Ca\BUMER• VOL. 23 NO. 5 JUNE 1989 *

ULCERSScreaming Or Silent, Watch Them With Care

Louis W. Sul l ivan, M.D.

Secretary, U.S. Department ofH e a l t h a n d H u m a n S e r v i c e s

Frank E. Young, M.D., Ph.D.Commissioner of Food and Drugs

Jeff NesbitAssociate Commissioner forP u b l i c A f f a i r s

Marian G. Segal/Acting Editor

Jesse R. Nichols/Art Director

Michael L. Herndon/Production Manager

Carol L. Ballentine/Copy Editor

Cover Design: Richard C. Thompson, Jr.

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T H E O F F I C I A L M A G A Z I N E O F T H E U . S . F O O D A N D D R U G A D M I N I S T R AT I O N

VOL. 23 NO. 5 JUNE 1989

Produc t Labe l s : F i r s t - L i ne P ro tec t i on f r om Ha rmThere's probably not a drug or medical device on the market that'scompletely safe; misuse of some could even prove fatal. CommissionerFrank Young explains how FDA monitors adverse reactions and changesproduct labeling to warn of possible harm.

Drugs and Pregnancy: Often the Two Don't MixIt's not just drugs of abuse that can cause serious birth defects in childrenwhose mothers use them during pregnancy. Many prescription and nonprescription medications can also harm the unborn child.

'Healthy Tan'—A Fast-Fading MythSun worshipers are finally getting the message that the skin that's soakingup those warm rays is getting more than a rosy glow. Wrinkles, that leatherylook, and skin primed for cancer often come with the package. Enters u n s c r e e n s .

Ulcers: Screaming or Silent, Watch Them with CareDoctors don't yet know just what causes ulcers, but it's not just somethingyou ate. Treatment for ulcers ranges from the old antacid standbys to newsurgical techniques—and there are some new ideas about prevention.

Mary Mallon's Trail of TyphoidTracking 'Typhoid Mary" was not an easy task, but a New York Cityengineer's persistence finally paid off, putting an end to an 11-year-oldreign of typhoid terror.

Artificial Nail Remover Poses Poisoning RiskFederal agencies are working to prevent accidental poisonings from anartificial fingernail glue remover that so far has claimed the life of onech i l d .

Updates Investigators' Reports

AIDS Page Summar ies o f Cour t Ac t i ons

N o t e b o o k

■ I n s i d e F r o n t C o v e r P h o t o :

Only six weeks after conception, a human embryo has a beatingheart and is forming a brain, blood vessels, a spine, and tiny armsand legs. But the road ahead can be risky. For information on howdrugs can affect the developing fetus and how to avoid harm to thebaby, see page 7.(Photo courtesy of Photo Researchers, Inc.)

FDA Consumer /June 1989 i 1

updates

Get Rid of the Garlic, FDA Says

People who eat certain commercial or homemadechopped garlic-in-oil mixes that are left at room temperature risk getting botulism—a type of food poisoning thatcan be fatal, according to FDA.

Last April, the agency told manufacturers to stop making any garlic-in-oil mixes that require refrigeration forsafety, and urged consumers to promptly discard anygarlic-in-oil mixtures that do not contain microbial inhibitors. FDA also informed manufacturers that to be safe

they must add microbial inhibitors or acidifiers such as

phosphoric or citric acid to prevent the growth of Clostridium botulinum bacteria in garlic-in-oil mixtures thatthey manufacture in the future. The bacteria producebotulin, the toxin that causes botulism.

FDA first issued a warning to consumers in March afterthree New Yorkers were hospitalized with botulism aftereating bread that was spread with a commercial choppedgarlic and oil mix that had not been kept refrigerated.

Investigation by New York health officials implicated"Colavita Chopped Garlic in Extra Virgin Olive Oil."The manufacturer recalled the product but told New Yorkofficials that distribution was stopped more than a yearago. The mix was marked "Keep Refrigerated."

Botulism is a potentially fatal food poisoning characterized by blurred or double vision, speech and breathingdifficulty, and progressive paralysis. Without promptdiagnosis and appropriate treatment, one-third of thosediagnosed may die.

Approval Criteria for Cancer Drugs

Safety and effectiveness assessments of new cancerdrugs must factor in therapeutic gains other than lengthened survival, FDA said in agreeing with key recommendations developed by a National Cancer Institute advisorycommittee. The committee was organized after NCI'sDivision of Cancer Treatment's Board of Scientific Counselors met with FDA Commissioner Frank E. Young,M.D., Ph.D., and other FDA staff to discuss the agency'sdrug approval process.

In evaluating a cancer drug's efficacy, the committeesaid, patient survival should not be the only consideration. A drug that significantly improves symptoms andquality of life should be considered for approval, even ifthere is substantial toxicity. FDA and the committeeagreed, however, that these gains should not come at theexpense of "very much" survival.

FDA also agreed with the committee's recommendationthat although randomized, controlled trials comparing anew drug to a standard therapy are preferred, other study

2 / J u n e 1 9 8 9 / F D A C o n s u m e r

designs are acceptable—especially in cancers that do notrespond to standard therapy.

The recommendations basically reflect currentapproval practices for cancer drugs, the agency said.

Hypoallergenic Baby Formula? Maybe NotFDA has notified three infant formula manufacturers

that labeling their products as hypoallergenic could befalse and misleading.

The agency asked Carnation (maker of Good Start),Bristol-Meyers (Nutramagen and Pregestimil), and RossLaboratories (Alimentum) to submit sound scientific evidence that the products are hypoallergenic as claimed, orface misbranding charges.

All the products are safe and wholesome formulas, conforming to the agency's requirements for nutrient levels ininfant formulas. Label claims that they are useful in managing severe food allergies, sensitivity to intact protein, andgalactosemia (the inability to metabolize one milk sugar)are, however, unsubstantiated, the agency said.

In letters to the companies in January and February1989, FDA cited flaws in several studies submitted in support of hypoallergenic claims for the companies' products.The supporting evidence was found to be inadequate.

Carnation has since announced it is changing the GoodStart label by removing "hypoallergenic" from the frontof the package.

Bristol-Meyers and Ross Laboratories have submittedmore information to FDA for review.

Juiceless Apple Juice Convictions Overturned

Convictions of the two top executives involved in thelargest case ever tried under food, drug, and cosmeticlaws have been overturned on a technicality.

Beech-Nut Nutrition Corp., Canajoharie, N.Y., and itspresident, Niels L. Hoyvald, vice president, John F.Lavery, and two suppliers were found guilty in 1988 ofmore than 800 violations of federal law in the manufac

ture and sale of millions of containers of sugar, water andflavoring marketed as 'TOO percent" apple juice (see"Juiceless Baby Juice Leads to Full-Strength Justice" inthe June 1988 issue of FZM Consumer).

Hoyvald and Lavery were each sentenced to a year anda day in prison, but were freed on bail pending the outcome of appeals. Now, the U.S. Court of Appeals for theSecond Circuit in New York has ruled that the EasternDistrict of New York federal court in Brooklyn, ratherthan the Northern District of New York federal court in

Albany, should have been the location for the three-month-long trial.

"It was a very technical ruling and does not addresstheir guilt or innocence," U.S. Attorney Andrew Maloneyof Brooklyn said.

Prosecutors indicated further legal action is likely.

FDA Consumer /June 198913

AIDS Page

Progress Reports in the Battle Against Acquired Immune Deficiency Syndrome

F D A P a n e l R e v i e w s N e w D a t aOn Drug to Prevent Blindness

In May, FDA's Anti-Infective DrugsAdvisory Committee reviewed new information on the safety and effectiveness ofa drug that may be critical to the sight ofmany AIDS patients. The review willhelp the agency decide whether to approve the drug.

In the meantime, recognizing the needfor patients to have access to the drug, theagency, the drug's manufacturer, and theNational Institute of Allergy and Infectious Diseases have been working to ensure the drug is available to greater numbers of patients.

The informat ion under review comesfrom studies FDA approved last November to evaluate the drug ganciclovir intreating cytomegalovirus (CMV) retinitis,an infection that can lead to blindness.CMV retinitis is one of several "opportunistic" diseases that plague AIDS patients because their weakened immune

systems cannot fight certain organismsthat healthy people ward off. The studydesigns were developed by ganciclovir'smanufacturer, Syntex Corp. of Palo Alto,Calif., and the National Institute of Al

lergy and Infectious Diseases (NIAID) inresponse to a recommendation in October1987 by the advisory committee, citingthe need for addit ional control led cl inicalstudies to evaluate the safety and effectiveness of the drug.

Under the terms of the studies, patientsat immediate r isk of bl indness from CMVretinitis were given ganciclovir. Patientswhose retinitis was not immediatelysight-threatening were enrolled in cont r o l l e d t r i a l s : S o m e r e c e i v e d i m m e d i a t e

treatment; others had to wait for treatment, receiving it later if their conditionw o r s e n e d .

Pending a final decision on whether ornot to approve ganciclovir for CMVretinitis, FDA is working with NIAIDand Syntex to ensure that all patients withany stage of the disease can have accessto the drug through an "open use" proto

col. In this study, doctors must carefullymonitor their patients and submit medicalstatus reports to the sponsors on a regularbasis. Physicians seeking information onany current ganciclovir protocols can callthe Ganciclovir Study Center at (301)497 -9888 .

N e w A I D S T r e a t m e n t S t u d i e s

FDA recently authorized clinical testing of two experimental treatments—avaccine and an anti-viral drug—forpeople infected with the AIDS virus(HIV).

VaxSyn HIV-1, which in August 1987became the first experimental vaccine tobe cleared for clinical testing to preventAIDS infection, will now be studied as ameans for bolstering the immune systemsof HIV-infected people who have not yetshown symptoms of the disease. The genetically engineered vaccine contains aprotein found on the surface of the AIDSvirus. Its developer, MicroGeneSys Inc.of West Haven, Conn., will sponsor thisnew study, which will be conducted atWalter Reed Army Medical Center inWashington, D.C.

An anti-viral drug, SC48334, will betested as a treatment for people withAIDS or advanced AIDS-re la ted com

plex. The clinical studies, sponsored bythe drug's manufacturer, G.D. Searle &Co. of Chicago, 111., will be conducted atsix test centers around the country.

New AIDS Blood Test Licensed

In March, FDA licensed the first filterpaper procedure for use with an antibodytest for the AIDS virus. With this procedure, small blood samples—usuallydrawn from finger or heel pricks—arecollected on filter paper. This eliminatesthe need for drawing larger bloodsamples from the subject's vein and storing them in test tubes. Developed by Genetic Systems Corp. of Seattle, Wash.,the procedure will be used in conjunctionwith the company's approved AIDS antibody test kit.

N e w A I D S S c r e e n V o t e d D o w n

FDA's Blood Products Advisory Com-mittee voted 8 to 1 against recommending licensing of an AIDS antigen test toscreen blood donors. At a meeting onMarch 23, 1989, the committee concluded that the test—developed by Abbott Laboratories of Abbott Park, 111., todetect the presence of proteins (antigens)found on the AIDS virus—is not significantly more reliable than the AIDS antibody tests already in use.

The committee also voted 8 to 1

against recommending licensing the testfor screening blood plasma donors. According to the committee, current AIDSantibody tests and processing proceduresto inactivate the AIDS virus in productsmade from plasma, such as Factor VIIIconcentrates (blood-clotting preparationused to control bleeding in hemophiliapatients), already ensure safety.

In a 6-to-3 vote, however, the committee recommended that FDA l icense the

antigen test for diagnostic and prognosticuse in people known to carry the AIDSv i r u s .

The advisory committee's recommendations, while not binding on FDA, willbe considered by the agency in its reviewof the test.

No Risk of AIDS from Plasma

Universal screening of blood plasmafor AIDS antibodies, combined withprocesses to destroy any AIDS virus inthe plasma, has virtually eliminated therisk of transmitting AIDS through transfusion of blood-clotting preparations usedto control bleeding in hemophilia patients. That is the reassuring message ofstudies presented at a meeting on March9 and 10, 1989, cosponsored by FDA andthe National Heart, Lung, and Blood Inst i tu te.

4/J l ine 1989/FDA Consumer

Health Talk With Dr. Frank Young

Product Labels: First-Line Protection from Harmby Frank E. Young, M. D., Ph. D.Commissioner of Food and Drugs

When safety concerns force a drug or a medical device off themarket, many people recognize that FDA has done exactlywhat it's supposed to do. For example, when reports of liverfailure associated with the blood pressure drug ticrynafen(Selacryn) and allergic shock caused by the pain reliever zome-pirac sodium (Zomax) led to their removal from the market in theearly 1980s, the general reaction was that FDA had taken the onlyappropriate action to protect the public.

But market withdrawal is certainly not the only way FDAcan address such problems. In fact, most of the time we canensure that the public safety is protected—which is our highestresponsibility—by less dramatic but far more appropriatemeasures. Often we can resolve the problem through changes inthe warnings and other information in the product's labeling. In

recent years, new labeling warnings have allowed a variety ofvaluable medical products to remain on the market, under conditions of safe use. Among recent examples; a drug to treat severeacne, another to control glaucoma, and a powerful medicaldevice that allows physicians to "see" inside the body withoutpotentially harmful X-rays.

These changes in product labeling—the FDA-approvedinformation that doctors receive about a drug or device—arean important part of the agency's effort, not only to protectconsumers, but also to improve the quality of health care.

