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• • • government planners as it is unsupported. Conslder this account of FDA's 1978 approval of vafproote sodium for treating epilepsy: Athough this drug was acted on with alacrtty in the glare of unprecedented publlctty ir+the flnat stages leading to Its NDA approval.,,lts early hJstory is not one of speed..7he 1ND sNdy on this drug was submftted In December 1974, bywhich tlme The drug had been marketed abroad for severat years and was afready recognt[ed as a drug of choice for certaln types of epilepsy. Nevertheless, the FDA's classitfcotlon system assigned tt to class $ (l.e., not meriting the fast-tTock treatment}, tt was not untA October 1977 that the drug was first referred to the FDA's Neurobglc Drug Advisory Committee. The fact The the FCA's system failed to recognizs The importance of on already- marketed drug of cholce does not moke one sangulne about the FDA's claimed abllityto Identify Important new drugs even earller, I.e., at the investfgational stage-before a drug's therapeuttc potential can be predIcted by anyone-when tne research process Is most svsceptiVe to Inh(bitory reguiotfon.3' Just as the AIDS cris£s has not produced any fundamental reform of FDA, It has also not improved the media's urxierstanding of the agency's role In drug development. Most FDA actions are not agency accompfishments; they ore the termination of FDA restralnts on private accomplishments. Despite countless storles on AIDS protests, drug smuggling and underground testing, however, reporters continue to get this simpfe fact wrong. In eariy 1990, for example, FDA allowed AZf's manufacturer to halve the drug's recommended dosage, a very significant step given AZf's high cost and toxicity. The dosage cut, however, was almostuntversally reported as an FDA achievement, despite the fact that ag the agency had done was to approve a request mode by the manufacturer several months earf(er.22 The recent FDA reforms, moreover, are jeopardzed by new moves to tighten the drug approval process. The generic drug scandal, In which certain firms were found to have bribed FDA staffers to delay their competitors' NDAs, has created a leglslative backlash to the little deregutatfon that FDA has accomplLshed. 41

• • • I' Simllarfy. the General Accounting Office recently reported that more than hdf of the drugs introduced In 1976 to 1985 hod side effects that were dlscovered only after they had been opproved?' In Its demand for pte-approval omnlscience, of course, GAO totally {gnores the extent to which a more elaborate NDA review process would further delay new drug approvaF-an inexplicable approach, especially since GAO Itself has criticized FDA's slowness." GAO's new report, requested by a leading congressionai advocate of stricter FDA regulation, has become another supposedly weighty argument against FDA reform. The AIDS crisis became an exception to drug lag's Invisibllity because of gay political power. Hod those at risk for A1DS been less organized, as Is the case with victims of most critical diseases, the ava0ab4ity of AIDS treatments would be a fractton of Its current level. This may be the way politics works, but It is not the way medicine should worsc. PUTTING SOME NUMBERS ON THE FACELESS FDA claims to assi.ue drug safety and efftcacy. Just what these qualities are, and whether government Is in fact necessary for their assurance, are debatable questlons. But regardless of how we ultimately answer them, we should have some handle on what FDA's drug approval regime costs us. After all, when a salesman tells you that his product is absolutety essential, It usually Is not a bad Idea to ask the price. FDA's S100 million drug review budget 1s the most obvious component of this price, but It Is also the most mtnor. The major cost Is the invWb1e one-the therapeutfc benefits of new drugs that we lose while these drugs are under revlew. For example: Misoprostol and Gashic Ulcer Bleeding In December 1988, FDA announced Its approval of rnisoprostol-the first diug to prevent the gastsic ulcers thQt ore caused by asplrin and other nonsteroldal antt- tnftammatory drugs CNSAtDS?. These medications are frequently taken In large doses by arttuitts sufferers, and the gastric ulcers whlch frequenty reault undetected from their use cause 10D00 to 20A00 deaft each year through Internal bleeding and other compiications. Misoprostol Is reported to produce a 15-fold reduction In these gastrk

