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FDA ConsumerThe Magazine of the U.S. Food and Drug Administration

March-April 2001 • Vol.35 No.2

Tommy G. ThompsonSecretory of Health ortd Human Services

Bernard A. Schwetz, DVW, PhDActing Principal Deputy Commissioner

Lawrence Bachorik, PhDAssociofe Commissioner for Public Affairs

Larry Thompson / Editor

Patricia N. Edwards / Art Director

Michael L. Herndon / Production Manager

Jan Elicker / Copy Editor

Linda Bren, Raymond Formonek Jr.,Carol Lewis, Michelle Meadows / Stoff Writers

Cover Illustration: Jack Pardue

FDA on the Internet: www.fda.gov

FDA Consumer (ISSN 00362-1332) is published bimonthly by theEood and Drug Administration (HEI-40), 5600 Eishets Lone,Rockville, MO 20857, U.S. Public Henltii Service, Dapcrlment ofHealth and Huinon Services.

Editorial Matters

Address for editorial matters is FDA Consumer, food and DrugAdministration (HFI-40), 5600 Eishers Lone, Rockville, MD 20857.Articles in FDA Consumer my be republished without permission.Credit to FDA Consumer os the source is oppreciuted. FDA Consumeris indexed in the Header's Guide to Periodical Literature. The currentFDA Consumer Index is ovailcble on FDA's Website ot

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A Inside Front Cover Photo:

WkConsumerThe Magazine of the U.S. Food and Drug Administration

March -Ap r i l 2001 • Vo l . 35 No .2

7 Making Medical Progress: A Look at FDA Approvals in 2000FDA approved 160 new products in 2000 that advance the prevention,diagnosis and treatment of cancer, diabetes, AIDS and other serious illnesses.

9 Proposed Rules Issued for Bioengineered FoodsProducers would be required to consult with FDA before marketing bioengineered foodsunder new proposed rules. The agency also is developing labeling guidelines.

12 Trying to Keep "Mod Cow Disease" Out of U.S. Herdsimport restrictions and rigorous animal feed rules ore designed to keep BSE, andthe associated human neurological disease, out of the United States.

15 Highlights of FDA Food Safety EffortsProposed rules for unpasteurized fruit juices and on advisory about fish with potentiallydamaging levels of mercury ore port of a recent FDA food safely package.

18 The Power of Accutane: The Benefits and Risks of o Breakthrough Acne DrugAccutane, though effective, con cause birth defects and other serious adverse effects.Patient education and strict prescribing guidelines aim to reduce the risk.

Cover Story24 Frances Oldham Kelsey: FDA Medical Reviewer Leaves Her Mark on History

The FDA physician whose work has been influential in setting the course of modern drugregulation has joined other extraordinary American women in the Notional Women'sHall of Fame.

30 Grappling With the Quality of LifeThe benefits of drug therapies may go beyond disease treatment. FDA and the drugindustry ore looking at how to evaluate quality-of-life claims.

Deportments

2 O b s e r v a t i o n s

3 Letters to the Editor

4 Updates

36 fdo.gov

37 Investigators' Reports

4 0 T h e L o s t Wo r d

Acne usually occurs on the face, neck, back, chest, and shoulders. Treatment con helpprevent scarring and reduce the number of painful lesions. See page 1 8 for more on acneand the drug Accutane. Photograph by Picture Quest/Stephen Frisch

FDA Consumer / March-April 2001 / 1

O b s e r v a t i o n s

This issue of FDA Consumer

marks the completion of my firstyear as editor. It's also the last issueof FDA Consumer that I will edit. I

will soon leave the Food and DrugAdministration and join the NationalHuman Genome Research Institute,a part of the National Institutes ofH e a l t h .

But before I go, I would like tosay thank you to the magazine'sreaders. And I would like to thank

the magazine's staff. Officially, the magazine speaks with thevoice of the agency, but I want to tell you that the writers, editors and graphic artists have a fierce loyalty to the reader.They take deserved pride in doing everything they can to communicate the actions of the agency—and its reasons for thoseactions—clearly and effectively. With the help of FDA experts, the editorial and artistic staffs deliver authoritative, reliable, scientifically based information that readers can use tomake informed choices about their own health.

Over the last year, there have been many changes in themagazine. We've added more color and informational graphics. We've added a letters to the editor department so you canreact to the articles we print. We've added new voices to themagazine, such as those found in the "Last Word" column.We've tried to write the "Investigators' Reports" articles likethe detective stories that they are. We've instituted shorter articles, a wider mix of story subjects, and an increased emphasis on providing the reader with current insights about theagency's mission to protect the public health.

Making the mission understandable is critical to FDA'spartnership with the American public. Surveys during the pastdecade consistently show that public opinion is with FDA.Last September, a Harris poll found that 61 percent of respondents felt FDA did an excellent or pretty good job. Only 6 percent said it did a poor job. When asked what governmentagency the public most tru.sts to protect the safety of thenation's food supply, a May 2000 survey showed FDA had a45 percent lead on the next closest government organization.

When the agency talks about powerful therapeutics, suchas prescription medications, a September 2000 survey foundthat 80 percent of the public trusts FDA a lot or somewhat.And when the agency uses the bully pulpit to warn the publicabout a dangerous product, the public listens. Last November,FDA warned consumers to stop using over-the-counter coldand diet preparations containing phenylpropanolamine because it increases the risk of stroke; nearly half of those

surveyed reported following the story very closely or fairlyclosely. Such credible communication saves lives.

FDA communicates much of its life-saving information inthe pages of this magazine. Consider the story on acne andAccutane. A single treatment with this powerful drug canmake intractable acne disappear, but its use during pregnancycan leave a baby deformed or stillborn. As FDA's scientistsand policy makers struggle to find the right balance betweensafety and efficacy, their most effective tool is information thathelps Accutane users make the right choices.

Drugs and unexpected adverse events, especially birth defects, have played a critical role in the history of this agency.The current cover story tells the tale of a long-time FDA scientist who almost single-handedly saved America from a prescription drug disaster that deformed thousands of newbornsin European and other countries nearly four decades ago. Dr.Frances Kelsey has long been a legend both within FDA andamong public health aficionados. And while most know thather work on thalidomide led to substantially strengthened legal authority for FDA in the early 1960s, few appreciate thatDr. Kelsey, as a graduate student at the University of Chicago,also participated in one of the other most important publichealth events of the last century: She helped solve the cause ofdeaths from Elixir Sulfanilamide, then a new form of antibiotic that went into use in the 1930s. The sweet-tasting solventproved lethal. In response. Congress passed the Federal Food,Drug and Cosmetic Act of 1938, the first modern consumerprotection law in the nation's history.

As I leave FDA after a relatively brief tenure of five years,I do so with a sense of deep respect for this important publicinstitution. It protects you in so many ways that we have yet todescribe in the pages of this magazine. So as the years unfold,I hope you come to appreciate—as have I—the dedication ofthe agency professionals who defend the nation's publichealth. And I hope you keep reading FDA Consumer.

FDA Consumer accepts letters to the editor. Letters canbe e-mailed to [email protected], or mailed toFDA Consumer, Food and Drug Administration (HFI-

40), 5600 Fishers Lane, Rockville, MD 20857. Lettersshould be 300 words or less, signed, and include an address and telephone number for verification. The editorreserves the right to edit letters for space and appropria t e n e s s .

Larry Thompson, Editor

1 / March-April 2001 / FDA Consumer

To The Edi tor

LiposuctionThe article "Planning to Look Flab-U-

Less? Know the Facts About

Liposuction" (November-December2000 FDA Consumer) failed to mentionthe most important fact: Whenliposuction is performed under local anesthesia by board-certified dermatologicsurgeons in an outpatient setting, theprocedure carries a phenomenal safetyrecord. In fact, dermatologic surgeonspioneered tumescent liposuction and developed guidelines of care for the procedure nearly 10 years ago.

Accordingly, the American Society forDermatologic Surgery takes exception tothe article's suggestions that one specialty group or medical board has exclusive domain over performing liposuctionsurgery. And, the suggestion that thechief criterion for selecting a surgeonshould be whether the physician hashospital privileges is similarly incorrectand prejudiced.

The simple facts are that no deathswere reported from office-based tumescent liposuction performed by dermatologic surgeons based on a study of thelast five years experience. Moreover, independent physician insurance datademonstrate that patients undergoingliposuction in a hospital accounted forthe majority of malpractice claims.

The public deserves to know thetruth—hospital operating rooms are notthe answer to safe liposuction surgery.Rather, patient safety is best ensuredwhen the skin surgery experts who originally developed liposuction as an outpatient procedure under local anesthesiaperform the procedure.

Harold J. Brody, MDPresident, American Society

for Dermatologic Surgery

Perspective on Medical ErrorsThank you for providing a forum for

such timely articles ("Make No Mistake:Medical Errors Can Be Deadly Serious,"September-October 2000 FDA Consumer). It is imperative that the public aswell as health professionals be updatedand informed. With the rapid changesthat occur in health delivery and the tremendous cutbacks in heal th insurance

coverage, situations and practices arisethat warrant investigation.

1 am writing regarding the practice ofmandating health-care professionals towork up to and beyond 16 to 18 hours ina given workday. In the state of Pennsylvania, this is "not uncommon," according to the Pennsylvania State Nurses Ass o c i a t i o n .

1 have witnessed RNs literally fallingasleep on their feet in their 15th hour. Itis not uncommon that RNs are mandatedbeyond 16 hours and with less than onehour notice. This is done in lieu of clos

ing beds when staffing is at low levels.This takes a toll physiologically andpsychologically in rendering care for ourpatients.

This is a public health issue and a hazard. 1 encourage nurses to lobby for reform as we must not add injury to insultby continuing to allow this to occur.

A. Shackelford, RN, CCRNDanville, Pa.

C o n c e r t a f o r A D H DIn your article on Once-a-Day

Concerta (Updates, November-December 2()(K) FDA Consumer), you indicatethat Ritalin "must be taken two or threetimes a day when given in the immediate-release form; the new extended-release formulation requires only a singledaily dose." Then, in the second paragraph, "Concerta is administered once inthe morning, as opposed to current immediate-release forms of methylpheni-date, which must be taken two or threetimes daily."

Is Concerta then the same thing asRitalin-SR, which is a sustained releaseform of methylphenidate, and if so, whyis it being compared to the Ritalin thatis prescribed in the immediate-releaseform? Is it or is it not the same drug asRital in-SR? The art ic le makes i t soundas if this were a new drug, and in fact,my primary care physician has indicatedthere is a new "one dosage" medicineo n t h e m a r k e t f o r A D D .

This is all very misleading and unclear for the consumer.

K a t h l e e n M i l l e r

Durham, N.C.

E d i t o r ' s n o t e : T h e F D A m e d i c a l o f fi c e rwho reviewed the Concerta applicationexplains, "The active ingredient in allthree is, of course, methylphenidate.Both Rital in SR and Concerta are formulations of methylphenidate approvedfor once a day dosing. The method offormulating the pills to provide a prolonged release of methylphenidate isdifferent, however."

H e a l t h F r a u dIn your article "How to Spot Health

Fraud" (November-December 1999FDA Consumer), you quote MarjoriePowell of the Pharmaceutical Researchand Manufacturers of America under"Paranoid Accusations," someone fromthe drug industry's trade association.Your own Web site lists hundreds ofviolations on the part of this industry formisleading the public and doctors withtheir ads. How about a more objectivesource next t ime?

Maryann NapoliCente r fo r Med ica l Consumers

N e w Y o r k


Updates

New Drug and Device Approved to Monoge DiobetesType 2 diabetes is characterized by

abnormal handling of nutrients by thebody, particularly sugar (glucose). Thisis caused by a combination of an inability to produce sufficient insulin, as wellas to respond fully to the insulin that isproduced. In addition to elevations infa.sting glucose, people with Type 2 diabetes have an ineffective response to therise in blood sugar (glucose) that occursnormally after eating a meal.

In December, FDA approved Starlix(nateglinide), an amino acid derivativeand the second in a relatively new classof oral drugs that stimulates the patient'spancreas to secrete additional insulin. Inthis respect, Starlix shares a commonmechanism of act ion with a much olderclass of drugs called sulfonylureas(glyburide and glipizide, for example).Starlix and the related drug Prandin(repaglinide), differ from the sulfonylureas in their relatively rapid onsetand short duration of action. As such, iftaken three times daily immediately before meaks, they exert their glucose-lowering effects mostly on the fluctuationsin blood sugar that follow in the several

Photo courtesy of Abbott Laboratories

hours following each meal.Starlix alone has quite modest effects

on overall glucose control. When givenin combination with another diabetesdrug, Glucophage (metformin), the twodrugs give greater control of blood sugar

than either drug alone (that is, the effectappears approximately additive).

Star l ix and Prandin at recommendeddoses generally will have less effect onglucose control than sulfonylureas. Because of Starlix's modest efficacy, theincidence of hypoglycemia, the mainacute complication of therapy aimed atlowering blood glucose in Type 2 diabetes, was low in the clinical trials of thedrug. Starlix is made by Novartis AG ofBasel, Switzerland.

Glucose control can help prevent serious complications of diabetes, such askidney failure, blindness, and amputations. To control their blood sugar,people with diabetes must frequentlytest their blood glucose levels. Of themany types of home blood-glucosemonitors available to help patients manage their diabetes, Sof-Tact is one of themost recent to come on the market.

Manufactured by Abbott Laboratories ofBedford, Mass., and cleared by FDA inNovember, Sof-Tact is a .semi-automatedsystem that uses a light-suction vacuumto hold the skin in place while an integrated apparatus lances the skin. The de

vice automaticallytransfers a smallamount o f b loodto a biosensor

strip, and theblood glucose testresult is deliveredin 20 seconds.The device can beused on the forearm or upper arm,

eliminating theneed for the tradi

tional finger-sticking method.

Nearly 16 million people in the UnitedStates, or 6 percent of the population,have diabetes, according to the American Diabetes Association. Approximately 90 to 95 percent of diabetes patients have Type 2 diabetes.

Ointment Brings Relief for EczemoFDA has approved a new treatment

for eczema, a skin condition that cancause redness, itching, and oozing lesions. Protopic Ointment is for patientswith moderate to severe eczema who areunable to tolerate or benefit from stan

dard eczema therapies.FDA based its approval on results of

three 12-week studies that indicated that28 to 37 percent of patients usingProtopic experienced greater than orequal to 90 percent improvement of theirskin condition. Two one-year studies indicated the drug is safe for intermittentlong-term use. Common side effects associated with this drug include temporary stinging or burning sensationswhere the drug is applied.

An animal study revealed thatProtopic Ointment may accentuate adverse effects of ultraviolet light on theskin. So patients should avoid sunlightand sunlamps, tanning beds, and treatment with ultraviolet A (UVA) or ultraviolet B (UVB) light. Patients who needto be outdoors after applying Protopicshould wear loose-fitting clothing thatprotects the treated area from the sun.Patients should also ask their health-careproviders about other sun protection tou s e .

Protopic Ointment should not be usedby patients who are allergic to its activeingredient, tacrolimus, or to its inactiveingredients. Women who are breastfeeding should also avoid using the ointment, and women who are pregnant orplanning to become pregnant shouldcheck with their physicians before usingthis product.

Protopic will be marketed by FujisawaHealthcare Inc. of Deerfield, 111.


Rx for Hord-to-Read Drug Inserts: Better Informed PrescribersFDA has proposed a new, user-friendly format for the package inserts that give

physicians information on prescription drugs. FDA believes the new labeling formatwill help reduce medical errors in drug prescribing.

Product labeling represents a primary way to share critical drug informationwith physicians, and one FDA study revealed that practitioners found current labeling lengthy, complex, and hard to use.

The proposed labeling will cut down the time physicians spend looking for information and make it easier to spot warnings. One major proposed change is theaddition of a bulleted "Highlights" section that would include information that practitioners consider most important and need to refer to frequently.

Because these labeling changes are most critical for newer and less familiardrugs, the proposal will apply only to relatively new prescription drug products.FDA reviews and approves drug product labeling that manufacturers propose.

Manufacturer Gets More Time to Support Keeping Poultry Drug on MorketFDA Consumer previously reported on the risk of people getting antibiotic-resis

tant bacteria from eating poultry or other food contaminated from contact with rawpoultry that has been treated with a fluoroquinolone (antibacterial) drug. (See "Antibiotic Resistance From Down on the Chicken Farm," January-February 2001 FDAConsumer.) FDA's Center for VeterinaryMedicine (CVM) proposed to withdrawapproval of Bayer Corporation'sfluoroquinolone product, Baytril, for usein poultry. This action was based, in part,on a national surveillance program thatshowed an increasing number of drug-resistant Campylobacter infections in peoplewho ate poultry or other food contaminated by poultry treated with the drug.

