged, read the label. If it is being sold loose or
   by the portion, ask the store manager or waiter to check the
   ingredient list on the product's original bulk-size packaging.

 * Avoid processed foods that contain sulfites, such as dried fruits,
   canned vegetables, maraschino cherries, and guacamole. If you want to
   eat a potato, order a baked potato rather than hash browns, fries, or
   any dish that involves peeling the potato first.

 * If you have asthma, have your inhaler with you when you out to eat.
   Similarly, if you've experienced a severe reaction to sulfites in the
   past (such as breaking out in hives), carry an antihistamine and make
   sure you have handy a self-administering injectable epinephrine, such
   as EpiPen, so that if you have a reaction you can stabilize your
   condition until you get to an emergency room.

"It takes some doing, but you can take steps to minimize your contact
with sulfites if you are diagnosed with asthma or sulfite sensitivity,"
says Ziyad. "But you may not even know you have a problem with sulfites
until a reaction occurs. Undiagnosed people are at risk because even if
they know that sulfites can cause adverse reactions, they often don't
associate sulfites with their own health problems," says Ziyad.

"Regulations can go a long way towards protecting people, but there's no
substitute for knowledge."

For more information on sulfites, call (1-800) FDA-4010.

Ruth Papazian is a writer in Bronx, N.Y.

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Homeopathy:
Real Medicine or Empty Promises?

by Isadora Stehlin 

Some of the medicines of homeopathy evoke positive images--chamomile,
marigold, daisy, onion. But even some of Mother Nature's cruelest
creations--poison ivy, mercury, arsenic, pit viper venom, hemlock--are
part of homeopathic care.

Homeopathy is a medical theory and practice that developed in reaction
to the bloodletting, blistering, purging, and other harsh procedures of
conventional medicine as it was practiced more than 200 years ago.
Remedies made from many sources--including plants, minerals or
animals--are prescribed based on both a person's symptoms and
personality. Patients receiving homeopathic care frequently feel worse
before they get better because homeopathic medicines often stimulate,
rather than suppress, symptoms. This seeming reversal of logic is a
relevant part of homeopathy because symptoms are viewed as the body's
effort to restore health.

The Food and Drug Administration regulates homeopathic remedies under
provisions of the Food, Drug, and Cosmetic Act.

Kinder, Gentler Medicine 

In the late 1700s, the most popular therapy for most ailments was
bloodletting. Some doctors had so much faith in bleeding that they were
willing to remove up to four-fifths of the patient's blood. Other
therapies of choice included blistering--placing caustic or hot
substances on the skin to draw out infections--and administering
dangerous chemicals to induce vomiting or purge the bowels. Massive
doses of a mercury-containing drug called calomel cleansed the bowels,
but at the same time caused teeth to loosen, hair to fall out, and other
symptoms of acute mercury poisoning.

Samuel Hahnemann, a German physician disenchanted with these methods,
began to develop a theory based on three principles: the law of
similars, the minimum dose, and the single remedy.

The word homeopathy is derived from the Greek words for like (homoios)
and suffering (pathos). With the law of similars, Hahnemann theorized
that if a large amount of a substance causes certain symptoms in a
healthy person, smaller amounts of the same substance can treat those
symptoms in someone who is ill. The basis of his theory took shape after
a strong dose of the malaria treatment quinine caused his healthy body
to develop symptoms similar to ones caused by the disease. He continued
to test his theory on himself as well as family and friends with
different herbs, minerals and other substances. He called these
experiments "provings."

But, as might be expected, the intensity of the symptoms caused by the
original proving was harrowing. So Hahnemann began decreasing the doses
to see how little of a substance could still produce signs of healing.

With the minimum dose, or law of infinitesimals, Hahnemann believed that
a substance's strength and effectiveness increased the more it was
diluted. Minuscule doses were prepared by repeatedly diluting the active
ingredient by factors of 10. A "6X" preparation (the X is the Roman
numeral for 10) is a 1-to-10 dilution repeated six times, leaving the
active ingredient as one part per million. Essential to the process of
increasing potency while decreasing the actual amount of the active
ingredient is vigorous shaking after each dilution.

Some homeopathic remedies are so dilute, no molecules of the healing
substance remain. Even with sophisticated technology now available,
analytical chemists may find it difficult or impossible to identify any
active ingredient. But the homeopathic belief is that the substance has
left its imprint or a spirit-like essence that stimulates the body to
heal itself.

Finally, a homeopathic physician generally prescribes only a single
remedy to cover all symptoms--mental as well as physical--the patient is
experiencing. However, the use of multi-ingredient remedies is
recognized as part of homeopathic practice.


FDA Regulation 

In 1938, Sen. Royal Copeland of New York, the chief sponsor of the Food,
Drug, and Cosmetic Act and a homeopathic physician, wrote into the law a
recognition of any product listed in the Homeopathic Pharmacopeia of the
United States. The Homeopathic Pharmacopeia includes a compilation of
standards for source, composition and preparation of homeopathic drugs.

FDA regulates homeopathic drugs in several significantly different ways
from other drugs. Manufacturers of homeopathic drugs are deferred from
submitting new drug applications to FDA. Their products are exempt from
good manufacturing practice requirements related to expiration dating
and from finished product testing for identity and strength. Homeopathic
drugs in solid oral dosage form must have an imprint that identifies the
manufacturer and indicates that the drug is homeopathic. The imprint on
conventional products, unless specifically exempt, must identify the
active ingredient and dosage strength as well as the manufacturer.

"The reasoning behind [the difference] is that homeopathic products
contain little or no active ingredients," explains Edward Miracco, a
consumer safety officer with FDA's Center for Drug Evaluation and
Research. "From a toxicity, poison-control standpoint, [the active
ingredient and strength] was deemed to be unnecessary."

Another difference involves alcohol. Conventional drugs for adults can
contain no more than 10 percent alcohol, and the amount is even less for
children's medications. But some homeopathic products contain much
higher amounts because the agency has temporarily exempted these
products from the alcohol limit rules.

"Alcohol is an integral part of many homeopathic products," says
Miracco. For this reason, the agency has decided to delay its decision
concerning alcohol in homeopathic products while it reviews the
necessity of high levels of alcohol.

"Overall, the disparate treatment has been primarily based on the
uniqueness of homeopathic products, the lack of any real concern over
their safety because they have little or no pharmacologically active
ingredients, and because of agency resources and priorities," explains
Miracco.

However, homeopathic products are not exempt from all FDA regulations.
If a homeopathic drug claims to treat a serious disease such as cancer
it can be sold by prescription only. Only products sold for so-called
self-limiting conditions--colds, headaches, and other minor health
problems that eventually go away on their own--can be sold without a
prescription (over-the-counter).

Requirements for nonprescription labeling include:

 * an ingredients list
 * instructions for safe use
 * at least one major indication
 * dilution (for example 2X for one part per hundred, 3X for one part
   per thousand).

Over the past several years, the agency has issued about 12 warning
letters to homeopathic marketers. The most common infraction was the
sale of prescription homeopathic drugs over-the-counter. "It's illegal,
it's in violation, and we're going to focus on it," says Miracco.

Other problems include:

 * products promoted as homeopathic that contain nonhomeopathic active
   ingredients, such as vitamins or plants not listed in homeopathic
   references

 * lack of tamper-resistant packaging

 * lack of proper labeling

 * vague indications for use that could encompass serious disease
   conditions. For example, a phrase like "treats gastrointestinal
   disorders" is too general, explains Miracco. "This phrase can
   encompass a wide variety of conditions, from stomachache or simple
   diarrhea to colon cancer," he says. "Claims n to be specific so the
   consumer knows what the product is intended to treat and the
   indication does not encompass serious disease conditions that would
   require prescription dispensing and labeling."

In addition to enforcement, the agency is also focusing on preventing
problems by educating the homeopathic industry about FDA regulations.
"Agency representatives continue to meet with homeopathic trade groups
to tell them about problems we've had, difficulties we've seen, and
trends we've noticed," says Miracco.

FDA is aware of a few reports of illness associated with the use of
homeopathic products. However, agency review of those reported to FDA
discounted the homeopathic product involved as the cause of the adverse
reaction. In one instance, arsenic, which is a recognized homeopathic
ingredient, was implicated. But, as would be expected, FDA analysis
revealed the concentration of arsenic was so minute there wasn't enough
to cause concern, explains Miracco. "It's been diluted out."

Homeopathic Treatment 

Homeopathy consists of highly individualized treatments based on a
person's genetic history, personal health history, body type, and
present status of all physical, emotional and mental symptoms.

Jennifer Jacobs, M.D., who has a family practice and is licensed to
practice homeopathy in Washington state, spends at least an hour and a
half with each new patient. "What I do is review the lifetime history of
the patient's health," she explains. "Also I ask a lot of questions
about certain general symptoms such as food preferences and sleep
patterns that usually aren't seen as important in conventional medicine.
In looking to make the match between the person and the remedy, I need
to have all of this sort of information."

Why does someone trained in conventional medicine turn to homeopathy?
"With chronic illnesses such as arthritis and allergies, conventional
medicine has solutions that help control the symptoms but you don't
really see the patients getting better," says Jacobs. "What I have seen
in my homeopathic work is that it really does seem to help people get
better. I'm not saying I can cure everyone but I do see where people's
overall health is improved over the course of treatment."

Jacobs' hasn't abandoned conventional medicine completely. "My daughter
is 17 and she's never taken antibiotics, but I would have no hesitation
to use antibiotics if she had pneumonia, or meningitis, or a kidney
infection," says Jacobs.

