F MTHE MAGAZINE OF THE U.S. FOOD AND DRUG ADMINISTRATION -

VOL. 28 NO. 3 APRIL 1994

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Food Label Close-Up

I U W

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F D ACONSUMER

Donna E. Shalala, Ph.D.Secretary of Health andHuman Services

David A. Kessler, M.D.Commissioner of Food and Drugs

James A. O'Hara I I IAssociate Commissioner forPublic Affairs

Judith Levine Willis / Editor

Patricia N. Edwards / Art Director

Michael L. Herndon / Production Manager

Carol L. Ballentine / Copy Editor

Cover Photo: Lawrence Ruggeri

FDA Consumer {\SSN 00362-1332) is publishedby the Food and Drug Administration (HFI-40),5600 Fishers Lane, Rockville, MD 20857, U.S.Public Health Service, Department of Health andHuman Services. It is published monthly, exceptfor combined issues for July-August andJanuary-February. Use of funds for printing FDAConsumer has been approved by the Office ofManagement and Budget.

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Inside Front Cover Photo:

THE MAGAZINE OE THE U.S. FOOD AND DRUG ADMINISTRATION

VOL. 28 NO. 3 A P R I L 1 9 9 4

New Food Code: A Menu of Modern Safety Standards

Keeping pace with new and changing food-home illnesses, FDA has revisedthe Food Code it offers as a guide for local legislation affecting restaurantsand other food service establishments.

A Gentler Jolt and Tickle for Trembling Hearts

Implanted defibrillators and pacemakers have undergone miniaturizationand other technical advances, making them gentler and more efficient in

steadying abnonnal heartbeats. But glitches still occur.

Food Label Close-UpAs recent nutrition labeling legislation goes into effect, consumers may wantto take a closer look at all the helpful features of today's food labels, fromthe ingredient list to health claims and the net weight.

Treatment Pales Rosacea's Red Face

Red pimples on a frequently flushed face may he a sign of a common butoften undiagnosed skin condition called rosacea. Effective ways to preventand treat it can lessen its impact.

Interleukin 2: New Tberapy for Kidney CancerFDA's recent licensing of a genetically engineered homione-like substancethat shrinks tumors has given new hope to some patients with kidney cancel.Researchers around the world are now working to tame its toxicities.

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Updates

N o t e b o o k

2 I n v e s t i g a t o r s ' R e p o r t s

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The late comic W.C. Fields is a well-known sufferer of a common ailmentthat thousands of others don't even know they have. See page 20.(Photo courtesy of Photri. inc.)

FDA Consumer/April 1994/1

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Major Seafood Initiative

In a major food initiative, FDA will require the seafood industry to establishsafety controls subject to regulatory oversight and review.

The proposal, which was announced lastJan. 21 by Health and Human ServicesSecretary Donna E. Shalala, is based onprinciples of a system known as HazardAnalysis Critical Control Point (HACCP).

"This system of mandatory controlsdraws its strength from one simple principle: the notion that the best way to provide safe, high-quality food is to buildsafety in during processing," said FDACommissioner David A. Kessler, M.D."Today we inspect for safety after the fact.That's simply not good enough. We needto approach food safety by preventingproblems up front."

HACCP calls for a science-based analysis of potential hazards, determination ofwhere hazards can occur in processing,and institution of preventive measures andcorrective actions. Detailed record-keeping then allows government regulators tomonitor closely how well firms performon a continuing basis.

All seafood processors, packers and

warehouses will be required to adopt aHACCP plan appropriate to its business,to monitor it, and to keep records, whichFDA and state inspectors will inspectregularly.

For example, firms will have to document that fish and shellfish have not beenmade unsafe by pollution or natural toxinsand that ready-to-eat seafood has beencooked and stored at safe temperatures.The rules will apply equally to domesticand imported products.

FDA is accepting comments on the proposal until April 28, 1994. Written comments, citing docket number 93N-0195,should be sent to; FDA, Dockets Management Branch, HFA-305, Room 1-23,12420 Parklawn Drive, Rockville, MD20857 .

First Drug forDiabetic Kidney Disease

A drug previously approved for treatinghigh blood pressure and heart problems isnow the first dmg approved for treatingkidney disease in persons with insulin-dependent (Type I) diabetes.

FDA approved Capoten (captopril) forthis additional use last Jan. 28. Before thisapproval, such kidney disease, known asdiabetic nephropathy, could be treatedonly by dialysis or kidney transplants.

Kidney diseases affect about a third ofthe approximately 500,000 Americanswith Type I (also known as juvenile-onset)diabetes.

Although side effects from Capotentreatment are rare, some patients may experience swelling of the face, tongue,larynx, and other facial tissues, as well aslow blood pressure and neutropenia, a deficiency of white blood cells. FDA cautions that patients should not take the drug

during pregnancy because of possibledamage to the fetus.

FDA based its approval of Capotenlargely on results of a double-blind, placebo-controlled clinical trial involving 409patients at 30 U.S. and Canadian centers.Treatment was associated with a 50 percent reduction in the combined risk of

death or of kidney failure requiring dialysis or a transplant.

Several smaller studies revealed that the

drug could slow progression of diabetickidney disease. Capoten has not beenshown to delay kidney disease in non-in-sulin-dependent diabetics or in peoplewith adult-onset diabetes.

One added benefit of using the drug totreat diabetic nephropathy is that it lowershigh blood pressure, another major complication of diabetes.

Capoten is marketed by Bristol-MyersSquibb Co. of Princeton, N.J.

New Antidepressant Approved

Effexor (venlafaxine hydrochloride) received FDA approval last Dec. 28 as atreatment for depression.

Though in a new chemical class,Effexor is similar to tricyclic antidepressants, a class of drugs marketed for morethan 30 years. Clinical data, including six-week controlled trials of patients with major depression and a four-week trial of patients suffering from depression withmelancholia, show Effexor to be an effective antidepressant. But it is not demonstrably superior to older tricyclics or otherdrugs such as serotonin reuptake inhibitors. Trials have not shown if Effexor has

2 / A p r i l 1 9 9 4 / F D A C o n s u m e r

a faster onset of action than other antide

pressants.Like older tricyclics, Effexor affects two

critical neurotransmitters, serotonin and

norepinephrine. Studies have not established whether this treatment is an advan

tage over drugs that target only serotonin.Because the new drug has not been

studied for long-term use, FDA cautionsphysicians to periodically evaluatepatients who take the drug for extendedperiods.

Though Effexor may be less likely thanthe older drugs to cause cardiovascularproblems, it has other side effects, including a sustained increase in blood pressurerequiring regular monitoring.• (For more about depression, see "Inevitable Companions? Depression and Advancing Age" in the March 1993 FDAConsumer. )

New Epilepsy Drug

A drug that controls partial epileptic seizures when used with other epilepsy medications was approved by FDA last December.

The new drug, Neurontin (gabapentin),is the second new epilepsy drug approvedin the past year. Felbatol (felbamate) wasapproved on Aug. 2, 1993.

Neurontin is unusual among epilepsydrugs because it does not interfere with themetabolism of other anti-epileptic drugs.Patients taking Neurontin, therefore, require less laboratory monitoring and fewerdosage adjustments.

Epilepsy, a disorder characterized byseizures, affects about 2 million people in

the United States. Seizures occur whennerves in the brain fire spontaneously,causing symptoms ranging from shakingof a single limb to loss of consciousnessand generalized spasms. (See "ControllingEpilepsy: Science Replaces Superstition"in the May 1992 FDA Consumer.)

In clinical trials with more than 700

adults, Neurontin reduced the frequency ofpartial seizures, including those thatprogress to generalized seizures, whengiven in combination with other drugs.Side effects of Neurontin include dizziness

and drowsiness.Neurontin is manufactured by Parke-

Davis Pharmaceutical Research, MorrisPlains, N.J.

Breast-Feeding and Implants

A recent preliminary study published inthe Journal of the American Medical Association has sparked some concern aboutpossible health problems among childrenwho were breast-fed by women with silicone gel-filled breast implants.

The Jan. 19, 1994, article reported thatsix of eight children who were breast-fed

by mothers with these implants had abnormal esophageal motility—that is, a reduction in the normal wave-like motion of the

esophagus that moves food toward thestomach.

FDA views the study with interest, butnotes that because of limitations of the

study design, more research is needed before definite conclusions can be drawn.Women with implants who are considering breast-feeding and have concernsshould check with their doctors or callFDA's Breast Implant Information Line at(800) 532-4440 for the most current inform a t i o n .

Abnormal esophageal motility is seen ina number of other disorders, but often appears in children with systemic sclerosis,an autoimmune disease. There have beenallegations that leaking silicone couldcause certain autoimmune disorders.

The study evaluated 11 children—between 18 months and 13 years old—withchronic gastrointestinal problems whowere bom to women with silicone breast

implants. The children had abdominal painand at least one of the following: vomiting, difficulty swallowing, or poor weightgain.

Fight of the 11 had been breast-fed,while the rest were bottle-fed only. Six ofthe eight breast-fed children had significantly abnormal lower esophageal motilitycompared with the three bottle-fed children and with another group of childrenwhose mothers did not have breast implants.

The authors state there may be a relationship between breast-feeding by somemothers with silicone breast implants and

FDA Consumer/April 1994 /3

Updates (continued)

abnormal esophageal motility in their children. They acknowledge, however, thatdefinite conclusions cannot be drawnwithout further study. An editorial published in the same journal issue cautionsthat the results of the study have not beenc o n fi r m e d .

FDA agrees that more research isneeded, noting the small size of the studyand bias in selection of the patient populat i on .

Silicone gel-filled breast implants arecurrently available only to women in clinical studies. (See "Silicone Breast Im

plants: Available Under Tight Controls" inthe June 1992 FDA Consumer.) The informed consent document given to womenwho enter the studies stresses that onlylimited research has been done in this areaand further study is needed.

Another OTC Pain Reliever

A prescription arthritis dmg can now bemarketed in a nonprescription pain reliefstrength, FDA announced last Jan. 11.

The drug, naproxen sodium, is the second prescription nonsteroidal analgesic forsale over-the-counter. The first was

ibuprofen, which has been on the marketsince 1984 as Advil, Motrin and others.

Naproxen has been sold as a prescription drug under the trade name Naprosynsince 1976, and naproxen sodium has beensold as Anaprox since 1980.

The naproxen sodium product OK'd forOTC sale has the brand name Aleve. Approved nonprescription uses are for alleviating minor pain associated with headache, the common cold, toothache, muscleache, backache, arthritis, and menstrualcramps and to reduce fever.

As with ibuprofen, naproxen sodium in

excessive amounts can cause digestiveproblems such as heartburn and upsetstomach. Aleve will be sold in tablets con

taining 200 milligrams of naproxen and 20mg sodium. For people aged 12 to 65, themaximum daily dose is three tablets with8 to 12 hours between doses. People olderthan 65 should not take more than two tablets a day, or one every 12 hours. Childrenunder 12 should not use the dmg at all except under a doctor's supervision.

Aleve is produced by Syntex Laboratories of Palo Alto, Calif., and distributed byProcter & Gamble Co. of Cincinnati.

Duragesic Patch Use Restricted

The distributor of the Duragesic(fentanyl) analgesic skin patch is takingsteps to restrict the patch's use because afew instances of Duragesic misuse wereimplicated in preventable patient deaths,FDA announced last Jan. 18.

The company, Janssen Pharmaceuticaof Titusville, N.J., wrote to all health-careprofessionals warning about misusingDuragesic, revised the product's labeling,added a warning to the packaging, andwill revise patient instmctions to includewarnings of possible side effects.

The patch, approved by FDA in 1990,releases fentanyl, a strong narcotic, continuously at a fixed rate for 72 hours.

Duragesic is approved to be used only

for the management of severe chronic pain(such as cancer pain) that can't be managed with less powerful dmgs. Also, thepatch should be used only by patients whoare already on and tolerant to narcotictherapy and require continuous administrat ion.

The company reminded health professionals that, because serious or life-threat

ening breathing problems can occur,Duragesic is not to be used:• for acute or postoperative pain, including pain after outpatient surgery• for mild or intermittent chronic pain thatcan be managed with less powerful dmgs• at a starting dose higher than 25 micro

grams per hour• in children under 12, or by patients under 18 who weigh less than 110 pounds,except in FDA-approved research settings.

Duragesic is manufactured by theALZA Corporation, Palo Alto, Calif.

Corporate-Wide InjunctionCloses Two Device Plants

Under a consent decree for permanentinjunction, a respiratory device firmclosed two plants because of recurringmanufacturing problems that caused numerous recalls and safety alerts. This is thefirst corporate-wide injunction against adevice firm for not meeting FDA's requirements for good manufacturing practices and problem reporting. Previously,the agency targeted only specific plants.

The firm, Puritan-Bennett Corp., ofOverland Park, Kan., makes devices suchas ventilators and resuscitators, as well asa blood gas monitoring system.

The consent decree was signed by bothFDA and Puritan-Bennett, FDA an-

4/April 1994/FDA Consumer

nounced last January. In addition, the request for injunction was filed in the U.S.district court in Kansas against the firm, itspresident and chief executive officer. Burton A. Dole Jr., and its vice president andchief operating officer, John H. MorrowIII. The injunction requires all the firm'sfacilities to comply with FDA rules forgood manufacturing practices and medicaldevice reporting.

Puritan-Bennett's Boulder, Colo., facil

ity and one of its Carlsbad, Calif., facilitieswere immediately shut down. Its otherplants are also subject to closing if theydon't comply with the injunction.

In a complaint filed with the injunction,the government maintained that the devices from the two closed plants wereadulterated because tbe methods, facilitiesand controls used to make, pack and storethe products did not conform to FDA'sgood manufacturing practice mles. In addition, the government said the Boulderfacility and the firm's other Carlsbad facility did not report product complaints, asthe law requires.

370 Drugs and BiologiesApproved in 1993

A new drug for preventing the flu andthe first product ever approved to treatAlzheimer's disease were among the products FDA approved in 1993. The agencyapproved 70 new drugs, 51 biologicalproducts, and 249 generic versions of newdrugs, for a total of 370.

Twenty-five of the new drug approvalswere for new molecular entities (NMEs),

dmgs distinctly different in stmcture fromthose already on the market. Parke-Davis'Alzheimer's drug, Cognex, and ForestLaboratories flu preventive, Flumadine,fell into this category. Other NMEs included Biometric Research's Orlaam for

opiate addiction and Miles Inc.'s Trasylolfor preventing blood loss during heart surgery. Cognex, Trasylol and Orlaam wereapproved in less than 11 months.

Two of the 1993 approvals were forAIDS-re lated condi t ions: U.S. Biosciences' drug Neutrexin for treatingPneumocystis carinii pneumonia, andMiles Inc.'s biological productGamimune-N for decreasing the frequency of bacterial infections in childrenw i t h H I V .

Other important biological approvals include Kogenate from Miles Inc., the second clotting factor for hemophilia A produced by recombinant techniques; Chiron

A R R R O V E i

Corp.'s Betaseron for treating multiplesclerosis; and vaccines for various combinations of haemophilus, tetanus, diphtheria, and pertussis.

