The Food & Drug Administration is working to encourage one area of drug development more than any other. Is it oncology? No. Obesity and diabetes? No. Pediatric rare diseases? No. Alzheimer’s disease and dementia? No.

Antibiotics.

Surprised? It’s understandable. FDA’s attitude on the development of antibiotics is a mirror image of its view just a few years ago, when the agency raised approval standards by refusing to accept non-inferiority trials, and requiring much larger clinical studies to support approval. Also see "Getting the Bugs Out of Antibiotic R&D: Commercial Implications of a Higher Regulatory Hurdle" - Pink Sheet, 1 June, 2007. And that drove developers out of the market – or in some cases, out of business. Also see "An Emerging Approval Trend At FDA: More First-Time Sponsors" - Pink Sheet, 19 January, 2012.

Today, with the advent of multi-drug resistant infections, the conversation is much different. Rather than raising the approval bar, FDA is talking about raising industry’s participation in antibiotic R&D.

“There’s no area that we’re working on harder than trying to develop pathways that are feasible and scientifically rigorous for developing and approving new antimicrobials,” FDA Office of New Drugs Director John Jenkins said during his opening keynote at The RPM Report’s FDA/CMS Summit for Biopharmaceutical Executives in Washington, D.C. on December 10.

Getting to that point took years of conversations, but the consensus now among top drug officials is that new ideas are needed to spur antibiotic drug development. And FDA isn’t interested in old-school blockbuster indications like bacterial otitis media, but areas of true unmet medical need, like gram-negative bacteria, drug-resistant tuberculosis and methicillin-resistant Staphylococcus aureus (or MRSA).

For those drugs, that means shortened approval pathways and exclusivity incentives once products are on the market. Industry is already taking advantage of the antibiotic incentives passed as part of the fifth reauthorization of the Prescription Drug User Fee Act. Originally part of the GAIN Act, they are among the most generous R&D incentives ever awarded by Congress: five years of market exclusivity on top of other exclusivity periods the drugs would otherwise receive. Also see "GAIN Is Great: Now Who Gets the Benefits?" - Pink Sheet, 15 March, 2012.

FDA hopes that GAIN will re-energize antibiotic drug development. “Our hope is that we will be able to turn around what has been viewed as an exit from the market,” CDER Deputy Director Douglas Throckmorton said at the FDA/CMS Summit. “Turn around the decline in the development of new products in these therapeutic areas. The idea being that we all require these, obviously, as resistances emerge.”

Congress had also considered a measure that would have shortened the pathway for antibiotics used to treat patients with serious, multi-drug resistant infections or in areas where there is an unmet medical need. First proposed by the Infectious Diseases Society of America, the Limited Population Antibacterial Drug mechanism would allow FDA approval of new antibiotics for targeted patient groups with narrow labels based on smaller and shorter clinical trials. Also see "The Popularity of “Special Pop”: Antibiotics Incentives and PDUFA V" - Pink Sheet, 9 April, 2012.

That measure didn’t make it into PDUFA V, but under FDA Commissioner Margaret Hamburg, the agency has been pushing ahead with the idea anyway. Also see "Accelerating Antibiotic Drug Development: FDA Goes Beyond GAIN" - Pink Sheet, 24 October, 2012. Many questions remain, including how (indeed, if) off-label use of targeted antibiotics can be mitigated so as to not undermine the integrity of the entire program. There is also some debate over whether FDA needs legislation authorizing an abbreviated pathway from Congress, or if it can forge ahead on existing authority.

But is it enough to encourage industry investment in an area of drug development that until now has been a losing proposition? Traditionally, new antibiotics are expensive to develop, carry a relatively low price point and are often put on reserve by health care professionals as last-resort therapies. As a result, there has been a mass exit from antibiotics in recent years, most notably including Pfizer Inc.,the previous market leader.

