There is a consensus among the
U.S. government, industry and the medical community that the failure of
antibiotic development to keep pace with the evolution of bacterial pathogens
constitutes a public health crisis, and that new regulatory policies and
economic incentives are needed to create a continuous stream of new
The Generating Antibiotics
Incentives Now (GAIN) Act, which came into effect on Oct. 1, is a building block
for creating some of the changes that will be needed to get antibiotic drug
development back on track. And political changes have allowed FDA to begin
shifting its risk-benefit calculus.
But much more is needed.
Infectious disease specialists and biopharma drug hunters say FDA's
positive attitude now must be turned into endpoints and trial designs that
match clinical realities.
The agency has started down
this path, crafting guidance that will make it easier to develop drugs for
intra-abdominal infections, and telling companies that it has reconsidered bans
on prior treatment with antibiotics in lung infection trials.
More work is needed to make
endpoints in settings like pneumonia acquired in hospitals or associated with
ventilator use consistent with clinical practice.
There is also an urgent need to
create a regulatory pathway that will facilitate the development of new drugs
to combat emerging, rare pathogens, especially those that are resistant to
On both scores, Europe is ahead
of the U.S.
But in both Europe and the
U.S., new policies also are required to improve the economic incentives for
bringing new antibiotic drugs to market by making it possible to lower
development costs and enable attractive pricing.
The first indicator of whether FDA's new attitude is
translating into practice could come on Nov. 29, when the Anti-Infectives Drugs
Advisory Committee will review an NDA from Theravance
Inc. for use of Vibativ telavancin in nosocomial pneumonia.
The GAIN Act, which was
incorporated in the FDA Safety and Innovation Act that reauthorized
prescription drug user fees, provides added exclusivity for antibiotics and
earmarks antibiotics for Priority Review.
It also mandates the creation
of a pathogen-focused antibacterial drug development pathway.
Moreover, GAIN may remove some
of the impediments to financing antibiotic drug development. The ability to
develop drugs for emerging multi-resistant pathogens based on the bugs they kill
- regardless of the site of infection - should stimulate the creation of new
drugs as FDA and sponsors agree on minimum efficacy datasets that can be
obtained practically and rapidly.
But the most important effect
of the new law is its signal that Congress has reversed its attitudes toward
antibiotic drug development.
With GAIN, political pressure
to limit the risk of adverse effects from antibiotics has been replaced by
congressional calls to reinvigorate product development.
Attitudes at FDA mirror the
evolution in the political environment.
"The whole tone of the conversation has gone from 'no' to
'go,'" said John Rex, VP and head of infection, global medicines
development, at AstraZeneca
Senior FDA officials say the
agency is committed to rapidly replacing infeasible requirements for
antibiotics with pragmatic standards based on the realities of clinical
practice at a pace commensurate with the public health threat posed by rapidly
FDA is going to "reboot
our effort," said Janet Woodcock, director of the Center for Drug
Evaluation and Research (CDER). "It is not going to be on my watch that we
fail to develop antibiotics for the next generation of bugs," she told
Rachel Sherman, associate
director of CDER's Office of Medical Policy, stressed the public health mandate
during an interview on BioCentury This Week television (see
BioCentury This Week, Nov. 18).
"The slowdown in
development of these products is a public health crisis of the greatest
magnitude," she said. "We at the agency are aware of that, and we are
on top of it, and we are going to do everything in our power - and especially
involving all stakeholders - in making sure that there are clear and
predictable pathways that address this crisis."
Drug developers and the Infectious
Diseases Society of America (IDSA) have welcomed the GAIN Act and FDA's
reset, but think more needs to be done to improve the regulatory landscape and
the economics of antibiotic drug development.
In the U.S., "regulatory
disincentives resulting from the lack of clear and feasible antibacterial
clinical guidance for industry has become a towering impediment to antibiotic
development," IDSA President Thomas Slama stated in a letter to HHS
Secretary Kathleen Sebelius in August, after Congress passed GAIN.
Biopharma executives also say
the regulatory environment for antibiotic development in Europe is far better
than the U.S., and argue that Europe has implemented a more robust strategy for
funding antibiotic R&D to address public health priorities.
