Regulatory Focus™ > News Articles > Pharmaceutical Industry to FDA: Build Flexibility into GAIN Act

Pharmaceutical Industry to FDA: Build Flexibility into GAIN Act

Posted 17 May 2013 | By Alexander Gaffney, RAC

When legislators passed a sprawling piece of legislation known as the Food and Drug Administration Safety and Innovation Act (FDASIA), they considered a huge range of problems facing both the US Food and Drug Administration (FDA) and drug innovation and development in general. Among the provisions was one intended to spur the development of antibiotics known as the Generating Antibiotics Incentives Now (GAIN)Act, previously a stand-alone piece of legislation intended to give sponsors an additional five years of market exclusivity if they could create a drug to treat a "qualified infectious disease." But the legislation stopped short of naming those pathogens that would be considered "qualified," and now FDA is in the process of figuring out which ones are worth considering.


The statute itself defines a "qualifying pathogen" as one that "has the potential to pose a serious threat to public health." Legislators said they envisioned the GAIN Act being targeted at gram-positive pathogens, multi-drug resistant gram-negative bacteria, multi-drug resistant tuberculosis (TB) and Clostridium difficile (c-diff), but stopped short of generating any sort of exhaustive list, let alone one with specific pathogens.

The role of generating that list now falls to FDA, who has been seeking industry input on the question. The agency recently (December 2012) held a public meeting to discuss the topic, asking industry to consider pathogens that meet four criteria.

The organism must either be a current threat to public health as a result of its resistance to drugs, be an imminent threat due to growing rates of drug resistance, be highly deadly or dangerous to humans, or be increasingly found in humans while being resistant to drugs.

Additional questions generated from that meeting included whether FDA should consider any other factors to make determinations regarding qualifying pathogens, whether additional incentives might be useful, and which specific pathogens should be eligible for inclusion on FDA's list of qualified infectious diseases.

Industry: Give us Flexibility

The response for industry and other government agencies, including the Centers for Disease Control and Prevention (CDC), has been strong.

Pfizer, for example, proposed that the list be flexible, allowing for rapid updates if necessary. "The changing nature of microbial pathogens of public health importance requires a process that allows the accurate and timely modification and updating of this list," the company wrote in a submission to FDA's federal docket. "Since GAIN was enacted, two new bacterial pathogens… have emerged and are well recognized by experts in the field as significant public health threats." Without the ability to quickly update the list, Pfizer said, it would not be especially useful for combating the fast-changing pathogens that threaten society.

However, Pfizer said the question of which pathogens should qualify should largely be deferred to the expertise of national disease tracking agencies like the CDC's Emerging Infections Program, the National Antimicrobial Resistance Monitoring System (NARMS) and the National Healthcare Safety Network (NHSN). Further inter-agency collaboration between FDA, the US Department of Health and Human Services, the US Surgeon General and the CDC could be considered "if needed," Pfizer added.

Another company, Cubist Pharmaceuticals, an antibiotics manufacturer, mirrored Pfizer's concerns, noting that antibiotics are "wasting assets" that are only good for as long as pathogens do not become resistant to them. As a result, a continually-updated list of pathogens is essential, it said, reflecting "the latest epidemiological data and clinical concerns."

Unlike Pfizer, Cubist also proposed the addition of a pathogen to FDA's list: C. Difficile, a dangerous and difficult-to-treat pathogen that is the bread and butter of Cubist's product pipeline.

Presenters: Emerging Pathogens a Flashpoint

Certain considerations were also raised by industry that were not contained within FDA's notice. For example, Amanda Jezek of the Infectious Diseases Society of America (IDSA) raised the point that FDA should consider the ease with which certain pathogens confer resistance to other pathogens. These concerns were mirrored by others, including William Smith of the National Coalition of STD Directors. Smith said emerging pathogens like drug-resistant gonorrhea are "cause for concern for many reasons," and could benefit from more aggressive targeting by developers.

She also added that FDA needs to consider emerging pathogens that could potentially be harmful in the future, as well as diseases caused by fungus and molds. "With regard to fungal pathogens, candida species are the third or fourth most common cause of nosocomial bloodstream infections in the US, and they are demonstrating increasing drug resistance," Jezek said.

Other presenters disagreed. Jennifer Yttri of the National Research Center for Women and Families said that FDA's focus needs to be on actual, rather than conceptual, harms. "Emphasis should be placed on the patient, not test-tube results when determining which pathogens have a major impact on patient health and which antimicrobials are effective against disease. The rate of mortality and morbidity in humans needs to be the first and foremost consideration when determining pathogens that pose a serious threat to public health," she added.

Regulatory considerations were also raised by Yttri, who noted that newer generations of antibiotics tended to be more dangerous in regards to their safety profiles. She said she wanted FDA to require all antibiotics to undergo clinical trials, with the primary endpoint being the study of the drug's effect on mortality. "When the drug trial data focuses on minimum inhibitory concentration as a predictor of outcome and ignores patient factors, the claim 'It is better than nothing.' falls apart for lack of evidence, since the drug is not studied in patients."

The one thing, ironically enough, that the meeting did not determine: Which diseases deserve to be on the list of qualified pathogens. An afternoon session of the meeting did bring up some specific pathogens--Burkholderia species, klebsiella pneumonia, beta lactamase E. coli, C. difficile, pneumococcus, M. abscessus, among others-but no definitive recommendations were obtained.

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