The company was originally requiredto submit data and information by Jan. 2,2001, to support its request for a hearing tokeep its drug on the market. CVM has extended the deadline to Feb. 21 because some of the data cited in the Notice of Opportunity for Hearing (NOOH), published in the Federal Register Oct. 31, 2000, werefound to be incorrect. These data were taken from a CVM risk assessment entitled"The Human Health Impact of Fluoroquinolone Resistant Campylobacter Attributedto the Consumption of Chicken," published Oct. 18, 2000. CVM discovered that corrections were needed in the risk assessment model, which affected the estimate otthe number of persons infected with fluoroquinolone-resistant Campylobacter fromchicken and subsequently prescribed a fluoroquinolone.

As a result of the correction, along with incorporation of final data from a database called FoodNet, the estimated number of persons infected withfluoroquinolone-resistant Campylobacter from chicken who were prescribed afluoroquinolone drug in 1999 was 9,261 (revised from 11,477).

CVM does not believe that the revisions alter the premise of the NOOH. TheCenter has made the risk assessment and the program to run the calculations publiclyavailable through its Web site at www.jda.govlcvmlantimicrobiallRisk_asses.htm.

Consumers Approve of FDA FoodSofety Performonce

Consumers are s t i l l sat isfied wi th

FDA's performance in food labeling andwith its consumer alerts on food safetyissues, according to the second government-wide customer satisfaction surveyr e l e a s e d i n D e c e m b e r . C o n s u m e r s a l s o

continue to trust FDA to ensure food

safety. Theagency rec e i v e d a n i n

dex score of

68, justslightly abovelast year'srating.

Surveyquestions targeted principal groceryshoppers andf o o d

prepare rs ,a n d a s k e d

a b o u t F D A ' s

m iss ion toensure food

safety, the usefulness and clarity of nutrition labeling, customer awareness, andviews of effectiveness of inspecting,testing, and labeling efforts. As in the1999 report, the survey calls for an increase in public awareness of how FDAfood safety activities affect consumers.

Initiated last year by the NationalPartnership for Reinventing Government, this survey was developed to measure how well key government agenciesserve the public and to set a baseline formeasuring customer satisfaction. TheUniversity of Michigan conducted thesurvey using a model established for theAmerican Customer Satisfaction Index,which measures satisfaction with variousi n d u s t r i e s .


Updates (continued)

Study Suggests Cell Phone Use NotAssociated With Brain Cancer

Talking on cell phones isn't linked toan increased risk of brain cancer, suggests a recent study supported by Wireless Technology Research and the National Cancer Inst i tute.

Researchers interviewed 469 men andwomen aged 18 to 80 with brain cancerand 422 matched controls without brain

cancer between 1994 and 1998. Researchers asked subjects if they had eversubscribed to a cell phone service, andthey gathered such information as thenumber of years of use, the amount oftime used per month, and the year offirst use.

The median number of hours permonth of cell phone use was 2.5 for thecancer patients and 2.2 for those withoutcancer. The mean duration of use was2.8 years for cancer patients and 2.7years for those without cancer. The differences between the cancer patients andthose without the disease were not statistically significant. Researchers concluded there was no association withbrain cancer according to duration ofuse, but also stated that more studies onlong-term use of cell phones are needed.{Journal of the American Medical Association, Dec. 20, 2000)

Migraine and MensesWomen who suffer from migraine

headaches are more likely to experiencea migraine in the four days closest to theonset of their menstrual periods, according to recent research. The study, conducted by researchers at the JohnsHopkins School of Hygiene and PublicHealth and several other institutions,was one of the few that have looked into

the relationship between migraines andwomen's menstrual cycles in the generalpopulation.

Researchers had 81 migraine sufferers, selected randomly from householdsin Baltimore County, Md., keep diariesthat documented when in their menstrual

cycles their migraines occurred, notingspecific symptoms and the severity ofthe headaches. Women experiencedheadaches without aura (the visual andphysical symptoms that sometimespresage a migraine) more than two timesmore often in the two days after the startof menstruation. Participants did nothave the same cyclical increase in headaches with aura. The study group alsohad an increase in tension-type headaches at the onset of menstruation. Mi

graines that occurred at this time, however, were not more severe than those

experienced at other times.Researchers concluded that the

women's cyclical hormone changes, especially the drop in estrogen levels thatoccurs just before menstruation, are atrigger for migraines without aura, andthat tension-type headaches may be triggered in the same way. {Neurology, Nov.28, 2000)

Study: Caffeine-Miscarriage LinkPregnant women who drink five or

more cups of coffee a day may doubletheir risk of miscarriage, according to anew study that examined the relationshipbetween miscarriage and consumptionof caffeine. Researchers in Sweden andthe United States compared the caffeineintake of a group of Swedish womenwho had miscarriages in early pregnancywith that of women who had normal

pregnancies. Consuming the amount ofcaffeine in one to three cups of coffeeraised miscarriage risk by 30 percent;three to five cups, by 40 percent.

These conclusions support results ofprevious studies that showed increasedmiscarriage risk from high caffeine consumption. Researchers also collecteddata on smoking by mothers andwhether fetuses had genetic abnormalities, two separate factors that increasethe risk of miscarriage. They concludedthat caffeine consumption could increasemiscarriage risk for genetically normalfetuses. Because they couldn't determinehow smoking would change the risk forcaffeine drinkers, the study's conclusions are made only for non-smokingmothe rs .

The researchers acknowledged, in addition, that study results could beskewed because morning sickness inearly pregnancy may affect how muchcaffeine is consumed. Mothers with

healthy fetuses tend to have more severenausea, and often develop an aversion tocoffee, so women with less viable pregnancies may be able to drink more coffee without discomfort. {New EnglandJournal of Medicine, Dec. 21, 2000)

Caffeine is a natural component ofcoffee, tea, and chocolate. It is added tosome soft drinks, and appears in the ingredient listing on the label when it isadded to a food product. Some over-the-counter and prescription medicines contain caffeine, as well. FDA has advisedwomen since 1980 to avoid caffeine orconsume it only moderately throughoutp r e g n a n c y.

Serious Product Problem? Report ItHealth professionals can report serious adverse reactions or other product

problems to FDA's Med Watch program by:• Mail; Use the postage-paid MedWatch form, available from the FDA Web siteor by calling the toll-free number below.• Phone: 1-800-FDA-1088 (1-800-332-1088)• Fax: 1-800-FDA-0178 (1-800-332-0178)• Internet: www.fda.govlmedwatch

Call the 800 number or visit the Web site for further assistance.FDA encourages consumers to report through their doctors, but if they prefer,

they may submit the MedWatch form themselves.


Making Medical ProgressA Look M PDA Mprovals In

F.rom drugs that bring relief to devices that detect disease, many productsapproved in the year 2000 represent important advances in the prevention, diagnosis, and treatment of serious conditions. Last year, the Food and DrugAdministration approved 160 new drugs,biological products, and medical dev i c e s .

Three of FDA's centers—the Center

for Drug Evaluation and Research(ODER), the Center for Biologies Evaluation and Research (CBER), and theCenter for Devices and RadiologicalHealth (CDRH)—give premarket approval for new health-care products.They also prevent unsafe or ineffectiveproducts from going on the market, assure adequate labeling for approvedproducts, and monitor the effects of marketed therapeutics.

Along with approving 98 original newdrugs, CDER issued 244 approvals forgeneric versions of drugs on which thepatents had expired. FDA approved 20products classified as priority drugs in amedian t ime of six months. And FDA

approved 27 new molecular entities(products with ingredients never beforemarketed in the United States) in themedian time of 15.6 months. Along withapproving a host of important new medical products in 2000, FDA has continuedto exceed virtually all of its performancegoals under the Prescription Drug UserF e e A c t .

In addition to approving 53 originalnew medical devices, CDRH cleared forthe market 3,457 so-called 510(k) devices. These are products similar to devices already in use. CBER issued 13approvals for product license or biological license applications.

Among the important products thatpassed FDA's rigorous review for safety

2 0 0 0and effectiveness are Zyvox (linezolid),the first of a new class of antibacterial

drugs that addresses the emerging publichealth threat of vancomycin-resistantbacterial infections. Vancomycin has

been the treatment of last resort for an

organism called Enterococcus faeciumfor many years.

And the approval of Visudyne(verteporfin for injection) brought the

FDA Approvals in Year 2000Original New Drugs, Bioiogicai Products and Medical Devices

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FDA's Center for Drug Evaluation and Research (ODER) issued 98 approvals fororiginal new drug applications in the total median time of 11.2 months. The Center forBiologies Evaluation and Research (CBER) issued 13 approvals for product license orbioiogicai license applications in the median time of 25.1 months. The Center forDevices and Radiological Health (CDRH) approved 49 product marketing applicationsfor original devices in the median time of 9.6 months. CDRH approved four additionalproducts under FDA's Humanitarian Use Exemptions program (for devices with apatient population up to 4,000) in a median time of 3.5 months


first therapy to slow vision loss inpeople with wet age-related macular degeneration, a condition that annuallycauses bl indness in one mil l ion Americans over age 55.

Among the significant medical devices approved by FDA was the DaVinci Surgical System, which uses cutting-edge robotics technology to perform laparoscopic gall bladder and reflux disease surgery. The CordisCheckmate System and Novoste BetaCath System are approved devices thatuse catheters to deliver radiation inside a

coronary stent after a blocked artery isreopened. The radiation helps reduce therisk of repeated narrowing of the artery.

In addition to elderly patients andthose with heart disease, children,women, and patients with cancer areamong the groups that particularly benefit from FDA approvals in 2000. Hereare some examples:

P e d i a t r i c P r o d u c t sFDA approved an unusually high

number of health-care products forchildren. In recent years. Congress andFDA have stimulated increased pediatric submissions by offering limited pediatric exclusivity to manufacturerswho conduct studies for pediatric useof their products. Several new products were either designed for theyoungest patients or were adult drugswith pediatric indications.

The OxiFirst Fetal Oxygen Saturation Monitoring System represents thefirst major technological developmentin fetal monitoring in three decades.The system measures oxygen saturation in a baby's blood as a sign of fetalhealth during labor and delivery. FDAalso approved Prevnar, a vaccine toprevent invasive pneumococcal diseases that can cause brain damage anddeath. The vaccine is the first of its kindfor infants and toddlers under age 2.

Children with asthma can benefit fromlast year's approval of PulmicortRespules (budesonide inhalation suspension), the first anti-inflammatory corticosteroid for inhalation using a nebulizer in this age group. This is an

important feature because toddlers frequently cannot use metered-dose inhalers. FDA approved Relenza (zanamivir)to treat uncomplicated influenza A and Bin patients age 7 and up. And Tamiflu(oseltamivir phosphate) oral suspension received approval for the prevention of the influenza virus in patients13 and older. Influenza causes 20,000deaths and 100,000 hospitalizations ay e a r .

Examples of drugs approved lastyear that had both adult and pediatricindications are Kaletra, a combinationof lopinavir and ritonavir, which received accelerated approval for HIVtreatment; Unithroid (levothyroxinesodium), a thyroid replacement drug;and Protopic (tacrolimus), an ointmentthat treats moderate to severe eczema.FDA also added pediatric use to the labeling of 13 adult medications, including ibuprofens Motrin and Advil, andZantac (ranitidine) for stomach acidreflux. And the agency approved lowering the age for the Nucleus 24 Cochlear Implant from 18 months to 12months for infants who are profoundlyhearing-impaired.

Options for WomenThree-quarters of the more than 8 mil

lion Americans with rheumatoid arthritisare women. FDA approved Remicade(infliximab) to treat rheumatoid arthritisin patients with inadequate response tomethotrexate. Another approval that primarily benefits women is Novantrone(mitoxantrone hydrochloride), a cancerdrug, to treat advanced or chronic multiple sclerosis. This disease affects up to350,000 Americans, most of whom arew o m e n .

FDA also approved Mifeprex(mifepristone) for the termination ofpregnancy within 49 days from the beginning of the last menstrual period.And following clinical studies involving9,000 women, the agency also allowedcontinued marketing of two types of saline-filled breast implants that are approved for breast augmentation andbreast reconstruction in women 18 yearso r o l d e r .

Progress for Patients With CancerFDA approved three medical devices

last year to help fight cancer, the seconddeadliest disease in the United States,

affecting eight million Americans. TheOptical Biopsy System is a laser systemthat helps doctors distinguish small,harmless growths from precancerousgrowths in the colon.

The Senographe 2000D is a mammography system that produces digital images. Unlike radiographic film, digitalimages can be electronically stored andtransferred so specialists can evaluatethem at a remote location. The imagescan also be manipulated to correct forunder- or over-exposure. Early diagnosisremains the best weapon against breastcancer, which annually affects 185,000women, 46,000 of whom die of the dise a s e .

The third device in this category is theFocalSeal-L Surgical Sealant, approvedfor sealing air leaks in lungs following theremoval of cancerous tumors. Light activates the sealant, which is ''painted" on thelung. FDA reviewed the sealant on an expedited basis because of its potential importance for patients with lung cancer.

As for cancer medications, two—Trisenox and Mylotarg—were approvedfor cancers of the white blood cells.Trisenox (arsenic trioxide) was foundsafe and effective to treat acutepromyelocyte leukemia (APE) in patients who have not responded to, orhave relapsed following all trans-retinoic acid and anthracycline-basedchemotherapy. Trisenox, a priority drug,was approved in six months. Theproduct's total development time wasonly three years.

Other FDA approvals designed to benefit patients with cancer includedMylotarg (gemtuzumab ozogamicin) forthe treatment of CD33 positive acutemyeloid leukemia for patients 60 yearsor older who have relapsed for the firsttime and are not suitable candidates forthe standard cytotoxic therapy. FDA alsoapproved Novaldex (tamoxifen citrate)to reduce risk of invasive breast cancerfor women with preinvasive cancer ofthe ducts. ■

8 / March-April 2001 / FDA Consumer ILLUSTRATIONS BYJESSE R. NICHOLS

Proposed Rules Issued ForBIOENGINEERED

The shelves of just about every American supermarketare lined with foods that have been genetically altered to improve the product's taste,

shelf life, or resistance to insects and other pests.

Tomatoes, potatoes, squash, corn, and soybeans have been genetically alteredthrough the emerging science of biotechnology. So have ingredients in everythingfrom ketchup and cola to hamburger buns and cake mixes.

Most of the foods we eat today are the result of crossbreeding—a technique thatrelies on the laws of inheritance first described by Gregor Mendel in the 19th cen

tury—to obtain desired characteristics.Crossbreeding is inexact. It also involves trial-and-error and lots of time. Although

biotechnology is a more efficient way to introduce new traits, there are concerns.

Raymond Formanek Jr.

Some worry about the possibility of introducing new allergens into foods. Others worry about the potential effects thataltered crop species may have on wildlife and other plants.

However, many researchers say theability of biotechnology to isolate andintroduce a specific gene or just a fewgenes makes outcomes more predictable,including the ability to predict risks.Supporters say that biotechnology is atool that allows scientists and farmers toreduce damage from pesticides, boostcrop yields, and improve flavor, textureand nutr i t ional content .

FDA OversightThe Food and Drug Administration

proposed mandatory rules in Januarythat would tighten the scrutiny ofbioengineered foods. The rules wouldrequire that manufacturers of plant-derived, bioengineered foods and animalfeeds notify the FDA at least 120 daysbefore the products are marketed.

As part of the notification, the manufacturer would provide informationshowing that the foods or feeds are assafe as their conventional counterparts.Manufacturers have completed voluntary consultations on roughly 50bioengineered foods using scientificguidelines published by FDA in 1992.The proposal would make the currentpractice of voluntary consultations mandatory and require manufacturers to submit safety and nutritional information toF D A .

"Our basic policy with respect tobioengineered foods is that there is nothing inherently different with thesefoods," says Joseph Levitt, director ofthe FDA's Center for Food Safety andApplied Nutrition (CFSAN). ^^We willcontinue to examine each product on acase-by-case basis. We'll make sure thatdata on things like nutritional content ornatural toxicants are there. We want tobe sure that all the safety bases are cove r e d . "

Levitt says the evaluation processwould become "transparent" under theproposed rules. Information submittedby manufacturers, as well as FDA responses, would be posted on the CFSANWeb site at www.cfsan.fda.gov.

The FDA also has issued draft guidelines for companies that want to label

their products to indicate that a food orfeed has or has not been developed using bioengineering methods. Terms suchas "genetically modified" (GM), "genetically modified organism" (GMO),and "modified" are no t recommendedunder the guidelines.

On the other hand, Levitt says amanufacturer that wants to label a product as "genetically engineered" may doso ^^but consumer focus groups we metwith suggested that they should saywhy."

"We want the labeling to be informative, but not misleading," he says.

