New Antimicrobial

Approval and Withdrawal of NewAntibiotics and Other Antiinfectivesin the U.S., 1980-2009Kevin Outterson, John H. Powers, Enrique Seoane-Vazquez,Rosa Rodriguez-Monguio, and Aaron S. Kesselheim

Antibiotic use triggers evolutionary and eco-logical responses from bacteria, leading toantibiotic resistance and harmful patientoutcomes.^ Two complementary strategies supportlong-term antibiotic effectiveness: conservation ofexisting therapies and production of novel antibiot-ics.^ Conservation encompasses infection control,antibiotic stewardship, and other public health inter-ventions to prevent infection, which reduce antibioticdemand.^ Production of new antibiotics allows physi-cians to replace existing drugs rendered less effectiveby resistance."''

In recent years, physicians and policymakers haveraised concerns about the pipeline for new antibiot-ics, pointing to a decline in the number of antibiot-ics approved since the 1980s.'' This trend has beenattributed to high research and development costs,low reimbursement for antibiotics, and regulatorystandards for review and approval.*^ Professional soci-eties and researchers around the world have calledfor renewed emphasis on antimicrobial stewardship,''while also supporting antibiotic research and develop-ment through grants, changes to intellectual propertylaws to extend market exclusivity periods, and modi-fication of premarket testing regulations to reduceantibiotic development time and expenses.** In theUS, these legislative efforts recently culminated withthe enactment of the Generating Antibiotic IncentivesNow (GAIN) section of the Food and Drug Adminis-

tration Safety and Innovation Act of 2012, which wasintended to promote the discovery of new antibioticsby providing five years of additional market exclusivityfor new "qualified infectious disease products."-'' TheFood and Drug Administration Safety and InnovationAct also created a fast track system to reduce clini-cal trial development time for breakthrough drugs,including new antibiotics.'" The European Union hasalso been active in considering new therapeutic devel-opment incentives together with other efforts such asenhanced antimicrobial stewardship and support forbasic research."

While incentives for antibiotic development mayhasten the arrival of a larger number of drugs, pub-lic health will be best served if these new drugs havehigh clinical utility, discrete mechanisms of actionand narrow spectrums to delay resistance, and well-defined safety and eflicacy profiles." In recent years,however, there have been numerous high-profileexamples of approved antibiotics found to have safetyconcerns, including trovafloxacin, which was with-drawn from the US market, and telithromycin, whichhad two indications withdrawn in self-resolving dis-eases, but remains available for treatment of commu-nity-acquired pneumonia despite well-known safetyissues. Studies reporting simple counts of new anti-biotic approvals do not adequately consider the clini-cal impact of the antibiotics or subsequent safety-related withdrawals and therefore may provide

Kevin Outterson, J.D., LL.M., is a Professor of Law at Boston University. John H. Powers, M.D., FACP, FIDSA is an AssociateClinical Professor ofMedicine, George Washington University School ofMedidne. Washington, DC. Enrique Seoane-Vazquez,Ph.D., is an Associate Professor in the Division of Pharmaceutical Sciences, and Director of the International Center for Phar-maceutical Economics and Policy at the Massachusetts College of Pharmacy and Health Sciences, Boston, MA. Rosa Rodriguez-Monguio, Ph.D., is an Associate Professor in the School of Public Health and Health Sciences at the University of Massachusetts,Amherst. Aarou S. Kesselheim, M.D., J.D. M.P.H., s anAssistant Professor ofMedicine in the Division ofPharmacoepidemiol-ogy and Pharmacoeconomies in the Department ofMedieine atBrigham and Women's Hospital and Harvard Medical School.

688 JOURNAL OF LAW, MEDICINE & ETHICS

Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and Kesselheim.

an incomplete picture of antibiotic development. Tobetter understand recent trends, we analyzed threedecades of FDA antibiotic approvals, together withmarkers of antibiotic safety and efficacy. To put anti-biotic trends in context, we compared these resultswith approvals and withdrawals in other drug classes,including other antiinfectives. Comparisons to other

NMEs and BLAs were withdrawn from the US marketas of December 31, 2011. Withdrawals were identifiedin one of three ways: (l) publication by FDA of a noticeof withdrawal of approval in the Federal Register; (2)listing of the product in the Orange Book discontinu-ation section; or (3) removal of the product from theOrange Book approved applications section.

