Excerpts from:
FDA CONSUMER (March 1995)


Drug Testing from a Patient's Perspective
by Isadora B. Stehlin

     Ads in the paper. Referrals from personal physicians. Lots of
phone calls and months of waiting. These are the typical ways
people find out about and participate in drug studies. But for
Washington, D.C., psychiatrist Stephen Peterson, M.D., his
participation in a drug study began with lunch.
     On a spring day in 1994, Peterson joined two friends,
allergists Martha White, M.D., and Michael Kaliner, M.D., for lunch
at the Washington Hospital Center cafeteria. Peterson is the
chairman of the Department of Psychiatry at the center, and White
and Kaliner are with the center's Institute for Allergy and Asthma.
     During the meal, Peterson started talking about his asthma and
ended up being recruited for White's study of an asthma drug.
     "She got real excited," says Peterson. "She said if I was
taking [inhaled] steroids [for my asthma], I could be part of her
study."
     Peterson, 44, says that although the inhaled steroids he was
taking at the time had his asthma under control, "I was happy to
help out because I very much believe in the scientific method."
     What Peterson agreed to participate in is commonly called a
clinical trial--that is, an experiment done with people. These
trials are performed at hospitals and research centers around the
country. FDA reviews the data from clinical trials and other
research in deciding whether to approve a new drug application.

     The drug White and Kaliner are studying is Aerobid-M
(flunisolide), manufactured by Forest Pharmaceuticals, Inc. An
inhaled corticosteroid, Aerobid-M is used on a continuing basis to
prevent asthma attacks. FDA approved the drug in 1984 for adults
with asthma who require daily medication with corticosteroids. So
why are the scientists running another study?
     White explains that the approved dosage is two puffs, twice a
day. "What the drug company wants to know is if someone can take
four puffs just once a day and do just as well," she says. "They're
hoping to be able to simplify the dosing regimen. Clearly if you
can take a medication once a day instead of twice a day it's ~
easier on the patient [and therefore] will probably increase
     "We try to encourage these kinds of studies," says Cathie
Schumaker, a pharmacist and consumer safety officer in FDA's
division of oncology and pulmonary drug products. "Anything that
will help the drug be used more efficiently, encourage compliance,
or make it available to a wider population means people will get
better health care."
     Even though a drug--like Aerobid-M--is already approved, if a
study is being done to support a change in the approved labeling,
the manufacturer must submit an amendment to its original
investigational new drug application, explains Schumaker. Then,
when the study is complete, a supplement to the original new drug
application is required.
     Peterson says his asthma is relatively mild compared to other
people's. But it is serious enough to have kept him on  several
drugs over the past 11 years.
     Although he didn't realize it at the time, his asthma began in
1983.
     "I noticed when I was running, I was having a hard time
finishing my run, especially during high pollen times," he
explains. "A couple of times I found I was wheezing after running."
But, he says, he didn't really understand what the problem was
until, out of professional, not personal, curiosity, he went to a
lecture about asthma.
     After the lecture, "I talked to my colleague who's a
pulmonologist and he offered to give me a pulmonary function test.
The test was abnormal and that's how I found out I really had a
problem with asthma."
     Asthma is a lung disease that may be inherited or may develop
as a severe allergic reaction to pollen, viruses, dust, cigarette
smoke, and other "triggers" (but not everyone with allergies
develops asthma and not every asthmatic has allergies). Chronic
asthma occurs whenever sufferers are repeatedly exposed to a
trigger. Another common form is exercise-induced asthma, which
occurs only when a person exercises.
     Peterson's asthma is both exercise-induced and chronic,
triggered by pollen in the spring and summer, leaf mold in the
fall, and dogs.
     Once Peterson knew the cause and triggers of his asthma, he
began preventive treatment. While he's tried many different
treatment regimens, he's had the greatest success with inhaled
corticosteroids used daily and occasional use of a bronchodilator
about 15 minutes before running. Inhaled corticosteroids reduce
inflammation of the airways, decrease mucus production and
swelling, and may allow other asthma medicines to work more
effectively. Bronchodilators work very quickly to dilate (open) the
narrowed bronchial tubes, allowing oxygen to enter and carbon
dioxide to exit the lungs more freely.
     Peterson's history is typical of the people recruited to
participate in this study. "We are looking for participants who are
asthma success stories when on usual doses of inhaled
corticosteroids," says White. The study began in early 1994 and
should take a little over a year to complete. Between 250 and 300
patients across the country will have participated by the time it's
over.
     Peterson participated in the clinical trial four months.
First, he had to read and sign a consent form, required by law,
informing him that the dosing regimen he would receive is
experimental. It also explained the known possible side effects of
the drug.
     Corticosteroid inhalants can occasionally cause throat
irritation and thrush (a fungal infection in the mouth). Gargling
with warm water after using the inhaler helps avoid those problems.
Prolonged use of very high doses may increase the risk of side
effects such as high blood pressure, diabetes, osteoporosis, and
suppression of bone growth in children.
     Next, he underwent a complete physical exam. Then he, and
everyone in the study, took the already approved dose of two puffs
twice a day of Aerobid-M for a month.
     At the end of the month, White tested Peterson's lung 
function with a methacholine challenge test. The test involves
inhaling the drug Provocholine (methacholine chloride). In normal
people this drug has no effect. In asthmatics, it causes
bronchospasms and wheezing.
     "It's a very good diagnostic test," says White, "and it's also
used to determine just how severe the asthma is. The more severe
the asthma, the lower the dose that will cause tightness."
     As soon as someone reacts to the drug, a bronchodilator is
administered to bring the lungs back to normal.
     Peterson says that the worst part of the methacholine test
wasn't the wheezing but the preservative-like smell of the drug.
"It reminded me of anatomy class [in medical school]."
     Peterson then began the main part of the study. To prevent
bias that can sometimes lead to overrated positive results,
Peterson, like all the other trial participants, received four
different canisters. He was told to take two puffs from each of two
of the canisters in the morning and two puffs from each of the
other two at night. That made eight puffs total, but, at the most,
only four puffs were actually Aerobid-M. The other puffs were
placebos containing inactive substances. Not only was Peterson
"blind" to how much real medication he was receiving, the doctors
also were purposely ignorant of Peterson's regimen. When both
patients and researchers are unaware of the patient's drug regimen,
the study is considered to be "double-blind."
     In this study, the patients were divided into three groups:
One group took four puffs of Aerobid-M once a day; a second group
took two puffs of the drug in the morning and two puffs at night
(the labeled dosing regimen); and a third group took only two puffs
of Aerobid-M once a day. The purpose of the third group was to
determine the effectiveness of a reduced dose.
     "At first, most doctors put people on the recommended dose of
an inhaled steroid to get their symptoms under good control,"
explains White. "Then [the doctors] start backing down on the dose
to figure out how much is necessary to maintain them. But, as far
as I know there haven't really been any studies on this practice.
We've all been doing it in practice anyway. This study may give
some validity to it and perhaps some guidelines."
     This study had no placebo controls--people off corticosteroids
completely. "We were all uncomfortable doing that because these
were people who had already demonstrated the need to be on
corticosteroids," says White.
     Besides inhaling four puffs in the morning and four at night,
"I also needed to test myself twice a day with a peak-flow meter,"
Peterson says.
     A peak-flow meter helps asthmatics monitor their symptoms by
measuring how fast air is blown out of the lungs.
     During the trial, Peterson says, sometimes he felt better than
when on other drugs and sometimes worse. At the end of the three
months, White gave Peterson another methacholine challenge test.
     "Overall, he did fine," says White, "but the test was blinded,
so I don't know what dose [schedule] he was on."
     "I learned a great deal about pulmonary function tests,"
Peterson says. "I also learned that [for the researchers] doing a 
scientific study like this is a lot of work."
     Peterson says he would be glad to participate in another
clinical trial, and, as if to allay any doubts about his sincerity,
he still joins Kaliner and White for lunch several times a month. 

Isadora B. Stehlin is a staff writer for FDA Consumer.



Orthodontic Braces:
Perfect Smile Replaces Tin Grin

by Rebecca D. Williams

     When her four children, ages 9 to 16, all had braces at the
same time several years ago, Wanda Brown of Knoxville, Tenn.,
always knew what she'd be doing on her days off work.
     "I knew it was Tuesday because we were at the orthodontist,"
she says with a laugh.
     Today her children smile at the results of all those
appointments: The three oldest have straight, perfect teeth,
while the youngest has had some treatment but still awaits full
braces.
     "I really wanted braces," says daughter Diana, 17. "I'm glad
I had them because I feel a whole lot better about myself. I'm
always smiling now."
     Years ago, few teens had such a positive attitude about
braces. Orthodontic appliances triggered taunts like "metal
mouth" and "tin grin." But today, braces are almost a status
symbol among middle-class American teenagers. About 3 million
teenagers in the United States and Canada have braces, an
increase of about 30 percent in the last 10 years, according to
the American Association of Orthodontists.
     Teeth aren't any more crooked than in the past. It's just
that more teenagers want the perfect smiles that braces can give
them, and more parents are willing to foot the bills. Today there
are more orthodontic devices than ever before, allowing more
choices in how braces look and how long the patient must wear
them.
     "In general, people get braces for aesthetic reasons," says
D. Gregory Singleton, D.D.S., a senior dental officer with FDA's
Center for Devices and Radiological Health and an orthodontist in
private practice.
     "But that doesn't mean they won't get a functional benefit
in the process," he adds. A better bite and fewer jaw problems
are often the byproducts of what begins as a cosmetic procedure. 

The Crooked Smile

     Anyone who's spent time in an orthodontist's chair has seen
pictures and plaster molds of the "ideal" mouth. The top front
teeth extend over the lower front teeth slightly, while the
molars line up and meet on both sides of the mouth, top and
bottom. The teeth are straight and not crowded, spaced close
together like a string of pearls. 
     But in most mouths, variations on this theme are more
common. Some problems affect chewing or speaking, but most are
simply cosmetic issues. 
     Improper tooth alignment is called malocclusion.
Malocclusion is not a disease, but crooked teeth can decay faster
than straight ones because people have more trouble keeping them
clean. Severe misalignments may require extra flossing and
brushing. But malocclusion doesn't always cause jaw problems or
pain, and many people have lived long and healthy lives with
misaligned teeth. 
     Nevertheless, malocclusions can be embarrassing. There are
three types of malocclusions, plus a number of other bite
problems. The malocclusion types are: 

     Class I: Teeth line up correctly top to bottom, but they are
spaced too far apart or are crooked, crowded or turned.
     Class II: Upper teeth protrude and the lower teeth are too
far back. This is also called an "overbite."
     Class III: Lower teeth are too far in front and the upper
teeth are too far back. This is also called an "underbite." This
is the most difficult problem to correct, says Singleton, and may
require surgery. 
     Other orthodontic problems include:
     Open bite: Front teeth stay open even when biting down with
back teeth. This can make chewing food difficult or impossible.
     Closed bite: When biting down, upper teeth cover the lower
teeth completely. This is also called a "deep bite."
     Cross bite: When biting down, some upper teeth close inside
or outside lower teeth.