With attention from FDA and Congress, FDA says it is starting to see renewed interest. But the market – and the players involved – may be vastly different than the blockbuster days of Pfizer’s Zithromax and Johnson & Johnson’s Levaquin. While a few large pharmaceutical companies have stayed in antibiotic R&D – notably AstraZeneca PLC and GlaxoSmithKline PLC – the rest of the space has been taken up by small to mid-sized companies, many of which have little experience with FDA.

Some of those companies that remain say that the exclusivity period under GAIN and the shortened approval pathway in the proposed LPAD initiative isn’t enough, and that more incentives – like R&D tax credits or a guaranteed revenue stream post-launch – are needed to push developers into the market and encourage existing players to invest more in antibiotic drug development. Also see "GAIN Begins (Part 2): Infectious Disease Society and Start-Up Companies Push for More" - Pink Sheet, 15 February, 2013.

Given the current fiscal environment, any ideas that would add to the federal deficit seem a bit pie-in-the-sky. But one thing is certain: for the first time, antibiotic developers and community stakeholders have the attention of FDA and Congress. The question now is what they will do with it.

The Bottom of the Food Chain

No one argues that the rise in drug-resistant infections is not a public health crisis.

Gram-negative infections that get into the blood or lungs kill half of patients. The spread of some pathogens has meant that common conditions like urinary tract infections sometimes now require in-patient treatment with intravenous antibiotics. And with few new drugs available, physicians are turning to antibiotics like colistin, which was discovered in the 1940s but until recently was abandoned due to high kidney toxicity.

Here’s a statistic cited in a report from an antibiotic innovation conference in September 2011 that perfectly captures the current market: Howard Florey, the Australian pharmacologist and pathologist who helped discover penicillin, lived to see the development of 13 classes of drugs. Since his death in 1968, just two new classes of antibiotics have made it to the market. That’s two new classes of drugs in 45 years.

And when you look at the availability of novel antibiotics in existing classes, the picture is similar. Between 2008 and 2012, FDA approved just two new molecule entity systemic antibiotics. (See Exhibit 1.) In fact, the agency has not cleared a new antibiotic for marketing since the May 2011 approval of Optimer Pharmaceuticals Inc.’s Dificid (fidaxomicin) for the treatment of Clostridium difficile-associated diarrhea in adults. Since then, by comparison, FDA approved 16 novel cancer treatments.

Exhibit 1

A Declining Drug Market

Market forces and a tough regulatory environment have resulted in a significant decline of FDA-approved antibiotics.

Infectious Diseases Society of America

Of course, that’s not all FDA’s fault: after all, the agency cannot approve antibiotic applications that aren’t submitted by drug sponsors. And these days, that’s not happening.

There are a lot of reasons why. Historically, antibiotics offer a low return on investment compared to other therapeutic areas, at least compared to the chronic treatments for heart disease, ulcer, diabetes and arthritis that fueled the 1990s wave of blockbusters. The clinical trials needed for novel antibiotics are expensive to conduct, and once a new antibiotic is approved, it carries a relatively low price point – when it is used at all. Most new antibiotics are put on reserve until other drugs fail, which makes for a very slow commercial uptake for the first three to five years on the market.

At many larger pharmaceutical companies, that meant antibiotics were relegated near the bottom of the food chain, if they were studied at all.

Cubist Pharmaceuticals Inc. SVP-Scientific Affairs Barry Eisenstein recalls his time in charge of infectious disease discovery and clinical development Eli Lilly & Co. in the mid-1990s: “My main competitors when I was working at Eli Lilly were not Merck and Pfizer and Glaxo,” he says, “but rather the other therapeutic areas within Lilly that were able to be more successful in commercializing their products.”

Lilly has since exited the antibiotics market. Other large pharma manufacturers did the same, or significantly cut back on antibiotic R&D investment, including Roche, Sanofi-Aventis US LLC, Bristol-Myers Squibb Co., Johnson & Johnson and Abbott Laboratories Inc. Five years ago, Pfizer was the market leader in antibiotics, with 14% of the market. In 2011, the company closed its antibiotic R&D facility in Connecticut and moved its operations to China, where development has essentially stalled. Also see "Antibiotic Development: Where Wall Street Guidance Is Watching FDA Guidances" - Pink Sheet, 1 April, 2011.