Studies reporting simple counts of new antibiotic approvalsdo not adequately consider the clinical impact of the antibiotics or

subsequent safety-related withdrawals and therefore may provide anincomplete picture of antibiotic development. To better understand recent

trends, we analyzed three decades of FDA antibiotic approvals, together withmarkers of antibiotic safety and efficacy. To put antibiotic trends in context,we compared these results with approvals and withdrawals in other drug

classes, including other antiinfectives.

drug classes, such as cardiovascular drugs, can illumi-nate whether the outcomes of our study are unique toantibiotics or are common across several drug classes.Comparisons between antibiotics, antivirals and anti-retrovirals, and other antiinfectives can also identifyshifts in innovation wdthin the antiinfective therapeu-tic class.

DataDrug ClassificationsFrom publicly available data on the FDA websiteDrugs(a)FDA,^ 3 we identified all new drug applica-tions for new molecular entities (NMEs) and newbiologic license applications (BLAs) approved by theFDA from January 1, 1980 through December 31,2009. The dates of approval were confirmed using theApproved Drug Products with Therapeutic Equiva-lence Evaluations (Orange Book). We then classifiedeach drug based on its approved indication into a classof the Anatomic Therapeutic Chemical (ATC) clas-sification system maintained by the WHO Collabo-rating Centre for Drug Statistics Methodology of theNorwegian Institute of Public Health.'* 'Antiinfectivesfor systemic use" (class J) were further subclassifiedinto three categories: "antibiotics for systemic use"(subclass JOl), "antivirals for systemic use" (subclassJ05), and "other antiinfectives" (all other subclasses,which include antimycotics and vaccines). From thesame FDA databases, we identified whether eachdrug in our sample was granted priority review ororphan drug status by the FDA. Finally, using meth-ods described by Qureshi et al.,'^ ^ ^^ determined which

Characterization of Antibiotic WithdrawalsFor all withdrawn drugs in the antibiotic subclass JOl,we then identified the specific date when these vwth-drawn drugs were discontinued from the US market.Withdrawal of approval of an antibiotic generatesa specific announcement by the FDA, as describedabove. However, for some antibiotics, the companydiscontinued widespread sales of the antibiotic manyyears before regulatory withdrawal. Such informaldiscontinuations are rarely accompanied by a formalannouncement. We therefore dened the date of dis-continuation as the calendar quarter in which com-mercial sales in the US dropped below US$100,000,using data from IMS MIDAS (data available for 1993-2009 only). When IMS data were not available, weused the date of the official FDA regulatory action.

We then categorized whether each antibiotic with-drawal was associated with a safety issue. A safety-related withdrawal was defined as a withdrawal thatoccurred within a year after new safety-related warn-ings were added to the drug label, or one describedas such in regulatory notices published in the FederalRegister and other government reports, public com-pany filings with the Securities and Exchange Com-mission's EDGAR database, or other announcementsfound in the Westlaw databases.

Finally, we noted the peak US sales and the sponsor-ing company for all withdrawn antibiotics. We char-acterized an antibiotic as "commercially successful"if it achieved US sales exceeding $100 million (2010dollars) in any calendar year. All data were analyzeddescriptively.

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ResultsThe FDA approved 815 NMEs and BLAs during thestudy period, with a peak in the late 1990s. We foundthat 35 new drugs in the class of antiinfectives wereapproved in the 1980s (16% of all drug approvals),as compared to 49 in the 1990s (15%), and 27 (11%)in the 2000s. Among the subclass of antibiotics, 61NMEs were approved overall, with the greatest num-ber approved in the 1980s (29,13% of all drug approv-als), fewer in the 1990s (23, 7%) and still fewer the2000s (9, 4%). Among the subclass of antivirals, 38were approved overall, with the most in the 1990s (21,6% of all drug approvals) and 2000s (13, 5%), andthe least in the 1980s (4, 2%) (Exhibit 1). A majorityof these antivirals were antiretroviral drugs for HIV(n=24). Other antiinfective drug approvals totaled 2 inthe 1980s, 5 in the 1990s, and 5 in the 2000s, mainlyantimycotics and antimycobacterials (n=ll out of 12).