Causes
     Bite problems stem from a number of causes. Most are
inherited, but others are behavioral.

     Habits such as a reverse swallow, tongue thrust, or sucking
the thumb, fingers or the lower lip can apply pressure to teeth.
Over time, teeth spread. If these habits aren't corrected before
treatment, the teeth may spread even after the braces are
removed.
     Babies who suck their thumbs or pacifiers aren't generally
at risk, says Singleton. As long as they break those habits by
age 5 or 6, they usually don't cause malocclusion in their
permanent teeth.
     Baby teeth can greatly affect the look and health of
permanent teeth. If a baby tooth falls out too early or decays,
the other teeth may move to fill in the space, blocking permanent
teeth from coming in when they are ready. Similarly, if a baby
tooth does not fall out soon enough, the bigger tooth behind it
may come in crooked. And if a permanent tooth is lost to decay or
trauma and is not replaced, the other teeth will drift to fill up
the space, sending them out of alignment.
     The size of teeth can affect their alignment as well. Teeth
that are too small can drift, and teeth that are too large will
crowd. Mouth size can also cause drifting or crowding.

Bands and Brackets
     Braces and other orthodontic appliances can solve most bite
problems. Braces apply gentle pressure to teeth, moving them
slowly over a period of 12 to 36 months. As teeth move, the jaw
bones around them grow to fill in spaces left by the tooth roots.
The main advancement for braces in the last 15 years has been the
elimination of metal bands around front teeth. Today, small
brackets are bonded onto the front teeth instead, greatly
reducing the "metal mouth" look. 
     The brackets are tiny devices that attach each tooth to an
archwire. The wire acts as a track to guide teeth along. Metal
bands are now used only around the back teeth, which are stronger
and more difficult to move. 
     Today's brackets can also be made of more aesthetically
pleasing materials. Clear or tooth-colored materials can be used
to create almost invisible braces, although they tend to be more
expensive and difficult to work with. Some braces can even be 
hidden on the insides of teeth, although these are much more
difficult for the orthodontist to place and adjust. They can also
irritate the patient's tongue, which may hit them repeatedly.
Most teens and children get stainless steel brackets because
they're durable and less expensive than other kinds. 
     Another development has been "space age" wires. These wires,
made of nickel titanium alloys developed through the NASA space
program, hold their shape better than stainless steel wires. As a
result, they require fewer replacements and trips to the
orthodontist, often shortening treatment time.
     Other appliances include "elastics," small rubber bands that
apply extra pressure between the jaws. "Headgear," which fits
around the head or neck, helps move jaws into a new position, and
"functional appliances," worn sort of like a football player's
mouth guard, help align jaws and chewing muscles. "Retainers"
help keep teeth straight after treatment. Special-purpose
appliances can correct specific problems, such as the roof of the
mouth being too small. Most patients wear a combination of two or
more appliances over the course of treatment. 
     Some patients can even make a fashion statement with their
braces, getting multi-colored ligatures--the small wires or
elastics that hold the arch wires to the brackets. Elastics and
retainers also come in an array of colors. It's even possible to
put a logo or mascot on a retainer. 
     The latest development, although not widely used, is magnets
attached along the archwire to the upper or lower molars. Encased
in stainless steel and placed with opposing or attracting forces,
the magnets can help create or close spaces between teeth. In
some cases, they can replace headgear, one of the most
conspicuous orthodontic appliances.
     FDA reviews all new materials and orthodontic devices before
they go on the market. Manufacturers must file a pre-market
notification, showing through laboratory or clinical tests that
their device is substantially equivalent to others already in
use. Most older orthodontic devices were already on the market in
1976, the year device regulations went into effect. Unless FDA
receives evidence to the contrary, those devices are assumed to
be safe and effective.

Keeping Braces Clean
     Perhaps the biggest challenge of living with braces is
keeping them clean. The nooks and crannies formed by braces
create ideal hiding spots for bacteria that lead to cavities and
gum problems.
     Patients who don't take care of their teeth risk even more
dental decay than they would have without the braces. 
     "This is a problem especially for patients around 11 and 12
years old," says Singleton. Flossing and brushing for them is
often not a priority, he explains. 
     Orthodontic patients should brush thoroughly after every
meal and before bed. Flossing is more of a challenge because the
wires make maneuvering difficult. A floss threader, available
from an orthodontist or pharmacy, helps the floss slip behind the
archwire and get to the gums.
     Certain foods can damage braces. Sticky food, hard food,
crunchy food, and sweets are the four troublemakers for those who
wear braces.

     Sticky foods like gum, taffy and caramels can loosen cement
and damage the brackets. Hard food like apples and carrots must
be cut into bite-sized pieces so they won't break appliances.
Crunchy foods like corn chips, popcorn and nuts should be avoided
for the same reason. And sweets, because they feed bacteria when
caught between braces, should be avoided as much as possible.
Teeth should be brushed soon after eating sweets to prevent
decay.
     In fact, many orthodontists say that much of the success of
braces depends on the willingness of the patient to stay away
from harmful foods, keep teeth clean, and wear appliances
faithfully.

What Cost Beauty?
     The cost of braces varies with the patient, but typically
treatment runs from $1,800 to $4,500. Some insurance plans cover
a portion of the cost. 
     "It wasn't as high as I'd expected," Wanda Brown remembers.
"I guess I thought we'd have to sell the house to pay for it. The
cost was absolutely worth it--without question." 
     Aside from cost, braces can be physically uncomfortable. A
day or two of soreness is not unusual after every visit to the
orthodontist because of adjustments to the archwire. Also, some
patients must have teeth extracted to make room for others. 
     Fifteen-year-old Michael Brown, for example, had to have 11
teeth extracted before getting braces. Most of them were baby
teeth that hadn't come out on their own. 
     "That was pretty painful," he remembers. "Compared to that,
the braces weren't bad."
     In addition to pain and expense, orthodontic patients must
keep track of extra equipment daily. Elastics, retainers,
headgear--school lockers are full of orthodontic devices. More
than a few teens make the mistake of wrapping their retainers in
paper napkins while they eat and then accidentally tossing them
out. 
     "We've been through a few restaurant trash bins," Brown
remembers. 
     Did they find the missing retainer?
     "Oh yes!" she says. "I'm sure some people thought we were
crazy, but we always searched till we found it." 

Rebecca D. Williams is a writer in Oak Ridge, Tenn.

Braces: Not Just for Kids
     Just because braces weren't fashionable or affordable when
you were a kid doesn't mean you have to go through life with a
major malocclusion.
     In 1979, 17 percent of orthodontic patients were adults. By
1992, that number had risen to 23 percent. Of those, 70 percent
are women.
     Orthodontists have made adult braces more palatable by
fashioning them out of plastic and ceramic, which are clear or
tooth-colored. Some appliances can fit on the inside of teeth,
completely out of sight. Called "lingual braces," these devices
may not be appropriate for everyone. They are not as strong as
traditional braces so they usually have to be worn longer. They
are also more difficult to adjust, and they can be uncomfortable
because the patient's tongue hits them.
     FDA has found new appliances to be substantially equivalent
to older stainless steel brackets. Many of them, however, are
more expensive.
     Nevertheless, braces are increasingly popular among adults.
They have even gotten good press from famous patients: Cher,
Diana Ross, and Phyllis Diller have all sported "tin grins" and
beautiful smiles later. 

--R.D.W.



Labeling Rules
For Young Children's Foods
by Paula Kurtzweil

     How much fat should we eat to stay healthy? For adults, the
answer is clear: The Dietary Guidelines for Americans tell us to
restrict fat to no more than 30 percent of our total calorie
intake.
     But for infants and toddlers, the answer is less
straightforward; the Dietary Guidelines don't apply to children
under 2. In fact, health experts advise against restricting fat
in young children's diets because they need the calories and
nutrients fat provides to grow and develop properly.
     For this reason, FDA and the U.S. Department of
Agriculture's Food Safety and Inspection Service have established
special rules to govern the labeling of foods for children under
4. (USDA regulates labeling of meat and poultry products. FDA
oversees labeling of all other foods.)
     Just as for other foods, the regulations require labels for
foods for young children to include information about nutrients
important to health--for example, fat, sodium, carbohydrate,
protein, vitamins and minerals. This is to help parents choose
foods that contain the appropriate kinds and amounts of nutrients
their children need.
     But the new regulations forbid labels for foods for children
under 2 to carry certain nutrition information because the
presence of the information may lead parents to wrongly assume
that certain nutrients should be restricted in young children's
diets, when, in fact, they should not.
     In addition, the labels for foods for children under 4
cannot show how the amounts of some nutrients correspond to Daily
Values--recommended daily intakes. The reason is because Daily
Values for some nutrients, such as fat, fiber and sodium, have
not been established for children under 4. This is because
current dietary recommendations do not specify appropriate levels
for young children. FDA has set Daily Values only for vitamins,
minerals and protein for this age group because the National
Academy of Sciences has established appropriate levels of these
nutrients for this age group in the Recommended Dietary
Allowances. FDA incorporated those recommendations in the Daily
Values. (See "'Daily Values' Encourage Healthy Diet" in the May
1993 FDA Consumer.)

Up-to-Date Label

     These labeling requirements stem from the Nutrition Labeling
and Education Act of 1990, which, among other things, requires
labels of most foods--including those for children under 4--to
carry nutrition information.
     The children's nutrition labeling rules apply to most foods
whose labels suggest that the food is intended for infants and
toddlers. This includes infant cereals, infant strained meats,
vegetables and fruits, "junior" foods, teething biscuits, and
infant and "junior" juices. The regulations do not apply to
infant formula, which has special nutrition labeling
requirements.
     Many foods for infants and toddlers have carried some
nutrition information since at least the 1970s, when voluntary
nutrition labeling went into effect. But now, for many such
foods, the  information is required and more pertinent to today's
health concerns. (See "Good Reading for Good Eating" in the May
1993 FDA Consumer.)

Importance of Fat

     Concerns about excessive fat and cholesterol intake for most
of the population don't apply to children under 2, however. Fat
is one of six nutrient categories essential for proper growth and
development. (The others are protein, carbohydrate, water,
vitamins, and minerals.) At no other age does fat play such an
important role as in infancy and early childhood, a period of
rapid growth and development. Dietary fat serves as:
     a source of energy (infants and toddlers have the highest
energy needs per kilogram of weight of any age group)
     a carrier for the fat-soluble vitamins A, D, E, and K and as
an aid in their absorption in the intestine
     the only source of linoleic acid, an essential fatty acid.
     Fat also gives taste, consistency, stability, and
palatability to foods and converts to body fat, which is
necessary to hold organs in place, absorb shock, and insulate the
body from temperature changes.
     Some parents fail to realize fat's importance for young
children. According to a Gerber Products Co.'s telephone survey
of 1,076 adults, nearly one in five respondents said they reduce
the amount of fat in their baby's diet.
     Yet, according to Virginia Wilkening, a registered dietitian
and consumer safety officer in FDA's Office of Food Labeling,
case reports have shown that limiting fat intakes in very young
children can cause them to "fail to thrive."
     "Babies need fat and cholesterol in their diets for proper
growth and development," Wilkening said. "Parents should be aware
of this and avoid reducing fat in their young children's diets."