The “Nadir” of Antibiotic Development

Market forces have a lot to do with Big Pharma’s exit from antibiotic R&D. But drug companies say that FDA also has a role to play in encouraging antibiotic drug development. And until recently, they argue, the agency has been doing exactly the opposite: requiring unfeasible clinical trial programs for approval and delaying the release of much-needed guidance documents.

Those heightened requirements came as a direct result of the drug safety crisis with Sanofi’s telithromycin (Ketek). FDA approved Ketek in 2004 with much fanfare: the drug was considered part of a new ketolide class of antibiotics thought to have utility against drug-resistant strains of upper respiratory infections. But the approval was later found be based on fraudulent trial data, and the drug was associated with multiple deaths and liver-related adverse events.

The political fall-out from Ketek was unprecedented. Congressional hearings on the safety issues in early 2007 were brutal, with critics of the agency personally calling out FDA officials that were believed to have turned a blind eye on the issues with the original application. Also see "The Politics of Drug Safety: An FDA Whistleblower's Push for Reform" - Pink Sheet, 1 March, 2007. In response, FDA made the hurdles for antibiotic approval much higher, and (at least in the eyes of many sponsors) unfeasible. Also see "Ketek's Political Fallout" - Pink Sheet, 1 June, 2007.

Manufacturers that were still investing antibiotic R&D left the space. Cubist was one of the few that remained. “The morale at FDA had been hurt, significantly,” Cubist’s Eisenstein recalls. “The natural reaction was a shift toward a much more cautious, risk-averse culture of how they were going to look at antibiotics.”

The years 2006-2008 “represented a nadir in the willingness of the agency to understand the need for feasible trials,” Eisenstein says. “Rather, they pushed the boundaries over to the other extreme of trying to get as much detailed information as possible to make sure that they did not miss any important safety signals.”

That meant two large, Phase III studies that needed to enroll thousands of patients each for every new indication, and an often impossibly high bar for approval. For an indication like pneumonia, for example, FDA wanted patients to be drug-free for at least 24 hours before going on an investigational antibiotic. “If you wait until you can do those Phase III studies, then the epidemic is already here,” AstraZeneca VP-Clinical Infection John Rex says. “We’ve waited too long.”

The result was no new drugs – and a corresponding rise in number of resistant pathogens.

“Five years ago, the world had not yet seen untreatable tuberculosis,” Rex says. “We weren’t seeing healthy women with ordinary urinary tract infections that couldn’t be treated with a pill,” or untreatable gonorrhea. And, he says, the world had not seen New Delhi metallo-beta-lactamase-1 (NDM-1), the enzyme first discovered in India that makes bacteria resistant to antibiotics.

The Tide Starts to Turn

It took years for things to start turning around. The Infectious Diseases Society of America’s voice strengthened on Capitol Hill as the group raised concerns about the increase in multi-drug resistant pathogens and a lack of any new drugs. And drug manufacturers found ways to talk about the issue so as to underline the potential for a public health disaster.

“The regulatory agencies have come a long way in understanding this problem and in thinking with us how to solve the problem,” Rex says. “We have spent the last several years in serial discussions with the major regulatory agencies in which we have jointly explored this question. What you are seeing now if the fruit of many hours of discussion. It’s a real partnership.”

Drug sponsors started to see some positive signs come out of FDA as officials expressed a willingness to consider shortened approval pathways for antibiotics.

Back in 2010, CDER Deputy Director for Clinical Science Robert Temple brainstormed at a workshop about allowing a single-arm study in cases where a pathogen is highly resistant to treatment. Also see "FDA Catching Antibiotic Incentive Bug: Agency Primed To Consider Ways To Shorten Route for Resistant-Strain Drugs " - Pink Sheet, 1 October, 2010. Then in November 2011, FDA held an advisory committee meeting on community-acquired bacterial pneumonia to revisit approvability standards, and expressed a willingness to ease off of previously strict efficacy requirements. Also see "FDA Indicates Flexibility On Evidence To Support Efficacy In Pneumonia" - Pink Sheet, 1 November, 2011.