In our work at FDA, labeling means a great deal more than justthe information on the product's bottle or box. Where FDA-regulated prescription products are concerned, labeling includesdetailed information that tells physicians and other health professionals exactly what the product is, how it works, what sideeffects it can produce, how it should be used, and who should—and should not—use it.

Before FDA approves a new drug or medical device for marketing, our scientists and health professionals work with theproduct's manufacturer to develop its official labeling. The labeling summarizes the results of scientific research on the product,including studies in humans to assess safety and effectiveness.But these studies, which seldom involve more than a few thousand people, can't generate a perfect picture of how a drug ordevice will behave when it's used by hundreds of thousands ormillions of people. As a result, it's often hard to anticipate alladverse effects—those that may occur only once in 10,000 ormore uses, for example, or those that will only be seen in children, pregnant women, or the elderly—groups not usuallyincluded in drug or device studies.

That means, of course, that in addition to being as sure as possible that a product is safe and effective before it is approved, FDAhas to have in place systems to continue to monitor the safety ofapproved drugs and devices after they come into general use. Asthose systems disclose safety problems, we are able to take corrective action. And that usually is accomplished not by ordering aproduct off the market, but by making changes in the warningsection contained in the product's labeling.

Let me use the drug monitoring system to illustrate how theprocess works, though a similar program applies to medicaldevices as well.

Since 1962, sponsors of drugs newly approved for marketinghave been required to notify FDA of all reports of adverse reactions to their products. And since 1985, serious adverse reactionsthat are not mentioned in the approved labeling must be reportedto FDA within 15 working days. A serious reaction is one thatresults in death or severe or permanent disability, requireshospitalization or prolongs the stay of someone already hospitalized, or is life-threatening. Reports of overdose as well as reportsindicating the drug as a cause of cancer or birth defects are alwaysconsidered serious.

In addition to mandatory reports forwarded by drug sponsors, FDA receives adverse reports directly from physiciansand other health professionals. We encourage direct reporting because experience has shown it to be more complete and

F D A C o n s u m e r / J u n e 1 9 8 9 / 5

more timely than reports channeled through drug sponsors.In 1988, the agency received some 52,000 drug adverse reaction reports, about 10 percent of which came to us directly fromhealth professionals.

Each of those reports was checked against the agency'scomputerized adverse reaction reports data base. That notonly tells us how many times a specific reaction has beenreported, but also something about its rate. Is it occurring in onepatient out of a hundred? A thousand? Ten thousand? Is it anadverse reaction that is described in the product labeling but isbeing seen more often than expected or under circumstances thatthe labeling doesn't mention? Or is the reaction one that the labeling doesn't mention?

If adverse reaction reports tied to a specific product accumulate, we are faced with an important question: Is the problem soserious that the product has to come off the market, or can wedeal with it responsibly by adding a warning to the labeling or taking other steps to inform doctors and patients of the need to guardagainst the hazard? The recent history of an acne drug illustrateshow serious and complex that question is.

When isotretinoin, or Accutane, was approved in 1982 fortreating severe cystic acne unresponsive to other therapy, thelabeling warned against its use by pregnant women. The reason:Animal studies had shown that the drug could cause birth defects.Soon after it came into general use, however, we began to receivereports of human birth defects associated with the drug. About1 out of every 4 fetuses exposed to the drug was injured by it.Clearly, the warning against use by pregnant women was notbeing well heeded.

The labeling for Accutane was changed several times tostrengthen the warning against use in pregnancy. The drug's manufacturer sent letters to physicians reminding them of the risk of fetalinjury, and the FDA Drug Bulletin, which is mailed to more than1 million health professionals, published articles advising physicians that Accutane should not be given to women of childbearingage who were not using birth control. FDA Consumer magazinealso warned about the drug's risks. (See "New Warnings AboutAccutane and Birth Defects" in the October 1988 issue.)

We also sought expert advice from dermatologists, obstetricians, pediatricians, other federal agencies, and consumers.Opinion was sharply divided on whether Accutane should remainon the market. But it was our responsibility to decide. And we diddecide—not to remove the only effective drug for the treatment ofa serious, potentially disfiguring, and emotionally damaging disease, but to redouble efforts to alert health-care providers and thepublic about the risk of Accutane used by pregnant women.

The professional labeling for Accutane is again being revised tohighlight the birth defect risk and spell out precisely the conditions for safe use of the drug in women of childbearing age. Inaddition, the patient labeling for Accutane is being modified toinclude a stronger warning, accompanied by an explicit illustration showing the kinds of birth defects that the drug can cause. Wemean this as a powerful deterrent to women who might underestimate the drug's risk. The message that Accutane carries a l-in-4risk of fetal injury is emphasized in the patient labeling and in theconsent form that both physician and patient must sign when thedrug is being prescribed.

Labeling changes and other forms of information dissemination to address safety concerns are seldom as dramatic or as publicized as in the case of Accutane. Nevertheless, last year alone,adverse reaction reports reviewed by the agency flagged 52 possible safety problems with marketed drugs. Most of these were earmarked for continued close monitoring, but thus far, 26 havenecessitated labeling changes. For example:• The labeling for amiodarone, used to control irregular heartbeats, was changed to warn of the risk of inflammation of thetestes and a lowering of the platelet count.• Captopril, a drug for treating hypertension, was relabeled toalert doctors and patients that it could dangerously lower thesodium content of the blood.• A broad-spectrum antibacterial drug, norfloxacin, was relabeled when it was found to cause inflammation of the small intestine and colon.• A drug for gastric ulcers, famotidine, was relabeled because ofits association with liver damage and anaphylaxis (an allergicreaction that can produce life-threatening shock).

Including such warnings prominently in the professional labeling enables doctors to watch for these adverse effects and modifythe prescribed treatment if necessary.

Thanks to adverse reaction monitoring and evaluation in pastyears, drugs such as trazodone (Desyrel), used to treat depression, and timolol eye drops (Timoptic), to control glaucoma, havebeen relabeled to spell out newly discovered safety problems, andthese valuable drugs continue to be available.

Medical devices, too, are monitored to detect and correcthazards. Although safety problems associated with devices arevery different from those involving drugs, we have had importantsuccesses in meeting safety challenges through design andlabeling modifications.

For example, in mid-1984, FDA received reports that twoyoungsters, aged 17 months and 23 months, had been strangledwhen the security top of a hospital crib failed to close properly.FDA and the crib manufacturer promptly notified hospitals ofthis potential hazard. We also collaborated to revise the crib'slabeling so that hospital personnel would know exactly how toprevent the problem. To our knowledge, there have been nofurther accidents.

In a bizarre tragedy that occurred in 1985, a 63-year-old manwas injured during examination in a magnetic resonance imaging(MRI) device. The powerful magnetic field generated by the MRIdevice dislodged tiny metal fragments embedded in one of thepatient's eyes as a result of a previous occupational accident. Hewas blinded in that eye. To guard against a recurrence of this kind ofmishap, FDA had the MRI device manufacturer relabel the equipment cautioning personnel to check for metal particles beforepatients are exposed to the MRI's powerful magnetic fields.

Our goals in requiring new label warnings instead of removingproducts from the market are, first and foremost, to be sure thatthe public health and safety are protected and, second, to allowuseful products to remain available under conditions that promotetheir safe use. No drug or device is without risk. Recognizing that,we at FDA strive to be sure that risks are well disclosed when a

product is approved for marketing and as it takes its place in normal health care. Patient safety is always our highest priority. ■

6 / J u n e 1 9 8 9 / F D A C o n s u m e r

Drugs and Pregnancy:Often the Two Don't Mix

by Evelyn Zamula

In the summer of1986, a group ofscientists gathered in Boston to disc u s s — a n d t o c o m m e m o r a t e -an event that mined lives, torefamilies apart, and left thousands of women with unbearablefeelings of anguishand guilt. The occasion wasthe 25th anniversary of therecognition that the dmg thalidomide was a potent producerof birth defects.

One of the speakers at the conference was a young Canadianscientist who had first-hand knowledge of the effects of the drug.Because his mother took the sedative during her pregnancy, hewas born with no feet and was missing fingers on both hands. Heonce asked his parents a disturbing question: If prenatal diagnosishad been available at the time of his birth and could have detectedhis malformations in the womb, would they have chosen abortion? They answered, "yes," that based on doctors' opinions atthat time, they would have aborted. But now they were glad theyhadn't because, besides their love for him and pride in his accomplishments, they had gained an empathy with those less fortunatethan he .

If that was a bright note in the thalidomide epidemic, therewere few others. Although U.S. babies were almost entirelyspared thalidomide's devastating effects—FDA drug reviewerFrances O. Kelsey, M.D., did not approve the manufacturer's

application to market the drug here—in some countries deformedchildren were abandoned by their families to be raised in institutions, and it is believed that some were even left to die. About 40percent of the nearly 6,000 known cases of thalidomide children—born between 1956 and 1963—have already died.

Birth Defects Long Connected to DrugsThe unusual deformities caused by thalidomide generated

worldwide publicity and focused attention on the fact that certaindrugs taken at a critical time in pregnancy had the potential fordamaging the unborn baby.

Before thalidomide, most birth defects were thought to begenetic, even though observers in the long-ago past had noticedthe connection between drug-taking and birth abnormalities.Some of these ancient men of medicine were also aware that

though drugs were most dangerous in the early months of preg-

FDA Consumer /June 1989 / 7

FDA receives more than 50,000 written reports of adverse drug reactions eachyear from drug companies and health-care providers. Information about the patient, the suspect drug, and the reaction and its consequences is entered into acomputerized data base. FDA scientists use the data to spot patterns of adversereactions that may call for regulatory action, such as occurred with the acnedrug Accutane. Reports of birth defects in children born to women who usedthe drug while they were pregnant led to strengthened label warnings against itsuse during pregnancy.

T h i s 8 - m o n t h - o l d

baby has the characteristic features offetal alcohol syndrome—narrow eyes,drooping eyelids,short upturned nose,and missing centergroove above theupper lip.(Photo courtesy ofStreissguth, et al..University ofWashington, Seattle)

nancy, the fetus could be affected later, too.The Greek physician Hippocrates wrote almost 2,500 years ago

that for the safety of the fetus, drugs should be administered topregnant women only from the fourth to the seventh months. Inthe second century A.D., the Greek physician Soranus of Ephe-sus warned women not to take drugs at any time during pregnancy, but especially during the first trimester. In particular, hemaintained that when drugs taken to cause abortion did notproduce the desired result, "let no one assume that the fetus hasnot been injured at all. For it has been harmed: It is weakened,becomes retarded in growth, less well nourished, and in general,more easily injured and susceptible to harmful agents; it becomesmisshapen and of ignoble soul." (For an interesting fictionalaccount of just such a case, read Robertson Davies' What's Bred inthe Bone. )

According to the March of Dimes Foundation, each year morethan a quarter of a million U.S. babies—or about I out of every14—are born with birth defects. About one-third of the abnormalities are life-threatening, making birth defects—including lowbirth weight—the leading cause of infant mortality. A half millionmore potential lives are lost through miscarriage and stillbirth,usually because of faulty fetal development. About 1.2 millioninfants, children and adults are hospitalized each year for treat-

8/June 1989/FDA Consumer

ment of birth defects. Birth defects contribute to the death of morethan 60,000 Americans of all ages annually.

The causes of birth defects are unknown in about 65 percentto 70 percent of the cases; about 20 percent of the defects aregenetic, or inherited. (Infections account for 2 percent to 3 percent of congenital malformations, maternal health problems for1 percent to 2 percent, and chromosomal aberrations for 3 percent to 5 percent.) It is estimated that 2 percent to 3 percent ofbirth defects are due to chemicals or drugs, although it is suspected that the percentage may be higher since many women can'trecall all the drugs they took during pregnancy. American womentake an average of four prescription or over-the-counter drugsduring pregnancy, plus vitamin and mineral supplements.

The effects a drug has on an embryo or fetus (the unborn baby iscalled an embryo up to eight weeks after conception and a fetusfrom then until birth) depend mainly on whether a drug has theability to produce abnormalities, how much of it is taken, and atwhat point in the pregnancy it is taken.

A drug taken by an expectant mother enters her bloodstreamand in most instances passes through the placenta to her unbornchild. The drug then passes back through the placenta into themother's circulatory system and is eventually eliminated. Theplacenta's normal function is to supply oxygen and nutrients to thefetus and to remove its waste products.

Timing Is ImportantIf a teratogenic (ter-ah-to-JEN-ik) drug—a chemical that can

produce birth deformities—is taken in the earliest part of pregnancy (from conception until about 20 days), it will either causethe death of the embryo and subsequent miscarriage, or not affectit at all.

The possibility of harm to normal embryonic development isgreatest from the third to eighth weeks, when the organs are forming. In the third week, the brain, heart and blood vessels start todevelop and the spine begins to form; the arms and legs appear astiny buds. By the fourth week, the heart starts to beat, eventhough the embryo is only a quarter-inch long. At five weeks, thefirst signs of hands and feet appear. At eight weeks, the arms andlegs are separated into upper arm and forearm, thigh and lowerleg; the two halves of the hard palate (roof of the mouth) unite.

From then on, the fetus grows and its systems mature. Teratogenic drugs taken after this period usually don't cause majorstructural defects, but they can affect growth and organ function.Particularly vulnerable is the unborn baby's nervous system,which continues to develop throughout pregnancy and in infancy.For example, the antibiotic streptomycin taken at even late stagesin pregnancy may cause hearing damage in the baby. Other systems can also be affected. Tetracycline, another antibiotic, takenduring the second or third trimester, when the fetus' teeth begin tocalcify, will cause permanent staining of the baby teeth.

