Where have all the antibiotic patents gone? Martin L Katz, Lisa V Mueller, Mark Polyakov & Steven F Weinstock Patent and regulatory hurdles combined with low returns on investment are stifling antibiotic R&D in the pharmaceutical industry. .com/naturebiotec
Since the discovery of penicillin by major pharma companies are still players in Of the companies examined, only eight
Alexander Fleming in 1929, many bacterial
the antibiotics market, it seems that they are
seem to be currently conducting antibiotic
infections that were once fatal have become losing interest in these drugs. A 2004 study R&D: Pfizer, Merck, Johnson & Johnson, treatable with antibiotics. Although Fleming
reported that out of more than 506 drugs GlaxoSmithKline, Wyeth, Bristol-Myers Squibb,
never patented penicillin, virtually every newly
in development, only five were new antibi-
Sanofi-Aventis and Schering-Plough. Of these,
http://www
discovered antibiotic since 1929 has been pat-
otics1. We have updated this analysis using Pfizer is the leader, having obtained FDA
ented. These include erythromycin, vancomy-
company websites, annual reports and infor-
approval for three antibiotics since 1998. Of
oup cin, rifamycin, clarithromycin, ciprofloxacin mation available at the website of the US the three, only two represent new mechanisms
and azithromycin. The vast majority of pat-
Food and Drug Administration (FDA) and of action: Eraxis (anidulafungin) and Zyvox
ents related to antibiotics are assigned to phar-
other sources. Since 1998, only nine antibiot-
(linezolid). The third antibiotic is an extended-
maceutical and biotech companies. However,
ics or new uses of old antibiotics have been
release formulation of an oral suspension of
lishing Gr recent years have witnessed a marked slow-
approved by the FDA, and only six antibiotics
an existing drug, Zithromax (azithromycin).
down in the development of new antibiotics.
are in phase 2 or phase 3 clinical trials (Table
Currently, Pfizer has two antibiotics in phase 2
Accordingly, there are fewer patent applica-
1). In contrast, there are approximately 313
or phase 3 trials. In addition, since 1998, only
tions filed with the US Patent and Trademark
non-antibiotic drugs in phase 2 or phase 3 four other companies—Merck, Wyeth, Bristol-
Office (USPTO) for new antibiotics, and fewer
trials. Moreover, of the approved antibiotics,
Nature Pub 6 patents issuing from these applications. This only four are truly novel: that is, either exhib-
obtained approval for any antibiotics. These
article examines some of the reasons why there
iting a new mechanism of action or exhibiting
data strongly imply that pharma companies
200 is less antibiotic research and suggests some
a structure different from that of antibiotics
are developing fewer antibiotics in comparison
solutions that may alleviate this problem. Shifting research priorities One possible reason for the slowdown in Table 1 Antibiotic development at selected major pharmaceutical companies
antibiotic research may be the advances in
New antibiotics Number of Approximate total
healthcare that have prevented the occur-
or new uses of old New antibiotics antibiotics in number of drugs
rence of epidemics requiring new antibiotics.
antibiotics approved approved phase 2 trials in phase 2 trials
At the same time, there are still no satisfactory
since 1998 since 1998 or beyond or beyond
treatments for many chronic diseases such as
arthritis and cancer, and for some relatively
recent diseases, such as AIDS. Faced with
relatively little societal pressure to develop
new antibiotics, companies have shifted their
resources to developing other, more profitable
ceutical firms reveals that the pipeline of
new antibiotics is fairly scarce. Although the
Martin L. Katz, Lisa V. Mueller, Mark Polyakov and Steven F. Weinstock are at Wood Phillips, 500 West Madison Street, Suite 3800, Chicago, Illinois 60661-2562, USA. e-mail: mlkatz@woodphillips.com NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 12 DECEMBER 2006
by Replidyne and Forest Laboratories. In
December 2005, Replidyne submitted a new
drug application for four adult indications,
based on the results of eleven phase 3 clini-
cal trials and a safety database of more than
5,000 patients treated with the antibiotic6. In
October 2006, the FDA issued a ‘non-approv-able’ letter recommending further clinical
studies for all indications. Replidyne and Forest estimated that it would take at least
two years to complete the additional clinical
studies. Further, the FDA stated that for two
of the indications, superiority studies may be
needed. Whereas the current criterion used
by the FDA for evaluating new antibiotics
is non-inferiority (that is, the manufacturer
must demonstrate that the new antibiotic is
.com/naturebiotec
not inferior to currently available antibiotics),
there seems to be a shift by the FDA towards
Figure 1 Antibacterial sales forecasts from 2005 to 2015, and key patent expirations. The patent
a requirement of demonstrating superiority.