About a third of Jacobs' practice is children, and ear infections are
one of the most common problems she treats. "Ear infections are
something that seems to respond well to homeopathy," she says. "Of
course, if a child is not better within two or three days, or if the
child develops a high fever, or if I feel that there's a serious
complication setting in, then of course I will use antibiotics. But I
find that in the majority of cases, ear infections do resolve without
antibiotics."

In addition to treating patients, Jacobs has conducted a clinical trial
the results of which suggest that homeopathic treatment might be useful
in the treatment of acute childhood diarrhea. The results were published
in the May 1994 issue of Pediatrics. In the article, Jacobs concluded
that further studies should be conducted to determine whether her
findings were accurate. A subsequent article appearing in the November
1995 issue of Pediatrics indicated that Jacobs' study was flawed in
several ways.

Although Pediatrics is published by the American Academy of Pediatrics,
Jacobs' study and several others published in such journals as The
Lancet and the British Medical Journal are considered "scanty at best"
by the academy. "Given the plethora of studies that are published [on
other topics] in scientific journals, I wouldn't say there are a lot of
articles coming out," says Joe M. Sanders Jr., M.D., the executive
director of the academy. "Just because an article appears in a
scientific journal does not mean that it's absolute fact and should be
immediately incorporated into therapeutic regimens. It just means that
the study is [published] for critique and review and hopefully people
will use that as a stepping stone for further research."

More studies are under way. For example, the Office of Alternative
Medicine at the National Institutes of Health has awarded a grant for a
clinical trial of the effects of homeopathic treatment on mild traumatic
brain injury.

Even with the dearth of clinical research, homeopathy's popularity in
the United States is growing. The 1995 retail sales of homeopathic
medicines in the United States were estimated at $201 million and
growing at a rate of 20 percent a year, according to the American
Homeopathic Pharmaceutical Association. The number of homeopathic
practitioners in the United States has increased from fewer than 200 in
the 1970s to approximately 3,000 in 1996.

When looking for a homeopathic practitioner, it's important to find
someone who is licensed, according to the National Center for
Homeopathy. Each state has its own licensing requirements. "Whether that
person is a medical doctor or a physician's assistant or a naturopathic
physician, I feel that anyone who's treating people who are sick needs
to have medical training," says Jacobs.


Real Medicine or Wishful Thinking? 

Many who don't believe in homeopathy's effectiveness say any successful
treatments are due to the placebo effect, or, in other words, positive
thinking.

But homeopathy's supporters counter that their medicine works in groups
like infants and even animals that can't be influenced by a pep talk.
Jacobs adds that sometimes she mistakenly gives a patient the wrong
remedy and he or she doesn't get better. "Then I give the right remedy,
and the person does get better," she says. "So it's not like everybody
gets better because it's all in their head. I think it's only because we
don't understand the mechanism of action of homeopathy that so many
people have trouble accepting it."

The American Medical Association does not accept homeopathy, but it
doesn't reject it either. "The AMA encourages doctors to become aware of
alternative therapies and use them when and where appropriate," says AMA
spokesman Jim Fox.

Similarly, the American Academy of Pediatrics has no specific policy on
homeopathy. If an adult asked the academy's Sanders about homeopathy, he
would tell that person to "do your own investigation. I don't personally
prescribe homeopathic remedies, but I would be open-minded."

That open-mindedness applies only to adults, however. "I would have
problems with somebody imposing other than conventional medicine onto a
child who's incapable of making that decision," he says.

Even professionals who practice homeopathy warn that nothing in
medicine--either conventional or alternative--is absolute. "I'm not
saying we can cure everyone [with homeopathy]," says Jacobs.

Isadora Stehlin is a member of FDA's public affairs staff. 

------------------------------------------------------------------------
------------------------------------------------------------------------


Non-Hodgkin's Lymphoma Becomes
More Common, More Treatable

by Margie Patlak 

A relatively unknown yet deadly cancer has become more common in the
last few decades and is now the sixth most common cancer in the United
States, according to the National Cancer Institute. This cancer of the
immune system, known as Non-Hodgkin's lymphoma (NHL), became more
familiar to the general public as it struck such luminaries as Jackie
Kennedy Onassis, Senator Paul Tsongas, and the Shah Mohammed Reza
Pahlevi of Iran.

NHL has increased 75 percent over the last 20 years, making it the most
rapidly rising cancer after lung cancer and melanoma, NCI says. The
incidence of NHL increased from 8.5 per 100,000 people in 1973 to 15.1
per 100,000 in 1991, and mortality from the disease increased from 4.8
per 100,000 people in 1973 to 6.5 per 100,000 in 1991. Although recent
studies have provided some intriguing clues, the cause of what some
experts call the "NHL epidemic" is not known. (See accompanying
article.) Fortunately, advances in treatment seem to be keeping pace;
the five-year survival rate for NHL rose from 31 percent to 51 percent
over the past 30 years, according to NCI.


Cancers of the Immune System 

NHL is a collection of more than a dozen different cancers of the
lymphatic system, which generates the body's immune defenses. This
system includes a network of channels akin to blood vessels through
which lymphocytes--important white blood cells of the immune
system--patrol the body for invading microbes. Along these lymphatic
routes in the neck, armpits, abdomen, and groin are clusters of
bean-shaped lymph nodes that house platoons of the infection-fighting
lymphocytes. These cells also cluster in areas that serve as gateways to
the body, including the mucous membranes lining the respiratory and
digestive tracts, and the skin. Lymphocytes travel in the bloodstream,
as well. The lymphatic system also includes such organs as the spleen,
thymus and tonsils.

Because NHL can develop wherever in the body lymphocytes can be found,
the cancer can crop up nearly anywhere. Symptoms can vary widely,
depending on the cancer site. The most common symptom is a noticeable,
usually painless swelling of a lymph node. NHL in the digestive tract
can cause nausea, vomiting, or abdominal pain; in the chest, shortness
of breath or cough may develop. If the brain is involved, patients may
have headaches, vision changes, or seizures. If the bone marrow is
affected, lymphoma cells may crowd out red blood cell precursors,
causing anemia. Reddened patches on the skin can occur when lymphoma
cells there prompt localized inflammation.

Because NHL can foster a hyperactive immune response, it often causes
symptoms that develop when the body is fighting an infection, such as
fevers, night sweats, tiredness, and weight loss. Another NHL symptom is
widespread itching, apparently triggered by immune cells' release of
histamines, the same compounds that cause itchiness in allergic
reactions.

NHLs can affect people of all ages, although the incidence of NHL
increases with age. About half of all cases are in people aged 60 and
older.

The treatments for NHL include drugs and radiation therapy regulated by
the Food and Drug Administration.



Diverse Group of Cancers 

To diagnose NHL, doctors remove a small sample of the tissue thought to
be cancerous. This procedure, known as a biopsy, is usually done with a
local anesthetic. A pathologist examines the tissue under a microscope
to look for cancer cells. The appearance of these cells and the proteins
on their surfaces helps the pathologist determine the type of NHL the
cancer is. The various types have distinctive appearances, carry
different prognoses (predicted outcomes), and have different treatments.
Whereas one type may be extremely deadly, another may be highly curable.

NHLs are classed as low-, intermediate- and high-grade. This
classification scheme accurately predicts the survival of untreated
patients, but is not as reliable in predicting outcome after treatment.
Low-grade lymphomas are slow-growing tumors, and some patients can
survive for more than a decade without treatment. Although chemotherapy
often can shrink low-grade lymphomas, the cancer usually recurs within
five years. Recurrent tumors can also be treated with chemotherapy or
radiation, but over time, low-grade NHLs tend to become more aggressive
and less responsive to therapy. Consequently, these types of lymphomas
are not cured with currently available treatment.

In contrast, intermediate-grade and high-grade lymphomas are
fast-growing tumors that, without treatment, generally are fatal within
a year or two of diagnosis. Chemotherapy may cure many types of these
lymphomas.

Doctors determine the stage of the cancer according to the number and
location of tumors. This information, which also affects prognosis, is
obtained from a physical exam, blood tests, and x-rays, CAT-scans, or
ultrasound scans of various organs and tissues. Biopsies of the bone
marrow and lymph nodes often are necessary. Regardless of NHL type,
patients have a better prognosis with appropriate therapy if they have:

 * the cancer in only one lymph node area or in only one area or organ
   outside the lymph nodes

 * no tumors more than 10 centimeters in diameter

 * no systemic symptoms, such as fevers or night sweats.

Younger patients also usually fare better than older ones.

A number of studies have pinpointed the genetic flaws that characterize
different types or subtypes of NHL. Experts predict that this
information will soon foster a new classification scheme that more
accurately predicts outcome.

Treatment Varies 

Doctors tailor treatment of NHL to the type of tumor, the stage of the
disease, and the patient's age and general health. Most patients receive
chemotherapy, radiation therapy, or both.

Because low-grade lymphomas usually grow slowly and cause few symptoms
but eventually become resistant to treatment, doctors may postpone
treatment until the cancer shows signs of spreading, or causes systemic
symptoms (such as fevers or weight loss), or until the tumors become
excessively bulky or threaten vital organs such as the kidneys or lungs.
NCI researchers and others have shown that delaying treatment does not
adversely affect long-term survival and may actually improve patients'
quality of life, as the treatments themselves can be debilitating. A
substantial proportion of patients with low-grade NHL have spontaneous
remissions, although these disease-free periods rarely last for long.

Chemotherapy for NHL usually involves several different drugs given at
the same time. Some drugs, such as chlorambucil (marketed as Leukeran),
are given by mouth; others, such as cyclophosphamide (marketed as
Cytoxan), are injected into a vein or muscle. To treat disease that has
spread to the brain, chemotherapy may be delivered to the fluid that
surrounds the brain through a needle in the spine. Chemotherapy is
usually given in cycles: a treatment period followed by a rest period,
then another treatment period, and so on.

