The FDA user fee law may end up serving as a catalyst not only for the development of new antibiotics, but also for the agency’s revamping of its drug approval processes for anti-infective drugs.

A mix of new incentives specifically geared for antibiotics, such as additional marketing exclusivity and guidance on streamlining the drug development process, are expected to spur development of more antibiotics, including those targeting resistant pathogens.

Eligibility criteria for the five-year marketing exclusivity incentive is one area that will need agency clarification, attorneys say.

Many of the Generating Antibiotic Incentives Now provisions that were rolled into FDASIA took effect immediately upon the law’s July 9 enactment. The agency now faces the task of issuing regulations and guidance documents, and further clarifying how some aspects of the program will function.

Eligibility criteria for the five-year marketing exclusivity incentive for Qualified Infectious Disease Products (QIDP) is one area that industry attorneys already are flagging as requiring further clarity. The statutory language is unclear as to the types of “subsequent” applications that would be ineligible for exclusivity, attorneys say, and FDA’s interpretation of these provisions is likely to lead to litigation.

A Flexible Focus On Specific Pathogens

FDA already appears to be prepared to give speedier reviews to some antibiotic applications. The agency said that more priority and fast-track reviews of antibiotic applications are expected than in the past, mostly because GAIN requires them for products that target qualifying pathogens.

To count as a QIDP, a drug candidate must treat serious or life-threatening infections, including those caused by resistant pathogens. Although the agency must develop a list of pathogens it wants qualified products to target, the statutory text includes a number of examples, including resistant Gram positive pathogens, multi-drug resistant Gram negative bacteria, multi-drug resistant tuberculosis, and Clostridium difficile.

The pathogen-related language represented a compromise between House and Senate negotiators, since the two chambers had disagreed on how best to identify the pathogens that should be targeted.

House members listed the infections specifically, while the Senate provided examples of what types of products should receive the incentive. FDA opposed the House language because it would not have provided the flexibility to change the list as the industry and research evolved. The agency argued that the list in the bill is not one that would have been written two years ago and likely not the one that will be written two years from now ([A#00120618018]).

Cubist Pharmaceuticals Inc. Senior VP of Scientific Affairs Barry Eisenstein said the final package combined the best of the House and Senate versions, allowing flexibility while still providing the agency some direction.

“It gives the FDA a bit more confidence when they give the approval of a new submission to be in the QIDP category … that they’re not going to be second-guessed,” he said in a recent interview. “It makes me feel as if it’s more likely that the FDA is going to feel as if it has the wherewithal to do the right thing.”

FDA must adopt final regulations implementing the QIDP and exclusivity provisions within two years. However, the agency said companies may apply to designate a drug candidate as a QIDP before the regulations are issued. Exclusivity will not be awarded until the qualified antibiotic product is approved.

FDA is evaluating the need for guidances to implement GAIN but thinks many of the provisions can be administered directly from the statute.

“Many of the provisions in GAIN can be administered directly from the statute,” FDA said in a statement. “We are currently evaluating the need for specific guidance implementing GAIN.”

Sponsors are already embracing the promise of new incentives and preparing to approach the agency about obtaining QIDP designations.

Eisenstein said Cubist has two molecules in Phase III that could take advantage of the incentives and expects to be talking to FDA about approval in a couple of years. These products are a ceftolozane-tazobactam combination being developed for Gram-negative bacterial infections, and CB-315, which is intended for Clostridium difficile-associated diarrhea. Analysts at Brean Murray Carret & Co. said in a July 20 note that GAIN will extend patent protections for both products Also see "Moving Beyond Cubicin: Cubist Sets The Stage For Long-Term Growth" - Pink Sheet, 7 May, 2012..

Eisenstein said that his regulatory affairs staff thinks the designation should be available right away. The exclusivity and other incentives should work well to further de-risk development programs, he said.

“It gives us more confidence as a company,” Eisenstein said. “It means that we will have, in all likelihood, a longer opportunity to be able to [recoup] the investments that we’re making. … This is very good for ensuring a higher likelihood that new antibiotics are going to be coming out not just two years from now or three years from now, but five, 10 and 15 years from now.”

The Medicines Co. said it plans to approach FDA this quarter to request QIPD designation for oritavancin, a broad spectrum antibiotic targeting Gram-positive bacteria, including Staphylococcal strains with resistance to methicillin and vancomycin.

The company gained oritavancin through its 2009 acquisition of Targanta Therapeutics Corp. Also see "TMC Looks To Add cSSSI Drug, Antibiotic Capabilities With Targanta Offer" - Pink Sheet, 16 January, 2009.. The drug was the subject of a December 2008 “complete response” letter, with FDA requesting additional Phase III data before approval for complicated skin and skin structure infections.

Leerink Swann analysts in June estimated the additional five years of exclusivity provided under GAIN could at least double oritavancin’s value.

It All Comes Down To Interpretation, Implementation

As is the case with any law full of new mandates for the agency, GAIN’s ultimate impact will rest heavily on how FDA interprets and implements the statute.

Paul Kim, a partner at Foley Hoag, said in an interview that FDA should use the orphan drug process as a model for GAIN approvals. He said that was Congress’ intent, but was not clear. There is no legislative history outlining specific congressional intentions, which is why it is important to continue the dialogue, Kim stressed.

Rare disease drug candidates can receive an orphan drug designation, which confers tax and other incentives. FDA grants additional exclusivity to orphan drugs that are approved for marketing. GAIN appears set up in a similar manner: products receive the QIDP designation before filing of an NDA or supplement and then the added exclusivity is issued upon marketing approval.

Kim also advised that companies and advocates should monitor GAIN implementation to ensure it does not get buried among all the other mandates Congress required in FDASIA Also see "Did PDUFA V Pass Too Quickly?" - Pink Sheet, 25 June, 2012..