expirations of some of the leading antibacterial drugs will inevitably lead to further incursion into the
Although superiority may be a better indicator
market by generic drugs. Although the degree of generic incursion following patent expiration tends
of the usefulness of a drug, such a requirement
to vary considerably between different countries and also between individual products, most brands
may very well lead to even less research in the
experience declining sales following the launch of cheaper copies. Source: Datamonitor. Report:
http://www
Commercial Insight: Antibacterials, December 2006. Lost profits A raised utility bar
Development, the cost of developing a new Other factors affecting companies’ decisions
Although it seems that antibiotic R&D has drug rose from $231 million in 1987 to about
regarding antibiotic R&D programs include
become a low priority for many pharma and
$802 million in 2001, with one of the major
the difficulty in improving upon the efficacy
lishing Gr biotech companies, another possibility for the reasons for the increase being the rising cost of of currently available antibiotics and the low
decline in the number of patent applications
clinical trials3. Some antibiotics may be subject
return on investment compared with invest-
being filed and issuing may be the US patent
to particular scrutiny by the FDA because cer-
ing in the research of non-antibiotic drugs.
process. In order to obtain a US patent, an tain antiobiotics, such as grepafloxacin, have
Assuming the costs of developing antibiot-
invention must be new, useful (namely, possess
been found to cause cardiac problems, such as
ics and other drugs are about the same, it is
Nature Pub 6 ‘utility’) and nonobvious. In response to the the prolongation of the QT interval, which is inherently more profitable to develop non-
criticism that prior utility guidelines were too
a measure of the time between the start of the
antibiotic drugs. Whereas one patient might
200 liberal, in January 2001 the USPTO issued new
Q wave and the end of the T wave in the heart’s
require a full year of therapy for a chronically
guidelines2. Although these guidelines were electrical cycle. QT prolongation is known to
administered drug (such as an anticancer
stated to be applicable to all inventions, spe-
cause ventricular tachyarrhythmia, which can
drug, antiarthritis drug, etc.), most antibi-
cific examples were included for biotechnol-
cause sudden cardiac death4. If a new antibi-
otic drugs are administered for about a week,
ogy and large generic chemical applications.
otic is found to cause QT prolongation dur-
and therefore, it would take 52 patients to
Under the new guidelines, an examiner is
ing preclinical testing, millions of dollars in
achieve a similar financial return. In other
required to review an application to determine
additional R&D costs will be needed if the words, from a commercial perspective, it is
whether or not the applicant has asserted a antibiotic is to have any chance of receiving
more profitable for companies not to engage
“specific” and a “substantial” utility for the FDA approval.