A frequently used chemotherapy regimen for NHL combines
cyclophosphamide, doxorubicin hydrochloride (marketed as Adriamycin),
vincristine (marketed as Oncovin), and the anti-inflammatory drug
prednisone. Although used for about 20 years, recent studies suggest
this regimen is as effective and has less serious side effects than some
of the newer drug combinations, according to Alan Aisenberg, M.D., of
Massachusetts General Hospital.

An experimental NHL chemotherapy compound is a drug called fludarabine.
FDA approved this drug as Fludara in 1991 for treating a type of
leukemia, and, according to NCI's Bruce Cheson, M.D., early studies
suggest that more low-grade NHL patients go into complete remission when
they are treated with fludarabine than when they are treated with
standard drugs such as chlorambucil.

Chemotherapy kills off rapidly dividing cells. Although its prime
targets are the rapidly reproducing cancer cells, it also kills healthy
dividing cells such as blood cells and the cells lining the intestinal
tract and hair follicles. As a result, its side effects can include
anemia, an increased risk of infection, mouth sores or bleeding, hair
loss, nausea, and vomiting. Some of these side effects can be countered
with anti-nausea medication or injections of hormone-like compounds
called growth factors that help the body quickly restore its lost blood
cells.

Some of the chemotherapy drugs used to treat NHL, such as doxorubicin
and mitoxantrone, can damage heart tissue, making some people with heart
disorders unable to tolerate this treatment. These patients may be given
alternative kinds of chemotherapy and radiation therapy. Radiation
therapy alone may be the treatment of choice for some patients,
especially those who have only a single, small tumor. Some types of NHL
respond best to chemotherapy followed by radiation therapy.

Radiation therapy uses high-energy x-rays to damage cancer cells and
stop their growth. Radiation therapy is directed to the areas of the
body known to harbor cancer cells. As an extra precaution, radiation may
be directed to a broader area, such as to all the lymph nodes in the
region of a known cancerous site. The treatment is generally given on an
outpatient basis.

Radiation therapy can cause fatigue and red or dry skin in the treated
area. Radiation directed to the chest and neck can cause patients to
have a dry, sore throat and some trouble swallowing. Patients may also
have shortness of breath or a dry cough. Radiation therapy to the
abdomen may cause nausea, vomiting or diarrhea. Some patients who
receive radiation to the spine may also have tingling or numbness in
their arms, legs and lower back.

The chemotherapy used to treat NHL can cause sterility as can radiation
directed to the pelvis. NHL treatments may also make patients more
susceptible to other cancers, including those of the lung, brain,
kidney, bladder, skin, and blood.

Bone Marrow Transplants 

NHL patients with a poor prognosis may be candidates for high-dose
chemotherapy with or without radiation followed by a bone marrow
transplant. The transplant is necessary to restore the blood cells
killed by the intensive cancer therapy. Before therapy, a portion of the
patient's bone marrow is usually extracted and may be treated in an
attempt to purge any cancer cells. The bone marrow contains "stem"
cells, which are immature cells from which all blood cells develop. The
bone marrow is returned to the patient after therapy. Patients may also
receive stem cells harvested and enriched from their blood. Growth
factors to boost the production of blood cells are also used in
conjunction with bone marrow transplants.

Intensive radiation or chemotherapy followed by a bone marrow transplant
has a number of potential serious side effects, including
life-threatening infections, bleeding, damage to the liver, kidneys,
lungs or heart, and subsequent leukemia. Although FDA has approved the
chemotherapy drugs and growth factors most commonly used in conjunction
with bone marrow transplants for cancer therapy, it does not regulate
the procedure itself, just as it does not regulate other surgery and
medical procedures considered "practice of medicine."

Studies provide strong evidence that bone marrow transplants improve the
long-term survival of patients with intermediate- or high-grade
lymphomas that have relapsed but are still sensitive to chemotherapy.
There is little, if any, evidence of patients with low-grade lymphomas
benefiting from the procedure, according to NCI's Cheson. Also, bone
marrow transplants are usually not effective in NHL patients whose
tumors do not respond to chemotherapy. NCI is supporting more research
to assess the value of bone marrow treatment for different types of NHL.

Research is also under way to evaluate the safety and effectiveness of
monoclonal antibody therapies in NHL patients. Monoclonal antibodies are
synthetic antibodies that latch onto specific substances called
antigens. Some antigens are unique to lymphoma cells. Researchers have
designed monoclonal antibodies directed towards these lymphoma antigens.
The antibodies may be attached to radioactive compounds or toxins that
kill cells. Monoclonal antibody therapy is designed to more selectively
target cancer cells, resulting in less severe side effects than standard
therapy. Researchers are also testing the anti-cancer potential of a
number of compounds produced by immune cells. These compounds, which
include interleukin 2 and alpha interferon, are usually given in
addition to standard chemotherapy or radiation therapies.

"We're at an exciting time in lymphoma research," said Cheson. "There
are a lot of promising new drugs on the horizon." And people are eyeing
that horizon more intently as NHL becomes more common.

Margie Patlak is a writer in Elkins Park, Pa. 

------------------------------------------------------------------------

Patient Information

Patients who wish to participate in research evaluating experimental NHL
treatments should contact the National Cancer Institute at (1-800)
4-CANCER.


------------------------------------------------------------------------

Tracking the Cause of a Cancer Increase

Medical researchers have been trying to find a reason or reasons for the
rising incidence of Non-Hodgkin's lymphoma, which has been increasing in
this country since the 1950s. Suspects include: pesticides, hair dyes,
AIDS, immune-suppressing therapies, and improved diagnosis.

Studies on a possible relationship between pesticides and NHL were
prompted by two observations. First, the central part of the United
States, which is predominantly an agricultural area, has been a hot spot
for NHL since 1950. Second, NHL incidence also has been increasing more
rapidly in rural areas than urban areas. These findings suggest certain
pesticide exposures might cause NHL in some people. The National Cancer
Institute's Sheila Zahm, Sc.D., and others found a two- to eightfold
increase in NHL incidence among farmers who frequently used phenoxy
herbicides such as 2,4-D, which are widely used on crops such as wheat,
corn, oats, rye, barley, and sugarcane. These herbicides are also
commonly used to rid lawns of weeds. More research needs to be done,
however, to assess the possible link between NHL and pesticides.

Researchers are also examining the potential for hair dyes to cause NHL.
The largest study on this, conducted by the American Cancer Society and
reported in 1994, found women who used black hair dye for 20 years or
more were more than four times as likely to develop NHL than women who
didn't use hair dye. This finding confirms those of other studies. But
because only a small fraction of women who dye their hair use black hair
dye, this alone cannot contribute significantly to the increase in NHL
in recent years.

According to Carol Palackdharry, M.D., of the Medical College of Ohio,
changes in diagnostic criteria can account for only about 10 to 15
percent of the current cases of NHL. A similar percentage of cases can
be attributed to AIDS, researchers M.H. Gail and colleagues estimated in
a 1991 issue of the Journal of the National Cancer Institute. The immune
suppression AIDS induces makes people more susceptible to NHL. The
increased use of immune-suppressing therapies to prevent rejection of
organ transplants, and to treat rheumatoid arthritis, cancer, and other
disorders might also account for a small percentage of NHL cases,
according to Palackdharry.

Further research is needed to fully explain the rising incidence of NHL.
As Dan Longo, M.D., formerly at NCI and now at the National Institute on
Aging, sums up in the August 1994 issue of the journal Oncology, "... it
appears that lymphoma incidence is a building tidal wave. What remains
unclear is whether we can rapidly learn enough about the various causes
to implement successful prevention strategies that will enable us to
diminish the damage done by the coming wave."

--M.P. 


------------------------------------------------------------------------

Inside FDA:
Hazardous Duty in the Bering Sea

by John Henkel 

This is one in a series of articles on FDA activities and concerns. 

Snow was blowing horizontally that January day as the wind whipped into
a 50-mile-an-hour frenzy. Out in the Bering Sea, some 60 miles off
Alaska, two FDA investigators wrapped up their inspection of a floating
seafood processor.

Temperatures had dipped below freezing, and the sea was crashing with
15-foot waves. The investigators climbed down a rope ladder onto a
16-foot boat that was to carry them to a Coast Guard cutter about a
quarter mile away.

After the small boat got under way, the pilot radioed the cutter that he
wasn't sure the craft could make it through the severe weather. But he
forged on, finally reaching the cutter and delivering the two to safety.

"We barely made it back," says Janelle Main, investigator in FDA's Puget
Sound [Washington] resident post, who shared the adventure with
investigator Elizabeth Sheller. "It was really, really rough out there."

Another typical day in the life of an FDA investigator? Well, not
exactly. But it does illustrate the dangerous situations these folks can
find themselves in while on duty. Main is one of seven investigators
from FDA's Seattle district who have volunteered to inspect floating
processors. These vessels, 65 to 300 feet long, actually are "factories"
that catch, process, and prepare for market various types of fish while
at sea. More than 85 of the processors, registered in the United States,
operate off the coasts of Alaska, Washington and Oregon.

Inspecting processors in Alaskan waters poses major hazards, says Main,
largely due to the risk of hypothermia--a dangerous lowering of body
temperature--from the icy seas. "If you fall into the Bering Sea, you've
got about two minutes to be pulled out or there's a good chance you
could die," she says. When the seas are choppy, riders could be thrown
overboard from the small boats. Or the boats could capsize.

