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NUi7 1G 74 1( • i 1 r. i I. ~vrtF -~n r- , --- Journalff-~Reguta~',c Social Costs • • W hen the federal Food and Drug Adminlstration amounces lts approval of an Important new drug, ft event Is Invariably portrayed as an administrative achievement. this has always puaied me. It seems that a questton hangs over these announcements ttiat almost atways goes unasked, though I understand why FDA might not care to answer It. The question Ls this: If a drug that hos just been approved by FDA wi11 start saving lives tomorrow, then how many people died yesterday walting for the agency to act? 8y'yesterday" I do notJust mean the day before; I mean the two to three years that It generally takes FDA to approve a New Drug Application (NDA). Under federal law, no new drug can be marketed In this country until FDA approves It as safe and effective. FDA makes its tlrxling on the basis of the manufacfurer's NDA, wNch may contain over 100,000 pages of data from clinfcal tests that took from two to ten years to complete. During all this time the drug is unavailable to physicians and the public, except on a very Gmlted basis as part of some clfnical trial. FDA, of couuse. Is not the cause of all clinlcai testing; much of !t !s a necessary part of drug development and woWd occur even In the absence of FDA reguiation. 8ut It Is cleat that these reguiations have made the development of new drugs signUtcantly more expensive and time-comm(ng. Studies Indicate that FDA's requirements have more than doubled development costs Sam lca=an is Cemral Caunsel aE eta ca~cicsvs Dv=Kie Inxitue, a fne mt~c®c a&4a=y or3anizatSon headguare4red in Wshington, DC. M:. lcaur,an Ss agmdues oftoazLl Lhit=ity ard =/8uff4o Iav Sd=L Pie Ms lnag beea as.tK sap.inLto srr~ law, W+z; rq lttpz;eztyri4ts uz3 halch ard ss.fEty =9Lts=. 31

• • • HUz 1G 74 1 r • 1G r. il. ~.~r[r~,mrn , i_ i number of healthy subjects (uv.,ally under 100). Phase 2 tests study effecttveness as well as side effects, and generally InvoNe several hurxired subjects dtvided Into treatment and control groups. Phase 3 testing examines more detailed issues such as optimal dosage and Involves hundreds to thousands of subjects over muftFyeor periods. Under the 1962 amendments ail clinicai (I.e.. human) testing of new drugs, and of prevlously approvecf drugs being studied for new uses, must be cleared In odvance by FDA under Its Investigational new drug (iN0) procedures. FDA approval of.an IND application to begin clinicapy testing a new drug Nnges on such factors as the adequacy of pre-clin{cai (anlmaf) testing, the details of the proposed test plan and the rissc to which human participants wilt be subjected. Even after they are underway, approved teshs can be hclted lf FDA subsequently becomes dlssattsfied with them. FDA's powers were expanded In other ways as well. Under the 1938 act NDAs were automaticoly approved unless the agency denied them. Under the new low it is disapproval that Is automattc; for an NDA to be approved FDA now has to make an afflrmative fincSing of safety and ef8cacy. Moreover, the cialms that a manufactvrer can make for a drug are 6rNted to those approved by the agency for the drug's 4abel. 1he 1962 amendments fundomentally changed the nature of both the agency and the drug development process. 'FDA shifted after 1962 from essentlaRy an evaluator of evldence and research findings at the end of the R and D process to an active participant In the process itse4f,'2 producing a transfer of 'primary decision-making authority In pharmaceuticals from maricet mechanisrns to a centrolized regulatory authorlty.'' MORE GOVERNMENT, FEWER NEW DRUGS WhBe tne 1962 amendments were aimed at protecting pubiic health, it graduaily became evident that they were sarlousty restrScting pharmaceutlcal Innovation In this country. 8stween 1962 and 1967 the average review time for an NDA more than tripled, rEsing from seven months to ttbriy months.• Despite numerous ciaims of FDA, streamlWng In recent years. NDA review time has not Improved, and ended the 1980's at over 32 montts per appiicatton.s 33 r