In some cases, drugs can have delayed effects. Diethylstilbes-trol (DBS), a synthetic estrogen widely prescribed in the 1940s toprevent miscarriage and other problems, came to be seen as atime bomb in the children of some of the 4 million to 6 millionwomen who took it during pregnancy. Hundreds of young womenwho had been exposed to this drug as fetuses developed vaginalcancer after puberty. And a greater incidence of reproductive system abnormalities, such as undescended testes, also occurred inmale offspring.

FDA requires that every new drug that may be used by womenof childbearing potential be tested in pregnant laboratory animalsbefore it can be marketed. (Because any untested drug presents arisk of harm to the fetus, pregnant women cannot participate inthe human drug studies that are also required for pre-market

approval.) But animal testing alone is by no means foolproof;drugs in animals cannot be guaranteed to act the same way inhumans. Drugs that cause birth defects in animals may not causethem in people. Conversely, a drug that may be harmful to theunborn baby may not affect animals, or may not affect them to thesame degree. For example, humans are 100 times more sensitiveto thalidomide than are rats, and 50 times more sensitive than arerabbits. If a drug causes defects in a wide variety of animal species, however, it's almost certain that it will cause them in people,too. (See "The Beginnings: Laboratory and Animal Studies" and"Testing in 'Real People'" in the November 1987 FDA Consumer.)

Post-Market SurveillanceAfter an approved drug is marketed, FDA continues to gather

information about adverse effects from a number of sources.Drug manufacturers are required to report to the agency anyadverse drug reactions they learn of; doctors do so voluntarily.The U.S. Centers for Disease Control collects reports fromhospitals; and large monitoring studies both here and abroad-such as the Finnish Register of Congenital Malformations—gather and analyze information on birth defects. From this data,epidemiologists (scientists who study disease frequency and distribution) can detect a pattern between use of a certain drug andbirth defects.

To date, this system has worked so well since its inception thatnothing on the scale of the thalidomide tragedy has occurred inthe United States, even though potent teratogens do exist.Isotretinoin (Accutane), for example, is an extremely effectivetreatment for severe cystic acne, but a known teratogen as well.Women are warned not to take the drug if they are pregnant orintend to become pregnant while undergoing treatment. They runa risk of spontaneous abortion and have at least a 25 percentchance of bearing a baby with birth defects, including outer earmalformations, heart and central nervous system abnormalities,and cleft palate.

Since its approval in 1982, Accutane has been labeled in pregnancy category X, meaning it should not be used during pregnancy. (FDA classifies prescription drugs in five pregnancycategories—A, B, C, D and X—based on teratogenic risk. Drugsin category A appear to be least harmful, while those in categoryX have risks that clearly outweigh the benefits.) Because FDA,CDC, and the manufacturer continued to receive reports of birthdefects, warnings against using Accutane in pregnancy were considerably strengthened in 1988. Patients are now required to havea negative pregnancy test before starting therapy and are given aleaflet that contains a drawing of a baby with the birth deformitiesassociated with Accutane.

Fetal Alcohol SyndromeOne drug—alcohol—is so commonly used that some people

don't even think of it as a drug. But many experts consider it themost common teratogen in humans. Since more women andteenage girls than ever are drinking now—about 60 percent—andabout a quarter of them drink heavily, this has ominous publichealth implications.

One to three out of every 1,000 newborns, or about 5,000 babiesper year, are born with fetal alcohol syndrome (FAS). (A syndrome is a set of symptoms or characteristics that occur togetherwith reasonable consistency.) The syndrome was first describedin France in 1967 by a physician who noticed that children ofalcoholic mothers shared such distinct characteristics that adiagnosis of maternal alcoholism could be made by just lookinga t t h e m .

(Continued on next page)

FDA Consumer /June 1989 i 9

(Continued from previous page)In 1970, in the United States, a young pediatric resident at the

University of Washington Health Sciences Center in Seattle had asimilar experience. In reviewing newborns' medical records, shenoticed that four babies of alcoholic mothers had abnormally lowbirth weights. Further search revealed seven more cases. Whenthe 11 children were brought together to the Health SciencesCenter for examination, researchers in the birth defects unit werestruck by their resemblance to each other. Their heads wereabnormally small, and they all had small narrow eyes, droopingeyelids, short upturned noses, and wide upper lips in which thenormal center groove was reduced or missing. All were small fortheir age and all were mentally retarded.

Since FAS children do not usually improve in intelligence evenwhen placed in foster homes, the damage points to alcohol ratherthan the family environment, which is usually poor. As many as20 studies in various western countries indicate that FAS sur

passes Down's syndrome and spina bifida (a birth defect in whichpart of the vertebral column is missing) as a cause of mentalretardation. FAS children may also have defects of the heart andgenital and urinary organs and may have poor coordination, shortattention span, and behavioral problems.

Women who drink the equivalent of three ounces of purealcohol daily—six average mixed drinks or six cans of beer—frequently give birth to babies with the full range of FAS defects.They are also more likely to miscarry or have stillborn children orchildren who die in early infancy. Those who drink less but stillheavily (more than two drinks a day, according to the U.S. Surgeon General) may give birth to babies who have some, but notall, fetal alcohol effects. A new study points out that even two orthree drinks a week may trigger spontaneous abortion. Since noone knows at which point in the pregnancy alcohol does thegreatest damage or what amount can be consumed safely, pregnant women should drink no alcoholic beverages.

Cigarette SmokingAmong the warnings on packages of cigarettes is a statement

that smoking may complicate pregnancy. Still, of the approximately 32 percent of women who smoke cigarettes before pregnancy, 25 percent continue to smoke while pregnant. While nospecific malformations are connected with smoking, birth weightof babies born to smokers averages a half pound less than that ofbabies of nonsmokers. Low-birth-weight babies are 40 timesmore likely to die in infancy than those of normal weight. It isthought that nicotine, which constricts blood vessels, may reduceplacental blood flow, and thus the amounts of nutrients and oxygen to the unborn baby. The March of Dimes states that someresearch has shown that chest breathing motion in an unborn babytemporarily decreases sharply after its mother has smoked onlytwo cigarettes. Smoking may also increase the risk of miscarriage,stillbirth and death in newborns.

Drug AbuseAnd then there are drugs of abuse. Paula Crews, a licensed clin

ical social worker associated with Sharp Memorial Hospital inSan Diego, Calif., works with new mothers and their babies.'About 2 percent of the pregnant women in this area are abusingdrugs," she says, "which isn't bad compared to some big cityhospitals where it's as high as 30 percent or more.

"Cocaine, 'crystal' [methamphetamine], and heroin are themost popular, in that order, and marijuana is used in conjunctionwith all of them. Many drug abusers haven't had any prenatal careand walk in off the street to deliver. Some of them are high ordrunk during labor and delivery. 1 feel sorry for their babies. The

minute the umbilical cord is cut, the baby is on its own. It mustclear that drug out of its system. The most pitiful cases are thepoor heroin babies, who have classic withdrawal symptoms afterthey're born. They have feeding problems, sneeze, are irritable,and sometimes have seizures. That's a terrible way to start life."

But the baby's problems are just beginning. "Cocaine usersdon't have much appetite and are malnourished," continuesCrews, "so their babies have low birth weight. These mothers areso skinny that they hardly look pregnant even at term. Some don tmake it to term, because cocaine users are at high risk for premature delivery. As far as birth defects go, we don't notice any moreovert structural abnormalities among cocaine-exposed babiesthan usual, but they can sustain neurological damage, which isnot apparent at birth, but which we pick up later in infancy andchildhood. I've been told that some babies exposed to cocaine latein pregnancy have strokes in utero [in the womb] that can lead toretardation. When we do see malformations, we wouldn't haveany idea if a drug is responsible, or which drug is responsible,because many of these women are multiple drug abusers, plusthey drink and they smoke, and are often malnourished."

Medicines and PregnancyWomen who must take known teratogens to treat a chronic

underlying physical condition present a difficult case for theirdoctors. Drugs such as anticonvulsants used to treat epilepsy,antibiotics for tuberculosis, oral anticoagulants to prevent bloodclots, anti-cancer drugs, drugs to treat an overactive thyroid, andlithium for manic depression are some substances that cannotalways be avoided completely. Doctors must advise women takingthese drugs—before they become pregnant—of the risk to theunborn baby and how that risk can be reduced. In some cases,it may be possible to withhold the drugs, if only for the firstt r imester.

For the best outcome, a little prevention is worth a pound ofcure. Women who are pregnant or who think they may be pregnant should let their doctors know about their condition when

drugs are being prescribed for them. They should take no over-the-counter (OTC) drugs (or prescription drugs left over fromanother illness) without consulting their doctors. OTC drugs,which look harmless sitting between the candy and housewaresdepartments in drugstores, may not be harmless. Even a drug ascommonly used as aspirin can prolong labor and alter bleedingand clotting time if taken in the last three months of pregnancy.Many OTC labels warn: As with any drugy if you are pregnant ornursing a baby, seek the advice of a health professional beforeusing this product. It's worth paying attention to those words.

It's often true that the critical period for the development ofmost organs in the unborn baby is over by the time a woman issure she is pregnant. Nevertheless, it is comforting to know thateven women who have taken a known teratogen during the firsttrimester have given birth to healthy babies free from deformities.Probably a majority of fetuses whose mothers took thalidomide—one of the most potent teratogens known—resisted the effects ofthe drug. (A recent British survey reported that babies born towomen who had thalidomide-caused birth defects are having normal babies, which was expected.) Timing of exposure to a drug iscrucial, of course, but some experts think that other factors yetunknown—though perhaps genetic—appear to determine a fetus'vulnerability to a drug's effects.

For the safest pregnancy, the most sensible course is not todrink or smoke, and to take drugs only if necessary and only onthe doctor's advice. ■

Evelyn Zamula is a free-lance writer in Potomac, Md.

10 /June 1989 / FDA Consumer

'Healthy Tan'—A Fast-Fadir Myth

by Cheryl A. Sweet

Americans' rising health consciousness may finally be overriding theirobsession to obtain an enviable tan. At theheight of poolside-lounging sessions and ahost of other sun-drenching activities,we're beginning to realize that soaking upthe rays isn't as cheap as it once was. Thecost of a bronzed body is growing steeper,as a sometimes-fatal skin cancerbecomes alarmingly prevalent. Diagnosedin 1 of every 128 Americans, melanomakilled nearly 6,000 victims last year—a 93percent increase in the number of casessince 1980. Particularly troubling is thedeadly cancer's newest victims: Whiledoctors once rarely saw melanomapatients under age 40, today people in their20s are commonly treated for the disease.

At the current rate, researchers estimatemelanoma will strike 1 in every 90 Americans by the year 2000.

This year more than half a millionAmericans will develop melanoma andother less serious skin cancers, accordingto the New York-based Skin Cancer Foundation, a nonprofit organization thatconducts skin cancer public awarenesscampaigns. The current skin cancer figurecould double to more than 1 millionannual cases during the next 25 years.Contributing culprits are unprecedentedleisure time for outdoor activities, ozonedepletion, skimpier summertime attire,population growth in the sunbelt states,and sunbathing binges.

But we're modifying our sun-worshipping

ways—perhaps in response to the grimcancer projections. According to a surveyby the Skin Cancer Foundation and HealthMagazine, 95 percent of 1,000 Americansinterviewed believe repeated sun exposureleads to skin cancer, and 84 percent reportusing some kind of sun protection. Seventy-three percent say they have limited theirsun exposure in the past two years, whileonly 12 percent report taking no precautions in the sun. A testament to these findings is sales figures on sunscreens, whichhave replaced tanning lotions as the hottestsellers in the sun-care market. Sunscreensales hit the $390 million mark last year,and the market is expected to continue togrow over the next five years—reaching$560 million by 1992, according to Pack-

FDA Consumer /June 1989/11

Sales ofSunscreens

$ 3 9 0m i l l i o n

(so ld)1 9 8 8

$ 5 6 0m i l l i o n( p r o j e c t e d )

1 9 9 2

aged Facts, Inc., a New York marketresearch firm. Analysts say sun-careproducts now represent about 10 percent to15 percent of the sales for major cosmeticcompanies today—at least twice the levelof several years ago. Over the years, suncan irreversibly damage the elastin fibersin the skin, causing the sagging, wrinkling, and weather-beaten look associatedwith years of excessive tanning. But themajor threat of excessive sun exposure isskin cancer.

In the early stages of the disease, skincancer may not look like a growth; it canappear as just a discoloration of the skin.Particular attention should be paid to anychanges in the size, color, shape or thickness of moles, birthmarks, or otherirregularities. A spot or growth that beginsto itch, hurt, crust, scab, erode, or bleedcould signal a problem. The AmericanCancer Society recommends a monthlyself-examination to detect early skincancer warning signs. The best time forthis is after a bath or shower, using a full-length mirror and a hand mirror to checkmoles, blemishes or birthmarks from thetop of your head to your toes.