• uicers, and its life-saving potential led FDA to give its hlghest therapeutic potenttal rating, tA, to the drug's NDA26 The NDA was approved by the agency In a relatively rapid nine and a half months. Nonetheless, by the lime the drug was approved In the US It was already available In 43 foreign countries, In some of them sirzce 1985. In a press release accompanying the misoprostal approval, FDA Commissioner Frank Young stated, 'ltfits drug should save lives as well as costly hospitalizations.' Thus, the question with which this article begon-if a new drug will save lives after its approval, then how many lives were lost while It was being reviewed? This Is but one aspect of the drug lag that has been discussed above. It does not measure FDA's burden on pre-NDA development time. On the other hand, It avoids the complexity of International comparisons by focusing on a distinct time period during which a drvg's unavailabbity Is clearly FDA's doing--the period that begins with the flling of an NDA and ends with Its approval. Moreover, this approach Is similar to that tnicen by many federal agencies In publicizing the hazards of toxic substances and other health periis. Why not treat the hazards of FDA regulaflon In the same way? The calcuiatlon for misoprostol would be as follows. If the drug Is, as reported, 94 percent effective and If, as FDA estimates, there are 1QA00 to 20,000 gastric ulcer deotr-s annuafly due to NSAID use, then misoprostd potentfany couid have saved 8= to 15DC0 lives during FDA's nine and a halt month review perlod. This past-approval audit is admittedly Inexoct. Misoprostoi may never reach all of those who rNght beneflt tram it, and It certainly did not achieve such widespread use in Its first months on the market. On the other harxt, misoprostol's marketing was on hold for the full duration of FDA's review period; whatever level of use mtsoprostol reaches a year from now, we can assume that same level would have been reached Nne and a half months earlier were it not for thLs FDA review. In short, 8,000 to 15A00 lives ts a fair starting polnt for calculating the cost of FDA's review of mtsoprostol. FDA can come up with tts own flgcxes If It disputes this, but at least let It come up with something. Had Frank Young 43

• • • announced that 'misaprostoi will save lives, but we did lase several thousand people wtllie FDA went over the manufacturer's paperwork,' the publIc's perception of the agency might have undergone a rather fundamental shlft. As usual, however, the drug lag angle did not appear In coverage of the misoprostol story. Its approval was reported as a triumph of rapid admlrIstratNe action. Its manufacturer. pieasad with FDA's speed, was not about to antagonize the agency that controlled its Iivelihood. Those who might have been saved had the drug been available earlier rested in peace. Thrombolytic Therapy for Heort Attacks Drug lag was a more prominent Issue In FDA's 1987 approval of thrombolytic (ciot-dissolving) therapy for heart attacks, but it was stin ultimate(y skirted by the agency. In November 1987, FDA approved streptokinase as the first drug which could be Intraversously administered to reopen the blocked coronary arteries of heart attack victims. Streptokirlase had been shown to reduce Irr hospitol morta0ty among heart attack patients by 18 percent. In the US approximately 700,000 heart attack patients are hospitolized