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Can new regulatory pathways expedite antibiotic development while assuring appropriate prescribing?

Can new regulatory pathways expedite antibiotic development while assuring appropriate prescribing?

Last week the Pew Charitable Trusts, a signatory on Extending the Cure s recent Joint Statement on Antibiotic Resistance, hosted a one-day conference titled A New Pathway for Antibiotic Innovation: Exploring Drug Development for Limited Populations. The event brought together leaders from government, drug development, heath insurance, and antimicrobial stewardship communities to debate the merits of the Limited Population Antimicrobial Drug (LPAD) approval pathway a newly proposed regulatory fast-track for antimicrobials intended for populations where the need for new therapies is most urgent.

Today, the FDA is holding a public hearing to obtain input about the proposed pathway (webcast available here). Extending the Cure will be live-tweeting from the hearing – you can follow our feed here


The Infectious Disease Society of America (IDSA), a key backer of LPAD, describes it as an approval pathway where the drug’s safety and effectiveness would be studied in substantially smaller, more rapid, and less expensive clinical trials, similar to the FDA s Orphan Drugs program. The trials and approval will be restricted to a single indication where there is a critical shortage of effective antibiotics for instance, respiratory infections caused by carbapenem-resistant Klebsiella pneumoniae. In turn, LPAD antibiotics will carry special labeling clarifying that these products carry less precise estimates of risk and, as a result, the drugs marketing and use should be limited to the indicated population.

What is the rationale for LPAD? According to Dr. John Rex, vice president of AstraZeneca s Infection Therapy division, restricted approval pathways need to be quick and give regulatory certainty. Current clinical trial requirements for general populations impose onerous, unrealistic requirements. It takes a long time to recruit over 1,000 patients with a rare emerging infection. By the time enough patients are enrolled, an epidemic may be upon us, with no new drugs to respond to it said Dr. Rex.

In addition, frequently changing these standards can introduce regulatory uncertainty, as has been the case of telavancin, a novel drug whose developer (Theravance) was caught in the changing tide of regulations in the late 2000s.

Judicious Use of New Drugs

It is critical to assure these new drugs will be used appropriately and exclusively in the area of unmet need where their effectiveness has been evaluated. Dr. Edward Cox, director of the Office of Antimicrobial Products, emphasized the need to for the medical community to understand the new risk-benefit standards and assure judicious prescribing.

How will rational use be guaranteed? Robert Guidos of the IDSA pointed to role of special labeling and educational programs. More notably, LPAD proponents say pricing should act as the main deterrent to overuse. According to Dr. Nicole Mahoney of Pew s Health Group, a hypothetical LPAD drug designed to treat multi-drug resistant Pseudomonas aeruginosa infections could carry a price tag between $15,000 and $30,000 per treatment course (see page 4). 

Can prohibitive prices and special labels guarantee that new drugs will be used for the right populations? Practicing clinicians in the room were skeptical that this can happen without additional oversight. Dr. Pranita Tamma, head of pediatric antimicrobial stewardship at Johns Hopkins University, noted that most physicians don t read package inserts and are unaware of costs. Labels are intended to be informative, not to guide the practice of medicine, which often deviates from labels to permit clinical innovation and accommodate difficult-to-treat cases.  About 80% of pediatric drugs are used off-label said Dr. Tamma. However, she pointed out that supplementing LDAP drugs with antimicrobial stewardship programs could make a difference. 

The issue of diagnostic uncertainty surfaced multiple times during the discussions. The majority of antimicrobial use (and misuse) in acute care starts as empiric therapy, i.e., where there is no pathogen identified until clinical culture results come back from the lab. Current tests can take up to four days, if they yield a result at all. Without an identified organism, LPAD drugs cannot be used in accordance with their restricted label. This underscores the critical need for rapid diagnostic tests, as well as assuring that current equipment can be upgraded to work with LPAD drugs as soon as they are on the market.  

What are some potential solutions to these issues? Pointing to the role of public health agencies, Dr. Kavita Trivedi, head of California Antimicrobial Stewardship Program Initiative, suggested health departments should provide centralized laboratory services to bolster antimicrobial stewardship programs, particularly in long-term care facilities. Payors can mandate that in order to have LPAD drugs on their formularies, hospitals need to meet certain pre-qualification standards, such as having a stewardship program. Finally, one pharmaceutical company suggested a new scheme called Rewarding Antibiotic Development And Responsible Stewardship (RADARS) a prize-based model that couples drug development incentives with rewards for meeting antimicrobial stewardship targets.  

Looking Ahead

Overall, LPAD reflects a recent shift in the regulatory paradigm towards increasing incentives for drug developers and targeting innovation in areas of unmet need. In October 2012 Congress authorized the Generating Antibiotic Incentives Now (GAIN) act, which grants 5-year market exclusivity for qualified infectious disease products, and mandates new FDA guidance on pathogen-specific antibiotic development.  Similar to GAIN, a bill authorizing LPAD could be tacked onto upcoming must-pass legislation, such as the 2013 Animal Drug User Fee authorization act.

As Pew s New Pathways conference made clear, while LPAD may not bring big companies back into antimicrobial development, it offers brighter prospects for a host of smaller companies, which are more challenged by the regulatory hurdles of early-stage clinical trials. According to Dr. Michael Dudley, Chief Scientific Officer of Rampex pharmaceuticals, most anti-infectives research is now initiated at small companies, then usually sold and carried to market by Big Pharma (although the abovementioned drug telavancin was carried through approval by a single smaller firm). 

However, the event also highlighted awareness and concern among stakeholders that spurring innovation without building in incentives for appropriate use would be like supplying your alcoholic patients with a finer brandy. On a more hopeful note, Steven Solomon, Director of the CDC s Office of Antimicrobial Resistance, predicted that the next 12-18 months will see tremendous activity on the question of stewardship and improving antibiotic use a reassuring message that we are moving towards a balanced approach where replenishing the antibiotic pipeline is not the be-all and end-all of tackling our resistance problem.