W o m e n ' s H e o l t h P u b s

A free updated pamphlet about havingx-rays during pregnancy and a low-costnew edition of updated FDA Consumerarticles on women's health are now avail

a b l e .

To order single copies of tbe free pamphlet, "X-Rays, Pregnancy and You"(FDA 94-8087), write to FDA, HFE-88,5600 Fishers Lane, Rockville, MD 20857.To order 2 to 100 copies, write to FDA,HFI-40, at the same address, or fax yourorder to (301) 443-9057. Include the publ icat ion number.

To order copies of Current Issues inWomen's Health, 2nd Edition, An FDAConsumer Special Report (stock number017-012-00367-2), write to Superintendent of Documents, P.O. Box 371954,Pittsburgh, PA 15250-7954. The 110-pageanthology is $7 per copy, with an additional 25 percent for international customers. Include the publication number. GPOaccepts payment by check payable to Superintendent of Documents; by GPO deposit account accompanied by accountnumber; and by VISA or MasterCard accompanied by account number, credit cardexpiration date, and authorizing signature.

FDA Consumer we lcomes commentsfrom readers. Send letters to: Editor, FDAConsumer, HFI-40, 5600 Fishers Lane,Rockville, MD 20857.

FDA Consumer / April 1994/5

NewFbodCodeby Judith E. Foulke

6/April 1994/FDA Consumer

Nursing home cafeterias are

among the food service

facilities covered by changes

in FDA's Food Code.

A Menu ofM o d e r nSafetyS tanda rds

mhe carefully cleaned vegetables in the grocery saladbar, the fully-cooked hamburgers at the neighborhood fast-food restaurant,the fresh cold milk on the

lunch tray at the nursinghome—these foods are all

prepared by people whopay attention to details. If

they were not so careful, it's possible theycould unknowingly cause someone to getsick from any one of the many illnessesthat could be spread through food. And inthis day of emerging dangerous strains ofbacteria, attention to detail is especiallyimportant.

Most of the heightened awareness andthe food safety routines required of peoplewho prepare and serve food directly toconsumers originate with the Food andDrug Administration's Food Code. TheFood Code, revised in 1993 to combinethree documents into one, recommendsnew procedures for food establishmentworkers based on the latest scientificthinking on how to prevent food-bornedisease.

Included are new recommendations forcooking times and temperatures to killdangerous bacteria that could be present infood, and for holding times and temperatures to slow or prevent growth. And, forthe first time, the Code will give instructions for the proper use of food additives.Also included are basics, such as cleaninghands, employee health, cleaning foodpreparation and serving areas, and managers' responsibilities.

The Food Code is neither federal lawnor regulation. Rather, it is offered asmodel legislation to more than 85 stateand territorial agencies and 3,000 localregulatory departments that license and inspect the more than 1 million establish

ments in the United States offering fooddirectly to consumers.

State and local jurisdictions use the codeto develop or update their own food rules.Officials with experience using older editions of food codes helped with the 1993revision. The 1993 Food Code is the 12thedition. The first was published in 1934.

'The code gives the public health community the information it needs to speakwith one voice about what's important forfood safety and what it expects of food establishment operators," says Art Banks ofFDA's retail food protection branch andchief architect of the document.

Federal agencies that direct their ownfood services, such as the U.S. InteriorDepartment's Park Service and the Department of Defense, apply Food Code guidelines directly to their operations. The Navajo Nation has also adopted earliereditions of the Food Code for use in theirfood establ ishments.

Code Changes"The Food Code has changed a great

deal over the years," says Banks, "becausefood operations at the retail level havechanged significantly." Previously, thecode was three separate documents—oneeach for food service (last published in1976), food vending (1978), and foodstores (1982). The 1993 edition combinesthe three into one document and will be

updated every two years. Banks calls thenew combined edition a "full tool box"that covers all categories food operationsare likely to encounter.

Combining the codes was necessary, hesays, because "the lines have blurred" thatdistinguish the types of services offered byretail food operations. For example, somerestaurants now sell featured ingredientsfrom their own entrees, such as barbecuesauces and bakery items, as groceries.

FDA Consumer / April 1994 /

R̂estaurants and grocers are now using new ingredients andpreparing foods in ways that were not envisioned when previous codes were written.

H o w d e a n I s d e a n ?

How clean is clean enough for thehands of food service workers?

"A 20-second scrub for hands and exposed parts of the aims with soap, then arinse with clear water," says ArthurBanks, FDA's retail food protectionbranch chief "And if a worker has usedthe toilet, that worker must use a nailbrush with soap to clean fingertips andunder fingernails. Then the scrub withsoap alone is repeated for another 20seconds. That's much more time than most

people spend washing their hands," Bankss a y s .

Workers must wear single-use plasticgloves and use tongs or "deli" paper tissues or other means to avoid bare-handcontact with ready-to-eat foods that willnot be further cooked.

Hands need to be washed:• after touching bare human body parts• after using the toilet

• after handling support animals, such as

guard or seeing-eye dogs• after coughing or sneezing (even when

using a tissue), using tobacco, eating, ordrinking• after handling soiled equipment or utens i l s• immediately before and during food

preparation as often as necessary to remove soil and to prevent cross-contamination when changing tasks, such as changing from raw meat to raw produce• during food preparation when switchingbetween raw foods and ready-to-eat foods.

FDA says that bar soaps are acceptablefor hand washing. For years, there hasbeen concern that bar soaps might be capable of becoming contaminated with andtransmitting infectious organisms. Somehave argued that liquid or powdered soapfrom individual-portion dispensers mighttherefore be the best choice for handwashing.

The scientific data on this subject areinconclusive. Studies by two soap manufacturers show no bacterial transmissionthrough bar soap use, but studies by university researchers refute this.

Robert Haley, M.D., University ofTexas, formerly of the national Centers forDisease Control and Prevention, is quotedin a February 1984 article in the industiypublication Soap/Cosmetics/ChemicalSpecialties as saying, "more research isnecessary before any connection betweencontaminated soap bars and transmissionof sickness can be established." The article also pointed out that liquid soap hasoccasionally been found to be contaminated with disease-causing microorganisms that could be transmitted at the hand-contact surface of the dispensers, m

— J . E . F.

Grocery stores have self-service salad barsand ready-to-eat entrees in their delicatessens. Although enthusiasm for self-servebulk foods is fading somewhat, manystores still offer them. Convenience storesoften sell store-prepared fast food itemssuch as hot dogs, pizzas, and breakfastentrees. And many food store and foodservice operations have vending machines.

In addition, restaurants and grocers arenow using new ingredients and preparingfoods in ways that were not envisionedwhen previous codes were written. "Today, consumers' wants and needs go beyond the traditional," Banks says. "Cooksdon't always use the common spices youfind in most kitchens, and their equipmentis much more sophisticated." These ex

panded cooking styles and procedure.s—house-smoked sausage, for example-mean added re.sponsibilities for food service managers and restaurant inspectors.

"Today's re.staurant inspectors deal withfederally regulated food additives, such assulfites," continues Banks. Sulfites are sulfur-based preservatives legally used inmany foods, including most bottled lemon

S/April 1994/FDA Consumer

TJL he new Food Code includes special handling requirements

for ready-to-eat foods because of their potential to spoil or to

carry harmful food-home organisms.

juice and some frozen shrimp. Applieddirectly to produce, such as in salad bars,sulfites maintain color and perk up crisp-ness. But sulfites can cause life-threaten

ing reactions in people who are sulfite-sensitive, so federal law prohibits foodservice establishments from using them onfresh produce (see "A Fresh Look at FoodPreservatives' in the October 1993 FDA

Consumer). This is part of the Food Codeadvice on food additives.

As food processing technologyprogresses, food service operations increasingly depend on ready-to-serve foodsthat are sometimes used "as is" or combined with other ingredients. The newFood Code includes special handling requirements for ready-to-eat foods becauseof their potential to spoil or to carry harmful food-home organisms. "It used to bethat a cook prepared coleslaw from locallypurchased cabbage," says Banks. "Thesedays, that coleslaw might be prepared at afood processing plant several states away,or a pre-prepared entree could arrivevacuum-packed in plastic pouches," explains Banks.

Controlling Bad Bugs"One of the problems we have today is

the emergence of adaptive organisms—especially virulent pathogens transmittedthrough food that survive changing conditions," Banks says. "For example," he explains, "cooking hamburgers to a temperature of 140 degrees Fahrenheit used to besufficient to kill most harmful organisms.But in order to kill Escherichia coliOI57;H7, a bacterial strain of emergingimportance that has caused death in youngchildren, hamburger must now be cookedto 155 F and maintained at that temperature for at least 15 seconds." (Food serviceestablishments usually have equipment toprecisely measure cooking temperatures.However, since most homes do not, FDAand the U.S. Department of Agriculture

recommend, for assurance of safety, thatconsumers cook ground meat to the highertemperature of 160 F. (See "How to Outsmart a Dangerous E. Coli Strain" in theJanuary-February \99A FDA Consumer.)

Another problem is Salmonellaenteritidis. In the past, cracked and dirtyeggs were a common source of illnesscaused by Salmonella. Improvements inshell egg production, cleaning and packaging have greatly reduced the problem."The concern now," says Banks, "is thatone of the Salmonella strains that causesmost human infections. Salmonellaenteritidis. in some cases may be carriedinside the egg and transmitted by infectedhens before the shell is formed." (See "SoLong, Sunny Side Up" in the December1991, FDA Consumer.)

Another Salmonella strain has alsobeen found on cut melons, such as thoseserved in salad bars. Food safety expertsbelieve this type of contamination probably stems from not properly washing themelon before cutting, transferring bacteriastill on its surface from harvest to themelon's inside. It's also possible that bacteria are transmitted from improperlywashed hands or the knife used to cut them e l o n .

"Thorough cooking and proper preparation can eliminate food-borne problemssuch as E. coli OI57:H7 or Salmonellathat could occur upstream, before foodreaches the retail level," says Banks. "Butno one wants a hamburger that resemblesa hockey puck, or eggs cooked to the consistency of cardboard," he says.

To ensure that food is palatable as wellas safely cooked, the new Food Codeshows different cooking times, temperatures, and holding times for foods thathave the potential to cause illness. For example, safe cooking times and temperatures sometimes differ for the same food,depending on how it's prepared. A beefroast has different cooking and holding re

quirements than ground beef, and eggsbroken from the shell and prepared for immediate serving may be cooked differentlythan eggs that have been pooled for useduring the breakfast serving time. Thereare also time and temperature recommendations for poultry and game animals,corned beef, and other meat and fish products such as stuffed poultry, meat, fish,and pasta, and stuffing that contains meat,fish or poultry.

"It's impossible for cooks to rememberall those numbers without some ready reference," says Banks.

Working with Watchers"FDA can't watch everything," says

Banks. "There are well over a million retail food establishments in the UnitedStates in any number of localities andtypes of food preparation and services.That's where local inspectors and licensing agencies take on the Job of food safetysurveillance," he says.

Not every locality uses the Food Codein the same manner. For instance, DanSowards, a Texas Department of Healthofficial, says his state will not adopt theentire Food Code, but will use it to reviseand amend the Texas food code, whichaddresses food protection issues that arespecific to the region. Sowards finds particularly useful certain sanitation provisions. "The revised code deals very efficiently with employee hygiene and theresponsibilities of management for training employees in that area."

Both government and the food industryshare the responsibility for food safety.The Food Code, with its overlapping safeguards to prevent food-borne illness, isprovided to help ensure that consumerswill be able to eat out or shop for foodwith conf idence. ■

Judith E. Foulke is a member of FDA'spublic affairs staff.

FDA Consumer/April 1994/9

Implanted Defibrillators And PacemakersA Gentler Jolt and Tickle

for Trembling Heartsby Dixie Farley

On a Boston subway trainin December 1990, JohnThomas" heart stopped itsnormal steady beating. Instead. it began to quiverineffectively in a type ofcardiac arrest called fibrill a t i o n .

Automatically, built-in protection cameto the rescue. A medical device implantedin Thomas' abdomen delivered an electricshock to his malfunctioning heait, joltingit back to regular rhythm.

"1 lost consciousness for Just a few seconds." says Thomas, 36, a social worker inBoston. "Nobody on the subway knew./ wasn't even sure what had happened."That same day. his doctor confirmed thedevice had indeed responded.

The device is a cardioverter defibrillator, one of the newest heart-rhythm regulators in pacemaker-defibrillator evolution. ("Cardioverter" indicates the

capability to deliver low-energy shocks.)Thomas needs the device to treat primaryventricular fibrillation, a condition inwhich the lower heart chambers (ventricles) periodically have disorganizedelectrical activity and are unable to effectively pump blood to the body. He received his defibrillator after collapsingwith cardiac arrest at Cape Cod the previous Fourth of July.

Thomas' defibrillator gave his heartthree other jump-starts that fall and winter—his la,st one occurring in January1991. To reduce the frequency of theseepisodes, his doctor prescribed drugtherapy with Tenormin (atenolol), andThomas has been free of the episodes evers i n c e .

The Sta tsWhile most cardiac arrests result from

rapid heartbeat (tachycardia), some aredue to slowed heartbeat (bradycardia),which is often treated with an implantedpacemaker. The Food and Drug Administration estimates that doctors implantabout 15.000 defibrillators and 110,000pacemakers each year.

Clinical studies submitted to FDA showthe newest heart-regulating device—apacemaker-cardioveiter-defibrillator—coiTected nearly 98 percent of patients'abnormal heart rhythm or cardiac arrestepisodes. Some 400.000 Americans dieannually from abnormally fast or irregularheart rhythm, FDA said in announcing approval of the device in February 1993.

The Antian-hythmics v .̂ ImplantableDefibrillators (or AVID) pilot study at theNational Heart, Lung, and Blood Instituteis examining whether defibrillators or anti-arrhythmia drugs are more effective in reducing deaths.

Pacemaking, NaturallyResponsibility for pacing heartbeats,

which circulate blood, belongs to the sinusnode atop the heart's right atrium (one oftwo upper chambers). This naturalpacemaker's specialized cells fire electrical impulses that cause the atria and theirrespective ventricles to contract to movethe blood in perfect timing.

The impulses travel down the atria,which receive blood through the veinsfrom the body and lungs, and cause theircontraction to "top off the amount ofblood in the ventricles. The impulses continue through a conductive pathway intothe ventricles and cause their contraction.

resulting in the pumping of blood throughthe arteries to the body and lungs. Theright chambers circulate oxygen-depletedblood from the body to the lungs, whilethe left chambers circulate oxygen-richblood from the lungs to the body.

Aside from speeding up in situationssuch as physical activity and slowing during rest or sleep, the normal heart typicallycompletes 72 of these cycles a minute.

Some hearts, however, beat less than 60times a minute (bradycardia) or race atover 100 a minute (tachycardia). These"arrhythmias" may have any number ofcauses, such as a birth defect, injury,chemical imbalance, even anti-arrhythmiamedication. But the main predisposingfactor, according to the American HeartAssociation, is acquired heart disease.Some arrhythmias aren't serious enought o w a r r a n t t r e a t m e n t .