annually, of whom 9 percent dle !n-hospitai. Thus.streptoidnase couid potenttaUysave 11 A00 of these Uves each year. FDA's approval of thts use for streptokinase come a full two years after Its NDA was flled, which means that ?2AOQ deaths might have been prevented In the Interim.'6 Even after an FDA ad,risory committee recommended approval of the NDA in May 1987, It stilE took the agency six months to is,we its dec151on. The streptotcina.se approval was overshadowed by the agency's handling of TPA, a genetically engineered thrombolytic agent that appeored to be even better than streptoklnase. in 1985 the Nationai Heart, Lung and Bload li%stitute (NHLBI) hod obrupty halted a study cornporing the two drugs because TPA appeared to be so much more effective that Its resecrchers decided they could not ethically wlthhold TPA from any of their test sub;ects. TPA's rnanufacturer, Genentech, Aled its NDA in April 1986. At Its May 1987, meeting however, in a deciston th,at sturted many observers, the same FDA advisory committee that recommended approval of streptokinase voted against the TPA application. The committee was

• satisfied that TPA was effective In dLssolving clots, but It wonted mortality data os well-#zat fs, statistics showing that TPA-treated patients survived longer than untreated patienfs. Amorg Me committee's concerns was the Incidence of strokes that had occurred among some TPA patients. In short. while the HHL61 researchers viewed TPA's unavailability to some of their trfal subjects as so medkafly unethical as to require premature terrttiination of their study, the FDA advisory committee recommended that the drug be wit'nheid from the entire nation. . The advisory committee's recommendation was heavlty criticized in certain quarters. The Walr Street Journal ran a series of articles and editorials which ttxiicated that much of the dispute over TPA stemmed from a Jurisdictionci dispute between two FDA bureaus, one responsibie for drugs, the other for genetically engineered products. Science, one of the worid's most respected scientific Journals, editorfalized that when a regulatory agency Thor ncenses drugs tor heart attacks stumbies. It may nave not only egg on Its face but blood on its nands..A drug That dissolves blood clots shouid no longer have to answer wherner such an actfon prolongs rife n FDA did tfnally approve TPA shorfty atter It acted on the streptokinase NDA. By that time TPA was availabie In eight other countries, among them France. Auslria. New Zeoland and Germany. At his press conference announGng the approval, Commissioner Young brushed aside criticism of FDA's delay on TPA as the work of stock specuiators, stating that 'to be able to clean out on artery but at the some time produce a massive stroke would not be a very good resut.' To eat chicken but at the same time choke to death on a bone would not be a very good resutt either. it Is also a sitawman proposition. A bad outcome Is meaningless uniess we can weigh the likelihood of Its occurrence against the anticipated benefit of the action. Commissloner Young went on to Irstruct the public on the need for speed in treating a suspected heart attack. 'Don't deny the symptoms. Don't wait' he urged. 'Seek the care of a physician so that you con moke yoursstf available for this type of therapy.' This recommendotion was a far cry from FDA's own approach 45