Restrictions
     For foods for children under 2, the amount of saturated fat,
polyunsaturated fat, monounsaturated fat, cholesterol, calories
from fat, and calories from saturated fat in the food cannot be
listed on the label.
     Labels of foods for children under 2 also cannot carry most
of the claims about a food's nutritional content--such as "low-
fat" and "low-cholesterol"--that labels of other foods can. (See
"A Little 'Lite' Reading in the June 1993 FDA Consumer.) And,
they cannot carry the eight FDA-approved health claims about the
relationship between a nutrient or food and a health problem--for
example, dietary fat and cancer--that other labels can. (See
"Starting This Month, Look for 'Legit' Health Claims on Foods" in
the May 1993 FDA Consumer.)

Allowed Facts
     What information is allowed? The following is a list of
dietary components about which information is allowed on the
Nutrition Facts panel on the labels of foods for children under
2. Information usually appears on the side or back of the package
and is mandatory for underlined components.
     total calories
     total fat
     sodium
     potassium
     total carbohydrate
     dietary fiber
     soluble fiber
     insoluble fiber
     sugars
     sugar alcohol
     protein
     vitamin A
     vitamin C
     calcium
     iron
     other essential vitamins and minerals. (Information about
them is mandatory only when they are added to enrich or fortify a
food, or when a claim is made about them on the label.)
     Labels for foods for children 2 to 4 also must give the
amount of cholesterol and saturated fat per serving. They can
voluntarily provide the calories from fat and calories from
saturated fat, and the amount of polyunsaturated and
monounsaturated fat per serving.
     The %Daily Values for protein and vitamins and minerals
present in significant amounts must be listed. This helps parents
see how a serving of food fits into their child's total daily
diet. The amount of other nutrients is given in grams or
milligrams.

Serving Size
     The serving size, under "Nutrition Facts," is the basis on
which manufacturers declare the nutrient amounts and %Daily
Values on the label. It is the amount of food customarily eaten
at one time--not necessarily the amount recommended by dietary
guidelines.
     The serving size is based on FDA- and USDA-established lists
of "Reference Amounts Customarily Consumed Per Eating Occasion."
FDA has established 11 groups of foods specially intended for
children under 4. USDA has four such groups.
     The serving size must be stated in both common household
units and metric measures--for example, for dry instant cereal,
"1/4 cup (15 g)."
     These standardized serving sizes make it easier to compare
the nutritional quality of similar foods.

Nutrient and Health Claims

     FDA and USDA's regulations also extend to label claims.
     Among the few allowed in children's nutrition labeling are
claims that describe the percentage of vitamins or minerals in
the food as they apply to the Daily Values for children under 2--
for example, "provides 50 percent of the Daily Value for vitamin
C." This type of claim also is allowed in the labeling of dietary
supplements for children under 2.
     Also allowed for foods for children under 2 are the claims
"unsweetened" and "unsalted." FDA believes that for foods for
this age group, these claims refer to taste and not nutrition.
     Two claims--"no sugar added" and "sugar free"--are approved
only for use on dietary supplements for children under 2 because
they often contain added sugar.
     If presented with sound evidence, however, FDA will consider
allowing other nutrient content claims, as well as health claims,
in the labeling of foods for children under 2.
     These and other rules are intended to help consumers select
the best foods for children. The absence of some information
allowed in labeling for other foods can help them do that. 

Paula Kurtzweil is a member of FDA's public affairs staff.



Getting to Know Gout
by Ken Flieger

     Say the word "gout" and some people will think of a bloated
king surveying the remains of a sumptuous feast, wine glass in
hand, swollen foot propped on a pillow--looking for all the world
like the dismal product of a grossly overindulgent life.
     There are a couple of flaws in that conventional image. We
know, for example, that gout doesn't afflict only the privileged
classes and that women, too, are susceptible, though a lot less
than men.
     But still there's a good deal right with that picture. It
correctly reflects that:
     About 90 percent of people afflicted with gout are men over
40.
     Obesity in general, and in particular excessive weight gain
in men between ages 20 and 40, has been shown to increase the
risk of gout. In fact, about half of all gout sufferers are
overweight.
     Alcohol abuse and so-called "binge" drinking are associated
with gout, as is eating purine-rich foods such as brains,
kidneys, liver, sardines, anchovies, and dried beans and peas.
     In addition, careful scientific surveys have shown that
occupational exposure to lead, the use of certain drugs to
control high blood pressure, some surgical procedures, family
history (possibly a genetic predisposition), and trauma are all
linked to an increased risk of gout. Indeed, the prevalence of
gout--the number of gout sufferers for each 100,000 people--is
rising rapidly in the United States and other developed
countries. Some authorities believe the increase is related to
higher living standards.
     Our fanciful image of a gouty Henry VIII (or other bloated
monarch) can't show, however, the one common denominator that
ties together this mixed bag of risk factors: failure of the
metabolic process that controls the amount of uric acid in the
blood. For most people, the process works just fine. But in some
1 million Americans, uric acid metabolism has gone seriously
haywire. As a result, they suffer from gout.
     And suffer they do. An Englishman, Thomas Sydenham, writing
in the 17th century, left this unfortunately all-too-accurate
description of a typical attack of gout:

     The victim goes to bed in good health. About two o'clock in
     the morning, he is awakened by a severe pain in the great
     toe; more rarely in the heel, ankle, or instep. The pain is
     like that of a dislocation. [It] becomes more intense. So
     exquisite and lively meanwhile is the feeling of the part
     affected, that it cannot bear the weight of the bed-clothes
     nor the jar of a person walking in the room. The night is
     passed in torture.
     
A Crystal Culprit

     In spite of the agony and havoc it can cause, uric acid is a
normal constituent of the human body. Ordinarily about one-third
of the uric acid in our system comes from food, especially foods
like those noted earlier that are rich in purines. The rest we
produce ourselves through ordinary metabolism.
     The body converts purines to uric acid. The level of uric
acid in the blood fluctuates in response to diet, fluid intake,
overall health status, and other factors. Men normally have
somewhat more uric acid than women do (although the difference
begins to narrow after menopause), and in both sexes it tends to
increase with advancing age.
     Higher-than-normal amounts of uric acid in the blood, a
condition called hyperuricemia, is quite common and only rarely
warrants medical treatment. On the other hand, sustained
hyperuricemia is the primary risk factor for gout. It's safe to
say that, while not all people with hyperuricemia develop gout,
virtually everyone with gout is hyperuricemic. It works this way:
     At normal and even somewhat elevated levels, uric acid stays
in solution in the blood. It moves through the circulation, gets
filtered by the kidneys, and is excreted in the urine. When,
however, blood uric acid levels rise above a certain
concentration (which varies with temperature and blood acidity),
it forms needle-like crystals that lodge in or around a joint.
     In response to irritation caused by uric acid crystals, the
skin covering the affected area rapidly becomes tight, inflamed,
swollen, and red or purplish. These classical signs of
inflammation, together with sudden and extreme pain (just as
Thomas Sydenham described), strongly suggest an acute attack of
gout. The diagnosis is confirmed by laboratory finding of uric
acid crystals in fluid taken from the affected joint.
     Why is the big toe the most common site for an initial gout
attack? Perhaps because first, the extremities are a bit cooler
than other parts of the body, and uric acid crystals form more
readily at lower temperatures; and second, normal walking and
standing subject the feet to considerable stress. Together, these
factors might explain why the big toe, heel, instep, and Achilles
tendon are among the places that gout attacks first. Other
targets, especially in untreated patients who have recurrent
attacks of gout, are the knee, elbow, wrist, fingers and, less
often, the shoulder, pelvis, spine, and internal organs.
     Gout is classified as a form of arthritis because it is
initially and predominantly a disease of the joints. Other
similar conditions exist; one called ~pseudogout~ is somewhat
milder than true gout and is caused by calcium rather than uric
acid crystals. Infection or trauma to the affected area can mimic
gout and mislead both patients and health professionals. Accurate
diagnosis is essential for appropriate treatment.
     Without treatment, an initial acute attack of gout will run
its painful course within several days or a few weeks, by which
time all outward evidence of the disease disappears. The next
acute attack--50 or more percent of gout sufferers will have a
second attack--may not occur for months or years. Subsequent
attacks, however, are likely to be more frequent, more severe,
and more destructive to joints and other tissue unless the
problem is treated. Over time, uric acid crystals accumulate in
the body, causing gritty, chalky deposits called tophi that are
sometimes visible under the skin, particularly around joints and
in the edges of the ears. Tophi may also form inside bone near
the joints, in the kidneys, and in other organs and tissues,
causing permanent damage. Advances in  treatment, fortunately,
have made this kind of chronic gout extremely rare.

Treatment
     As with most illnesses, effective treatment of gout depends
on a correct diagnosis. Gout can be unequivocally diagnosed by
telltale uric acid crystals in joint fluid. But appropriate
treatment is often started after a "clinical" diagnosis based on
painfully obvious signs and symptoms and other relevant factors,
such as the patient's uric acid level, age, weight, gender, diet,
and alcohol use. If this picture adds up to a strong suspicion of
gout, treatment can be started with the immediate goal of
arresting the acute attack.
     Acute gout is treated with drugs that block the inflammatory
reaction. One of the oldest agents known to be effective against
acute gout is colchicine, which comes from a common European
plant, the autumn crocus, and is marketed in this country
primarily as a generic drug. An English clergyman, Sidney Smith,
said a century and a half ago that he had only to go into his
garden and hold out his gouty toe to the plant to obtain a prompt
cure. This may have been an exaggeration, but a rapid response to
colchicine suggests that the patient does indeed have gout.
     This old, powerful remedy is now used less often than it
once was because it can be quite toxic, causing nausea, vomiting,
diarrhea, and stomach cramps when taken by mouth and severe (even
fatal) blood disorders when taken intravenously. Moreover, modern
agents, specifically nonsteroidal anti-inflammatory drugs
(NSAIDs) are highly effective against acute gout and less toxic
than colchicine. To treat an acute case of gout, the first choice
of many physicians is the NSAID Indocin (and other brands of
indomethacin). Naprosyn (naproxen) is another NSAID commonly used
in acute gout.
     Steroid drugs, such as Deltasone (and other brands of
prednisone) and Acthar (and other brands of adrenocorticotropic
hormone), may be used if NSAIDs fail to control an acute attack.
Steroids may be taken by mouth or by injection into the
bloodstream or muscle.
     Drug treatment usually relieves the symptoms of acute gout
within 48 hours. Subsequent treatment, which may well be
lifelong, is aimed at preventing further attacks by controlling
uric acid in the blood--keeping it below concentrations at which
crystals can form. Two main treatment approaches are used, in
some cases simultaneously.
     One approach is to slow the rate at which the body produces
uric acid. Zyloprim (allopurinol) has been approved for the
treatment of gout and is frequently prescribed for gout patients
who have uric acid kidney stones or other kidney problems. Side
effects include skin rash and upset stomach, both of which
usually subside as the body becomes used to the drug. Zyloprim
makes some patients drowsy, so they need to be cautious about
driving or using machinery.
     The other approach to controlling gout following an initial
acute attack is to increase the amount of uric acid excreted in
urine. Two so-called uricosuric drugs commonly used for this are
Benemid (probenecid) and Anturane (sulfinpyrazone), both approved
by FDA for gout treatment. In addition to lowering blood uric 
acid levels, these drugs help dissolve deposits of uric acid
crystals around joints and in other tissue. Zyloprim is also used
to dissolve tophaceous gout in uric acid over-producers.
Uricosurics can cause nausea, stomach upset, headache, and a
potentially serious skin rash.
     Drugs to control uric acid levels may, paradoxically,
prolong an acute attack. For this reason, Benemid, Anturane and
Zyloprim are not used during the acute stage of gout. They may,
in fact, induce gout flare-ups during the early part of long-term
use. Accordingly, colchicine in a dose low enough to avoid toxic
side effects is sometimes prescribed to prevent acute attacks
during this phase of treatment.