To treat serious arrhythmias, doctorscan turn to a permanently implanted artificial pacemaker or defibrillator. (Temporary emergency pacing with an externalpacemaker is possible by threading leadwires through a vein to the patient's heart.Emergency defibrillation is possible withexternal defibrillator paddles.) Alternativetreatments are drug therapy and surgicalc o r r e c t i o n .

Artificial PacemakersThe pulse generator of the artificial

pacemaker corrects for a defective sinusnode or conduction pathway by emittingrhythmic electrical impulses similar tothose of the sinus node. Usually, it's madewith a titanium metal case and other materials compatible with the body and powered by a lithium battery system.

10/April J994/FDA Consumer

Above, cardiologist Peter Friedman,M.D., Ph.D., of Brigham and Women'sHospital in Boston, tells John Thomashow well his implanted defibrillator isworking. The device's voltage and otherindicators are measured by the programmer Friedman holds, as detected by the

transmitting wand that Julie Shea, R.N.,places on Thomas' skin over hisdefibrillator. At left, a close-up of theprogrammer and wand, with Thomas'previous defibrillator, which Friedmanreplaced last September.

PHOTOS BY BIACK STAR, INC.FDA Consumer / April 1994/11

FDA estimates that doctors implant about 15,000defibrillators and 110,000pacemakers each year.

The doctor implants the generator underthe skin in the upper left part of the chest,attaching it to lead wires threaded to theh e a r t .

Traveling along the wires, the impulses"tickle" the heart, stimulating it to beat ata normal pace, says Donald Dahms, chiefof the pacing and electrophysiology devices branch at FDA's Center for Devicesand Radiological Health.

The first pacemaker was implanted in1958. These early devices had only onewire and paced the ventricles at regular intervals. They paced at a single rate prescribedby the doctor—usually 70 beats a minute.

The first advance, around 1976, was adesign change that allowed "demand"pacing: A pacemaker would only pace ifthe patient's heait didn't beat within agiven time period.

Then, early in the 1980s, programmingcapability was introduced. The subsequentdevelopment of transmitting by telemetry,a system for sending and receiving electromagnetic signals as radiofrequency, enables the doctor to check and adjust thepacemaker. In addition, simple monitoringcan be done over the telephone.

Placing a transmitting wand (called aprogramming head) on the patient's skinoverlying the pacemaker, the doctor candetermine voltage, pacing rate, and thestatus of the wiring and electrodes and canmake adjustments to fit the changingneeds of the patient. For instance, an increase in voltage output might be neededif the connection to the heart gets bad,Dahms says.

"The problem with the early pacemakers' having only a constant rate," he says,"is when you need a faster rate—if yourun, for instance—they can't give it toyou. So your heart has, to strain to increaseits blood output to make up the difference.And if your heart beats on its own, thepacer continues beating, competing withyour natural heartbeat." A constant ratealso can cause adverse effects, such asdizziness, he says.

By 1983, the first dual-chamberpacemakers entered the market. Using

C a r d i o v e r t e rdefib r i l l a to r

Sensing-PacingLead System

D e fi b r i l l a t i o nLead System

P u l s eG e n e r a t o r

This implanted cardioverter defibrillator has two lead systems; One(right) continuously monitors heart activity, while the other (left) delivers electrical stimulation to restore a normal heartbeat.(Source: Ventritex, Inc., Sunnyvale, Calif.)

P a c e m a k e r

P u l s eG e n e r a t o r

Lead System Through improved technology, a pacemaker'spulse generator (left) issmall enough for implanting in the shoulderarea. A lead system carries electrical impulses

from the generatorthrough the veins to theheart (right) to maintaina regular heartbeat .(Source: Medtronic, Inc.,M i n n e a p o l i s )

J2/April 1994/FDA Consumer

/i pacemaker's electrical impulses ''tickle" the

heart, stimulating it to beat at a normal pace.

two lead wires, these devices pace theatrium and then the ventricle, when necessary.

"Dual pacing lets you synchronizepacing of both chambers, more like theheart's natural functioning," Dahms says."If you have a wire pacing away just onthe ventricle, your atrium might get out ofsynch, which reduces your blood output.Without the 'atrial kick' you have less efficient c i rculat ion."

Within the next couple of years, firmsdeveloped techniques to make single-chamber pacemakers "rate responsive."

These pacemakers contain a sensor todetect the need for increased rate. The

simplest ones, Dahms says, gauge response by body movement. Some, however, respond to the person's breathing.Still others base their response on changesin blood temperature. Thus, if a personstarts to walk or run, the device senses the

activity and increases the heart rate.Rate-responsive, two-wire, dual-cham

ber devices became commercially available in 1987.

Many pacemakers automatically provide for a slower heart rate at night orwhen the person rests. A very few devicesare clock-timed to slow at night.

Despite such sophisticated capabilities,miniaturization techniques have allowedpacemakers to become quite tiny in size,some as small as a quarter and less thanan ounce in weight. The many companiesmaking pacemakers today offer more thana hundred models.

Pacemakers last four to 12 years. Factors that shorten a pacemaker's life include the requirement to pace every beat,the size of the batteries, dual-chamberpacing, and the tightness of the electricalconnection to the heart, which is not completely controllable.

Another use for pacemakers has been totreat heart rates that are too fast, slowingthem back to a normal rhythm. But anti-tachycardia pacing can also pose a problem. If pacing doesn't stop a rapid heartbeat, Dahms says, it may accelerate it,possibly leading to fibrillation.

• arrhythmia—abnormal heart

rhythm• artificial pacemaker—correctsfor a defective sinus node (see"sinus node" entry) or conductionpathway by emitting a series ofrhythmic electrical discharges tocontrol the heartbeat• atria—the two upper heart chambers• bradycardia—slowed heartbeat,less than 60 beats a minute• cardiac arrest—stopped heart activity• defibrillator—electronic devicethat helps reestablish normal heartbeat in a malfunctioning heart• fibrillation—rapid, uncoordinated heart muscle contractions; thechamber involved can't pump effectively, so blood flow is comprom i s e d• sinus node—the natural pacemaker, whose cells in the top of theright atrium produce electrical impulses that travel to the ventricularmuscle, causing the heart to contract• tachycardia—fast heart rate, overICQ beats a minute• ventricles—two lower chambers

of the heart ■

D e fi b r i l l a t o r sNewer than the pacemaker in regulating

heartbeats is the implantable defibrillator,made of the same materials but poweredby a special higher energy battery.

Implanted under the skin in the upperabdomen, the defibrillator is connectedwith lead wires to two defibrillation electrodes placed surgically in or around theheart. There must always be two, Dahmssays, to provide the electric field neededacross the heart.

The defibrillator interrupts the abnormal

rhythm, allowing the normal rhythm to resume. The abnormal beating is so rapidand uncoordinated that the heart can onlyquiver ineffectively.

Sensors inside the generator monitor theheart. If a sensor detects an irregularity,such as fibrillation, the generator is programmed to deliver a strong electric shockdirectly to the heart. Being kicked in thechest by a horse is how some people describe this jolt.

Others, like Thomas, lose consciousnessbefore they experience the shock.

"I've never felt it," Thomas says. "I'mjust a little lightheaded, like when youstand up too quickly. Then I'm unconscious for 5 to 10 seconds. When it's happened at home, my wife has observed mybody jerk as though I'm having a seizure."

Although a patient may sometimes beunaware the defibrillator has been acti

vated, this information is stored in thedevice's memory. During periodic checkups, the doctor can therefore tell how frequently it has gone off and how muchshock it has delivered.

FDA approved the first defibrillator in1985, after clinical trials with the deviceproduced dramatic results. In the trials, theagency announced, the cardiac arrest deathrate was under 5 percent a year, downfrom a 27 to 66 percent annual rate previously reported (before the use of implanted defibrillators) for patients nothelped by medication.

These early devices were limited in detection and programming capability anddelivered only one level of therapy—apainful, jolting shock. Still, says Dahms,they provided almost certain protectionagainst death from cardiac arrest.

In 1988 and 1989, FDA approved thefirst cardioverter defibrillators, which offer the programmability of a two-stageshock treatment. The life-saving jolts ofthese defibrillators continued to be painful,causing significant psychological sufferingin some patients with frequent episodes.

The newer pacemaker-cardioverter-defibrillator monitors the heart and refrains from delivering a shock if the heartrhythm has returned to normal on its own.Using staged therapy, this first "third-generation" defibrillator measures varying degrees of rapid heartbeat so that it can deliver gentle pacing impulses to slow theheart, low-energy cardioversion shocks torestore normal rhythm when the pacing is

FDA Consumer / April 1994/13

To speed patient notification in case of a problem, manufacturers by law must track their pacemakers and defibrillators

from production, through distribution, to the patients.

M e d i c A l e r t

FDA encourages people implantedwith a pacemaker or defibrillator to

join the free Medic Alert International

Implant Registry by calling (1-800)344 -3226 .

Those who enroll will receive a freeMedic Alert bracelet or necklace to

notify health-care staff of the implantin the event of a medical emergency. ■

inadequate, or high-energy defibrillationshocks to restart the quivering heart.

Some devices also use "biphasic"pulses, which holds promise for extendingthe life of the device, as well as other possible benefits. (The biphasic wave-formpulse derives its name from the fact it delivers a pulse with a positive and negativepolarity.)

Last August, FDA approved a new leadsystem that can be implanted through avein, eliminating the need for open-chestsurgery when implanting a defibrillator incertain patients. In some of these patients,generators with biphasic pulses are usedwith the leads.

A defibrillator usually lasts two or threeyears, depending on how often it has todefibr i l la te .

Thomas' defibrillator was replaced lastSeptember. His concern about being offwork for the surgery and uncertainty aboutwhether the replacement, like the first device, would go off several times were soonalleviated. Unlike his first surgery, whichrequired opening the chest to attach thelead system to his heart, this implantationwas a minor outpatient procedure underlocal anesthetic because the leads were already attached to his heart. "It was mucheasier the second time," he says.

Although today's defibrillators are thesize of a deck of cards and weigh about 8ounces, Dahms says future devices, nowin clinical studies, will be small enoughfor implanting in the upper chest, likepacemakers.

Risks and PrecautionsAs with anything electronic, glitches

can occur in a pacemaker or defibrillator.Among possible causes of malfunction,says Dahms, are circuitry failure, leadbreakage, electrode displacement, andscarring around the electrodes. Regularcheckups by the doctor every two or threemonths are crucial so that any problems,including battery depletion, are detected asearly as possible.

There's no question that defibrillatorfailure due to battery depletion could belife-threatening. However, death is extremely rare following pacemaker failure.In almost all pacemaker-battery failures,the underlying natural heartbeat takes over(albeit at a slowed rate) until a new deviceis implanted or an external pacemakerapplied.

Nevertheless, as a precaution for pacemakers as well as defibrillators, FDA re

quires special labeling specifying a warning period when a battery is about to wearout, to allow for timely replacement. (Thewarning is detected during medical checkups.)

Extreme electromagnetic interferencecan cause some devices to malfunction.Someone implanted with a defibrillator,for instance, should avoid airport securityscans, because the interference can turnoff a device, in which case some devicesstart beeping. It is inadvisable for patientswith pacemakers or defibrillators toundergo magnetic resonance imaging, adiagnostic technique that pictures thebody's internal structures.

Some older pacemakers were susceptible to interference from microwaveovens. More recent models are shielded.Patients in doubt about any interferenceshould check with the doctor.

Under FDA regulations required by thetracking provisions of the Safe MedicalDevices Act of 1990, manufacturers musttrack pacemakers and defibrillators fromproduction through distribution to patients.This will speed patient notification if aproblem should arise. These regulationswent into effect on Aug. 28, 1993.

In addition, a few state laws prohibitdriving for a period of time afterarrhythmia-induced unconsciousness.While Massachusetts doesn't have such alaw, Thomas was under his doctor's orders to not drive for six months followingan episode.

Not driving that first year was hard,Thomas says, along with constant anxietyabout having an episode. As for today:

"It does tend to give me more perspective, so that little things don't bother me asmuch. Once in a while it's on my mind.And it impresses upon me how fragile lifecan be." ■

Dixie Farley is a staff writer for FDAC o n s u m e r.

14/April 1994/FDA Consumer

Food Label Close-Up

What do you look for whenyou read a food label? Fat

content, calories, ingredi

ents. brand name?

If so, you're not alone. A 1993 Food

Marketing Institute survey of 1,000 U.S.

shoppers found that such information was

sought by most label readers. Fat content

was No. 1. followed closely by ingredients,

calories, and other nutrient information.

But not everyone read the label for nu

trition information. A few said they read it

to learn the brand name, expiration date,

or package weight.

Their responses show just how diverse

label information has become. Some

of the information, such as the

manufacturer's name and address, is re

quired. Some, such as health claims and

terms that describe a food's nutrient con

tent. is voluntary. Much of it is regulated

by the Food and Drug Administration.

(The U.S. Department of Agriculture

regulates labeling of meat and poultry.

FDA regulates labeling of all other foods,

including game meats.)

Some information has just been—or

soon will be—added to the label. This is

PHOTO BY NORAAAN WATKINS

by Paula Kurtzweil

FDA Consumer / April 1994/15

he name of a food is called

the "statement of identity."

the result of two laws that become effec

tive in 1994: the American TechnologyPreeminence Act of 1991, which took effect Feb. 14, and the Nutrition Labelingand Education Act of 1990 (NLEA),which goes into effect May 8 (althoughsome manufacturers have already startedto relabel their products).

Under the Technology PreeminenceAct, food manufacturers have to list thenet contents of their products in both metric units and inch and pound units.

Regulations implemented under NLEAwill require:• nutrition information on almost all

f oods• a new format for presenting nutrition inf o r m a t i o n• set definitions for nutrient claims, suchas "low-fat" and "high-fiber"• appropriate use of seven scientificallyproven claims about the relationship between a nutrient or food and reducing therisk of a disease or health-related condit i on• ingredient listing on all foods with twoor more ingredients.

The changes—the most extensive infood labeling history—are designed tomake label information more complete,useful and accurate than ever before.Soon, consumers will not only be able toknow more about the foods they eat butwill also have more confidence in whatthey read on the label.

Here's a rundown of today's food label.

A Two-Panel LabelA food package usually has at least two

distinct areas: the principal display panel,or POP, and the information panel.

The POP is the part of the label consumers see first when they purchase aproduct. So, in almost all cases, the POPis the front of the package. This is whereFDA requires the name of the product andthe net quantity of contents statement.

The information panel is usually to theimmediate right of the POP. It is reservedfor the nutrition information; ingredientlist; and name and address of the manufacturer, packer or distributor. If there's insufficient space on the information panelfor these three pieces of information, theythen can be divided between the POP andthe information panel.

Also, these three items of informationmay be separated from each other onpackages with less than 40 square inchesavailable for labeling. On these packages,the nutrition facts may be moved to another panel if there is insufficient space forit on the information panel.

FDA has proposed to allow the nutritionfacts on larger packages to be moved toother panels, too, if there is insufficientspace on the PDP or information panel forall of the required information.