Public InputThe proposed rule for notification and

draft guidelines for labeling are the result of more than 18 months of discussion with consumers, manufacturers,

growers and others. "We heard viewsacross the entire spectrum," Levitt says."We have literally thousands of comm e n t s . "

The proposals can be viewed on theInternet at www.cfsan.fda. gov I-Irdjbiotechm.html. FDA will issue a finalrule after public comments are evaluatedthis spring.

No Known DangersBroadly speaking, growers have been

selecting certain beneficial characteristics such as faster growth or sweeterfruit since our nomadic hunter ancestorsbegan to cultivate crops thousands ofyears ago. Virtually every domesticatedcrop plant species today differs greatlyfrom its original, wild form due to human in tervent ion .

Companies seeking to market anybioengineered food product conductstudies to show that the new food is assafe as its conventionally crossbredcounterpart. The FDA has determinedthat normal safety and quality controlpractices used by plant breeders, such aschemical analyses and taste testing, generally are important. Nutritional andother tests also are done to provide additional safety assurances. Bioengineeredfoods actually are regulated by threefederal agencies: the FDA, the Environmental Protection Agency (EPA), andthe United States Department of Agriculture (USDA).

The Federal Food, Drug, and Cos

metic Act gives FDA the authority toregulate all foods, food ingredients, andanimal feeds derived from crops, including plant varieties developed throughbiotechnology. The USDAs Animal andPlant Health Inspection Service monitors genetically engineered plants forpotential risks to the agricultural environment. The EPA regulates pesticides—including those introduced into plantsthrough biotechnology. (See "StarLinkCorn Investigation and Recall," page 11).

F u t u r e G r o w t hA federally funded study by the Na

tional Research Counci l released in

2000 concluded, 'There is no evidence

suggesting that [bioengineered food] isunsafe to eat." The study also found thatthere is "no str ict dist inct ion" between

the health and environmental risks posedby genetically engineered plants andthose developed through conventionalcrossbreeding.

Bioengineered foods will not solve allof the world's nutritional and agricultural problems. However, the techniquesused to develop them likely will play animportant part in boosting food production, improving nutrition, and reducingthe needs for herbicides and pesticides.

DNA: The Root of BiotechnologyThe discovery that deoxyribonucleic

acid (DNA) was a sort of biological"software" in the mid-1950s set thestage for today's bioengineered foods,pharmaceuticals, transgenic animals,and gene therapy.

DNA molecules contain the geneticinformation necessary for life. This information is contained in four chemicalbases: adenine, cytosine, guanine andthymine. Specific chunks of DNA thatcarry the codes necessary for the production of a specific protein are calledgenes. These proteins contribute to theexpression of a specific trait by stimulating biochemical reactions, or by actingas structural or storage units of a cell.

The fact that DNA is a genetic building block in all organisms makes it possible to insert a gene or genes into plantsinstead of relying on cross-pollination.The inserted gene, called a transgene,may come from an unrelated plant, oreven from bacteria, viruses or animals.

For example, scientists have devel-


In September 2000, aconsumer group reportedthat a bioengineered variety of corn not approved for human consumption had beenfound in taco shells.

The corn, dubbedStarLink, was modifiedto contain a gene fromthe bacter ium Baci l lus

thiiringiensis that expresses a protein—Cry9C—toxic to certaininsects that eat up theprofits of corn growers.

T h e E n v i r o n m e n t a lProtection Agency(EPA) is responsible forreviewing the safety of pesticide substances in bioengineeredplants. The EPA approved Cry9C only for corn earmarked foranimal feed and industrial uses. The agency did not approvethe protein for human consumption due to lingering questionsabout Cry9C's potential to cause allergic reactions.

Although StarLink's developer, Aventis, was required toensure that the bioengineered corn did not go into food, somebecame mingled with corn destined for human consumption.

The presence of an unapproved pesticide infood means that the foodis adulterated under theFederal Food, Drug, andCosmetic Act, enforcedby the FDA.

Upon learning of allegations that the tacoshel ls conta inedStarLink corn, FDA began a full investigation.Kraft Foods, producer ofthe taco shells, initiatedits own investigationand voluntarily recalledmill ions of taco shells assoon as an independentlaboratory found that the

shells contained the Cry9C gene. The FDA subsequently confirmed the presence of StarLink in the taco shells.

Other recalls have resulted from FDA's continuingStarLink investigation. The agency has worked with EPA andthe U.S. Department of Agriculture (USDA) to ensure thatcorn products containing the Cry9C gene are limited to approved uses. Aventis has agreed to buy back the 2000 StarLinkc r o p . ■

oped a variety of rice capable of synthesizing beta-carotene, a precursor to vitamin A, by inserting genes from a soilbacterium and two genes from a daffodil. Although it's the staple food for halfthe world's population, rice is a poorsource of many essential nutrients andcontains no vitamin A. The geneticallyengineered rice someday could help millions of people worldwide who sufferfrom vitamin A deficiency, a conditionthat leads to blindness in a quarter million children annually in Southeast Asia.

A Long-Running DebateThe debate over genetically engi

neered plants began almost as soon asscientists learned to directly alter thegenes in plants in the early 1980s. Opposition to bioengineered foods has beenespecially strong in Europe and Japan.

Concerns include ethical issues relatedto potential long-term health effects ofeating bioengineered foods, labeling,and potential environmental risks. The

FDA has reviewed al l new bioen

gineered foods brought to market andhas found no reason to believe that theycould pose any threat to health.

Grocers began selling the "FlavrSavr" tomato—the first genetically altered food product to enter the U.S. foodsupply—in 1994. The Flavr Savr ripened slower, could remain on the vinelonger, and was expected to provide better quality than other tomatoes availablein winter.

Experiments arc now under way to develop tomatoes that have enhanced levels of lycopene, a plant chemical thatgives tomatoes their red color. Researchers say lycopene also may offer healthbenefits due to its apparent antioxidantproperties. Antioxidants are thought toneutral ize harmful molecules in the human body called "free radicals." Thesesubstances, which result from cell metabolism and other causes, may contribute to cancer and cardiovascular disease.

Many genetic modifications have been

designed to improve production. Abouthalf of the soybeans and about 25 percent of the corn grown by farmers in theUnited States have been bioengineered,according to the USDA. Most of thesetransgenic crop varieties have been designed to either better tolerate herbicidesor resist insects without the need for extensive spraying of pesticides. An estimated two-thirds of the processed foodsin U.S. supermarkets contain geneticallyengineered corn, soybeans or otherc r o p s .

Biotechnology also has the potentialof creating major advances in medicine. Scientists are looking into thepossibility of producing bananas thatcontain vaccines against cholera, hepat i t i s B and d iar rhea. Some researchers

say that food-based vaccines could beespecially useful in developing countr ies because the costs assoc ia ted wi th

refrigeration and needle sterilizationwould be greatly reduced or elimin a t e d . ■

FDA Consumer / March-April 2001 / 1 1

Trying To Keep"Mad (km Disease"

Out Of as. HerdsBy Linda Bren

Millions of British television viewers watched the harrowing final daysof 14-year-old Zoe Jeffries in October 2000. The ordeal of the young girl from Manchester,

England, began more than two years earlier. First she cried for two weeks, then came the hallucinations and continuous screaming. As the disease progressed, the pain in her legs worsened until she couldn't walk. Bedridden, her brain wasting away, she was reduced to commu

nicating through moans and grunts.


Zoe's mother, Helen Jeffries, let thetelevision cameras into her home to

demonstrate the plight of people likeher daughter—victims of new variantCreutzfeldt-Jakob disease, or nvCJD.The neurological illness is thought to bethe human form of bovine spongiformencephalopathy, or BSE—commonlycal led "Mad Cow Disease." The diseaseis thus far untreatable, incurable, and ul

timately fatal."It's a bad disease," says Lawrence

Schonberger, MD, MPH, an epidemiologist at the Centers for Disease Control and Prevention (CDC). "We believethat it is transmitted by food that hasbeen contaminated with the agent thatcauses BSE. Every case of nvCJD is amajor tragedy." Although the incubationperiod after initial exposure can be quitelong, once clinical signs and symptomsbegin, death usually occurs within abouta year.

The recent increase in reported casesof BSE in European cows and the increasing number of human nvCJD casesin the United Kingdom have raisedfears throughout the European Union(EU) of the risk of eating beef possiblycontaminated with the BSE agent. Although these concerns may have spreadto the United States, the diseases havenot. No cases of nvCJD in humans or

BSE in cows have ever been identifiedin this country.

BSE and nvCJD have thus far been

kept out of the United States largelythrough the combined efforts of theFood and Drug Administration, the U.S.Department of Agriculture (USDA), theCDC, other federal organizations, andstate regulatory and health agencies.These organizations have taken aggressive actions to reduce the risk that BSEcould be introduced and spread in thiscount ry.

BSE has infected more than 180,000cattle in the UK and about 1,800 cattleelsewhere in the EU, according to theEuropean Commission's Health andConsumer Protect ion Directorate, an

agency of the EU. Because of UK actions to eradicate BSE since it was firstidentified in 1986. the number of BSEcases is falling sharply in that country,but it is rising in a number of other European countries.

The sudden rise in reported BSE

cases may, in part, reflect increased testing to detect infected cattle by some EUmember countries, particularly France,according to Burt Pritchett, a veterinarian in FDA's Center for VeterinaryMedicine. "And because of the long incubation period of BSE (two to eightyears), cows being identified with BSEnow would have become infected several years ago," says Pritchett. "In December 2000, the EU imposed BSE testing EU-wide, which will likely furtherincrease the number of cases being reported."

How BSE Spreads Within CattleH e r d s

Evidence suggests that certain contaminated cattle feed ingredients are thesource of BSE infection in catt le. The

process that leads to the contaminatedfeed starts when livestock already harboring the BSE agent are slaughtered.After cows and sheep are killed, the edible parts are removed. The inedibleremnants are taken to a special plant,where they undergo a process called"rendering." This process creates twomajor products:• fat, which is used in an amazing arrayof products (such as soap, lipstick, linoleum, and glue), and• meat-and-bone meal (MBM), a pow

dery, high-protein supplement that is often processed into animal feed.Although the animal remnants are"cooked" at high temperatures duringthe rendering process, the BSE agent, ifpresent, is able to survive.

When this contaminated MBM is fedto cattle as a protein supplement, theBSE agent can be passed on to manynew cattle. It is believed that this is howBSE was spread through the UK cattleherds.

In 1997, scientists at the Institute forAnimal Health in Edinburgh, Scotland,and the Imperial College School ofMedicine in London presented studiesthat strongly pointed to the agent thatcauses BSE as the most likely cause ofhuman nvCJD. The UK governmentconc luded that v ic t ims of nvCJD most

likely acquired the disease by consuming food that had been made from cattlein fec ted w i th BSE.

Although BSE and nvCJD occur indifferent species, they both belong to a

family of fatal neurological diseasesknown as transmissible spongiform encephalopathies (TSEs), so named because of the sponge-like holes they leavein the brain. Currently, no test can reliably detect BSE in live cattle or nvCJDin live humans. A diagnosis is confirmedby examining brain tissue after death.

The agent that causes TSEs is not wellunderstood. The prevailing theory of thescientific community is that the agent isa "prion," an abnormal, slowly replicating protein.

"So little is known about prion diseases," says James Voss, DVM, of theCollege of Veterinary Medicine and Biom e d i c a l S c i e n c e s a t C o l o r a d o S t a t e U n i

versity. "It's a very difficult area tostudy because of the long incubation period of these diseases," says Voss, whois also the co-chairman of the TSE TaskForce of the Council for AgriculturalScience and Technology, a nonprofit research consort ium. "We bel ieve the r iskis very, very low that BSE could gainentry to this country, but no one can saywith 100 percent certainty that it won'thappen."

"We know that our cattle are not immune to this disease just because theylive on this side of the Atlantic Ocean,"

says Murray Lumpkin, senior medicaladv isor in FDA's Office o f the Commissioner. "Renderers, cattle ranchers, feedmanufacturers, feed lot operators, andstate and federal government agencieswil l al l have to continue to work to

gether vigilantly to assure safe cattle-feeding practices are scrupulously followed. This is our first line of defenseagainst the disease getting into American catt le herds."

Other TSEs are known to occur insheep, mink, deer, elk, and cats. The recent European outbreak of BSE mayhave originally resulted from feedingcattle with MBM-supplemented feedmade from sheep carcasses infected withscrapie—a TSE found in sheep andgoats.

Unlike BSE, other animal TSEs donot appear to be naturally transmitted tohumans, according to an October 2000report of the TSE Task Force. However,five TSEs do occur in humans—all ofthem rare. In 1957, scientists first recorded a human TSE, called kuru, in theFore natives of the New Guinea high-

ILLUSTRATION BY JESSE R. NICHOLS FDA Consumer / March-April 2001 / 13

lands. The Fores were cannibals—theyate parts of their fellow humans, especially brain tissue. It is believed thispractice contributed to further spread ofkuru in the population.

Tw o F o r m s o f C J DAnother human TSE, Creutzfeldt-

Jakob disease, in its classic form, occursworldwide at a rate of approximatelyone case per 1 million people per year.Classic CJD, unlike its new variant,nvCJD, is not known to be caused byconsuming food made from cows infected wi th BSE.

"CJD and nvCJD are best thought ofas two different diseases," says CDC'sSchonberger. "CJD was around long before the emergence of BSE in cattle."

Vict ims of c lassic CJD and nvCJD

may share some symptoms, but the pat

terns of the brain lesions are distinct. Todate, nvCJD has caused disease inyounger patients, and the mean durationof illness is more prolonged. (The average age for death of nvCJD has been27.5 versus 68 for CJD, and the averagetime to death after the onset of clinical

symptoms is 13 months for nvCJD versus less than six months for CJD.)

As of Feb. 2, 2001, a total of 94 casesof nvCJD have been confirmed or suspected in the UK, according to the UKDepartment of Health. Three cases inFrance and one in Ireland were reportedby the European Commission's Healthand Consumer Protection Directorate.

The U.S. ResponseThe focus for American animal and

human health officials has been prevention. "Using the best science known atthis time, the United States has an aggressive, multi-faceted program in placeto try to prevent the establishment andspread of BSE," says Stephen Sundlof,DVM, PhD, director of FDA's Centerfor Veterinary Medicine. FDA's restric

tions on certain cattle feed ingredientsand its import alerts on cattle productsare critical parts of this program. In addition, USDA has prohibited certain animals and animal products from enteringthe country.

Since 1989, USDA's Animal and PlantHealth Inspection Service (APHIS) hasbanned the import of live ruminants(cattle, sheep, and goats) and most ruminant products from countries where BSEhas been reported. In addition, in 1990,APHIS began a program of active survei l lance of cer ta in American cows forevidence of BSE. While FDA inspectsfeed production facilities, the USDAsurveillance program condemns andtests any cows displaying signs of neurological problems at slaughter. As ofOctober 2000, approximately 12,000cattle brains from nearly every state and

Puerto Rico had been examined, with noevidence of BSE found. More than 60diagnostic laboratories continue to examine hundreds of cattle brains eachy e a r .

In August 1997, FDA established aregulation that prohibits the use of mostmammalian protein in the manufactureof animal feeds for ruminants. With the

strong support of renderers, cattle owners, feed manufacturers, and feed lotowners, FDA launched a complianceand education program, including a rigorous inspection program. The goal ofthese efforts is to achieve as close to100 percent compliance with this newregulation as possible. FDA and stateregulators have conducted nearly 10,000inspections of renderers, feed mills, ruminant feeders, dairy farms, proteinblenders, feed haulers, and distributorssince January 1998. More than three-quarters of these establishments werefound to be in compliance. And most ofthe establishments that initially hadproblems were found in complianceupon re-inspection.

Education is also an extremely important part of the compliance program."We've put a lot of effort into gettingthe word out about the regulation," saysSundlof. FDA has sponsored workshopsfor state veterinarians and feed control

officials from all 50 states, Puerto Rico,the U.S. Virgin Islands, and Canada. Inaddition, FDA has held briefing sessionswith trade associat ions and consumer

groups, and has developed additionalguidances for complying with the regul a t i o n .

FDA is continuing its compliance efforts by conducting additional inspections and re-inspecting non-compliantfacilities. Based on an evaluation of the

inspections conducted from 1998through 2000, FDA will revise its compliance strategy to try to assure its goalof 100 percent adherence to the feeding

regulations.FDA and USDA re

cently took emergencyaction to prevent potentially cross-contaminated productsfrom entering theUnited States. On De

cember 7, 2000,APHIS banned al l im

ports of rendered animal proteins, regardless of species, from the more than30 countries that either are known tohave BSE in their cattle or otherwisepresent undue risk for introducing BSEinto the United States. FDA has also announced an import alert, allowing its inspectors to detain shipments from thesecountries of animal feed (including petfood), animal feed ingredients, and certain other products of animal origin intended for animal use.