The push by governments for
antibiotic-friendly policies is intended to reverse a decades-long decline.
FDA antibiotic approval numbers
illuminate the problem. There were 16 new systemic antibiotics approved from 1983 to
1987. Approvals declined to 10 from 1993 to 1997, to five from 2003 to 2007,
and to just two since 2009.
At least 53 new systemic
antibiotics are in clinical development, including 14 that are not based on
chemical classes of any approved human systemic antibiotics (see "A
But relatively few of the
products in development are targeted at Gram-negative bacteria, one of the most
serious short-term threats (see "Less than Meets the Eye," A4).
As big pharma started exiting
the antibiotics space in the 1980s and 1990s in favor of drug classes with
potential for greater payoffs, the pace of drug development began to lag behind
the evolution of dangerous bacteria.
Today, higher opportunity costs
compared with other therapeutic classes remains a major reason for the lack of
investment by large companies in antibiotics.
"When I talk to my colleagues in the big companies, those
that are still involved in any degree of anti-infectives tell me that their
competitors are not the other big companies, but rather the therapeutic areas
within their own company," Barry Eisenstein, SVP for scientific affairs at
Pharmaceuticals Inc., said on BioCentury This Week.
Today, only two big pharmas, GlaxoSmithKline
plc and Novartis
AG, have disclosed they are testing unapproved compounds in the clinic
to treat bacterial pathogens that are common in the U.S. and Europe. Johnson
& Johnson and AstraZeneca also have TB drug candidates in the
Pharma's pivot away from
anti-bacterial drugs was partly mitigated starting in the 1990s by the
entry of biotech companies, attracted by what was then a clear regulatory
pathway and the possibility of large markets to treat common community-acquired
For the U.S. market, both of
these advantages vaporized in 2006 after antibiotic drug regulation entered the
political arena when prominent members of Congress shifted blame for allegedly
unsafe drugs from the companies that manufactured them to the officials
responsible for regulating them.
Concerns about rare side
effects caused by the antibiotic Ketek telithromycin were amplified, and
politicians went so far as to accuse senior FDA regulators of conspiring with
drug companies to expose the public to dangerous products (see BioCentury,
June 26, 2006).
The toxic atmosphere around
Ketek helped tip the scales in a long-running internal debate at FDA over
efficacy standards for antibiotics, especially about the use of non-inferiority
studies. Efficacy thresholds were raised substantially and trial requirements
reflected the perspectives of biostatisticians more than those of physicians
who treat infectious diseases.
"In 2006 there was a lot
of work looking at clinical trial designs and looking in particular at
non-inferiority trial designs to try and get to very scientifically sound
trials," Edward Cox, director of the Office of Antimicrobial Products at
CDER, told BioCentury This Week.
Cox acknowledged that by making
antibiotic trial designs more rigorous, FDA inadvertently imposed infeasible
It has become "apparent
that some of those designs were not practically feasible," he said. "A
lot of the effort over the last couple of years has been to try and get to
feasible trial designs so that we can have new antibacterial drugs developed."
Cox and Sherman co-chair FDA's
Antibacterial Drug Development Task Force.
The task force, announced in
September, will help implement GAIN's mandate for FDA to review and if
necessary revise three guidance documents per year associated with
antibacterial and antifungal drugs.
GAIN's sponsors believe that
market failures are the primary impediment to refilling the antibiotic
The law thus was crafted to "provide
the important incentives that are necessary for the investments that are
required for the research and development" of antibiotics, Sen. Richard
Blumenthal (D-Conn.), one of the bill's sponsors, told BioCentury This Week.
Blumenthal cited concerns about
the "dwindling supplies" of new antibiotics and the emergence of "so-called
super bugs that are antibiotic resistant and cause some of the most pernicious
and insidious infections and diseases like MRSA, E. coli, Acinetobacter
brought back by the troops from Iraq and Afghanistan."
Blumenthal also acknowledged
that antibiotics are not blockbusters. "They are used for days or a few
weeks and then hopefully needed no more, and so there need to be new financial
incentives for drug companies to develop them," he said.