But industry became really encouraged when top FDA officials started attending industry meetings on antibiotic R&D, including meetings organized by Pew Health Group, and a series of closed-door sessions sponsored by the Brookings Institution.

It was at the first of those Brookings meetings, in May 2012, that Center for Drug Evaluation & Research Director Janet Woodcock declared that the agency needed to “reboot” its approach to antibiotic drug development, and announced the creation of a CDER task force to focus specifically on the issue.

For Melinta Therapeutics Inc. VP-Corporate Development Jarrod Longcor, that was a major turning point in the way FDA was talking about antibiotic drug development. “She said ‘we recognize that some of our actions have resulted in this, and we will not allow these drugs not to come to market,’” he says. “It was the first real and very clear sign that they were going to make a path forward for drugs in this arena.”

It was at the second Brookings meeting, in August 2012, that CDER policy officials described a new risk-benefit approach to the review of antibiotics. Going forward, in addition to the traditional questions about efficacy and safety, the members of the review team would also have to explicitly denote the medical need, other drugs that are available to treat the infection, and the public health consequences of not approving the drug.

“This is the missing part of the risk-benefit discussion,” says one executive who attended the closed-door Brookings meeting. “If you limit risk-benefit only to the new drug, out of the context of what else is available and what can happen if there were no other drugs available, you always drive the discussion toward the more conservative risk-averse point of view.”

“When you take into account the broader public health perspective, as this new approach is demanding, you make the reviewers recognize what the global perspective is, and what the medical need is.”

AstraZeneca’s Rex, who was also at the Brookings meeting, adds that “it seems likely that the sponsor would need to make the case for the unmet need addressed by the new antibiotic,” as well as the reason for proposing the use of the pathway. “Importantly, however, the test for ‘unmet need’ should recognize that having one drug for a difficult bacterium does not end the battle – the global community needs the diversity offered by also having antibiotics 2, 3, and 4 for that bacterium.”

That type of analysis also provides terrific political cover for FDA, Cubist’s Eisenstein suggests. If an antibiotic is approved and three years later a rare but serious side effect causes the need for a major labeling warning or market withdrawal, “at least we will have had a record of what we were thinking of the time.” And that could provide justification to critics that might blame FDA for approving a risky drug, and avoid a debacle like Ketek.

FDA’s “Spate” of QIDP Designations

One other sign that the culture at FDA is changing is the rapidness with which the agency is designating qualified infectious disease products under the GAIN Act. Antibiotics that receive a QIDP designation from the agency qualify for “Fast Track” and priority review, plus five years of additional market exclusivity, after the end of other exclusivity periods, like Hatch-Waxman or orphan drug.

FDA started issuing QIDP designations within a few months of the passage of the FDA Safety & Innovation Act, and has continued at a rate of one or two a month. As of February 12, FDA says it has issued 11 QIDP designations for eight products. Seven of those designations have been announced publicly by drug sponsors, including two each from Cubist and Rib-X. (See Exhibit 2.)

Cubist is encouraged by the pace of the QIDP designations. FDA is using a “crisp and very logical, rational approach,” Eisenstein said. “It means the FDA is taking the Congressional mandate very seriously, and recognizing the fact that Congress really wants [it] to approve a bunch of new antibiotics because of the crisis in drug resistance. So I would put the recent spate of QIDP approvals as another strong indicator of the change in the culture.”

Exhibit 2

Antibiotics GAIN a New Incentive

FDA has deemed eight antibiotics, including 11 indications, to be qualified infectious disease products under the GAIN Act provisions in the FDA Safety& Innovation Act. A QIDP-designated product qualifies for “Fast Track” and priority review from FDA, and an additional five years of market exclusivity. Most antibiotics that have qualified for QIDP status have been publicly announced, and are listed below.