Getting into the boats is a trick in itself. Boarding a floating
processor usually involves descending a rope ladder from a Coast Guard
cutter and taking a small boat to the processing vessel. Riders then
must step--or sometimes leap--from the boat to another rope ladder.
Going up this ladder, which may be as long as 30 feet, is not easy,
especially in rough seas. "I've fallen off the rope before," says Main,
"but fortunately I fell into the boat and not the water." She injured
her knee in that incident and had to undergo physical therapy.

Why put your life on the line for this work? Because, Main says, it is
important to ensure that floating processors, like seafood factories
found on land, provide products that are safe for consumers. This means
the processors must adhere to strict procedures for sanitation, storage
and refrigeration.

In the past, FDA relied on Alaska state officials to inspect floating
processors while they were docked. But because these ships don't process
fish when in port, the state inspections didn't look at operations while
they were going on.

In 1994, former Seattle investigator Debra DeVlieger set up a joint
inspection program with the Coast Guard that allows FDA investigators to
ride along on cutters as the Coast Guard conducts its own inspections of
vessel safety and seaworthiness.

In August 1994, FDA boarded the first processing vessels under the
program during hake season off Washington and Oregon. Since then, Chris
Rezendes, FDA supervisory investigator, has expanded the program into
Alaska. Investigators have gone into the Bering Sea during pollack A
(January and February) and pollack B (August and September) seasons.

An investigator can inspect as many as 11 processors during a trip,
which usually lasts two weeks. "Some trips have been less fruitful,"
says Main. "Because of weather, only two or three boardings could be
made." Also, the cutters are sometimes diverted to search-and-rescue
missions.

Main calls the joint inspection program "a good use of taxpayers'
money." The Coast Guard does not charge FDA for lodging on board the
cutters and charges only about $5 a day for meals. By comparison, an air
flight to Alaska can cost as much as $800. "We've saved many thousands
of dollars," says Main.

She adds that the program has paid dividends in other ways. Though the
inspections have resulted in some warning letters, FDA investigators
have set up "a really good relationship" with processors. In the
off-season, FDA holds meetings to discuss concerns with quality control
officials and others representing processors. By sharing information
about what FDA is looking for in inspections, the agency receives a high
degree of compliance and cooperation.

"I'm confident that the program is worthwhile and that conditions are
better on the processors because we have a presence out there," Main
says.

Besides Main and Sheller, the other FDA volunteer investigators are Jody
Robinson, Gretchen Weber, Jim Vik, Gordon Wales, and Bob Williams.


John Henkel is a member of FDA's public affairs staff.

------------------------------------------------------------------------

Updates

Public Can Comment on Animal Organ Transplants

The public has until Dec. 23 to submit written comments on a proposed
guideline about xenotransplantation--the transplantation of animal
organs and tissue into humans.

FDA, the national Centers for Disease Control and Prevention, and the
National Institutes of Health developed the guideline to reduce public
health risks while not impeding medical innovation.

People may send comments to FDA's Dockets Management Branch, HFA-305,
Room 1-23, 12420 Parklawn Dr., Rockville, MD 20857.


The recommendations include:

 * Taking appropriate safety measures for pre-transplant animal
   screening to keep as low as possible any chance that animal diseases
   may be transmitted to human recipients.

 * Archiving biologic samples, such as plasma and tissues, from source
   animals and human recipients for potential public health
   investigations.

 * Selecting xenotransplant team members for their expertise in
   providing adequate safeguards and in conducting research that will
   yield useful data.

 * Having local review boards evaluate the operati to assess infectious
   disease risks.

 * Monitoring patients after xenotransplants for infectious agents,
   including not yet recognized animal organisms that may cause diseases
   in humans.

The three agencies are collaborating with the Health Resources and
Services Administration to develop a pilot program for a national
registry to provide a central database for public health research and
investigations.

The guideline was published in the Sept. 12, 1996, Federal Register. To
obtain a copy, send a self-addressed adhesive label with your order to
FDA's Manufacturers Assistance and Communications Staff, HFM-42, Center
for Biologics Evaluation and Research, 1401 Rockville Pike, Rockville,
MD 20852-1448; or fax your order to (1-888) 827-3844. The guideline is
also available on the World Wide Web at
http://www.fda.gov/cber/cberftp.html; by file transfer protocol at
ftp://ftp.fda.gov/CBER/; and by E-mail at Xeno@al.cber.fda.gov.

A copy of an FDA backgrounder, "Fact Sheet on Xenotransplantation," may
be ordered by writing to FDA, HFI-40, Rockville, MD 20857, or faxing
your order to (301) 443-9057. Include the publication number: BG 96-6. 

Policy Change for Emergency Treatments

Promising experimental therapies may now be used in life-threatening
situations to treat patients who can't give their consent. This change
in policy is reflected in a new FDA final rule and a companion document
by the National Institutes of Health.

Before, patients in a life-threatening situation could not take
advantage of experimental therapies if they were unable to provide the
required informed consent or did not have a family member or other legal
representative readily available to provide it. But in the new rule,
published in the Oct. 2 Federal Register, FDA establishes the criteria
under which such patients may receive, without consent, treatment with
promising experimental drugs and medical devices.

The new policy is expected to offer critically ill, unconscious patients
who cannot be successfully treated with conventional therapies the
benefits of experimental intervention.

FDA's rule allows patients to be enrolled in clinical trials without
their consent provided that an independent doctor and an institutional
review board, or IRB, agree that the clinical trial addresses a
life-threatening situation and that other criteria are met. An IRB is a
committee of experts and lay people established to review research.

Also, patients may receive the experimental therapy only if:

 * available treatments are unproven or unsatisfactory

 * research cannot otherwise be carried out to determine whether the
   therapy is safe and effective

 * it is not feasible to obtain informed consent from the patient or the
   patient's legal representative

 * risks and benefits of the experimental procedure are reasonable,
   compared with those associated with the patient's medical condition
   and standard therapy.

The rule also includes additional protections, such as consultation with
the community, public disclosure of study design and attendant risks
before the study's commencement, and public disclosure of study results
when the study is completed. Also, FDA reviews protocol design and other
information on the proposed therapy before the study can proceed.

The NIH companion document, "Emergency Research Consent Waiver," applies
to all agencies in the Department of Health and Human Services. Both FDA
and NIH are part of the department. NIH's document reaffirms the
government's policy of protecting human research subjects. It contains
the same criteria as FDA's final rule. 

New Device for
Degenerative Disc Disease

A new implantable medical device for stabilizing and fusing the spine is
the first of its kind to receive FDA approval as a treatment for certain
people with degenerative disc disease. It provides an option for doctors
to treat patients who do not respond to nonsurgical treatment.

The BAK Interbody Fusion System was approved only for people who need
surgical fusion of adjacent vertebrae above and below a diseased disc.
The device is a hollow metal cage about an inch long that is implanted
into disc space between two vertebrae to stabilize the spine and to
allow for fusion of the vertebrae. The device is not intended for people
with general back pain.

In degenerative disc disease, discs between the vertebrae break down and
cause lower back and leg pain. Conventional treatments include back
braces, physical therapy, and, in some people, surgery to remove the
disc. Fusion with hooks and rods has been used in some cases.

When implanting the BAK system, the surgeon removes bone from the
patient and packs it inside the implant. Over time, the bone can grow
through the holes in the wall of the cage and around the outside of the
cage, fusing the vertebrae and often reducing back pain.

In a clinical study, the device was implanted in 947 patients aged 21 to
65 who needed spinal fusion surgery for degenerative disc disease.

After two years, 254 patients were evaluated. The device was successful
in 184 patients (72 percent). For this group, the spine had fused, pain
was decreased, and there was no loss of muscle strength or function--the
ability to sit, walk, or put on shoes. Complications were similar to
those reported from conventional surgery and included damage to the
nerve and blood vessels, infection, and the need for more surgery to
further stabilize the spine.

As a condition of approval, the manufacturer must conduct postmarketing
studies to determine the device's long-term effectiveness and to examine
any devices removed from patients for any reason. The company also must
provide information that would help potential patients make informed
decisions about the surgery.

Spine-Tech Inc., of Minneapolis, makes the BAK Interbody Fusion System. 


New Brain Cancer Treatment

A recently approved implantable wafer is the first technology to deliver
an anticancer drug directly to the site of a surgically removed brain
tumor in recurrent brain cancer.

Gliadel wafers were approved by FDA on Sept. 24 to treat glioblastoma
multiforme, an aggressive type of brain cancer in the malignant glioma
class of cancers. Glioblastoma multiforme, which occurs mainly in
adults, has been extremely difficult to treat effectively with cancer
therapies such as surgery, radiation, and traditional chemotherapy.

Implanted into the cavity of the brain created when a tumor is removed,
the wafers--seven or eight of them, depending on the cavity's
size--deliver the anticancer drug BiCNU (carmustine) directly to the
affected area of the brain. The direct delivery lessens the exposure of
the rest of the body to the drug.

In a study of 222 patients with recurrent malignant glioma who had been
initially treated with surgery and radiation, the six-month survival
rate in those with glioblastoma multiforme who received Gliadel was 56
percent, compared with 36 percent for those who received a placebo. In
patients with diagnoses other than glioblastoma multiforme, Gliadel did
not affect survival rates. A small 32-patient study supported these
results.

Patients should be monitored closely after implantation for possible
complications such as seizures, infections, abnormal wound healing, and
brain swelling.

Approval followed a June 15, 1996, recommendation for approval by FDA's
Oncologic Drug Advisory Committee. Since October 1995, Gliadel had been
available under a Treatment IND to patients with recurrent malignant
glioma.

Gliadel is manufactured by Guilford Pharmaceuticals Inc., of Baltimore. 


New Bronchial Device

A new device to detect bronchial tissue abnormalities in patients with
previous, current or suspected lung cancer has been approved by FDA.