By comparison, during this time period, cardiovas-cular drugs had the largest number of NME approvalsin the 1980s (40,18%), although the number of newcardiovascular drugs fell in the 1990s (39, 12%) and2000s (18, 7%)- Antineoplastic and immunomodulat-ing agents showed a different trajectory, with fewerNME approvals in the 1980s (13, 6%), but becom-ing the largest therapeutic class for new approvals inthe 1990s (52,15%) and 2000s (51, 20%) (Exhibit 2).Overall, the number of approvals in all classes peakedin the 1990s but improved slightly from the 1980s tothe 2000s (1980s=225; 1990s=339; 2000s=25l).

Exhibit

Regulatory Classification of AntiinfectivesIn our study period, the FDA approved 57 antiinfec-tives after priority review (1980s=l6 (16% of all prior-ity reviews), 1990s=24 (18%), 2000s=17 (20%)). Thus,antiinfectives as a class claimed an increasing share ofall priority review approvals over time. Within the twolargest antiinfective subclasses, priority review antibi-otics fell sharply after the 1980s (l980s=ll (11% of allpriority reviews), 199Os=3 (2%), 2000s=3 (4%)), whilepriority review antivirals grew dramatically to a peakin the 1990s (1980s=3 (3% of all priority reviews),199Os=17 (13%), 2000s=ll (13%)), most of which wereantiretrovirals for HIV (n=22) (Exhibit 3). Overall, 51%of approved antiinfectives and 28% of approved anti-biotics received priority review, compared to 37% ofdrugs approved in all other therapeutic classes.

Orphan drug designation was given at the time ofinitial FDA approval to 3 antiretrovirals and 3 otherantiinfectives during our study period, but none weregiven to antibiotics. By comparison, 153 drugs overallreceived orphan drug designation, representing 20%of all drugs approved after 1983.

Withdrawn AntibioticsAmong the 61 NME approved antibiotics, 26 werewithdrawn (43%), a rate far higher than was observedamong non-antibiotics (13%). The 26 withdrawnantibiotics are described in Exhibit 4. The mean datefrom approval to withdrawal was 15 years (inter-quartile range: 9-19 years). Withdrawals for safety-related reasons (n=6) generally occurred sooner afterapproval, from 4 to 76 months after approval (mean:

FDA Approvals of New Systemic Antiinfectives, by Class and Subclasses, 1980-2009

Systemic antibiotics Antivirals "Otherantiinfectives


Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and Kesselheim

Exhibit 2FDA Approvals of New Drugs, Percent of Totals, by ATC Class, 1980-2009

0% 5% 10% 15% 20% 25%

Alimentary Tract and Metabolism

Antiinfectives for Systemic Use

Antineoplastic and Immunomodulating Agents

Antiparasitic Products, Insecticides and Repellents

Blood and Blood Forming Organs

Cardiovascular System

Dermatologicals '

Genito Urinary System and Sex Hormones

Musculo-Skeletal System

Nervous System

Respiratory System

Sensory Organs

Syst. hormonal preps, excl. sex hormones & insulins

Various

Exhibit 3FDA Approvals of New Systemic Antiinfectives through Priority Review, 1980-2009

25

20 -

15

10 -

5 -

0 -

--1

1^980s

Systennic antibiotics

^^ H^ mil^^ ^' mu

1990s 2000s

Antivirals "Other antiinfectives

INSTITUTIONAL CORRUPTION AND THE PHARMACEUTICAL INDUSTRY EALL 2013 691

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33 months). Withdrawals were greatest for drugsapproved in the years 1980-1984 (71%) and lowest fordrugs approved in the years 1985-1989 (33%). None ofthe antibiotics approved in the 2000s was withdrawnas of August 1, 2013.

This review of antiinfective approvals andwithdrawals suggests that reports warningof a decrease in antibiotic approvals overtime and current-day nadir in antibioticapprovals may be overstated.

Only 2 withdrawn antibiotics received priorityreview designation at initial approval (moxalactamand cefonicid). Few of the withdrawn antibioticswere commercially successful (n=3, although com-mercial sales data were available for 1993-2009 only)and most were discontinued from the market severalyears before formal withdrawal. Withdrawn antibiot-ics were concentrated among cephalosporins (n=10)and fiuoroquinolones (n=9). Six of the 26 (23%) vwth-drawn antibiotics were safety-related withdrawals,all of them fiuoroquinolones approved in the 1990s:temafioxacin (approved in 1992), sparfioxacin (1996),alatrofioxacin (1997), trovafioxacin (1997), grepafioxa-cin (1997), and gatifioxacin (1999).^ *'

After adjusting for withdrawals, the data for netFDA approvals of antibiotics, antivirals, and otherantiinfectives are shown in Exhibit 5. Amongst anti-biotics not withdrawn as of August 1, 2013, 13 wereapproved in the 1980s, 13 in the 1990s, and 9 in the2000s. For antivirals not withdrawn as of August 1,2013, 4 were approved in the 1980s, 19 in the 1990s,and 13 in the 2000s. For other antiinfectives not with-drawn as of August 1, 2013, 2 were approved in the1980s, 5 in the 1990s, and 5 in the 2000s.