Rep. Phil Gingrey (R-Ga.), who
sponsored the GAIN Act in the House, told BioCentury This Week he pushed
for its enactment because "pharmaceutical companies in this country a
number of years ago really quit working in that space for all intents and
purposes, because the opportunity to recover the investment - sometimes
billions of dollars before they get a product to market - was just not there."
Like the Orphan Drug Act, GAIN
provides additional market exclusivity to designated products.
Under GAIN, a qualified
infectious disease product (QIDP) is a new "antibacterial or antifungal
drug for human use intended to treat serious or life-threatening infections,
including those caused by an antibacterial or antifungal resistant pathogen,
including novel or emerging infectious pathogens" or caused by a pathogen
from a list FDA will create.
FDA has scheduled a meeting on
Dec. 18 to solicit public comment on which pathogens should be on the list.
QIDPs will receive an
additional five years of market exclusivity on top of the five years of
exclusivity provided to all new chemical entities (NCEs) and seven years
provided to NCEs that are Orphan drugs. In practice, this will add market life
only to products with patent protection shorter than the 10 years of
exclusivity provided to NCE QIDPs, or 12 years for Orphan QIDPs.
automatically receive Priority Review. This is of largely symbolic value
because virtually any compound that meets the QIDP criteria would already be
eligible for Priority Review (see Online Links, A22).
The first two publicly disclosed QIDP designations were
awarded to delafloxacin and radezolid from Rib-X
Rib-X has conducted four Phase
II trials of delafloxacin, which the company is developing in oral and IV
formulations for acute bacterial skin and skin structure infections (ABSSSIs)
and community-acquired bacterial pneumonia (CABP).
The company has completed two
Phase II trials with an oral formulation of radezolid, in uncomplicated skin
and skin structure infections (uSSSIs) and in CABP, and a Phase I study with an
Even though patents on the two
products expire after the additional exclusivity period, QIDP designation
reassures potential investors by taking some uncertainty about potential patent
challenges off the table, Rib-X President and CEO Mark Leuchtenberger said on BioCentury
It's important to be able to
tell investors "this is what the revenues are going to be on an exclusive
basis out to this year," he said. "It makes a big difference."
Prabhavathi Fernandes, president and CEO of Cempra
Inc., said Congress is right to focus on the economics.
"The big problem with
antibiotics is people use them for four to six days, the cost of development is
the same as any other drug, and people think we should price them for five or
six dollars," she told BioCentury. "We cannot spend $150-$200 million
developing an antibiotic if we have to price it at less than a bottle of water
at a hotel."
Fernandes, however, doesn't
think the exclusivity added by GAIN will change the economics of antibiotic
drug development. More must be done, she said, to reduce development costs.
While the added exclusivity has
received the most attention, the most important provision of the GAIN Act is a
132-word section tacked on to the bottom. This section requires FDA to publish
draft guidance by June 30, 2013, that "specifies how preclinical and
clinical data can be utilized to inform an efficient and streamlined
pathogen-focused antibacterial drug development program that meets the approval
standards of the Food and Drug Administration."
The draft guidance, and a final
version due by Dec. 31, 2014, also must provide "advice on approaches for
the development of antibacterial drugs that target a more limited spectrum of
Top FDA officials have discussed the guidance in meetings
hosted by the Brookings
University's Clinical Trials Transformation Initiative, and PhRMA.
"We are having meetings
for development of drugs for multi-resistant organisms with different
companies," Woodcock told BioCentury.
FDA recognizes it will be
difficult or impossible to enroll large numbers of patients with infections
caused by a rare pathogen, but it is important to get new drugs into physicians'
hands before the bugs become common enough to study in traditional trials.
"That's a life-threatening
situation, so we are treating it differently" from typical drug
development, Woodcock said.
guidance will make it feasible to make products that right now I would struggle
to develop," especially antibiotics targeting pathogens that are resistant
to multiple antibiotics and emerging pathogens, said AstraZeneca's Rex.