Common-Sense Measures
     Better understanding of what gout is, what causes it, and
how to treat it has perhaps dispelled some of the traditional
myths about what has been erroneously called "the disease of
kings." Then, too, folk wisdom about gout, coupled with good
science and medicine, points to measures that prudent people can
take to prevent or at least lessen the severity of the condition.
     Many authorities and the Arthritis Foundation, which
supports research and public service programs relating to gout,
advocate weight control as a logical aid to gout prevention. They
point out, however, that people who are overweight should get
professional guidance in planning a weight-reduction program,
because fasting or severe dieting can actually increase uric acid
levels.
     Experts generally agree that people with gout can eat pretty
much what they want, within limits. People who have kidney stones
caused by uric acid may need to avoid purine-rich foods. But this
problem can usually be handled effectively with drug treatment.
     Curbing alcohol use and avoiding "binge" drinking can reduce
the likelihood of acute attacks. So can drinking six or eight
glasses of water a day, which dilutes uric acid and aids its
removal by the kidneys. Some medicines--in particular the
thiazide diuretics ("water pills") used to control high blood
pressure--tend to increase uric acid levels. A gout patient
taking one of these drugs may have to switch to another type of
diuretic or blood pressure medicine.
     Finally, although uncommon, it might be helpful to find out
if an environmental or occupational exposure to lead is playing a
role in a patient's problem with gout.
     While a cure for gout--a treatment that gets rid of the
condition once and for all--isn't on the horizon, reliable and
effective ways of diagnosing gout and keeping it under control
constitute one of the more impressive success stories of modern
medical science.
     There may be no sure-fire way to keep a person from having
that first agonizing attack, but prompt treatment can minimize
the risk of further attacks and virtually rule out the damaging
and crippling effects of chronic gouty arthritis. 

Ken Flieger is a writer in Washington, D.C.




Drug Advisory Committees
Getting Outside Advice for Close Calls
by Dixie Farley

     "Viewpoints vary between concerns of individual clinicians
and what may affect the doctor-patient relationship, or how a
drug affects a patient circumstance.  A professional woman on the
committee, for instance, takes the position of the woman patient,
asking whether medicine is doing something too intrusive,
exercising too many prerogatives, or presenting an unreasonable
risk for the patient."
--Ezra Davidson Jr., M.D., professor and chairman, Department of
Obstetrics and Gynecology, Charles R. Drew University of Medicine
and Science, Los Angeles, discussing the Food and Drug
Administration's Fertility and Maternal Health Drugs Advisory
Committee, which he chairs.
     Ezra Davidson Jr., M.D., serves on one of 17 committees that
advise FDA about the safety and effectiveness of drugs--
particularly on decisions that are "close" calls.
     Of the 11 members of his committee, 10 are educators. Seven
of the physicians specialize in obstetrics and gynecology--three
also in reproductive biology. Two are epidemiologists
(specialists in the incidence and prevalence of disease). Other
areas represented are nursing and behavioral sciences. Committees
meet in the Washington, D.C., area, generally at FDA headquarters
in Rockville, Md., and those on Davidson's committee travel from
as far away as Hawaii. The executive secretary, an FDA medical
officer, connects the committee with the agency.
     It may seem unnecessary for FDA to seek outside advice.
After all, the agency employs its own full complement of
scientific specialists. But outside experts add a wide spectrum
of judgment, outlook, and state-of-the-art experience to drug
issues confronting FDA.
     "We seek scientists with a broad range of expertise and
different backgrounds," says John Treacy, director of the
advisors and consultants staff in FDA's Center for Drug
Evaluation and Research.
     These expert advisers add to FDA's understanding, so that
final agency decisions will more likely reflect a balanced
evaluation. Committee recommendations are not binding on FDA, but
the agency considers them carefully when deciding drug issues.

Members
     Most members of FDA's drug advisory committees are
physicians whose specialties involve the drugs under the purview
of their committee. Others include registered nurses,
statisticians, epidemiologists, and pharmacologists (who study
drug effects in the body).
     Consumer-nominated members serve on all committees. As
voting members, they must possess scientific expertise to
participate fully in deliberations. They must have worked with
consumer groups so they can assess the impact of decisions on
consumers.
     The committees range in size from 10 to 15 members, but most
have 11. Each committee advises a corresponding FDA drug review 
group.
     All government advisory committees are regulated by the
Federal Advisory Committee Act of 1972, although FDA began using
panels of outside experts in 1964. Each committee must be renewed
by FDA every two years, or its charter automatically expires.
Renewals must be approved by the Secretary of Health and Human
Services and the Administrator of the General Services
Administration.
Committee Independence
     To encourage the committees' independence, FDA recruits
members from a broad range of qualified candidates. Sources of
nominations--with emphasis on identifying women and minority
candidates--include professional, scientific and medical
societies; medical and other professional schools; academia;
government agencies; industry and trade associations; and
consumer and patient groups.
     FDA's Office of Consumer Affairs, in particular, seeks
suggestions for consumer-nominated representatives through agency
field offices, current and former consumer-nominated
representatives, and diverse consumer organizations with national
and local interests and a widely varied membership, representing
women, older people, African Americans, Hispanics, and Asians.
     Requests for candidates also appear in the Federal Register.
     FDA staff review the nominations (which can exceed 200
candidates) to identify the best mix of expertise for the
particular committee. A list of nominees is then sent to the
Office of the Commissioner for final selection. Committee chairs
are also selected by the commissioner; they are not elected by
the committees.

Meetings
     Committees typically meet two to four times a year, but may
meet as often as FDA needs them. FDA announces upcoming meetings
in the Federal Register.
     Members receive $150 a day while attending committee
meetings, and reimbursement for costs of travel, food and
lodging. This attendance is a public service on the part of many
members, who forgo seeing patients or conducting research or
teaching activities to serve FDA.
     Thanks to the aptly named "Government in the Sunshine Act"
of 1977, meetings of drug advisory committees (as well as those
of committees advising about other products FDA regulates) are
public, except when a topic's open discussion would be an
invasion of privacy or when confidential, commercial, or trade
secret information or law enforcement investigations are
presented or discussed.
     Even at a closed meeting, there must be an open portion at
which the public--as time allows--can give presentations, ask
questions, and take part in general discussion. Most meetings are
entirely open.
     FDA almost always sets the agenda and prepares the questions
for each meeting. Anyone, however, may ask that a specific drug
issue be brought before the appropriate committee. When a
committee itself asks to review a matter within its purview, this 
is granted whenever possible.

Types of Advice
     FDA may especially want a committee's opinion about a new
drug, a major new indication for an already approved drug, or a
special regulatory requirement being considered, such as a boxed
warning in a drug's labeling.
     The committees may advise FDA on necessary labeling
information, and help with guidelines for developing particular
kinds of drugs, such as those for anesthesia, heartbeat
irregularities, and cancer.
     They also may address such questions as whether a proposed
study for an experimental drug should be conducted and whether
the safety and effectiveness information submitted for a new drug
is adequate for marketing approval.
     For instance, Cognex (tacrine), the first drug approved to
treat Alzheimer's disease, was the subject of several meetings of
the Peripheral and Central Nervous System Drugs Advisory
Committee during its clinical testing.
     When the committee first met to consider Warner-Lambert
Co.'s application for Cognex, in March 1991, it concluded that
available evidence did not support approval.
     On the basis of additional data submitted in July, the
committee still recommended against approval, but advised that
studies be conducted with a higher dose, over a longer time. The
committee also recommended a treatment IND (investigational new
drug)--an FDA procedure for promising drugs for serious diseases
that provides for wider use than is usual during the preapproval
stage, provided no satisfactory approved treatment exists and
patients won't be exposed to unreasonable risk.
     FDA granted the treatment IND in December 1991, after
finding the drug appeared to slightly improve mental function in
some patients at low doses and might be more effective at larger
doses.
     The treatment IND, begun in February 1992 and involving more
than 7,400 patients, showed that Cognex provided a small but
clinically meaningful benefit for some patients with mild-to-
moderate Alzheimer's disease. Meeting again in March 1993, the
committee recommended approval of the marketing application. FDA
approved Cognex in September, after reviewing the additional
information from studies.

Adverse Reactions

     FDA's advisory committees may also consider reports of
adverse reactions to an already marketed drug. If there are
severe reactions or deaths and it's not clear what's going on,
the agency might call a special meeting.
     Typical questions include:
     Should the dosage schedule be changed?
     Should certain groups of patients receiving the drug not be
getting it?
     Should the contraindications (situations when the drug
should not be used) be changed?
     Are the reactions to the drug also seen with other drugs in
its class?
     FDA received some 50 reports of serious reactions, including
three deaths, to Omniflox (temafloxacin) in the first three
months of marketing. A fluoroquinolone--one of a newer class of 
anti-infective drugs--Omniflox had been approved in January 1992.
     Side effects included dangerously low blood sugar levels in
elderly patients, anemia due to excessive destruction of red
blood cells, kidney failure, blood-clotting problems, and
abnormal liver function. The manufacturer voluntarily withdrew
the drug.
     FDA then asked its Anti-Infective Drugs Advisory Committee
to discuss the problem and consider implications for quinolones
in development.