DiscussionThis review of antiinfective approvals and withdraw-als suggests that reports warning of a decrease in anti-biotic approvals over time and current-day nadir inantibiotic approvals may be overstated. Simple enu-meration of annual drug approvals says little aboutclinical impact. Withdrawal from the market is one expost indicator of modest clinical impact. After adjust-ing for products withdrawn from the market, net anti-biotic introductions over the past three decades havedeclined at a slower rate than previously reported,while antivirals and other antiinfectives demonstrateeven more favorable trends by comparison.

Our data on antibiotic withdrawals have impor-tant policy implications for efforts to incentivize newantibiotic development. Withdrawals among anti-biotics in our sample occurred at more than triplethe rate of all other drugs. One explanation for this

high withdrawal rate is the substantial num-ber of follow-on products approved. In oursample, most withdrawn antibiotics couldbe generally characterized as secondary ortertiary (or later) drugs in one of two impor-tant drug classes: cephalosporins (n=10)and fiuoroquinolones (n=9). For example,most of the withdrawn cephalosporins wereapproved after the introduction of commer-cially successful first, second, and third gen-eration classes of cephalosporins by other

companies (cefadroxil in 1978; cefuroxime in 1987;and ceftriaxone in 1984). Eight of the 9 withdrawnfluoroquinolones were approved after Bayer intro-duced the blockbuster ciprofioxacin in 1987. To ourknowledge, none of the drugs were withdrawn due toemergence of significant antibiotic resistance, as suc-cessful drugs with similar resistance profiles remainmarketed and widely used. Many antibiotics areapproved on the basis of non-inferiority trials, whoseprimary hypothesis is to rule out how much worsea new antibiotic might be compared to an olderantibiotic."'Therefore these studies do not directlymeasure whether new antibiotics have additionalbenefits over currently approved therapies. Whilesuch sequential innovation can sometimes bring bet-ter drugs to market, the high number of sequentialinnovations later withdrawn after poor sales suggestslow levels of clinical significance for these drugs. In arecent review, Pulcini et al. identified 33 "forgotten"antibiotics with potentially significant clinical value,but amongst the 26 withdrawn antibiotics, only cefo-perazone appears on their list, and only in combina-tion form with sulbactam.^^

Priority review status is one ex ante indicator ofexpected clinical value.^ ^ We found that as a class,antiinfectives had more priority review drug approv-als than average, with an increasing rate during thepast three decades. Over time, priority reviews inthe antiinfective class have shifted from antibioticsto antivirals (including antiretrovirals). Few priorityreview antibiotics were subsequently withdrawn, andnone for safety-related reasons. It therefore makessense to focus antibiotic development incentive pro-grams on particularly novel products that might qual-ify for priority review. Notably, the GAIN language inthe recent Food and Drug Administration Safety andInnovation Act limits its applicability to "serious andlife-threatening conditions,"^" which is promising, but


Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and Kesselheim,

Exhibit 4New Systemic Antibiotics Approved by the FDA 1980-2009, but Subsequently Withdrawn or Discontinued