If a self-examination uncovers anythingunusual, it is best to consult a physician. Ifthe doctor is suspicious of the lesion, he orshe will usually do a biopsy. This involvestaking a specimen of the questionablelesion for laboratory analysis to determinewhether the growth is benign, precancerous or cancerous. Major treatments for

precancerous and cancerous lesionsi n c l u d e :• Excisional surgery - the physicianremoves the growth and, for a safety margin, a surrounding border of normal skin.The surgical site is then closed withstitches, and the tissue is sent to thelaboratory to determine if all the malignant cells have been removed.• Electrosurgery - the diseased skin tissue is scraped with a sharp, ring-shapedinstrument. Then an electrical needle isused to burn a safety margin of normalskin around the tumor and at the base ofthe area that has been scraped. The technique is repeated several times to ensurecomplete removal.• Cryosurgery - the tissue is destroyed byfreezing with liquid nitrogen.• Radiation therapy— X-rays are used todestroy the diseased tissue.• Chemotherapy - treatment with anticancer drugs may be used to treat malignancies that have spread to the lymphnodes, for example.

There are three types of skin cancer-basal cell carcinoma, squamous cell carcinoma, and malignant melanoma. All havebeen linked to sun exposure. The mostcommon is basal cell carcinoma, comprising about 80 percent of the skincancers, or some 400,000 cases each year.Characterized by raised translucent nodules that may crust, ulcerate and sometimes bleed, basal cell carcinomas occurmost often on the face and other exposed

areas of the body, but can crop upanywhere.

The next most common skin cancer issquamous cell carcinoma, with about100,000 cases reported each year. Thegrowths look like raised, pink, opaquenodules or patches, which often ulcerate inthe center. They may grow anywhere onthe body, but, like basal cell carcinomas,most often show up on exposed areas.

The most deadly skin cancer, malignantmelanoma, usually appears as a smallbrown-black or larger multicolored patch,plaque or nodule with an irregular outline.Melanomas may crust on the surface orbleed. Detected early, the Skin CancerFoundation says, all three skin cancershave at least a 90 percent cure rate. (Formore on skin cancer, see "Out of theBronzed Age," in the June 1987 FDAConsumer.)

With increasing awareness of thedangers of excessive exposure to the sun'sdamaging rays, more people are turning tosunscreens for protection. Sunscreenswork by absorbing, reflecting or scatteringultraviolet light, thereby reducing theamount that reaches the skin. While sunscreens traditionally have been aimed atfiltering ultraviolet B (UVB) radiation,future products are expected to offergreater protection against ultraviolet A(UVA) rays. UVB rays cause burning, tanning, and increased cancer risks, whileUVA radiation penetrates more slowly anddeeply into the skin, causing changes inblood vessels, creating sags and bagsassociated with premature aging, andadding to the cancer risk of UVB rays.Research on mice has shown that animalsexposed to both UVA and UVB have amuch higher incidence of skin cancer thanthose exposed just to UVB light.

Choosing a sunscreen is highly subjective. "You just sort of have to use your ownjudgment," says Jeanne Rippere, a microbiologist with FDA's over-the-counterdrug evaluation division. "Look at yourskin and know your history. If you burnreadily with minimum exposure, youwould want to pick a sunscreen with ahigher SPF [sun protection factor], especially in a hot climate."

To maximize protection, it's importantto apply the right amount of sunscreen.While most labels advise applying sunscreens liberally and often, this can beconfusing since lotions, creams, gels,liquids, and sprays all cover the skindifferently. Recent studies indicate thatmost people use only about half as muchsunscreen as necessary for full protection."As a rule of thumb, you'll get the labeled

12 /June 1989/FDA Consumer

SPF protection by using about an ounce tocover your entire body," according to aConsumer Reports article evaluating sunscreens. It is best to apply a sunscreenabout 30 minutes before exposure so it canbe absorbed and is less likely to be washedoff by perspiration.

Many dermatologists recommend dailysunscreen use to protect against insidioussun damage. Ultraviolet rays don't feelhot, so it's easy to be lulled into a falsesense of security if there is a cool breeze orovercast sky. But shade—or even thinclothing—offers little protection. Ultraviolet radiation can also reflect off sandand water, pass through gauzy robes andwet T-shirts, and penetrate several feetunderwater.

Although a few cases of skin cancer arecaused by overexposure to X-rays and bychronic exposure to chemicals such asarsenic, the chief villains are the sun'sultraviolet rays. Our bodies keep score onthe amount of radiation we take in, andwhen the numbers get too high, the bodyreacts. Normally, if abnormalities occurduring cell division, enzymes repair thedamage. Radiation from too much sun, oranother source, can put these enzymes outof commission.

Recent sunscreen developments includeproducts that are greaseless, hypoaller-genic, waterproof, or PABA-free. PABA,or para-aminobenzoic acid, is a once-popular sunscreen chemical that can irritate skin and stain clothing. The allergicreaction manifests itself as redness and

itching about 24 hours after the sunscreenis applied. If you suspect you are sensitiveto PABA, apply the sunscreen to a smallpatch of skin, preferably on the undersideof the forearm, and cover the area with anadhesive bandage. After 24 hours, removethe bandage and expose the area to sunlight for 15 minutes. If you're sensitive toPABA, a reaction will appear the next dayin the form of redness and swelling. Manysunscreens contain PABA derivatives, so ifyou're allergic to the chemical, look forPABA-free products with benzophenonesand anthranilates. Allergies to these chemicals are less common. Moreover, theseagents offer protection against both UVAand UVB rays, while PABA products protect only against UVB.

Marketers are also earmarking morewaterproof sunscreens for children, whosweat more heavily than adults and dash inand out of water more frequently, therebyeasily removing products that are notwaterproof.

To help consumers select products bestsuited for their skin types, FDA worked

with several sun-care manufacturers from1974 to 1976 to outline categories andprocedures for determining sun protectionfactor numbers. In 1978, an FDA panelrecommended SPFs from 2 to 15. The SPFnumber indicates the amount of protectionthe sunscreen provides against ultravioletrays and sunburn. An SPF of 10, for example, enables a person who is likely to sunburn after half an hour's exposure to safelysunbathe for five hours, or 10 times longerthan usual.

Until 1986, the highest sunscreen SPFavailable was 15, which is the highest number currently endorsed by FDA. Today,there are sunscreens with SPFs as high as50. These products do not yet require FDAapproval, since the agency is still evaluating whether to endorse higher SPFs."This is a gray area," admits Rippere."Many SPFs are exempt from legal actionunless there's a safety problem." Rippereestimates an SPF decision will be reachedin two years. Under current FDA consideration are whether higher SPFs are reallynecessary and whether testing proceduresaccurately determine SPF values, saysRippere. "We're pretty sure that testingprocedures can accurately determine anSPF of 8, but we don't know if they candetermine the effectiveness of a 30." Sunscreens with SPFs higher than FDA'sallowable protection factor could ulti

mately be pulled off shelves, says Rippere.Meanwhile, debate continues on the

necessity and effectiveness of higherSPFs. "I think there's possibly some justification for SPFs up to 30. For someonewith very fair skin, a 15 might not beenough," says Rippere. "But I think youget a diminishing return when you get tohigher numbers. SPFs of 49 or 50 areabsurd, in my view." Besides the still-unanswered question of higher SPF effectiveness, there is concern that higherstrengths cause increased irritation amongpeople sensitive to the active ingredients ins u n s c r e e n s .

Despite an increase in sunscreen use,only time will tell if America will be ableto reverse its spiraling skin cancer rate.Some speculate it will take another generation for noticeable cancer reductions.While experts agree the media have done agood job of publicizing the sun-cancer linkand some progress is evident, confirmedsun-worshippers nevertheless remainreluctant to forego tanning sessions. Perpetuating the problem is the long-held perception equating a suntan with status and a"healthy" look—a belief that's unlikely tofade as quickly as a tan. ■

Cheryl A. Sweet is a free-lance writer inPhoen ix , Ar iz .

FDA Consumer/June 1989/13

Ulcers have frequently been the targetfor humor in describing the stereotypical aggressive, pressured, goal- orcareer-oriented person. But for those whohave them, ulcers are no laughing matter.Peptic ulcers strike 1 out of every 50Americans each year. There were4,580,000 new cases in 1987, according tothe National Center for Health Statistics.

Peptic ulcers, which are in the stomachand the duodenum (the first part of theintestine leading from the stomach) canoccur at any age and affect both men andwomen. Untreated, sufferers can look forward to a long siege with them. But today'speptic ulcer sufferers have a brighterprospect for relief than did those of even asingle generation ago. There's now lessthan 1 chance in 18 that surgery will everbe necessary. New medications act fasterand better to assuage the fires within.

Symptoms Sometimes SilentUlcers in your upper digestive tract can

be seen through an endoscope (a flexible,tube-shaped device using special light-reflecting properties to allow the doctor tosee inside the body). They show up ascrater-shaped sores, generally one-quarterto three-quarters of an inch in diameter.Ulcers may feel like little volcanic eruptions to some, but not all ulcers causepain, particularly duodenal ulcers. Somepeople, especially the elderly and thosewho take nonsteroidal anti-inflammatorydrugs (NSAIDs), such as aspirin, mightnever notice pain even though they haveserious or repeated ulcer attacks. (Seeaccompanying article, "NSAIDs andUlcers.")

Once you've developed an ulcer, othersare likely to appear in the future. Then,some research suggests, ulcer disease will"burn out," decreasing in severity or disappearing after about 7 to 15 years.

The warning sign of active ulcers you'llmost likely experience—if you get anywarning at all—is a gnawing discomfort inthe middle or upper abdomen that typically comes between meals or in the middle of the night. Food or liquids, includingantacids and milk, can provide temporaryrelief, but milk might not be all that good aremedy since it stimulates production ofhydrochloric acid and other digestivejuices responsible for the pain.

Antacids, blended from aluminum, calcium or magnesium salts, have long beenthe nonprescription drugs most peoplereach for to get quick relief from pains intheir stomachs. But, because antacidsinterfere with absorption of some medications, be sure to tell your doctor you'retaking them.

ULCERSScreaming OrSilent, Watch

ThemWithC a r e

byVeniModeland

Don't Take an Ulcer LightlyYou should never ignore any warning

signs of ulcers. Ulcer complications areserious and can be life-threatening. If painpersists after more than 10 to 14 days ofself-treatment or comes back when self-treatment ends, you should see your doctor. Black or tarry stools, while possiblycaused by something else, can be an urgentwarning of a bleeding ulcer. Vomiting, orfrequent reflux of stomach secretions orrecently eaten food, may mean that ulcerscar tissue is blocking the duodenum,stopping food from moving out of thes tomach .

Bleeding ulcers can cause anemia or, ifthe ulcer crater expands into a major bloodvessel, a leak can turn into a hemorrhage,with only minutes available for life-savingemergency treatment. Ulcers can alsoperforate—erode completely through thewall of the stomach or duodenum. If thishappens and the stomach's contents flowinto the abdominal cavity, severe infectioncan result. A perforated ulcer is an emergency that requires immediate surgery.

The CausesThere's mounting evidence that some

thing other than smoking, drinking, spicy

meals, or a battle with the boss may beassociated with ulcers. It could be a bugthat bothers your belly; Campylobacterpylori.

C. pylori is an S-shaped bacterium withwhip-like appendages (flagella) that itwiggles to scoot about in the slurry-likeenvironment of the stomach's inner surface cells. While rarely found in peopleunder the age of 20, C. pylori may infectmore than 60 percent of Americans overage 65, researchers say.

The bacteria thrive in clusters amongsurface cells that line the digestive tract.Irritation caused by the organisms seemslikely to lead to gastritis (inflammation ofthe stomach lining). Whether it also is aprecursor of stomach and duodenal ulcersand precancerous conditions is not knownfor certain. Ulcers appear to be the resultof a combination of conditions, thedynamics of which researchers don't fullyu n d e r s t a n d .

Was It Something You AteOr Something Eating You?

Here's some good news. Spicy pizza andpeppery Mexican meals may not pose therisk of long-term damage to your stomachthat they've long been blamed for. David Y.Graham, M.D., of Baylor College ofMedicine in Houston, Texas, and othersstudied the effect of spicy foods in a dozenpeople with normal, healthy digestive systems. They reported in the Dec. 16,1988,Journal of the American Medical Association, that no damage to the digestive tractwas observed in the study subjects for upto 24 hours after they had eaten the spicyfoods. Current thinking on ulcer diets isthis: If a food bothers you, don't eat it. Ifyou favor spicy foods, though, don'tassume you have to deny yourself thepleasure just because you have an ulcer.

Another study, published in the February 1988 issue of Gastroenterology, reinforces an old but sound idea—that it is notwhat you're eating but what's eating youthat is a major contributor to ulcer disease.This study in Texas and California examined the mix of smoking, drinking alcoholic beverages and coffee, and takingaspirin in a group of men with ulcers.Researcher Pamela Walker, andcolleagues concluded that, among thosestudied, it was emotional stress—"not somuch a function of their life events as theunique way that they react to theseevents"—that distinctly set apart thosewith ulcers from those without them. Thestudy found no connection between ulcersand coffee or alcohol.

Smoking, however, doubles your riskfor ulcer disease, many physicians and

14 /June 1989 / FDA Consumer

researchers have found. Ulcers heal moreslowly for smokers, and smokers also havea higher relapse rate.

And you're definitely at risk for ulcers ifyou take NSAIDs. High-dose aspirin,ibuprofen, naproxen and piroxicam areamong NSAIDs in wide use today formany conditions, especially to relieve painand swelling among the millions of peoplewho have arthritis. These medications canirritate the stomach's lining and cause gastrointestinal bleeding.