Manufacturer	Drug	Indication	Phase in Development	Date Announced
Rib-X Pharmaceuticals	delafloxacin	acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, including those caused by methicillin-resistant Staphylococcus aureus	Phase 3 in ABSSSI to start in first half 2013	September 17, 2012
Rib-X Pharmaceuticals	radezolid	acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, including those caused by MRSA	Phase 2	October 10, 2012
Durata Therapeutics	dalbavancin	acute bacterial skin and skin structure infections, including those caused by MRSA	Phase 3	November 5, 2012
Cubist Pharmaceuticals	ceftolozane/tazobactam	complicated intra-abdominal infections caused by Gram-negative bacterial infections including Pseudomonasaeruginosa	Phase 3	December 6, 2012
Cubist Pharmaceuticals	surotomycin	Clostridium difficile-associated diarrhea	Phase 3	December 6, 2012
Paratek Pharmaceuticals	omadacycline	acute bacterial skin and skin structure infections and community-acquired bacterial pneumonia, including those caused by MRSA	Phase 3 starting in ABSSSI and Phase 2 in CABP	January 3, 2013
Trius Therapeutics	tedizolid	acute bacterial skin and skin structure infections and hospital-acquired/ventilator-associated bacterial pneumonia, including those caused by MRSA	Phase 3 and Phase 2, respectively	January 7, 2013

The RPM Report

For the QIDP designations issued thus far, the process has been pretty straightforward: FDA has stuck to the list of pathogens specified in the GAIN Act, and has asked sponsors for clinical evidence that the antibiotic can treat the specified pathogen. QIDP designations are based on a specific indication; some sponsors, like Rib-X and Paratek Pharmaceuticals Inc., have drugs that qualified for multiple indications.

For Cubist, because the targeted pathogens were listed in the bill language, “we didn’t think there was going to be much trouble,” Eisenstein says. And indeed, he adds, the process “didn’t take very long.” Cubist has two other Phase II/III programs for ceftolozane/tazobactam (complicated urinary tract infection and hospital-acquired/ventilator-associated bacterial pneumonia), and is evaluating whether to apply for QIDP status.

Based on the pathogens listed in the GAIN Act, other potential designees include The Medicines Co.’s oritavancin, which has shown efficacy against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus aureus. Forest Laboratories Inc. has two combination products in a partnership with AstraZeneca PLC that would also appear to qualify – avibactam/ceftazidime (Phase III) and avibactam/ceftaroline (Phase II). Forest says it is evaluating whether to submit a QIDP request.

For Cubist, which has more experience at the agency, GAIN ensures that the company will continue to invest in antibiotics. “GAIN continues our continued desire to want to reinvest in anti-infectives,” Eisentein says. “We see the GAIN Act as providing extra reassurance and assistance in allowing us to do what we are doing successfully.”

But as AstraZeneca’s Rex points out, the GAIN exclusivity period might be worth less than expected, since it only extends exclusivity (such as the five-year new chemical entity exclusivity or the seven-year orphan drug exclusivity), but does not extend patents. “Depending on how your patents run...it could be that the [GAIN] exclusivity in part, overlaps with patent life that you might already have,” he notes. “The size of the effect is variable.”

On average, GAIN might offer two or three more years of exclusivity that wasn’t already covered by a patent, Rex says, pointing to a research paper he co-authored with Brad Spellberg (assistant professor of medicine at the David Geffen School of Medicine at the University of California-Los Angeles) that was published in the February issue of Nature Review Drug Discovery.

However, if a drug company had an “imperfect patent,” having overlapping GAIN exclusivity could be quite valuable, because of the additional protection it would afford. “The GAIN extension certainly has some value, but you have to do the math and understand that the value doesn’t come for a while,” Rex says. But overall, he says, the incentives provided by GAIN are “very important.”