FDA and USDA will continue to aggressively enforce their regulations andto work closely with those in the cattleand feed industries to minimize the riskof BSE introduction or spread in U.S.cattle herds. FDA will develop newguidances and regulations as the scientific knowledge about BSE expands.Working together with many counterpartagencies in the United States and aroundthe world and with various industry andconsumer groups, FDA will continue todo its best to protect the health ofAmericans and of our American cattleherds . ■

No cases of nvCJD in humans or BSEin cows have ever been identified in

this country.


Food Safety Efforts:Fruit Juice, Mercury In Fish

By Raymond Fonnanek Jr.

c trict rules for egg producers and makers of

I fruit or vegetable juices, and consumptionlimits for pregnant women and women con

sidering pregnancy on fish containing high levels of

mercury highlight a comprehensive food safety pack

age issued by the Food and Drug Administration.The vast majority of fruit and vegetable juices sold in the

United States are pasteurized to kill potentially harmful bacteria during the manufacturing process. Juice processors whodon't pasteurize their products now must take other germ-killing steps such as an ultraviolet light treatment or specially

treating peels before squeezing citrus fruit for juice, accordingto a rule issued in January by FDA's Center for Food Safetyand Applied Nutrition (CFSAN).

Unpasteurized fruit and vegetable juices have posed serious public health risks in recent years. Seventy people—including a child who died—became ill in 1996 after drinkingunpasteurized apple juice contaminated by a strain oi Escherichia coli bacteria. In 1999 and 2000, unpasteurized orangejuice contaminated with salmonella bacteria sickened hundreds of people in the United States and three Canadian provinces. The 1999 outbreak contributed to one death.

Under the new rule, juice processors are required to followHazard Analysis and Critical Control Point (HACCP) principles, a quality control system initially developed by NASA

ILLUSTRATION BY JESSE R NICHOLS FDA Consumer / March-April 2001 / 15

Juice processors who don't pasteurize their products nowmust take other germ-killing steps before squeezing citrusfruit for juice.

to prevent food-borne illnesses amongastronauts. Manufacturers using HACCPsystems conduct science-based analysesof food production processes, locatewhere the hazards can occur, take stepsto prevent problems, and respond rapidlyto problems. FDA inspectors will dospot-checks to ensure that the processors' FIACCP systems are working.

Packaged unpasteurized juices produced and sold at retail establishmentsmust carry a warning label under thenew rule.

Large companies have a year from thepublication of the regulation to implement HACCP programs. Small companies must comply within two years afterpublication, and roadside stands andother very small operations must complywithin three years. The FDA estimatesthat between 16,000 and 48,000 juice-related i l lnesses occur in the UnitedStates each year.

For more on juice safety, see the FDAnews release at www.cfsan.fda.govl-lrdihhsjiiic4.html.

Mercury, Fish and Pregnant WomenPregnant women and women consid

ering pregnancy should not eat shark,swordfish, king mackerel or tilefish because they could contain enough mercury to harm an unborn infant's nervoussystem, according to an FDA advisory.

The advisory says that young childrenand nursing women also should avoidthose species of fish, which tend to livelonger and have higher mercury concentrations in their tissues.

The National Academy of Sciences e.s-timates that 60,000 children born eachyear might be exposed to levels of mercury during gestation high enough to potentially interfere with brain and nervous.system development.

In its advisory, the FDA says that fishare an important source of protein andpart of a healthful diet. Joseph Levitt, director of CFSAN, says pregnant women

safely can eat 12 ounces of other typesof cooked fish each week. Levitt saysthat it's important to eat a variety ofother kinds of fish.

Mercury, a silvery element, occursnaturally. About half of environmentalmercury occurs from vapors escapingfrom the earth's core. Most of the restcomes from smokestack emissions,wh ich the Env i ronmenta l P ro tec t ion

Agency (EPA) regulates under the CleanAir Act. The EPA estimates that solid-waste incinerators and coal-fired powerplants arc responsible for more than 80percent of the man-made mercury emissions in the United States.

Bacteria in both fresh and salt waterconvert mercury into methylmercury, atoxic form that accumulates in fish.

CFSAN plans a comprehensive education program to reach pregnant women,women of childbearing age who may become pregnant, and their health-care

providers concerning the hazard posedby methylmercury to the unborn child.As one of its priorities for fiscal year2001, the center also will develop a public health strategy for future regulationof methylmercury in commercial seaf o o d .

For more on the FDA advisory on methylmercury in fish, check out the FDATalk Paper at www.cfsan.fda.govl-Ird!tphgfish.html.

L i s t e r i aThe bacterium Listeria monocyto

genes can be found nearly everywhere—soil, dust, sewage, and even water. It'stough too. It can thrive in hot, salty oracidic environments that are deadly tomany other bacterial strains.

Even cold temperatures don't stop listeria, which can cause a potentially life-threatening disease called listeriosis. Thebacterium continues to multiply—albeitmore slowly—until temperatures reachzero degrees Fahrenheit. Most otherfoodborne bacteria stop growing at 40 F.

Researchers have known since the

early 1900s that listeria infects animals,including birds and fish. The bacteriumwas recognized as a human pathogen in1929. However, scientists didn't knowthat listeria could be spread throughfood as well as by animal contact untilthe early 1980s.

Listeriosis causes an estimated 2,500serious illnesses and 500 deaths in theUnited States each year. Foodborne illness caused by listeria in pregnantwomen can result in miscarriage, fetaldeath, and severe illness or death of anewborn infant. Others at risk for severe

illness or death are older adults andthose with weakened immune systems.

Listeria often may pass through the digestive systems of healthy people, causing only mild, flu-like symptoms orwithout causing any symptoms at all.

The FDA and the U.S. Department ofAgriculture's Food Safety and Inspection Service have released a draft riska.ssessment of the potential risks of listeriosis from eating certain ready-to-eatfoods and an action plan designed to reduce the risk of foodborne illness causedby listeria.

The government advises that consumers can reduce their risk of listeriosis by:• Using perishable items that are precooked or ready-to-eat as soon as poss i b l e• Cleaning refrigerators regularly• Using a refrigerator thermometer toensure that temperatures remain at 40 Fo r l o w e r

The FDA and USDA say that pregnantwomen, older people, and those withweakened immune systems should takethe following steps to avoid li.steriosis:• Do not eat hot dogs or luncheon meatsunless they are reheated until steamingh o t .• Do not eat soft cheeses such as feta,brie or Camembert, blue-veined chee.sesor Mexican-style cheeses such as quesobianco fresco. Hard cheeses, semi-soft


Pregnant women and women considering pregnancy shouldnot eat shark, swordfish, king mackerel or tilefish ... youngchildren and nursing women also should avoid those species.

cheeses such as mozzarella, pasteurizedprocessed cheeses, cream cheese, andcottage cheese may be eaten.• Do not eat refrigerated pates or meat

spreads. Canned or shelf-stable patesand meat spreads may be eaten.• Do not eat refrigerated smoked sea

food, unless it is part of a cooked dish,such as a casserole. Refrigerated smokedseafood—such as salmon, trout, white-fish, cod, tuna or mackerel—most oftenis labeled as "nova-style," "lox," "kippered," "smoked," or "jerky." The products are found in the refrigerator sectionor sold at deli counters of grocery storesor delicatessens. Canned or shelf-stablesmoked seafood may be eaten.• Do not drink raw (unpasteurized) milkor eat foods that contain raw milk.

Final action on the listeria draft risk

assessment and the action plan will betaken after considerat ion of commentssubmitted by March 20, 2001. For moreinformat ion on l is ter ia and foodborne

illness, see the news release on theInternet at www.hhs.govjnews!press!200]presl20010118c.lilinl.

Safety oflmported FoodsThe FDA has developed new proce

dures that target "bad actor" importerswho violate the rules and undermine the

country's food-handling system bybringing unsafe food into U.S. markets.

The procedures now require that foodshipments from "suspect" importers beheld in a secure storage facility at theimporter's expense until released by theFDA. Those who falsify documents orotherwise try to elude customs procedures also may be subject to fines up tothe total value of the merchandise.

Some importers attempt to get aroundFDA regulations by "port shopping," atactic in which the importer seeks admittance through another U.S. port when attempts at a first port have failed. In a bidto thwart the practice, FDA has proposed a rule that would require marking

food shipments refused for safety reasons to indicate that the product hadbeen previously denied entryinto the United States.

In addition, FDA is

developing a proposed rule thatwou ld es tab l i sh

standards for im

porters and otherswho use sample-c o l l e c t i o n s e r v i c e s o r

private laboratories todemonstrate compliancew i t h F D A l a w.

The procedures and proposals were developed in response to a July 1999 presidential directive to the secretaries ofFlealth and Human Services and

Treasury to work together to address the movement of unsafe foodinto the United States.

For more on the effort to tighten therules on imported foods, read the FDATalk Paper available on the Internet atwww.cfsaii.fda.gov/~lrdltpimport.html.

Egg SafetyYou may like them sunny side up or

over easy, but it's safer to eat eggs thatare cooked well. The FDA has issued afinal regulation that soon will requireshell egg cartons to bear the followings t a t e m e n t :

" S A F E H A N D L I N G I N S T R U CTIONS: To prevent illness from bacteria: keep eggs refrigerated, cook eggsuntil yolks are firm, and cook foodscontaining eggs thoroughly."

In addition, the rule requires that eggsbe promptly refrigerated at 45 degreesFahrenheit or lower upon delivery atfood-preparation establishments, including supermarkets, restaurants, delicatessens, caterers, vending operations, hospitals, nursing homes, and schools.

The new rule aims to preventfoodborne i l lnesses f rom the bacter ium

Salmonella enteritidis, which has beenassociated with undercooked eggs andfoods containing undercooked eggs. Refrigerating eggs at 45 F or cooler slowsthe growth of the bacteria.

It's estimated that about one in 20,000eggs produced in the United States iscontamina ted w i th sa lmone l la . Personsinfected with salmonella may experiencediarrhea, fever, abdominal cramps, headache, nausea, and vomiting. Children,older people, and those with weakenedimmune systems may develop severe oreven life-threatening illnesses.

FDA's new egg safety rule is part of alarger egg safety action plan, a joint effort between FDA and the U.S. Department of Agriculture that seeks to eliminate egg-associated salmonella illnessesby 2010. For more information on eggsafety efforts, see the FDA Talk Paper atwww.cfsaii.fda.govl~lrdlhhseggs2.html. m

ILLUSTRATION BY RICHARD THOMPSON JR FDA Consumer / March-April 2001 / 17

ACCU A N EBy Michelle Meadows

As powetful asAccutane can he in

improving patients'lives, its adverseeffects can he just aspowetful.

Julie Harper, MD, assistant

professor of dermatology at tfie

University of Alabama-

Birmingham, says her desire to

help patients with skin disorders

grew out of her own

experience with severe acne.

1 8 / March-April 2001 / FDA Consumer

The Benefits And RisksOf A BreakthroughAcne Dru

AryipJL JLV^ I r V/ plagued Julie Harper throughout high school and college.

She depended on makeup and wore her hair down over the side of her face. She gave

up chocolate and french fries, only to find that neither made a difference. And she

went through medicine after medicine, from over-the-counter creams to oral antibi

ot ics.

These were not occasional pimples that vanish after a couple of days. This acne

covered her face and left scars on her neck. "I had tried everything and felt frus

trated all the time," says Harper, now a physician and assistant professor of derma

tology at the University of Alabama-Birmingham—a career she chose due in large

part to her struggle with acne.

Harper finally found a successful treatment nine years ago at the age of 22. She

took a drug called isotretinoin (trade name Accutane) and watched her skin improve

in just a couple of months. By the third month, her acne had disappeared. She says

with clearer skin came more self-confidence and higher self-esteem.

Considered the biggest breakthroughin acne drug treatment over the last 20years, Accutane is the only drug that hasthe potential to clear severe acne permanently after one course of treatment.One course, which is typically fivemonths, results in prolonged remissionof acne in up to 85 percent of patients. Amember of a class of drugs known asretinoids, Accutane is highly effective.But it doesn't work for everyone, andsome patients need more than one

course of treatment. Dr. Harper took asecond course of Accutane one year after the first and has been free of severeacne ever since, now only occasionallyusing a topical medication.

No other acne medicine works as wellfor severe acne. Patients generally haveto keep using other medications becausethey only suppress acne temporarily. Butas powerful as Accutane can be in improving patients' lives, its adverse effects can be just as powerful. The drug is

known to cause miscarriage and severebirth defects. Patients taking Accutanemay develop potentially serious problems affecting a number of organs, including the liver, intestines, eyes, ears,and skeletal system. And some patientstaking Accutane have developed seriouspsychiatric problems, including depression. More rarely, patients have developed suicidal behavior and killed thems e l v e s .

Because it is a high-risk drug,Accutane should be reserved for cases of"severe recalcitrant nodular acne," ac

cording to the product's labeling. Thistype of acne is resistant to standard acnetreatment, including oral antibiotics, andis characterized by many nodules orcysts—inflammatory lesions filled withpus and lodged deep within the skin.These lesions can cause pain, permanentscarring, and negative psychological effec ts .

"Sometimes people tend to dismissthe impact of acne because it's not life-threatening, says Kathy O'Connell, MD,PhD, a medical reviewer for Accutane inFDA's division of dermatologic and dental drug products. Center for DrugEvaluation and Research (ODER). "Butpatients with severe acne know all toowell the very real suffering caused bythis disfiguring disease."

FDA approved Accutane in 1982, andsince then, about 5 million people in theUnited States and 12 million worldwidehave been treated with it, according toits manufacturer, Hoffmann-Ua Roche ofNutley, N.J. The number of patients taking the drug has increased, and half arefemales, most of whom are in theirchildbearing years (age 15-44). Becauseof concern about the drug's risks, FDAcontinues to evaluate Accutane and workwi th the manufacturer to max imize safeuse of the drug.

Warning about Pregnancy RisksWhen FDA approved Accutane, the

drug was known to be teratogenic—ableto cause birth defects. It was designatedas Category X, meaning that it must beavoided under all circumstances during

pregnancy. Nursing mothers also shouldn o t u s e A c c u t a n e .

PHOTOGRAPH BY BLACK STAR/ MIKE CLEMMER FDA Consumer / March-April 2001 / 19

Though not every fetus exposed toAccutane becomes deformed, the riskof birth defects among pregnant womenis extremely high. These defects includehydrocephaly (enlargement of the fluid-filled spaces of the brain) and microcephaly (small head), heart defects, facial deformities such as cleft lip andmissing ears, and mental retardation.

Reports in the literature suggest thatabout 25 to 35 percent of babies willsuffer a malformation after exposure,a n d t h a t d o e s n ' t a c c o u n t f o r o t h e r d e

fects, such as learning disabilities, thataren't detectable at birth. Miscarriagesand premature births have also been reported.

Though FDA approved labeling in1982 that warned Accutane should notbe used in pregnant women, reports ofsevere birth defects associated with the

drug began to arrive in June 1983. Overthe following years, a series of labelingchanges and letters to pharmacists andprescribers of the drug stressed pregnancy warnings and sought to increaseawareness about reported malformat ions .

Then, after an FDA review of pregnancy exposures to Accutane, Rochelaunched the Pregnancy Prevention Program (PPP) in late 1988 to further educate women using Accutane and theirphysicians about the dangers. The goalwas to ensure that prescriptions wouldonly be given to women with severe recalcitrant nodular acne who could comply with contraceptive requirements.

Roche sent PPP kits to physicians andencouraged them to review pregnancyprevention materials with patients before starting the drug. Materials included a contraceptive booklet, checklists to help assess whether patientscould adhere to the drug's requirements,and consent forms that patients sign toacknowledge their understanding of therisk of birth defects. Roche also set up atoll-free line, made contraceptive information available in 13 languages, andoffered to pay for contraceptive counseling and pregnancy testing by a specia l is t .

To further reinforce pregnancy prevention, Roche began packagingAccutane in blister packs that includered and black warnings, along with adrawing of a malformed baby and the

"Avoid Pregnancy" symbol.Even though Accutane's labeling rec

ommended use of two rel iable forms of

contraception, there have been reports ofpregnancies occurring in patients whoused hormonal contraception, includingpills, injectable.s, and implantables,while taking Accutane. Accutane's labeling was updated in the summer of 2000.One change emphasized the need fortwo reliable forms of contraception forat least one month before takingAccutane, during treatment, and for onemonth after discontinuing Accutane,e v e n w h e n o n e o f t h e f o r m s o f c o n t r a

ception is hormonal.