Nonprescription Drugs
     Over-the-counter drugs, too, benefit from advisory committee
deliberation. From 1972 to 1981, at FDA's request, 16 special
panels evaluated the effectiveness and safety of all classes of
OTC drugs then on the market.
     During hearings before the Advisory Review Panel on OTC
Miscellaneous External Drug Products in 1980, New Jersey
pharmacist Carmine Varano cited disastrous incidents involving
camphorated oil: A 2-year-old died after exposure to camphorated
oil on the chest for nearly 80 hours, a 15-month-old became
confused and had seizures after crawling through spilled spirits
of camphor, and an infant nearly died after camphor ointment was
rubbed on its chest. Varano reported he had data from a Detroit
hospital about 26 camphorated oil poisonings between 1975 and
early 1979. FDA accepted the panel's advice to put camphorated
oil in its place--off the U.S. market.
     Those OTC panels completed their review tasks and have been
disbanded. OTC issues are now brought to the agency's
Nonprescription Drugs Advisory Committee, which includes a voting
consumer-nominated representative and a non-voting industry
representative. On a given issue, the committee will ordinarily
meet jointly with another committee with special expertise in
that issue.
     There have been a few instances in which FDA has not
followed a committee's recommendations.
     Treacy cites the Rx-to-OTC switch last year of the pain
reliever naproxen sodium, previously sold only by prescription
under the trade name Anaprox and now also over-the-counter as
Aleve.
     In June 1993, the combined arthritis and nonprescription
committees voted 7 to 4 against the switch.
     "They had a lot of reasons," Treacy says. "The dose was too
high. The labeling for people over 65 was incorrect because they
excrete the drug at a slower rate. The members requested labeling
for children because the drug makes the skin more photosensitive,
and children already sunburn more easily than adults. Also, the
members were uncomfortable with FDA's policy of allowing a
manufacturer to mention in the label any of a list of several
types of pain on the basis of studies of just any two types on
the list. Although this policy had been suggested by an advisory
panel before being accepted by the agency, members suggested that
our scientific knowledge has increased to the point where we can
be more specific."
     The manufacturer, Syntex Laboratories, listened to all the
objections, Treacy says, and, working with FDA, immediately
altered the dose interval and the dose, and changed the labeling 
for people over 65 and for children.
     FDA had a follow-up meeting to brief the committees on the
changes and its decision to approve the switch.
     "The bottom line is FDA's," Treacy says. "The committees are
advisory only. In approving the switch, we took into account the
objections of the members. However, we treated it just like all
the other OTC painkillers in terms of the labeling in order to
give it parity with other OTC analgesics."
     Nevertheless, Treacy emphasizes that FDA carefully considers
committee recommendations, "so we're reevaluating what is
appropriate labeling for all OTC painkiller products. In fact, at
another advisory committee meeting on Sept. 8 and 9, 1994, the
members discussed what indications for the products must be
studied."
     As these many examples show, recommendations from advisory
committees supplement FDA expertise and add to the quality and
credibility of the agency's decisions.
     Advisory committee members benefit, too. Says Fertility and
Maternal Health Drugs Advisory Committee chairman Davidson:
     "It's a great educational opportunity, whatever the issue.
As an ob-gyn, academician, and otherwise inquisitive person, I
find this advisory panel to be a mixture of science and policy
that attracts my interest." 

Dixie Farley is a staff writer for FDA Consumer.

Managing Conflicts
     The National Academy of Sciences' Institute of Medicine
published findings in December 1992 of a study it did--at FDA's
request--of the agency's advisory committees. FDA had been having
increasing difficulty identifying potential members with needed
expertise, but without financial or professional interests that
could lead to conflicts of interest or the appearance of
conflicts.
     The institute confirmed that the system was fundamentally
sound and did not need major changes. But it recommended a number
of administrative and procedural changes regarding committee
membership, committee operations, integrity of the committee
system, and FDA organization and management of the system.
     While the institute's study was going on, FDA conducted its
own analysis of its advisory committee system. The outcome of the
two reviews led the agency to concur with nearly all the
institute's recommendations, which are reflected in how members
are recruited and meetings are managed today.
     "We did a lot of work to strengthen the integrity of the
system by resolving conflicts of interest up front," says John
Treacy, director of the advisors and consultants staff for FDA's
Center for Drug Evaluation and Research.
     Throughout the government, advisory committee members are
subject to federal laws and regulations prohibiting participation
in any official action in which they have financial interests--
which the law says include those of their regular employing
organization. If a member is on the faculty of a university that
has a grant from the pharmaceutical firm to study the drug to be
reviewed by that committee, the member can't act on that issue,
Treacy says.
     The law does allow waiver of the interest.
     "Before every meeting," Treacy says, "we send members a
questionnaire, stating the issues coming up and the companies
with financial interests. We ask, 'Do you own stock or have

grants or contracts involving these issues or firms?' If there is
a conflict, we exclude the person, or, if our need outweighs the
conflict, a waiver may be granted."
     In a typical meeting with 11 members, there are usually two
or three who have waivers, he says. (Sometimes there are none;
other times, more than three.)
     Criteria for granting a waiver are based on many factors,
such as the amount of the financial interest, what percentage of
a person's net worth that interest is, and the impact on the firm
if a given product is approved or disapproved.
     For example, a waiver would not be granted, Treacy says, if
a member owned more than $100,000 in stock in a firm whose drug
was coming before the committee, and this was more than 5 percent
of the person's net worth.
     "On the other hand," he says, "if the member's university
had a grant of less than $15,000 to study a drug to be discussed,
and the member was not involved with the grant, we'd generally
grant the waiver."

--D.F.


For More Information 
     For information about FDA advisory committee meetings, call
(1-800) 741-8138. In the metropolitan Washington, D.C., area,
call (301) 443-0572. This information may also be obtained by
accessing the FDA Electronic Bulletin Board Service, via modem,
at (1-800) 222-0185 and choosing the topic "meeting." In the D.C.
metropolitan area, dial (301) 594-6849 or (301) 594-6857.
     For information about how to nominate a consumer
representative, write to Office of Consumer Affairs, FDA, HFE-88,
Room 16-85, 5600 Fishers Lane, Rockville, MD 20857. 



Drug Firm President and Other Officials Sentenced
by Dixie Farley

     "It was a business decision. If FDA says take the product
off the market, take it off the market. So I'll lose a million
dollars in sales. But look at all the money we made while I was
selling it."
--Jay Marcus, former president of Halsey Drug Co., Inc.,
Brooklyn, in a tape-recorded conversation.

     Marcus' "business decision" was to use an unapproved formula
for a generic version of quinidine gluconate, a drug to treat
irregular heartbeat. The product was one of numerous generics the
firm manufactured illegally. In the end, Marcus got more than
money from his business practices. He received a jail term and a
fine.
     Marcus and four other Halsey officials instructed employees
to use unapproved formulas contained in what they called "phony
cards." The employees were told to keep the cards in their
pockets to hide their wrongdoing from FDA investigators. A
federal investigation exposed the scam, the firm pleaded guilty
to charges in an information, and a grand jury indicted the
individuals.
     The result: jail terms for the officials and a quarter-
million-dollar fine for Halsey for conspiring to obstruct FDA's
regulatory function and shipping adulterated, unapproved new drug
products in interstate commerce. Halsey and four officials signed
plea agreements; a fifth official stood trial and was convicted.
     On June 17, 1994, Muhammad Uddin, former assistant vice
president of research and development, was sentenced to five
months in prison, five months of home detention with electronic
monitoring, and two years' supervised release. On Sept. 23, 1994,
Hedviga (Heidi) Herman, former vice president of manufacturing
and the defendant who stood trial, was sentenced to 18 months in
prison and two years' supervised release. On Oct. 14, 1994,
Marcus was sentenced to 41 months in prison, and Amirul Islam,
former vice president of technical services, to five months in
prison and five months of home detention. At press time,
Frederick Shainfeld, former senior vice president of technical
and regulatory affairs, hadn't yet been sentenced.
     FDA first suspected a problem with Halsey when an agency
reviewer found a discrepancy in one of Halsey's abbreviated new
drug applications (ANDAs) to market a generic drug. The ANDA
showed a drug batch with 75,000 tablets, while a Halsey letter
showed the batch had 100,000.
     When FDA's New York district office inspected Halsey in the
spring of 1990, the agency found that the quantities of active
drug ingredient listed as received were insufficient to make the
quantities of finished product purported in batch records. The
firm also had deficient good manufacturing practices (GMPs).
Confronted with these findings, the firm withdrew two ANDAs, but
did little else to correct its problems.
     In June 1991, FDA referred the case to the Department of
Justice's office of consumer litigation, which forwarded the

referral to the U.S. Attorney for the District of Maryland. FDA 
agents of the special prosecutions staff, working with Assistant
U.S. Attorney Christopher Mead and Susan Strawn of the office of
consumer litigation, conducted the criminal investigation.
     In October, FDA informed Halsey by letter of the agency's
fraud policy and called for audits of the ANDAs. When an auditor
hired by Halsey found continuing GMP problems, the firm withdrew
seven more ANDAs.