AZ1G 12 '94 17: 11 P.M.COkrUKh ivn S • • 32 for approved drugs and have substantially reduced the rate at which new drugs are Introduced, creating a large log In the avaqablpty of new drugs In this country as measured against comparable foresgn countrles.' Whlte FDA's defenders dispute the magnitude of these impacts, their essentlal argument Is that these effects are far outweighed by the protection that FDA provides against unsafe and Ineffective drugs. Their arguments Inevitably go bock to the event that led to the present day FDA and that Is paradigmatic In any discusston of drug regutatory pol}cy-thalidomtde. ' THAtIDOMIDE AND THE EXPANSION OF FDA 7-sdkiomide was introduced In Germany In 1957 as a sedattve distingtQshed by {ts nontoadcity. It was eventually sold In over 40 co+.ntries before its link to severe birth defects became apparent. In the United States approval for thafidomide, requested In 1960, was withheid by its FDA reviewer. Dr. Frames Kefsey, while she Investigated reports Mat the drug caused peripherai nerve damage. In 1961 news of trialidomide's fetal effects led to the drug's withdrawal from the world market. Because of Dr. Kelsey's actions the drug was never sold In this country, and the US was largely spared the thousands of birth defects that occurred abroad. Dr. Kelsey received the President's Gold Medal for Dlstinguished Service for her work. The ttsaffdornide catastrophe was the catayst for a major expansion of FDA's powers In 1962 under the Kefawer-Harris amendments to the Food. Drug and Cosmetic Act. The earlier statute, enacted In 1938, had prohibited the markettng of new drugs until they were found to be safe by FDA. The 1962 amendments added a new requUement-drugs wouid now txYve to be found to be both safe and effectfve before they couid be Introduced. This was Ironic. because the threat posed by tholidomide was one of safety, not eftlcGcy, and FDA's review powers under the 1938 act had succeeded In barring it from the American market. The 1962 amendments also gave FDA far greater power over human testing of new drugs. CM1cal iriats of new drugs are generally performed in tEvee stages: Phase 1 tests are aimed at obtaining basic data on drug toxicity and side effects, and are usually conducted on a srnan

HU~7 1G 7~+ 1 f • 1G r. i i. ~ vM rvi-1, n i y- i a a The hlgher standards for NDA approval under the new law led to an Increase In manufacturers' pre-NDA Investigatlonal work as wetl. The total development time for a new drug, whEch averaged from 4 to 6 years In the earty 1960's. has now doubled to ten years.° (See Chart 1. page 35.) Development time 1s not the only factor that has worsened. The number of new drugs under development In the US declined as well. From 1975 to 1979 the number of naw domestically developed drugs that entered human testing for the first time dropped to half the rate for the ' preceding decade. According to one study of thts decline the most common explanation gfven by the Industry people wos that severe scientlAc and pooffcal pressures were exerted In the mid-1970s on the Industry's pre-ciinicol research. The Increased FDA requirements were for more tests...and. perhaps more lmportontty, for large Increases In the detall, standards, and documentatton of the tesflng...One Indust:y manager sald that the simultaneous lncrease In...standcrds and attacks on partlcular drugs caused many Industrlal loboratories to vfrtuolly cease reaeareh on new drugs and to dvert their resources Into auditing their old data instead of working on new INDs...' The most dramdtic evidence of the effect of the 1962 amendments Is the shlft in drug Irnovatlon leadership between the US and Great Britain, which has scfentiflc and medical standards comparable to ours. In the period Immediately following the new low, before Its full effects were felt, the US led &italn In new drug Introduction. For the mutually available drugs (that Is, drugs ovallable In both countries) that were Introduced between 1962 and 1965, the US had, on average, a sJx month lead in being the country of first Introduction. However, from 1966 to 1971 Great Britain took the lead; on average, muttlalty ovoilable drugs were introduced 15 months eartfer In Brltaln than In the tJS! Brfitain had a similar lead In exclusively avaIIable drugs-that ts, drugs Introduced Into only one of the two countries. Of the 98 drugs that become exclustvely CvaBable between 1962 and 1971, 77 were Introduced tirst In Brltaln ° The most recent report on these trends shows that