The Xillix Life-Lung Fluorescence Endoscopy System uses a tube inserted
through the mouth into the bronchi (tubes leading from the trachea to
the lungs) to deliver a blue laser light to the bronchial tissue. The
laser light elicits a fluorescence from the tissue, which projects an
image on a video monitor. Normal tissue appears green; abnormal tissue
appears reddish-brown. A biopsy of suspicious tissue can then identify
cancer or another abnormality.

The system was approved last Sept. 19 for use with conventional white
light bronchoscopy, in which a white light is used to illuminate lung
tissue to help physicians identify abnormalities. The new system detects
more tissue changes than can be seen with the white light alone.

The manufacturer, Xillix Technologies Corp., of Richmond, British
Columbia, sponsored a study that examined 700 spots on the bronchial
tubes of 173 patients at seven medical facilities in the United States
and Canada. Patients first underwent white light bronchoscopy and then,
with the bronchoscope still in place, the fluorescence endoscopy. The
patients either had symptoms or x-ray findings indicating possible lung
cancer or had previously had the disease.

Subsequent biopsy of all 700 suspicious lesions found that 75 patients
had one or more abnormal spots. Of those, 28 patients, or 37 percent,
were correctly identified by white light bronchoscopy as needing biopsy.
The fluorescence system combined with white light correctly identified
56 patients, or 75 percent, as needing biopsy--twice as many as white
light alone.

Few adverse effects were associated with the new system. However, the
fluorescence exam generated 196 additional biopsies, of which only 60
proved to have significant cellular abnormalities.

As a condition of approval, which was based on the study data and on the
recommendation of FDA's Ear Nose and Throat Devices Panel, the
manufacturer must conduct a postmarketing study to see if doctors will
generally agree on which images are positive and which are negative. 


Recall of Factor Used to Treat Hemophilia A

One lot of Monoclate-P, an antihemophilic factor (factor VIII) used to
treat hemophilia A, has been voluntarily recalled by the manufacturer,
Centeon L.L.C. of King of Prussia, Pa.

The recalled lot is P72304, with an expiration date of April 12, 1998.
It was recalled in early October as a precautionary measure. At press
time in October, FDA had not received any reports of illness associated
with this product.

Individuals or institutions who have any vials of the recalled lot
should return the product immediately to the manufacturer. The company's
customer support telephone number is (1-800) 683-1288.

The recall of the lot of Monoclate-P was prompted by the possibility
that it had been damaged and possibly contaminated as a result of a
manufacturing problem. Similar manufacturing problems may be related to
reports linking one lot of Centeon's human albumin, Albuminar-25, to
septicemia, a life-threatening blood infection. This lot was recalled by
the manufacturer last Sept. 23, followed by the recall of nine other
lots.

On Oct. 9, as a precautionary measure, Centeon L.L.C. voluntarily
recalled all Albuminar brand human albumin and Plasma Plex brand plasma
protein products, distributed under the Centeon and Armour labels.
Because these products are typically administered in hospitals and other
health-care facilities, it is unlikely that consumers have any.
Health-care professionals with questions may call the company's medical
information line at (1-800) 551-0210.

FDA is asking health professionals to report any adverse events
associated with these products to MedWatch, the agency's adverse event
reporting program, at (1-800) FDA-1088, and to the company. 


Devices to Have Preproduction Quality Controls

Firms that make medical devices posing a medium or high risk to patients
must now incorporate quality controls in the products' design, according
to a new FDA rule. Such controls before production will save lives and
greatly reduce risks from unrecognized design flaws.

The quality system rule, published in the Oct. 7, 1996, Federal
Register, requires that manufacturers:

 * establish performance requirements for a device before production
 * ensure that device components are compatible with each other
 * select adequate packaging materials
 * when appropriate, do a risk analysis.

For example, when designing defibrillators for emergency use in
hospitals and ambulances to restart the heart, firms must consider all
aspects of use in the ambulance as well as in the hospital. Firms must
consider such ambulance-related factors as storage temperature, road
shock and vibration, two-way radio interference, and electrical noise
generated by the siren. They must review their design throughout
development to make sure it is meeting all requirements.

In a review of medical device recalls over six years in the 1980s, the
Government Accounting Office found that design defects accounted for
about 44 percent of the products' quality problems and that proper
design controls could have prevented the problems. Design-related
defects have been found in critical products such as heart valves,
catheters, defibrillators, pacemakers, ventilators, patient chair lifts,
and laboratory tests.

The quality system rule will make standards for U.S. medical devices
consistent with quality system requirements worldwide. The rule's
standards closely follow the international standard, ISO 9001,
fulfilling a mandate of the Safe Medical Devices Act of 1990 to
harmonize these requirements. The rule also includes purchasing and
manufacturer servicing controls and clarifies requirements of FDA's
current good manufacturing practices. Firms may develop their own
methods for meeting the objectives of each control tool.

The rule takes effect June 1, 1997, but FDA will not enforce the design
control provisions until after June 1998, when equivalent provisions
become mandatory in Europe.

A subsequent proposal and final rule will cover firms that service or
refurbish devices outside the original manufacturer's control. 


Calls to FDA Office Now Free

The Office of Consumer Affairs at FDA has a new free telephone number
for consumer inquiries: (1-800) 532-4440 (in the D.C. metropolitan area,
call (301) 827-4420). Inquiries about breast implants, previously
directed to the breast implant information line, should be directed to
this number. 

Three Free Reprints

The following FDA Consumer reprints, listed with their publication
numbers, are available free from FDA:

 * Boning Up on Osteoporosis (FDA) 96-1257
 * How Folate Can Help Prevent Birth Defects (FDA) 96-2306
 * Adults Need Tetanus Shots, Too (FDA) 96-9017.

To order single copies, write to FDA, HFE-88, Rockville, MD 20857. To
order 2 to 100 copies, write to FDA, HFI-40, at the same address, or fax
your order to (301) 443-9057. Include the publication number.


------------------------------------------------------------------------


Notebook

The Notebook: a potpourri of items of interest gathered from FDA news
releases, other news sources, and the Federal Register (designated FR,
with date of publication). The Federal Register is available in many
public libraries. It is also available electronically through GPO Access
at the Government Printing Office.

The infant formula regulations comment period has been extended to Dec.
6 by FDA. Revisions the agency is proposing include:

 * setting standards for current good manufacturing practice

 * amending requirements on quality control procedures, notification,
   records, and reports

 * requiring infant formulas to contain, and be tested for, certain
   nutrients.

Written comments should be submitted to the Dockets Management Branch
(HFA-305), FDA, Room 1-23, 12420 Parklawn Drive, Rockville, MD 20857.
(FR Sept. 23)

Folic-acid-fortified grain products marketed before Jan. 1, 1998--when
fortification becomes mandatory--do not have to be labeled as containing
folic acid unless a health claim for the nutrient is made, according to
an FDA final rule. FDA originally had required fortification before Jan.
1, 1998, to be indicated on labeling. But the agency reconsidered after
receiving a letter from the March of Dimes pointing out that though
manufacturers want to fortify earlier than the deadline, many are
holding off because they could not use existing label stocks. FDA
mandated folic acid fortification because of evidence that the nutrient
can reduce the risk of neural tube birth defects such as spina bifida.
(FR Sept. 5)

Blood collection and distribution facilities must quarantine whole blood
and blood products taken from a donor who initially tests negative for
HIV antibodies but later tests positive, according to a final FDA rule.
Facilities also must prepare and follow written standard operating
procedures that define steps to be taken when screening tests show later
batches of a donor's blood to be reactive to HIV antibodies. Facilities
then must perform a licensed, more specific HIV antibody test. (FR Sept.
9)

Administering streptokinase to stroke victims more than three hours
after the stroke is not helpful and may cause more serious problems,
according to Australian research. Streptokinase is a
blood-clot-dissolving drug. The study of 340 patients sought to
determine if giving the drug within four hours of the onset of acute
ischemic stroke (insufficient blood supply to the brain) would reduce
disability or death. The trial was stopped early because of unacceptably
high complication rates. The researchers say larger trials are needed to
test further the effectiveness of therapy given within three hours. They
add that public education may be needed to increase the number of
patients who seek treatment early after a stroke. (Journal of the
American Medical Association, Sept. 24)

High school students who drink alcohol or use illegal drugs, including
anabolic steroids, are more than twice as likely as teenagers who don't
use drugs to carry a weapon or get into a fight. A survey of more than
12,000 high school students in the United States shows the increased
risk of violence is similar among adolescents regardless of gender.
(Archives of Pediatrics and Adolescent Medicine, 1996)

------------------------------------------------------------------------


Investigators' Reports


Undercover Cows Help Get Guilty Pleas

by Tamar Nordenberg

For the first time in FDA history, beeper-carrying cows were used in an
undercover investigation to track down evidence against two cattle
dealers who sold medicated livestock for use as human food.

The cattle dealers were brothers Richard Eugene Gorr and Jeffery Lee
Gorr, owners of Gorr Livestock of Petersburg, Mich. Both pleaded guilty
July 18, 1996, in the U.S. District Court for the Eastern District of
Michigan to buying and selling cattle between 1988 and 1994 that
contained illegal levels of drugs. Cows headed for slaughter with
signal-emitting beepers in their stomachs and FDA agents close behind
helped secure the guilty pleas.

Both brothers were sentenced Oct. 10, 1996. They were each fined
$25,000--five times higher than the recommended sentencing
guidelines--because of the extent of their conduct and their
profit-making motive. Also, each must serve three years' probation and
perform 150 hours of community service.