• • i° In approv(ng the drug.2' The post-approval audit described above could be applled to any newly approved drug. By puttfng numbers on an otherwise invisible cost of FDA review, such an audit would bring some balance to public perception of FDA's tunction. Ls such an audit feasible? Commissioner Young didn't doubt It when I asked him about this in 1989: 'Yes, I thlnk the bclances can be done. Have they been focused on In that way? Absolutely not.' Would FDA do.such an audit? This got a different' response from the Commissloner: We think that. fn part, th(s is something that should be studled by omers. We do have a job of getiing drugs that ore safe and eftective on the market at a tfine when we con hardly meet our tlme limits as ft ls, though mtis scholarshlp ts very Important?' In short, don't hold your breath waiting for the agency to come out with these numbers. On the other hand. FDA Is not the only organization that could conduct a post-approval audit. Within the federal government such agenGes as the Council of Economk Advisers and the Oftlce of Management and Budget would be well equipped to undertake such an audlt, either perlodically-examining all new drugs approved within a given time perSod-or on the occasion of major FDA drug approvals. Outside groups such as the National Academy of Sciences could perform the audit as well. What Is Important is that the numbers come out. so that FDA's announcements are received by something more than the uncritical applause that usually greets them. ACCESS TO DRCfGS-WITH FDA'S ADVICE, BUT WITHOUT ITS CONSENT A post-approval audit would put needed pressure on FDA, but more is needed if we are to avoid the toll of the current system. Attempts at flne-tun)ng the regulotory process, such as treatment INDs. may produce small temporary improvements, but they Inevitably run Into the brick wa0 of a system committed to playing 1t safe no matter how deadly the consequences. Moreover, FDA's safety and efficacy crlter4a are valued by too large a segment of the public to make their abolition politically

• • • feas~ble. There Is. however, a simple way to preserve FDA's crIterla whpe eliminating the deadly costs of the current regime: change FDA's veto power over new drugs to a system of certiAcation. Let the agency continue to review safety and efficacy, but allow unapproved drugs, clearly labelled as such. to be availabie by prescription. Under this approach those patients and phy5icfans who wish to be gulded by FDA's Judgments would face no obstacle whatsoever; they could simply restrict themselves, as they do now, to approved drugs. But a crfticaliy m indivldual, faced with the need to go beyond this circle of official approval, could do so under the care of a physJcian. This approach would bring pharmacology in tlne with the rest of medical care, where government approval Is the exception, not the rule. FDA, after all, does not approve surglcal methods, yet we do not worry about podiatrists doing In-offk:e brain transplants. Physlcians prescrlbing unapproved drugs would need good reasons under malpractice low for doing so, especlapy If approved alternatNes were avaUable. Patlents using such drugs would know they were taidng a special risks ur,approved drugs would bear the regulatory equivalent of a skuU-and- crossbones and would be accompaNed by tnforrned consent docurnentation. And If FDA approval Is truy medically valuable, then the use of these drugs would be remain relatively srnaq. Would snake oll be sold? Would patients be conned? Wouid unscrupuious doctors connive with fy-by- Nght drug makers to sell us elixirs that were worthless or worse? Perhaps, but these inequtles already occu, and there Is no reason to suppose that their costs outwcy the advantages of such an approach. In fact their Inc4dence might • well decline as unapproved drugs moved from the medical underworld into leg{flmacy, Just as alcohol poisonings dropped when Prohibition was repealed.'0 It !s the current centrallzed decisionmaking process, wtth Its lnherent b{as, that holds the potential for true catastrophe. Drug safety Is not a hard and fost concept. At the scientific level, It is often the subject of Intense disputes among experts. At the level of personal values and decisbns, therapeutic risks that are acceptable to one person may be out of the question for another. At nelther d7