By the time a bug that is
resistant to multiple antibiotics is common enough to enroll large numbers of
patients in a trial, it might be too late to avert a public health crisis. "When
you are talking about less common pathogens or newly emerging forms of
resistance, if you are able to get a few thousand cases of it, that means you've
waited too long," Rex said.
For traditional antibiotic
indications, he noted, regulators typically require studies with more than
1,000 patients who have infections in the same part of the body.
The pathogen-specific guidance
should make it possible to build an efficacy case with a small number of
patients who may have infections from all over the body, supported by a larger
safety database, Rex said.
Europe is ahead
In developing pathogen-specific
guidance, FDA is consulting closely with EMA, which already has released
a draft guidance that outlines parameters for developing antibacterial drugs in
"circumstances in which only limited clinical data can be generated."
EMA described its approach in a
draft document released in June.
The document envisions
approvals for drugs to treat multi-drug resistant organisms based on trials in
an indication like hospital-acquired pneumonia/ventilator-associated pneumonia
(HAP/VAP) that "are not expected to enroll sufficient numbers of patients
infected with multi-resistant organisms to allow for an assessment of efficacy."
Clinical efficacy could be "based
only on well-documented cases collected from a prospective non-randomised study
that enrolls patients regardless of the site of the infection."
The addendum is a "roadmap
that is a big step in the right direction," Rex said. He predicted FDA's
pathogen-specific guidance will be very similar to EMA's policy on limited
clinical data (see Online Links, A22).
development is not the only area of antibiotic regulation where Europe is ahead
of the U.S.
EMA continues to approve antibiotics based on clinical cure
rate at the test of cure visit, and it has more realistic policies about prior
treatment with antibiotics and non-inferiority margins, according to David
Shlaes, president of Anti-Infectives
"EMA operates in a
different legislative environment; they have more flexibility," Rex noted.
"EMA's guidances are more consistent with prior approaches, and those of
us who work in the area view those approaches as common sense."
If the U.S. adopted a more
European approach, the cost of developing antibiotics could be cut
substantially, according to Leuchtenberger. "Europe is moving faster, both
in terms of funding, and in terms of clarity of regulations, and both of those
things have a huge impact on the amount of money you need to spend in order to
get these drugs approved and commercialized," he said.
In addition to adopting more
pragmatic regulations, Europe has invested more aggressively than the U.S. to
target the development of drugs to address bacterial public health threats.
Medicines Initiative has committed €223.7
million ($281.6 million) to the NewDrugs4BadBugs (ND4BB) initiative to combat
ND4BB is funding Phase II and
III trials of a GlaxoSmithKline antibiotic and is prepared to spend an
additional €92 million for trials of two compounds from
AstraZeneca (see BioCentury, June 4, 2012).
In the U.S., the Biomedical
Advanced Research and Development Authority (BARDA) funds trials of
antibiotics only if there is potential bioterrorism application.
"The trouble with BARDA is
that it's focused on biothreats, bioterror," according to Eisenstein. "What
we need is something broader - something that includes the organisms that are
brought back by our soldiers from Iraq, the Acinetobacter, the folks
that are in the intensive care unit in our hospitals who are getting nosocomial
hospital-acquired pneumonia, intra-abdominal infections, urinary tract
infections and bacteremia."
Draft guidance on
hospital-acquired bacterial and ventilator-associated bacterial pneumonia
(HABP/VABP) published in November 2010 illustrates the shifting regulatory
The draft guidance raised
serious concerns among antibiotics developers for two reasons: it barred
enrollment of subjects who had received an antibiotic within 30 days prior to
enrollment, and it mandated a new primary endpoint of all-cause mortality
within 28 days after randomization.
FDA suggested it was open to
revising the prior antibiotic exclusion at a November 2011 meeting of the
Anti-Infective Drugs Advisory Committee. The panel urged the agency to allow
prior antibiotic therapy of less than 24 hours' duration for HABP or VABP
trials (see BioCentury, Nov. 14, 2011).
According to Cox, FDA now is "working
to change" the prior antibiotic preclusion for HABP and VABP. "We're
working through the scientific issues. Through the discussions of the advisory
committee, some science was brought forth that made it reasonable to allow 24
hours of prior therapy," he said on BioCentury This Week.