No injuries were attributed to the Gorr cattle, but cows with illegal
drug residues can pose significant health hazards if the cows are used
for human food, according to FDA. People allergic to antibiotics can
suffer severe, even fatal, allergic reactions to the residues. Also,
illegal antibiotic residues can cause diarrhea and other stomach and
intestinal problems, vitamin deficiencies, and resistance to antibiotic
medications.

To ensure a food is free of harmful drug residues when eaten, FDA
requires a "withdrawal period" between the time an animal is medicated
and the time it is slaughtered for human food. This gives the drug time
to metabolize.

FDA's undercover investigation revealed that Gorr Livestock bought sick,
old cattle that were often treated with antibiotics and other
drugs--either by the farmers who sold the cattle to the Gorrs or by the
Gorrs themselves--and sold the cattle without regard to the withdrawal
periods.

FDA first became aware of the extent of the Gorrs' violations in 1992,
when a Michigan Department of Agriculture inspector traced slaughtered
dairy cows with illegal drug residues to Gorr Livestock.

In March 1993, FDA Detroit district employees Michael Owens, an
investigator, and Judith Jankowski, a tissue residue monitor, went to
slaughterhouses in western Michigan to follow up on reports of about 300
violative tissue samples in the Gorr Livestock area. The violations had
been reported to FDA by the U.S. Department of Agriculture, which
collects cattle tissue samples from slaughterhouses, tests them for
antibiotics and other drugs, and reports illegal drug residues to FDA.

In Michigan, Owens interviewed farmers who were believed to be the
source of animals with violative residues. The interviews revealed that
in many cases, the animals didn't really come from their farms. In one
case, a farm thought to be the source of a violative dairy cow didn't
even keep dairy cows--only steers.

The discrepancies led FDA to suspect the Gorrs of widespread violations,
including switching the medicated cows' identifying tags so they
couldn't be traced to Gorr Livestock.

"It became clear the Gorrs did this a lot--selling medicated cattle with
the hope that USDA wouldn't test the cattle and detect the illegal
residues," says Ross Parker, an assistant U.S. attorney in Detroit who
prosecuted the brothers.

Between September 1988 and February 1996, FDA and the Michigan
Department of Agriculture warned Gorr Livestock about findings of 36
illegally medicated cattle. In addition, USDA warned the Gorrs in
writing 12 times about illegal drug residues.

To get proof that the Gorrs were violating animal drug laws, FDA's
Office of Criminal Investigations conducted three "sting" operations, in
June, August and November 1994.

OCI special agents, with the help of Owens and Jankowski, began by
observing the Gorrs' daily routine, including the days they usually took
their cattle to auction or to slaughterhouses. Then, the agents posed as
cattle dealers in southeastern Michigan, observing the Gorrs' illegal
activities and documenting them on audio- and videotape.

For each sting operation, the agents obtained a cow headed for
slaughter. With the assistance of the Michigan Department of
Agriculture, they placed a transponder, or beeper, in the cow's stomach.
The beeper was inserted through the cow's throat using a speculum, the
way a cow is given medication.

Because transponders allow authorities to track an animal without a
telltale mark like an ear tag, they have been used in Africa to catch
poachers, according to investigator Owens. "But Gorr Livestock was a
unique case," he says. "It was the first time FDA had ever used a
transponder in a cow for a criminal investigation."

Each beeper-carrying cow was placed on a farm with other animals. Posing
as a farmer, an OCI agent told the Gorrs he wanted to get rid of a
sickly cow, but he wasn't sure it could pass USDA inspection because it
had been medicated recently. The cows were not actually medicated,
though.

All three times, the Gorrs bought the cow, and the agents watched the
brothers and waited, sometimes for up to a week. The beepers allowed FDA
to track the cows to slaughter. The agents kept a receiver in their car.
When the Gorrs loaded cows on a truck to transport them to an auction or
slaughterhouse, the agents drove past the truck. If the receiver picked
up a signal, they knew their cow was on the truck, and they followed the
truck to its destination.

The Gorrs sold all three cows without waiting until the withdrawal
period expired. "The more quickly they moved them, the more money they
made," says an OCI agent. "Otherwise, they would have had to feed and
take care of them."

The FDA investigators followed each beeper-containing animal to
slaughter and retrieved the beeper, which cost several hundred dollars.
"I had to cut open the slaughtered cow's stomach and stick my hands in
to fish around for the beeper," Owens says.

The stings came off with only one minor hitch. After the first buy, a
steer belonging to the farm FDA agents were using broke down the farm
fence and eluded agents for over a mile, until they recruited a local
cowboy to lasso the animal.

Armed with the evidence collected by FDA, the U.S. Attorney's Office for
the Eastern District of Michigan obtained a search warrant on Jan. 20,
1995, and FDA special agents seized the Gorrs' records and drugs.

In their plea agreements, the Gorrs agreed to cooperate with law
enforcement agencies in related investigations into other farmers'
illegal practices. Also, they agreed to keep detailed records about
their livestock.

After sentencing, FDA will closely monitor Gorr Livestock's record
keeping.

Tamar Nordenberg is a staff writer for FDA Consumer. 

------------------------------------------------------------------------

Unapproved Dental Drug Goes Up in Smoke

Root canal filler containing a toxic substance was destroyed under court
order at FDA's request because it was an unapproved drug whose safety
and effectiveness had never been established. An environmental services
company burned the product in an incinerator.

Harvey Altholtz, D.M.D., president of the Connecticut firm that
distributed the filler, had asserted that because his White One-Step
Endodontic Formula was widely used, it was generally recognized as safe
and effective and therefore not a new drug requiring FDA approval. But a
U.S. district judge ruled that adequate and well-controlled studies are
required to establish drug safety and effectiveness and, since study
data on the root canal filler had never been submitted to FDA, ordered
the product destroyed.

Stephen Souza, an investigator with FDA's Hartford, Conn., resident
post, inspected Altholtz's Dental Clearing House, in Simsbury, Conn., on
Jan. 18, 1992, following numerous complaints from health professionals
that advertisements claimed the one-step formula "meets FDA standards"
and was "FDA sanctioned." Agency records showed no approved new drug
application (NDA) on file for the product.

Souza found Altholtz was distributing the formula in 60-gram (2-ounce)
bottles of white powder and 30-milliliter (1-oz.) bottles of liquid. One
bottle of each was to be mixed at the ordering dentist's office to
create the filler.

"Altholtz had the powder and liquid made to his specifications at
contract laboratories," Souza says. "The records showed that the liquid
contained an approved dental analgesic-antiseptic, eugenol, and some
inert ingredients. But the active ingredient in the powder was
paraformaldehyde, a toxic preservative that has no approved use in drug
products."

A month later FDA wrote to Altholtz, warning him that seizure or other
legal action might ensue if he didn't stop selling the unapproved drug
and advertising it with statements that imply approval, such as "meets
FDA standards."

Altholtz wrote back, saying that an FDA official had told the formula's
original owner in a 1982 letter that the agency would take no regulatory
action until it reviewed the product to determine its safety and
effectiveness.

"If the FDA now feels it is not a safe and efficacious product," he
wrote, "I think you should poll some of the dentists who have used it
and also the patients who have benefitted from its effectiveness so that
you will have a total picture of its place in the modern dental world."
He said FDA had suggested the precise formula at that time "so that we
would be able to market in interstate commerce without requiring a
prescription. ... Our boasting that this is a 'sanctioned' formulation
is nothing more than a way of giving credit to the man and the agency
which suggested its very makeup."

In an April 2, 1992, letter to Altholtz, FDA pointed out that while the
agency official had indeed indicated FDA would defer action until after
reviewing the product, the official also had informed the original owner
that the product had no approved NDA on file with FDA. "This product
still does not have an approved NDA," the agency stated in the letter,
"and is in violation of the Food, Drug, and Cosmetic Act when introduced
or delivered for introduction into interstate commerce."

The letter further explained that FDA does not "poll" users to determine
drug effectiveness. "The responsibility for determining this rests with
the drug manufacturer and must have some basis in science not
testimonials," the letter stated, adding that adequate and
well-controlled studies provide the basis for the agency's evaluation of
a drug. The letter also explained that the agency had not suggested the
precise formula but had quoted it from a letter from the original owner.
"We strongly object to reference that this product is FDA sanctioned
because not only is it misleading, it is entirely false." FDA warned,
"Continued marketing of this unapproved new drug is at your own risk."

A year later, FDA still had no approved NDA on file for the White
One-Step Endodontic Formula. On July 22, 1993, Souza inspected the firm
again to determine the product's marketing status.

From the firm's records, Souza learned that in August and September
1992--despite FDA's warning that the formula was an unapproved
product--Altholtz had ordered about 3,000 units of the powder, which at
the firm's current sales rate amounted to a six-year supply.

"I asked Dr. Altholtz if he was aware that his product did not have an
approved NDA," Souza recalled. "Dr. Altholtz explained he thought
someone had applied for an NDA, but he wasn't sure." Souza explained to
Altholtz that he must apply for his own NDA and that this generally
involves animal and clinical testing to prove the product is safe and
effective.

Altholtz replied that this would be too costly. He then showed Souza
FDA's 1982 letter to the original owner of the formula and claimed that
the FDA official's statement about not taking regulatory action until
reviewing the product allowed him, Altholtz, to market the product.
Souza reiterated that Altholtz needed his own NDA.

Souza collected product samples and promotional literature, noting that,
as required for approved drugs, no additional labeling, insert or
instructions accompanied the product. He noticed, however, that Altholtz
had removed references to FDA in the promotional literature.

On Feb. 25, 1994, at FDA's request, the U.S. attorney in Hartford filed
in the U.S. District Court for the District of Connecticut a complaint
for forfeiture and a warrant for the arrest of the White One-Step
Endodontic Formula. U.S. marshals seized the product March 22 at the
Dental Clearing House and ordered the company to detain the product
until further court order.