• • S Aa level should this be the subject of adminkstrative edict. Drug sofety'can be mevNngfully defined only In terms of indiv(dual choice, not soclety-wide judgments of 'safety and ef>icacy."" Government may attempt to educate us. but it has no buslness Issuing across-the-board mandates on how we should protect our heaith and our lives. We have all seen pictures of thalidomide babies, but we know nothing about the vlctims of FDA's 1 Qyear delay In approving beta blockers, or of Its 2-year delay on ' cordloc thrombolytics, or.of anyy of the other Sags that It has silently caused. fiks imbalance in knowledge is the driving force behind FDA's current drug approval system. That system Is consLstent with neither good government nor good science nor respect for IndNldual liberty and dignity, and It Is time we moved beyond It. .4

• ENDNOTES • Rh0 foAo%.UtQ on.OmOnq the fcey ttert7Rxe on drUO bQ: S OetriRtion, k1.(7ubfIOrt el PMrmxeurcvlk»owhon(1916): W. 1d Wadel & L lasopraM r4i;vfonon a-,C Avp Gewbpment (197b): Fi G, Grobovsfd & J. M, Vernon, The Rep Jafbn d Phormoceaseaa (19R4). ntt]bowsld 6a V.rnort. swp+a of 4 (1963). sid ~_ Pettanon, svpn n 1, at 16 (197m, 'PT+orrt»eeuticolMarxdactI.;rers.lssoo{otbn. New Onq/pp+ovv§tt 19®9G,1. "GrobowsBJ & verron, st,ta+o n 1. at 3635 'Word.A, May & TAmbb,'Nev Dtup De"bpmeM OV UneeC Stcr.s Pt+amtocw.tcd Fsttn,' 32 Cbs Phv/n A IFw+vp.wlEs A01, 415 (196a, The decir+o rGs founa n's®!- orfpurot®d' rsew d+uprthot b, wmpoutds be'vq tast.d by tt+.lJS rmns that rod developed t)wen The tate ot sesm+q vu0.enwruH nereaseo n " 196os. 4Pettzman. aup o n 1. at 76 tiA+orCef! & LmoqnaL ec,p+o n, 1, at 66b0. '1(a+th. Marttson. Normhqion & Lmopna.'R e Oru;i (aQ An Update of N.w DrLq 4'erOth=brr h the U+vted Stat.s and h the UrtRed I(inacbm, 19771tMOUon 1981; dA CAn. PAmm 4 Trierop.vtta 1y1(1969a l'1d at 13S >sfhesw or. 9.nero0y refered to os Type I onC typ. I ertors See, ..Q., Grai ovsti • Vea+on. +upia n 1, at 9A11 '1s quote0 h GrobowslJ & Vemon, syora tt. 1, at S. '9r. MbhoeI Murphy of ko.chst't7aULseI, os Quoted h'Vlbhifa Fp7b Catb trV FpA'. Wa1 Str.et.bumoL s.prt 29, 1966, of 2IZ wConcer+r-sfnvre: NCS ckuqf umouy aebvea'. Cnkapo 1npune..la-xny 5,1989.014. uf4Medtr. 'A Cal•n Look at ' Drup lap'. 239 ,lA+NA 423, 42S (1976). vVJan,ief,'A C1ose kvpectlon of tne 'CCfm looK; 239 JAMA 20Dd, 2010 (197n s'S®., e, Q., 'Dtup ADprovo! F rt Conp»ss onot Por+ef Isws Scatt, np Report On Ucsrv',nQ of D+up lmpt,eateo h 30 DearRS' WauJVrcn vosr,4eaQn. Juy 21, 1967. ar a, •7l SeMrcrtL 'A't.tLocle' Drup That LoVusFe? Amors9 the Womu'. Wa1 St tselJound, Jt}y 16, 1969, at A22 25" ..p.,'Pfr1s to Speed Apprad of Tect Crvps FIds SmoD Cort+ponies Aparr 6ip Cnei•, woll SheaJou+no( Aprtt 3. 1987, ot 3S irWotdet, suye n. 17. aSeRr 1YpiCd rrOCJfin.3 v+ete •U.S HatW:OosOqO FOr Ai0$ DRp,' (IV®w Yorr rfslt) cr+d 'AZT Ams-Ap6 Medeatbn Cut {n Ho( dy P0&' (ulrohrt7k» rrrrws). Th. oOenfnp me in CneR',er newnprxyrf s Aory b.qan' FDA todatr hd,evd th" roeommona 6w_: (WOstwpron Pos12 Th. WalSrn.rlourds ortiele vo; a notob+. ercepttY+, neodirred 'FCA lefs wolcome Cttt Dotape_' (The stotses oE opDeored fn tt'~ .)ar tay 17, 1990. wds of H," omve newspop.rn) gC'aAO, PCSA Ortp lhi v*,r-POtf ApproW! ?aJV, 1976-65, Apa 1990 (GAQ! PEMD-91>15). &-se GAO. FDA Onip Appmao!-,t (enArnrPzooos TtsorDefoys 1r,eAvotoomy of YsfP+o AoN New LSn:px May 1980 (HQ4-0"11 RG. D. Searte & Co„ Preu ReL.or. DecemLer 27, 196d. wlnromboMVe 1herapy rn)qhrt ewnluoUy go beyond hosplial sae, and 1:. oorrraerea tyy paromaCfes ona otMrs Yn v.iMkret' homef and worYpizef. CJr.-yhNon 474 (19L7). tf Wt.ISd th6B begvm to t9pCh th9 400.LL70 h.art pftoc k viC2iR9 wR10 Cie OMtLay WOA rexnNq o Jwaplral. To the cd.rd tt+at FDA's detoyed oppvvd Imp.d.0 tra unenafen o/ ttwtttbotys's, llt eReat h f.rms of Ms bst b.ven Qt.ol.r, The dnrp bQ eompsAotion for streptokinca. 's t6pluy oompricottro Dy me fact tt+at, to o ve+y cwrued eraerr, tt e dnq vroc awlbble for ttvomboi{tie P,eoR Cnoct tr,erop}r plor to 1967, k+ 1982 FOA opprov.d the drUQ for daaot lryootion hto cotoray, oAolSas. a 49