FDA also is considering changes
to its policy on prior use of antibiotics in CABP trials.
"We're thinking about ways
to allow some degree of prior antibiotic therapy in community-acquired
pneumonia trials in order to make those trials practical and feasible, and
still have good scientific evidence of how the drug works," Cox said.
Jeffrey Stein, president and CEO of Trius
Therapeutics Inc., told BioCentury the industry appreciates FDA's
flexibility on prior antibiotic use for pneumonia trials - but it does not go
"The initial guidance
specified no prior antibiotics allowed, and at the same time it required that
these be very severe lung infections," Stein said. "These are
mutually exclusive criteria. A patient admitted to hospital with severe lung
infection automatically gets a drug."
Although FDA has stated it "will
allow a single dose of a short-acting antibiotic, most sponsors would love to
see additional flexibility," Stein said. "These patients do not have
their lung infections cured by a single dose of a drug, so allowing a
longer-acting drug would be greatly appreciated by Trius."
Trius is developing tedizolid
phosphate, an oxazolidinone antibiotic, for CABP, HABP, VABP and ABSSSI. It has
completed the first of three planned Phase III trials for ABSSSI.
Stein said he is chairing and
helping organize a coalition of CEOs and senior executives from American
antibiotic developers that will "speak with a single voice to FDA and
enlist local congressional representatives to help communicate the necessity to
get more feasible regulations in place."
FDA's restrictions on prior use
of antibiotics are stymieing development of treatments for indications other
than lung infections, particularly urinary tract infections, Shlaes told
In nosocomial pneumonia, FDA's
requirement for a mortality endpoint also is a sticking point.
"Companies are still
pushing back against the all-cause mortality endpoint," Stein said. "These
patients are so severe that they are dying for reasons in addition to
infection. For example, a chest trauma patient is admitted to hospital, he
contracts an infection and dies. You can't tell if that patient died from an
infection or something else."
Shlaes predicted FDA will
rescind the all-cause mortality endpoint on Nov. 29 when the Anti-Infective
Drugs Advisory Committee meets to discuss Theravance's NDA for the use of
Vibativ to treat nosocomial pneumonia, including VAP known or suspected to be
caused by methicillin-resistant Staphylococcus aureus (MRSA).
In a 2009 complete response
letter for Vibativ to treat HABP/VABP, FDA requested an all-cause mortality study,
according to the company.
In contrast, EMA approved
Vibativ for the indication in September 2011 based on a non-inferior clinical
cure rate vs. vancomycin at test of cure visit.
The upcoming meeting will be
closely watched as an indicator of FDA's evolving position on antibiotic drug
"We will get a sense at
that meeting of whether or not FDA is modifying its approach - if FDA is
putting its money where its mouth is," said Robert Guidos, VP of public
policy and government relations at IDSA.
Speaking on an Oct. 30 earnings
call, Rick Winningham, Theravance's chairman and CEO, said the company had "collected
data that allowed us to create 28-day Kaplan-Meier survival curves and
specifically in the population that FDA seem to be interested in."
FDA's September draft guidance
on drugs to treat complicated intra-abdominal infection (cIAI) is an example of
the agency's flexibility and new pragmatism in antibiotic development,
according to Eisenstein.
Cubist is conducting two Phase
III trials of CXA-201, a combination of the cephalosporin antibiotic CXA-101
and the beta lactamase inhibitor tazobactam, for cIAI.
The draft guidance "clearly
states that a single Phase III trial, as long as there's backup with other very
strong evidence - like another Phase III trial in a different but related
indication, for example, urinary tract infection - would together cross-support
each other," Eisenstein said.
This approach signals FDA's
realization "that you've got to balance feasibility, - practicality, if you
will - with scientific rigor, and that you sometimes, in a public health
crisis, have got to be willing to move things along in a more rapid manner,"
Looking beyond the GAIN Act,
academic infectious disease experts, FDA and industry are working on proposals
for a new restricted approval pathway that would speed the development of new
antibacterial drugs and could address some of the economic disincentives that
have driven most pharma companies out of the space.
