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August 27, 2012 7:43 pm

Proposed EMA guidelines to further steer anti-infectives developers to seek European drug approvals before US - experts

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This article is provided to readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market.


Anti-infectives developers Cubist (NASDAQ:CBST), Theravance (NASDAQ:THRX) and Forest Laboratories (NYSE:FRX)/AstraZeneca (LON:AZN), among others, will increasingly move toward European drug filings prior to the US, infectious disease consultants told BioPharm Insight. They highlighted that the European Medicines Agency’s (EMA) recently released draft addendum to its antibacterial development guidance exemplifies Europe’s reasonable Phase III trial expectations compared to the US’ overly rigorous process.

Even the recent passage of the Generating Antibiotic Incentives Now (GAIN) Act by the US Congress offers scant stimulus to drug developers while problematic US Food and Drug Administration (FDA) trial designs are in place, the experts noted.

The development of new antibiotics is important to counteract the growing problem of drug resistance. Because of antibiotic resistance, many bacterial infections have become impossible to treat. Low returns on investments and an unpredictable and often infeasible FDA approval pathway have caused many companies to leave the antibiotics market, according to the Infectious Diseases Society of America.

AstraZeneca and several other companies have publicly stated they would pursue EU approval first, noted Dr Helen Boucher, associate professor of medicine, Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston.

Cubist, Theravance, Forest and AstraZeneca declined to specifically comment on the EMA guidance.

EMA issued the revised addendum 4 July in response to requests for more detailed guidance on issues such as how to select patients and appropriate primary endpoints for clinical trials, according to the agency’s website. A final version will be published in 2013.

Development impact

If the FDA cannot put feasible trial design guidance in place rapidly, there will be an acceleration of the current trend of companies going to EU before the FDA, said Dr David Shlaes, founder, Anti-Infectives Consulting, Connecticut.

EU approval will likely be preferred first considering the EMA guidelines are “extremely well-written,” agreed Dr G. Ralph Corey, professor of medicine and infectious diseases, Duke University Medical Center, North Carolina. The EMA sets outs reasonable trial parameters unlike the irrational restrictions from the FDA, he said, such as the limits on prior antibiotic use. For example, the FDA allows clinical trials to enroll patients who had prior antibiotic therapy only in cases where the prior treatment did not work, he said. The EMA allows enrollment of patients who have used only one drug before trial start.

The FDA’s guidelines are unfeasible, said an anti-infectives consultant. She agreed that limits on prior antibiotic use makes recruitment difficult. This scenario is particularly difficult in the case of ventilator-associated pneumonia (VAP), which has rapid onset and where physicians look to treat immediately to reduce mortality, she said.

Besides inclusion criteria, the FDA’s barriers also extend to trial endpoints. Boucher noted the EMA guidelines suggest more traditional endpoints such as overall success after therapy is complete, as opposed to FDA’s endpoint of overall success after 24-48 hours of therapy.

Shlaes highlighted that the EMA addendum uses the standard clinical response at test of cure, or a test to determine the absence of the original infection, as the desired endpoint. EMA’s suggested non-inferiority margins are much more in tune with real-life scenarios than the FDA’s margins, he noted. EMA’s parameters state that the drug under investigation is not worse than the comparator by more than prespecified, small amounts. FDA has traditionally set the margin for complicated skin infection trials at 10%.

Also, Shlaes praised EMA for suggesting a pathway for an oral-only antibiotic for community-acquired infection (CAP), which is an option that does not exist at the FDA.

Finally, the EMA, unlike the FDA, opens the door for various superiority or open-enrollment designs for drugs targeting specific pathogens, Shlaes said. Having these trial designs, rather than non-inferiority protocols, allows for enrolling smaller patient populations to demonstrate effect, he explained.

Two of the consultants said the FDA might feel pressure to revise its own 2010 anti-infectives guidelines. “FDA is committed to support the development of new antibacterial drugs, but we are not able to comment on future guidance,” an agency spokesperson responded.


Congress recently passed another iteration of the Prescription Drug User Fee Act; within the legislation is a section titled “Generating Antibiotic Incentives Now.” The GAIN Act was designed to provide pharmaceutical and biotechnology companies with incentives to develop new innovative antibiotics for the treatment of life-threatening infectious diseases caused by drug-resistant pathogens.

FDA is committed to support the development of new antibacterial drugs, but the agency is not able to comment on future guidance, an FDA spokesperson said.

As part of GAIN, the FDA is accepting requests for “Qualified Infectious Disease Product” (QIDP) designations, an FDA spokesperson said. An application for a product designated as a QIDP will be granted priority review, and upon approval, the product could be awarded a five-year extension of marketing exclusivity.

A Cubist spokesperson said it expects CXA-201 for complicated urinary tract infections and complicated intra-abdominal infections as well as CB-315 for Clostridium difficile to be QIDP-designated.

Shlaes and the anti-infectives expert though noted that unless a drug has a short patent life, the new guidelines do not offer much advantage. The expert added that unless the FDA changes its mandated Phase III trial designs, GAIN offers few benefits.


For more information or to inquire about a trial please email or call Americas: +1 212-500-1384 or Europe: 44 (0)20 7059 6202

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