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 antibacterial products.

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 multiple antibiotics.

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.

Priority to antibiotics

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 plc.

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 evolving pathogens.

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 BioCentury.

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.

Dwindling pipeline

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 Class Apart").

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 Cubist 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 clinic.

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 infections.

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 requirements.

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.

GAINing traction

GAIN's sponsors believe that market failures are the primary impediment to refilling the antibiotic pipeline.

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.

QIDP-designated products 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 Pharmaceuticals Inc.

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 IV formulation.

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 This Week.

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.

Pathogen-specific guidance

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 pathogens."

Top FDA officials have discussed the guidance in meetings hosted by the Brookings Institution, Duke 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.

The "pathogen-focused 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).

Pathogen-specific drug 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 Consulting LLC.

"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.

The Innovative Medicines Initiative has committed €223.7 million ($281.6 million) to the NewDrugs4BadBugs (ND4BB) initiative to combat antibiotic-resistant pathogens.

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."

Shifting pneumonia goalposts

Draft guidance on hospital-acquired bacterial and ventilator-associated bacterial pneumonia (HABP/VABP) published in November 2010 illustrates the shifting regulatory terrain.

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 far enough.

"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 BioCentury.

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 development.

"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," he said.

Limited populations

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) approval mechanism.

"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.


Achaogen Inc., South San Francisco, Calif.

Advanced Life Sciences Holdings Inc. (Pink:ADLS), Woodridge, Ill.

Anacor Pharmaceuticals Inc. (NASDAQ:ANAC), Palo Alto, Calif.

Anti-Infectives Consulting LLC, Stonington, Conn.

AstraZeneca plc (LSE:AZN; NYSE:AZN), London, U.K.

Basilea AG (SIX:BSLN), Basel, Switzerland

Biomedical Advanced Research and Development Authority (BARDA), Washington, D.C.

Brookings Institution, Washington, D.C.

Cempra Inc. (NASDAQ:CEMP), Chapel Hill, N.C.

Cubist Pharmaceuticals Inc. (NASDAQ:CBST), Lexington, Mass.

Duke University, Durham, N.C.

Durata Therapeutics Inc. (NASDAQ:DRTX), Morristown, N.J.

European Medicines Agency (EMA), London, U.K.

Forest Laboratories Inc. (NYSE:FRX), New York, N.Y.

GlaxoSmithKline plc (LSE:GSK; NYSE:GSK), London, U.K.

Infectious Diseases Society of America (IDSA), Arlington, Va.

Innovative Medicines Initiative (IMI), Brussels, Belgium

Johnson & Johnson (NYSE:JNJ), New Brunswick, N.J.

The Medicines Co. (NASDAQ:MDCO), Parsippany, N.J.

Nabriva Therapeutics AG, Vienna, Austria

Novartis AG (NYSE:NVS; SIX:NOVN), Basel, Switzerland

Pharmaceutical Research and Manufacturers of America (PhRMA), Washington, D.C.

Polymedix Inc. (OTCBB:PYMX), Radnor, Pa.

Rib-X Pharmaceuticals Inc., New Haven, Conn.

Theravance Inc. (NASDAQ:THRX), South San Francisco, Calif.

Toyama Chemical Co. Ltd. (Tokyo:4518), Tokyo, Japan

Trius Therapeutics Inc. (NASDAQ:TSRX), San Diego, Calif.

U.S. Biomedical Advanced Research and Development Authority (BARDA), Washington, D.C.

U.S. Food and Drug Administration (FDA), Silver Spring, Md.