Congressman Phil Gingrey (R-GA)’s Generating Antibiotic Incentives Now Act (H.R. 2182, known as GAIN) is a shoe-in for inclusion in the pending Prescription Drug User Fee Act reauthorization package, but there’s disagreement over one key issue: what drugs will qualify for the benefits?

GAIN lists specific qualifying pathogens: persistent gram positive pathogens (MRSA, VRSA, VRE), multi-drug resistant gram negative bacteria (Acinetobacter, Klebsiella, Pseudomonas, E. coli species), and multi-drug resistant TB. In addition to the specific targets, the legislation would allow FDA to designated other pathogens that qualify.

At a March 8 Energy & Commerce Health Subcommittee hearing on PDUFA add-ons, it became clear that the idea of specifically enumerating pathogens—rather than just letting the agency identify them—is a bit contentious.

Center for Drug Evaluation and Research Director Janet Woodcock suggested that the list of pathogens might prove counterproductive due to the quick evolution of resistance. A better approach, she suggested, might be for Congress should spell out a broader set of criteria to qualify for the incentive, and then let FDA make the designation of specific projects that qualify in the context of discussions with individual sponsors about development plans.That approach is much like the way the agency handles other incentives, like the Orphan Drug Act.

Gingrey doesn’t want to give up on the specific list. The ones identified in the bill are causing severe illness no matter where they strike, he pointed out, and he reminded Woodcock that the law allows FDA to add to the list. Gingrey and co-sponsor John Shimkus (R-IL) said that a more general definition of qualifications wouldn’t be a clear enough incentive for sponsors—especially if sponsors fear that FDA may take something off the list after they already began development.

Once again, Woodcock sees an analogy to the Orphan Drug Act. For orphan products, eligibility standards are clear but rewards aren’t guaranteed until approval—and yet sponsors see it as a strong incentive. Also see "FDA Antibiotic Legislation Should Focus On Criteria, Not Bacteria, Woodcock Says" - Pink Sheet, 8 March, 2012.

“Special Pop”

The “qualifying pathogen” provision is clearly an item to watch in GAIN. If indeed the legislative list does move forward, then there is likely to be further discussion of exactly what is (or is not) on the list. In that case, the issue may be what pathogens are “serious enough” to qualify: that, at least, has already been a theme of public debate. As GlaxoSmithKline PLC head of antibacterial discovery David Payne said at an industry conference on antibiotic development challenges last year, GAIN's focus on resistance is the "differentiating factor that we need." Also see "GAIN Act Update: Antibiotic Pipeline Problem is Politically Ripe" - Pink Sheet, 1 November, 2011.

At the time, the Infectious Diseases Society of America had a proposal to create a board tasked with determining which drugs would be incentivized by GAIN. Gingrey staffer Robert Horne argued that the GAIN approach would be better, with the flexibility of allowing the administration to add a pathogen, but without the uncertainty of a pure “case-by-case approach.” Board recommendations could be problematic given the lengthy nature of the drug development process and create a chicken-and-egg problem. A VC might invest in an idea that qualifies for an incentive, but without an investor already it would be hard for an entity to engage in a process to petition for a designation.

IDSA has since dropped the board proposal; in its written testimony submitted to the March 8 hearing, the group said that to ensure GAIN is applicable as new pathogens occur and because FDA currently approvals antibacterial drugs by indication based on infection and not pathogen, IDSA “agrees with others” that it would be best to modify the GAIN definition of “qualified infectious disease product.” Its suggestion:

“an anti-infective (including antibacterial, antifungal, and influenza antiviral drugs) for human use that meets the statutory definition of a new chemical entity; is indicated for use in a serious or life-threatening infections; and which demonstrates the potential to address unmet medical needs for such disease or conditions.”

IDSA has an even bigger change in mind: the group is proposing a new approval pathway for anti-infectives that would modify the infection-only approval standard. IDSA’s proposed “Special Population Limited Medical Use” mechanism would allow sponsors to study certain drugs in far fewer patients in exchange for targeted indications and an emphasis on stewardship. The “Special Pop” concept appears to have FDA’s support. Also see "FDA Exploring Limited-Use Approvals For Antibiotics Based On Small Development Programs" - Pink Sheet, 7 March, 2012.