Generic NameBacampicillin

Cinoxacin

Sisomicin

Mezlocillin

MoxalactamAziocillin

Cefoperazone

Ceftizoxime

Netilmicin

Amdinocillin

Cefonicid

Ceforanide

Cefmenoxime

Cefotiam

Cefmetazole

Cefpiramide

Enoxacin

LoracarbefLomefloxacin

TemafloxacinDirlthromycin

Sparfloxacin

Alatrofloxacin

Trovafloxacin

Grepafloxacin

Gatifloxacin

Antibiotic classPenicillin with extended spectrum

Fluoroquinolone

Aminoglycoside

Penicillin with extended spectrum

Third-generation cephalosporinPenicillin with extended spectrum

Third-generation cephalosporin


Aminoglycoside

Penicillin with extended spectrum

Second-generation cephalosporin






Fluoroquinolone

Second-generation cephalosporinFluoroquinolone

FluoroquinoloneMacrolide

Fluoroquinolone

Fluoroquinolone

Fluoroquinolone

Fluoroquinolone

Fluoroquinolone

Approvalyear1980

1980

1980

1981

1981*1982

1982

1983

1983

1984

1984*

1984

1987

1988

1989

1989

1991

1991 00

1992

199211995

I996t

I997t

1997 | oo

19971

1999 1

Withdrawal or Discontinuation DatesWithdrawn from Drug Product List Feb 2006; discontin-ued before 1Q 1993Withdrawn as not marketed (Dec 2007); discontinuedbefore IQ 1993Withdrawn as not marketed (ANDA, Nov 1995); discon-tinued before IQ 1993Withdrawn as not marketed (ANDA, Feb 2002) (NDA,Mar 2005); discontinued 4Q 1999Withdrawn as not marketed (Oct 1996)Withdrawn by FDA as not marketed (Sept 1997); discon-tinued before IQ 1993Withdrawn from the Drug Product List in June 2008;discontinued 2Q 2002Withdrawn as not marketed (Sept 1997); discontinued2Q 2007Withdrawn as not marketed (Aug 2003); discontinuedbefore IQ 1993Withdrawn as not marketed (Qct 1996); discontinuedbefore IQ 1993Withdrawn as no longer marketed (Feb 2002); discontin-ued 4Q 1998Withdrawn as not marketed (Aug 2003); discontinuedbefore IQ 1993Withdrawn as not marketed (june 2006); discontinuedbefore IQ 1993Withdrawn as not marketed (June 1997); discontinuedbefore IQ 1993Withdrawn as not marketed (Aug 2001 ); discontinuedbefore IQ 1993Withdrawn as not marketed (Aug 2003); discontinuedbefore IQ 1993Withdrawn as not marketed (Mar 2005); discontinuedbefore Dec. 31, 1997Withdrawn 2006; discontinued 2Q 2006Withdrawn from Drug Product List, June 2008; withdrawnas not marketed (May 2009); discontinued 2Q 2001Withdrawn June 1992; discontinued 2Q 1992Withdrawn as no longer marketed (Nov 2007); discontin-ued IQ2004Withdrawn as not marketed (Mar 2005); discontinued 4Q2000Withdrawn as not marketed (june 2006); discontinued 4Q2000Withdrawn as not marketed (june 2006); discontinued 4Q2000Withdrawn as not marketed (june 2007); discontinued 4Q1999Withdrawn for reasons of safety or effectiveness (Sept2008); discontinued 3Q 2006

* Granted priority reviewf Safety-related withdrawalI Commercially-successful (1993-2009 data only)Source: Authors' analysis and IMS MIDAS,January 1993-December 2009, IMS Health Incorporated.

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Exhibit 5New Systemic Antiinfectives Not Withdrawn in the U.S. as of August 1,2013, by Decade of FDA Approval,1980-2009

4035302520151050

1980s 1990s 2000s

I Systenriic antibiotics Antivirals Other antiinfectives

is by definition more inclusive than the priority reviewprogram, which is reserved for drugs treating a seriousor life-threatening condition that offer patients a sig-nificant improvement in safety or effectiveness com-pared to available therapies.

We found that trends in the rate of antiinfec-tive approvals were comparable to those of otherdrug classes. For example, while the relative share ofapproved antiinfective drugs declined, we found thatseveral other classes faced an even sharper drop, includ-ing drugs for the cardiovascular system, musculoskel-etal system, and skin. In particular, the cardiovascularresults are inconsistent with the oft-repeated complaintthat antibiotics are uniquely disadvantaged because tbecourse of treatment is short, as compared to long-termmaintenance drugs such as those intended to treat highcholesterol or hypertension.^' By contrast, the rates ofapproval of antineoplastic and immunomodulatingagents rose substantially, despite the relatively shortcourses of therapy they often require. Reasons for thegrowth in antineoplastic drugs may relate to allocationsin government funding for basic research, relative sci-entific progress in therapeutic categories, unmet chni-cal needs, and the fact that reimbursement levels forcancer drugs have been robust. Indeed, the revenuesassociated with recent antineoplastic drug developmenthas led commentators to suggest enhancing antibioticreimbursement as a way of promoting research in thisarea, including through delinkage mechanisms such as

value-based reimbursement and goal-oriented prizesthat reward innovation delinked from unit sales.^ ^

Finally, our data support the hypothesis that inno-vation within the antiinfective class shifted fromantibiotics to antivirals and antiretrovirals in the lasttwo decades. Given the magnitude of the global HIV/AIDS epidemic, such a shift might be consideredappropriate.