HU(M 1g~ ':;4 ir•L:, r. . -,,, • Drug Development and Approval Process Precliniccl Testing YEARS 1 2 Test Laboratory and Animal Population Studies P U R Assess safety and P biological activity 0 S E % of all new dfugs that poss • S F I L E I N D Phase I Phase 1! Phase IlI 3 a 5 6 7 8 20 to 80 Healthy 100 to 300 1,000 to 3,000 Volunteers Patient Volunteers Patient Volunteers Evaluate Verify effectiveness Determine effectivenessm monitor adverse safety and Look for side reactions from dosage effects. long-term use. E:pedeed Rev4e.~ Pt~oses II ond Ip cornbined ro snort.r apprava! Process on row rn®dlcInes for setous dc Vte-threateryng dlseates. 70 % of 33 % of 27 % of INDs INDs INDs FDA N D A Approval 9 10 Post-marketing sofety monitoring Review Large-scale manufacturing usually takes about 2 to 3 years Distribution Education 20 % of INDs From: Pt~crmaceutico! Manufactuxers Asociotton. NewOtug Approvals In 1989. 35 ft talcos c decade on overaga for an exasrfrnentai ctn4 to trQVei from sab to rnediolro ctumt. Or+l~+frve In 6,U00 coniC}ounds aUe®ned fn precLrice} testir+g rnoke It to humon teetfng, Ora of these fiv® tasted in peop~ 6 opproved.

• • • HUb 1G :-, ii i.r r., , .- " - .,, 36 they have continued through the 1980s, From 1977 to 1987, 204 new drugs were introduced in tt~e US; of these. 114 were available In Britain, with an average leadtlme of more than five years per drug. On the other hand, of the 186 new drugs fntroduced Into Britain during this period, onty 41 were already avallable In the US and then only by an average of two and a half years. As for exclusfvey avaBable drugs, ttsere were 70 In Britain but anly 54 In the US. The greatest lag tvnes for the US were In the areas of cardlovascuiar, respiratory, central nervous system and cancer drugs.10 .' Just as alleged FDA reform has had no effect on NDA review time, It has simllarly faded to reduce US drug lag. Average Brftlsh {eadtfine in the second half of the period studied above, between 1983 and 1987, was as large as It was in the first half. The studys authors conaluded that Important drugs sntl become avallable Iarer fn the UNted Stotes, same much later. than In the UrUted fQngdom. This ls true both for drugs representing importantrherapeutlc gains, as well as for those representing modest or uttte gains. Moreover, me smaB dtference in safety dscontinuatlons In the two countries does not support me argument thar delaY protects the pubflc from serious unforeseen aaYerse effects." THE INVISIBLE RESULTS OF INEVITABLE BEHAVIOR There are two basic types of errors which a drug regulator can make: the t[rst ts to mistakenly approve a drug which later tums out to have serious adverse side effects; " second type of error i,s to mistakenly reJect, or even dek7y in approving. a beneficial drug. From a public health standpoint, both types of errors are equaly serious In nattue, because both will lead to the uruvcessary loss of qfe. Overcautian in approving a needed drug can be Just as deadly as lack of caution In approving a bad drug.'2 The ft.ndamenta( problem at FDA Is that It is overcautious In approving new drugs. This does not stem from Its budget or from staff morale or from the individuals appointed to run it; it !s a problem that ls Inherent In the agency/s political nature, which makes tt a creature of congressionai oversight and mada pressure. The thalidomide tragedy, the source of FDA's current powers,