Evaluating ComplianceYolonda Lawrence of Santa Monica,

Calif., says there was no way she couldmiss the point about pregnancy prevention before she used Accutane for severeadult-onset acne in 1998. "I got a pamphlet, 1 signed papers, the doctor told meover and over, and the pictures of whatcan happen were very clear—babieswith no ears" and other deformities, shes a y s .

But reports of Accutane-exposed pregnancies continue, and that's enough tomake FDA concerned, says Peter Honig,MD, director of FDA's office ofpostmarketing drug risk assessment(OPDRA) in CDER.

Shortly after the Pregnancy Prevention Program began, Roche sponsored asurvey of women taking Accutane to assess compliance with the program, andthe company encouraged doctors to enroll patients. Run by the Slone Epidemiology Unit at Boston University'sSchool of Public Health, the survey setout to track pregnancy rates and outcomes, patients' awareness of risks, andpatient and physician behavior.

Of the 500,000 women enrolled in the

Slone survey from 1989 to 1998, therehave been 958 pregnancies, 834 ofwhich were terminations (either elective, spontaneous or due to ectopicpregnancies), 110 that resulted in livebirths, and 14 patients that had unknown outcomes. Of the 60 infants withavailable medical records, eight hadcongenital abnormalities. SinceAccutane's approval, Roche has received close to 2,000 reports ofAccutane-exposed pregnancies, 70 percent of which occurred after the PPP be

g a n .

According to FDA, exactly how wellthe PPP has worked is unclear. Expertssay the PPP is a significant program thathas prevented many pregnancies and isthe first of its kind initiated by a pharmaceutical company. Roche has madeextraordinary efforts to educate patientsthat they must not become pregnantwhile taking Accutane, says a Rochespokesperson.

At a September 2000 meeting ofFDA's Dermatologic and OphthalmicDrugs Advisory Committee, a Rocherepresentative reported that from thecompany's perspective, pregnancy rateshave declined. Amarilys Vega, MD, anFDA medical officer, agreed. However,because use of the product has increased over the years, the actual number of pregnancies occurring while taking Accutane has not declined. Onelimitation is that the survey is voluntaryand only captures about 30 to 40 percent of all patients on Accutane. Sothere's no way to know exactly howmany pregnancy exposures there havebeen, according to FDA experts. Of serious concern is that women who enrollin the survey may be more likely tocomply with the contraceptive requirements than those who don't enroll in the

survey. This leaves open critical ques-

To learn more, visit FDA's Accutane page on theInternet: www.fda.govlcderldruglinfopagelaccutane.To report adverse events related to Accutane, call RocheMedical Services at 1-800-526-6367 or FDA's MedWatch

Program at 1-800-FDA-1088.


Because it is a high-risk drug, Accutane should he reserved forcases of "severe recalcitrant nodular acne."

Monthly Accutane PrescrptionsEnsure Foltow-Up

Evelyn Germanakos of Los Angeles,Calif., recalls forgetting to have a bloodtest before returning to her dermatolo

gist for a monthly visit while takingAccutane. "He sent me right away to getit and said he wouldn't renew the pre

scription without it," she says.Experts say that kind of follow-up is

critical. Doctors should only give one-month prescriptions for Accutane andshould conduct urine or blood preg

nancy testing and contraceptive counseling each month of treatment.

Monthly blood tests also allow doctors to monitor patients for other adverseeffects. Elevated triglyceride levels,which can be associated with pancreati

tis, have occurred in about 25 percent ofpatients in clinical trials for Accutane,and about 7 percent of patients showedan increase in cholesterol levels.

Alan N. Moshell, MD, director of the

skin diseases branch at the National In

stitute of Arthritis and Musculoskeletal

and Skin Diseases, says he's heard aboutsevere adverse effects such as liver dam

age in cases where a full dose ofAccutane has been prescribed with inad

equate follow-up. "It has usually been asituation in which the full five-month

course has been prescribed at the firstvisit and then the patient was not

brought back, or simply failed to follow

instructions about follow-up visits andblood tests." In such cases, patients may

keep taking the drug and only return tothe doctor when it's too late and they've

experienced an adverse effect.More common s ide effects of

Accutane include lip inflammation anddrying of the skin and mucous membranes. Germanakos says her mouth was

incredibly dry. "1 drank about 15 to 16glasses of water a day, and I was stillthirsty," she says. She also experiencedskin peeling on her eyelids and dry nasalpassages, and she says her acne gotworse before it got better.

— M . M .

tions about how representative the PPPgroup is and about unreported pregnancies among women who don't enroll int h e P P P.

Most patients in the Slone surveyhave reported that they understoodAccutane may cause birth defects. Andaccording to Roche, the percentage offemale patients who reported they werepregnant when they began Accutanedropped from 30 percent of pregnanciesreported in 1989 to 11 percent of pregnancies reported for the period of 1991to 1997. But substantial noncompliancewith the PPP continues to be reported.

For example, a 1997 report on the survey shows that 25 percent of women inthe program did not report having apregnancy test before starting Accutane,and 33 percent did not report postponingthe start of Accutane until a pregnancytest result was known. It is estimatedthat 40 percent of women takingAccutane are sexually active.

The only patients exempt fromAccutane's contraceptive requirementsare men, and women who have had a

hysterectomy or who say they will abstain from sex during treatment. But thechallenge is that going from sexually inactive to active can happen overnight.

Possible Psychiatric LinkMany patients say they feel better

about themselves after receiving successful treatment for acne. EvelynGermanakos, of Los Angeles, Calif.,struggled with acne as an adult, and saysshe felt like her old self after Accutanecleared up lumpy blemishes in 1997. "Ihad gotten to the point where I didn'teven want to go outside or be withpeople, let alone look in the mirror," shesays. But while Accutane may help liftpsychosocial distress such as embarrassment, evidence suggests that it may actually cause serious psychiatric disorders in some people.

Though the drug's label previously(continued on page 23)


Why Acne Forms,and How AccutaneKnocks it Out

A c n e i s t h e m o s t c o m m o n s k i n d i s

order, and while it usually appears inadolescence, adults can get it too.A c n e o c c u r s w h e n h a i r f o l l i c l e s a n d

the sebaceous glands inside the foll i c l e s a r e i n fl a m e d . S e b a c e o u s

glands make an oily substancec a l l e d s e b u m . To o m u c h s e b u m c a n

clog the follicles and lead to bacterialgrowth and inflammation.

According to the American Academy of Dermatology, the four basicmechanisms contributing to acne arehormones, increased sebum production, changes inside hair follicles,and bacteria. Acne usually occurs atage 11 to 14 when the body startsproducing male hormones called androgens. Androgens can over-stimulate sebaceous glands and makethem produce more sebum.

Dead cells inside hair follicles nor

mally are shed and come out ontothe surface of the skin. But in peoplewith acne, the cells are shed faster,stick together, mix with sebum, andclog the follicle. Then bacteria contaminate the skin cell and sebummixture and grow. When the body'simmune system tries to destroy thebacteria, inflammation results.

Accutane helps the function of thefollicles return to normal, lowers production of sebum, slows the growthof a bacterium called Propionibacte-rium acnes {P. acnes), and reducesinflammation and the chance forscarring. The drug is unique in itsability to affect all main underlyingcauses of acne formation.

— M . M .

epidermal cellssebum

sebaceous gland

hair follicle

pllosebaceous unit

(1) Acne begins inpilosebaceous units, whichconsist of sebaceous glandsand a single hair follicle.The sebaceous glandsproduce an oily substancecalled sebum.

blackhead

blocked follicle

open comedo

(2) Sometimes, hormonesproduced in the adrenal glandstrigger the production of excesssebum, clogging the follicle andleading to bacterial growth. Theresulting plug can appear darkand is called a blackhead, or opencomedo.

whitehead

sebum

closed comedo

pustule

inflamed tissue

sebum and pus

ruptured follicle

(3) If the plug is below the skinsurface, it is called a whitehead,or closed comedo.

(4) But, if the pocket of sebumand bacteria becomes too large,the follicle will rupture, spilling itscontents into the surroundingtissue. These tissues aredamaged when the body'simmune system attempts arepair, resulting in a papule,pustule, cyst or abscess.

■a

5"


It is recommended that doctors act as if/iccuianecould have psychiatric effects until there is more information.

(continued from page 21)listed depression as a possible reaction,FDA strengthened the label warning in1998 after reviewing cases with seriousoutcomes reported in the years after thedrug was approved. The new labelingstates that Accutane may cause depression and psychosis, and that in rarecases it may cause suicidal ideation(thoughts of suicide), suicide attempts,a n d s u i c i d e .

The label also advises providers thatsimply discontinuing the drug may notremedy any psychiatric problems andthat further evaluation may be necessary.'1n some cases, stopping Accutane alonemay not be enough to relieve the moodchanges," says Jonathan Wilkin, MD, director of CDER s division of dermatologicand dental drug products. "Psychiatrictreatment may also be needed."

The relationship between Accutaneand depression remains unproven, butsome patients have reported that theirdepression subsided when they stoppedthe medication and came back when

they resumed taking it. And some whohave reported problems with depressionwhile taking Accutane had no previouspsychiatric history. FDA considers thenumber of reports of serious depressionassociated with Accutane high compared to other drugs in its database.

From 1982 to May 2000, FDA received reports of 37 U.S. Accutane patients who committed suicide, 24 whileon the drug and 13 after stopping thedrug. In addition to suicides, FDA received reports of 110 U.S. Accutane users hospitalized for depression, suicidalideation, and suicide attempt during thesame time period. As of May 2000, FDAhad received reports of 284 Accutaneusers with non-hospitalized depression.

Several factors make it hard to defini

tively link depression with Accutane.

Depression is a common problem, andsome patients may be suffering from itbefore starting Accutane therapy. Additionally, some patients who reported depression with Accutane had previouscourses of the drug without depression.Even so, it is recommended that doctorsact as if Accutane could have psychiatriceffects until there is more information,says FDA's Wilkin.

T h e F u t u r e o f A c c u t a n eRoche does not want to have any

Accutane-exposed pregnancies, a company spokesperson says, and plans tocontinue educational efforts. This yearRoche launched a targeted PregnancyPrevention Program that focuses onwomen who are at highest risk of becoming pregnant while taking Accutane.

Experts agree that pregnancy prevention education should remain a key partof risk management for Accutane use.But more labeling changes and lettersare not likely to make a significant difference, according to FDA's Honig."During all the time the drug has beenon the market and after all of those la

beling changes, there are still pregnancies," he says. "It is not expected thatanother labeling change or 'Dear Doctor' letter will change behavior at thispoint." Psychiatric adverse events havealso continued after labeling changes.

FDA's Dermatologic and OphthalmicDrugs Advisory Committee met in September 2000 to discuss options forAccutane, and to evaluate whether aframework for safer use of the drug can bedeveloped. One change since then is thatall Accutane prescriptions now come witha new Medication Guide that contains

warnings about pregnancy and psychiatricissues, plus other important warnings andprecautions regarding potentially seriousor life-threatening effects.

FDA has also proposed a mandatoryregistration of patients taking Accutane,prescribers, and pharmacists. "The mainreason is to ensure that pregnancy testing is done before the drug is prescribed/' says Julie Beitz, MD, of FDA'soffice of postmarketing drug risk assessment. The goal would be to have doctorsdocument negative pregnancy tests andto have pharmacies dispense the drugonly to women who have had negativepregnancy tests. The program to trackAccutane patients is expected to be inplace by summer 2001.

The registry for prescribers may involve a continuing education course thatdoctors would have to take to be able to

prescribe Accutane. According toHoffmann-La Roche, about 85 percentof Accutane prescriptions come fromdermatologists and 15 percent comefrom primary care physicians. Thecourse would be open to all medicaldoctors. And all Accutane patientswould have to sign a mandatory consentform that would address both pregnancyand psychiatric issues, Beitz says.

The American Academy of Dermatology and the Dermatologic Nurses Association were among those who testifiedat the September 2000 committee meeting in opposition to a mandatory registration, saying that it would be a disservice to patients, making it harder forthem to obtain the drug. Others, including the March of Dimes and the PublicCitizen's Health Research Group, testified that they want to see stricter measures for Accutane.

FDA's experts say it's a balancing act.The value of Accutane is clear, but whenit comes to even one report of death—whether it's suicide, miscarriage, orsome o the r cause—FDA mus t makechoices that will best protect the public'shea l t h . ■


ranees Oldham KelseyIt was early 1942 and war was raging in the jungles of the Pacific, in addi

tion to fighting the Japanese, Allied troops found themselves under attack by malaria-carrying mosquitoes.

And since enemy soldiers had already captured several plantations of cinchona trees, the source of the anti

malarial quinine, the search was on for an effective quinine substitute to combat the disease.

A possible treatment—in the form of a dark, inky substance—arrived for testing in the pharmacology de

partment at the University of Chicago. Pharmacologist Frances Oldham Kelsey, like many other university

researchers throughout the country, had enlisted in the search for synthetic cures for malaria.

As it turned out, the inky substancehad been sent by a veterinarian in Texas."Fie said that he had just tried it on hissecretary without ill effects," saysKelsey, "and he planned next to try iton cat t le . I t showed the re lat ive value

placed on women and cattle in Texasat that time," Kelsey says with amusement. The good humor and equanimityKelsey displays at this slight aresymptomatic of the way she ap

proached most of life's adversities.The war ended without finding a

good substitute for quinine. But Kelseydid learn something valuable from theexperience. She learned that rabbits metabolized quinine rapidly, but pregnantrabbits had less ability to break downthe drug, and embryonic rabbits couldnot break it down at all. She alsolearned that drugs could pass throughthe placental barrier between mother

and unborn child. These insights wouldserve Kelsey well some 15 years laterwhen in early 1960, as a new Food andDrug Administration employee, she wasasked to evaluate a drug most thoughtwas harmless. That drug was thalidom i d e .

Although pressured by the manufacturer to quickly approve a drug alreadyin widespread use throughout the rest ofthe world, Kelsey held her ground.

F D A M e d i c a lR e v i e w e rL e a v e s H e rMark On

HistoryBy Linda Bren

As a graduate student at the University ofChicago (below left), Kelsey helped Professor E.M. K. Geiling to find out why people were dyingfrom Elixir Sulfanilamide. The 107 deaths spurredthe passage of the Federal Food, Drug andCosmetic Act of 1938.

The story of Kelsey's two-year battle to keepthalidomide out of the American market spreadrapidly after she made headlines on July 15,1962 (below). Congress responded by passingthe Kefauver-FHarris Amendments, a landmark

drug law.

Wtien sine repeatedly aslced for moredata and effectively forestalled the approval of thalidomide, Kelsey did morethan keep a dangerous drug off the market. She set into motion a series ofevents that would forever change theway drugs are tested, evaluated, and int roduced in Amer ica .

In recognition of Kelsey's vigilance,President John F. Kennedy, on Aug. 17,1962, presented her with the highe.sthonor that can be bestowed upon a U.S.civilian: the medal for DistinguishedFederal Civilian Service. And nearly 40years later, Kelsey was once again honored. On Oct. 7, 2000, she was inductedinto the Nat ional Women's Hal l of Famein Seneca Falls, N.Y. Kelsey joins suchother women of distinction in the Hall asAmer ican Red Cross founder Clara

Barton, first American woman physicianElizabeth Blackwell, and human rightsactivist and first lady Eleanor Roosevelt.

The Thalidomide TragedyAll they wanted was a good night's

sleep, and a drug called thalidomidegave it to them. It brought a quick, natural sleep for millions of people who hadtrouble drifting off, and it also gavepregnant women relief from morningsickness. The drug's German manufac-

low in «i'pp«r 60j. l»>lurdiy's teinpora; -lVrt^: Klgti,"81'ilctfoes il:6 p. mj*

t r a W T T T T n i r m Tr ? a . m .IVcftllicr >fap end Dcwlli on Pflpe'«<. f i-p Srimes' eralh' -85lli Year • ■ • U N D A Y J U L Y 1 g i A Twror-TV (9) iu . i io ( isoo) .

n o fl l n l f o n u o d I l n b l c . s

'Heroine' of FDADrug Uff of Mi

Keeps,a i k e l

U.b. Captainfgjfulletlinled Attaelf

This U the SIi k c p l i e i s m M d t t u h b o r n rpf I -Coverntnenl physieteanrevciilcd whti could havebeen an appallins .A.merfcaniragcdy. the birth ol hundroili |uc indeed thousands ot atless and tcelcsj ehltdren.

The. s tory ot Dr. Krances '•O ldham Kc lscy. i Food-and ;

Orus Administration medicalnHiecr, It not onr of Inspired ;.prophealcs nor ot drama 'search brcahthrausbs.