     FDA New York district investigators again inspected Halsey
from Oct. 29, 1991, to March 23, 1992, and still found GMP
problems. Despite many complaints to FDA about tablets with
defects such as chipping, the investigators found no such
problems noted in the firm's batch production records. The firm
attributed the reported defects to rough handling after the
products left Halsey. When FDA examined the firm's retained
samples, they showed chipped tablets. Islam blamed Halsey's own
packaging and warehouse personnel for throwing bottles around
like a "football," says investigator James Liubicich.
     On Sept. 2, 1992, an anonymous informant, a Halsey employee,
called FDA, claiming the firm falsified batch records to show
that drugs were made according to approved ANDAs when, in fact,
they were not.
     In October, investigators Liubicich, Connie Gallagher, and
Christina Ryan began a four-month inspection. While they couldn't
prove the caller's allegations, their suspicions were raised. For
example, experienced workers often seemed unfamiliar with written
mixing instructions. Also, Liubicich says, "When excess powder
came off the machine for compressing tablets, instead of
discarding it, as GMPs require, the employees threw it back in
the hopper for recompressing, a practice that could cause the
problems being reported."
     On Feb. 5, 1993, the informant--who had been fired--met with
FDA's New York district office. He said Halsey used an unapproved
formulation and manufacturing changes to make quinidine gluconate
tablets. He gave FDA a Halsey formula "phony card," saying that
supervisors would retrieve the cards and keep them in their
pockets when FDA investigators were present. The investigators
would be shown batch records prepared as if approved formulas
were followed. He said that instead of discarding problem batches
as required, employees usually reprocessed them by regranulating,
adjusting moisture, or adding ingredients.
     The district forwarded this information to the prosecutions
staff. An investigation by the staff found the man had used a
false name at the Feb. 5 meeting. Staff agents Melvin Szymanski
and Wayne Mitchell, an FDA lawyer assigned to the staff at that
time, discovered his real name, and the informant agreed to
become a witness for the government.
     In March 1993, Szymanski and Mitchell learned that a Halsey
production supervisor, Marlon Forde, was an illegal alien from
Trinidad. On March 3, along with two FBI agents, Szymanski and
Mitchell approached Forde to cooperate with the government's
investigation. If Forde would agree to fully cooperate, Assistant
U.S. Attorney Mead promised he would not prosecute him and also
offered to help him try to gain legal residency in the United
States.
     Forde agreed to wear a body wire to record conversations at
Halsey.
     The next day, as instructed, Forde told Herman that FDA
agents approached him outside his house that morning and asked
him about wrongdoing and "phony cards" at Halsey. She called
Shainfeld into the room, had Forde say it again, and told him how
he should lie to FDA, Szymanski says. "She asked, 'You gave me
back all the phony cards before, right?' He said, 'Well, no, I've
still got some.' She said, 'Give them back to me immediately. You
know you're supposed to come in my office when you make the
product. You ask for the phony card, and I give it to you. And
then as soon as you make it, you give it back.'"
     Forde gave FDA copies of a "phony card." The next day he
recorded conversations with Marcus, and the next week, with
Uddin.
     The district meanwhile was checking the informant's
allegations on Feb. 5 about quinidine gluconate. On March 15,
Shainfeld met with FDA and said he would stop making and selling
the drug and begin a recall.
     The next day, investigators Liubicich, Peter Abel, and John
Cook, and analysts Gary Lehr and Kim Cruse-Thomas, began an
inspection that would extend through May 1993. Liubicich insisted
on seeing specific batch testing in Halsey's quality assurance
test room. He and Abel, with Islam, saw a woman test tablets and
record information in a spiral notebook. Liubicich noticed
similar notebooks on the lab bench behind her. Since Halsey let
FDA review documents in plain view in the manufacturing area,
Liubicich went over to take a look at the other notebooks.
     "Lo and behold," he says, "I found records of reprocessing
for the past 10 years. It was incredible, because no matter what
we did before, Halsey kept us from getting proof of what was
going on. Now here it was--documented batches, lot numbers,
dates, what management said, who said it."
     According to Liubicich, the employees said they kept the
books because they wanted to be sure that if anything happened,
they could say, "He told me this, or she told me this."
     Mitchell and Szymanski bought two bottles of quinidine
gluconate in Baltimore to establish the drug's sale in Maryland,
where the staff tries its cases. "Tests showed they both
contained the lubricants magnesium stearate and stearic acid,
ingredients not listed in the approved ANDA," Mitchell says.
     At the end of March, Mead informed the Halsey corporation
about this evidence of fraud and the recorded conversations of
its officers.
     At FDA's request, on June 29, 1993, a complaint for seizure
was filed against Halsey in the U.S. District Court, Eastern
District of New York.
     With respect to the criminal charges, on June 23, 1993,
Halsey entered into the plea agreement with the U.S. Attorney's
Office in Baltimore. The judge for the U.S. District Court,
District of Maryland, accepted the agreement July 9. The
agreement called for dismissing the five officials. Halsey's new
management agreed, among other stipulations, to cooperate with
the investigation, stop selling illegal products, and meet FDA
manufacturing requirements. On July 12, 1993, the grand jury
returned its indictment. On Nov. 19, 1993, Islam and Uddin signed
plea agreements; on May 5, 1994, Shainfeld and Marcus signed plea
agreements; and on June 2, 1994, Herman was convicted on four 
counts.
     FDA received one report of a patient with arrhythmias who
was hospitalized because Halsey's quinidine gluconate didn't
work. With treatment, the patient recovered.

Dixie Farley is a staff writer for FDA Consumer.


Former Stuntman Sentenced in Drug Violation

     An 85-year-old former Hollywood stuntman was sentenced to
five years' probation and fined $20,000 last spring for selling
illegal "fountain-of-youth" drugs, including sexual tonics.
     Harry M. Pack, of San Diego, Calif., was sentenced in the
U.S. District Court for the Southern District of California April
21, 1994, after pleading guilty to one count of conspiracy to
sell unapproved new drugs illegally imported into the United
States. Pack ran a clinic from his home, where he bought, sold
and administered various drugs. These included several so-called
anti-aging drugs and a drug whose promotional literature said it
was used to preserve and enhance "male potency."
     "He had a gold mine of a clinic," said Dannie Rowland, a

compliance officer with FDA's Los Angeles district office. "He
was earning as much as $5,000 a day."
     The clinic was in business from at least 1987 to 1991,
according to seized documents. Banking and financial documents
showed that Pack had made millions of dollars.
     FDA learned about the clinic through "Operation Big Mouth,"
a massive effort by FDA, the U.S. Customs Service, the U.S
Attorney's Office, and other government agencies to identify and
prosecute illicit drug traffickers. It was so named because
defendants cooperated with authorities by admitting guilt and
identifying other drug traffickers. Cooperating defendants also
helped FDA make undercover purchases of various "fountain-of-
youth" drugs and anabolic steroids.
     Armed with information about Pack, as well as a search
warrant, on Oct. 17, 1991, FDA investigators, accompanied by U.S.
marshals and U.S. Custom Service officials, searched Pack's house
and seized a large number of illegal drugs. FDA's Rowland
estimated there was $400,000 worth of drugs stored throughout the
house. Promotional literature also was seized, along with
invoices and other documents.
     Numerous types of "fountain-of-youth" drugs were found,
including:
     injectable "cell therapies" made of protein from the organs
and tissues of sheep and cattle or the fetuses of these animals.

Accompanying literature claimed that cell therapies can treat
more than 100 medical conditions, ranging from acne and eczema to
osteoporosis and senility.
     "Gerovital H3," a derivative of the anesthetic procaine
hydrochloride, for preventing disorders associated with aging,
including arthritis, senility, graying, and hair loss.
     "Zumba Forte," a purported sexual tonic made of plant
substances, some of which were promoted for stimulating the
nervous system, and methyltestosterone, a derivative of the male
hormone testosterone.
     None of these three potentially dangerous drugs has been
approved by FDA. Cell therapies may increase the risk of
contracting animal diseases, such as brucellosis, Q-fever, and
bovine spongiform encephalitis (also known as "mad cow disease").
Cell therapies also can lead to allergic reactions, shock and
death.
     Procaine hydrochloride derivatives can cause a number of
side effects, including low blood pressure, convulsions, and
breathing difficulties. And yohimbine, an ingredient of Zumba
Forte, has been linked to kidney disease.
     Various documents showed that Pack bought many of the
fountain-of-youth drugs from German and English companies. Pack
admitted he smuggled the drugs into the United States through the
mail.
     Pack also dealt with a wide variety of alternative
medicines, including the unproven cancer drug Laetrile.
     In addition to his fine and sentence, Pack was ordered to
undergo psychological and drug testing and ordered not to engage
in his former drug business.
     FDA is not aware of any illnesses or deaths related to
Pack's activities.
--Paula Kurtzweil

Oxygen Supplier Corrects Problems
After Product Seizure

     A Pennsylvania medical oxygen supplier is back in business
after reconditioning oxygen seized last spring because the firm
had failed to comply with FDA good manufacturing practice
regulations.
     Liquid bulk medical oxygen and a storage vessel, valued at
$10,000, were seized on May 17, 1994, at Butler Gas Products,
Co., New Brighton, Pa., after two inspections and a warning
letter had failed to bring the company into compliance.
     Butler's one medical oxygen customer, Medic Rescue Health
Care, supplies liquid oxygen for home use by people with
respiratory difficulties or heart problems.
     During a routine inspection of Butler June 14 through 16,
1993, Gladys Casper, an investigator with FDA's Pittsburgh
office, found the firm had:
     no records to show that the equipment used to analyze the
oxygen's purity had been calibrated for at least the last six
months
     no certificate of analysis for the reference standard oxygen
used to calibrate the analyzer
     no written procedures on how to fill oxygen tanks
     no supervisory review of batch production records for oxygen
transferred into tanks
     no record of tests to ensure that liquid oxygen received
from the supplier is of appropriate strength, purity and quality.
     On July 14, FDA's Philadelphia district office, which
oversees the Pittsburgh area, sent a warning letter to John T.
Butler, president of the firm, at the company's headquarters in
McKees Rocks, Pa. The firm replied on July 23, promising to
correct all violations by Aug. 3.
     However, when Casper returned to Butler on March 10, 1994,
the firm had not corrected any of the violations cited in the
warning letter.
     "During my first inspection, the [firm's] headquarters
office had faxed a copy of the filling procedures to this site, 
and they made me a copy," says Casper. "When I returned, I had my
copy, but they had not kept theirs."
     The most serious consequence of the violations, according to
FDA compliance officer William Knipe, was that even if the firm
was analyzing the oxygen it received, the analyses were worthless
since the calibrations on the analyzer were based on gas of
unknown purity.
     "The oxygen may have been fine," says Knipe. "There aren't
many contaminants [in liquid oxygen] unless it's not liquid
oxygen in the first place. But you still need to demonstrate that
the drug product is good through record keeping and analysis."
     Because of the continuing violations, on May 17, at FDA's
request, U.S. marshals seized the oxygen.
     Butler filed a claim for the seized oxygen on May 23, and on
June 16, signed a consent decree agreeing to recondition the
oxygen and establish controls and procedures to ensure future
compliance with good manufacturing practice regulations.
     On June 29, FDA investigator Dan Tammariello, with the
agency's Pittsburgh office, visited Butler. James S. Glessner,
Butler's vice president for quality assurance, told Tammariello
that all employees were being trained and tested on the firm's
new written filling and testing procedures. Tammariello then
watched as several employees calibrated the analyzer and tested
oxygen for purity. All calibrations were performed correctly, and
results of the analysis showed the oxygen in the tank to be at an
acceptable level of 99.6 percent pure. He also found that all
support documents were correct, up-to-date, and on site.
     FDA received no reports of illness or injury among patients
using Butler's oxygen.
--Dori Stehlin



