With the growing problem of antimicrobial resistance putting the spotlight on the need for novel antibiotics, FDA has opened the debate on whether incentives, similar to the orphan drug system, are needed to prompt R&D in the area. But at a recent workshop on the issue, advocacy groups suggested that any such incentives need to be partnered with a more active role on the part of FDA.

Most experts participating in the April 28 public workshop agreed that some form of R&D incentive would help to get ahead of the emerging public health crisis of antimicrobial resistance. The meeting was held as a requirement of the FDA Amendments Act. Topics on the meeting's agenda included strategies to limit the development of antimicrobial resistance and the possible effectiveness of economic incentives in promoting development of new antimicrobial agents.

"Big pharma had a big investment in the antibiotic business early [on] ... but at the present time they're bowing out, and the big pharma companies that had large armies of people very well-trained in new drug development simply don't want to do it anymore," John Bartlett, chair of the Infectious Diseases Society of America's Task Force on Antimicrobial Availability, told the workshop.

"Some have formally said, 'We will not develop another antibiotic,' [while] others have just sort of shifted people to other parts of the company. But by and large big pharma is not doing it anymore."

"What the pharmaceutical companies are telling us is that other markets are better. So that's part of the equation," he noted.

But while IDSA recommended some sort of incentive system be developed, Bartlett stressed that companies also would like to see more guidance and regulatory certainty coming from FDA. Many of the novel antibiotics to reach FDA in recent years have been met with "approvable" and "not approvable" letters.

"The companies really need to see that they have a probability for success and they can't succeed unless it gets through the agency," he said.

Based on IDSA's surveying of pharmaceutical companies, Bartlett reported that "their impression is that the agency is indecisive, the expectations are unclear, there are many starting rules that are then changed at the time the results are presented. Delays have become expected and they therefore are fearful of the review process."

"Almost all of the drugs that we currently talk about that are in the pipeline are really conjugates of drugs that have been around for a long time. So we don't have really new mechanisms to deal with resistant bacteria. What we would love is new molecular entities, but that's small picking right now from industry. They don't want to go there," Bartlett said.

The dwindling stock of novel antibiotics, and the dearth of new options in the pipeline, has been a trend for several years ("The Pink Sheet," Oct. 16, 2006, p. 17). However, similar to the resurgence in activity in the vaccines area, as companies face dwindling pipelines across the board, more antibiotics are reaching late-stage development (¹ Also see "2007 NME Prospects Plentiful For Wyeth, Novartis – Other Firms Fall Short" - Pink Sheet, 15 January, 2007., p. 26).

Pfizer is one of the companies demonstrating a renewed interest in antibiotics (² Also see "Pfizer Infectious Disease Pipeline Spreads Roots In Competitive Areas" - Pink Sheet, 24 September, 2007., p. 12). The firm's dalbavancin is one of the antibiotics that have met with an "approvable" action. Johnson & Johnson/Basilea's ceftobiprole and Astellas/Theravance's telavancin also recently received "approvable" letters. Other novel antibiotics under FDA review include Targanta's oritavancin and Arpida's iclaprim.

The Orphan Drug Act: A Possible Model

Starting with the incentive half of the equation (as opposed to the half that involves a more active, involved FDA), experts at the workshop considered whether a scheme for antibiotic incentives should be modeled after the privileges given to orphan drug developers through the Orphan Drug Act.

The act's main motivating factors include: seven years exclusivity during which no other company is allowed to sell the same drug for the same disease; FDA orphan product research grants to support pivotal clinical trials; 50 percent tax credit on every dollar a company spends on clinical research; written protocol assistance; and a waiver of FDA user fees for qualifying companies.

The idea of using orphan incentives for antibiotics was included in FDAAA and therefore discussed at the meeting, but the stakeholders did not necessarily endorse the idea of using the orphan system for this situation.

In fact, the representative from the National Organization for Rare Disorders questioned whether antibiotic drug development really needed the same sort of spurs for R&D.