Nevertheless, each of these items of information is considered one piece, and asa general rule they cannot be broken upwith intervening material. For example, aUniversal Product Code (UPC) cannot appear in the middle of the nutrition facts.And a health claim or product trademarkcannot appear in the middle of the ingredient list.

F o o d N a m eThe name of a food is called the "state

ment of identity." It's easy to spot becauseit's one of the principal features of theprincipal display panel. It must be in English, although foreign language versionsmay accompany it. Its common or usualname also must be given: for example,"whole kernel com," "honey," or "tunapacked in spring water." When appropriate, it must describe the form of the food,too, such as "sliced peaches" or "wholepeaches."

A brand name can serve as the statement of identity if the name is commonlyused and understood by the public to refer

to a specific food—for example. CocaCola and Pepsi Cola.

Net QuantityThe net quantity of contents statement

helps consumers in two ways: First, it letsconsumers know how much food is in a

container, and second, it aids in price comparison.

It refers only to the quantity of food (including any liquid or juice usually eaten inwhich the food may be packed) in a package or container. It does not include theweight of the container or wrappers.

Shoppers will find the net quantity ofcontents statement in the lower third of the

principal display panel.Starting in 1994, the net quantity of con

tents will have to be stated in both inch or

pound units and metric units. Many companies are already complying with this requirement. On the label, the statementwould appear like this: Net Wt 8 oz (226g). ("Oz" is an abbreviation for ouncesand "g" for grams.)

Also, instead of the term "weight,"manufacturers may choose to use "mass"when stating the quantity of a solid food."Net content" will continue to be one ofthe optional terms for liquid foods.

Manufacturers may voluntarily continueto state the net quantity of contents in adual manner for the inch or pound units—for example, 20 fluid ounces (1V4 pint)—but they no longer will be required to dos o .

N u t r i t i o n F a c t s

Starting in May 1994, almost everyfood will have to carry information aboutits nutritional content. (See "Good Reading for Good Eating" in the May 1993FDA Consumer.) This information willcome under the heading "Nutrition Facts."

This title will replace "Nutrition Information Per Serving," which is requiredunder the current nutrition labeling pro-

16/April 1994/FDA Consumer

statement ofIdentity

PrincipalDisp iay

P a n e l

N u t r i e n tClaim

(optional)

Product Code(optional)

Net Quantity ofConten ts Copyright

Symbol

Nutrition Facts

i n f o r m a t i o nP a n e l

Ingredients

CompanyName andAdd ress

FDA Consumer/April 1994/17

^̂focd label must identify thefirm responsible for the product.

gram, established in the mid-1970s. Underthis program, nutrition labeling is requiredonly for foods with added nutrients orwhose labels bear nutrition claims.

(For more information about nutritionlabeling, see '"Nutrition Facts' to HelpConsumers Eat Smart" and '"Daily Values' Encourage Healthy Diet" in the May1993 FDA Consumer.)

IngredientsThe ingredient list helps consumers

identify foods that have substances theyare allergic to or want to avoid for otherreasons. It also helps them select foodswith ingredients they want.

An ingredient list will be required on allpackaged foods composed of two or moreingredients, even standardized foods(which previously had to list only optionalingredients). Foods with two or more discrete units, such as cherry pie—which hasfilling and pie crust—may have a separateingredient list for each of the units.

Ingredients must be listed in descendingorder by weight. This gives consumers anidea of the proportion of an ingredient in afood.

(For more information, see "IngredientLabeling: What's in a Food?" in the April1993 FDA Consumer.)

Company NameA food label must identify the firm re

sponsible for the product (either the manufacturer, packer or distributor) and thefirm's city, state and zip code (or anothermailing code if the product is imported). Astreet address is not required if the name islisted in a current telephone book. A telephone number is not mandatory.

The required information is theremainly so that consumers have a point ofcontact if they find something wrong withthe product.

P roduc t Da tes

Consumers can use the dates that are

given on food packaging if the manufacturer is using "open dating." On the otherhand, consumers cannot use "code dating."

In open dating, dates are stated alphanu-merically, such as "Oct. 15," or numerically, such as "10-15" or "1015." In codedating, the information is coded in letters,numbers and symbols so that usually onlythe manufacturer can translate it.

Some dates for which open dating isused are:• Pull date. This is the last day that themanufacturer recommends that the product remain for sale. This date takes intoconsideration additional time for storageand use at home, so if the food is boughton the pull date, it still can be eaten at alater date. How long the product should beoffered for sale and how much home stor

age is allowed are determined by themanufacturer, based on knowledge of theproduct and the product's shelf life.• Quality assurance or freshness date.This date shows how long the manufacturer thinks a food will be of optimal quality. On the label, it may appear like this:"Best if used by October 1994." Thisdoesn't mean, however, that the productshouldn't be used after the suggested date.• Pack date. This is the date the food was

packaged or processed. It may enable consumers to determine how old a product is.• Expiration date. This is the last day onwhich a product should be eaten. Stategovernments regulate these dates for perishable items, such as milk and eggs. FDAregulates only the expiration dates of infant formula.

A common type of code dating is theproduct code. This code enables the manufacturer to convey a relatively largeamount of information with a few small

letters, numbers and symbols. It tells whenand where a product was packaged. In thecase of a recall, this makes it easier to

quickly identify and track down the product and take it off the market. FDA en

courages manufacturers to put productcodes on packaging, especially for products with a long shelf life.

H e a l t h C l a i m sFDA now allows manufacturers to

make certain claims linking the effect of anutrient or food to a disease or health-related condition. Only claims supported byscientific evidence are allowed. And theycan be used only under certain conditions,such as when the food is an adequatesource of the appropriate nutrients.

The claims may show a link between:• a diet with enough calcium and a lowerrisk of osteoporosis• a diet low in total fat and a reduced risk

of some cancers• a diet low in saturated fat and cholesterol and a reduced risk of coronary heartdisease• a diet rich in fiber-containing grainproducts, fruits and vegetables and a reduced risk of some cancers• a diet rich in fruits, vegetables and grainproducts that contain fiber and a reducedrisk of coronary heart disease• a diet low in sodium and a reduced riskof high blood pressure• a diet rich in fruits and vegetables and areduced risk of some cancers.

In addition, FDA has proposed allowinga claim for folic acid and a reduced risk ofneural tube defects in offspring. While thisclaim is now authorized on dietary supplements, the agency expects to issue a finalrule on the use of this claim on all foods inthe near future.

Consumers can use these claims to identify foods with desirable nutritional quali-

18/April 1994/FDA Consumer

The ingredient list helps consumers identifyfoods that hove substances they are allergic

to or want to avoid for other reasons.

One Source for FoodLabeling Info...The articles cited here, as well asother FDA Consumer stories aboutthe new food label, ore availablein the FDA Consumer special report Focus on Food Labeling.G)pies ore $5 each and con beordered from the Government

Printing Office. Write to: Superintendent of Documents,P.O. Box 371954, Pittsburgh,PA 15250-7594. Ask for publication number FDA 93-2262. ■

Like health claims, these terms also canhelp consumers quickly spot foods with adesirable nutrient content.

(For more information, see "A Little'LiiQ Reading" in the June 1993 FDAConsumer.)

O t h e r I n f o r m a t i o nOther types of information may appear

on the food label. Among them:• Grades and standards. Some foods—

such as milk, butter, eggs, orange juice,and meat—carry a grade on their label thatattests to their quality. The grades show upas letters, such as AA, A, and B for eggs;words, such as "choice" and "select" formeat, or "substandard" for some cannedvegetables; or as some kind of logo ormark, such as the Grade A shield on orange juice containers. Such foods sold ingrocery stores usually cauy the highestgrades given. USDA establishes some otthese standards for foods, such as meat.

butter, eggs, and fruit juices. FDA hasstandards for a number of foods, includingcanned vegetables. The National MarineFisheries Service grades fish on a fee-for-service basis.• Trademarks and copyrights. The symbol "R" on a label indicates that a trademark used on the label is registered withthe U.S. Patent and Trademark Office. A

"C" means that the literary or artistic workof the label is protected under U.S. copyright laws.• Religious symbols. Any number ofmore than 50 symbols may appear onfoods to indicate that the food has been

processed according to Jewish dietarylaws. One of the more common is a letter"U" inside the letter "O." This means thatthe food has been authorized as "kosher"

by the Union of Orthodox Jewish Congregations of America. FDA does not regulate any of these symbols.• Universal Product Code. The UPC is a

bar code with a 10-digit number. It is usedwith computerized grocery store checkoutequipment to give an automated inventorysystem. The Uniform Code Council Inc.,of Dayton, Ohio, monitors this system.• Safe Food Handling Instructions. TheU.S. Department of Agriculture has proposed requiring safe handling and cookinginstructions on raw meat and poultry products. These instructions would state that"some food products may contain bacteriathat could cause an illness if the product ismishandled or cooked improperly." Theyalso would give tips on safe storage of rawproducts, prevention of cross-contamination between raw and cooked foods, safecooking procedures, and handling ot leftovers. The proposed requirements may gointo effect this year. ■

Paula Kurtzweil is a member of FDA \s

public affairs staff.

ties. They will probably find a reference tothe claim on the front label, but the claimitself may appear elsewhere on the label.

(For more information, see ''StartingThis Month, Look for 'Legit' HealthClaims on Foods" in the May 1993 FDAConsumer.)

N u t r i e n t C o n t e n t C l a i m sBesides the seven health claims, FDA

also has set conditions for the use of termsthat describe a food's nutrient content.Eleven basic terms have been defined thatrelate to several nutrients. They are:• f r e e • l o w • r e d u c e d • f e w e r• l e a n • h i g h • l e s s • m o r e• extra lean • good source • light

The term "sodium free," for example,means that the food contains less than 5 milligrams of sodium per serving of the food.

These terms will probably appear on thefront label, although manufacturers mayplace them on other parts of the label, too.

FDA Consumer/April 1994/19

Treatment PalesRosacea's Red Face

by Margie Patlak

20/April 1994/FDA Consumer

I M O fi J H m ^ t e e n a g e r a n dI gS js her fr iends were1 # H g bemoaning them M W B whiteheads andS » B ^ blackheads eruptingW k m H # f a c e s , M a r c i a

Ws Meyer of Kensington,W W Md., had a clear, ruddy

complexion. She was surprised, then, when her face broke out inpimples for the first time when she was inher 20s. Feeling she was "too old for this,"Meyer says, and upset over her appearance, she went to see her dermatologist,who told her she had a skin disorderknown as rosacea.

Although few people ai'e familiar withthe disease, rosacea is a common skin disorder that afflicts about 1 in 20 people inthis country, estimates dermatologist androsacea expert Jonathan Wilkin. M.D., ofOhio State University in Columbus. Despite its prevalence, many people with thecondition go undiagnosed, he says.

Wilkin has seen patients who seek carefor other skin disorders and don't realizethey have rosacea until he points it out tothem. "Most people with rosacea are surprised to hear it's something the medicalfield can help them with," he says, "because they think it's just a complexionproblem that runs in their family."

The disorder can be effectively curbedwith various dmgs, laser treatments, andsurgery, including products regulated bythe Food and Drug Admini.stration, as wellas by preventive measures. Without propercare, in contrast, rosacea may progress to amore disfiguring condition.

Although it can occur among adults ofany age and of any skin color, rosacea ismore prevalent among fair-skinned peoplebetween the ages of 30 and 50. The dis

ease is more common in women, butmore severe when it strikes men. Peoplewho flush easily are more prone torosacea, as are people with peaches-and-cream complexions, including many withIrish, English, or Eastern European ancestry, a survey by the National Rosacea Society suggests. The tendency towardsrosacea appears to be inherited; often several people in a family have the condition.

R e d M a s k

Rosacea usually begins with frequentflushing of the face, particularly of thenose and cheeks, although sometimes theredness spreads to the chin and foreheadas well. The flushing is caused by swelling of the blood vessels under the skin ofthe face and can la.st as little as a few minutes to as long as a few hours. In mostcases, however, eventually the blood vessels stay dilated and a sunbum-like redness becomes a permanent feature on thecentral areas of the face.

This red mask can serve as a red flagfor attention. Meyer notes that peopletend to tease her about being out in thesun too much. "I'm probably the only person who uses makeup to tone down herface, rather than the reverse," she says.

Once the redness becomes permanent,it often is accompanied by pus-filled orsolid red pimples. There are no blackheads or whiteheads with rosacea, and the

pimples are usually limited to the centralportion of the face. Thin red lines that resemble a road map also tend to surface.These lines are actually small blood vessels in the upper layers of the skin thathave become enlarged. If rosacea is nottreated, a condition called rhinophymacan develop in some people. Rhinophymaoccurs much more frequently in malesthan in females. The hallmark of

rhinophyma is a big bulbous red nose likethe one sported by the late comedian W.C.Fields, who had rosacea with rhinophyma.The nose can also become thicker at thebase.

This disfiguring condition "has neverkilled anyone," notes Wilkin, "but it hasruined a lot of lives."

Rosacea can also cause a persistentburning and grittiness of the eyes or inflamed and swollen eyelids. In severecases, vision may become impaired.

Waxing and WaningRosacea is a chronic ailment that waxes

and wanes. Between flare-ups, somepeople have no signs of the disorder. Butother people still have facial redness or redlines, accompanied by pimples duringflare-ups.

Dermatologists usually diagnose rosaceaby its symptoms; no tests are available, buton rare occasions skin biopsies can pinpoint the condition. Few people withrosacea have all the symptoms of the disorder, which can make it tricky to diagnose at times, Wilkin admits. He stronglysuspects rosacea in people with just a fewsymptoms of the disorder if other peoplein their family have the condition.

There is also a condition known as ste

roid-induced rosacea, which occurs insome people after applying corticosteroidointments to their face for a long period totreat eczema or other rashes. The onset ofthis condition is sudden. The same telltaleredness, pimples, and thin, wavy red linesappear on the face as in standai'd rosacea,but people with steroid-induced rosaceausually have these symptoms wherever thesteroid ointment was applied—up to thehairline—and not just centrally located onthe face, for example. People with steroid-induced rosacea also often have a distinc-

FDA Consumer/April 1994/21

tive shine to their facial skin.Steroid-induced rosacea is treated first

by stopping the steroid and then by takingthe same medications as with standard

rosacea. Although it can take severalmonths of treatment before symptomssubside, steroid-induced rosacea is notlikely to recur unless corticosteroids areapplied again on the face. Less commonly,o r a l o r i n h a l e d c o r t i c o s t e r o i d s c a n a l s o i n

d u c e r o s a c e a .

Searching for a CauseAlthough dermatologists have been

speculating about causes for standardrosacea for more than a century, nonehave been definitively proven. Most experts think the condition can be provokedby several different factors, some of whichmay work together to cause rosacea.

One might be an underlying vasculardisorder that cau.ses blood vessels in theface to expand and fluid to build up in theskin. This fluid can trigger an inflammatory response that manifests as facialpimples or excess tissue growth on then o s e .