She fjw her duty In sternly '' simple terms, and she carried Iit out, l ivlna the while withInsinuations that she was abureaucratic niiplcNer. unrtalonab le — c fcn , she - l a id ,stupid That such attributes |could ha»c been aitr ibed toher is, by licr own achnowl-Wicmcm. not lurprisins. eon.i tdcr tn ; a t t o( the e i rcu iTi '

W h a t s h e fl i O " O i l r e l u s c . .

be hurried Into iiiprovint on" that the terrible cfteets of theappl icat ion lor marhct lnE a drug abroad woro widelynew ilrug. She regarded lu.psncil in ihla country. Wi

"sf.Iety as unproved, despite, remains to be told is how jconildorablo dsU arguing that why -Dr. Kclsoy blocked '' i t w a s u l t r a s a f e . [ I n u o d u e t i o n o f t h e d r u g b e

l l was not unt i l lasi Apr i l , foro Uiosc efleei i *19" months atltc ine applica- pemed by anyone,tlon was tiled with the FDA.! Dr. Kelsey invoked

I s e d a t i r e , h u g o q u a n i l t' i t were sold over the coun

be fo re i t was pu t en a pi p t l o r t b a s t s . I t g a v e

p romp t , ' deep , na tu ra l - s l eept h a t w a s n o t f o n c w c d b y ah a n g o v e r . I t w a s c h e a p . I t' • Jlcd to km even the would

: s u i c i d e s w h o s w a l l o w e dassivc doses.And there werfl ' ' ihe repor ts

1 cxperlmci i t i •wi th animals.Only a few wcoks ago' theA m e r i c a n l i c e n s e e t o l d o fgivlns the drug to rats indotot a to CO . t imet ( i rca ler

i n t h e e o m p i r a b l c h ilaga. Qf 1510 pflsprlng,t dcl l i -ored with • 'evldmal fo rmat ion . "

In a separate study, uno rat, . J . de l i ve r a ma l fo rmed o t t -s i r i n g , b u t t h e d o s a g e h a dbeen 1500 times the usual one.R a b b i t s t h a t w e r e i n j e e i e d

with six t imes the comparablehuman ' dose also werepor ted to have producedmal lornied bir ths.

Recen t l y, the TDA pub l i c l ySee bnUG. 'AS,

. Dy Peter Arnetl !SAIGON. South V

Nam. Jufy 14 {AP)- Noar-y 5 0 0 Communist, gtjjr-

Hllas amhushtid'a'g'o'vcrn'-ment convoy 40 miles northot Saigon this morning andkilled a U. S. Army captaina n d a t l e a s t 2 3 V i e t n a m e s e

s I n a fi e r c e b u ts h o r t l i a t t l c -

T h e D u f c n a e D i

President DesisnatiSMayor of .GlevelandAs Secretary- of" HEW

turer claimed it was non-addictive,caused no hangover, and was safe forpregnant women. And, unlike barbiturates, its lack of toxicity made it a poorchoice for a suicide attempt.

By 1957, thalidomide was sold over-the-counter in Germany. By 1960, it wassold throughout Europe and SouthAmerica, in Canada, and in many otherparts of the world. To introduce it intothe United States, the Richardson-Merrell pharmaceutical company of Cincinnati submitted an application to FDAin September 1960 to sell thalidomideunder the brand name Kevadon.

The application was assigned to medical officer Kelsey, who had joined FDAjust one month earlier. It was her firstdrug review assignment.

Under the law at that time, FDA had60 days to review a drug application. Ifan FDA med ica l o fficer no t i fied the

company that the application was incomplete, it was considered withdrawnand the company would have to resubm i t i t w i t h a d d i t i o n a l d a t a . W i t h e a c h

resubmission, the 60-day clock wouldstart again.

Kelsey had concerns about the drugfrom the beginning. So did the pharmacologist and chemist who assistedKelsey in the drug review. The chronic

toxicity studies were notlong enough, the absorption and excretion datawere inadequate, and themanufacturing controlshad shortcomings. "Wewere concerned about the

non-absorption," saysKelsey. "That you couldgive enormous amounts,both to animals and hu

mans, without toxicity.We felt that there mightbe conditions, illnesses,or other drugs that mightchange the absorption,and toxic effects mightappear." After Kelsey detailed these deficienciesin a letter to Richardson-

Merreli, lire companysent in additional information—but not enoughto satisfy Kelsey.

"The clinical reportsw e r e m o r e o n t h e n a t u r e

R i b i c o t f ' s P o s tIs Slated to GaTo Cclebreztcf .

0>- Edw.r t i T. FoUia i r t

HYANNIS PORT. N.iss..July 14 — President Kennedy today announced jjijIntention to appoint .i\n.Ihony J. Cclcbrcztc. Mjyoro( Clcvclnnd, as Secretaryof Ilcalth. Education andW e l f a r e .

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from the eabinet Fridyto r Un i ted S la te * Svna -

. . n C o n n e e l l f u t . "Celcbrc j tc . 55. «a> U- i j

(c) 1962, The Washington Post. Reprinted with permission


Kelsey's testimony before Congress in 1962 (above) supported thepassage of the Kefauver-Harris Amendments, strengthening regulation ofthe pharmaceutical industry.

Kelsey received the President's Award for Distinguished FederalCivilian Service from President John F. Kennedy in 1962 (left) for sparingthe United States the horrors of birth deformities caused by thalidomide.

Surrounded by friends and family on the White Flouse lawn (below),Kelsey displays her award from President Kennedy.

of testimonials," says Kelsey, "ratherthan the results of well-designed, well-e x e c u t e d s t u d i e s . "

Kelsey continued to request moredata to show the drug's safety, and witheach request, the 60-day clock restarted.Dr. Joseph Murray, Richardson-Merrell's representative, grew increasingly frustrated. He made repeatedphone calls and personal visits toKelsey, and complained to her superiorsthat she was unreasonable and nit-picking, and that she was delaying thedrug's approval unnecessarily.

But Kelsey did not cave under thepressure.

"I think I always accepted the factthat one was going to get bullied andpressured by industry," says Kelsey. "Itwas understandable that the companieswere very anxious to get their drugs approved."

Richardson-Merrell may have been"over-eager," Kelsey admits. "Theywere particularly disappointed becauseChristmas is apparently the season forsedatives and hypnotics (sleeping pills).

They kept calling me, and then justcame right out and said, 'We want to getthis drug on the market before Christmas,because that is when our best sales are.'"

In December of 1960, three monthsa f t e r R i c h a r d s o n - M e r r e l l s u b m i t t e d i t s

application, the British MedicalJournalpublished a letter from a physician,Leslie Florence, who had prescribed thalidomide to his patients. Florence reported seeing cases of peripheral neuritis, a painful tingling of the arms andfeet, in patients who had taken the drugover a long period of time.

After reading the journal letter, Kelseyimmediately contacted Richardson-Merrell, requesting further informationon this serious side effect. Recallinghow quinine had affected adult rabbitsand fetuses differently, Kelsey wonderedwhat effects thalidomide may have ifused during pregnancy. She suspectedthat a drug that could damage nervescould also affect a developing fetus. Hersuspicions soon proved to be grimly acc u r a t e .

European physicians began reportinga disturbing phenomenon. A growingnumber of women were giving birth toterribly deformed babies. Some had abnormally short limbs, with toes sprouting directly from the hips, and flipperl ike arms—a cond i t ion known as

phocomelia. Others had malformed internal organs or eye and ear defects.Women were miscarrying or giving birthto infants who died shortly after.

At first, no one knew the cause. But

by November 1961, a German pediatrician, Widukind Lenz, determined it wasthalidomide. Upon questioning his patients, Lenz found that 50 percent of them o t h e r s w i t h d e f o r m e d c h i l d r e n h a d

taken thal idomide in the first t r imesterof pregnancy.

L e n z w a r n e d t h e G e r m a n m a n u f a c

turer, Chemie Grunenthal, about thedangers of thalidomide. Ten days later,German health authorities pulled thedrug from the market—against thecompany's wishes. Other countriesclosely followed its lead. ChemieGrunenthal continued to dispute thefindings, but in March 1962,Richardson-Merrill withdrew its applic a t i o n f r o m F D A .

Unfortunately, by then, it was too latefor many.

More than 10,000 children in 46 countries were estimated to have been born

with deformities as a consequence ofthalidomide use. The damage in theUnited States was small by comparison,but no less devastating to the 17 childrenborn in Amer i ca w i th tha l i domide-asso-

c i a t e d d e f o r m i t i e s .

R i c h a r d s o n - M e r r e l l h a d d i s t r i b u t e d

more than 2 .5 mi l l ion tha l idomide tablets to more than 1,000 doctors throughout the United States on what was called

an investigational basis. The doctors, inturn, gave thalidomide to nearly 20,000patients, several hundred of whom werepregnant women.

FDA's field staff located the doctorswho had been given thalidomide andurged them to contact patients who hadbeen given the drug. But not all of thedoctors kept records of the drug's distribution. Through news releases, FDAwarned women of the danger of takingthe drug, but it is unlikely that all ofthese women were reached.

Kelsey's Early CareerBorn in 1914 in Cobble Hi l l on

Vancouver Island, British Columbia,

Kelsey grew up in the country where shecollected everything from bugs to birdeggs. "I always knew I'd be some kindof scientist," she says.

Graduating from high school at age15, Kelsey went on to earn a BSc in1934 from McGill University inMontreal. She then hoped to work in alaboratory, but it was the depth of theDepression and men were selected to fillthe few openings that existed. "This situation led me to realize that my choiceswere either to do graduate studies or tojoin the bread line," says Kelsey. "I decided graduate work would be more interesting."

After earning her MSc at McGill inpharmacology in 1935, Kelsey, on herprofessor's urging, wrote to E. M. K.Gelling, MD. Geiling, a noted researcher, was starting up a new pharmacology department at the University ofChicago.

When Kelsey read Ceiling's letter offering her a research assistantship andscholarship in the PhD program at Chicago, she was delighted. But there wasone slight problem—one that "tweakedh e r c o n s c i e n c e a b i t . "


Thalidomide TodayThalidomide never disappeared. Since

the discovery in the 1960s of its abilityto cause birth defects, the drug has continued to be studied throughout thew o r l d t o t r e a t c a n c e r a n d o t h e r l i f e -

threatening or disabling conditions. FDAapproved the drug for the first time inthis country in 1998 under the brandname Thalomid, manufactured byCelgene Corporation of Warren, N.J. Itwas approved for one condition only:erythema nodosum leprosum (ENL), asevere and debilitating complication ofleprosy (Hansen's disease).

Because of the dangers the drug stillpresents to the unborn, FDA took unprecedented regulatory steps to controlThalomid's marketing. Extensive patienteducation about risks, a patient registryof those taking the drug, and mandatorypregnancy testing at least monthly forsexually active women of childbearingage are all part of the program to preventanother thalidomide tragedy.

Thal idomide cont inues to be evaluatedin similarly controlled FDA-approvedstudies. The drug inhibits the growth ofnew blood vessels in tumors, and has

shown the most promise in treating multiple myeloma (a cancer of the bonemarrow) and Kaposi's sarcoma (anAlDS-related cancer), says WilliamFigg, PharmD, a senior investigator att h e N a t i o n a l C a n c e r I n s t i t u t e . T h a l i d o

mide has also shown potential to treatsolid tumors in the prostate and brain, aswell as graft-versus-host disease, a complication of bone marrow transplants.

Kelsey served on FDA's workinggroup, formed in 1994, to develop andimplement uniform standards of safetyfor clinical studies using thalidomide."She provided this moral and scientificbackbone to the group, given her previous experience with the drug," saysDebra Birnkrant, MD, the workinggroup's chairperson.

Kelsey knows that thalidomide cangive relief to patients with leprosy andperhaps other diseases, but is concernedabout its widespread use—particularlywith the availability of Internet sales."We need to take precautions," she says,"because people forget very soon." ■

— E . / l .

As a student of Ceiling, Kelsey helpedc o n d u c t a n i m a l s t u d i e s t o fi n d o u t w h i c h

was the toxic element. After testing vario u s c o m b i n a t i o n s o f s u l f a n i l a m i d e a n d

solvent, it became apparent that thetoxin was the solvent—diethylene glycol—which is s imi lar to ant i f reeze.

T h e i m m e d i a t e o u t c o m e o f E l i x i r S u l

fanilamide was tragic—it caused 107deaths, many of them in children. It alsoled to the suicide of Massengill's chemist and to a fine of $26,100 leviedagainst Massengill, the highest that waslegally allowed at the time. Since themanufacturer was not required to demonstrate its product's safety, FDA couldnot hold Massengill accountable for thedeaths. The company could only befined for "misbranding" its product. Anelixir, by definition, contained alcohol,but there was no alcohol present inE l i x i r S u l f a n i l a m i d e .

The long-term effects were also remarkable. Public outrage spurred thepassage of the Federal Food, Drug andCosmetic Act of 1938. The new druglaw required companies to show evidence of safety before their productcould be marketed, and warnings of thepotential hazards of drugs were required.And for the first time, medical devicesand cosmet ics were included in FDA's

authority.In the same year the new drug law

went into effect, Kelsey received herPhD in pharmacology from the University of Chicago and joined the faculty.Later, in 1943, she met and married another faculty member, Dr. Fremont EllisKelsey. While in medical school, shegave birth to her two daughters.

In the decade after earning her MD atChicago in 1950, Kelsey held jobs reviewing articles for Journal of theAmer i can Med ica l Assoc ia t i on and

teaching pharmacology at the Universityo f S o u t h D a k o t a . S h e a l s o w o r k e d a s a

temporar)' doctor in a number of smallcommunities throughout that state. In1960, Kelsey was offered a position atFDA in Washington, D.C. It was there thatshe would leave her mark on history.

The Road to Stronger Drug LawsT h e h e a d l i n e r e a d " ' H e r o i n e ' o f F D A

Keeps Bad Drug Off of Market." Thestory appeared on the front page of TheWashington Post on July 15, 1962. Re-

See commentary, "Living in a World With Thalidomide: A Doseof Reality," in the Last Word, page 40

The letter began "Dear Mr. Oldham,"Oldham being her maiden name. Kelseyasked her professor at McGill if sheshould wire back and explain thatFrances with an "e" is female. "Don't be

ridiculous," he said. "Accept the job,sign your name, put 'Miss' in bracketsafterwards, and go!"

So Kelsey went. She left Montreal andm o v e d t o I l l i n o i s .

"To this day, I do not know if myname had been Elizabeth or Mary Jane,whether I would have had that first bigstep up," says Kelsey. "And to his dyingday. Professor Ceiling would never admit one way or the other."

In 1937, Kelsey's second year at theUniversity of Chicago, FDA askedCeiling to help determine why peoplewere dying after they drank "Elixir Sulfanilamide." Sulfanilamide, introduced

in 1935, was extremely effective infighting bacterial infections. But the sulfanilamide pills were pretty unpalatable.One manufacturer, the S. E. MassengillCompany of Bristol, Tennessee, askedits chemist to find a liquid solution inwhich the drug could be dissolved, making it more pleasant-tasting, especiallyto ch i ldren.

"The solution was put right on themarket with a little pink coloring and alittle cherry flavoring, and it sold likewildfire," says Kelsey. Under the law atthat time, the Food and Drugs Act of1906, a company could sell a drug without showing its safety.

Soon after the elixir hit the market, reports of deaths involving the solutionstarted flowing in—but no one was surew h e t h e r i t w a s t h e s u l f a n i l a m i d e o r t h e

s o l v e n t t h a t w a s t o x i c .


Kelsey continues to work for FDA in the agency's Center for Drug Evaluation and Research.

porter Morton Mintz told the tale of"how the skepticism and stubbornnessof a Government physician preventedwhat could have been an appallingAmerican tragedy, the birth of hundredsor indeed thousands of armless and legless chi ldren."

Mintz's article catapulted Kelsey tostardom. It also inspired a flurry of follow-up articles on drug control in TheNew York Times, Saturday Review, Life,and other mainstream media of the day.

In Ihe wake of the furor these articles

created, the American public soon cameto realize how narrowly they had averteda major tragedy. And politicians whohad been fighting for years for tighter

drug controls were finally taken seriously. A controversial bill introduced bySen. Estes Kefauver of Tennessee several years earlier was resurrected fromits congressional committee graveyardand rewritten. President Kennedy signedthe bill generally known as theK e f a u v e r - H a r r i s A m e n d m e n t s i n t o l a won Oct. 10, 1962. This landmark druglaw, which modified the earlier FederalFood, Drug and Cosmetic Act of 1938,strengthened FDA's control of drug experimentation on humans and changedthe way new drugs were regulated.

Under the 1938 law, drug manufacturers had only to show that their drugswere safe. Under the 1962 law, for the

first time, they also had to show that allnew drugs were effective. Kelsey wasthere for both of them. She participatedin the creation of two of the most important public health laws in the nation'shistory. But she was no orator or visionary or politician. She was simply a scientist trying to understand what had happened and how the public health couldbe protected.