What Helps and HowLast December, FDA approved a new

medication that targets the dangerous sideeffects of NSAIDs. It is misoprostol (tradename Cytotec), a synthetic prostaglandinthat controls the amount of acid secreted

by the stomach and helps replace substances in stomach tissue that are depletedby NSAIDs.

Another category of prescription drugscalled histamine-receptor antagonists, orhistamine blockers, has helped build a$2.2 billion business in makingantacids and ulcer drugs. Histamineblockers reduce the amount of hydrochloric acid that a billion or so cellsin the stomach turn out to digest food.They also affect cholinergic agents, thechemicals that transmit electrical impulsescarrying messages between cells, and thesecretion of gastrin, which stimulatesproduction of gastric juices. Cimetidine(trade name Tagamet), famotidine (Pepcid), misoprostol, nizatidine (Axid),ranitidine (Zantac), and sucralfate (Cara-fate) are prescription histamine blockersapproved by FDA to treat ulcers.

When No Drug Works, What Then?Surgery is the "big hammer" medical

option in the treatment of what the doctorcalls intractable peptic ulcers—ulcers thatdo not respond to medical treatment. But,thanks to modern medications and improvements in medical management, fewer than2 out of every 100 Americans who hadulcer disease in 1987 required surgery.

For patients who do require surgery, themost common procedure is a vagotomy.The surgeon severs branches of the vagusnerve that stimulate part of the stomach tom a k e a c i d .

For more severe or recurrent ulcers, thesurgeon may opt to do a gastrectomy inaddition to the vagotomy. The surgeonremoves as much as two-thirds of thestomach, then attaches the remaining partto the small intestine. The modifiedstomach will eventually stretch to makeroom for nearly the same volume of foodthe patient is accustomed to eating, but

(Continued on page 17)

NSAIDs and Ulcers"The incidence of ulcers with com

plications appears to be rising amongmy older patients, particularly thosewho take nonsteroidal anti-inflammatory drugs," says Alex Hover, M.D.

Dr. Hover is a gastroenterologist inSpringfield, Mo., where, due to theregion's attractions for retirementliving, older people are the fastestgrowing age group. Hover says: "We'reseeing more people—mostly the olderpeople—for whom bleeding or perforation is the first sign of their ulcers. It's amajor cause for concern."

Nearly 6 out of every 100 Americanstake prescription medications forarthritis pain or swelling. They are consuming high doses of nonsteroidal antiinflammatory drugs—NSAIDs such asaspirin, ibuprofen (Advil, Medipren,Motrin and Nuprin), naproxen (Naprosyn), or piroxicam (Feldene).

The irritation of ulcers from use ofNSAIDs tends to be painless.Researchers studying these so-called"silent" ulcers say NSAIDs may bemasking the pain signals, or thatpatients taking NSAIDS may alreadybe used to living with some pain anddon't recognize ulcer symptoms.

NSAID complications can be serious. As many as 2,000 deaths and20,000 cases of ulcer-related NSAIDside effects are linked each year to the68 million prescriptions written forarthritis symptoms, according tostudies by the Center for UlcerResearch and Education at the UCLAMedical School in Los Angeles.

Earlier this year, FDA revised requirements for labels for all prescriptionnonsteroidal anti-inflammatory drugs.Labels now must warn that bleeding,ulceration and perforation can occur atany time, with or without symptoms, inpeople who take these drugs regularly.These serious side effects occur inabout 2 to 4 of every 100 people takingNSAIDs, FDA says. ■

*

Campylobacter pylori (dark specks at the center of the photo) cluster amongsurface cells in the digestive tract. Irritation from C. pylori infections seemslikely to lead to gastritis - inflammation of the stomach lining - and perhapsu l c e r s .

(Photomicrograph courtesy of Lesley C. Alpert, M.D., Department of Pathology,The Methodist Hospital, Houston, Texas)

FDA Consumer /June 1989 /15

Physician 's-eye view of active peptic ulcers as seenthrough a fiberoptic endoscope inserted into thestomach through the patient's mouth. Above left; Awell-formed ulcer is visible in the mucosal lining ofthe middle portion of the stomach. Middle: This ulcer is in the wall of the duodenum, the first part ofthe small intestine leading from the stomach. Right:Double trouble. Two active ulcers appear in this second view of a section of the duodenum shown inthe middle photo.

(Photos by Stanley B. Benjamin, M.D., chief, division of gastroenterology, Georgetown UniversityMedical Center, Washington, B.C.)

16 /June 1989 / FDA Consumer

{Continued from page 15 )

removal of the lower part of the stomachreduces its ability to make acid byreducing the number of acid-secretingcells present.

Other surgical modifications can restructure the stomach to make it empty its contents more rapidly into the intestine. Orthe surgeon can remove a small part of thestomach where a hormone that stimulatesacid secretion is produced. Proceduresalso have been introduced that stopbleeding by directly injecting drugs thatdilate blood vessels in the stomach or byusing lasers or heater probes guided by theendoscope to cauterize sites of bleeding.

While surgery can drastically reduceulcer recurrence, there are infrequentsevere digestive side effects that occasionally require follow-up surgery. There alsois evidence that ulcer patients surgicallytreated have a twofold risk of developingstomach cancer 20 years after theoperation.

Preven t ion Poss ib i l i t i esWill diet someday again assume a

leading role in your doctor's bag of optionsfor managing ulcer disease? Possibly,according to a 1986 report in the Britishjournal Gut.

Reduced incidence and severity of peptic ulcers in the past two decades may belinked to a major concurrent change in ourdiet. During these 20 years, physiciansand nutritionists have been after us toswitch from animal fats and tropical oils toplant protein and vegetable fats forcooking. The goal was to reduce serumcholesterol levels for the benefit of ourcardiovascular systems. But vegetable oilsalso may do our digestive systems a favor.Polyunsaturated fatty acids—particularlyarachidonic and linoleic acid—promoteproduction of prostaglandins in thestomach and help protect its inner liningand accelerate the healing of ulcers.

The incidence, severity and risk of deathfrom peptic ulcer disease have been declining steadily the past 20 years, according toa summary report on the disease in theJune American Journal of Gastroenterology. Stephen Sontag, M.D., andothers conclude that dietary therapy mayhave a place in the future for treatingulcers, but individualized treatment withmedications or surgery are today's mostpractical solutions. ■

Vem Modeland is a member of FDA'spublic affairs staff.

FDA Consumer /June 1989 /17

^aimoneua in eggs: Domiism rromOgarlic-in-oil! Listeria in cheese! Itseems that every day newspapers areshouting headlines about outbreaks offood-borne illnesses. Just within the pastyear, for example, eggs contaminated withSalmonella bacteria have sickened scoresof consumers in the northeastern UnitedStates, airline food tainted with Shigellabacteria brought down members of theMinnesota Vikings football team, andthree residents of New York state were

hospitalized with botulism after they atean unrefrigerated garlic-in-oil mix. Infact, FDA scientists estimate that tens ofmillions of cases of food-borne diseaseoccur every year in this country.

But these recent outbreaks, serious asthey are, can't match the 11-year reign oftyphoid epidemics caused by one personat the beginning of the 20th century.

Mary Mallon, known to history as"Typhoid Mary," was born sometimearound 1870. (Her age, as well as herclaim to have been born in the UnitedStates, was never verified.) She was thefirst typhoid carrier identified in theUnited States who never displayed a singlesymptom of the disease herself. But beforeshe was captured and quarantined for life,she directlv infected at least 51 people.

m r e e o r w n o m a i e u , a n a m a m

countless others.

Typhoid, or typhoid fever, iinfectious disease caused by Styphi bacteria. The bacteria erthrough contaminated food ortrate the small intestine, and tlthe bloodstream, where they cpoisoning and carry infection v^xxx^xparts of the body.

Early symptoms of the disease beginsuddenly with headache, general achesand restlessness, coughing, nosebleeds,bloody diarrhea or constipation, and fe>A rash on the torso appears a week or tvlater. If the victim manages to survive, tfever begins to decline after about fourweeks and gradually returns to normal.But if complications arise, such as heartfailure and ulceration or perforation of tintestinal wall, typhoid is generally fata

About 30 percent of people infectedwith typhoid remain carriers, excretingthe organism in their stool or urine forweeks or months. About 5 percent arelong-term carriers, like Mary Mallon,who shed the organism for years. Thesecarriers show no apparent ill effects butharbor the bacteria in their gallbladdersand bile ducts. (When health authorities(Continued on vase 20)

/

Before she was apprehended and quarantined for life, history's most celebrated typhoid carrier, "Typhoid Mary"Mallon, passed her disease to at least 51 people, three ofwhom died, and probably to countless others. Though shehad no symptoms, Mary Mallon was confined to RiversideHospital for Communicable Diseases on North BrotherIsland, New York City, in 1915. She died there in 1938.(Photo courtesy of UPI/Bettman Newsphotos)

(Continued from page 18 )urged Mallon to have her gallbladderremoved, she refused, claiming it wasjust a pretext for killing her. But, according to a March 1984 Science Digestarticle by Warren Boroson, Mallon laterwrote in an unpublished letter that she wasskeptical of having her gallbladderremoved because the doctors could not

agree on exactly where in her body thebacteria were located.)

Mallon's case came to light in 1904when an epidemic of typhoid spreadthrough New York's Oyster Bay and adjacent towns on Long Island. A sanitary

engineer with New York City's Department of Health named George Soper wasasked to investigate. He found that Mallonhad been employed as a cook in each of thestricken households. Even though at thattime, it was not widely known that peoplewho were themselves healthy might nonetheless be disease carriers, Soper deducedthat Mallon was the source of the outbreaks. When he confronted her with his

suspicion and offered medical care at nocharge, she vehemently refused, going sofar as to threaten the investigator with arolling pin. She then disappeared.

But a persistent Soper, convinced Mallon

was a typhoid carrier, tracked her for threeyears. He found her again in 1907, workingas a cook in a Park Avenue home in Manhattan. Mallon was brought—literallykicking and screaming—to the RiversideHospital for Communicable Diseases onNorth Brother Island, where, upon examination, she was found to be, in Soper'swords, "a living culture tube" of typhoidbacteria. The authorities committed her tothe isolation center, and, despite a legalappeal that was ultimately denied by theU.S. Supreme Court, she stayed at thecenter until 1910, when she was releasedafter promising never to work as a foodhandler again.

But four years later, when typhoidepidemics broke out at a sanatorium inNewfoundland, N.J., and Sloane Maternity Hospital in Manhattan, Soper learnedthat Mallon had worked as a cook at bothplaces and the search was on again.

She was found at last in 1915 andarrested at a friend's home in suburbanWestchester County, N.Y., while makingdessert. She was returned to Riverside,where she remained for the rest of her life.In her later years, she worked as a hospitalvolunteer and did a creditable job. A paralytic stroke led to her slow death in 1938. ■

Catherine Carey is a member of FDA'spublic affairs staff.

2 0 / J u n e 1 9 8 9 / F D A C o n s u m e r

Winning the BattlePollution of public water supplies has

been responsible for most major typhoidepidemics. However, food and milkmay be contaminated by a carrier—like"Typhoid Mary" Mallon—employedin handling and processing them, or bythe use of polluted water for cleaning.Shellfish—particularly oysters-harvested from polluted water and freshvegetables grown in soil fertilized orcontaminated by sewage are particularlyrisky as potential sources of typhoid.

Prevention of typhoid and other food-borne illnesses depends on proper sewage treatment, filtration and chlorinationof water, and proper food handlingpractices among food service workers.(See "Mother Nature's Regulations onFood Safety" in the April 1988 FDAConsumer.) Food handlers shouldalways:• Wash their hands after every visit tothe bathroom.• Practice good personal hygiene andbe in good health.

• Never leave food out unnecessarily.Hot foods should be kept at a temperature of at least 165 degrees Fahrenheitand cold foods at 40 F or colder.• Wash and sanitize utensils, cuttingboards or work areas, and equipment,like blenders, pots and pans, afterevery use.

Doctors used to be able to treat onlythe symptoms of typhoid, but after 1948,antibiotics—especially chloramphenicol (accompanied by cortisone)—proved to be effective in killing the bacteria, thus curing the infection. Today,only about 500 cases of typhoid are diagnosed in the United States each year,and over half of those are contractedabroad. Virtually all recover.

In Third World countries, wheremodern methods of sanitation and sewage disposal aren't generally practiced,the fatality rate from typhoid remainsas high as 10 percent, constituting aserious public health problem.

Travelers to developing countriesshould avoid drinking untreated water,drinks served with ice, peeled fruits,and other food that is not served hot.They should also see their physiciansabout being vaccinated before the trip.A typhoid vaccine was developedaround the turn of the century. Firstgiven to military personnel and peoplein institutions, it substantially loweredthe incidence of the disease. Still, thevaccine provides only partial protection(other vaccines are currently beingstudied), so even travelers who havebeen vaccinated should take appropriate food precautions. ■

FDA Consumer /June 1989 / 21

Mifidd Nail Remover Poses Poisoning Riskby Dale Blumentha!

In late 1987 in Los Angeles, 12 hoursafter swallowing a mouthful of solventused to remove sculptured artificial fingernails, a 16-month-old toddler died ofcyanide poisoning.

In fall of the same year in Utah, a 2-year-old boy was rushed to the emergency roomfor rigorous intensive care after his parentsfound him in bed vomiting, moaning andunresponsive, an open bottle of the samesculptured nail remover by his side. Onceagain, a child's curiosity had resulted incyanide poisoning.