Wilkin says several findings supportthis theory. One is that researchers detected structural abnormalities in the smallblood vessels in the facial skin of patientswith rosacea. Another is that rosaceaworsened when people with the conditiontake drugs such as theophylline and nitroglycerin, which dilate blood vessels. Also,people with rosacea are more likely tosuffer from migraines, which are alsothought to be caused by a vascular disorder. A vascular cause for rosacea mightalso explain why the condition is morecommon in older women, who are morelikely to have swelling of the facial bloodvessels as part of the menopausal "hotflashes."

In addition to vascular disorders, another factor that might play a role in fostering rosacea is a microscopic mite by thename of Demodex folliculonim. This mite,

Some factors that

aggravate rosacea

are drinking hot

beverages, smoking, anxiety, spicy

foods, large meals,excessive sunlight,and overindulgencein alcoho.

a normal resident in human skin, lives inhair follicles, where it dines on ca.st-offskin cells. They have been retrieved fromalmost every area of human skin, but theyhave a taste for the face.

Two recent studies revealed that themites were significantly more numerous infacial skin samples of people with rosaceathan of people without the condition. Inaddition, the mite population peaked onthe skin samples of these patients in thespring, when rosacea tends to flare up. Thestudies were done by Frank Powell, M.D.,and colleagues at the Mater MisericordiaeHospital in Dublin, Ireland, and by F.Forton, M.D., and B. Seys, M.D., of theSaint PieiTe University Hospital in Brussels, Belgium.

According to Powell, other studies showthat patients with steroid-induced rosaceaalso had a boosted mite population ontheir faces. This population dropped whenthe rosacea subsided after treatment witha n o i n t m e n t t h a t k i l l s m i t e s .

Although these findings do not provethat the skin mite causes rosacea, they dosuggest that Demodex might play a role infostering the disorder. The mites may provoke rosacea by clogging skin follicles,which in turn might trigger an inflammatory response. Rosacea may also be triggered by an allergic-like reaction to theseskin mites or to the bacteria the mites har

bor. Forton proposes that an underlyingvascular disorder of the face that fosters

flushing could create an environment particularly hospitable to Demodex mites.These mites could then multiply excessively or penetrate more deeply into theskin, triggering an inflammatory responsein the form of pimples.

Other Flare-Up TriggersSeveral other factors have been found to

aggravate (but not necessarily cause)rosacea, mainly by triggering flushing.These factors include drinking hot beverages, smoking, certain emotions (such asworry and anxiety), spicy foods, largemeals, exposure to temperature extremes,wind, excessive sunlight, and overindulgence in alcohol. (Although alcohol canworsen rosacea, a nondrinker can developa case of rosacea just as severe as someone fond of alcohol.) Make-up, moisturizers, sunscreens, or other skin productsused on the face that contain alcohol orother irritating ingredients can also foster arosacea flare-up.

What worsens one person's rosaceamay not have any effect on anotherperson's symptoms—it's very individual."Many patients can actually reduce oreliminate the need for medications to control their rosacea," said Wilkin, "by avoiding the factors that trigger it."

22/April 1994/FDA Consumer

Demodex folliculorum

Scientists are investigating whether this microscopic mite plays a role in rosacea.

Tr e a t m e n t E f f e c t i v eIf preventive measures aren't effective,

however, the pimples can often be effectively treated with certain drugs. FDA hasapproved Metrogel (metronidazole), atopical antiprotozoal and antibacterial, totreat rosacea. Doctors may also use severalother approved drugs to treat rosacea-in-duced acne. Such drugs include oral andtopical antibiotics, particularly those in thetetracycline family, and these are alsooften used to treat eye manifestations ofrosacea. (Pregnant women should not taketetracycline because it can discolor the un-bom child's teeth.)

Such therapy for acne is effective inabout three-quarters of rosacea patients,usually within a few months, according todermatologist Seymour Rand, M.D., of FDA.

Removing Unsightly VesselsWilkin says that some rosacea patients

find antibiotic therapy not only relievestheir acne, but also decreases facial redness, which had been hiding the spideryred lines of enlarged blood vessels. Dermatologists can usually rid the face ofthese enlarged blood vessels by destroyingthem with an electrical needle or a laser.Patients who have this treatment experience little or no discomfort. Their facesmay look somewhat baiised for about aweek after the procedure, and may scab,peel or cinst.

To treat the more extensive facial redness, dermatologists can use lasers to destroy the expanded blood vessels in theskin that cause it. One recent study by SanDiego dermatologist Nicholas Lowe,

M.D., and associates found laser therapyeffective in more than three-quarters oftreated patients. In more than half of those,the therapy not only rid the face of the redness or red lines, but also stemmed theacne. This finding further supports a vascular cause for rosacea, according toW i l k i n .■ Lasers or electrical devices are also used

t o r e m o v e t h e e x c e s s t i s s u e t h a t a c c u m u

lates on the nose in patients withrhinophyma. The tissue can also be removed with a scalpel or a rapidly rotatingwire brush, which is often used by dermatologists to scrape away tissue in a proced u r e k n o w n a s d e m i a b r a s i o n . L o c a l a n e s

thesia numbs patients' noses beforetreatment. The nose looks red for a year orso following tissue removal and then assumes a normal skin color, according toWilkin. "I've seen people whose noseswere the size of baseballs look great aftertreatment," he says.

One of the most difficult barriers to

countering rosacea is convincing peoplewith the disorder to seek care. Even afterMeyer knew she had rosacea, for example,she delayed seeking medical treatment fora flare-up because she thought the emotional stress she was experiencing at thetime was behind her "acne."

"Even though my personal problemshadn't gone away," she said, "within aweek of treatment, my 'acne' did. My appearance improved so quickly, I wished Ihadn't waited so long to see my dermatologist. I hope others won't be so slow to goto the doctor."

Many people don't see a doctor becausethey don't realize they have a conditionthat can be treated. But, as Wilkin notes,"People with rosacea can be very hopeful,whatever stage they've got, becausethere's something that can be done foreveryone." ■

Margie Patlak is a writer in ElkinsP a r k , P a .

FDA Consumer / April 1994/23

Interleukin̂New Therapy fo r jKidney Cancer

by Ricki Lewis, Ph.D.

The 59-year-oldwoman was in fora distressing surprise when she returned to the hos

pital for a routinechest x-ray 10months after her

cancerous kidney had been successfullyremoved. Although she felt fine, the x-rayshowed several ominous spots in bothlungs, some as large as grapes. The cancerhad spread. It wasn't a complete surprise,though.

Her doctors had said that despite surgery, kidney cancer eventually spreads,usually to the lungs, in about half of the20,000 new cases diagnosed yearly in theUnited States. In the past when this happened, there was virtually no treatment.

"Conventional chemotherapy has a vei-yunsuccessful response rate for advanced,metastatic [spread] kidney cancer of onlyabout 4 percent, and radiation doesn'twork," says Eugene Schonfeld, Ph.D.,president of the National Kidney CancerAssociation in Chicago.

But in this case, the woman was

lucky—she participated in a clinical trialof interleukin-2 (IL-2), and got a secondchance at life. Her success with the treatment contributed to FDA's licensing inMay 1992 of IL-2 for the treatment of kidney cancer. IL-2 is a naturally occurringprotein that stimulates an immune response. The biological product is mar

keted under the brand name Proleukin

(generic name, aldesleukin).

Rough RoadThe route to recovery with IL-2 isn't

easy. Two months after the devastatingchest x-ray, after tests showed her heart,lungs, and remaining kidney to be functioning well and her head, bones and abdomen to be free of tumors, the womanbegan her first treatment cycle with IL-2.In the hospital, every eight hours, for fiveconsecutive days, she received the medication intravenously. The IL-2 caused herimmune system to produce more cancer-tlghting lymphocytes (a type of whiteblood cell), along with other biochemicals,called cytokines, that cause some of thelong list of side effects she experienced.

She lost her appetite, developed a rash,was very tired, and her urine was scantand contained protein, signs of strain onher kidney. But these problems vanisheddays after stopping treatment. Her secondIL-2 cycle (two five-day treatments ninedays apart) seven weeks later brought thesame side effects, but so much more severe that her doctors halved the doses inthe remaining cycles of the six-monthregimen.

But more was happening in her bodythan temporary misery. After only twotreatment cycles, the spots in her lungs began to shrink; by six months, her chestx-ray was cleaid When the woman's casewas reported in a medical journal, Semi-

ILLUSTRATION BY JACK PARDUE FDA Consumer/April 1994 / 25

nars in Oncology Nursing, in August1993, she had been completely free of

cancer for 10 months.

A Tr e a t m e n t W h e r e T h e r e Wa s N o n eIL-2 is now the state-of-the-art, conven

tional treatment for advanced, metastatickidney cancer, says Schonfeld, who underwent surgery for kidney cancer himselffour years ago and who presented FDAwith evidence in support of the treatmentat various points along the road to approval.

In 1990, the agency concluded evaluation of data submitted by the manufacturer, Cetus Oncology of Emeryville,Calif., from several clinical trials, including a total of 106 kidney cancer patientswho received the proposed regimen ofinterleukin-2. Although results lookedpromising, the agency requested more information. The number of favorable re

sponses was small, most occurred in onemedical center, and toxicity was substantial. This made it difficult to judge thevalue of the therapy.

By 1992. Cetus had submitted morecases, showing "significant clinical benefitin a minority of 255 patients," accordingto Richard Fisher, professor at LoyolaUniversity Medical School in Chicago,who presented the data at an FDA meeting. Fifteen percent of the patients showeda partial response (tumor shrinkage), and4 percent showed a complete response (nosign of tumor)—but 4 percent died fromthe treatment.

Controlling Side EffectsSide effects seem to be part and parcel

of taking lL-2. The patient brochure fromthe manufacturer says that eveiyone hassome side effects, but the nature and severity vary. Nearly eveiyone experiencesfever, shaking and chills shortly after receiving the first dose. This is an expectedresponse to the body's receiving a hugedose of interleukin-2, which is normallypresent in the body in only very smalla m o u n t s .

Other side effects stem from a phenom-

A i s n o w t h e

state-of-the-art, con

ventional treatment for

advanced kidney can

cer that has spread.

enon called "capillary leak syndrome."Capillaries are microscopic blood vessels,their walls only a single cell thick, joinedlike bathroom tile and folded to form tinytubules. lL-2 causes the fluid portion ofblood to leak from inside capillaries to thetissue spaces outside, the areas betweenorgans. This both robs organs of theirblood supply, and swells the body. As aresult, the patient gains weight and haslower blood pressure, kidney strain, andrespiratory distress.

Patients usually require fluids and drugsto support their blood pressure and occasionally require dialysis or mechanicalventilation (machines to assist kidneys andlungs). They may also experience neurological changes such as mood alteration,lethargy, agitation, coma, or seizures. Fortunately, lL-2 toxicities usually clear upwithin a few days after IL-2 treatmentstops, although fatigue may linger for afew weeks.

H o w I L - 2 W o r k sResearchers still aren't sure precisely

how lL-2 combats kidney cancer, becauseits role in the immune system is quitecomplex.

lL-2 is a cytokine, a hormone-like substance secreted by the cellular branch ofthe immune sy.stem, which also includes Tlymphocytes, or T cells. (The otherbranch, the humoral immune system, includes B lymphocytes, or B cells, and theirsecreted substances, antibodies.) There are

many different types of cytokines, whichinteract together, so teasing apart the roleof just one is difficult.

Birth of a TherapyIL-2 was discovered in 1976 and de

scribed as a protein that supports thegrowth of certain T cells in culture. In1983, researchers identified the gene encoding lL-2, making it possible to mass-produce the protein in genetically engineered bacteria, a technology that avoidsthe contamination that can happen whenbiological substances are collected fromhuman donors and increases productivecapacity.

Between 1984 and 1986 came the

groundbreaking work that placed lL-2 onthe pathway to clinical use. Steven A.Rosenberg, M.D., and his colleagues at theNational Cancer Institute showed that

lL-2, given to mice either alone or withthe lymphocytes that they stimulate (calledlymphokine-activated killer cells, or LAKcells), shrunk tumors that had spread tothe lungs, liver and skin. (The effect oflL-2 on tumors was not direct. Instead, the

lymphocytes, whose numbers they in-crea.se, attack the tumor.) So spectacularwere the results of lL-2 on mice that phase1 clinical trials began in 1984 and 1985 inpatients with advanced cancer who hadexhausted existing treatments. These trialsestablished safety and the maximum tolerable dose of lL-2.

A 1987 study by Rosenberg comparedlL-2 alone to lL-2 given with LAK cells.The cells were removed from the patients,cultured with lL-2 in the laboratory, andthen injected into the patients. For kidneycancer, there appeared to be little or nodifference in receiving lL-2 alone or withL A K c e l l s .

Refining IL-2 TherapyThe story of lL-2 is still in its opening

chapter. Researchers are attempting totame the toxicities so that the cancer-fighting effects can be brought to more pat i e n t s .

"The FDA approval is for the high-dose

26/April 1994/FDA Consumer

regimen, which is very toxic," says JaySiege!, acting director of the division ofclinical trials at FDA's Center for

Biologies Evaluation and Research. "Wehad considerable concerns. How shouldIL-2 be given—subcutaneously or intravenously? Intermittently or continuously?There were a range of trials, and a lot waslooked at." The approval was for a high-dose regimen, Siegel adds, because thelargest experience was with the high-doseregimen and the available data suggestedthat response rates were considerablylower at lower doses.

Physicians around the world are nowexperimenting with variations on the high-dose theme of IL-2 therapy. Many physicians, say McDonald and Schonfeld, aregiving patients lower doses than that approved by FDA, which is legal. "Morephysicians are giving IL-2 in moderate-dose protocols. This has made it a lot moreaccessible—people who couldn't toleratethe high-dose regimen are getting low-dose IL-2, and some are benefiting," saysSchonfeld.

However, Siegel points out that littledata documenting an effect at lower doseshas been reported to FDA.

But lower-dose IL-2 protocols can begiven on an outpatient basis. The approved high-dose plan requires hospitalization, usually in a cancer unit, but sometimes in intensive care if side effects are

severe. Jerome Ritz and co-workers at theDana-Farber Cancer Institute in Bostonconducted a phase I clinical trial in which21 kidney cancer patients received IL-2 asoutpatients for three months. The researchers noted minimal toxicity and anincrease in the number of a certain type oflymphocyte in the patients' blood, concluding, "therapy with low-dose IL-2 canbe given safely in an uninterrupted fashionfor prolonged periods of time in an outpatient setting." A phase II trial will evaluatewhether outpatient IL-2 therapy shrinkst u m o r s .

What about altering the rate at whichIL-2 enters the body? The Extramural IL-2/LAK Working Group at the University

1̂atients taking IL-2usually require fluids

and drugs to support

their blood pressure.

of Texas Health Science Center in SanAntonio compared IL-2 given in three injections daily to continuous infusion.Would a continuous supply of the toxictreatment be more tolerable? It wasn't.Data from studies submitted to FDA indi

cated that patients receiving the continuous infusion regimen had comparable sideeffects but fewer responses to treatmentthan those on a three-times-a-day regimen.