The 1962 amendments required informed consent from patients used indrug studies, and sponsoring drug companies were required to report to FDAany adverse reactions to the drug. FDAmade Kelsey head of its investigationaldrug branch, created to evaluate andmonitor clinical trials for compliancewith these new drug regulations.

FDA grew along with its increasedregulatory responsibilities. In 1960,Kelsey was one of only seven full-timeand four young part-time physicians reviewing drugs at the agency. Today thereare nearly 400 medical officers at FDA,but they are not as accessible to the drugcompanies as they were in the 1960swhen Kelsey was pressured by the thalid o m i d e m a n u f a c t u r e r. " M e d i c a l o f fi c e r s

today are insulated from the drug company by the consumer safety officer andproject manager staff," says Janet Woodcock, MD, director of FDA's Center forDrug Evaluation and Research (CDER).

Kelsey continues to persevere in safeguarding public health. At age 86, sheserves as deputy of scientific and medicalaffairs in CDER's office of compliance.

Though Kelsey, from the time she wasa little girl, always knew she would be"some kind of scientist," she never foresaw the role she would play in the history of drug law. Fler efforts in twoevents—the testing of Elixir Sulfanilamide and the prevention of thalidomide's approval—led to turning pointsin the nation's drug regulations and thefederal government's role as protector ofpublic health.

"It has been an interesting career,"says Kelsey, in her understated manner.And of her first drug review assignmentat FDA in 1960—the thalidomide application—she notes, "They gave it to mebecause they thought it would be aneasy one to start on. As it turned out, itwasn't all that easy." ■

PHOTOGRAPH BY JACK PARDUE FDA Consumer / March-April 2001 / 29

S a

m m r - Vt .

K

c .

Bonnie Clayton is one of thousarielsof irritable bowel syndrome sufferers wfio was helped byLotronex. Following announcementof the drug's withdrawal from themarket by Glaxo Wellcome,

JQayton refilled all of herprescriptions as soon as she heardthe news. Here, she is shown \yith

3st fijf her.supply.

30 / March-April 2001 / FDA Consumer PHOTOGRAPH BY BLACK STAR/ ROBIN NELSON

Grappling WithPatients, FDA And Drug Companies Struggle

To Link Therapies With Weii-Being

By Carol Lewis

or years Bonnie Clayton rarely made it to the bathroom in time. The 70-year-old Columbus,

Ga., resident remembers many a humiliating stop by the side of the road. Then in February

2000, she began taking Lotronex, the only drug to give her instant relief from the urgent at

tacks of diarrhea that constantly plagued her. But just eight months after her miracle drug was

approved, the manufacturer took Lotronex off the market—and with it, Bonnie's quality of lifeand her one chance to be free from the stranglehold of irritable bowel syndrome (IBS).

For three-time survivor Teddy McMillon, breast cancer set a frenzied pace. When the 66-year-old woman from

Weatherford, Okla., wasn't having hot flashes, she was hallucinating. Once her heart was stabilized, her lungs

gave out. Then there were the countless drugs, the vials of blood, a mastectomy—all between, during and afterthe CAT scans, x-rays, and chemo treatments. Add to that excruciating back pain, painful, cracking skin, and

numbness in her fingers and toes. While many of the problems have been caused by the drugs that control her

cancer, none of it is enough to make McMillon stop using Xeloda—the one drug that controls the cancer that hasnow spread to her bones.

Bonnie and Teddy suffer from very different diseases, but they face the same problem: maintaining the quality

of their lives while battling their disorders. They are among millions of people undergoing medical treatments

that in some way affect how they function every day. But since the quality of a person's life is rooted in daily and

momentary experiences, the value placed on everyday living in the face of illness or disability varies from personto person.

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Bonnie, for example, would gladlyrisk ihe known and unknown adversereact ions that come with Lotronex

(alosetron) because the drug relievedher symptoms for the first time in 25years. For her, Lotronex made life livable. Similarly, cancer patients likeTeddy are often willing to suffer severeside effects because the therapies preserve their lives.

But for others, like colon cancer patient Sallie Forman, the toxic effects oftreatment are so severe that any extension of life "just isn't worth it." Shesays only someone who has livedthrough constant side effects, every timethey take a certain drug, can know whatt h a t ' s l i k e .

The issue of an individual's perception about his or her quality of life nowcommands new importance in medical

the fact that there is no consensus aboutthe preferred terminology—quality oflife; health-related quality of life; healthstatus—nor is there agreement on whatstandards should be used to allow such aclaim. The complexity of these issues hascaused FDA to begin reevaluating its approach to regulating how manufacturerscommunicate these important but difficult-to-define qualities in the information theyprovide about their products.

The division of drug marketing, advertising and communications(DDMAC) in FDA's Center for DrugEvaluation and Research (CDER) regulates all drugs marketed in the UnitedStates. DDMAC is in the process of developing a policy regarding the claimsmade in labeling and advertising aboutthe impact of drugs on the quality oflife, in cooperation with FDA's Center

provide evidence before FDA would allow it to make that kind of claim. Other

examples might include estrogen replacement that quells the hot flashes ofmenopause; Accutane, which helps overcome acne; and Propecia, which maygrow hair on a bald pate.

A Case in Po in tThe television commercial portrays an

elderly woman on chemotherapy, planning her daughter's wedding. Thewoman claims the chemotherapy treatm e n t s m a k e h e r t o o w e a k a n d t i r e d t o

sew the wedding dress. A brief narrativedescribes Procrit (epoetin alfa)—a drugu s e d t o i n c r e a s e r e d b l o o d c e l l s l o s t d u r

ing chemotherapy, and consequently, toboost energy—and how it provides"strength for living." The camera thenpans not only to the completed dress, but

As manufacturers increasingly seek to make quality-of-life

claims, FDA is working with the companies and medical expertsto determine which claims are justified and which are not.

decision-making. It's no longer enoughto know how a medical treatment preserves life or holds disease at bay.People have very real ideas about whatstates of physical well-being are desirable or undesirable. And becau.se thepatient's perspective is of great interestto those who make decisions about druguse, pharmaceutical companies want toincorporate findings about a treatment'simpact on the quality of life into the labeling and promotion of their products.As manufacturers increasingly seek tomake such quality-of-life claims, FDAis working with the companies andmedical experts to determine whichclaims are justified and which are not.

But the agency's job of regulatingthese claims is not easy because littleconsistency exists in the way quality oflife is measured and interpreted. Moreover, the issue is further complicated by

for Biologies Evaluation and Research.The policy will ensure that all relevantinformation about risks and benefits, including quality-of-life benefits, is supported by substantial evidence.

Pharmaceutical companies want tomake direct quality-of-life claims fortheir products, or use equivalents suchas "enhances social life," "expect abright future," or "lead more activelives," because it helps them expandtheir markets. A growing number oftherapeutics could even be consideredlifestyle drugs because some of the disorders they treat are not life-threatening,and, depending on the individual, theycan certainly add to life's enjoyment.The manufacturer of the drug Viagra, forexample, might want to try to claim thatas a result of reversing impotence, thedrug enhances one's overall marital satisfaction. The company would need to

to the same elderly woman, energetically dancing at her daughter's wedding.

Epoetin alfa was first introduced in1989 by Amgen under the name Epogento treat anemia associated with life-threatening end-stage renal disease(chronic kidney failure that requiresregular dialysis or kidney transplantationfor survival). Epoetin alfa is also marketed by another company under thename Procrit and used to treat othercauses of anemia, such as elective surgery or chemotherapy, as portrayed inthe ad. But FDA required additional evidence to support the acceptability of theclaims that Procrit could restore energyand reduce fatigue, which are symptomsof anemia, when conveying the benefitst o c o n s u m e r s .

Measuring Quality of LifeThe World Health Organization


A growing number of therapeutics could even be consideredlifestyle drugs because some of the disorders they treat arenot life-threatening, and, depending on the individual, they

can certainly add to life's enjoyment.

defined "quality of life" inits constitution in 1948 toinclude physical, mental,and social well-being, andnot just the absence of disease or illness. Although itsdefin i t ion ra ised cons iderable question as to whetheror not quality of life couldbe measured, the comprehensiveness of the definition has set a standard bywhich many measurementefforts have been judged.Increasingly, however, experts have come to realizethat the measurement ofthe quality of life is subjective, and the final determination will always be madeby the patient.

Sometimes, the qualityof a person's life can beimproved with interventions that have little thera

peutic benefit, but greatimpact on perception. After receiving acute medicalcare for his heart attack,51-year-old Phillip Terryfrom Dal las became tentative about his life. But

then, advised by his doctor to start a newcholesterol-lowering diet, Terry's ownperception about the quality of his lifebegan to improve.

To help assess the patient's own perception about quality of life, pharmaceutical companies have begun to use disease-specific questionnaires that try todetermine what qualities are importantto patients and those that have been improved by the treatment.

The Pediatric Asthma Quality of LifeQuestionnaire, for example, was designed to gather information about how

the disorder interferes with the daily activities of children between 7 and 17.Qnce a baseline for interference is established, doctors can measure whether adrug or treatment lessens the interference or somehow restores what the childor the parent considers to be a betterquality of life.

But these studies are not always easyto conduct or interpret. "Quality of lifecan be influenced by many aspects oftreatment, including side effects," saysLaurie Burke, RPh, MPH, of DDMAC.And one of the biggest questions, she

says, is "whether the outcomes measured even addto what is already knownabout a product's effects onsymptoms and functionalstatus." Although thesequestionnaires have beenused extensively for several decades, the measureswere initially developed toclassify the degree of one'sillness and not necessarilyto evaluate changes infunc t iona l s ta tus .

Two adequate and well-controlled studies are generally required to supportany clinical treatment outcome claim. That ensures

that the evidence is strongenough to reach a conclusion and is not the result ofchance or bias. "A claim

must not mislead either the

patient or the practitionerinto believing that a benefit may be achieved thathas not been adequatelydemonstrated," Burkesays. Claims can be misleading unless they tell thewhole story, both good and

bad, and there must be fair balance ofthe supporting data—the benefits, aswell as any limitations.

Current policy for quality-of-lifeclaims, says Burke, is complex, case-specific, and dependent on the quality-of-life measurement, the disease, the intervention, and the population studied.

"We know that individuals weighquality of life differently," adds JanetWoodcock, MD, director of CDER."And we also believe that health claimsare about more than just the symptomsof a disease."


Incliistrv's PerspectivePharmaceutical companies struggle in

a highly competitive marketplace. Eachis trying to differentiate its prescriptiondrugs from others that treat the samedisease. Aggressive campaigns that relyon quality-of-life claims to change pre-scrihers' habits can help separate onedrug from the pack, especially whenmarketed directly to the consumer. Butthese distinctions must be based on qual-ity-of-life approaches that have beenvalidated. If not, the increasing use ofquality-of-life claims could mean misleading promotions, increased health-carecosts, and inappropriate prescribing.

Kati Copley-Merriman, chairperson of

says it gave her back some semblance ofa lite. But, while it has helped her, it hasbeen fatal to others. And that's not an effect FDA takes lightly, e.specially whenthe disease itself is not life-threatening.

"FDA approved Lotronex because itsbenefits outweighed its risks for thepopulation of intended patients," saysWoodcock. But clinical trials only testnew drugs in several thousand patients;when a drug goes on the market, it maybe used by millions of people and thenrare but serious side effects can show

up. Another reason some risks, like thesevere constipation and even deaths assoc ia ted w i th Lot ronex, don ' t showthemselves during clinical studies, she

e-mails that FDA tried to work with themanufacturer to find a way to keep thedrug on the market safely. The agencyhad serious concerns about the severityand number of adverse reactions resultingfrom the use of Lotronex, but believed thata restricted drug distribution programwould allow .safe u.se of the drug in appropriately informed and closely monitoredpatients. Instead, the manufacturer choseto withdraw the drug.

O n t h e H o r i z o nFor now, several groups, including

PhRMA, are working with FDA to consider the agency's regulatory approachto quality-of-life claims. This initiative

Claims can be misleading unless they tell the whole story,

both good and bad, and there must be fair balance of the

supporting data—the benefits, as weli as any iimitations.

the Health Outcomes Committee at thePharmaceutical Research and Manufacturers of America (PhRMA), the tradeorganization that represents thecountry's research-based pharmaceuticaland biotechnology companies, saysquality-of-life claims are about morethan making profit. "What drugs are doing for patients extends beyond the traditional measures of safety and efficacy," she says. "The forthcomingguidelines for quality-of-life claims currently under review will help to broadenthe value statements manufacturers canmake about products and will more accurately reflect the patient's own beliefsconcerning the effects of a drug."

T h e L o t r o n e x D i l e m m aThe recent controversy surrounding

the withdrawal of Lotronex—a drugused to treat irritable bowel syndrome inwomen—is one such example of how adrug can have a profound impact on thequality of a patient's life. Lotronex wasthe long-awaited "magic bullet" forBonnie Clayton, the IBS patient. She

adds, has to do with how drugs arc usedin the real world. In clinical trials, patients are carefully monitored. After adrug is out on the market, all kinds ofdifferent patients will be treated with thedrug. Some won't even have the condition for which the drug was approved—unlike Bonnie, who has known for moreyears than she cares to remember thatshe suffers with IBS.

"1 am literally in tears," she says. "Mylife, which had just begun to achievesome normalcy again, will now revertback to the horror it once was."

While the withdrawal of Lotronex hasbeen difficult for the patients it hashelped—more than 2,000 Lotronex patients sent e-mails to CDER chief Woodcock complaining about the decision toremove the drug from the market—thecase presents a clear example ol how thesafety and efficacy of a treatment can beinextricably linked to quality-of-lile issues. From the agency's viewpoint,however, quality-of-life concerns cannotoutweigh the safe use of a drug.

Woodcock reminds those who sent the

is part of an ongoing effort with international counterparts to harmonize whatever regulations emerge, and to bringsome order to the field. As this field ofresearch develops and reliable standardsfor marketing claims are put in place,clinicians can start to understand which

type of medical or clinical interventionoffers a better quality of life for patients.

The challenge FDA faces in definingand measuring quality of life, and inregulating quality-of-life claims madeabout drug therapies, comes back to thevery personal perceptions of patientsand what they value as they grapple withlife-altering diseases and equally life-altering therapies. Heart patient PhillipTerry is an example of how importantthe.se intangible influences can be to apatient's perceived quality of life; Although most of the dietary changes hehas made will likely have little impacton his medical condition, they give hima sense of control. And that, he says, canmake all the difference. "Sometimes aperson just needs to gain his confidenceb a c k . " ■


fda.govHot spots and cool links on FDA's Web site and beyond.

By John Henkel

A Visionary ProcedureChances are you've seen or heard ads for LASIK, a form of surgery that uses

a special laser to improve vision by reshaping the cornea. Maybe you've wondered if undergoing the procedure would be the right choice for you. To helpyou understand what LASIK is, as well as its benefits and risks, FDA's Centerfor Devices and Radiological Health has created a site (www.fda.govlcdrhllasik) that offers a helpful crash course in the procedure. The site explains theeye's anatomy and how refractive surgery techniques such as LASIK can correct certain vision disorders. A detailed glossary is included, along with achecklist to help you determine "When is LASIK not for me?" The site also hastips for finding a doctor and a description of what to expect before, during, andafter surgery.

A Weighty MatterMore than half of all American adults—about 97 million—are overweight or obese. Carrying

around this extra weight increases the risk of developing diseases such as stroke, diabetes, heartdisease, some cancers, and gallbladder disease. Other conditions such as sleep apnea (interruptedbreathing during sleep) and osteoarthritis (wearing away of the joints) also can occur in overweightpeople. But losing excess weight helps prevent and control these disorders, says the National Heart,Lung, and Blood Institute. In "Aim for a Healthy Weight" {www.nhlbi.nih.gov/health/public/heart/obe-sity/lose_wt/patmats.htm), the institute explains how you can assess your risk of developing obesity-related diseases, and it gives tips for safe and effective weight loss. Included is a calculator forgauging body mass index, an important measurement of weight relative to height. The site also discusses waist circumference and other risk factors such as high blood pressure and physical inactivity. If you determine that you are potentially at risk, the site can help you choose an effective weight-loss program.

Understanding Those Nutrition FactsYou see them all the time—those rectangles on the sides of

food packages that contain loads of valuable informationabout the food within. Whether found on macaroni andcheese, cereal, or a box of cookies, these "Nutrition Facts" cantell you at a glance what you need to know to make prudentdecisions about eating that food product. Though it's easy tocheck the label for figures such as calories, fat content, andsodium concentration, the label actually has six sections, withinformation about daily nutrition that can help you plan ahealthful diet. To learn more, go to the FDA Center for FoodSafety and Applied Nutrition's handy guide to the food labelat www.cfsan.fda.govl~dmslfoodlab.html. In it, you'll learnwhich items on the label should be limited—saturated fat, forexample—and which, such as dietary fiber, should be consumed in recommended amounts daily. The site also explainslabel terms such as "daily value" and tells how the footnote,which is the lower part of the panel, can be used as a referencefor recommended daily dietary amounts.

