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C_4M=ZWAmiVrq mustaw(est aking a pre- ~ scription medication is an enormous art of trust. You trust that your doctor has prescribed the best drug for yuur condition. You trust that your pharmacist has filled the prescrip- tion correctly. You trust that the manu• facturer has put all the right sub- stances into each little pill. And above all, you trust that ~-i-'l the drug is safe, because it has been Tek.~,!"~ approved by the ._._-..~~....~~,..~.. al F d and f d IF you depend on the $c'7vernrrient to wecd out dangerous drugs, think again C,y Katjltcen • McCtcary r e oo e Drug Adtnimstration (FDA). This chain of trust has its strengths and weaknesses, but it's the last link- the FDA-that many Americans assume to be the strongest. After all, the United States has the most rigorous drug• approval process in the world. In fact, many people believe it's too rigorous: Witness the frequent headlines criticizing the FDA for dragging its feet in approving AIDS medications. tiowever, despite the FDA's reputed thoroughness, serious questions about drug safety remain. Last May the Gen- eral Accounting Office (GAO), an investi- gative agency of Congress, released a study looking at "post-approval" risks- side effects that may appear years later, after a medication has been widely avail- able.lhe group found that more than half of all drugs approved between 1976 and 1985 produced reactions serious enough to warrant significant labeling changes or even removal from the market-pretty scary stuff, considering that these side effects included such problems as convul- sions, heart attacks and kidney failure. The study is a sobering reminder that drugs are basically toxic substances, and anyone who takes one can develop an unforeseen reaction. You, and even your doctor, can know only what drug compa- nies and the FDA tell you about a medication. To really asse5~ how safe a drug is, you need to understand not only how to interpret its label, but also how, when and why the drug was approved. FROM LAB TO MARKET The FDA does not test drugs: It relies on studies done by pharmaceutical compa• nies and research organizations. On aver- age, bringing a medication to market costs $231 million and takes 12 years. The process begins when drug- company scientists create a chemical compound in a test tube. The substance is then given to animals in very high doses to create 'toxicity," so researchers know what to watch out for in humans, says Ronald Kuntzman, Ph.D., vice president for research and development at Hoffr,ann-La Roche. (Despite the efforts of the animal-rights movement, the FDA still insists that drugs be tested on animals before they're tried on humans.) The FDA gets involved at the human- testing stage. Drug companies have to submit an investigational new-drug appli- cation, including a detailed description of how the studies will be conducted. Once the FDA approves the application, clinical trials begin. These studies, which are conducted by physicians and hospitals working with the drug sponsor, occur in three phases. In Phase 1, which lasts about a year, researchers test the medication on 20 to 100 healthy pcople. "You get better data about how the drug interacts with the body with healthy volunteers," explains Kuntzman, "because the data aren't complicated by the disease." Barring unexpected side effects, re- searchers move on to Phase 11 trials, 3 1 pntiqiuruc! ~ra We Safe From the ~Da? NEALTH • APP.IL 1991

rM which determine whether the medication actually works. These trials last up to two years and involve at least two carefully controlled clinical studies of 150 to 500 volunteers who have the diseaw the drug is designed to treat. If the medication passes muster, researchers open the studies up to 1,o0U to 5,QOU people for Phase III trials. These studies, lasting about three and a half years, seek to confirm the drug's effectiveness and to detect its risks. The results of all these studies are finally piled together into a new-drug application, a daunting document of up to 100,0(10 pages that is sent to the FDA for approval. The review time for the 23 drugs approved in 1989 ranged from six and a half months to six and a half years. WHY DRUGS BACKFIRR Still, testing cari t reveal all of a medica- tiong side effects. Even studies con- ducted on as many as 5.000 people won't show problems that occur in one person in 10,000, They may not show how the drug affects pregnant women, older peo- ple or people taking other medications. "Its an unequiVVcal truth that during the first three to five years after a drug is marketed, new information comes along, and some of it is adverse," says Robert Temple, Ai.D., director of the FDA's Office of Drug Evaluation I. By law, drug companies must relay ail "adverse information" to the FDA. Seri• ous unexpected reactions-those involv- ing 2 hospital trip, disability or death- must be reported within 15 days, If the benefits are still deemed to outweigh the danRers, the drug remains on the mar- ket, but its label may be changed to reflect the new risk, tn extremc cases medications are recalled. The GAO reviewed these labeling changes when it set out to determine the frequency of post•approval risks. Of the 198 drugs approved from 1976 to 1985, an aLarming 96 required labeling changes that reflected serious risks, such as birth defects and blindness. Six drugs were yanked from the ntarket: the anti- inflammatory drugs zomepirac sodium, suprofen and benoxaprofen; the growth hormone somatotropin; the tranquilizer nomifensine and the antihypertensive drug ticYynafen. In other words, more than half of the drugs studied had severe or fatal side effects that weren't included in the labeling. And it's possible that some post- approval risks go unreported. Indeed, the FDA's drug-monitoring system seems startlingly informal. Although drug companies are legally obligated to report adverse reactions to the FDA, the com- panies rely on doctors to infortn them of any new side effects that turn up in their patients. "The problem," says Sidney Wolfe, M.O., director of the Public Citizen Health Research Group in Wash- ington, D.C., "is that there's no require• ment on the part of physicians or hospi- tals to report an adverse reaction." THE FDA FiGHTS BACK The FDA takes issue with the conctu- sions of the GAO study, Many of the labeling changes the GAO considered serious "«vre rare events, things that would occur in one in 10,000, one in 100,000, one in a r,iillion," Temple ar- gues. Other changes reflected "rei,ne- mettts of things we already knew," I' e says, For instance, the FDA strenfitn- ened the risk statements for the ncn- steroidal anti•inflammatory drugs su- lindac and piroxicam, which are com- monly used to treat arthritis. The original label warned that the drugs could cause gastrointestinal bleeding and ulcers, but did not mention that these conditions occasionally lead to death. Several years Thv best of the Longs. Introducing Always Longs. The cleaner, drier pantiliner.