After all, new molecular entities that qualify under GAIN are guaranteed 10 years of exclusivity—no matter what happens on the patent side.

Still, in some cases, the most exciting thing about GAIN might not be the exclusivity extension. The law also requires FDA to develop what drug companies have been waiting years to get from the agency: clear guidance on clinical development programs for specific pathogens. A draft of the pathogen-focused guidance document is due June 30, with a final guidance in December 2014.

The pathogen-specific guidance will be “invaluable,” Rib-X’s Longcor says. “That is a huge need and benefit for the industry to develop antibiotics.” AstraZeneca’s Rex agrees: “That, to my eye, is a very powerful thing.”

And on a much higher level, the passage of the GAIN provisions means that Congress is aware of the drug resistance issue and has blessed the need to incentivize antibiotic drug development. Especially after the Congressional backlash to Ketek, “FDA needed Congress to drive the culture change as well,” Cubist’s Eisenstein says.

Are More Push Incentives Needed?

But market exclusivity may not be enough. While the five years of additional exclusivity under the GAIN Act is nice, it doesn’t help ease the pre-approval burden. Clinical trials for antibiotics are costly, and in cases of infections that are resistant to multiple antibiotics, impossible to conduct: There simply aren’t enough patients for the types of studies that FDA has historically wanted to see.

That’s where the Limited Population Antibacterial Drug mechanism, or LPAD, could come into play. LPAD would target a much narrower universe of antibiotics than GAIN: the highest-need drugs for multi-drug resistant pathogens where there are few, if any, treatment alternatives. Drugs would be approved for very limited patient populations based on much smaller clinical trials.

One big question remains: how to mitigate the potential for inappropriate use. LPAD antibiotics would be intended for use when everything else fails, so if they were used too often, it would undermine the entire pathway. Based on the discussions at recent industry meetings, many stakeholders think the potential for inappropriate use could be mitigated by product labeling, physician education and strict stewardship programs at hospitals, although FDA officials still have some concerns. ([A#00130211011])

FDA’s Woodcock sees the value in an incentive like LPAD. “I believe that probably a narrow development program [that] we could offer legally, a radically smaller development program than for an antibiotic intended for broad uses, is a stronger incentive than exclusivity,” she said during a House Energy and Commerce Health Subcommittee last April. Also see "Antibiotic Incentives: FDA’s Woodcock Says LPAD Could Be Better Than Exclusivity, But Questions Remain" - Pink Sheet, 19 April, 2012.

IDSA says it knows of at least seven drug companies with products under development that would potentially qualify for the LPAD mechanism; Rib-X is one of them. Rib-X Chief Scientific Officer Erin Duffy pegs the preclinical RX-04 program, which focuses on the multi-drug and extremely drug-resistant Gram-negative infections, as a potential LPAD candidate.

“When we think about LPAD, we are particularly excited for our RX-04 program,” Duffy says. For Rib-X to develop RX-04 drugs under the traditional clinical pathway, “that’s going to take a long time, and a heck of a lot of money,” she says. Under LPAD, RX-04 antibiotics would get to the market much sooner, albeit with a much narrower label.

And for Rib-X, that’s perfectly fine, because it means the drugs can carry a premium price tag. “When you go into these limited populations from a marketing perspective, you’ve got to allow a high price to get the value back,” Longcor says. And, he says, those high prices will drive appropriate use: “it will have a significant impact on diminishing off-label or incorrect utilization of these compounds.”

Payers’ reactions to LPAD have been mixed. A Pew Health meeting on antibiotic drug development January 31 was among the first opportunities for payers to respond to the LPAD model, and some were more price-sensitive than others, notes Allan Coukell, deputy director of medical programs at The Pew Charitable Trusts.

While the Centers for Medicare & Medicaid Services did not seem particularly shocked by the potential cost of an LPAD-type antibiotic, “other payers said that to cover drugs at that price point they would be looking for some data,” Coukell says. “It wouldn’t necessarily need to be pre-approval, but they would be looking for some outcomes data on something tangible: length of hospital stay, days on a ventilator and/or hospital re-admissions.”