A Biomedical Who's WhoJulius Axelrod. Christian Anfinsen. Joshua Lederberg

O '

Oswald Avery. These may not be household names, butthese men have touched our lives in many ways. They areprominent 2()th century biomedical scientists, each responsible for discoveries that advanced understanding of how thehuman body works. Anfinsen, for example, received a NobelPrize for his work on the function of proteins in living cells.Avery's findings proved that genetic material is composedof DNA. You can read about these accomplished researcherson "Profiles in Science" {www.piofiles.nlm.nih.gov), a Website run by the National Library of Medicine. Published andunpublished papers from each scientist are included, alongwith diaries, letters, photographs, audiotapes, and otheraudiovisual materials. The site offers a fascinating glimpseat the lives of these men, and it should interest anyone fascinated by the processes of the human body. At the moment,"Profiles in Science" is concentrated primarily on Nobellaureates who did their prizewinning work in National Institutes of Health labs, but the library plans to add other prominent researchers to the site in the near future.

John Henkel is a member of FDA's Website management staff.


Investigators' Reports

fOnline Laetrile Vendor Ordered to Shut DownBy Carol Lewis

Cyberspace vendors beware: sell illicitdrugs online and be prepared to be shutdown. And shut down he was, whendrug supplier Jason Vale used theInternet to promote the sale of a falsec a n c e r c u r e .

President of Christ ian Brothers Con

tracting Corporation based in Queens,N.Y., Vale signed a consent decree ofpermanent injunction on Nov. 16, 2000,agreeing to stop making and sellingamygdalin products, better known as la-etrile, vitamin B-17, and apricot kernels.Despite warnings from the Food andDrug Administration, Vale, who operated several Web sites out of the basement of his home, promoted and dispensed these products with falsepromises that they could prevent, andeven cure, cancer. The consent decree,which resulted from inspections ofVale's home office and several under

cover purchases, ensures that the drugsupplier keeps his commitment to FDAand never sells laetrile again.

Laetrile products have been the subject of much controversy over the last 25years. In particular, though laetrile is notthe same as the chemical amygdalin—aplant compound found in the pits ofmany fruits, raw nuts and other plants—the two names are used interchangeablybecause laetrile (an acronym forlaevorotatory and mandelonitrile) is apurified form of amygdalin. Andmandelonitrile is a structural componentof both. But while some champion theu.se of amygdalin and laetrile productsfor treating and controlling cancer, neither has ever been proven effective forthis purpose, nor have they been ap

proved by FDA for any purpose. Moreover, a National Cancer Institute-sponsored study by Charles Moertel, et al.,published in the January 1982 issue ofThe New England Journal of Medicineconcluded that laetri le is not effective asa cancer treatment and can be harmful. In

fact, once it breaks down in the intestinal

Jason Vale, shown here conductingbusiness from his basement home office

before FDA officially shut down Christian

Brothers.


Investigators' Reports (continued)

tract, laetrile releases hydrogen cyanide, which can result in deadly cyanidepoisoning.

Yet Vale sold it to desperately ill cancer patients.

FDA first learned of Vale 's Internet

promotions through reports of unsolicited e-mai ls consumers received fromChristian Brothers that promoted the laetrile products for cancer preventionand as a cure. Concerned about the con

sumer complaints, FDA investigatorsinspected Vale's home office in Queens,N.Y., unannounced, on Nov. 12, 1997.Vale not only watched inspectors collect samples of his laetrile products, buthe also acknowledged having full responsibility for marketing them throughh i s I n t e r n e t s i t e .

Several months later, FDA investigators went undercover and ordered fromChristian Brothers a "starter package"for $248.65 that included injectable laetrile, laetrile tablets, and apricot kernels. Christian Brothers shipped theproducts from New York to a locationin New Jersey, along with various promotional materials, including a bookand v ideo ent i t led "Wor ld Wi thout Cancer." The materials were accompaniedby a cover letter advising users to "Eatseeds," and telling them that "Peopleare dying all over from a disea.se thatcan so simply be prevented." The labelon the video box invited customers to

visit the apricotsfromgod.com Web site.Following the undercover purchase

and results of the November 1997

.sample collection, FDA sent Vale andChristian Brothers a warning letter onOct. 28, 1998, stating that his laetrileproducts were unapproved new drugsand that he was breaking the law. Theletter said that FDA could bring an enforcement action against Christian Brothers, which could shut the company down.Through its lawyer. Christian Brothers responded in a Dec. 16, 1998, letter, claiming that the laetrile products were considered food for special dietary use by virtueof their ingredients.

Christ ian Brothers cont inued to sel l

the laetrile products.An undercover FDA investigator tele

phoned Christian Brothers in January1999 and purchased laetrile productsspecifically to treat melanoma. A manidentifying himself as "Jason" guaranteed the investigator that laetrile products could "cure melanoma in sixweeks." On Jan. 19, 1999, the investigator received a starter package from a location in Pennsylvania that containedsimilar items to those in the previous undercover purchase.

In February 1999, FDA conducted afollow-up inspection of Vale's home office. Inspectors found in a refrigeratoreight units of 100 mg "Amigdalina B-17" tablets and eleven 16-ounce bags ofapricot kernels. Vale also refused toshow investigators shipment records orinvoices for laetrile products that theagency learned had originated inMex ico . And Chr is t ian Bro thers cont in

ued to deny that its products were drugs,claiming instead that they were intendedfor use as "dietary supplements." Vale'sattorney, however, did tell FDA that hisclient no longer intended to distribute laetrile in its injectable form.

But an FDA investigator, this timeposing as a patient with kidney cancer,phoned Christian Brothers on May 29,1999, asking specifically to purchase injectable laetrile. As requested by the operator, the investigator sent to the firm amoney order for $238.95 and a letterstating that he wanted to order the"starter package" of laetrile products forthe treatment of kidney cancer. And onJune 4, the investigator received theproducts he had ordered, including theinjectable laetrile that Vale had earlierassured FDA he was no longer selling.

After receiving the illegal drug, FDAinvestigators further searched theInternet and found chr is t ic inbro-

tliers.com, heavenlyliealing.com, andcanceranswer.com l isted as Vale's otherWeb sites. These sites described the nature of cancer and the failure of chemo

therapy to treat it. They also containedletters and testimonials from people who

had supposedly bought and used theproducts, and offered a list of frequentlyasked questions such as, "How longdoes it take for the cancer to die out after taking laetrile products?" ChristianBrothers answered, "The cancer cellsstart dying immediately." As of May 28,1999, 62,299 hits had been recorded onthe christianhrothers.com site, alone.

In November 1999, FDA filed a com

plaint for permanent injunction againstChristian Brothers and Vale for sellingunapproved new drugs. Knowing that Valecould continue to sell the illicit drugswhile his legal case was pending, FDAfiled a motion for a preliminary injunctionto temporarily shut Vale down. On April20, 2000, Judge John Gleeson of the U.S.District Court for the Eastern District ofNew York granted the motion.

As a result of the preliminary injunction and the subsequent consentdecree of permanent injunction. Valewas ordered never again to sell laetrileproducts. ■

Company Gets o Guilty Reading in Glucose Monitor Cose

By Michelle Meadows

A device designed to assure diabetespatients they could "be sure at everystep" when measuring their blood glucose (sugar) levels turned out to be defective, giving false readings that landedsome patients in the hospital.

LifeScan Inc., a Johnson & Johnson

.subsidiary in Milpitas, Calif., marketedits SureStep blood glucose monitoringsystem to people with diabetes who haddifficulty performing daily blood tests,such as patients with shaky hands or visual impairments. But the SureStep system had two major problems thatLifeScan fai led to reveal to customersand to report, as required, to the Foodand Drug Administration.

The first problem was that the metersometimes displayed an Error 1 (ERl)message instead of showing a "HI" read-


ing when a patient's blood glucose levelexceeded the highest number the systemcould handle—500 milligrams per deciliter (mg/dl). LifeScan didn't reveal whatthis ERl message could mean, evenwhen customers called to complainabout it. The second problem was thatthe meter sometimes produced inaccurate low readings when a test strip wasnot fully inserted into the meter. Meterinstructions stated that the strip shouldbe inserted properly, but didn't indicatethat failing to do so could produce inaccurate low results.

According to Jud Bohrer, specialagent in charge of FDA's Office ofCriminal Investigations (OCl) in LosAngeles, "LifeScan not only failed toadvise customers of these design defects, but the medical device reportsthey did file contained false, incompleteor misleading information because ofnondisclosure of either problem as required by law."

LifeScan learned its SureStep systemwas defective in 1993, but applied toFDA for clearance to market the productin 1994, without reporting any problems. Based on the company's reports,FDA cleared the application in 1995,and LifeScan marketed SureStep inCanada, Japan, and the United Statesfrom 1996 to 1997. The company didn'ttell consumers about the product's defects until at least late 1997, and didn'tinform FDA until 1998. In a recent pressstatement, LifeScan apologized for itsmistakes and said that no one at the

company intentionally sought to misleadconsumers or the government.

Around February 1997, the companyfiled an application for clearance to market another device called the SureStepPro Hospital Meter. This product alsoproduced false low results if test stripswere improperly inserted, but LifeScanfailed to mention that in its application,according to David W. Bourne, the resident agent in charge in the San Francisco office of FDA's OCl. The SureStepPro was similar to the SureStep, but hadan added feature of being able to store

up to 6,()()() glucose readings. Still unaware of any defects in the SureStepsystem, FDA cleared the SureStep Profor marketing in May 1997.

Two internal whistleblowers came forward later in 1997, a move that kickedoff a three-year investigation ofLifeScan by government agencies, including FDA's OCl, the U.S. Department of Justice, and the U.S. Attorney'sOffice for the Northern Dist r ic t o f Cal iforn ia. I t wasn' t unt i l June 1998—after

the OCl began its investigation—thatLifeScan instituted a voluntary recall ofall SureStep meters made before July27, 1997.

On Dec. 15, 2000, LifeScan pleadedguilty to misdemeanor charges andagreed to pay $60 million in criminaland civil fines, according to court documents filed in the U.S. District Court inSan Jose, Calif. The company admittedthat SurcStep's labeling was deficient,that the company failed to file medicaldevice reports when it should have, andthat reports it did file contained false ormisleading information because theydidn't disclose problems with theSureStep system.

From 1996 to 1998, LifeScan receivedmore than 2,000 complaints of inaccurate low readings, some because of incomplete strip insertion, and more than700 complaints about "ERl" messages,some that should have been "HI" read

ings. At least 61 of the error messageswere associated with illness or injury,including some hospitalizations.LifeScan corrected these problems in1997 and 1998, and says that its currentSureStep products that remain on themarket are not affected by the recent legal settlement.

As part of its three-year probation,LifeScan has to provide written procedures for handling medical device reporting and customer complaints toFDA's Center for Devices and Radio

logical Health (CDRH). And when customers call, LifeScan representativeswill have to ask questions from a scriptthat CDRH approves. LifeScan will also

have to conduct a new study to determine whether the SureStep and SureStepPro meters meet FDA's requirements,and present its results to CDRH for review before April 2001. ■

C o u r t O r d e r s R e f u n d t o P u rchasers of Gas Grill Igniters

A U.S. District Court judge has ordered the maker and distributor of gasgrill igniters marketed for pain relief tobegin refunding approximately $82 toeach purchaser of the fraudulent medicaldevice, called the Stimulator.

Starting on Nov. 30, 2000, letterswere mailed to more than 500,000 consumers who bought the device betweenMay 4, 1995, and Dec. 22, 1997, indicating that they are entitled to receivetheir money back. Some 800,000 Stimulators were sold between 1994 and1997. (See "Scheme to Sell Gas GrillIgniters for Pain Relief Backfires,"July-August 2000 FDA Consumer.)

The device was manufactured andsold through Universal ManagementServices, owned by Paul M. Monea andhis son, Paul Monea, of Akron, Ohio,and through Natural Choice, a distributor managed by Universal Management.Disappointed consumers began complaining to FDA that the Stimulator didnot work in 1994.

Universal Management Services madethe Stimulators by outfitting gas grill igniters with finger grips. Users were instructed to apply the tip of the Stimulator to so-called accupressure points onthe body and press a plunger to send anelectric current into the body. The companies also sold an accessory cordcalled the Xtender to help consumersreach hard-to-reach areas of the body,such as the spine. Ads claimed theStimulator could relieve many kinds ofpain, including migraine headaches,painful swollen joints, allergies, and carpal tunnel syndrome.

The refund program is being administered by Gilardi &. Co., 1116 MagnoliaAve., Larkspur, CA 94131. ■


The Last Word

Living In A World With Thalidomide:A Dose Of Reality

By Randolph Warren

"We will never accept aw o r l d w i t h t h a l i d o m i d ein it; however, we areforced to prefer licens-

of the drug that dis-' abled us for eoinpas-

s i o n a t e r e a s o n s a n d t o

prevent uncontrolledaccess to the drug."

This has been themantra of the Thalidomide Vic t ims Assoc ia

tion of Canada since wediscovered that thalidomide was back, and, in fact, that it hadnever left us. The association was created in 1988 to assist itsmembers in living with the disabilities they had. That was thesole focus ... until, in 1992, we discovered thalidomide wasbeing given new life.

Thalidomide was being reborn as the next "wonder drug" forType II leprosy, HlV/AlDS wasting, and many forms of cancer.The very properties that arrested the development of babies werethe ones responsible for arresting progre.ssion of many terriblediseases, and even reversing the effects of others.

Around the world, some 10,000-12,000 babies were bornwith severe phocomelic disabilities as a result of their mothersingesting thalidomide. Of these, 5,000 adults survive today.No one will ever know how many babies were spontaneouslyaborted or were stillborn. For the families, the tragedy wasmassive. For society, thalidomide created change. The field ofchild prosthetics leapt forward, drug control agencies aroundthe world tightened licensing processes, and no longer wasthere an "assumption of safety" attached to new substances.

One woman, just doing her job, prevented thalidomidefrom being licensed in the United States. As a result of Dr.Frances Kelsey's efforts, America was spared the full effect ofthe thalidomide tragedy. Canada was not so fortunate. Thevery American company seeking approval in the United Statesreceived approval from the Canadian government. Today thereare 120 thalidomiders in Canada, 90 percent of whom are disabled because of the American drug company.

Disability instantly shatters any naivete a person couldhave and replaces it with skepticism and a full dose of reality.After "60 Minutes" aired a segment showing a woman ingesting thalidomide for macular degeneration, one can well imagine the shock of the thalidomide survivors. Not only was thalidomide back, but it was being taken by a woman on national

television. It appeared that the world was preparing to licensethe drug all over again. And we knew the first place that wouldundertake licensing was in our own backyard, America! Ourlargest fear as Canadians was that whatever happens next door,eventually happens here at home.

Having accepted the fact that there was really nothing wecould do to prevent the drug's return, we determined that itwas our role to ensure that the drug was managed in the safestpossible way, and that all the risks associated with it wereknown. This was a delicate balancing act for us, and oftenwrenching. Discussing risk versus benefit in cold scientifictones was difficult. Dealing with the drug company who wasseeking approval seemed to us to be a betrayal at times ofthose who died because of ruthless drug companies. Handlinga media who wanted a .sensational story was taxing. Meetingpersons who were saying "thalidomide took me out of mywheelchair," when two thalidomide tablets had put me inmine, was confusing.

In 1996, FDA invited us to participate in its deliberationsabout returning thalidomide to the marketplace. We brought ahuman component to the table. We were the visual remindersof why this drug was different.

We took every opportunity to warn people about the dangers of thalidomide. We also reviewed all educational materials about thalidomide, and suggested changes to make thingsclearer to the public.

Why we undertook this mission is obvious: to prevent another thalidomide tragedy.

The Thalidomide Victims Association of Canada is a groupof 120 Canadian survivors who proved that even the small caninfluence the giant (in this case the FDA and the drug company). By being involved in thalidomide's return, we tookover the drug which had haunted us. This has been a catharticexperience for us if nothing else, and has filled our memberswith confidence and pride. After all, thalidomide is now thestrictest regulated drug in U.S. history, and so far there havebeen no foetal exposures to this substance.

Today, we remain watchdogs of thalidomide. We educatethe public of the most notorious pharmaceutical disaster inhistory, and "dispense" information about the dangers of thedrug. Most of all, however, we live daily with the consequences of thalidomide ... and we live our lives! ■

Randolph Warren is a founder and executive director of theThalidomide Victims Association of Canada and lives in London, Ontario, Canada.


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