• • • later, the tnanufacttuer was required to stipulate that, in some cases, the bleed- ing could be severe or fatal. °-1'here was no new infortnation, no new discovery. To describe that as a serious post- approval risk is just sdly," Temple says. He considers only about 20 percent of the labeling changes "serious." GAO project manager Ken Litkowski has a different view of the FDA's "refule- ments." "lt may be fine that the FDA knows these things, but the people who need to know are those who depend on drug labels for information. And if changes occur in that information, that's of some importance" The next step, currently underway at the GAO, is a look at how post-approval risks may be re- lated to the drug-approval process. PROTECTING YOURSELF So what does this all mean for the big question of whether you shuuld put a pill in your mouth? Because many important risks surface after a medication is ap- proved, the Publ;c Citizen Health Re- search Group recommends avoiding tak- ing drugs until they've been on the market for four or five years unless they offer an important therapeutic advance over eatisting medications. A good indica- A ir1es M*et1 bK tabW tr+M pea lsrrrsxttt or : tlte f*s:ia't Mt Ea•hroaaG, ct>Iec up its kncfrts x+d rstt- W s4txtsW netdtt d il tYst pears d testiat r.qtQe1 bll t1M FOII. tabslt are .ritlett by tfe dnK coptptties. ~ ~ "tttt bw eqj+r iM iRto SInt p9ec iate hbeirrt," ttlt Rabai ieaqlk M.D., 1 1 ~ ~ 11 ~~ did hr t1~e F~A. "YiM drap ~mtsania Ko4os+ ~, +nd ~e cdtt•at iL" A 1,~tS Md ppnNt ks lb srctiorts, in~ fne tlW1 rdatt te stfehl: 'taatraid0Ztiees" >ats .Y~ d~i ~iceittelI ri.it dtl koi iw tU aLe, iseu ot ItiMr caad'itioes, a "'*rrirta" Coatsirs inbtrndtioe (mah WdiOtrl rittti a Mt) iYwi sailaS afrerx rta'ctiaas .aA sthty lanrii N"1r.uatiwu' ists tiN wfat (,~ ~s b rcm ttw ~• "Ahsrse Atkfiom" fats pnttY n+c~ stryli~irtj Nsat.:ght ouu rftit use ~ J.f tite irt~ nu M rm cues..'~rrdoz~e" apiru RAtt U dtt i too mudt M tiK druA is a ~lt V'. tahee rt+erier ta iedaa Aaiitiq a~ad strae tow im*tat, br esrqk. DStet uctire~ a~a. alut tM 64 w trut, how mucY t• take, >d UeR it wcrls Atry iaforaution tlstt is Gmfd sr rki~niss li~t~d n W~ai i~9r#ut >r~ satieaY b. t#e fint Hiaj ~en resd, sars 5ideeY M6#fe, M.D~ drectx af nw h*k ab2M stab r641rek arow - xx tion of a drug's "age" is whether it's available in generic form. Second, to make sure you understand the drug's knmrc+r risks, ask your pharma- cist for a copy of its label. This is dif ferent from the label stuck on the bottle; rather, it's the sheet given to the pharmacist along with each prescription medication. The same information can be found in the Physicimts' Aesk Reference, available at the public hbrary. The book is updated yearly. (For more on reading a label see "What's in a Label?" nboer.) Finatly, keep in mind that ali drugs involve some risk. The equation that the FDA-and doctors and patients-must always weigh is whether a medication's bH:nefits outweigh its risks, © K.arxt.tBN MeCLsARr is a free-lance wriler based in Alexandria, Vlrgfaia. Information on specific risks jor »rore than 250 drugs can be jound in Worst Pills, Best Pills, publishtd by Public Citizen Neatth Research Grotip. Seud $12.00 to Public Citizen at 2000 P St. Nfy Kash- itrgtou, DC 20036. The test of the Longs. Wi•,m,• applk•J t,tnhcr kW4turudin0 wl lxc V dt.7.iY (tn tt1p 1hw.tun•~~IicJ ttiN+.r.Lt~tuMdttxY lttth ()n a1rL, thr %urfxk, una dn r.` Ah.ay-,' LcmFs top 311, ther Iunl; pantilinvr,:. H+viu~e %\v h:nY Dri•Vi~w-, the amazinF uopshcet that pulls moisturc right into the (ianti linrr... aa,n• fr om ttiiu, S~, n'hile (xher Nntllint:rti can u n Ntit.<m top, Alura)'S hungs sta} cleaner and driec. But lhat:5 not the only reau>n wu're tettcr protected. wru*re longer than :nnI other long pantiliner, coo. Always Longs patntitiners. The cteaner, drier'ivay to a fresh day. c v~r. t-A