claimed invention. If an asserted utility is spe-
The risks inherent in developing new anti-
As with other therapeutic areas, the com-
cific and substantial, the examiner must deter-
biotics are further demonstrated by two recent
mercially successful development of some
mine whether or not the asserted utility would
cases. The first surrounds Sanofi-Aventis’s antibiotics is often a result of the discovery
be “credible.” For example, patent applications
Ketek (telithromycin), which was approved by
of a new use of an existing drug. However,
claiming recombinant proteins that assert that
the FDA in 2004. In June 2006, an FDA offi-
companies may not be as likely to invest in the
such proteins are useful for treating certain cial warned that Ketek might cause severe liver
development of a drug for a new use, as patent
types of bacterial infections may be receiving
damage, blurred vision, loss of consciousness
protection for new uses is not as effective as
and even death. Moreover, the official stated
for the drug itself. Although US patent laws
that there was no evidence that Ketek worked
allow one to obtain a patent for the discov-
Regulatory hurdles
any better than any of the other, safer drugs
ery of a new use of an existing product, such
Another factor contributing to the low number
already on the market5. Although Ketek is patents are hard to enforce. Once the patent
of antibiotics in the R&D pipeline may be the
still on the market, this incident underscores
for the drug itself expires, generic companies
significant time and cost involved in discover-
the risks companies face in developing new
are free to market generic versions for a frac-
ing and developing a new drug and obtaining
tion of the cost of the brand name compound
marketing approval from the FDA. According
The second case relates to faropenem (Fig. 1). Although there may exist a pat-
to the Tufts Center for the Study of Drug medoxomil, a novel antibiotic being developed
ent protecting a second indication for the
VOLUME 24 NUMBER 12 DECEMBER 2006 NATURE BIOTECHNOLOGY
decisions made by pharmaceutical companies.
accelerated review process at the FDA and
to sue doctors who may still prescribe it for
Clearly, pharmas are assigning a lower prior-
providing financial incentives to companies
the second use. Additionally, because doctors
ity to antibiotic R&D programs or eliminating
engaged in antibiotic research. These incen-
and patients may often use a formulation them altogether. Contributing factors include
tives could include extending market exclusiv-
approved for one use to treat another indica-
higher R&D costs associated with developing
ity for antibiotics (especially when second uses
tion, pharma companies may not be inclined
new antibiotics and then guiding these drugs
are discovered) and providing longer patent
to develop a new dose, dosage form or brand
through the FDA, difficulties in improving term extensions to compensate for longer and
name for a second use (which would have pro-
the efficacy and safety of new antibiotics, and
costlier developments of antibiotics as com-
vided more effective protection). Therefore,
difficulties in discovering new drugs effective
there are fewer incentives for companies to against multiple strains of bacteria. invest in a product for a second use as com-
According to the Infectious Disease Society
1. Bad bugs, no drugs: as antibiotic R&D stagnates. a
pared with a new drug. One possible solution
of America (IDSA), one of the main problems
public health crisis brews (Infectious Diseases Society
for this problem may lie in extending market
with currently available antibiotics is the rise
of America, Alexandria, Virginia, 2004).
2. Utility Examination Guidelines, 66 Fed. Reg. 1092
exclusivity for the compound once a second
in antibiotic resistance. In 2004, more than
http://www.uspto.gov/web/officer/com/sol/notices/
70% of pathogenic bacteria were estimated
3. Tufts Center for the Study of Drug Development pegs
to be resistant to at least one of the currently
cost of a new prescription medicine at $802 mil-
Conclusions
available antibiotics1. It is therefore crucial
lion. http://csdd.tufts.edu/NewsEvents/RecentNews. .com/naturebiotec
There seems to be less antibiotic R&D, and that new antibiotics be developed. Although
4. Fermini, B. & Fossa, A.A. Nat. Rev. Drug Discov.2,
accordingly fewer patent applications being there is no impending silver bullet, some of
filed for antibiotics and even fewer patents the IDSA’s recommendations seem advisable,
5. Harris, G. Approval of antibiotic worried safety officials.
issued. The reasons for this are wide-ranging
such as simplifying the FDA’s approval process
New York Times (19 July 2006).
6. FDA rejects Replidyne drug application. Denver
and relate to both patent law and business for antibiotics, granting priority antibiotics
Business Journal (23 October 2006). http://www lishing Gr Nature Pub 6 NATURE BIOTECHNOLOGY VOLUME 24 NUMBER 12 DECEMBER 2006
NOTICE: INFORMATION DE L’UTILISATEUR WELLBUTRIN XR 150 mg comprimé à libération modifiée WELLBUTRIN XR 300 mg comprimé à libération modifiée Veuillez lire attentivement cette notice avant de prendre ce médicament. - Gardez cette notice.Vous pourriez avoir besoin de la relire. Si vous avez d’autres questions, interrogez votre médecin ou votre pharmacien. Ce médicament
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