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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
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Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and
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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
690 JOURNAL OF LAW, MEDICINE & ETHICS
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Outterson, Powers, Seoane-Vazquez, Rodriguez-Monguio, and
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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
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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
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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
Third-generation cephalosporin
Aminoglycoside
Penicillin with extended spectrum
Second-generation cephalosporin
Second-generation cephalosporin
Third-generation cephalosporin
Second-generation cephalosporin
Second-generation cephalosporin
Third-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
694 JOURNAL OF LAW, MEDICINE & ETHICS
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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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