Phony Doctor Sentenced

     A Reno, Nev., clinic owner falsely claiming to be a medical
doctor was sentenced and ordered to stop practicing medicine last
July.
     A cancer patient at the Global Alternative Medicine Clinic
in Reno, Nev., collapsed three years ago, after receiving an IV
infusion of vitamin C and possibly, according to a relative of
the patient, the unproven cancer drug Laetrile. The infusion was
administered by clinic owner Vera J. Allison. After the patient
collapsed, Allison gave him two injections--one of epinephrine,
the other, an unknown substance. When these failed to revive
the patient, she suggested to those present--the patient~s wife and
clinic personnel, that they call 911. The patient was declared
dead on arrival at a local hospital.
     A judge sentenced Allison to five years' probation last July
and ordered her to stop practicing medicine and naturopathy (a
system of treating diseases without surgery or drugs, using
instead special diets, herbs, vitamins, and massage, for
example). The judge warned Allison she'd get three years in
prison if she violated her parole.
     The preceding May, Allison pleaded guilty to one felony
count of practicing medicine without a license. In exchange for
her plea, 10 other criminal charges against her were dropped.
     According to the Reno Police Department, Allison was not a 
medical doctor but a formerly licensed naturopath who for almost
six years ran a clinic that specialized in treating patients with
cancer and AIDS. (The Nevada law licensing naturopaths expired in
1987.) A review of medications seized from her clinic revealed
she dealt in unapproved drugs, such as Laetrile, as well as legal
prescription drugs. One drug was labeled "To be used or ordered
by a veterinarian physician."
     The case began when the deceased patient's daughter-in-law
called FDA investigator Ed Harris at the agency's Reno resident
post in May 1992. She told him she and other family members had
become suspicious of her father-in-law's death because they
thought he was receiving only intravenous vitamin C, which they
believed was unlikely to cause his death. She said they visited
the clinic and talked to Allison, who referred to herself as a
medical doctor and told them she treated patients with Laetrile.
     The daughter-in-law, a registered nurse, told Harris she
suspected that Laetrile was in the IV solution her father-in-law
was receiving when he collapsed, and she believed the cyanide in
the Laetrile caused his death. Because an autopsy was not done,
her suspicion could not be substantiated.
     The daughter-in-law also told Harris she was suspicious of
Allison's credentials. Harris referred her to the Nevada Board of
Medical Examiners. Shortly after, the Reno Police Department and
Washoe County District Attorney's Office, with help from the
Nevada Board of Pharmacy, began an investigation. Presenting a
warrant, the police searched Allison's clinic on Nov. 3, 1992,
and arrested her for practicing medicine without a license and
possessing and furnishing prescription drugs. She was released on
$8,500 bail.
     FDA met several times with Reno police detectives and a
county district attorney investigator in November and December
1992 to examine the seized evidence, which included diagnostic
devices, patients' records, personal computers, promotional
literature, and large quantities of injectable drugs.
     Some of the drugs were approved by FDA but are legally
available only if prescribed by a licensed doctor. They included
the hormones chorionic gonadotropin, progesterone, and
epinephrine and the anticoagulant heparin sodium. Other drugs
were not approved, including several under import alert:
Laetrile; Wobe-Mugos, an unproven cancer therapy from Germany;
and Gerovital H3 (procaine hydrochloride), an unproven anti-aging
medication.
     FDA's San Francisco, Seattle and Philadelphia district
laboratories analyzed the drugs and verified labeling
information. Wallace Winters, M.D., Ph.D., FDA's Pacific Region
medical officer, and another physician with the U.S. Public
Health Service reviewed the medical records of about 37 patients.
Their findings indicated that Allison had treated patients with a
variety of health problems, including cancer, arthritis, high
blood pressure, diabetes, psychiatric disturbances, and aluminum
and nickel toxicities.
     On Dec. 16, 1992, a Washoe County grand jury indicted
Allison on 11 counts of furnishing dangerous drugs without a
prescription, obtaining money by false pretenses, and possessing
controlled substances (certain prescription drugs), as well as 
practicing medicine without a license. Winters had testified
before the jury.
     Under the terms of Allison's probation, police are
authorized to conduct a search and seizure of her residence or
office without a warrant if there is suspicion that she has
controlled substances or restricted drugs and is involved with
the practice of medicine or naturopathy.
     Allison also faces a hearing, as yet unscheduled, to
determine if she owes restitution to her former patients.
--Paula Kurtzweil



SEIZURE ACTIONS

Food/Contamination, Spoilage, Insanitary Handling

PRODUCT: Figs, dried, at Chicago, IL (N.D. Ill.); Civil No. 93-C-
3164.
CHARGED 5-26-93: While held for sale, the article contained
insect filth--402(a)(3).
DISPOSITION: Default--ordered destroyed. Article destroyed in
connection with a seizure of wheat flour and other food stocks at
Ziyad Brothers, Chicago, Ill. (F.D.C. No. 66693; S. No. 93-662-
106; S.J. No. 1):

PRODUCT: Sardines, canned, at Jacksonville, FL (M.D. Fla.);
Civil No. 94-328-Civ-J-20.
CHARGED 4-4-94: When shipped from Southern Packaging and
Distribution Center, Jacksonville, Fla., the articles labeled ***
"DOLORES *** SARDINES ***" contained a poisonous and deleterious
substance--402(a)(1).
DISPOSITION: Default--destroyed. (F.D.C. No. 66932; S. No. 93-
682-697; S.J. No. 2)

PRODUCT: Scallops, at New Bedford, MA (D. Mass.); Civil No. 91-
13103-S.
CHARGED 11-26-91: While held at Mar-Lees Seafood, Inc., New
Bedford, Mass., the article was decomposed--402(a)(3); and the
scallops were soaked in a substance not declared on the label--
403(i)(2).
DISPOSITION: Default--destroyed. (F.D.C. No. 66326; S. No. 91-
649-174/75; S.J. No. 3)

PRODUCT: Shrimp, frozen, imported from India, at Secaucus and
Jersey City, NJ (D.N.J.); Civil No. 91-5371 and 91-5372
(consolidated).
CHARGED 12-10-91: While held at Flag Imports, Inc., Secaucus,
N.J., and Union Terminal, Jersey City, N.J., the articles of food
contained a poisonous and deleterious substance, which might
render them injurious to health--402(a)(1); and the articles were
adulterated because they consisted in part of decomposed shrimp--
402(a)(3).
DISPOSITION: Motion for summary judgment filed by the plaintiff--
the court denied motion for summary judgment on 7-19-93, and the
goods were destroyed. (F.D.C. No. 66292/93; S. No. 1692755 et
al.; S.J. No. 4)

PRODUCT: Tuna, canned, at Green Bay, WI (E.D. Wis.); Civil No.
93-C-1190.
CHARGED 10-29-93: While held by Super Valu Stores, Inc., Green
Bay, Wis., the article contained rodent hair, cat or dog hair,
and other animal hair--402(a)(3).
DISPOSITION: Default--destroyed. (F.D.C. No. 66786; S. No.
93-718-835; S.J. No. 5)

Food Additives
 
PRODUCT: Evening primrose oil (EPO) in bulk, Efamol EPO and
vitamin E capsules, Efamax, black currant oil (BCO) and fish oil
combination capsules, and Efamol PMS BCO and fish oil combination
capsules, at Portland, ME (D. Maine); Civil No. 88-010P.
CHARGED 3-30-88 and amended 2-17-89: When shipped by Champlain
Cosmetic Supply, Plattsburg, N.Y., and while in transit from
Plattsburg, N.Y., to Efamol Research, Inc., Canada, the articles
labeled (bulk drums) "For Manufacturing, Processing Or Repacking
~ d-Alpha Tocopheryl Acetate ~ Eisai Co., Ltd. ~ Tokyo, Japan ~
Quarantined ~ Banner Gelatin Products Corp. ... EFAMOL," (carton)
"Fullchange Limited ~ Marine Capsules," (carton) Capsules Efamol
Ltd. Efamol House Guildford Surrey," (capsule) "Efamax," and
(carton) "Manufactured for Efamol House ~ Oil of Evening Primrose
Softgels" contained nonconforming food additives (i.e., evening
primrose oil and/or black currant oil--402(a)(2)(C); and the
labeling of the articles lacked adequate directions for their
intended uses--502(f)(1).
DISPOSITION: The district court granted summary judgment for the
government and ordered the condemnation and destruction of the
seized articles, Evening Primrose Oil (EPO) and Black Currant Oil
(BCO). The court held that both articles were intended for use as
food because they were promoted as a nutritional or dietary
supplement, and that they were adulterated because they were not
generally recognized as safe by qualified experts. With respect
to EPO, in ruling for the government and against the claimant,
the court gave collateral estoppel effect to a 1989 order in a
related seizure case in California involving the same parties. In
that case, the court granted summary judgment to the government,
ruling that EPO was an adulterated food additive. With respect to
BCO, the Maine court ruled that the uncontroverted evidence
presented by the government was sufficient to establish that the
article was an adulterated food additive. The claimant did not
appeal the ruling. (F.D.C. No. 65400; S. No. 88-471-084 et al.;
S.J. No. 6)

PRODUCT: Pure Vegetable Oil, at Chatsworth, CA (C.D. Calif.);
Civil No. 89-0073.
CHARGED 1-6-89: While being held under Los Angeles County
Department of Health embargo at Banner Gelatin Products,
Chatsworth, Calif., this article of food was adulterated in that
it was a food containing the food additive Oil of Evening
Primrose--321(f); the article was unsafe because there is no
regulation in effect prescribing the conditions under which the
additive may be used safely--348(a); the article was misbranded
in that its labeling was false and misleading--343(a)(1); and the
article~s labeling failed to bear the common or usual name of the
article--343(i)(1).
DISPOSITION: The district court granted the government's motion
for summary judgment on all counts on Nov. 30, 1989. The claimant
filed an appeal on Dec. 11, 1989. On April 7, 1992, the Court of
Appeals for the Ninth Circuit affirmed the district court~s
decision granting summary judgment to FDA on adulteration and
misbranding charges in a civil seizure case involving evening
primrose oil (EPO) labeled as a dietary supplement. The appellate
court held that the district court correctly ruled that EPO was 
an unsafe food additive because the claimant, Efamol Ltd., had
not met its burden of establishing that the substance was
generally recognized among qualified experts as safe. The Ninth
Circuit found that the evidence upon which Efamol relied was not
from studies to establish EPO's safety as a dietary supplement,
was not published in the scientific literature, and, therefore,
was insufficient to show a genuine issue of material fact. In
addition, the Ninth Circuit upheld the district court's finding
that the seized article--which was labeled "pure vegetable oil"--
was not labeled with the food's common or usual name--EPO--and
that the article was not exempt from the labeling requirement.
     The claimant filed a petition for certiorari on July 28,
1992. It was denied. The district court entered a final judgment
and destruction order on Dec. 9, 1992. (F.D.C. No. 65417; S. No.
88-424-853 et al.; S.J. No. 7)

Drugs/Human Use

PRODUCT: Oxygen, U.S.P., at New Hyde Park, NY (E.D. N.Y.); Civil
No. 91-3141.
CHARGED 8-21-91: While held by Best Medical Supply Corp., New
Hyde Park, N.Y., the circumstances used for the processing,
packing and holding of the article failed to conform with current
good manufacturing practice--501(a)(2)(B).
DISPOSITION: Consent--authorized release to the dealer for
attempting to bring into compliance. The claimant also agreed to
not manufacture, pack or process medical oxygen unless and until
a government inspector records and notifies the claimant that its
operations appear to be in compliance. Ultimately, the claimant
came into compliance and was authorized to resume operations.
(F.D.C. No. 66095; S. No. 91-626-564; S.J. No. 8)

PRODUCT: Oxygen, U.S.P., at Cambridge, MD (D. Md.); Civil No. 93-
2134.
CHARGED 7-22-93: While held by Dorchester Home Medical Supplies,
Inc., Cambridge, Md., the circumstances used for the processing,
packing and holding of the article failed to conform with current
good manufacturing practice--501(a)(2)(B).
DISPOSITION: Consent--authorized release to the dealer for
attempting to bring into compliance. The claimant also agreed to
not manufacture, pack or process medical oxygen unless and until
a government inspector records and notifies the claimant that its
operations appear to be in compliance. Ultimately, the claimant
came into compliance and was authorized to resume operations.
(F.D.C. No. 66744; S. No. 93-585-791/2; S.J. No. 9)

PRODUCT: Taurine with B-6, at Rockville Centre, NY (E.D. N.Y.);
Civil No. 91-4173.
CHARGED 10-25-91: While held by Barth Vitamin Corp., Rockville
Centre, N.Y., the article did not have an approved New Drug
Application--505(a); the labeling of the article contained false
and misleading claims for blood pressure control--502(a); and
adequate directions for the article's intended use could not be
written--502(f)(1).
DISPOSITION: Consent--destroyed. (F.D.C. No. 66255; S. No. 91-
600-519; S.J. No. 10)
 
Medical Devices

PRODUCT: Attends, adult protective garment, at Tulsa, OK (N.D.
Okla.); Civil No. 92-C-1093E.
CHARGED 11-3-92: The article of device was adulterated because it
consisted, in part, of a filthy substance, dirt and dirt stains--
501(a)(1); the article was misbranded because it was in package
form and lacked labels containing the name of the place of
business of the manufacturer, packer or distributor--502(b)(1);
and it lacked an accurate statement of the quantity of the
contents in terms of weight, measure and numerical count--
502(b)(2).
DISPOSITION: Consent--destroyed. (F.D.C. No. 66615; S. No. 92-
673-761; S.J. No. 11)

PRODUCT: Condoms, at Cincinnati, OH (S.D. Ohio); Civil No. C-1-
93-363.