Similarly, a large group of investigatorsled by Michael B. Atkins at the New England Medical Center in Boston suspectedthat combining IL-2 with anothercytokine, alpha interferon, might be moreeffective, because interferon attacks cancer cells differently than does IL-2. ButIL-2 alone was more effective, with a 17

percent response rate, compared to only11 percent for the combined cytokineapproach.

Other ApproachesIn another approach, researchers at the

Surgery Branch of the National Cancer Institute are combining IL-2 with whiteblood cells called "tumor infiltrating lymphocytes," or TILs. These cells are foundwithin a specific tumor, and theoreticallyfight only that tumor. They are not thesame as LAK cells, which circulate in theblood and have a much more generaleffect. TILs are up to 100 times more effective than LAK cells in killing certaint u m o r c e l l s .

NCI researchers reported in the Novem

ber 1992 issue of Contemporaiy Urologxthat they are developing a "tumorreimplantation protocol." When the cancerous kidney is removed, a small piece ofit will be implanted underneath the skin ofthe patient's thigh. (The skin is a site of intense immune system activity.) Threeweeks later, the researchers will collect

lymphocytes from a lymph node near thetumor implant. They will separate out thetumor-specific TILs, grow them to largernumbers in the laboratory using IL-2, andthen reinfuse them into the patients. Thehope: that the nurtured and boosted TILswill seek and destroy any remaining cancer cells in the body, while the implantedbit of tumor continues to alert the immune

system.Yet another approach is to add IL-2

genes to TILs in the lab, so that they maketheir own IL-2 when reintroduced into the

body.In the February 1992 issue of the Jour

nal of Urology, German researchers EdithHuland, M.D., and colleagues reported onadministering IL-2 more directly—byaerosol in a device similar to those thatdeliver asthma medication—to patientswhose kidney cancer has spread to thelungs.

"They apply IL-2 directly to lung tumors, where it activates TILs locally thatare the most sensitive to the tumor because

they are already there," says Schonfeld.Clinical trials of this approach in theUnited States have just begun, he adds.

With a demonstrated ability to treat anuntreatable cancer and many new variations in the works, IL-2 therapy for advanced kidney cancer has begun to showi t s v a l u e .

Concludes Schonfeld, who may one dayundergo the treatment himself for his kidney cancer, "When IL-2 works, it reallyworks well. Some of our members withadvanced disease in both lungs had a totalresponse—they've walked away, afterIL-2 treatment, cancer free." ■

Ricki Lewis is the author of college textbooks on biology and human genetics.

FDA Consumer/April 1994/27

N o t e b o o k

The Notebook: a potpourri of items of interest gathered from FDA news releases,other news sources, and the Federal Register (designated PR, with date of publication). The Federal Register is available inmany public libraries.

m Decorat ive ceramic ware wi l l soonbear a conspicuous stick-on label statingthat the item is not for food use and that it

may poison food, according to a finalFDA mle effective July 13, 1994. (FR Jan.12)

>o>o>o>o»o>o><y

■ Copies of the revised Food Code arenow available. To order Food Code: 1993Recommendations of the United StatesPublic Health Sendee and Food and DrugAdministration, call the National Technical Information Service at (703) 487-4650. Request PB94-501285/AS for diskettes ($17.50 each) or FB94-113941/ASfor spiral-bound printed copies ($23each). (FR Jan. 28)

■ In vitro diagnostics guidelines are nowavailable from FDA. "Guideline for theManufacture of In Vitro Diagnostic Products" identifies acceptable practices forensuring in vitro diagnostic products'safety and effectiveness. For a free copy,request docket number 88D-0087 fromDivision of Small Manufacturers Assistance (HFZ-220), FDA, 5600 FishersLane, Rockville, MD 20857; telephone(1-800) 638-2041. or (301) 443-6597. (FRJan. 10)

■ Toxicology and cancer studies on acetaminophen. furan, o-nitroanisole. andpentachloroanisole toxicology andcarcinogenesis studies are available fromthe National Toxicology Program. Acetaminophen is a common pain reliever;furan is used in packaging laminated surfaces that contact food; o-nitroanisole isused in making dyes; and pentachloroanisole is a chlorine compound widelyfound in the environment. Free copies areavailable from Central Data Management.NIEHS. MD AO-01. P.O. Box 12233, Research Triangle Park, NC 27709; telephone (919) 541-3419. (FR Jan. 14)

■ "Dubby" pacifier thermometers havebeen recalled by M.J. Harris and Associates, according to the Consumer ProductSafety Commission. During testing, thenipples separated from the pacifiers' base,posing a choking hazard. The pacifiersshould be returned to the store where purchased. For additional information, callM.J. Harris at (1 -800) 531 -5486.

■ Award entries for the 12th annual HHS

Secretary's Award for Innovations inHealth Promotion and Disease Prevention

are being accepted from undergraduateand graduate students of the health professions until April 19. First prize is $5,000.For more information, contact the dean orhead of the program at your academic institution. (Public Health Reports, November-December 1993)

■ "Health, United States, 1992" reportscontinuing progress against chronic disease and premature death but seriousshortcomings in progress toward manyhealth goals, according to the NationalCenter for Health Statistics. Copies areavailable from the Superintendent ofDocuments, U.S. Government PrintingOffice, Washington, DC 20402, for $29(stock no. 017-022-01218-9). (PublicHealth Reports, November-December1993)

■ May meetings of health-care organizations include:• American Associat ion for Retired Per

sons, May 3-5 in Anaheim. Calif; call(202) 434-2277• American Associat ion of Cri t ical Care

Nurses. May 9-12 in Atlanta; call (1-800)8 9 9 - 2 2 2 6• American Society of Clinical Oncology,

May 15-17 in Dallas; call (312) 644-0828.

28/April 1994/ FDA Consumer

Investigators' Reports

t

Psychiatrist Sentenced for Research Fraudby John Henkel

A prominent University of Minnesotachild psychiatrist was sentenced to sixmonths in a federal correctional facilityand six months of home detention with

work release for engaging in mail fraudand making false statements in documentsabout clinical studies of the psychiatricdrug Anafranil (clomipramine hydrochloride).

Barry Garfinkel, M.D., former directorof the university's child and adolescentpsychiatry department and a leading teensuicide expert, was free at press timepending appeal. His sentencing last Nov.19 in the U.S. District Court for the District of Minnesota followed conviction on

five felony counts.The court also sentenced Garfinkel to

pay $214,000 in fines and perform 400hours of community service. The jury acquitted him of 18 other charges. Gaifmkelalso could lose his medical license if hisconvictions are upheld.

Gaifmkel, 46, was chief researcher in a$250,000 study begun in 1986 to determine whether Anafranil, an antidepressant, was safe and effective in treatingchildren and adolescents with obsessive-

compulsive disorder (OCD). OCD hasseveral forms, one of which is an obsession with cleanliness that manifests it.selfwith repetitive hand washing or showering.

FDA approved Anafranil for commercial marketing in late 1989, but the agencydid not use Garfinkel's data.

The Swiss-based drug company Ciba-Geigy, which sponsored the drug, chosethe University of Minnesota in 1986 asone of five U.S. sites for the Anafranilstudies. The approved research protocolsfor the study required that patients undergo weekly psychiatric evaluations andbe monitored for benefits and adverse sideeffects of the medication. Patients werenot to take other medications that affectthe central nervous system.

Rather than follow these proceduresstrictly, Garfinkel "established and executed his own research protocols butdidn't tell anybody—not the university,Ciba-Geigy, or FDA—about it," saysMark Brown, associate FDA chief counselwho co-prosecuted the case.

Garfinkel's wrongdoings came to lightin March 1989, when his study coordinator, Michelle Rennie, complained of re

search misconduct to university and Ciba-Geigy officials. Both launched inquiriesright away. The university's investigationfound iiregularities but no intentional misdeeds. But in June 1989, Ciba-Geigy notified FDA that it would not includeGarfinkel's data in its new drug application for Anafranil approval due to problems it found with the university study.

FDA conducted its own investigationfrom January 1990 through May 1991.The probe was delayed because the university refused to share its findings withFDA. The government subsequently obtained these findings through a subpoena.Ultimately, FDA collected an investigative file of more than 10,000 pages. Evidence confirmed widespread misconductin Garfinkel's study.

In mid-1992, the U.S. attorney's officein Minnesota further investigated the caseand led Garfinkel's prosecution.

In court, the govemment's case centeredon the evidence FDA had gathered, suchas patient record forms Garfinkel submitted to Ciba-Geigy falsely representing thathe had followed research protocols. Attrial, the prosecution presented evidencethat in as many as 140 instances, requiredoffice visits and psychiatric evaluationseither did not occur or were conducted byemployees with little or no medical training. For example, Rennie testified thatGarfinkel told her to make up data for theofficial forms and to provide therapy to

FDA Consumer/April 1994/29

Investigators' Reports (continued)

some study participants despite her lack oftraining. Other evidence showed thatGarfmkel sometimes "examined" patientsby having Rennie talk to them over thephone and that he administered medicationprohibited in the study protocols.

Yet Garfmkel signed documentsthroughout the study falsely representingthat he complied with required protocols.

The Garfmkel case "underscores the importance of the federal drug approval system," says FDA's Brown. "The system issupposed to ensure that any new drug issafe and effective before being madeavailable. By falsifying data, Garfmkel undermined the integrity of this system."

In addition to GaiTinkel's appeal, FDAalso is appealing the sentence on the

grounds that the court should have appliedsentencing guidelines more strictly, resulting in a stiffer sentence. Garfmkel couldhave received up to 125 years in prisonhad he been convicted on all 25 counts

originally named in his indictment.

John Henkel is a stajf writer for FDAC o n s u m e r.

Illegal Drug TraffickersR e c e i v e S e n t e n c e

A multi-district FDA investigation ledto the conviction of an Arizona manufacturer and supplier of an unapproved dmgcalled gamma hydroxybutyrate (GHB)and guilty pleas by two of his distributors.A customer of the distributors also

pleaded guilty to misbranding and sellingG H B .

On Nov. 3. 1993, a federal jury in theU.S. district court in Tucson, Ariz., foundMark Thierman, operating as Amino Discounters in Tucson, guilty of manufacturing and distributing GHB. At press time,Thierman awaits sentencing.

Jerald Bloch and Edward Byrd, operating as California Body Club (CBC) in SanFrancisco, had pleaded guilty in May 1991in the U.S. district court in San Franciscoto distributing GHB. Bloch was sentencedto three years' probation and 300 hours ofcommunity service. Byrd was sentencedto six months' home detention and six

years' probation.Jeffrey Dyer, operating as Champion

Distributors in Philadelphia, a customer ofCBC, had pleaded guilty in August 1992to misbranding and selling GHB. He wassentenced in the U.S. District Court for theEastern District of Pennsylvania to 18months' probation, 100 hours of community service, and a $500 fine.

GHB is promoted illegally for strengthtraining, muscle building, weight loss, and

as a replacement for L-tryptophan, a foodsupplement that EDA ordered removedfrom the market in 1989 after it was linkedto a rare blood disorder. GHB is also soldand used as a hallucinogen and a sleep inducer. FDA has not approved the drug formarketing in this country for any use.

FDA first became aware of significanthealth concerns associated with GHB inthe summer of 1990 through reports fromthe California, Florida and Georgia healthdepartments of illness linked to its use.Symptoms ranged from nausea and vomiting to severe respiratory problems, seizures, and coma. FDA alerted all the

agency's district offices to watch for sales.In August, FDA San Francisco investi

gators, working with the Poison ControlCenter of Califomia, found 100-grambottles of GHB (about 3.5 ounces) sellingfor about $35 each at a health food store.The labels showed the distributor as

Biosky Research Group, San Francisco.FDA learned there was no such businessin San Francisco, or elsewhere.

FDA investigators traced the product toCBC and found that the firm was

repacking 100- and 250-gram bottles frombulk quantities of GHB it had purchasedfrom Thierman in Tucson. Bloch received50- to 75-kilogram (110- to 165-pound)drums of GHB at his home and storedthem in a neighbor's garage.

On Nov. 12, Byrd telephoned FDA'sSan Francisco office to ask about the status of GHB. Paul McKim, the district'sdirector of investigations, told Byrd thatGHB was an unapproved new drug andcould not be sold in this country. FDA investigators leai'ned that about that same

time, one of Byrd s customers—a gym inLas Vegas—sent CBC a copy of a Nov. 8EDA press release that infoiTned the public of illicit sales of GHB, and warned ofthe severe side effects associated with its

u s e .

In December, EDA's Philadelphia district learned that an individual was treatedin a hospital emergency room for convulsions suffered after using GHB purchasedfrom a New Britain, Pa., health club. Thehealth club had obtained the GHB from

Dyer. EDA traced Dyer's supply to Califomia and to an order CBC placed with achemical manufacturer in North Carolina.

On Jan. 14, 1991, EDA again warnedByrd about his illegal sales of GHB. ButCBC continued to order more than 500kilograms of the drug.

FDA set up surveillance of Bloch'shome, and on Jan. 25, when Bloch signedfor a delivery of GHB, he was .served witha warrant to search the house. FDA foundand seized a small amount of GHB andfound a copy of FDA's Nov. 8 press release about the drug.

The grand jury returned criminal indictments against Thierman. Bloch and Byrd.and the Department of Justice filed acriminal information against Dyer.

Bloch and Byrd pleaded guilty to twofelony counts of distributing GHB with intent to defraud and mislead, and to aidingand abetting in the commission of a crimin a l a c t .

Dyer pleaded guilty to one count ofcausing the misbranding of GHB after re-

30/April 1994/FDA Consumer

ceipt in interstate commerce, and onecount of shipping GHB without an approved new drug application.

Thierman was tried and found guilty oftwo felony counts of con.spiracy to manufacture. promote and distribute GHB. andone count of distributing GHB. He wasconvicted of charges in two separate indictments. The first indictment chargedthat from December 1989 through March1991. Thierman conspired with others tomanufacture GHB in secret laboratories inTucson and sold the drug, labeledSomatomax PM, to health food stores andbody builders throughout the UnitedStates.

Evidence at the trial showed that beginning May 1991. after the first indictment.Thierman again manufactured GHB forcommercial distribution in another secret

laboratory. An explosion in the laboratoryduring manufacture of the drug caused aworker to suffer third-degree bums. A fewmonths after the explosion, Thiermanopened yet another secret laboratory tomake GHB. and that facility also explodedand burned another worker.—Judith E. Foiilke

Chicago Area Firm ClosesAfter Failing to Meet GMPs

A Chicago drug company stopped operating after it failed to comply with government manufacturing requirements.

Esquire Pharmaceuticals, Westmont,III, closed in June 1993 after repeatedlyfailing to meet FDA's good manufacturingpractices (GMPs). Esquire manufactured avariety of prescription and over-the-counter (OTC) products, including liquidcold medicines, antihistamines, and vita

mins. About 25 percent of the firm's products were for infants and children.

FDA first inspected Esquire in 1988.when the firm registered with the agencyto produce dmg products.

"Our first inspection was fairly limitedbecau.se the firm was new and reallyhadn't started to manufacture its full product line." said FDA Chicago district compliance officer Stephen Eich.