"Do antibiotics need special incentives?" asked Diane Dorman, vice president for public policy at NORD. "One has to ask why they are not being developed, and then design incentives to address those particular disincentives. No one can claim that antibiotics are not profitable. Perhaps they are not as profitable as a large multi-national pharmaceutical company would [prefer], but small and mid-size companies would likely jump at a chance to develop an antibiotic."

Dorman also cautioned that orphan drug exclusivity allows one company to be the sole provider of treatment for a disease unless another company can prove that its drug is clinically superior. "This is not an easy thing to do, so you have to be concerned that modestly different antibiotics might be blocked from the market if you adopt legislation based on the Orphan Drug Act."

Speaking from the other side of the spectrum, representatives from IDSA said that while the ODA provides neither the right mechanism nor the right incentives necessary to promote development of priority antibiotics, a parallel incentive structure created outside of ODA could.

"We urge FDA leaders to develop a legislative proposal seeking to create a parallel path with incentives to spur the development of antibiotics and relevant diagnostic vaccines," IDSA Director of Public Policy and Governmental Relations Robert Guidos stated. He said that the fact that both rare microorganisms and common microorganisms can cause the same infections is the reason why ODA will not work in this area.

"Arguably, FDA is really not the best organization to have to look into what the best incentives are to motivate drug companies," Guidos said. "They don't have expertise in house, as far as pharmacoeconomic incentives, and there are conflict of interest situations."

IDSA recommended that FDA commission a study through an organization like the Tufts Center on the Study of Drug Development to identify what the drugs are in the pipeline and come up with a list of recommendations that would be helpful to spur the development of antibiotics across each phase of drug development for the larger companies as well as biotechs and academia.

Despite the debate on how and what type of policies should be enacted to jumpstart antibiotic drug development, the experts at the FDA hearing agreed that sitting around waiting is no longer an option.

"It takes five to eight years to develop antibiotics," Bartlett said. "We in this room are now preparing for the drugs that will be available in 2012, 2015. Does anybody in the room right now think what we have is going to be adequate? And if we look at the pipeline we have to be depressed. We've got to find a way to foster more drug development."

Congress Trying To Spur Antibiotic Action

Congress has a series of bills up for adoption which would provide some incentives. One such effort, the Strategies to Address Antimicrobial Resistance Act., H.R. 3697, directs HHS to monitor antimicrobial resistance, develop strategies to combat resistance and identify research priorities.

Among other things, the bill creates an Office of Antimicrobial Resistance in HHS whose responsibility it is to update a public health action plan published in 2001 for dealing with antimicrobial resistance. The act was introduced September 2007 by Reps. Jim Matheson, D-Utah, and Mike Ferguson, R-N.J., but no further action has been taken (³ Also see "Antimicrobial Drug Reviews Would Need To Consider “Resistance” Under Bill" - Pink Sheet, 15 October, 2007., p. 9).

"The point I want to make is that we don't need to wait for Congress to enact a bill in order to make progress," said Bartlett. "There are certain things we can do now, by enacting guidance rather than reacting to resistance."

A Failure To Act

Many presenters harped on the fact that FDA has not taken major action on antimicrobial resistance in almost a decade, despite pressures from a number of outside organizations.

The December 2000 report of FDA's Task Force on Antimicrobial Resistance said the "highest priority is therapeutic options for resistant infections," and a Critical Path report from 2004 said "product development in areas crucial to public health goals, such as antibiotics, has slowed significantly during the past decade." But the task force's nine recommendations were never enacted.

Among those recommendations were to improve and facilitate innovative product development, create an advisory board, protect "drugs of last resort," and coordinate resistance activities with other agencies, all of which IDSA recommended to FDA during the hearing (see chart: " ⁴ IDSA's Recommendations For FDA ").

"FDA should move forward to immediately implement its own task force's recommendations on antimicrobial resistance," said Neil Fishman, chair of IDSA's Antimicrobial Resistance Work Group. "We need to improve and facilitate antimicrobial agents, diagnostics and vaccines, we need to form an advisory board, we must protect drugs of last resort, and we need to coordinate activities with other agencies."

