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FDA Has Two Years to Hit the Books on Antibiotic Homework

By Mari Serebrov
Washington Editor

In passing PDUFA V, Congress piled on the homework for the FDA, and much of it has nothing to do with user fees. Some of the assignments, for instance, deal with implementing incentives for new antibiotics.

The Generating Antibiotic Incentives Now (GAIN) program, included in the FDA Safety and Innovation Act (FDASIA), gives the FDA, through the Department of Health and Human Services (HHS), until July 2014 to come up with a list of pathogens that qualifying drugs must target and to develop regulations for the antibiotic incentives.

While the agency can issue interim guidance before then, the FDASIA timeline provides no immediate certainty to offset the investment challenges sponsors have faced in focusing on infectious diseases.

"Antibiotics generate a historically poor return on investment because they are designed for short-term use and are best prescribed on a limited basis to slow development of resistance," according to a new FDASIA report from PwC Health Research Institute.

Given the difficulty in attracting investment for drugs that fight infectious diseases, many drugmakers have shifted their R&D to chronic disease drugs, which generate higher revenue and ongoing demand, the report noted. As a result, R&D for new antibiotics has languished while more and more bacteria become resistant to the drugs already on the market.

Between 2008 and 2010, only two new antibiotics were approved in the U.S., compared with 16 approved from 1983 to 1987. The GAIN provisions are intended to turn those numbers around. (See BioWorld Insight, June 11, 2012.)

Under GAIN, only new drugs can qualify for the incentives; they will not be awarded for supplemental applications, including new indications or changes in an existing drug. To get the incentives, drugmakers must request the "qualifying infectious disease product" designation before they submit an application to the FDA. The agency will then have 60 days to determine whether the proposed drug qualifies.

Once the designation is granted, it can only be revoked if the FDA finds it was granted based on a request that included an "untrue statement of material fact," according to the law. If a drug gets the designation, it will be given six-month priority review, fast-track approval and an additional five-year market exclusivity.

In the past, antibiotics were subject to the standard 10-month review period. They also weren't eligible for fast track, which speeds "the development and approval process through earlier and more frequent correspondence with FDA officials on items like trial design and application submissions," PwC said. In addition, fast track allows a rolling submission of a drug application as each section is ready.

The designation hinges on whether a new drug treats a serious or life-threatening infection caused by one of the pathogens on the HHS list or by an antibacterial- or antifungal-resistant pathogen, including new or emerging pathogens, according to FDASIA. While the list may not be available for at least two years, HHS can issue guidance for sponsors seeking the designation prior to release of the final rules.

Sponsors also can get an idea of what may be on the list from FDASIA itself, as the law provides examples of possible qualifying pathogen targets, including resistant Gram-positive pathogens, multidrug-resistant Gram-negative bacteria, multidrug-resistant tuberculosis and Clostridium difficile.

In developing the list, HHS must consult with infectious disease experts at the FDA, Centers for Disease Control and Prevention, and the medical and clinical research communities while considering such factors as morbidity, mortality and the rate of growth of drug-resistant organisms in humans. The list is to be reviewed and updated at least every five years, and HHS must make public the methodology it used to develop the list.

Guidances on the Homework List

Besides offering incentives for new antibiotics, the GAIN provisions will force the FDA to review and revise its guidances on how clinical trials are to be conducted for antibacterial and antifungal drugs, ensuring that they provide clarity on what's needed for approval and that they reflect scientific, medical and technological developments. The agency must review at least three relevant guidances each year, Congress instructed.

The guidance review is to include appropriate animal models of infection, in vitro techniques, valid microbiologic surrogate markers, use of noninferiority vs. superiority trials, study enrollment, data requirements and appropriate delta values for noninferiority trials.

Also on the FDA's homework list is a new draft guidance, to be released by June 30, 2013, specifying how preclinical and clinical data can be used to inform an efficient, streamlined development program for pathogen-focused drugs. The second part of the assignment is to provide advice on approaches to develop drugs that target a more limited spectrum of pathogens. The due date for the final guidance is Dec. 31, 2014.

In addition to the guidances, GAIN allows sponsors to request written recommendations for nonclinical and clinical investigations the FDA considers necessary for development of a specific drug.

Another item on the FDA's to-do list is a five-year report to Congress on how the GAIN program is working and whether it's accomplishing its goals. The report is to include a description of regulatory challenges facing antibiotic development and the steps being taken to ensure regulatory certainty and predictability.

Whether incentives and regulatory certainty are enough to address the investment challenges that have slowed antibiotic development remains to be seen. While the incentives might add some value to late-stage assets, some drugmakers don't see them transforming the funding landscape for antibiotics.

"The priority review might decrease by three to six months the amount of capital required by a company in late-stage clinical development, but it's not going to be a deciding factor in whether an investor chooses to fund a company," Jeffery Stein, president and CEO of antibiotic specialist Trius Therapeutics Inc., recently told BioWorld Today.

What could make a real difference, though, are more success stories like Optimer Pharmaceuticals Inc.'s Dificid (fidaxomicin), which was approved last year to treat C. difficile-associated diarrhea. In its first six months on the market, the drug achieved $21 .5 million in net U.S. sales and saw rapid formulary adoption. By the end of the year, it was covered by 90 percent of the targeted commercial payers and 82 percent of the targeted Medicare Part D payers, according to Optimer's 2011 annual report. (See BioWorld Today, March 31, 2011, and March 30, 2012.)

The fact that Dificid is the first antibiotic to be covered under the Centers for Medicare & Medicaid new technology payment add-on program (NTAP) also could help makers of antibiotics attract investment. While the GAIN incentives should help spur R&D in the field, NTAP should help with reimbursement issues and market uptake, said Hemal Shah, Optimer's senior vice president of medical affairs and health economics and outcome research. Both are needed to bring in new investment. (See BioWorld Today, Aug. 6, 2012.)

Editor's note: This is the first in an occasional series on some of the nitty-gritty details of FDASIA.