"The inspection found several deviations from good manufacturing practices,including failure to validate their watersystem—to test water samples to makesure there are no contaminants. However,

there wasn't enough activity in the firm towarrant any formal action." he said.

In October and November. 1990. FDA

again inspected the firm, which by thenwas manufacturing and marketing a largenumber of prescription and OTC products.

Again, investigators found that the firmhad not validated its water system. Theyalso found that the firm:• released products for sale that did notmeet their own product specifications• failed to test incoming raw materials• failed to perform annual reviews• used inappropriate laboratory tests toanalyze finished products.

FDA's GMP regulations include requirements that drug manufacturers: testincoming raw materials to ensure therehave been no changes during shipment; review annually all production and operating records for each product to evaluate

trends that may not be apparent from individual batch records; and analyze eachcomponent of a completed product to ensure the drug has been manufactured properly.

In April 1991, FDA sent Esquire a regulatory letter outlining the firm's GMP violations. The firm responded with its plansto correct the problems.

But many of the same problems werestill apparent when FDA investigatorsreinspected the firm from Dec. 16. 1991.to Feb. 11. 1992.

"The inspectors also found significantproblems with the firm's weighing operations. Their batch records and the weightsthey recorded didn't always agree withweighing records." Eich said.

For example, the weighing record forone lot of Multi "Vita Drops with Fluoride,an infant vitamin formula, showed the

weight of the niacinamide as 215 grams(7.5 oz.), whereas the master formulacalled for 5.25 kilograms (11.5 lbs.) ofn i a c i n a m i d e .

"With a factor like that." Eich said, "a

drug could be there at 10 percent when anormal dosage is 0.1 to 1 percent or viceversa. That is a really scary problem."

In addition, inspectors learned that inMay 1991 the firm used water contaminated with E. coli and other unidentifiedcoliform bacteria in the manufacture of thefinished product. "They tested it and thenreleased their products saying that, withthe preservatives, the bacteria didn't represent a danger to the product or user." Eichs a i d .

The finn also had problems with thepackaging of some products. Specifically,the antihistamine Alledryl Elixir was being packaged in clear plastic bottles. Itshould be packaged in an opaque plasticbottle that keeps out light, because the ac-

FDA Consumer/April 1994 / 31

Investigators' Reports (continued)

live ingredient, diphenhydramine hydrochloride, is unstable and quickly degradesin light.

"Some of the Alledryl samples showedsevere degradation." Eich said.

As a result of these findings, the Chicago district recommended a mass seizureof all the firm's liquid products, and onJune 8, 1992, at FDA's request, the U.S.attorney filed a complaint for forfeiture inthe U.S. District Court for the NorthernDistrict of Illinois. The next day, U.S.marshals seized approximately 240,000units of liquid drug products estimated tobe worth $225,000.

On Oct. 23, 1992, Esquire signed a consent decree that required the firm to eithershow the products were manufacturedproperly, recondition them, or destroythem.

"Esquire attempted to show the products were manufactured in compliancewith GMPs and that they should be released," Eich said.

But, given the firm's many problems,FDA refused the proposal, and on May 5Esquire destroyed the products.

As part of the consent decree, FDA conducted a follow-up inspection of the firmfrom Jan. 25 to 28, 1993. Investigatorsfound that the firm had dismantled itswater system and stopped manufacturingall liquid drug products.

Esquire was not permitted to sell anyproducts until it proved it was in compliance with GMPs. Compliance could notbe demonstrated, since the firm hadstopped manufacturing.

In June 1993, FDA again tried to inspect the firm, but it still was not operating. At press time it remained closed.

FDA has no reports of injury or illnessresulting from use of the firm's products.—Kevin L. Ropp

Manufacturer Pays First FineUnder Safe Medical Devices Act

A Massachusetts medical device manu

facturer recently paid a $290,000 fine formarketing an unapproved product. Thecivil money penalty was the first imposedby FDA under the Safe Medical DevicesAct of 1990.

Infusaid, Inc., of Norwood, Mass., adivision of Pfizer Ho.spital ProductsGroup, agreed Nov. 23, 1993, to pay thefine imposed for distributing an unapproved implantable drug infusion pump.The firm also failed to manufacture the device according to good manufacturingpractice (GMP) regulations. Infusaidagreed to pay the fine without admittingliability, wrongdoing or illegal conduct.

FDA uncovered problems with the device when the agency's Boston district office inspected the firm in January 1992 tocollect information on a recall of its Model400 infusion pumps, which the firm hadinitiated the previous month. Infusaid hadordered the recall after receiving 10 complaints that the device leaked.

"Implanted infusion pumps are designedto deliver medicine, such as insulin, heparin, or anti-cancer drugs, at a prescribedrate," explains Boston district complianceofficer Karen Archdeacon. "Leaking couldcause too much of the drug in the pump'sreservoir to be delivered, possibly endangering health."

Adverse effects would vary dependingon the drug. Archdeacon says. For example, leakage of chemotherapy drugscould cause nausea and vomiting; toomuch morphine could cause oversedationand respiratory depression; and an overdose of the blood thinner heparin couldcause hemorrhaging, leading to stroke, severe bleeding, and possibly death.

During the January inspection, investigator David Elder discovered that Infusaidhad modified the design and material usedin manufacturing the infusion pump the

agency had originally approved in 1982.Modifications that affect a product'ssafety and effectiveness must be approvedby FDA before the device can be marketed. Infusaid did file a pre-market approval (PMA) supplement, as required, onDec. 21, 1988, but it shipped numerouspumps before receiving approval inAugust 1989.

Elder also found during the inspectionthat Infusaid did not specify in its supplement that the material used to manufacture

the septum of the device had beenchanged, nor did the company test themodified device to validate its safety andeffectiveness, as is required under GMPregulations.

"The pump is about the size of aperson's palm," says Archdeacon. "Theseptum is the area on the pump you accessthrough the skin to fill the drug reservoir.Infusaid included in the PMA supplementsome of the changes they made—for example, that they increased the surfacearea—but they didn't specify that theychanged the material and durometer value[measure of hardness] of the pump."

Elder notified Infusaid's vice presidentof regulatory and clinical affairs of hisfindings when he completed the inspectionon Jan. 15.

On Dec. 4, 1992, the Boston office recommended to FDA's Center for Devicesand Radiological Health that Infusaid paya fine for the violations, noting that thefirm "should not have shipped their newlydesigned infusion pumps before agencyapproval, should have notified the agencyof a change in the septum material, andshould have validated the design and material to assure that these changes did notaffect the safety or efficacy of the device."

On Dec. 21, the Center for Devices andRadiological Health approved the recommendation, and in November 1993Infusaid signed a consent agreement topay the civil penalty.—Joseph Raulinitis

32 / April 1994 / FDA Consumer

Summaries of Court Actions

%

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

Food/Contamination, Spoilage, Insanitary Handling

PRODUCT; Crabs, cooked, frozen, at Portland, Dist. Ore.; CivilNo, 93-95-BE.CHARGED 1-25-93: While held for sale, the ailicle contained adecomposed substance or was otherwise unfit for food because itwas rancid—4()2(a)(3).DISPOSITION: A con,sent decree of condemnat ion ordered thearticle destroyed except that Point Adams Packing Co.. Portland.Ore., was authorized to take post-seizure samples of the article forpossible evidentiary uses in support of the firm's claims. (F.D.C. No.66652; S. No. 93-667-723; S.J. No. 1)

PRODUCT: Olives, stuffed, brined, in bulk drums, at Chicago. N.Dist. 111.; Civil No. 91-C-1400.CHARGED 3-7-91: While held for sale, the article was unfit for

f ood^02 (a ) (3 ) .DISPOSITION: The article was claimed by Bob Gordon & Assoc..Ltd., Chicago. 111., who denied the charge. Upon the claimant'smotion, the court authorized additional testing of the stuffed greenolives and provided for maintaining proper pH levels of the articlepending final determination of this action. The government movedfor summary judgment. Subsequently, the claimant moved forsummary judgment. The court noted that FDA analysis revealed thepresence of yeast in all six subsamples of the olives and that the FDAanalyst stated that the stuffing cavity in some olives contained yeast.The claimant did not contest the findings of the presence of yeast, butasserted that yeast was normal and naturally occurring in thisproduct and was harmless when proper pH levels were maintained,as in this case. In contrast to when the olives were received and storedin bulk drums, the product sold to consumers was washed, rinsed,repacked, and "re-brined." The court reviewed the conflictingassertions of the govemment's and the claimant's experts, andvisually inspected ajar of the .seized olives provided by the claimant.

The court stated that it could not confirm the conclusions reached

by either-party regarding the flavor of the olives, and that whether theolives were "unfit for food" remained a triable issue of fact. Thecourt denied both summary judgment motions, stating that a benchtrial would be held to resolve the issue of the fitness of the olives.Subsequently, a consent decree condemned the article and authorized its release to the claimant for bringing into compliance with thelaw. (F.D.C. No. 66056; S. No. 91-576-677; S.J. No. 2)

PRODUCT: Tomatoes, peeled, canned, at Perth Amboy, Dist.N.J.; Civil No. 93-693 (HAA).CHARGED 2-18-93: When shipped by Federation WarehousingCorp., Brooklyn, N.Y., the aiticle (which consisted of commingledcans labeled either "Hellas. . .Plum Style Tomatoes. . .Distributedby Aliments Hellas Inc., Montreal Canada . . . Packed By: R.S.I.A.... Product of Spain" or "Heritage . . .Peeled Plum Style Tomatoes

. .. Prepared For . . . Aliments Heritage Foods Inc. . . . Montreal,Quebec. Canada . .. R.S.I. A. Product of Spain") was unfit for fooddue to swollen cans evidencing de-tinning and hydrogen ga.s—402(a)(3); and the article's labels lacked an accurate quantity ofcontents statement in terms of weight.DISPOSITION: Default—ordered destroyed. (F.D.C. No. 66664;S. No. 92-643-324; S.J. No. 3)

A n i m a l F o o d

PRODUCT: Tuna cbunks, canned, at Tampa. M. Dist. Fla.; CivilN o . 9 2 - 6 8 5 - C i v - T- 1 5 B .CHARGED 5-22-92 : Wh i le he ld fo r sa le , the a r t i c le con ta ined

decomposed tuna fish—402(a)(3); the article was pet food relabeledas human food, thus concealing its inferiority—402(b)(3); and thearticle was offered for sale under the name of another food—403(b).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 66437;S. No. 92-556-042 et ah; S.J. No. 4)

Drugs/Human Use

PRODUCT: Nitroas oxide, U.S.P., in bulk tanks and bigb-pressure cylinders, at Grand Rapids. W. Dist. Micb.; Civil No. 1:93CV 88.CHARGED 2-3-93: While held by Grand Rapids Welding SupplyCo.. Grand Rapids. Mich., the circumstances used for the manufacture. processing and holding of the article failed to conform withCLin-ent good manufacturing practice—501(a)(2)(B).DISPOSITION: A consent decree authorized release of the articlesto the dealer for bringing into compliance. In addition, the consentdecree provided that the claimant should not fill or pack nitrousoxide or other ga.ses for medical use unless and until the claimant'sfacility and records had been inspected and the claimant had beennotified that its operations appeared to be in compliance. Similarly,if within five years the claimant was advised that any articles ofmedical gas processed or held at any of the claimant's facilities wasadulterated as above, the claimant was to discontinue all suchoperations. Subsequently, the .seized articles were brought intocompliance, the fimi was inspected by FDA, and the firm wasauthorized to resume normal operations. (F.D.C. No. 66634; S. Nos.92-596-608/9; S.J. No. 5)

PRODUCT: Oxygen, U.S.P., at Rochester, W. Dist. N.Y.; Civil No.9 3 - C V- 6 1 0 6 - L .CHARGED 3-11 -93: While held by RochesterTherapy Service Co.(Edward L. McCarthy), Rochester, N.Y., the circumstances used forthe manufacture, processing, packing, and holding of the articlefailed to confomi with cument good manufacturing practice—501(a)(2)(B).DISPOSITION: Consent—authorized release to Edward L.McCarthy, Rochester, N.Y., for salvaging. (F.D.C. No. 66665; S.No. 93-672-387; S.J. No. 6)

FDA Consumer/April 1994/33

Summaries of Court Actions (continued)

Drugs/Veterinary Use

PRODUCT: Polyvinyl pyrrolidone iodine boluses, at Hanford, E.Dist. Calif.; Civil No. F-93-5072-OWW.CHARGED 2-8-93: While held by Veterinary Fhannaceuticals,Inc., Hanford, Calif., the article's labeling lacked adequate directions for the dealer's intended uses (metritis in lactating dairycows)—502(f)(1); and the article was not included in a requiredlisting—502(o).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 66650;S.No. 92-664-111; S.J. No. 7)

M e d i c a l D e v i c e s

PRODUCT: Elekiban adhesive magnetic disc, at Amherst, W.Dist. N.Y.; Civil No.91-242S.CHARGED 4-11-91: The article (which bore labeling such as"Elekiban . . . Rel ieves St i f f Muscles and Tension . . . Adhesive

Magnetic Disc.. .Manufactured by Pip-Fujimoto Co., Ltd., Osaka,Japan ... Imported by Unic International Corp., Toronto. Buffalo.Los Angeles, London") was a class III device, and no approval of apre-market approval application was in effect—501(0(1)(B); thelabeling of the article contained false and misleading claims forimproving circulation, for relieving sore, painful and aching muscles,for providing such relief for three to seven days, and for beingapproved by FDA—502(a); the labeling for the device lackedadequate directions for the intended uses—502(f)( 1); and the articlewas not listed as required—502(o).DISPOSITION: The article was claimed by Physio Meditec Corp.,Amherst. N.Y., who denied the charges and as affirmative defensesasserted that the charges were barred because the govemment hadfailed and refused to review the article's classification and becausethe claimant had voluntarily suspended sale and promotion of thearticle. The claimant served discovery requests on the govemment.The govemment served written interrogatories and requests foradmissions and for the production of documents on the claimant.Subsequently, the parties agreed to the forfeiture of the article andto an order disposing of the article in accordance with law. Pursuantto such order, the article was destroyed. (F.D.C. No. 66045; S. No.90-602-967; S.J. No. 8)

PRODUCT: Glutaraldebyde-based cold sterilizers and disinfectants for medical devices, and their components, at Parker, Dist.Colo.; Civil No. 91-B-2019.CHARGED 11-19-91: The articles, which were held by the manufacturer Metrex Research Corp., Parker, Colo., had not had pre-market notification submitted prior to marketing as required bysection 510(k) of the statute and by specified regulations—502(o).DISPOSITION: The articles were claimed by Metrex ResearchCorp., Parker, Colo., who denied the charge and stated that a 510(k)application had been filed with FDA. The claimant served requestsfor admissions on the govemment. The claimant filed a motion foran order to show cause for the release and/or pemiission to sell itssterilizer/disinfectant products. The claimant also filed a motion todismiss the action. The govemment opposed such motions, .statingthat FDA had notified the claimant that its 510(k) submission was"on hold" and that FDA had wamed against shipment of the

34/April 1994/ FDA Consumer

products. The claimant also requested an immediate trial and movedto shorten the response time for discovery.