FDA’s application of the five-year exclusivity provisions, particularly the limitations on exclusivity for certain supplemental and subsequent applications, will be particularly important given the confusing and ambiguous language used in the statute, attorneys said (see box).

Limitations To New QIDP Exclusivity

The new five-year exclusivity period applies only with respect to a “drug that is first approved under section 505(c)” on or after July 9, 2012. The exclusivity does not apply to the approval of the following:

“(1) a supplement to an application under section 505(b) for any qualified infectious disease product for which an extension described in subsection (a) is in effect or has expired;

‘‘(2) a subsequent application filed with respect to a product approved under section 505 for a change that results in a new indication, route of administration, dosing schedule, dosage form, delivery system, delivery device, or strength; or

‘‘(3) a product that does not meet the definition of a qualified infectious disease product under subsection (g) based upon its approved uses.”

Although the limitations clearly bar a five-year exclusivity extension for NDA supplements of drug products previously awarded such exclusivity, “it is unclear how the limitation provisions act to block QIDP-qualifying improvements to a post-FDASIA drug not originally approved with a QIDP exclusivity extension,” attorneys at Hyman, Phelps and McNamara said in a summary and analysis of FDASIA.

“While the limitation provisions seek to block a QIDP exclusivity extension from applying to a drug submitted in a ‘subsequent application,’ it is unclear what the application must be subsequent to,” the summary states. “Moreover, a new indication is usually submitted for approval via an NDA supplement rather than an original NDA. Therefore, a second indication that otherwise qualifies for a QIDP exclusivity extension and that is submitted as an NDA supplement to a non-QIDP NDA first approved on or after July 9, 2012 would seem to receive the QIDP exclusivity extension.”

Furthermore, while the “subsequent application” limitation spells out the types of changes that would not qualify a product for the new exclusivity – such as a new indication or route of administration – this limitation does not take into account other types of modifications to an approved product, such as a different bioavailability profile. The ambiguity raises the question of whether changes beyond those spelled out in the statute would lead to an additional five years of marketing protection under GAIN, said Venable LLP partner David Adams, who also questioned whether a 505(b)(2) application, submitted by a different sponsor, would fall within the exclusivity provision limitations.

Adams, who worked at FDA from 1978 to 1994 and served as associate chief counsel for drugs, said the lack of precision in the GAIN statutory language will create a lot of difficulties for the agency and there will be a period of uncertainty as to how the exclusivity provisions will work.

“Congress is incapable of writing coherent exclusivity provisions,” said Adams, who was involved in implementing the Hatch-Waxman Act exclusivity provisions during his time at FDA. “Every time they have touched exclusivity provisions, they have written something that is incoherent and does not work as written.”

Changes In FDA Thinking, Practices

In addition to developing the list of qualified pathogens and regulations implementing the QIDP exclusivity measures, FDA is faced with several other tasks under GAIN. These include review and, as appropriate, revision of at least three guidance documents per year on conducting clinical trials of antibacterial and antifungal drugs.

The agency also is required to issue a new draft guidance by June 30, 2013 aimed at facilitating the development of drugs for serious or life-threatening bacterial infections, particularly in areas of unmet need. The guidance must specify how pre-clinical and clinical data can be used to inform an efficient and streamlined pathogen-focused antibacterial drug development program that meets FDA approval standards and provide advice on approaches for the development of antibacterial agents that target a more limited spectrum of pathogens. A final version of the guidance must be published by Dec. 31, 2014.

John Rex, vice president and head of infection in Global Medicines Development at AstraZeneca PLC, said this new guidance provision is aimed at filling the gap between the traditional drug development program encompassing two clinical trials and the animal efficacy rule, which is used to support approval when clinical trials are not feasible.

A pathway that navigates this gap could enable approval of drugs that target emerging, resistant pathogens but which may not be possible to study in traditional large-scale clinical trial programs due to the limited number of people affected, Rex said.

The benefits of such an approach may not be so much a speedier development time but, rather, development at all, according to Rex. “This idea of spanning the gap between the traditional drug paradigm and the animal rule, I would say don’t underestimate the importance of that.”

A Commitment To Help, Not “Land On The Moon”

While GAIN supporters were happy with the final bill because it more closely reflected how antibiotics were developed and approved, they were not ready to say the measure will solve all the problems currently hindering antibiotic development efforts.

Eisenstein agreed, saying people are looking for several different types of incentives to boost the antibiotic sector.

“It’s not the equivalent of a commitment to land on the moon,” he said. “What we do have is a commitment to provide help. … It’s not as if it’s a single shot on goal that people are looking for. They’re looking for multiple shots.”

Kim said there appears to be a number of members of Congress interested in the issue, so GAIN may not be the last time antibiotics development incentives are addressed.

The Infectious Diseases Society of America warned that more work should be done to stimulate the antibiotics pathway. The group could not get its Limited Population Antibacterial Drug approval pathway into FDASIA, which would have allowed quicker antibiotic approvals for narrowed indications Also see "Senate Prevails On PDUFA Antibiotic Incentive As House Vote Nears" - Pink Sheet, 19 June, 2012..

FDA liked the LPAD proposal and suggested it may be more effective at attracting new antibiotic sponsors than additional exclusivity. But Rep. Phil Gingrey, R-Ga., who was a lead sponsor of GAIN, said the idea came too late in the user fee reauthorization process to have all questions answered and be incorporated into the final bill Also see "Antibiotic Incentives: FDA’s Woodcock Says LPAD Could Be Better Than Exclusivity, But Questions Remain" - Pink Sheet, 19 April, 2012..

With GAIN In Place, Antibiotic Improvements Depend On FDA Implementation

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