Pressing Need For Diagnostics

Presenters at the hearing stressed how important it was to first develop better diagnostic tools to aid with diagnosis and treatment decisions. "We really do a lousy job in identifying organisms that cause infections in order to be able to direct our therapies more appropriately. We need to be able to identify resistance reservoirs within the various health care settings," Fishman said.

Diagnostics also would be more cost effective. "Diagnostic tests help make more efficient use of expensive, fourth-generation antibiotics by limiting their use in unnecessary situations," said Michele Shoonmaker, director of Government Affairs for molecular diagnostics firm Cepheid. "Rather than taking a shotgun approach to treatment while waiting for identification of any infection agent, in some circumstances, rapid identification of a particular element may help determine the appropriate patients that would likely be responsive to a specific drug."

Peter Applebaum, Hershey Medical Center, suggested "a big survey" to look for particular phenotypes and start thinking about how to treat them. "We're really in for a very difficult time with this group of phenotypes and this is going to be our future, and we can't consider preventing something if the general diagnosis is not made," he said. "And we don't realize we have a very serious problem. We very badly need a reliable diagnostic method to identify the phenotype."

FDA Should Seek External Input...

Many presenters at the FDA hearing recommended the agency create an advisory board specifically for antimicrobial resistance.

"We'd like to see an advisory board in the area of antimicrobial resistance to inform and advise the interagency task force," said Fishman. "Advisory boards have been active and successful in other areas. It would allow us to leverage non-governmental expertise to attack the problem of resistance."

The board's potential responsibilities, he said, would include reviewing ongoing efforts to address resistance, providing timely insight into evolving issues, help focus and direct efforts with respect to emergence of resistance, and to identify and prioritize research needs and goals.

IDSA also recommended creating an independent commission, in addition to the advisory board, that would specifically focus on whether public health and medical needs have been met, or whether it needs to be focusing on new product development.

...And Give More Of Its Own Input Too

While intervening at these various other places will improve the overall system for controlling antimicrobial resistance, what the workshop participants seemed most interested in - even more than an incentive system - is more guidance from FDA on regulatory standards and parameters to facilitate antibiotic development.

It is not a new request. At a workshop on CAP clinical trial standards in February, industry representatives criticized FDA for not providing clear guidance on what it is looking for in anti-infective drug development, and not offering enough incentives for sponsors to continue R&D in the area (⁵ Also see "FDA Still Needs Convincing On Use Of Non-Inferiority Trials For CAP – Temple" - Pink Sheet, 4 February, 2008., p. 30).

Bartlett pointed to the example that FDA set with HIV drug development, where it took an active role providing clear advice, amending its guidance as needed and working with outside groups.

"The AIDS part of it has been very aggressive and effective in moving the field along," said Bartlett. "AIDS in 1985 was an inevitable death. In 2008, it is probably the greatest accomplishment in medicine over the last 50 years. Now the agency has been a really wonderful part of that story: They changed the endpoint, they made it a biologic endpoint instead of a clinical endpoint. It's very clear, exactly what we need."

Using this as a model, FDA could enact clear guidelines that would help in the fight against antimicrobial resistance.

Still, presenters said, it rests with FDA to take the initiative and put things in motion once they are in place.

"Once all the gears are in place, it's actually the FDA that holds the key to make this machine run," Fishman said. "FDA can actually run this engine and lead to the decrease in resistance simply by enacting certain guidelines and policies [rather] than reacting to resistance as we've been forced to in the past."

It does seem that the agency is more willing to take an active role, and with the momentum from the FDAAA mandate on antimicrobial resistance, it seems that the time is right for policy change.

At the meeting, FDA Deputy Commissioner in the Office of Policy Randy Lutter stressed that "this is a listening exercise for FDA. ... We're only here to listen and ask clarifying questions of the speakers. Our next steps will be driven by what we hear today." The docket for comments is open until May 26.

- Lauren Smith (lauren.smith@elsevier.com)

Antimicrobial Resistance Rallies Calls For Active FDA, R&amp;D Incentives

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