At a hearing on the claimant's motion to dismiss, the courtconverted the motion into a motion for summary judgment andgranted the claimant summary judgment, stating that a 510(k)submission had been filed by the claimant, that the court did not readthe statute to require FDA approval of the 510(k) prior to marketingin this case, and that, as the complaint was drafted, there was nogenuine issue of material fact that the articles were not misbranded.Having dismissed the action and having denied the government'soral motion to amend the complaint to allege another charge, thecourt indicated that the govemment might refile the complaint.However, in the court's written order of judgment, the court orderedthe action and complaint dismissed with prejudice.

The govemment moved that the court amend its order to providethat the complaint be dismissed without prejudice. The court deniedthe govemment's motion to amend, stating that the court's benchruling and the written order of judgment dismissing the action withprejudice did not conflict. In addition, even if they conflicted, thewritten order superseded the prior comments from the bench.(F.D.C. No. 66179; S. No. 91-474-598 et ah; S.J. No. 9)

PRODUCT: Ultratherm fluid warmer. Model 3703-1, atChanhassen, Dist. Minn.; Civil No. 4-93-230.CHARGED 3-4-93: The article (which was manufactured by PMTCorp., Chanhassen, Minn., and was intended for use to warm blood,plasma and other fluids prior to infusion into the human body, andwhich had had significant changes in the design that increased itsmaximum temperatures) was a class III device, and no approvedapplication for pre-market approval was in effect—501(f)(1)(B);the circumstances used for the article's manufacture, packing andstorage failed to confomi with current good manufacturing practice—501 (h); the article's labeling lacked adequate directions for itsintended uses—502(f)(1); and required information respecting thearticle had not been submitted—502(o).DISPOSITION: Default—ordered destroyed. (F.D.C. No. 66678;S.No. 93-657-122; S.J. No. 10)

C R I M I N A L A C T I O N S

DEFENDANTS: Javid Naghdi (also known as David Naghdi.Gregorio Reynolds. Khukon Reynolds, and Dr. Behrouz Mansouri);two criminal actions, at Los Angeles. C. Dist. Calif, and San Diego,S. Dist. Calif.; Criminal Nos. 87-0368-K and 88-0768-X.CHARGED 4-28-87 by grand jury in Los Angeles action: Conspiracy to traffic in goods with counterfeit trademarks, to ship amisbranded diaig, to make and keep a punch, die, plate, and otherthings to reproduce the trademark for Naprosyn and Syntex. to usesuch things to create a counterfeit drug, and, with intent to defraud,to cause a diug to be a counterfeit drug, and to cause the sale,dispensing and holding of such counterfeit dmg. In furtherance ofthe conspiracy, various overt acts were committed, including thefollowing: receiving 150,000 acetaminophen tablets and 75,000aspirin tablets, transferring to an interested purchaser approximately275 bottles of counterfeit "Naprosyn," which were explained to behospital overstock, ordering and receiving 50 100-kg barrels ofacetaminophen, asking a printer for a bid for reproducing 10.000

copies of a "Naprosyn" carton, ordering 12,600 500-cc amberbottles, picidng up 10,000 bottle liners, and selling 205 500-tabletbottles of counterfeit drug to a medical supply firm—18 U.S.C. 371.

In addition to the conspiracy charge, with intent to defraud andmislead and without authorization from Syntex (U.S.A.), Inc.,approximately 1,200 500-tablet bottles of aspirin, acetaminophen,and other compounds that had not been manufactured by Syntexwere manufactured, packaged with labeling, and hou.sed in cartonsthat bore the trademark, trade name, and other marks of Naprosyn375 mg. thereby falsely representing the tablets to be Naprosyn 375mg—30I(i)(3). There was intentional trafficking in counterfeitgoods and knowing u.se of counterfeit marks (i.e., "Syntex.""Naprosyn" and the Syntex logo) on bottles, cartons and inseitspertaining to a 172-bottle sale of drugs—18 U.S.C. 2320. Withintent to defraud and mislead. 172 bottles of counterfeit drugs weresold bearing identifying marks of Naprosyn 375 mg. thereby falselyrepresenting such drugs to be genuine Naprosyn 375 mg. when infact such bottles contained no Naprosyn at all—303(i)(3).DISPOSITION of Los Angeles action: Guilty plea—impri.sonmentfor 13 years and probation for five years.CHARGED 9-23-88 in San Diego action: That there was a .schemeto defraud potential purchasers of prescription pharmaceuticals bymeans of false and fraudulent pretenses regarding the manufacture,sale and distribution of counterfeit drugs (e.g., counterfeit Tagamettablets, counterfeit Anspor capsules, and counterfeit Naprosyntablets); part of which scheme involved an insurance policy andother documents indicating that specified drugs were being insuredfor $579 million, were being stored in a bonded warehou.se inTampico, Mexico, and were legally owned by Naghdi International;other parts of which scheme included involvement in some of thefollowing: a contract with Naghdi International to purchase 8million bottles of such drugs, a meeting in London. England,regarding such contract, the use of forged and fraudulent certificatesof drug origin (prepared on fake letterheads, and containing logos,lot numbers, and expiration dates), a contract to sell 1 million bottlesof Tagamet and to pay $27 million upon receipt of the Tagamet inTampico, Mexico; and that, for the purpose of executing the schemeto defraud, a number of specified telephone calls were madebetween Javid Naghdi in England and a government agent inCali fornia—18 U.S.C. 1343.DISPOSITION of San Diego action: The defendant (having beenextradited from England) pleaded not guilty and moved to tran.sferthe action to the Central District of California and moved to have thecase declared to be complex. The motion to transfer was denied, butthe motion to declare the case to be complex was granted. Thedefendant also moved to dismiss the indictment, to dismiss a numberof specified counts, to suppress statements and evidence (includingstatements and evidence obtained at the time of his airest in a hotelroom in London), and for further discovery.

The defendant notified the government that he intended to rely onpublic authority as a defense, and he sought to subpoena variouswitnesses and documents, including various government officialsand CIA files concerning arms shipments to foreign nations. However, such request appeared to be too broad. For trial purposes, thegovernment agreed to narrow the case to nine counts of wire fraudpredicated upon phone calls between the defendant and one govem-ment agent. After a number of hearings regarding the defendant's

subpoenas requesting witnesses that could involve the disclosure ofclassified information, the requests for such witnesses were denied.

The case came on for trial before court and jury. After four weeksof trial, the jury returned a verdict of guilty on the nine counts. Thedefendant was .sentenced to imprisonment for 14 years, to be servedconsecutively to the sentence in the initial case. (Misc. No. 932; S.J.No. 11)

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

DEFENDANTS: Medical Concepts, Inc., t/a American MedicalProducts, and Joseph R. Cottone Jr., manager, and Bill F. O'Ryan,owner and financial officer. Caitersville. N. Dist. Ga.; Givil No.4 : 9 3 - C V- O O I 4 - H L M .CHARGED 1-20-93 in a complaint for injunction: That the defendants manufactured, processed, packed, labeled, stored, and distributed in interstate commerce various medical devices, includingsterile equipment covers used to maintain a sterile field duringinvasive cardiac surgical procedures. The circumstances used forthe manufacture, packing and storage of such devices failed toconform with current good manufacturing practice—501(h); suchdevices had been prepared, packed and held under insanitary conditions whereby they may have been contaminated with filth or mayhave been rendered injurious to health because they were notsterile—501 (a)(2)(B); the purity or quality of the devices fell belowtheir purported purity/quality, because the devices were labeled"sterile," when, in fact, they had not been subjected to an adequatesterilization process—501(c); the labeling of the devices had thefalse and misleading claim "sterile"—502(a); and the articles weredangerous to health when used as directed, since the articles had notbeen subjected to an adequate sterilization process—502(j). FDAinspection revealed numerous violations of good manufacturingpractice, as well as rodent pellets in the firm's warehouse, and thedistribution of approximately 4,440 surgical equipment coverslabeled as sterile but which had not been subjected to a sterilizationprocess. The government believed that, unless restrained by thecourt, the defendants would continue such violations.DISPOSITION: A consent decree of permanent injunction enjoinedthe complained-of violations. The defendants were also enjoinedfrom shipping in interstate commerce any of their devices and fromprocessing any device at their facilities unless and until a number ofspecified conditions had been met, including the following: establishment of current good manufacturing practice; certification by anexpert that the defendants' facilities were in conformity with currentgood manufacturing practice; examination of all devices under thedefendants' control; analysis of those devices necessary to ensurethat the devices were not adulterated; and institution of all-necessaryrecalls of specified devices.

In addition to the above provisions, the defendants were to beagain enjoined to immediately cease operations if. based on theresults of any subsequent inspection and/or the analysis of samples.FDA notified the defendants that the circumstances for their manufacturing. packing and storing of devices were not in substantialcompliance with good manufacturing practice. Although FDA hadoccasion to invoke the latter provision, a subsequent notice authorized resumption of operations contingent on several specifiedfactors. (Inj. No. 1307; S. No. 92-601-971; S.J. No. 12)

FDA Consumer/April 1994 / 35

Summaries of Court Actions (continued)

DEFENDANTS; Orentreich Medical Group (a partnership), andNorman Orentreich, M.D., Michael A. Kalman, M.D., andDavid S. Orentreich, M.D., New York, S. Dist. N.Y.; Civil No. 92Civ 1468(TPG).CHARGED 3-10-92 in a complaint for injunction: The defendantsobtained, used, administered, processed, manufactured, and promoted liquid injectable silicone at their New York city offices; theyheated, filtered and further processed liquid silicone; and theyinjected such silicone into the faces of their clients to treat facialaberrations, such as wrinkles and acne scars. Such silicone is adevice—201(h)—that is classified as a class III device; and such adevice may not be used unless an application for pre-marketapproval (PMA) has been approved or unless an investigationaldevice exemption is in effect. Neither an approved PMA nor anexemption was in effect for such silicone, and the defendants'processing and injection into clients of such silicone was done inviolat ion of the law whi le the s i l icone was held for sale af ter

shipment in interstate commerce—501(f)(1)(C). The governmentasked that the defendants be enjoined from such action and that allof the silicone in their custody be destroyed.DISPOSITION: The defendants denied any liability or wrongdoingbut consented to a decree of permanent injunction. The decreeenjoined the complained-of violations and ordered the destruction ofall liquid injectable silicone on hand. (Inj. No. 1277; S.J. No. 13)

M I S C E L L A N E O U S A C T I O N S

SUBJECT: Electroencephalography, electronic surveillance implant device, and denial of claims, Bridgeport, Dist. Conn.; CivilN o . 5 - 9 2 C V 2 0 0 W W E .CHARGED on or about 3-21-92 by Pedro Luis Tosado, Bridgeport,Conn., against Deputy Clerk of Court Carol Cannady, the Departments of the Treasury and Health and Human Services, and variousgovemment officials, in a complaint charging violations of federaland state law: That the federal officials were sued under the Bivensprovisions providing for suits against violations of rights by federalofficials acting under color of federal law; that the Treasury Department was charged pursuant to the Racketeer Influence and CormptOrganizations Act; that the plaintiff had visited FDA's Bridgeport,Conn., office and had been advised that an electroencephalographyprocedure was noninvasive and that [since the plaintiff s allegationsconcerned surveillance equipment being surgically implanted in hisbody] his allegations did not appear to fall within FDA's jurisdiction. In addition, the plaintiff made assertions to the effect that FDAwas supposed to investigate such torturing of a victim after beingkidnapped; that FDA was supposed to investigate two state hospitals; and that the plaintiffs complaint was to be refiled as requestedafter the complaint was lost without the fault of the plaintiff. Theplaintiff sought to recover damages for various injuries and losses.DISPOSITION: The plaintiff Tosado moved to dismiss CarolCannady because she was not needed for adjudication. The courtgranted that motion and dismissed that defendant. The federaldefendants moved to dismiss the complaint and requested an injunction prohibiting the plaintiff from filing any further suits in thisdistrict against federal officials, federal agencies, or the federalgovemment without leave of the court.

The court denied the govemment motion for an injunction butgranted the motion to dismiss the complaint since the court coulddiscem no possible cause of action in the complaint. The court statedthat it had previously indicated that it did not look kindly on theplaintiff s repeated assertions of meritless claims; and that, althoughthe court was unwilling to impose an injunction on the plaintiff at thistime, it did not rule out that possibility should the plaintiff continueto file frivolous suits. (Misc. No. 964; S.J. No. 14)

SUBJECT: Nontoxic formulations and confiscation by FDA,Santa Ana, Orange and Anaheim, C. Dist. Calif.; Civil Nos. 92-I434WDK, 92-1972KN(Ex).PETITIONED: 4-1-92 and 6-3-92 by Lance Crews Griffin(Omnipathy Products), Santa Ana, Calif, against EDA complianceofficer Dannie E. Rowland and consumer safety officer Mark H.Hackman, the Food and Dmg Administration, the United States ofAmerica, and others, in complaints for retum of seized property andfor a temporary restraining order, injunction, mandamus, abuse ofprocess, and conspiracy: That all seized property {e.g., phone book,product notebooks, cassette tape with phone messages, customerlists, glycerin & licorice extract, liver injection extract, oxy-sleepcapsules, Omnipathy business checks, Diapid nasal spray, pangamicacid literature and labels, and infusion and standard IV sets) beretumed to Griffin, and that $500,000 in compensatory damages and$I million in punitive damages be paid Griffin. Griffin also petitioned that the defendants be enjoined from conducting any moreillegal searches and seizures, asserting that a packet belonging to thepetitioner had been sent by U.P.S. and illegally seized and confiscated at a mailing service in Orange, Calif, as were all mail andpackages for the petitioner at a mailing service in Anaheim, Calif,and that the warrant and subpoena should be quashed on the groundsthat they were improperly procured and improperly executed.DISPOSITION: The initial action for the retum of the seizedproperty was withdrawn by Griffin. As to the subsequent action.Griffin's motion for a preliminary injunction was denied by thecourt. The court noted that the underlying action arose from theissuance of a subpoena and search warrant that led to the seizure ofvarious chemicals, chemical substances, computer disks, and piecesof mail from the plaintiff. Although the court recognized thatinjunctions regarding govemment functions were permitted inextraordinary circumstances, in the absence of such circumstances,the courts were not to intervene in an ongoing executive investigation. The court did not find it unreasonable that an investigator mightbelieve that certain pieces of mail were within the scope of thewarrant, and the seizure of such items did not rise to the level of suchextraordinary circumstances. Moreover, Griffin's unsupported assertion that he had not earned on any illegal activity did not justifyenjoining FDA's investigation. Stating that the court would notenjoin a govemment investigation solely because its subject proclaimed his innocence, the court denied Griffin's motion for apreliminary injunction.

Subsequently, the court issued a show cause order requiringGriffin to show cause why the action should not be dismissed. WhenGriffin failed to respond, the court ordered the action dismissed(Misc. No. 976; S.J. No. 15)

36/April 1994/FDA Consumer irU.S. GOVERNMENT PRINTING OFFICE 1994-301-035/00001

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