• • has become the guldIng model for the agency. Every new drug Is potentially another thalkiomide. From the FDA commissioner to the bureau heads to the lndividual NDA reviewers, the message Is clear: If you approve a drug with unanticipated side efiects, both you and the agency wu face the heat of newspaper headanes, teievlslon coverage and congressJonal hearings. On the other hand, it FDA (nslsts on more and more data from the marwfactvrer, and 1lnaily approves a drug which should hcve been on the market months or years before, there Is no such price to pay. Drug lag's victims and their families will hardly be complaining. because they won't know what hit them. They do not know what INDs and NDAs Ys waiting for approval at FDA, nor do they follow pharmaceutical news from abroad or progress reports on cUnlcal trtals. (Unless, that ls, they are strftlciently lucky, rich or politically connected to get Into such a trlal.) They only know that there Is nothing their doctors can do for them. From the standpoint of media and polittcs, they are Invisible. As former FDA Commissioner Afexarxier Schrnidt once stated, In all of FDA's hlstory. I am unabfa to fund a stngle instance where a Con9ressionai comrnittee Investigated the fallure of FDA to approve a new drug. But, the tlmes when heorinfls have been held to critic'sze our opprovai of new drugs nave been so frequent tt'1ot we aren't able to count them...The message to FDA staff could not be clearer. Whenever a controversy over a new drug Is resoived by Its opprovd, the Agency and the Individuals involved likefy will be Inve.stigated. tNhenever such a drug Is disapproved, no Inquiry wlll be made, The Congressional pressure for our negatlve octton on new drug opplicatlons Is, therefore, Intense, And rt seemsto be {ncreasfng..." The clinical research director of a major pharmaceuticat company Involved ln Alzheimer's research put It more directly: There won't be any breakttirough products out there because every tlme the trials run Into setzure or liver enzymes, the risk will be emphostzed and me benefrt w11 be Ignored." Similar sentiments were expressed by offlcials of the 37

S 38 National Cancer institute. who accused FDA of being 'mired 1n a 1960s pNiosophy of drug develoQment, viewing aU new agents as...polsons.' 1a The poiSttcal lnvistbiitfy of drug !ag's victGrs fs the major reason for FDA's Inherent overcaution In approving new drugs. Caution may soumd like a good ttzing when !t comes to public health, but there are times when overcauflon can be deadlier than lack of caution, which is why we do not elaborately stress-test a rope before throwing it to a drowning man. A stark example of FDA's skewed treatrnent of risks and beneflts Is the agency's ten year delay (from 1967 to 1976) In approving a variety of beta blockers to reduce heart attacks. FDA Cammissloner Donald Kennedy defended thts delay as follows: A major reason...was the suspidon that a number of B•btockers might be turnorl9enic, and the resulting (FDA3 requirement that long-term anlmcl studies be undertaken to Investlgate this posslbilfty.,,lt (now) appears that certain B-bockers are poteMital tumorigens,,,Slnce B•blockers (are) Intended for fong• term use In c great many patients. the FDA't...decision to require long-term carcinogeNc• effecttesting before dinical use spared patfents In the US a potentlally dangerous kind of ezposure.`• But to Dr. William M. Wardell, a major scholar of drug reguiatlon, this's a very minor side of the story: The proper use of (the 8-blocker) practolol...couid now be saving 10.000 aves each year In the US at a cosi. In terms of side effects, that con now be made trivlal by comporison,..These important advances ore whot Dr. Kennedy trlumphantly takes credit for 'protecting' us from; the concept of risk avoidance has been turned pytrhicauy on Its head. In addNion to 'saving' tne US from the on/y drugs that had. up to 1977. been deftnitely shown to reduce postinfarctton mortality, the FDA's B-blocker policy has set bac~c ccralovascular therapy (n thls country by years. At a tSme when the frontiers of B-blocker research throughout the world hod moved on to the questlon of preventk)g coronary death and reinforctton. economic, clinical, ond Intellectual resources of born the FDA and Industry in The US weM Into reexamining... efflcacy and toxiclty.,,(about •