But while FDA generally likes the LPAD idea, it is unlikely to act on its own. Like the GAIN incentives, agency officials would much prefer to have the blessing of Congress, and the question there is whether lawmakers would pass another antibiotic R&D incentive so soon after GAIN. But should the Hill move forward, attaching LPAD to the animal drug user fee legislation seems the most likely option this year.

Is It All Enough?

But even LPAD has its limitations. “LPAD is not the ultimate solution,” IDSA’s VP-Public Policy & Government Relations Robert Guidos acknowledges. “It’s an important solution. It’s a game changer for the most urgently needed drugs. But we need other drugs to treat other infections that are perhaps not those caused by multi-drug resistant pathogens that we can’t study any other way except in small trials because there’s not that many patients that we can find to study.”

For example, an LPAD pathway could not be used to develop new drugs for community-acquired pneumonia, Guidos says. But “we still need drugs in those spaces.”

And so antibiotics stakeholders are pushing for more “push” incentives, like R&D tax credits, or a guaranteed market for antibiotics once they have been approved by FDA. One idea floated by relative newcomer Rempex Pharmaceuticals Inc. envisions guaranteed, government-subsidized payments from hospitals to assure a minimum threshold of revenues for new anti-infectives.

The idea is to create a new payment model for antibiotics that would “de-link” volume of sales from return on investment – a notion that is already under active consideration in Europe, IDSA’s Guidos notes. But while Congress appears open to hearing ways to combat drug-resistant pathogens, programs that would add to the federal deficit would seem to be a bit of a reach. Still, those ideas are interesting to consider, and certainly to move the conversation along. Also see "GAIN Begins (Part 2): Infectious Disease Society and Start-Up Companies Push for More" - Pink Sheet, 15 February, 2013.

While no drug companies have spoken publicly, Guidos says he has heard in private conversations that the incentives discussed to date are not adequate to encourage companies that have exited the market to get back into the business of antibiotic development, or for existing players to invest more in the field.

“There are folks that are not sure that the incentive is significant enough on the back end,” Guidos says. “That’s why we need to consider additional push incentives, like the creation of the LPAD, like R&D tax credits, that perhaps are transferable.” And payers need to get on board as well: “hopefully there will be linked to it some kind of reimbursement model that pays at a premium for these products.”

The FDA official in charge of reviewing antibiotic applications, Office of Antimicrobial Products Edward Cox, is more optimistic. “We have seen some early sign of renewed interest in antibacterial drug development focusing on patients with serious infections,” Cox said at the recent Pew conference ([A#00130211003])

And here’s another, small sign that the incentives may be paying off: Genentech Inc.’s $111 million agreement with venture-backed RQx Pharmaceuticals to develop novel antibiotics to treat multi-drug resistant Gram-negative infections. Genentech isn’t known for antibiotic development; the company has one Phase I product in the pipeline to treat infectious diseases, referenced simply as “new molecular entity.”

Genentech had penned an earlier deal with the same venture capital company (Avalon Ventures) for Afraxis Inc., so the antibiotic R&D agreement may not be a direct consequence of the policy developments in Washington. But the fact that a drug manufacturer best known for its high-priced oncology products is investing in an infectious disease R&D program is certainly an interesting development.

That’s precisely where Rib-X thinks the antibiotic resurgence will begin: renewed interest in start-up companies from larger pharmaceutical manufactures and venture capitalists. “It makes it very attractive for new companies to start up and go after this, and it makes it attractive from an investor perspective,” Longcor says.

There are those in Big Pharma that agree. “My fervent wish is that we begin to see enough activity in this area that we have again, a diverse, vibrant pipeline,” AstraZeneca’s Rex says. “What’s so exciting about the past 12-18 months has been the amount of momentum and understanding that has built” about the need for a new development paradigm for antibiotics.

GAIN Begins (Part 1): FDA Completes Turnaround On Antibiotic R&D

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