This study has several limitations. The data arelimited to NMEs and BLAs, excluding approvals ofgeneric drugs and brand-name drug approvals thatare not NMEs. The designation of safety-relatedwithdrawals might be over-inclusive. The literaturelacks a clear definition of safety-related v^dthdraw-als for antibiotics.^^ Some researchers have reliedon the CDER Annual Reports to exhaustively definethe universe of safety-related withdrawals, but thesereports rely on agency self-identification of errorand may miss subsequent safety-related antibioticwithdrawals. Our designation of safety-related with-drawals might also be under-inclusive. We excludedsome withdrawn antibiotics despite known safetyissues because the safety issue was not closely enoughassociated in time to the withdrawal. For example,moxalactam received serious safety warnings butcontinued with diminished sales for several yearsbefore being taken off tbe market, and was thereforenot considered a safety-related withdrawal. Bleedingconcerns also are noted in the medical literature withcefoperazone and cefmetazole.^* Phototoxicity and


Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and Kesselheim

While there is certainly a need for new antibiotic products to combat evolvingresistance among bacteria, policies seeking to remedy a perceived lack ofantibiotic innovation should focus on drug quality, not just quantity. Thehistorical data presented here provides evidence that simply emphasizingfaster approval of antibiotics based on more limited clinical evidence or

stronger intellectual property rights may encourage the approval of productsthat have limited clinical impact or are subsequently withdrawn from

the marketplace for safety or other reasons. Neither represents thetype of antibiotic innovation needed today.

central nervous system effects have been noted withlomefioxacin.^^ Some antibiotics that were not com-pletely withdrawn had specific indications withdravwisuch as telithromycin for acute bacterial sinusitis andacute exacerbations of chronic bronchitis due to lackof evidence of efficacy as well as adverse effects. Inaddition, the withdrawal data were right censoredbecause we could not capture potential future with-drawals. For example, we did not treat telithromycinas withdrawn since it remained on the market at thetime of our analysis although with decreasing usageit maybe completely withdrawn in the future. Finally,while the data are analyzed only descriptively, that isconsistent with the existing literature on trends inantibiotic approvals.

In conclusion, we found that simple numericaldeclines in antibiotic approvals give an incompletepicture of drug innovation. Drug approvals are downin many classes, including cardiovascular drugs, sothe observed trend may have little to do with anti-biotics per se. Nor should policymakers emphasizesimple numeric targets without careful focus on thepotential clinical value of newly approved agents andtheir demonstrated benefits over currently availabletherapies. Numerous antibiotics have suffered fromproblems after approval, including withdrawals,safety-related withdrawals, and a lack of clinical orcommercial significance. While there is certainly aneed for new antibiotic products to combat evolvingresistance among bacteria, policies seeking to rem-edy a perceived lack of antibiotic innovation shouldfocus on drug quality, not just quantity. The histori-cal data presented here provides evidence that sim-ply emphasizing faster approval of antibiotics basedon more limited clinical evidence or stronger intel-lectual property rights may encourage the approvalof products that have limited clinical impact or aresubsequently withdrawn from the marketplace forsafety or other reasons. Neither represents the typeof antibiotic innovation needed today.

Approval and Withdrawal of New Antibioticsin the U.S., 1980-2009

List of ExhibitsExhibit 1. FDA Approvals of New Systemic Antiinfec-tives, by Class and Subclasses, 1980-2009Exhibit 2. FDA Approvals of New Drugs, Percent ofTotals, by ATC Class, 1980-2009Exhibit 3. FDA Approvals of New Systemic Antiinfec-tives through Priority Review, 1980-2009Exhibit 4. New Systemic Antibiotics Approved by theFDA 1980-2009, but Subsequently Withdrawn orDiscontinuedExhibit 5. New Systemic Antiinfectives Not With-drawn in the U.S. as of August 1, 2013, by Decade ofFDA Approval, 1980-2009

AcknowledgementThis work was supported hy a grant from the Public Health LawProgram of the Robert Wood Johnson Foundation. KO was alsosupported by a grant from the David Saul Smith Foundation.

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