On March 28, 1996, U.S. District Judge Janet Bond Arterton ordered the
seized unapproved new drug condemned, forfeited and destroyed and
ordered Dental Clearing House to pay all costs.

On June 20, 1996, Russell Sinni, supervisory deputy U.S. marshal, and
Patricia Murphy, FDA consumer safety officer, met Altholtz at the site
of his now defunct Dental Clearing House to identify the seized product.
Jesse McCool, of Clean Harbors Environmental Services, Bristol, Conn.,
placed the bottles into a 5-gallon drum and sent the drug by truck to
Natick, Mass., to be processed. From there, the product was sent to a
toxic-waste disposal site in Nebraska, where it was burned in an
incinerator and buried.


--Dixie Farley 

------------------------------------------------------------------------


Ex-Bard Executives
Sentenced to Prison 

Three former executives of the first company approved to market balloon
heart catheters in this country were sentenced to 18 months in prison
each for conspiring to defraud FDA by selling illegal catheters. They
received the maximum sentence allowed under sentencing guidelines. 

The former executives for C.R. Bard Inc., of Murray Hill, N.J., and
Bard's U.S.C.I. Division, in Billerica, Mass., approved the illegal
activities in the late 1980s to boost company profits and maintain
Bard's market share in an increasingly competitive field, according to
the U.S. Attorney's Office, which prosecuted the case. Bard is a major
medical device manufacturer.

U.S.C.I. produces the company's heart catheters.

Chief Judge Joseph Tauro of the U.S. District Court for the District of
Massachusetts sentenced the three men Aug. 8, 1996, almost one year
after the three were convicted following an eight-week jury trial. In
addition to prison, he sentenced them to two years of supervised release
and assessed them a $50 special fee.

Bard pleaded guilty to similar charges in 1993, and agreed to pay what
was at that time the highest penalty ever imposed in a health-care fraud
case--$61 million. Bard also had to implement numerous measures to
prevent such illegal activities from occurring again.

The government estimated that total sales of the illegal catheters
amounted to $77 million.

Catheters now made by Bard's U.S.C.I. Division have been approved by
FDA.

The former Bard executives are appealing their conviction and sentence.
They are David Prigmore, 56, of Natick, Mass.; John Cvinar, 50, of
Winchester, Mass., and Lee Leichter, 46, of Fort Myers, Fla. Prigmore
was a corporate executive vice president responsible for the U.S.C.I.
Division. Cvinar was U.S.C.I. president, and Leichter was U.S.C.I.
director of regulatory affairs and quality assurance.

Bard was the first company to obtain FDA approval to market a balloon
angioplasty catheter in the United States and remained the only U.S.
distributor of heart catheters from about 1980 to 1985, after which
other U.S. companies began developing and marketing their own.

Heart catheters are used in angioplasty, a procedure to clear clogged
arteries. The device, a wire with a balloon-like tip, is threaded into a
clogged heart artery, where the balloon tip is inflated to flatten the
clogging material against the vessel wall and then deflated and removed
from the artery. The procedure helps widen the path for blood to flow to
the heart muscle, thus reducing the risk of heart attack.

Investigators with FDA's New England district office collected evidence
during a four-month investigation of the company in 1990. That evidence,
introduced in the 1995 trial, showed that the company, with the
defendants' approval, redesigned heart catheters already approved by FDA
and sold them before obtaining FDA approval. The redesigning began about
1987, partly to address problems that doctors reported having with the
original catheters.

Under medical device regulations, companies must file applications for
premarket approval and receive approval from FDA before they can market
their devices in the United States. Supplements for premarket approval
applications also are required for changes made to approved devices,
when the changes affect the device's safety or effectiveness. Such was
the case with the Bard heart catheters.

By allowing the catheters to be put on the market, the executives
essentially allowed the devices to be used experimentally in humans
without patients' consent or knowledge, without doctors' knowledge, and
without FDA approval. Federal law prohibits using humans in experiments
of medical devices that present significant risks unless FDA has
reviewed and approved the studies and the patients have consented to
participate.

The redesigned heart catheters often malfunctioned, according to reports
doctors made to Bard. Common problems were balloons failing to deflate
in patients' arteries, balloons wrapping around the catheter, and
balloons and catheter wire tips breaking in arteries.

Although the three former executives received reports of these
malfunctions, they failed to report the problems to FDA, as required.
And they failed to mention the problems when applying to FDA for
premarket approval of the redesigned catheters.

They learned, for instance, during illegal human clinical trials and
while the company's Probe B catheter was under FDA review, that the
Probe B catheter tip was likely to break off in the arteries in 2 of
every 100 patients. Yet, Cvinar and Leichter decided to keep this
information from FDA and proceed with plans to commercialize the
catheter when approved by FDA without changing the labeling to inform
doctors of the risk of catheter tip breakage. FDA approved the device in
January 1989, unaware of the tip breakage problem identified by the
company during the illegal clinical trials.

Within three months, after receiving 33 reports of tip breakage during
angioplasty with the Probe B, Bard redesigned this catheter, calling the
new model Probe C. In March 1989, the company began distributing the
Probe C without FDA approval for human experimentation.

In June 1989, after learning of catheter malfunctions, FDA met with Bard
representatives and informed them that their catheters were illegal and
subject to seizure. In June 1989, Bard initiated a recall of the Probe B
catheter. In August 1989, FDA regulators, in a letter to Bard officials,
told them that the Probe C catheter violated federal law because it had
not been evaluated for safety and effectiveness and approved by FDA.

In September, Bard recalled the Probe C. Then, employees slightly
modified Probe C, renamed it, and continued to distribute it to a few of
its accounts for about another month. 

After FDA told Bard later that month that it needed a new premarket
approval application for its Probe C, the company discontinued that
model and reintroduced Probe A, the original catheter that had problems
of its own and led the company to replace it with the Probe B. But,
because of Probe A problems reported to the agency, FDA seized 1,815
Probe A catheters on Feb. 22, 1990, and witnessed their destruction on
Nov. 20, 1990.

Another illegal practice in which Bard executives participated was to
allow manufacturing of the company's Simplus catheter in a manufacturing
facility not yet approved by FDA. In approving class III medical
devices, such as heart catheters, FDA also must approve the
manufacturing facilities to ensure compliance with medical device good
manufacturing practices (GMPs).

In its 1987 premarket approval application for the Simplus catheter,
Bard said it would make and package the catheter in its Billerica,
Mass., facility, an FDA-approved manufacturing plant. However, by this
time, Bard had already begun to make the Simplus catheter at the
company's newly acquired plant in Haverhill, Mass. Former company
executives determined it would be too costly to shift the manufacturing
to the facility approved by FDA. So, the company continued to make,
package and eventually distribute Simplus catheters from the unapproved
Haverhill plant. When FDA inspected the Haverhill site in March 1988,
inspectors identified several GMP deviations.

A grand jury for the U.S. District Court for the District of
Massachusetts handed down a 393-count indictment against the three
former executives and others in January 1995.

In sentencing the three former Bard executives, Judge Tauro emphasized
that corporate entities do not commit crimes, people do, and that
executives running other companies who might engage in such conduct
should bear in mind the prison terms imposed in this case.


--Paula Kurtzweil 

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No Place for Critters

Happy Valley Food was once home for some probably very happy rats--and
insects and other animals. Here, according to FDA inspections, the
critters had free rein in a warehouse filled with bags of rice, flour
and other foods.

But not any more. A Sept. 6 inspection by FDA's Baltimore district
office found the warehouse finally clean and free of pests.

This came about after Happy Valley Food Inc., Washington, D.C., agreed
in a consent decree with FDA and the Department of Justice to clean up
its warehouse and recondition all potentially contaminated food.

The contamination problem became evident when investigator Linda Hunt of
FDA's Baltimore district office inspected Happy Valley's warehouse Jan.
18 through 30, 1996. The inspection was part of the district's 1996 work
plan.

Hunt found insects, animals and general filth throughout the warehouse,
including five live and eight dead rats, two live cats, a live dog,
several rodent nests, and hundreds of rodent excreta pellets. She also
found bags of rice, flour, and potato starch with rodent-gnawed holes
and noted many holes in the walls where rodents could easily enter and
openings along the bottom of closed doors where rodents could hide and
build nests.

Hunt took samples of several products, including rice, potato flour, and
wheat flour. FDA chemists in the Baltimore district laboratory verified
that the samples contained rodent nesting material, urine and excreta,
and animal hair.

During the inspection, Johnny C. Chan, president of Happy Valley, told
Hunt he would clean up the warehouse, repair structural defects, and
withhold from distribution all products that appeared to be rodent
adulterated. He also hired an exterminator, who, between Jan. 24 and 30,
killed at least 10 rats, according to Chan.

However, when Hunt returned to Happy Valley on March 6, she found that
conditions had not improved. Also, some of the food Chan said he
wouldn't sell because of contamination had been sold.

Because contamination was so widespread, on March 12 FDA asked the U.S.
attorney for the District of Columbia to file a complaint for seizure of
all the company's food products, except for canned and refrigerated
products, which showed no evidence of contamination.

The complaint was filed March 15 in the U.S. District Court for the
District of Columbia, and on March 19, the U.S. Marshals Service seized
food products worth more than $52,000.

During a visit to the warehouse on March 21 to ensure that the seized
products were still intact, Hunt and a deputy U.S. marshal found two
cartons missing and the tape used to secure the items torn. They
discovered more seized items missing during a visit on March 26. Tony
Chan, vice president of Happy Valley, said employees had mistakenly
taken the seized products. To prevent future mistakes, U.S. marshals
returned to Happy Valley on April 2 and moved all seized merchandise to
a rear storage area of the warehouse where it could be easily monitored
by management.