Sculptured nails are acrylic artificialfingernails that are glued onto the realnail. It takes a special glue remover toremove these fake long nails. However,some brands of sculptured nail removersare extremely poisonous when swallowed.FDA warns: Keep them out of the reach ofsmall chi ldren.

These products contain 98 percent to100 percent acetonitrile, a chemical thatbreaks down into cyanide when swallowed. Studies show that 150 milligrams ofacetoni t r i le—about 1/200 of an ounce-will kill 50 percent of laboratory rodentsthat are given the chemical, says HeinzEiermann, director of FDA's division ofcolors and cosmetics.

Toby Litovitz, M.D., who heads theAmerican Associat ion of Poison ControlCenters' data collection committee, wouldlike to see acetonitrile-containing sculptured nail removers withdrawn from themarket. However, despite the fact that theproduct is poisonous if swallowed, FDAdoes not have the authority to restrict itssale unless the injury results from usingthe product according to directions. Sincethe product is not intended to be swallowed, FDA cannot take it off the market.Regulation falls through the loopholes offederal health and safety laws.

For instance, the Federal HazardousSubstances Act, which covers householdproducts such as cleaners, prohibits thesale of substances that contain concentrations of cyanide greater than 25 parts permillion. Acetonitrile contains 4,000 to80,000 parts per million of a cyanideequivalent, according to Litovitz. But,under the Federal Food, Drug, and Cosmetic Act, sculptured nail removers arenot considered household products, but

Keep Out of Reach of Children. This woman knows that even a smallamount of the solvent she uses to remove her artificial nails can be lethalIf swallowed. The Consumer Product Safety Commission Is considering arequirement that all such products be marketed In chlld-reslstant conta iners .

22!June 1989/FDA Consumer

cosmetics. And the Hazardous SubstancesAct, which is enforced by the ConsumerProduct Safety Commission, doesn't covercosmetics. No comparable law exists thatwould ban a cosmetic that is dangerous forother than its intended use.

Smells Like GrapesAt the very least, Litovitz is calling for

child-resistant packaging of sculpturednail removers. The products now come inglass bottles with screw-on caps, easy for achild to open. Also, says Litovitz, sheknows of at least one brand that is dyedpurple and smells like grapes, furtherinviting childhood misuse.

Last December, Litovitz and colleagueE. Martin Caravati, M.D., published apaper in the. Journal of the AmericanMedical Association calling attention topoisonings from acetonitrile cosmetics.They cited the two cases mentionedearlier. Since then there have been others,Litovitz says, although none resulted indeath: Another 2-year old suffered convulsions after swallowing a small amount ofsculptured nail glue remover, and an adultwoman became comatose after a suicideattempt involving the substance. At leastthree others—all children—have escapedwith little or no harm after swallowing nailremover containing acetonitrile.

The highly poisonous glue remover isavailable not just to professionals, but toanyone. In the JAMA article, Litovitz andCaravati reported that the "highly toxic,cyanide generating product" was purchased by parents of the victims atwholesale-retail beauty supply outlets.Similar products also are marketed insupermarkets and drugstores.

Read the LabelIn January, FDA sent a memo to its dis

trict office in Los Angeles, where firmsmarketing these products are located. Thememo instructed investigators to collectsamples and labeling of acetonitrile-containing products. Seven sculpturednail glue removers were specifically citedin the memo. "Of special interest," itsaid, "is any warning or caution statementmade in the labeling and promotion ofthese products."

Scientists in FDA's division of colorsand cosmetics in 'Washington, D.C., havereviewed the samples collected in the

■ ' . v w - f . . . A

Acetonitrile, a chemical in some glue removers used to take off artificialnails, can break down into cyanide when swallowed. One toddler died andother children became ill from cyanide poisoning after ingesting the nailremover, yet one brand is colored purple and made to smell like grapes.Gaps in consumer protection law make it hard to regulate these productseffectively.

field, finding that these products do contain nearly 100 percent acetonitrile.

Labels on the packaging caution:"Poisonous—Do not ingest," "Poisonous& Flammable. Do not swallow or inhale. . . Keep away from children," or "Donot take internally." FDA's Fiermann saysthat if a nail remover containing acetonitrile "didn't have any cautionary statement, then the agency probably could takeaction." But the statements on the packages appear "conspicuously as comparedto other words" on the label, thereforemeeting the minimum requirements of theCode of Federal Regulations.

Child-Resistant PackagesThe responsibility for requiring child-

resistant packaging lies with the Consumer Product Safety Commission underthe Poison Prevention Act. Under that law,child-resistant containers may be requiredfor products that can cause serious personal injury or illness because of the waythe substance is packaged.

CPSC is reviewing a petition that child-

resistant packaging be required foracetonitrile-containing products, saysAlan Brauninger, an attorney at thecommission. The petition was submittedby the Cosmetic, Toiletry and FragranceAssociation, which represents thecosmetics industry.

Keep Away from ChildrenConcern about the safety of sculptured

nails and their accessories is not new. Lastyear, FDA Con^amer published an articlewarning of possible infections, allergicreactions, fingernail loss, and otherproblems caused by sculptured nails,especially when used improperly ("Artificial Fingernails: Apply with Caution,"February 1988).

FDA continues to monitor sculpturednail products and to warn consumersto read product labels and keep poisonous substances out of the reach of smallch i l d ren . ■

Dale Blumenthal is a member of FDA'spublic affairs staff.

FDA Consumer /June 1989 / 23

The Notebook

The Notebook: a potpourri of items of interest gatheredfrom FDA news releases, other news sources, and the Federal Register (designated FR, with date of publication).The Federal Register is available in many public libraries.

m The Environmental Protection Agency proposesbanning captan as an ingredient in fungicides exceptin specific applications where benefits outweigh risks.Animal studies suggest an increased risk of cancer inhumans exposed to captan and captan-treated crops (FRFeb. 24).

■ A revised edition of "Guidance on the Use of Methadone in Maintenance and Detoxification Treatment ofNarcotic Addicts," reflecting changes in methadone regulations, is available free from the FDA Legislative, Professional and Consumer Affairs Branch (HFD-365), 5600Fishers Lane, Rockville, Md. 20857 (FR March 2).

■ Guidelines for phased submissions of new animaldrug applications are outlined in the "Guide 1240.3040 tothe CVM Policy and Procedures Manual." Free copies areavailable from the Industry Information Branch (HFV-11),Center for Veterinary Medicine, FDA, 5600 Fishers Lane,Rockville, Md. 20857 (FR March 14).

■ Applications to export unlicensed human biologicalproducts should be sent to Boyd Fogle Jr., Center for Bio-logics Evaluation and Research, FDA, Room 217,7520Standish Place, Rockville, Md. 20855 (FR March 14).

■ FDA has denied approval of 36 applications for newanimal drugs that contain sulfamethazine, sulfaquinoxa-line, sulfamerazine, sulfathiazole, sulfapyridine, or sulfanilamide (FR March 15. Also see FR Sept. 15,1988).

■ After investigation by the Council of Better BusinessBureaus, Redken Laboratories, Inc., Canoga Park, Calif.,stopped using advertising claims stating that 79 percent ofusers of Vivagen Hair Treatment experienced "decreasedhair loss."

■ Revised "Guidelines for Preparing CompressedGases for Medical Use" are available free. Write; Legislative, Professional and Consumer Affairs Branch (HFD-365), Center for Drug Evaluation and Research, FDA,5600 Fishers Lane, Rockville, Md. 20857 (FR March 22).

■ A "Guide to Acceptable Market Names for Food FishSold in Interstate Commerce" (The Fish List) is nowavailable for $2.75 per copy from the Superintendent ofDocuments, U.S. Government Printing Office, Washington, D.C. 20402. Ask for GPO Stock No. 017-012-00341-9(FT? March 24).

24 /June 1989/FDA Consumer

m Poly vinylcyclohexane has been approved for use in themanufacture of certain plastics intended for use in foodpackaging (FR March 27).

■ FDA has amended animal drug regulations for saferesidue levels in beef of the implanted drug trenbolone acetate (FR March 28).

T H E F I S HL I S T F D A G u i d e t o A c c e p t a b l e M a r k e t N a m i

F o r F o o d F i s h S o l d i n I n t e r s t a t e C o m n

XHEFISH

tInvestigators'Reports

Biggest Drug Research Fraud CaseIn FDA History

Doctor Gets Jail Term for Faking Drug Tests

by Judy Folkenberg

After pleading guilty to pocketingnearly $2 million from pharmaceuticalfirms for experimental drug tests that henever performed, prominent New Jerseyphysician Robert A. Fogari was sentencedto four years in prison on Feb. 2. He wasalso fined $2 million and ordered to makefinancial restitution to the drug companieshe defrauded. After serving his prisonsentence, Fogari will be placed on probation for five years.

"This is one of the worst cases Fve everseen, and I would not have believed it if Ihad not seen it," said Judge Garrett Brownof the U.S. District Court for the Districtof New Jersey, who presided over the trial."What you did was worse than dealing indrugs and murder," he told Fogari. "Youbetrayed the public trust. Our system ofdrug testing relies on honesty."

The judge said the sentence was ascompassionate as possible consideringthe circumstances.

Fogari's case is believed to be the biggest investigational drug fraud case inthe history of FDA, according to Alan B.Lisook, M.D., chief of FDA's clinicalinvestigations.

At the beginning of his trial last Sept. 27,Fogari, an arthritis specialist, had pleadednot guilty to 20 charges of fraud andobstruction of justice. But seven days intowhat was expected to be a month-long trialhe changed his plea and admitted guilt onfour counts: conspiring to falsify drug testdata, making two false statements to FDA,and obstructing justice by having a falseaffidavit submitted to FDA.

Fogari also admitted that he concealedthe deaths of two patients "enrolled" in thebogus drug studies because he wanted to"maintain a favorable impression" withthe pharmaceutical companies that hadhired him, according to assistant U.S.attorney Paul Weissman, who prosecutedthe case. However, Fogari said the deaths

were not related to the experimentaldrugs, and FDA had no evidence to contradict him. (Although Fogari neverconducted any formal research, he mayhave used the experimental drugs in ahaphazard fashion.)

Between 1977 and 1985, pharmaceuticalcompanies that were seeking FDAapproval for anti-inflammatory arthritisdrugs paid Fogari to conduct clinicalstudies. Payment was based on the numberof patients enrolled, the number of officevisits, and the number of procedures performed during the study. According toWeissman, Fogari submitted thousands offalsified reports to drug companies.

During the week-long trial, formeremployees, who were given immunity, testified that Fogari instructed them to list thenames of persons who were not enrolled inthe study, make up patients, and continueto include patients who had dropped out ofthe study. Fogari also failed to conducturine, stool, and blood tests necessary forthe study. Under questioning from Weissman, Fogari admitted to forging the signatures of radiologists and other specialiststo documents attesting that X-rays andother tests or exams had been performed.

The most damaging testimony camefrom Patricia Cunningham Czorniewy, aformer assistant to Fogari who admittedunder questioning that the doctor hadpressured her to sign an affidavit falselystating that she had invented study data. Itwas after her testimony that Fogarichanged his plea from innocent to guilty.Questioned by Weissman, Fogari admittedit was he who falsified all data and that hedid not conduct any legitimate researchduring the entire eight-year period.

Fogari participated as an investigator inat least IB experimental drug studies fornine drug manufacturers, including Ciba-Geigy, Johnson & Johnson, Warner-Lambert, Pfizer, Upjohn, Syntex, andMerck, Sharp & Dohme. The drugs hewas supposed to test included Voltaren,Maxicam, Seldene, and Naprosyn. How-

FDA Consumer /June 1989 / 25

ever, Anthony Panzica, director of FDA'scompliance branch in the Newark districtoffice, emphasizes that the drug manufacturers deleted Fogari's data from theirmarketing applications after they werenotified of his disqualification. Panzicasaid that most of the drugs have not yetbeen approved by FDA, and those that weredid not depend on his data for approval.

"His research did not influencedecisions to put any drugs on the market,"

Another Case of Fraud

As New Jersey physician RobertFogari faced trial in the biggest caseof fraudulent drug research in FDA's history (see preceding article), a board-certified urologist pleaded guilty in theU.S District Court of Massachusetts oncharges of faking research data.

On July 14, 1988, Constantinel. Kostaspleaded guilty to one count of making afalse statement to a federal agency and onecount of mail fraud.

Although he faced a maximum penaltyof 10 years in prison and a $500,000 fine,Kostas instead received a one-year suspended prison sentence, was fined$30,000, and was ordered to perform 400hours of community service.

Miles Pharmaceuticals of West Haven,Conn., had hired Kostas as a clinicalinvestigator to test the drug ciprofloxacin(brand name Cipro) for treating urinaryinfections. The firm's officials becamealarmed when, during a routine audit,serious discrepancies—such as givingantibiotics instead of Cipro to somepatients—were discovered in Kostas'data. When the firm informed Kostas itintended to conduct a full audit, he confessed that only 15 of the 85 subjects listedin the study had actually received theexperimental drug.

In addition, Kostas included in the studypatients who did not meet the medicalcriteria of the research protocol, and hefaked results of nonexistent lab tests andoffice examinat ions.

Kostas admitted that he thought thestudy would be easy to conduct, but he hadbeen dogged with problems from the start.The physician said he pressured himself tocontinue the study and "wouldn't admitthat he couldn't do it," according to EdWarner, assistant regional director foroperations for the northeast region.Kostas' study had no bearing on FDA's

said Panzica.