IDSA anticipates (and notes it is “likely to be of great interest to companies”) that the “Special Pop” mechanism be used to facilitate development of an antibiotic to treat serious infections caused by the same resistant pathogen at multiple disease sites. Clinical data could be pooled from infections not usually studied together (like pneumonia, bloodstream, intra-abdominal), and this data, combined with in vitro, animal model, etc., could support approval for user in serious infections due to resistant pathogens.

That proposal is not yet part of the PDUFA draft legislation circulating on Capitol Hill. But it may well be an add-on to the GAIN provisions.

But it still won’t answer the question of precisely how the determination will be made that a given target infection does or does not qualify for incentives or special review handling.

Noses Full of Staph

Infectious disease physician and former FDAer John Powers was among the witnesses at the hearing who strongly urged that incentives focus on getting companies to develop diagnostics for diseases vs. diagnostics for organisms. Having a bug doesn’t mean someone has a disease, Powers said. While at FDA, Powers was one of the co-chairs of the Inter-agency Task Force on Antimicrobial Resistance.

Cubist Pharmaceuticals Inc. Senior-VP Scientific Affairs Barry Eisenstein acknowledged Powers’ argument. He pointed out how many people in the hearing room likely have staphylococcus aureus in their noses (a lot, and some even the MRSA strain), but that doesn’t mean any of them should be treated. “That said, if the patient appears to have a pneumonia and you’re able to recover a pure culture of staph aureus from the sputum, you know that the patient is suffering from staphylococcal pneumonia and every hour that goes by that you don’t treat that patient, the likelihood of the patient dying goes up.”

Gingrey suggested a law enforcement analogy to support the inclusion of at least some specific targets for incentives. To focus instead on general criteria would be like ignoring a description of a prime suspect. “You’ve got a known thief out there, and you don’t make every effort to apprehend him or her, but rather you have all of your law enforcement and your security measures and you pick three banks in the local neighborhood to protect, because those are the areas in which he might strike next.”

Powers responded to Gingrey by expanding his own analogy: “I think the concern is if you see a bank robber and he’s wearing a blue coat, and we say we’re going to go out and arrest everybody who’s wearing a blue coat.”

Powers harkened back to Eisenstein’s description of everyone with staph in their nose but not needing to be treated, adding that the same organisms can lead to less severe disease and more severe disease. “Can we focus the bill so we can ensure we do what we think we want to do without causing more harm?”

“Multi-Drug Resistant” Does Not Equal “Serious”

Henry Waxman (D-CA) asked about Powers’ concern that targeting specific bacteria with GAIN is “both inappropriate and unusual” for FDA and his suggestion that a better approach would be to focus on new antibiotics targeting serious infections where there is unmet medical need.

“I think the issue is that antibiotics can be used to treat a wide vary of infections, including those with the same organism,” Powers said. He described companies seeking FDA approval for pneumonia caused by multi-drug resistant organisms but also for sinus and ear infections caused by the same organisms. The latter infections predominantly get better on their own, and FDA didn’t grant approval for those uses.

“It’s not clear whether resistance in the test tube has much of an impact on patient outcomes in a disease where people get better anyway,” Powers said. “So it seems to make sense to focus on the areas where when you have a resistant disease that’s going to kill you.” He added that priority review, accelerated approval, fast track, and subpart E all are all focused on treatments for serious, life-threatening disease with unmet medical need.

Powers would actually like to go one step further, and endorsed something like the “Special Pop” proposal. “I think that allowing FDA to have the authority to designate where the drug should be used appropriately is a big step,” he said. “In the past, FDA’s had the authority to restrict drugs where they weren’t safe and effective. Here we’d be saying, well maybe these drugs could be used in less life threatening diseases, but we really think they ought to be reserved for these specific serious diseases. That would be novel. I think giving FDA the authority to do that would be really important. “

GAIN Is Great: Now Who Gets the Benefits?

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