The consent decree, signed April 30, required the firm to post a
$104,000 bond and established the steps the company would have to take
to recondition the food and clean up and repair the warehouse. FDA
approved Happy Valley's reconditioning plan, which included looking at
each bag and box for evidence of rodent pellets and gnawed material. In
addition, the plan called for each bag and box to be examined by a black
light for the presence of rodent urine. Those bags and boxes with
evidence of contamination had to be destroyed. The company also had to
repair all holes in walls and window screens to prevent pests from
entering the building. The reconditioning and repairs were done under
FDA supervision at the firm's expense.

By Aug. 27, the reconditioning was complete, and Hunt and several deputy
U.S. marshals observed the destruction of $7,500 worth of contaminated
food.


--Isadora Stehlin 

------------------------------------------------------------------------


Summaries of Court Actions


Summaries of Court Actions are given pursuant to Section 705 of the
Federal Food, Drug, and Cosmetic Act. Summaries of Court Actions report
cases involving seizure proceedings, criminal proceedings, and
injunction proceedings. Seizure proceedings are civil actions taken
against goods alleged to be in violation, and criminal and injunction
proceedings are against firms or individuals charged to be responsible
for violations. The cases generally involve foods, drugs, devices, or
cosmetics alleged to be adulterated or misbranded or otherwise violative
of the law when introduced into and while in interstate commerce.

Summaries of Court Actions are prepared by Food and Drug Division,
Office of the General Counsel, HHS, and are published by direction of
the Secretary of Health and Human Services.


------------------------------------------------------------------------

SEIZURE ACTIONS


Food/Contamination, Spoilage, Insanitary Handling

PRODUCT: Milk, condensed, at Chicago, Ill. (E.D. Ill.); Civil No.
95C-4148.

CHARGED 7-18-95: While held for sale after shipment in interstate
commerce at La Bodega, Inc., in Chicago, Ill., the article was
misbranded in that the statement of identity, declaration of net
quantity of contents, and the statement of ingredients were not in
English--403(f). The article was also misbranded in that the name and
place of business of the manufacturer, packer or distributor did not
appear on the label in the required type size, and the label failed to
bear nutrition information--403(f) and 40 3(q)(1).

DISPOSITION: A default decree of condemnation, forfeiture and
destruction ordered the articles destroyed. (F.D.C. No. 67098; S. No.
94-741-379; S.J. No. 1)


PRODUCT: Riga Sprats, at Elizabeth, N.J. (DNJ); Civil No. 95-1148 (AJL).

CHARGED 3-8-95: While held for sale after shipment in interstate
commerce at SeaLand Container Service Station, in Elizabeth, N.J., the
articles were adulterated in that they were prepared and packed under
conditions whereby they might have been rendered injurious to
health--402(a)(4).

DISPOSITION: A consent judgment and final order of forfeiture ordered
the articles destroyed. (F.D.C. No. 67048; S. No. 95-647-620; S.J. No.
2)



PRODUCT: Similac infant formula, powdered, at Deer Park, N.Y.
(E.D.N.Y.); Civil No. CV-96-0938.

CHARGED 3-1-96: While held for sale after shipment in interstate
commerce at Krantor Corp., in Deer Park, N.Y., the article was
adulterated in that it failed to bear a lot code--412(a)(3). The article
was misbranded in that it was represented to be for special dietary use
in that the label declared the product as "infant formula." The article
lacked nutrient information regarding the product when prepared in
accordance with label directions for infant consumption, a statement of
the number of fluid ounces supplying 100 kilocalories, and the weight
and volume of powdered formula to be reconstituted--403(j).

DISPOSITION: A default decree of condemnation and destruction ordered
the article destroyed. (F.D.C. No. 67129; S. No. 96-782-071; S.J. No. 3)



PRODUCT: Tuna, chunk light, at Tampa, Fla. (M.D. Fla.); Civil No.
94-609-CIV-T-23C.

CHARGED 4-12-94: While held for sale after shipment in interstate
commerce at Winn Dixie Warehouse, in Tampa, Fla., the article was
misbranded in that it failed to meet the standard of fill for canned
tuna, and the label did not state that the article was below such
standard--403(h)(2).

DISPOSITION: A default judgment ordered the articles donated to a
charitable institution. (F.D.C. No. 66934; S. No. 93-681-942; S.J. No.
4)



PRODUCT: Tuna, chunk light, at Pascagoula, Miss. (S.D. Miss.); Civil No.
1:94cv164RR.

CHARGED 3-29-94: While held for sale after shipment in interstate
commerce at Starkist Food, Inc., d/b/a Heinz Pet Products, in
Pascagoula, Miss., the article was misbranded in that it failed to meet
the standard of fill for canned tuna, and the label did not state that
the article was below such standard--403(h)(2).

DISPOSITION: A default judgment ordered the articles donated to a
charitable institution. (F.D.C. No. 66927; S. No. 93-651-183; S.J. No.
5)



PRODUCT: Tuna, raw, frozen, whole, at Long Beach, Calif. (C.D. Calif.);
Civil No. 95-4257 KN.

CHARGED 6-26-95: While held for sale after shipment in interstate
commerce at Sea-Land Service, in Long Beach, Calif., the article was
adulterated in that it consisted of decomposed tuna--402(a)(3).

DISPOSITION: A default judgment ordered the article destroyed. (F.D.C.
No. 67095; S. No. 95-714-095; S.J. No. 6)




Drugs/Human Use

PRODUCT: Exachol, capsules, at Hastings-On-Hudson, N.Y. (S.D.N.Y.);
Civil No. 87 Civ. 7779 (RWS).

CHARGED 5-20-88: While held for sale after shipment in interstate
commerce at U.S. Health Club, Inc., in Hastings-On-Hudson, N.Y., the
articles were adulterated in that they were unapproved new
drugs--505(a). The articles were misbranded in that they failed to bear
adequate direction for use--502(f)(1).

DISPOSITION: A consent decree ordered the article destroyed. (F.D.C. No.
65277; S. No. 87-459-661; S.J. No. 7)



Medical Devices

PRODUCT: Intraocular lenses, at Azusa, Calif. (C.D. Calif.); Civil No.
93 6928 WDK.

CHARGED 11-18-93: While held for sale after shipment in interstate
commerce at Optical Radiation Corp., in Azusa, Calif., the articles were
adulterated in that the methods used in, and the facilities and controls
used for, their manufacture, packing and storage were not in conformity
with current good manufacturing practice requirements--501(h).

DISPOSITION: A consent decree ordered the articles destroyed. During an
inspection, it was discovered that the firm destroyed some of the
articles without FDA's supervision. The firm agreed to pay the value of
the destroyed articles. Consequently, FDA released the firm from the
rest of the bond. (F.D.C. No. 66754; S. No. 93-663-878; S.J. No. 8)


PRODUCT: Sharper Image Relaxation Systems, at North Little Rock, Ark.
(E.D. Ark.); Civil No. LR-C-94-563.

CHARGED 9-1-94: While held for sale after shipment in interstate
commerce at ABF Freight System, Inc., in North Little Rock, Ark., and at
The Sharper Image in Little Rock, Ark., the articles were adulterated in
that they were class III devices without an application for premarket
approval--501(f)(1)(B). The articles were misbranded in that information
regarding the articles was not provided as required--502(o).

DISPOSITION: A consent decree of condemnation was filed. The articles
were reconditioned as set forth in the consent decree. (F.D.C. No.
67003; S. No. 94-687-982; S.J. No. 9)



PRODUCT: Various Articles of Device, at Seattle, Wash. (W.D. Wash.);
Civil No. C94-883R.

CHARGED 6-10-94: While held for sale after shipment in interstate
commerce at Synetic Systems, Inc., in Seattle, Wash., the articles were
adulterated in that they were class III devices without an application
for premarket approval--501(f)(1)(B). The articles were misbranded in
that information regarding the devices was not provided as
required--502(o).

DISPOSITION: A consent decree of condemnation was filed. The articles
were reconditioned as set forth in the consent decree. (F.D.C. No.
66918; S. No. 93-629-464; S.J. No. 10)



PRODUCT: Viro-Gloves, at Pompano Beach, Fla. (S.D. Fla.); Civil No. 94
7224 CIV-HURLEY.

CHARGED 12-19-94: While held for sale after shipment in interstate
commerce at Knight Industries, Inc., in Pompano Beach, Fla., the
articles were adulterated in that the methods used in, and the
facilities and controls used for, their manufacture, processing,
packing, and holding did not conform to current good manufacturing
practice requirements--501(a)(2)(B). The articles were misbranded in
that they failed to bear adequate directions for use--502(f)(1).

DISPOSITION: A consent decree of condemnation and destruction ordered
the articles destroyed. (F.D.C. No. 67000; S. No. 94-682-477; S.J. No.
11)





INJUNCTION ACTIONS

DEFENDANTS: Smith Family Farms and Paul Steven Smith, at Clyde, N.Y.
(W.D.N.Y.); Civil No. 94 CV 6260T.

CHARGED 6-2-94: The defendants introduced into interstate commerce
adulterated cattle and held the cattle for sale after shipment in
interstate commerce--301(a) and 301(k). The cattle were adulterated in
that they contained an unsafe new animal drug--402(a)(2)(D). The cattle
were also adulterated in that they were held under insanitary conditions
whereby they might have been rendered injurious to health--402(a)(4).

DISPOSITION: A consent decree of permanent injunction was filed. The
defendants later were found in compliance with the decree. (Inj. 1350;
S. No. 93-543-575; S.J. No. 12)


------------------------------------------------------------------------
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