Fogari was first investigated by FDA in1983 after officials at Ciba-Geigy becamesuspicious because his data were "too perfect," said Weissman.

Fogari's sentence angered many patientsand former patients. He had a "great following among his patients, and peoplecouldn't believe what had happened," saidDiane Kolaitis, a compliance officer inFDA's Newark office. He was known as a

approval of the drug.According to his probation officer,

Kostas fulfills the community service obligations of his sentence by giving physicalexams to people who go before court at thePeabody District Court Clinic. He retainshis medical license and continues to practice medicine in Peabody, Mass.

Snaring SmugglersOf Animal Drugs

A former veterinary drug companyexecutive pleaded guilty in January tocharges of illegally importing and sellingunapproved animal drugs. The plea followed a four-year investigation by FDA,the U.S. Customs Service, and the Justice

kind doctor, and long lines of patients werea familiar sight at his office, according tonewspaper accounts.

Fogari can no longer practice medicinesince the New Jersey State Board of Medical Examiners revoked Fogari's medicallicense as of March 17, according to DeputyAttorney General James F. Lafargue.

Judy Folkenberg is a member of FDA'spublic affairs staff.

Department into a nationwide bulk veterinary drug business with international connections. More than 30 tons of animaldrugs, with a wholesale value of more than$600,000, were seized in Illinois andNebraska in connection with the case. Theformer executive, Jeffrey A. Engel, waspresident and general manager of CustomFeed Blenders, Fort Dodge, Iowa.

The investigation followed a growingnumber of complaints from legitimateveterinary drug sources about the availability throughout the country of illegalbulk drugs. Investigators eventuallyuncovered an illegal path of distributionthat reached from Eastern Europe andChina, where the drugs were produced, toCanada, then Iowa, and, from there,across the United States. The drugs weresmuggled into the United States by tractor-trailer truck, concealed under loads of hayor wood chips, investigators said. Theoperation began in May 1983 and ended inOctober 1988, although Custom FeedBlenders closed in the spring of 1986while under investigation.

Custom Feed Blenders made and distributed drugs for sale to veterinarians,farm supply outlets, and farmers throughout the nation, according to the JusticeDepartment. Engel and the company werelinked to the illegal operation in 1984along with 13 others. They were chargedwith working together—or, in some cases,separately—to import, manufacture orsell high-potency, unapproved bulk animaldrugs, and with making false statements tofederal agents.

Others pleading guilty in the case wereRex J. Blunk of Callender, Iowa; GaryVan Dusen of Mississauga, Ontario,Canada; Jon L. Engel of Omaha, Neb.,brother of Jeffrey Engel; Timothy J.Hoffman of Omaha; Bradley Langmo andGregory S. Langmo of Litchfield, Minn.;Ronald L. Nissen of Fort Dodge; JamesRhodes of Fort Dodge; Wesley J. Thoreson

26!June 1989/FDA Consumer

of Ellsworth, Iowa; Larry Tipton ofWinona, Minn.; and Dana Wolf of FortCalhoun, Neb. As of April 1, Hoffmanhad been fined $9,000, Thoreson $2,500,and Wolf $4,500. At press time, theothers, along with Jeffrey Engei, wereawaiting sentencing.

In addition, Heinz G. Call of Ossining,N.Y., and Robert M. Clack of Pittsfield,111., were charged with 25 counts of illegally importing and distributing animaldrugs. They pleaded not guilty afterbeing indicted last November by a federalgrand jury in Cedar Rapids, Iowa, and areawaiting trial.

Two businesses dealing in the smuggledveterinary medicines—InternationalManufacturing and Sales of Omaha, Neb.,and Zetapharm Corp., New York—werecharged with misbranding and adulteration of animal drugs since the drugs weremade under conditions that presented noassurance as to their safety or strength.International Manufacturing has beenfined $40,000. Fines of up to $100,000 to$250,000 per count are possible.

The unapproved animal drugs includedamprolium, carbadox, chloramphenicol,chlortetracycline, dimetridazole,ipronidazole, levamisole, nitrofurazone,oxytetracycline, potassium penicillin,rifampin, spectinomycin, tetracyclinehydrochloride, tylosin, and other antibiotics. Unapproved drugs pose a threat toan animal's health because their safety andeffectiveness have not been scientificallydetermined. They may also endangerhumans if they leave cancer-causing orotherwise toxic drug residues in meat,milk or eggs from feed animals-.

The nationwide investigation is continuing, with more charges expected.

Blood Bank Put on Notice

The American Red Cross Blood Services Center in Albany, N.Y., almost lost itsFDA license last March because of continuing problems that led to the release ofmore than 300 units of potentially contaminated blood—most of which weretransfused. The most critical problem wasthat hepatitis testing was done incorrectlyfor nearly five months because the center'semployees had failed to recognize aninappropriate computer setting. To date,retesting of the 112 donors who gave theblood in question has not shown anyhepatitis contamination.

Numerous problems with the Red Crossregional blood banking operations over thepast several months had prompted FDA to

step up its inspections of the centers.Indeed, in 1988, the agency visited everyFDA-regulated blood bank. During theAlbany center inspection, from May 2 toJune 6, an investigator from FDA's Buffalodistrict found a number of deficiencies—notably, the distribution of blood components from five units that hadn't beenproperly tested for AIDS (acquiredimmune deficiency syndrome) virus antibodies. The donors are being retested and,so far, all tests have been negative.

Meanwhile, FDA had been workingwith the Red Cross to remedy such seriousdeficiencies. On Sept. 14, 1988, the RedCross signed an agreement to monitor itscenters more tightly, to establish uniformblood collection standards that wouldinclude improved employee trainingprocedures and auditing procedures, andto analyze computer hardware and software as a further measure to prevent therelease of unsuitable blood.

FDA conducted a follow-up inspectionof the Albany center from Dec. 6, 1988, toJan. 18, 1989, to see what changes were inplace. Shortly before the inspection,however, the manufacturer of the automated test equipment had conducted a routine check and noticed the computer wasin the wrong mode. The center immediately informed FDA. The agency's subsequent investigation confirmed the errorand found significant problems in theblood bank's hepatitis testing, including:

Faulty procedures that caused inaccurate test results from July 12 to Dec. 2,1988.

Lack of complete instructions forperforming hepatitis testing with automated equipment.

Failure of supervisors or managersto review original test results so as toensure technicians were using thecorrect procedure.

Some test records that were incompleteor improperly filed.

In a letter dated Feb. 14, 1989, FDAadvised the American Red Cross nationalheadquarters that it would revoke theAlbany center's license unless the centerpromptly submitted a plan to bring bloodhandling procedures into accord with FDAstandards and regulations. The Albany RedCross submitted such a plan on March I,1989, and FDA is reviewing it.

— This small sample of reports from thefield was prepared by Dixie Farley, JudyFolkenberg, and Vern Modeland.

FDA Consumer/June 1989 / 27

Summaries of Court Actions

Summaries of Court Actions are given pursuant to section 705 ofthe Federal Food, Drug, and Cosmetic Act. Summaries of CourtActions report cases involving seizure proceedings, criminalproceedings, and injunction proceedings. Seizure proceedings arecivil actions taken against goods alleged to be in violation, andcriminal and injunction proceedings are against jinns or individualscharged to be responsible for violations. The cases generally involvefoods, drugs, devices or cosmetics which were alleged to be adultera t e d o r m i s b r a n d e d o r o t h e r w i s e v i o l a t i v e o f t h e l a w w h e nintroduced into and while in interstate commerce or while held forsale after shipment in interstate commerce.

Summaries of Court Actions are prepared by Food and DrugDivision, Office of the General Counsel, HHS.

Published by direction of the Secretary of Health and HumanServ ices.

S E I Z U R E A C T I O N S

Foods/Poisonous and Deleter ious Substances

PRODUCT: Swordfish chunks, at Monterey, N. Dist. Calif.; CivilNo. C-84-20140-WAI .CHARGED 3-1-84: When shipped by the boat "Arista" after beingcaught in waters outside of the boundaries of California, the articlecontained the added poisonous or deleterious substance mercury(approx. 1.25 ppm)—402(a)(1).DISPOSITION: Consent—ordered destroyed. (F.D.C. No. 64178;S. No. 84-324-126 etal.; S.J. No. 1)

Foods/Contamination, Spoilage, and Insanitary HandlingPRODUCT: Pecan meats, at Fargo, Dist. N.D.; Civil No.A 3 - 8 8 - 6 2 .CHARGED 5-5-88: When shipped by Pippin Pecan Co., Inc.,Albany, Ga., the article contained a filthy substance (E. coli) andhad been prepared, packed and held under insanitary

conditions—402(a)(3), 402(a)(4).DISPOSITION: Default—ordered delivered to eleemosynary institution for feeding wildlife. (F.D.C. No. 65458; S. No. 88-472-556;S.J. No. 2)

PRODUCT: Rice, at St. Louis, E. Di.st. Mo.; Civil No. 88-0153-C-6.CHARGED 1-27-88: While held for sale, the article had been heldunder insanitary conditions—402(a)(4).DISPOSITION: Consent—ordered destroyed. (F.D.C. No. 65375;S. No. 88-526-181 et al.; S.J. No. 3)

PRODUCT: Rice, and other food stocks, at Chicago, N. Dist. 111.;Civi l No. 88-C-3170.CHARGED 4-13-88: While held by Golden Country Oriental FoodCo., Chicago, 111., the articles had been held under insanitary conditions, and one lot of rice contained rodent filth—402(a)(3),402(a)(4).DISPOSITION: Consent—authorized release to the dealer for sal

vaging. (F.D.C. No. 65441; S. No. 88-503-907 et al.; S.J. No. 4)

PRODUCT: Rye, in bulk, at Hereford, N. Dist. Texas; Civil No.2-88 -0069 .CHARGED 4-11-88: While held by Arrowhead Mills, Inc.,Hereford, Texas, the article contained insects—402(a)(3).DISPOSITION: Consent—authorized release to the dealer for sal

vaging. (F.D.C. No. 65422; S. No. 88-517-427; S.J. No. 5)

PRODUCT: Shrimp "rounds," breaded, frozen, SeaPak, atBrunswick, S. Dist. Ga.; Civil No. 288-207.CHARGED 9-19-88: While held by Rich-SeaPak Corp., Brunswick, Ga., who manufactured the article with minced importedshrimp, the article contained decomposed shrimp, and the article'slabel lacked the required statement "made from mincedshrimp"-402(a)(3), 403(a)(1).DISPOSITION: Default-ordered destroyed. (F.D.C. No. 65526;S. No. 88-435-797; S.J. No. 6)

28/June 1989/FDA Consumer

Foods/Economic and Labeling ViolationsPRODUCT: Cheeses, provolone, and low-moisture mozzarella,at Edison, Dist. N J.; Civil No. 88-20.CHARGED 1-5-88: When shipped by Sun-Re Corp., Sunbury,PA., the articles, labeled "Mamma Mia . . . Whole Milk—LowMoisture Mozzarella Dist. By Marlboro Foods . . . Mfg at Plant#42-264" and "Mamma Mia . . . Midget Provolone . . . Manutac-tured By Sun-Re Cheese . . . Plant #42-264," had had the valuableconstituent milk fat omitted in part from the articles—402(b)(1); thearticles' labels lacked the address of the distributor and/ormanufacturer—403(e)(1); the articles' labels lacked an accuratequantity of contents statement in terms of weight—403(e)(2); andthe articles failed to conform to the definition and standard of identity for low-moisture mozzarella cheese and provolone cheese,because the articles contained less than 45 percent milk fat and morethan 45 percent moisture—403(g)(1); and the articles' labels lackedthe name of the food ("cheese") specified in the definition and standard and lacked the common names of all the articles'ingredients—403(g)(2).DISPOSITION: Default—ordered destroyed. (E.D.C. No. 65363;S. Nos. 88-438-153/4; S.J. No. 7)

PRODUCT: Fish fillets, "flounder," frozen, at Charlotte, W. Dist.N.C.; Civil No. C-C-88-72-M.CHARGED 2-II-88: While held for sale, after shipment by Greenwood Packing Corp., Middletown, N.Y., who had relabeled "CapeHaddie" fillets as "flounder" fillets, the article had had an unknownfish (labeled with the fictitious name "Cape Haddie") substitutedfor flounder—402(b)(2); the article's labeling falsely and mis-leadingly claimed that the only fish in the article wasflounder—403(a)(1); the article was offered for sale under the nameof another food, flounder—403(b); the label of the article lacked thename and place of business of the manufacturer, packer ordistributor—403(e)(1); and the article's label lacked the common orusual name of the article, because "flounder" was not the article'scommon or usual name—403(i)(I).DISPOSITION: Consent—ordered destroyed or constructivelydestroyed by donation to a bona fide charitable organization. (F. D.C.

