FDA Antibiotics Incentives List Goes Beyond GAIN Act

The agency’s proposed rule on qualifying pathogens is longer than the initial legislative list, but industry still awaits regulations on the law’s exclusivity bonus, which are only achieved through a separate qualified disease product designation.

FDA’s proposal of 18 pathogens or pathogen species be listed as “qualifying pathogens” that have the potential to pose a serious threat to public health as part of the Generating Antibiotic Incentives Now (GAIN) Act, more than double what was suggested by Congress in the law. But further advice on achieving the coveted regulatory and marketing perks for developing antibiotics to treat such pathogens is still to come.

The agency’s proposed rule, announced in the June 12 Federal Register, includes Congress’ recommendations (see page 86 of FDASIA) but also incorporates many of the pathogens stakeholders suggested it consider for inclusion on the list such as gonorrhea and streptococcus pneumonia (Also see "Antibiotic Exclusivity: Which Vision Will GAIN Upper Hand In FDA List-making?" - Pink Sheet, 18 Dec, 2012.).

Established as part of the 2012 FDA Safety and Innovation Act, the GAIN Act encourages the development of antibacterial and antifungal drugs for serious or life-threatening conditions. Manufacturers developing such products can seek a qualified infectious disease product (QIDP) designation making it eligible for priority review, fast track designation and five years of additional marketing exclusivity. The law also mandated that FDA develop and maintain a list of qualifying pathogens.

A drug that is intended to treat an infection caused by a pathogen on the qualifying pathogen list is not guaranteed eligibility for QIDP designation and a drug that treats an infection caused by a pathogen not on the list isn’t automatically excluded from QIDP designation. However, drug makers aiming to target a qualified pathogen should have at least some additional confidence in their ability to snag the QIDP perks as FDA notes that despite being “distinct processes with differing standards,” there is “overlap.”

FDA’s proposed rule explains how it interpreted Congress’s four selection criteria for qualifying pathogens (the impact on public health due to drug-resistant organisms; the rate of growth of drug-resistant organisms; the increase in resistance rates; and the morbidity and mortality in humans). It also provides detailed justification for why it selected each particular pathogen on the list.

Comments on the agency’s proposed rule are due Aug 11. FDASIA mandates that FDA issue final GAIN Act regulations, including the pathogens list no later than two years after the act’s enactment.

Long-Term View Of Drug Resistance

Addressing antibiotic resistance was a major focus. The agency said it took a long-term view of the drug resistance problem, considering the “totality of the available evidence,” including on its list pathogens that have long been resistant to treatments and those with newly emerging resistances, even if most documented infections are currently drug-susceptible. Such a holistic and flexible approach was advocated by Pfizer Inc. in written comments to the agency.

FDA also included pathogens that are currently causing U.S. public health problems and those that are predicted to in the future. And it included pathogens that cause diseases typically in very specific populations of patients and those that could affect the wider population.

For example, it included fungi of the Aspergillus genus, which typically cause serious infections in immunocompromised people such as those who receive lung transplants or patients with cystic fibrosis. On the other hand, FDA included the Camplyoacter genus, which comprises several species of gram-negative bacteria and is estimated to cause over 1.3 million cases of enteric infections in the U.S. each year.

And FDA included S. agalactice (group B streptococcus or GBS) even though recent epidemiological surveillance shows resistance to the mainstay of treatment and prevention of GBS infections, beta-lactam antibacterial drugs, has not been identified in the U.S. because of the potential of chromosomally-mediated mechanisms conferring decreased susceptibility to the drugs.

The agency also listed Vibrio cholerae, a gram negative bacterium that can cause cholera despite it being found mainly in developing countries with poor sanitation and unsafe water supplies because it said the disease may occur in travelers returning from such countries or from contaminated food and because the bacterium has the potential to cause pandemic and remain endemic because infected people may shed the bacteria for several months after infection. Antibacterial drug resistance in cholera-causing strains of V. cholerae increased in the U.S. between 1990 and 2000, FDA added.

The 18 pathogens or pathogen species on the FDA’s proposed list are:

• Acinetobacter species;
• Aspergillus species;
• Burkholderia cepacia complex;
• Campylobacter species;
• Candida species;
• Clostridium difficle;
• Enterobacteriaceae (e.g. Klebsiella pneumonia);
• Enterococcus species;
• Mycobacterium tuberculosis complex;
• Neisseria gonorrhoeae;
• N. meningitides;
• Non-tuberculous mycobacteria species;
• Pseudomonas species;
• Staphylococcus aureus;
• Streptococcus agalactiae;
• S. pneumoniae;
• S. pyogenes;
• Vibrio cholera.

FDA can update this list as necessary, a provision that was advocated for by industry, FDA and other stakeholders who wanted the flexibility to change the pathogen list as the industry, research and pathogens evolve (Also see "PDUFA Negotiations: REMS Mud-Slinging, Supply Chain Compromising, GAIN Diminishing?" - Pink Sheet, 18 Jun, 2012.).

FDA also noted that it doesn’t intend for the list to be used for other purposes such as the allocation of research funding, setting of research priorities, or direction of epidemiological resources.

How FDA Selects Pathogens

Congress mandated that FDA explain how it will choose listed pathogens. When determining a proposed pathogen’s impact on the public health due to drug-resistant organisms in humans FDA examined evidence such as the transmissibility of the pathogen, the availability of effective therapies for treatment of infections caused by the pathogen including the feasibility of treatment administration and associated adverse events. It did not consider financial costs.

FDA evaluated the rate of growth of drug-resistant organisms in humans and the increase in resistance rate in humans largely using the same factors such as the proportion of patients whose illness is caused by a drug-resistant isolate of a pathogen; the number of resistant clinical isolates of a particular pathogen; and the ease and frequency with which a proposed pathogen can transfer and receive resistance conferring elements. In keeping with its forward-looking mindset, FDA said evidence of a pathogen’s strong potential for a meaningful increase in resistance rates could be considered.

For the morbidity and mortality criteria FDA looked at mortality and morbidity rates associated with infection by that pathogen overall, and for drug-resistant strains of the pathogen but adhered to its “totality of the evidence” approach by not setting any quantitative thresholds. It measured morbidity by looking at duration and severity of illness, risk and extent of sequelae from infections caused by the pathogen and risk associated with existing treatments for such infections.

QIDP Designation Rules Coming

FDA’s June 12 notice said the QIDP designation process will be addressed separately at a later date. FDASIA gives the agency two years to adopt final regulations implementing the GAIN Act.

Despite the lack of regulations, FDA said it handed out 11 QIDP designations for eight products as of February 12. Seven of these designations were announced publicly by drug sponsors and all target pathogens on the FDA’s proposed list such as staphylococcus aureus, Pseudomonas aeruginosa, and Clostridium difficile (Also see "GAIN Begins (Part 1): FDA Completes Turnaround On Antibiotic R&D" - Pink Sheet, 20 Feb, 2013.).

Meanwhile, both FDA and Congress are taking interest in combating antibiotic resistance by other mechanisms, with both groups looking into how to slow the rate of resistance development and get more life out of antibiotics. This topic, which involves limiting the use of drugs, is less popular with industry, which wants to develop drugs that can be widely used (Also see "Antibiotic Resistance Gets Attention Of FDA, Congress" - Pink Sheet, 6 Jun, 2013.).