IDSA is promoting a version of
the concept, which it calls the limited population antibacterial drug (LPAD)
"Under the LPAD mechanism,
a drug's safety and effectiveness would be studied in substantially smaller,
more rapid, and less expensive clinical trials," like those typically used
to support Orphan Drug approvals, according to an IDSA description (see
Online Links, A22).
LPAD products "would be
narrowly indicated for use in small, well-defined populations of patients for
whom the drugs' benefits have been shown to outweigh their risks."
Labels for products approved
under LPAD would include a description of the indicated population, the
rationale for limiting use, and a logo signifying its LPAD status.
"Through this information,
FDA would be providing notice to the health care community and payors that
these products carry less precise estimates of risk and, as a result, the drugs'
marketing and use should be limited to the indicated population,"
according to IDSA.
While regulators are prohibited
from advocating specific legislation, Woodcock and other senior FDA officials
have expressed support for the LPAD concept.
"One of the most urgent
areas of focus is developing drugs for patients who don't have satisfactory
treatment options currently, and a more limited development program is
appropriate in that scenario," Cox told BioCentury.
Antibiotic drug developers also
are enthusiastic about LPAD.
It would slash the number of
patients required to gain approval from about 1,400 for the typical antibiotic
indication to 100 or less, cut development time in half, and reduce regulatory
uncertainty, Trius' Stein told BioCentury.
A limited-use pathway also
would address one of the biggest barriers to antibiotic development - pricing -
according to Leuchtenberger.
With a mechanism like LPAD, "you
could finally see a chance where you could price appropriately, like an
oncology drug, like a rare disease, and you would be paid proportionately for
saving people's lives," he said.
Rep. Gingrey told BioCentury he
is working with Rep. Henry Waxman (D-Calif.) and other members of the House
Energy and Commerce Committee on bipartisan follow-up legislation that would
include the LPAD mechanism.
"We're working very
closely right now on that proposal with industry," Gingrey said. "It's
not quite ready for prime time yet. We're going to have to make sure that all
the stakeholders agree that the language is right."
Gingrey said the legislation
could be enacted next year.
Just as the GAIN Act was
attached to PDUFA reauthorization, LPAD could be attached to legislation that
must be enacted in 2013 to prevent the expiration of animal drug user fees.
Inc., South San Francisco, Calif.
Life Sciences Holdings Inc. (Pink:ADLS), Woodridge, Ill.
Pharmaceuticals Inc. (NASDAQ:ANAC), Palo Alto, Calif.
Consulting LLC, Stonington, Conn.
plc (LSE:AZN; NYSE:AZN), London, U.K.
AG (SIX:BSLN), Basel, Switzerland
Advanced Research and Development Authority (BARDA), Washington, D.C.
Institution, Washington, D.C.
Inc. (NASDAQ:CEMP), Chapel Hill, N.C.
Pharmaceuticals Inc. (NASDAQ:CBST), Lexington, Mass.
University, Durham, N.C.
Therapeutics Inc. (NASDAQ:DRTX), Morristown, N.J.
Medicines Agency (EMA), London, U.K.
Laboratories Inc. (NYSE:FRX), New York, N.Y.
plc (LSE:GSK; NYSE:GSK), London, U.K.
Diseases Society of America (IDSA), Arlington, Va.
Medicines Initiative (IMI), Brussels, Belgium
& Johnson (NYSE:JNJ), New Brunswick, N.J.
Medicines Co. (NASDAQ:MDCO), Parsippany, N.J.
Therapeutics AG, Vienna, Austria
AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland
Research and Manufacturers of America (PhRMA), Washington, D.C.
Inc. (OTCBB:PYMX), Radnor, Pa.
Pharmaceuticals Inc., New Haven, Conn.
Inc. (NASDAQ:THRX), South San Francisco, Calif.
Chemical Co. Ltd. (Tokyo:4518), Tokyo, Japan
Therapeutics Inc. (NASDAQ:TSRX), San Diego, Calif.
Biomedical Advanced Research and Development Authority (BARDA),
Food and Drug Administration (FDA), Silver Spring, Md.