CHARGED 6-2-93 and amended 6-28-93: The quality of the articles
(which had been imported from Seoul, Korea, and which bore
labeling such as "Aegis 12 Condoms ~ Aegis International
Healthcare Corporation ~ Torrance, California") fell below the
articles' purported quality due to excessive holes--501(c); and
the articles' labeling statement, "Prevention of Sexually
Transmitted Diseases," was false and misleading since the
articles contained excessive holes--502(a).
DISPOSITION: Default--destroyed. (F.D.C. No. 66690; S. No. 93-
669-873; S.J. No. 12)

PRODUCT: Ear candles, at Fayette, OH (N.D. Ohio); Civil No. 93-
CV-7702.
CHARGED 12-3-93: The article, which was located at Quality Health
Products, Fayette, Ohio, was a class III device, and there was no
approved premarket approval application in effect--501(f)(1)(B);
the article had been manufactured, packed and stored under
circumstances lacking current good manufacturing practice--
501(h); the article's labeling contained false claims for
reducing ear wax, fever and infections associated with a ruptured
eardrum--502(a); the article was dangerous to health when used as
directed in the labeling--502(j); and the labeling failed to bear
adequate directions for use--502(f)(1).
DISPOSITION: Default--destroyed. (F.D.C. No. 66785; S. No. 93-
671-958; S.J. No. 13)

PRODUCT: Lintro-scan, a transillumination breast imaging device,
at Lite Touch Breast Imaging, Inc., Carol Stream, IL (N.D. Ill.);
Civil No. 93C-2031.
CHARGED 4-5-93: The article was misbranded because its labeling
suggested that the device was adequate for early detection of
breast cancer and could accurately and reliably detect breast
cancer, was as effective as x-ray mammography for the detection
of breast cancer, and was approved by FDA--352(a); and its
labeling failed to bear adequate directions for its intended
uses--352(f)(1).
DISPOSITION: Default--destroyed. (F.D.C. No. 66679; S. No. 93-
575-597; S.J. No. 14)

CRIMINAL ACTIONS

DEFENDANT: John Emmanuel Botzolakis, Baltimore, MD (D. Md.);
Civil No. HAR-91-0328.
CHARGED 10-6-91: Generic drug fraud. Conspiracy to commit an
offense against the United States--18 U.S.C. 371--specifically,
that the defendant stole trade secrets of Parke-Davis and sold
the information to an employee of American Therapeutics, Inc.
DISPOSITION: In an amended notice of judgment, Botzolakis was
sentenced to one year in prison on a work release basis, 200
hours of community service, and three years' probation, and was
ordered to pay a special assessment of $50. (F.D.C. No. 66527;
S.J. No. 15)

DEFENDANT: Sanyasi Raju Kalidindi, Baltimore, MD (D. Md.); Civil
No. HAR-91-0327.
CHARGED 10-6-91: Generic drug fraud. Making a false statement in
a matter within the jurisdiction of a federal agency--U.S.C. 18
Section 1001; aiding and abetting--18 U.S.C. 1002.
DISPOSITION: The defendant pleaded guilty to one count of making
a false statement to FDA, and was sentenced to 500 hours of
community service, placed on three years~ probation, and ordered
to pay a $50 special assessment. (F.D.C. No. 66534; S.J. No. 16)

INJUNCTION ACTIONS

DEFENDANTS: Keyser Brothers Inc., and R. Calvin Keyser and Norman
A. Keyser, Lottsburg, VA (E.D. Va.); Civil No. 3:92cv852.
CHARGED 12-29-92 in a complaint for injunction: Food (crab meat)
was adulterated in that it contained a poisonous and deleterious
substance--402(a)(1); had been packed, or held under insanitary
conditions--402(a)(4); and was adulterated when introduced or
delivered into interstate commerce--331(a).
DISPOSITION: A consent decree of permanent injunction enjoined
the complained-of violations. The decree specified that all crab
meat must be subjected to an adequate thermal process prior to
interstate shipment or processed according to a HACCP plan. (Inj.
1313; S. No. 90-586-352; S.J. No. 17)

DEFENDANTS: Physio-Control Corporation, Richard Martin, Ralph
Anderson, and Michael Willingham, Redmond, WA (W.D. Wash.); Civil
No. C-92-1163.
CHARGED 7-24-92 in a complaint for injunction: That the proposed
defendants were engaged in the manufacture and interstate
distribution of medical devices (defibrillators, cardiac
monitors, and noninvasive pacemakers) and that the devices failed
to conform with current good manufacturing practice--501(h); and
that the defendants failed to furnish required material or
information with respect to various devices--502(t)(2).
DISPOSITION: A consent decree of permanent injunction shut down
the manufacturing facility immediately. In May 1993, FDA
authorized Physio-Control to resume manufacturing and
distribution of some LifePak defibrillator models, whereby a
number of 510(k) related issues surfaced. In February 1994, all 
GMP deficiencies had been remedied and Physio-Control was given
authorization to resume manufacturing of all defibrillator models.
However, the 510(k) issues were unresolved with respect
to LifePak 300, so these devices could not be distributed. In
June 1994, Physio-Control resumed distribution of these devices
based on 510(k) approval. (Inj. 1302; S. No. 92-668-423 et al.;
S.J. No. 18)

MISCELLANEOUS ACTIONS

SUBJECT: New animal drug violations and assertions of selective
FDA enforcement against a distributor of such drugs, Grand
Rapids, MI (W.D. Mich.); two cases, Civil Nos. 90-1062 and 90-
1063, and (upon appeal) 91-1837 and 91-1839.

Part I
CHARGED 12-18-90, in case No. 1 (90-1062) by Pan American
Pharmaceuticals, Inc., and Dan Lee, Grand Rapids, Mich., against
an FDA district enforcement director and an FDA inspector, in a
complaint for damages:

Part II
CHARGED 12-18-90 in case No. 2 (90-1063) by Pan American
Pharmaceuticals, Inc., and its president, Dan Lee, Grand Rapids,
Mich., against the Commissioner of the Food and Drug Commission,
two other FDA officials in Rockville, Md., an FDA district
enforcement officer, and an FDA inspector in a complaint for
mandamus and injunction: That among the products deemed by FDA to
be new animal drugs requiring prior approval were the plaintiffs'
"Avian Neo-meth," Oti-Dry," "Burrows H. Solution," "Pet Shield
Shampoo," and "Lipo-pan injectable"; and that the defendants
routinely did not enforce the law against drug manufacturers and
distributors of a majority of new animal drugs but intentionally
chose to enforce the law only against the plaintiffs, with the
purpose and intent of depriving the plaintiffs of their right to
equal protection of the law and due process of law. The
plaintiffs requested that the court order the defendants to
enforce the pre-approval provisions for new animal drugs against
all persons or, in the alternative: (1) order the defendants
enjoined from applying it against anyone, including the
plaintiffs, and (2) enjoin the defendants from threatening,
harassing and intimidating the plaintiffs' manufacturers,
suppliers and customers. The plaintiffs also requested an
adjudication of the rights and responsibilities of the parties as
to whether the defendants could invidiously apply the law
regarding certain products only against the plaintiffs.
DISPOSITION: Case No. 90-1063 --The plaintiffs moved for a
preliminary injunction. The government moved to dismiss on the
grounds that:
(1) The court lacked jurisdiction to enjoin enforcement of the
Federal Food, Drug, and Cosmetic Act or to compel wider
enforcement of such law.
(2) The plaintiffs were collaterally estopped.
(3) The plaintiffs had failed to state a proper claim.
DISPOSITION: Case No. 90:CV:1062 --District Court--The federal
defendants moved for a summary judgment of dismissal on the
grounds that:
(1) The action was barred by the doctrine of sovereign immunity.
(2) The plaintiffs had not exhausted their available
administrative remedies.
(3) The plaintiffs were collaterally estopped from raising their
claim of selective prosecution.
(4) Selective enforcement did not constitute an actionable common
law or constitutional tort.
(5) The plaintiffs had failed to make a colorable showing of
selective prosecution.
     Alternatively, the federal defendants moved for summary
judgment. Subsequently, the district court ruled for the federal
employees, holding that to the extent that a claim for damages
for selective prosecution was sought, the action was barred by
collateral estoppel, because such claim had already been decided
previously in an injunction brought by the government. As to the
plaintiffs' only other alleged basis for damages, the defendants
had failed to exhaust their administrative remedies as required
by the Federal Tort Claims Act. The plaintiffs moved for
reconsideration of the court's order of dismissal, but the court
denied such motion. The plaintiffs appealed.
     The plaintiffs~ brief was not filed as scheduled, and
accordingly the plaintiffs' appeal was dismissed for want of
prosecution. (Misc. No. 936 and Misc. No. 937 [consolidated];
S.J. No. 19)

DEFENDANTS: Rich SeaPak Corp., and Frank W. Holas, president,
Hamsa A.P. Thota, director of new products, and William Patrick
Donahoo, director of quality assurance and regulatory affairs,
Brunswick, GA (S.D. Ga.); Criminal Nos. 290-0001/4.
CHARGED June 1990: Corporation only--one count of knowingly using
false documents in a matter within the jurisdiction of FDA and
the U.S. Customs Service--18 U.S.C. 1001.
CHARGED June 1990: Individuals--when shipped in interstate
commerce, an article labeled "Round Shrimp ~n Batter~ contained
decomposed shrimp--402(a)(3).
DISPOSITION: Guilty pleas; Corporation fined $78,200 with
probation for six months. Individuals--$750 fines with probation
for one year. (Misc. No. 884; S. No. 88-435-797 et al.; S.J. No.
20)


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