No. 65381; S. No. 88-423-685; S.J. No. 8)

PRODUCT: Fish fillets, "flounder," frozen, Middletown, S. Dist.N.Y.; Civil No. 88 Civ. 1107 (JMW).CHARGED 2-18-88: While held by Greenwood Packing Corp.,Middletown, N.Y., the article (which the dealer had had labeled"IQF Flounder Fillets Prod, of Canada" using an unknown fish-not flounder—that had been previously labeled with the fictitiousname "Cape Haddie") had had an unknown fish substituted forflounder—402(b)(2); the article's label was false and misleading inclaiming that the fish in the article was flounder—403(a)(1); thearticle was offered for sale under the name of another food,flounder—403(b); the article's label lacked the name and place ofbusiness of the manufacturer, packer or distributor—403(e)(1); andthe article's label failed to bear the common or usual name of thefood, because "flounder" was not the article's common or usualname—403(i)(l).DISPOSITION: Default—ordered constructively destroyed bydonation to a charitable organization. (F.D.C. No. 65379; S. No.88-423-685; S.J. No. 9)

PRODUCT: Fish pieces, frozen, at Brooklyn Park, Dist. Minn.;Civi l No. 3-87-350.CHARGED 5-26-87: While held for sale, the label of the article(which was being sold as "Pacific Ruffle") failed to bear the common or usual name of the food (grouper)—403(i)(I).DISPOSITION: Default—ordered constructively destroyed bydonation to a charitable organization. (F.D.C. No. 65207; S. No.87-445-698; S.J. No. 10)

Food Add i t i ves

PRODUCT: Betel nuts, at Los Angeles, C. Dist. Calif.; Civil No.88-02134 WMB (Ex).CHARGED 4-19-88: While held for sale, the article contained thenonconforming food additive arecoline, and no regulationprescribed conditions for use of the additive—402(a)(2)(C).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65438;S. No. 88-300-009; S.J. No. II)

FDA Consumer /June 1989/29

PRODUCT: Calcium orotate tablets, and tablets and capsules ofother salts of orotic acid, at Oceanside, E. Dist. N.Y.; Civil No.88-1517 (Mishler).CHARGED 5-13-88: While held for sale, the articles contained thenonconforming food additives salts of orotic acid—402(a)(2)(C).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65420;S. No. 88-424-163 etal.; S.J. No. 12)

Drugs/Human UsePRODUCT: ImmuVir topical analgesic ointment, at LakeOswego, Dist. Ore.; Civil No. 88-341-FR.CHARGED 3-28-88: When shipped by Bio PharmaceuticalsCorp., Portland, Or., the article (which was represented foruse in the cure, mitigation or treatment of diseases, includingherpes) was a new drug without an effective approved New DrugApplication—505(a).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65403;S. No. 88-423-046; S.J. No. 13)

PRODUCT: Parenterals, small-volume, in ampules and vials, atRosemont, N. Dist. 111.; Civil No. 88C-5784.CHARGED 7-6-88: When shipped by LyphoMed, Inc., Orlando,Fla., the circumstances used for the articles' manufacture andprocessing failed to conform with current good manufacturingpractice—501(a)(2)(B).DISPOSITION: The articles were claimed by the shipper. Pursuantto stipulation of the parties, five similar seizure actions in Florida,Georgia, New Jersey, California and Texas were consolidated fortrial with this action. Subsequently, a consent decree condemnedthe articles and ordered the destruction, reconditioning, or otherspecified disposition of the articles in each action. In addition, all ofthe shipper's potassium chloride injection of lot no. 480099(including the seized articles, recalled articles, and not-seized buton-hand articles) was to be destroyed, as were all seized asepticallyfilled articles. Additional provisions covered articles subsequentlyfound to be non-sterile and articles of terminally sterilized products,and covered the Florida plant (which was then closed) where the

drugs had been manufactured. (F.D.C. No. 65503; S. No.88-443-906etal.; S.J. No. 14)

PRODUCT: Parenterals, small-volume, in ampules and vials,five seizure actions, at Orlando, M. Dist. Fla.; Stone Mountain, N.Dist. Ga.; Edison, Dist. N.J.; Vernon, C. Dist. Calif; and Car-rollton, N. Dist. Texas; Civil Nos. 88-573-Civ-ORL-18,6-88-CV-I489 JTC, 88-2971, CV 88-041I2-IH, & CA 3-88-I591-G.CHARGED 7-5-88, 7-12-88, 7-6-88, 7-6-88 and 7-7-88: Whenshipped or while held by LyphoMed, Inc., Orlando, Fla., the circumstances used for the articles' manufacture and processing failedto conform with current good manufacturing practice—501(a)(2)(B).DISPOSITION: Upon stipulation of the shipper and the government, the five seizure actions were consolidated for trial with asimilar seizure action in the Northern District of Illinois (see thepreceding S.J.). Subsequently, a consent decree of condemnationwas entered in the consolidated actions, which ordered specifieddestruction and salvaging of specified articles. (F.D.C. Nos. 65499,65500, 65001, 65502 and 65504; S. No. 88-443-906 et al.;S.J. No. 15)

PRODUCT: Sunscreen creams colored orange, yellow, pink,green, blue or red, at Fairlawn, Dist. N.J.; Civil No. 87-2829.CHARGED 7-15-87: While held for sale after some of the articleshad been imported from Austraha and some of the articles had beenmanufactured locally from interstate color ingredients, the articles(both drugs and cosmetics, which were labeled "Le Zink AdvancedFormula High Protection Sunscreen . . . perfect sun protection forall outdoor sports" and which contained Rhodamine 6G, C.I. Solvent Yellow B5, C.I. Fluorescent Brightener 61, and an unidentifiedred color) contained nonconforming color additives—501(a)(4)(A),601(e); the articles were processed, packed and labeled in anunregistered facility—502(o); the articles' labels lacked a statementof active ingredient—502(e); the labels lacked a statement of theplace of business of the manufacturer, packer or distributor—502(b); and the articles' labeling lacked adequate directions foruse-502( f ) (2 ) .

30/June 1989/FDA Consumer

DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65200;S. No. 87-438-121 etal.; S.J. No. 16)

PRODUCT: Tanning lotions (with sun protection factors of 15,8,5 and 0), Coco-Loco, at Honolulu, Dist. Hawaii; CivU No. 87-0376VA C .CHARGED 5-9-87: When shipped by Basjian Distributing, Tuk-wila, Wash., the articles (with sun protection factors 15, 8 and 5)were drugs which had been manufactured and processed under circumstances that failed to conform with current good manufacturingpractice; and those drugs had been processed, packaged and labeledin an unregistered facility; their labeling contained the false andmisleading claim that the drugs contained no mineral oil; theirlabels lacked a statement of the active ingredient para-aminobenzoicacid; and their labeling lacked adequate directions for use—501(a)(2)(B), 502(o), 502(e), 502(f)(1); the article with sun protection factor 15 was a new drug without an effective approved NewDrug Application—505(a); all of the articles (including the articlewith sun protection factor zero) were cosmetics and their labelingcontained false and misleading declarations claiming that the articles were a blend of all natural coconut ingredients, representingthat the articles did not contain mineral oil or any synthetic ingredients, and suggesting that BHT/BHA were required—602(a); thearticles were also in violation of the Fair Packaging & Labeling Act,since the cosmetics' label failed to bear, with prominence and con-spicuousness, an accurate ingredient statement, since the partialingredient declaration was not visible to consumers under conditions of retail sale, and since some ingredients (e.g., mineral oil andpropylene glycol) were not declared—15 U.S.C. 1456.DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65156;S. No. 87-450-03 etal.; S.J. No. 17)

Med ica l Dev i ces

PRODUCT: Condoms, at Savannah, S. Dist. Ga.; Civil No.4 8 8 - 1 7 1 .

CHARGED 8-30-88: The article, which Okamoto U.S.A., Inc.,

Stratford, Conn., had initially attempted to import through PortNewark, N.J. (but the article was rejected), and subsequently hadattempted to import at Savannah, Ga., and which were labeled"Lubricated—Sldnless Skin - Harmony Manufactured by OkamotoIndustries, Inc., Tokyo, Japan," had a quality that fell below its purported quality since the article contained an excessive number ofholes—501(c).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65527; S.No. 88-161-801 etal.; S.J. No. 18)

PRODUCT: Condoms, at Brooklyn Center, Dist. Minn.; Civil No.3-88-595 .CHARGED 9-1-88: The quality of the article, which was packagedby Mentor Corp., Brooklyn Center, Minn., and labeled "MentorSafety-Seal No-Slip Condoms. . . Mentor Health Care ProductsMinneapolis, Mn.," fell below the article's purported quality, sincethe article contained excessive holes—501(b); and its labeling forprevention of disease was false and misleading because the articlecontained holes—502(a).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 65528;S. No. 88-562-786etal.; S.J. No. 19)

I N J U N C T I O N A C T I O N S

DEFENDANTS: Bleyhl Farm Service, Inc., Fred L. Harris,general manager, Robert L. Eucker, feed department manager, andOllie M. Dodd, feed mill manager, Grandview and Granger, E.Dist. Wash.; Civil No. C-87-349-AAM.CHARGED 5-26-87 in a complaint for injunction: That defendants,at their Granger, Wash., feed mill, manufactured, processed,packed, labeled, stored, held for sale, and distributed in interstatecommerce various medicated feeds containing interstate components; that such medicated feeds had been manufactured,processed, packed and held under conditions which failed to conform with current good manufacturing practice—501(a)(2)(B); thatsuch medicated feeds (such as those containing amprolium, lin-comycin and monensin in combination, monensin and chlortetracy-

FDA Consumer/June 1989/31

dine in combination, and monensin, chlortetracycline andsulfamethazine in combination) contained new animal drugs, andno approvals of New Animal Drug Applications were in effect withrespect to the use and intended use of such drugs—501(a)(6); thatthe purity and quality of certain medicated feeds fell below, or theirstrength differed from, their purported strength and quality, becausethey did not contain their represented amount of drug—501(c); thelabeling of certain medicated feeds represented that the feeds contained a drug or drugs different from those actually used inmanufacturing the feeds—502(a); that FDA inspections and FDAlaboratory analyses documented various violations; and that thedefendants were well aware that their activities violated the law.DISPOSITION: A consent decree of permanent injunctionenjoined the complained-of violations and enjoined interstate medicated feed operations, unless and until a number of specified conditions were met, including adherence to current good manufacturingpractice and adherence to New Animal Drug Applications for themedicated feeds. (Inj. No. 1172; S. Nos. 87-420-004 et al.;S.J. No. 20)

DEFENDANTS: Odessa Union Warehouse Co-op, Cecil A.Schell, secretary-treasurer of the corporation at Odessa, E. Dist.Wash., Edward Sewall, agent-manager at the Harrington, Downsand Moher stations, Gary L. Schmauder, agent-manager at theDavenport and Rocklyn stations, and Marvin Kleyn, agent-manager at the Ephrata station; Civil No. C-86-608-AAM.CHARGED 7-20-86 in a complaint for injunction: That the defendants prepared and held for sale quantities of wheat at their grainelevator stations; that, when shipped, such wheat was, in part,moldy and insect damaged, and contained insect and rodent filthand had been held under insanitary conditions; that FDA inspections of the defendants' elevator facilities had disclosed numerousinsanitary conditions and abundant evidence of food adulteration;and that the defendants had continued to ship wheat without sanitaryand adequate food warehousing and storage procedures—402(a)(3), 402(a)(4).DISPOSITION: District Court—Tht government moved for apreliminary injunction. In response to the filing of the action andprior to the hearing on the government's motion, the defendant firm

acted to improve the sanitation at its facilities by cleaning andfumigating wheat, destroying rodent tunnels, sealing the elevatorsto prevent future infestations, and employing a sanitation expert.The District Court denied the government's motion, since the courtfelt that a preliminary injunction should issue only "when the circumstances truly permit no other course, when the crisis is currentor at least appears to be recurrent, that the response of the respondent is recalcitrant and clearly so, and that the total impact of theOrder must be assessed."Court of Appeals—Tht government appealed the denial of itsmotion for a preliminary injunction. The Court of Appeals reversedand remanded, because the District Court's standard was far toorestrictive compared with the standards applicable to the issuance ofan injunction authorized by a statute of the United States to enforceand implement Congressional policy. The Court of Appeals statedthe following: that, once Congress, exercising its delegated powers,has decided the order of priorities in a given area, it was for thecourts to enforce them when asked; that the District Court shouldhave presumed that the government would suffer irreparable injuryfrom a denial of its motion; and that, because of presumed irreparable injury, the District Court needed only to find some chance ofprobable success on the merits.

As to the elements of the balancing of hardships and the likelihood of recurring violations, the Court of Appeals noted that thepublic interest in the purity of its food was so great as to warrantimposing the highest standards on distributors, and that Odessa'sprogress towards improvement must be weighed in light of Odessa'sextensive history of violations because an inference rose fromOdessa's past violations that future violations were likely to occur.District Court Upon Remand—A consent decree of permanentinjunction was entered, even though the parties agreed—and thecourt found—that the defendants' facilities were in compliance atFDA's last inspection. The defendants were enjoined for two yearsfrom receiving, preparing, packing or holding food at their facihtiesunless and until a number of specified conditions (including the purchase and installation of equipment for applying insecticides and fordetecting rodent and insect activity, as well as the employment of asanitarian to monitor conditions) were met. (Inj. No. 1147; S. No.85-463-828 etal.; S.J. No. 21)

32/June 1989 / FDA Consumer U.S. GOVERNMENT PRINTING OFFICE 1989-241-270/00012

Too often, kids get the worst of their parents' bad day at work.In the form of verbal abuse at home. If that's been happening to you,

you've got to work to change things. Words can hit a child as hard as a fist.And leave scars you can't see. Think about what you're saying.

Stop using words that hurt. Start using words that help.

Slot> Ufii Wbnis tM hurtFor helpful information, write: National Committee for Prevention of Child Abuse, Box 2866E, Chicago, IL 60690