• • • whtch tne answers were alreaW wen known,,,); this sclentiAc wheet-spinning fasted for approxlmatefy seven years..." FDA's act'ion may make little medical sense. but unfortundtely it makes perfect political sense. In terms of congressional reaction and media covera9e, the post- approval discovery that certain beta blockers induced tumors would have been devastating to FDA. Even a score of unanticipated deaths from a new drug ore enough to set Congress off," whtle the loss of several thousand iNes due to a delayed approval has practically no political impact. FDA's skewed Incentives have other results as well. When the agency belleves that satisfactory treatment for a certain iilness is already available, new drugs for It will frequently have to pass an even higher standard of proof. Treatments thus tend to become frozen at levets that are only moderately successful-after all, why take a chance on something new when the old Is adequate? (,Ar)d If the new drug has some unrealFzed potential, who'll complain about its absence?) The possibility of unapproved use can also become a back-door factor In the denial of on NDA. L.evamisole, for example, has recently shown such great promise In treating colon cancer that FDA is permitting its distribution while clinical tests are stili underway. The original levamisole NDA, however, filed In the early 1970's for its use as an anti-worm drug, was never approved by FDA. The ofiicial reason was that adequate anii-worm agents were already avaUable. The real reoson oppeared to be concern that levamisole would be put to unauthorized use against cancer, since reports of the drug's immunity-booating effects were already circulating at that time.19 ThLS, yet another revolutionary drug turns out to be a breakthrough in twreaucracy rather than in medicine. RU-486, the new French obortion pili, may meet a simliar fate. Its consideration by FDA will undoubtedly be mired in the abortion debate. The drug, however, has also shown promise against brain and spinal tumors-uses which will be submerged by pollt4cal opposition to Its availability. The FDA process has also created a regulatory structure which benefits certain segments of the pharrnaceutical industry. Large, established firms have 39

• • developed an expertise In dealing with FDA that probably accounts for a good part of their capital value; they are also able to spread the costs of FDA compllance over a large product ljna. For new enfrants In the fleld, on the other hand. FDA regulation Is a sizable competitive barrler.70 AIDS AND THE ILLUSION OF FDA REFORM The major exception to drug log's invisibility has been the A1DS crisis and the emergence of a nationwide network of AIDS activist organlzatlons. More than any , ottser public health Issue, AIDS has highlighted the grotesque consequences of FDA policy. It has presented the spectacle of federal officials denying unapproved drugs to incurably llI people on the ground that the denlal Is for their own good, while AIDS victims and their supporters resort to drug smuggHng In order to preserve their dignity and autonomy. The October 1988 AIDS demonstration at FDA headquarters marked the rlrst time that the agency has been physically conftonted, en masse, by Ita victims. The AIDS crtsis has sparked a number of minor reforms. Access to experimentai drugs has been made sllghtly easier through such new procedures as -treatment INDs' and 'paraNel tracking,' under which promising drugs can be used for treatment before they receNe flnal FDA approval. FDA is allowing the limited Importation of unapproved foreign drugs by indivlduals (though at the some time, paradoxicalty, these some drugs still cannot be legally obtained from domestic manufacturers). The agency has begun to accept test data on experimental dnlgs from community-based programs, a signiAcant departure from ttie centralized ciinical trials that were previourty an absolute prerequisite for FDA approval. These changes sound Impressive, but they are only the latest In a long series of agency reforms that have failed to sigrdfkantfy Improve drug regulatfon. in 1975, for example, the agency began a 'priority review' to speed the approval of promising new drugs. 7rits fast-tracking has had some apparent successes-AZT, for example, the only drug yet approved for treating AIDS, went through the NDA process In a recordbreaking 107 days. Nonetheless, fast-tracking deperxfs on FDA's alieged abiqty to pick winners In advance-a clairn that Is as ublqultous among